Stem cell injections for osteoarthritis of the knee

Abstract

Background

Stem cells are specialised precursor cells that can replace aged or damaged cells and thereby maintain healthy tissue function. Stem cell therapy is increasingly used as a treatment for knee osteoarthritis, despite the lack of clarity around the mechanism by which stem cell therapy may slow down disease progression in osteoarthritis, and uncertainty regarding its benefits and harms.

Objectives

To assess the benefits and harms of stem cell injections for people with osteoarthritis of the knee. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase on 15 September 2023, unrestricted by date or language of publication. We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for relevant trial protocols and ongoing trials.

Selection criteria

We included randomised controlled trials (RCTs), or trials using quasi‐randomised methods of participant allocation, comparing stem cell injection with placebo injection, no treatment or usual care, glucocorticoid injection, other injections, exercise, drug therapy, surgical interventions, and supplements and complementary therapies in people with knee osteoarthritis.

Data collection and analysis

Two review authors selected studies for inclusion, extracted trial characteristics and outcome data, assessed risk of bias and assessed the certainty of evidence using the GRADE approach. The primary comparison was stem cell injection compared with placebo injection. The primary time point for pain, function and quality of life was three to six months, and the end of the trial period for participant‐reported success, joint structure changes and adverse event outcomes. Major outcomes were pain, function, quality of life, global assessment of success, radiographic joint progression, withdrawals due to adverse events and serious adverse events.

Main results

We found 25 randomised trials (1341 participants) comparing stem cell injections with placebo injection (eight trials), no treatment or usual care (analgesia, weight loss and exercise) (two trials), glucocorticoid injection (one trial), hyaluronic acid injection (seven trials), platelet‐rich plasma injections (two trials), oral acetaminophen (paracetamol) (one trial), non‐steroidal anti‐inflammatory drugs plus physical therapy plus hyaluronic acid injection (one trial) and stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone (three trials) in people with osteoarthritis of the knee. Trials were predominantly small, with sample sizes ranging from 6 to 252 participants, with only two trials having more than 100 participants. The average age of participants across trials ranged from 51 to 66 years, and symptom duration varied from one to 10 years.

Placebo‐controlled trials were largely free from bias, while most trials without a placebo control were susceptible to performance and detection biases. Here, we limit reporting to the main comparison, stem cell injection versus placebo injection.

Compared with placebo injection, stem cell injection may slightly improve pain and function up to six months after treatment. Mean pain (0 to 10 scale, 0 no pain) was 4.5 out of 10 points with placebo injection and 1.2 points better (2.5 points better to 0 points better) with stem cell injection (I² = 80%; 7 studies, 445 participants). Mean function (0 to 100 scale, 0 best function) was 46.3 points with placebo injection and 14.2 points better (25.3 points better to 3.1 points better) with stem cell injection (I² = 82%; 7 studies, 432 participants). We are uncertain whether stem cell injections improve quality of life or increase the number of people who report treatment success compared to placebo injection, because the certainty of the evidence was very low. Mean quality of life was 45.3 points with placebo injection and 22.8 points better (18.0 points worse to 63.7 points better) with stem cell injection (I² = 96%; 2 studies, 288 participants) at up to six months follow‐up. At the end of follow‐up, 89/168 participants (530 per 1000) in the placebo injection group reported treatment success compared with 126/180 participants (683 per 1000) in the stem cell injection group (risk ratio (RR) 1.29, 95% CI 1.10 to 1.53; I² = 0%; 4 trials, 348 participants).

We downgraded the evidence to low certainty for pain and function due to indirectness (as the source, method of preparation and dose of stem cells varied across studies), and suspected publication bias (up to three larger RCTs have been conducted but withdrawn prior to reporting of results). For quality of life and treatment success, we further downgraded the evidence to very low certainty due to imprecision in addition to indirectness and suspected publication bias.

We are uncertain of the potential harms associated with stem cell injection, as there were very low event rates for serious adverse events. At the end of follow‐up, 5/219 participants (23 per 1000) in the placebo injection group experienced serious adverse events compared with 4/242 participants (16 per 1000) in the stem cell injection group (RR 0.72, 95% CI 0.20 to 2.64; I² = 0%; 7 trials, 461 participants) and there were no reported withdrawals due to adverse events. We downgraded the evidence to very low certainty due to indirectness, suspected publication bias and imprecision.

Radiographic progression was not assessed in any of the included studies.

Authors' conclusions

Compared with placebo injections and based upon low‐certainty evidence, stem cell injections for people with knee osteoarthritis may slightly improve pain and function. We are uncertain of the effects of stem cell injections on quality of life or the number who report treatment success. Although the putative benefits of stem cell therapies for osteoarthritis include potential regenerative effects on damaged tissues, particularly articular cartilage, we remain uncertain of the effect of stem cell injections on structural progression in the knee (measured by radiographic appearance). There is also uncertainty regarding the safety of stem cell injections. Serious adverse events were infrequently reported, although all invasive joint procedures (including injections) carry a small risk of septic arthritis. The risk of other important harms, including potential concerns related to the use of a therapy with the theoretical capacity to promote cell growth, or to the use of allogeneic cells, remains unknown.

Plain language summary

What are the benefits and risks of stem cell injections for knee osteoarthritis?

Key messages

• Compared with placebo injection, stem cell injection for people with knee osteoarthritis may slightly improve pain and function.

• We are uncertain whether stem cell injection slows down the progression of the disease, improves quality of life or the chance of treatment success, or whether stem cell injections are safe.

What is osteoarthritis?

Osteoarthritis is a disease of the joints. The joint loses cartilage and other changes to the structure of the joint may occur. This can lead to pain and reduced ability to use the joint.

How is osteoarthritis treated?

Most treatments aim to relieve symptoms, although few are effective. Joint replacement surgery is the only definitive treatment, and is reserved for people with severe disease who have not experienced any benefit from other treatments.

Stem cells are a special type of cell that can develop into mature cells in different parts of the body, including cells that produce cartilage, bone and fat tissue. Thus, in theory, these stem cells could lead to regrowth of damaged cartilage in the joint, which has led to their use as a treatment for osteoarthritis.

What did we want to find out?

We wanted to find out if stem cell injections improve pain, function, treatment success and quality of life, slow down disease progression or lead to harm in people with knee osteoarthritis.

What did we do?

We searched for studies that investigated stem cell injection compared with placebo, no treatment or usual (routine) care, or other treatments in knee osteoarthritis.

We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as variability in the stem cell injections, completeness of the evidence and study size.

What did we find?

We found 25 studies (1341 participants), including 8 studies (459 participants) that compared stem cell injection into the knee with a placebo injection. The remaining studies compared stem cell injection with no treatment or usual care (2 studies, 30 participants), intra‐articular glucocorticoid injection (1 study, 33 participants), hyaluronic acid injection (7 studies, 429 participants), platelet‐rich plasma injection (2 studies, 142 participants), oral acetaminophen (paracetamol; 1 study, 51 participants), NSAIDs (non‐steroidal anti‐inflammatory drugs) plus physical therapy plus hyaluronic acid injection (1 study, 57 participants) and stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone (3 studies, 140 participants). Studies were conducted worldwide, including Europe, the Middle East, Asia, the USA, South America, the United Kingdom and Australia.

Main results

Compared with placebo injections, stem cell injections may improve pain and function slightly.

Pain measured on a 0 to 10 scale (0 is no pain) at six months was 1.2 points better with stem cell injection.

• People who had stem cell injection rated their pain as 3.3 points.

• People who had placebo injection rated their pain as 4.5 points.

Function measured on a 0 to 100 scale (0 is best function) at six months was 14.2 points better with stem cell injection.

• People who had stem cell injection rated their function as 32.1 points.

• People who had placebo injection rated their function as 46.3 points.

It is unclear if stem cell injections improve quality of life measured on a 0 to 100 scale (0 is best function) at six months.

• People who had stem cell injection rated their quality of life as 68.1 points.

• People who had placebo injection rated their quality of life as 45.3 points.

After stem cell injection, 153 more people per 1000 rated their treatment a success at 12 months.

• 683 per 1000 reported treatment success with stem cell injection.

• 530 per 1000 reported treatment success with placebo injection.

After stem cell injection, seven fewer people per 1000 had serious adverse events at 12 months.

• 16 per 1000 people experienced a serious adverse event with stem cell injection.

• 23 per 1000 people reported a serious adverse event with placebo injection.

No withdrawals from the study due to harms from stem cell or placebo injections were reported.

Disease progression was not assessed in any study.

What are the limitations of the evidence?

Our confidence in the estimates for pain and function is low, as the optimal preparation and dose of stem cells is unknown, and varied across studies. Further, up to three larger studies could not be included, as they were conducted but withdrawn by their investigators before reporting results.

We are uncertain whether more people report treatment success, or improvement in quality of life. We are uncertain of the risk of serious harms and harms leading to treatment discontinuation because, in addition to the variation in stem cells used across studies and missing results from larger studies, there were a very small number of events.

How up‐to‐date is this evidence?

The evidence is up‐to‐date to 15 September 2023.

Editorial note: This is a living systematic review. We search for new evidence every three months and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Summary of findings

Summary of findings 1. Stem cell injection versus placebo injection.

Patient or population: adults with osteoarthritis of the knee Settings: outpatient or clinic Intervention: stem cell injection Comparison: placebo injection
Outcomes	Anticipated absolute effects* (95% CI)			Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Placebo injection	Stem cell injection	Difference
Paina (0 to 10, 0 is no pain) Follow‐up: 6 months	Mean pain 4.5 pointsb	Mean pain 3.3 points	1.2 points better (0 points better to 2.5 points better)	‐	445 (7 studies)	⊕⊕⊝⊝ Lowc,d	Stem cell injection may slightly improve pain.
Functiona (0 to 100, 0 is best function) Follow‐up: 6 months	Mean function 46.3 pointsb	Mean function 32.1 points	14.2 points better (3.1 points better to 25.3 points better)	‐	432 (7 studies)	⊕⊕⊝⊝ Lowc,d	Stem cell injection may slightly improve function.
Quality of lifee SF‐36 MCS (0 to 100, 100 is best quality of life) Follow‐up: 6 months	Mean quality of life 45.3 points	Mean quality of life 68.1 points	22.8 pointsbetter (18.0 points worse to 63.7 points better)	‐	288 (2 studies)	⊕⊝⊝⊝ Very lowc,d,f	We are uncertain if stem cell injection improves quality of life.
Participant‐reported global assessment of success Follow‐up: 12 months	530 per 1000	683 per 1000 (583 to 811)	153 more per 1000 (53 more to 281 more)	RR 1.29 (1.10 to 1.53)	348 (4 studies)	⊕⊝⊝⊝ Very lowc,d,f	We are uncertain if stem cell injection increases the number of people who report treatment successg.
Radiographic joint progression	‐	‐	‐	‐	‐	‐	Radiographic progression was not reportedh.
Withdrawals due to adverse events Follow‐up: 6 to 12 months	0 per 1000	0 per 1000	Not estimable	Not estimable	153 (5 studies)	⊕⊝⊝⊝ Very lowc,d,f	No withdrawals due to adverse events with stem cell or placebo injection were reportedi.
Serious adverse events Follow‐up: 6 to 12 months	23 per 1000	16 per 1000 (10 to 66)	7 fewer per 1000 (23 fewer to 32 more)	RR 0.72 (0.20 to 2.64)	461 (7 studies)	⊕⊝⊝⊝ Very lowc,d,f	We are uncertain whether stem cell injection results in more people reporting serious adverse eventsj.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; No.: number; RR: risk ratio; SF‐36 MCS: Short Form‐36 Mental Component Score
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

^aPain: mean pain assessed on a 0 to 10 scale (Khalifeh Soltani 2019; Kim 2023; Lee 2019; Shapiro 2017); mean change in pain (0 to 10) (Emadedin 2018; Kuah 2018), and WOMAC (Western Ontario and McMaster Universities Arthritis Index) pain measured but not reported in Garza 2020. Function: mean function assessed on WOMAC function subscale (0 to 68 transformed to 0 to 100) (Kim 2023; Lee 2019); mean change in WOMAC function subscale (Emadedin 2018; Kuah 2018); mean WOMAC short‐form total score (0 to 100 scale), high‐ and low‐dose stem cell groups combined in Garza 2020; mean KOOS (Knee injury and Osteoarthritis Outcome Score) ADL (Activities of Daily Living) scores (0 to 100, direction was reversed so 0 is best function) (Khalifeh Soltani 2019).

^bControl group risk was estimated from the mean placebo value at follow‐up from Kim 2023 for pain: mean 4.5 on a 0 to 10 scale; and for function: mean 46.3 on a 0 to 100 scale.

^cDowngraded due to indirectness as the source, preparation, storage and dose of stem cells varied across studies; the optimal treatment regimen is unknown.

^dDowngraded due to suspected publication bias, as up to three larger randomised controlled trials have been conducted but were withdrawn prior to reporting of results.

^eQuality of life assessed on SF‐36 MCS (Mental Component Summary subscale of the Short Form‐36 Health Survey) in two studies (Kim 2023; Sadri 2023), and measured in Kuah 2018, but numerical data were not reported (only, "no statistically significant differences in the AQoL‐4D (Assessment of Quality of Life ‐ 4 Dimensions) utility scores between placebo and the PRG (stem cell) groups at any timepoint").

^fDowngraded due to imprecision, as the 95% confidence intervals (CIs) do not rule in or rule out a clinically important change (defined as 1.5 points on a 0‐ to 10‐point pain scale, 10 points on the 0‐ to 100‐point function and quality of life scale); or for dichotomous outcomes the total number of participants was small, or number of events was small (< 200), or the CIs around the risk difference exceeded 5%, or data were from a single trial only. Downgraded twice due to very low event rates for withdrawals due to adverse events and serious adverse events.

^gParticipant‐reported global assessment of success defined as minimum clinically important improvement in pain (threshold and scale undefined) at six months (Emadedin 2018); proportion achieving greater than 33% change from baseline in total WOMAC score at six months (Garza 2020); 30% improvement from baseline in VAS (visual analogue scale) pain score at 12 months (Kuah 2018); 20% improvement in VAS pain (Kim 2023).

^hRadiographic joint progression was measured in one study (Lee 2019), but numerical results were not reported (except: "Kellgren‐Lawrence grade did not change significantly over 6 months").

ⁱFive studies explicitly reported that there were zero withdrawals due to adverse events with stem cell or placebo injection. While Emadedin 2018 reported withdrawals (3/22 withdrawals from the stem cell group and 1/25 withdrawal from the placebo group), the reasons for withdrawal were not given, so we did not include the data in the analysis.

^jThree trials reported serious adverse events with stem cell injection or placebo injection (Emadedin 2018; Kim 2023; Kuah 2018), while four explicitly reported that there were zero events with stem cell or placebo injection (Garza 2020; Khalifeh Soltani 2019; Lee 2019; Shapiro 2017).

Summary of findings 2. Stem cell injection versus no treatment or usual care.

Patient or population: adults with osteoarthritis of the knee Settings: outpatient or clinic Intervention: stem cell injection Comparison: no treatment or usual carea
Outcomes	Anticipated absolute effects* (95% CI)			Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	No treatment or usual care	Stem cell injection	Difference
Painb (0 to 10, 0 is no pain) Follow‐up: 6 months	Mean pain 5.9 points	Mean pain 3.6 points	2.3 points better (1 point better to 3.6 points better)	‐	30 (1 study)	⊕⊝⊝⊝ Very lowc,d,e,f	We are uncertain if stem cell injection improves pain.
Functionb (0 to 100, 0 is best function) Follow‐up: 6 months	Mean function 34.5 points	Mean function 21.8 points	12.7 points better (28.5 points better to 3.1 points worse)	‐	30 (1 study)	⊕⊝⊝⊝ Very lowc,d,e,f	We are uncertain if stem cell injection improves function.
Quality of life (SF‐12, SF‐36, 100 is best score) Follow‐up: 12 months	‐	‐	‐	‐	‐	‐	Quality of life was not reported.
Participant‐reported global assessment of successg Follow‐up: 12 months	600 per 1000	852 per 1000 (498 to 1000)	252 more per 1000 (102 fewer to 858 more)	RR 1.42 (0.83 to 2.43)	30 (1 study)	⊕⊝⊝⊝ Very lowc,d,e,f	We are uncertain if stem cell injection increases the number of people who report treatment success.
Radiographic joint progression Change in joint space width in mm Follow‐up: 12 months	‐	‐	‐	‐	‐	‐	Radiographic joint progression was not reported.
Withdrawals due to adverse events Follow‐up: 6 to 12 months	0 per 1000	0 per 1000	Not estimable	‐	30 (1 study)	⊕⊝⊝⊝ Very lowc,d,e,f	No withdrawals due to adverse events were reported.
Serious adverse events Follow‐up: 6 to 12 months	0 per 1000	0 per 1000	Not estimable	‐	30 (1 study)	⊕⊝⊝⊝ Very lowc,d,e,f	No serious adverse events were reported.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; No.: number; RR: risk ratio; SF‐36: Short Form‐36; SF‐12: 12‐Item Short Form Survey
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

^aUsual care included analgesics, weight loss and exercise (Freitag 2019).

^bPain: 0 to 10 scale (Freitag 2019). Function: KOOS (Knee injury and Osteoarthritis Outcome Score) ADL (Activities of Daily Living) subscale 0 to 100 score reversed so 0 is best function (Freitag 2019).

^cDowngraded for risk of bias: performance and detection biases were likely due to the unblinded nature of the interventions and this may have biased the treatment in favour of stem cells.

^dDowngraded due to indirectness, as the source, preparation, storage and dose of stem cells varied across studies; the optimal treatment regimen is unknown.

^eDowngraded due to imprecision: the 95% confidence intervals do not rule in or rule out a clinically important change (defined as 1.5 points on a 0‐ to 10‐point pain scale, 10 points on the 0‐ to 100‐point function scale); or for dichotomous outcomes the total number of participants was small, or number of events was small (< 200), or the confidence intervals around the risk difference exceeded 5%, or data were from a single trial only. Downgraded twice due to very low event rates (zero events) for withdrawals due to adverse events and serious adverse events.

^fDowngraded due to suspected publication bias, as five randomised controlled trials have been conducted or are still ongoing, but no results are available yet.

^gParticipant‐reported global assessment of success, defined as the percentage of participants achieving a minimal clinically important difference, when combining all pain and functional outcome measures (Freitag 2019).

Summary of findings 3. Stem cell injection versus glucocorticoid injection.

Patient or population: adults with osteoarthritis of the knee Settings: outpatient or clinic Intervention: stem cell injection Comparison: glucocorticoid injection
Outcomes	Anticipated absolute effects* (95% CI)			Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Glucocorticoid injection	Stem cell injection	Difference
Paina (0 to 10, 0 is no pain) Follow‐up: 12 monthsb	Mean pain 4.1 pointsc	Mean pain 4.3 points	0.3 points worse (2.0 worse to 1.4 better)	‐	32 (1 study)	⊕⊝⊝⊝ Very lowd,e,f	We are uncertain if stem cell injection improves pain.
Functiona (0 to 100, 0 is best function) Follow‐up: 12 months	Mean function 38.4 pointsc	Mean function 41.6 points	3.2 points worse (21.2 worse to 14.8 better)	‐	32 (1 study)	⊕⊝⊝⊝ Very lowd,e,f	We are uncertain if stem cell injection improves function.
Quality of lifea (0 to 100, 100 is best quality of life) Follow‐up: 12 months	Mean quality of life 32.0 pointsc	Mean quality of life 40.2 points	8.2 points better (11.0 worse to 27.4 better)	‐	32 (1 study)	⊕⊝⊝⊝ Very lowd,e,f	We are uncertain if stem cell injection improves quality of life.
Participant‐reported global assessment of success Follow‐up: 12 months	176 per 1000	312 per 1000 (88 to 1000)	136 more per 1000 (88 fewer to 923 more)	RR 1.67 (0.48 to 5.83)	32 (1 study)	⊕⊝⊝⊝ Very lowd,e,f	We are uncertain if stem cell injection increases the number of people who report treatment successg.
Radiographic joint progression	‐	‐	‐	‐	‐	‐	Radiographic joint progression was not reported.
Withdrawals due to adverse events Follow‐up: 6 to 12 months	59 per 1000	62 per 1000 (40 to 918)	40 more per 1000 (55 fewer to 859 more)	RR 1.06 (0.07 to 15.60)	32 (1 study)	⊕⊝⊝⊝ Very lowd,e,f	We are uncertain whether stem cell injection results in more withdrawals due to adverse events.
Serious adverse events Follow‐up: 6 to 12 months	59 per 1000	62 per 1000 (40 to 918)	38 fewer per 1000 (58 fewer to 416 more)	RR 1.06 (0.07 to 15.60)	32 (1 study)	⊕⊝⊝⊝ Very lowd,e,f	We are uncertain whether stem cell injection results in more people reporting serious adverse events.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; No.: number; RR: risk ratio
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

^aMean pain measured on KOOS (Knee injury and Osteoarthritis Outcome Score) pain subscale (0 to 100: score reversed so 0 is no pain and scaled to a 10‐point scale) in Bastos 2020. Mean function KOOS ADL (Activities of Daily Living) (0 to 100) score reversed so that 0 is best function in Bastos 2020. Mean quality of life measured on KOOS quality of life subscale (0 to 100: 100 is best quality of life).

^bNo outcome data available at six months, therefore 12‐month data used for outcomes in this table.

^cControl group risk was estimated from the mean (standard deviation) placebo value at follow‐up from Bastos 2020 for pain: mean 4.05 (2.22); function: mean 38.4 (24.4); and quality of life: mean 32 (29.3).

^dDowngraded due to indirectness, as the source, preparation, storage and dose of stem cells varied across studies; the optimal treatment regimen is unknown.

^eDowngraded due to imprecision, as the 95% confidence intervals do not rule in or rule out a clinically important change (defined as 1.5 points on a 0‐ to 10‐point pain scale, 10 points on the 0‐ to 100‐point function scale); or for dichotomous outcomes the total number of participants was small, or number of events was small (< 200), or the confidence intervals around the risk difference exceeded 5%, or data were from a single trial only. Downgraded twice due to very low event rates for withdrawals due to adverse events and serious adverse events.

^fDowngraded due to suspected publication bias, as up to four randomised controlled trials have been conducted, but no results are available.

^gNumber of people with higher than expected improvement in KOOS global score at 12 months in Bastos 2020.

Background

Description of the condition

Osteoarthritis of the knee is one of the leading causes of pain and disability among adults. Its prevalence has steeply increased during the last six decades (Wallace 2017); approximately 10% of the world's population aged 60 years or older have symptomatic osteoarthritis of the knee (Zhang 2010). Globally, hip and knee osteoarthritis rank among the top 20 contributors to disability of all health conditions (James 2018). Typical clinical features include pain, swelling, stiffness and limited range of motion of the knee joint, often accompanied by a substantial decrease in quality of life (Alkan 2014).

Osteoarthritis is a complex chronic disorder of the entire knee joint, with multiple potential risk factors. While the main characteristic of osteoarthritis is loss of articular (joint) cartilage, it is now appreciated that osteoarthritis is a total joint disease (Felson 2013). In addition to changes in cartilage, osteoarthritis is often accompanied by structural changes in multiple tissues ‐ including degeneration of the menisci, inflammation of the synovium (joint lining), abnormal remodelling of subchondral bone (bone that lies beneath the cartilage) and the formation of bone spurs or osteophytes ‐ which ultimately result in structural failure of the joint (Felson 2016; Zhang 2011). Inflammation — mediated by factors produced within joint structures, such as the synovium, cartilage and bone, as well as circulating signalling molecules, including pro‐inflammatory molecules released by adipose (fat) tissue — is an important contributor to osteoarthritis (Benito 2005; Berenbaum 2013; Stannus 2015). Alteration in the function of immune cells and mesenchymal stem cells within the joint environment may also play a role in the pathologic process (McGonagle 2017; Ponchel 2015).

Description of the intervention

Stem cells are specialised precursor cells, which retain the ability to self‐renew, expand in number and develop into mature cells of a particular body tissue; they can replace aged or damaged cells and thereby maintain the function of the organ or tissue in the adult (Pittenger 1999).

A number of strategies currently exist for harvesting cells from adults that retain the potential to develop into cartilage and for optimising their function prior to injection into the osteoarthritic joint. Stem cells are harvested from various sites, including bone marrow, fat tissue, peripheral blood and the joint lining (Akgun 2015; Hopper 2015; Koh 2012; Wakitani 2002). The most commonly investigated cell type, the mesenchymal stem cell (MSC) (also referred to as the mesenchymal stromal cell or multipotential stromal cell), is thought to give rise to all mature cells that produce cartilage, bone and fat tissue. However, recent evidence suggests that the in vitro behaviour of MSCs may not accurately reflect their biological role in the adult human joint, and that articular cartilage may in fact be derived from a separate stem cell population (Worthley 2015). MSCs accumulate in osteoarthritic joints and adjacent bone marrow lesions, which suggests that they may play a role in the response to joint injury or pathology, and that the regenerative function of native MSCs may be altered or inadequate in osteoarthritis (Campbell 2016).

Although MSCs harvested from participants' own tissues (autologous MSCs) are typically used, it is thought that MSCs harvested from unrelated people (allogeneic MSCs) can also evade immune system detection (Ankrum 2014) and can theoretically be administered with little risk of rejection. In people who have received allogeneic MSCs injections for other diseases, no important immune safety issues were reported (Wang 2013). Since commercial preparations of allogeneic MSCs are increasingly available and obviate the need for harvest and manipulation of cells from individual patients, it is possible that their use may increase in clinical practice, although there are no robust data on their relative safety and efficacy versus autologous preparations in osteoarthritis of the knee.

While methods for stem cell preparation often involve the growth and preparation of harvested cells in the laboratory before injection, other methods for harvesting stem cell‐rich tissues exist. These include the direct injection of bone marrow concentrate, which contains a variety of autologous cells including MSCs and growth factors, and methods for enriching the stem cell concentration samples of adipose (fat) tissue prior to therapeutic injection (Jevotovsky 2018). For example, liposuction is used to extract a sample of adipose tissue and the stromal vascular fraction of the adipose tissue is isolated. The stromal vascular fraction consists of collagen, nerves, blood and lymph vessels and other cellular components including stem cells ‐ the tissue is digested with collagenase (an enzyme that breaks down the collagen in the sample), and centrifuged (spun down) to increase the stem cell concentration (Pak 2017). Microfragmentation can also be used, a similar technique which does not use enzymatic digestion of the adipose tissue (Tremolada 2016). Stem cells other than adult MSCs may possess cartilage‐producing potential, including embryonic stem cells and induced pluripotent stem cells (iPSCs), which are adult cells that are manipulated under laboratory conditions to revert to an embryonic form, restoring their ability to differentiate into multiple different cell lines (Diekman 2013).

Stem cells can be injected directly into the osteoarthritic joint, or introduced using various surgical techniques and biomechanical scaffolds that may theoretically enhance the regrowth of articular cartilage. This review focuses on intra‐articular (joint) injection of stem cells.

How the intervention might work

Osteoarthritis results in progressive loss of joint cartilage, which suggests that the mechanisms for restoring cartilage, bone and other tissues in the joint are impaired. There is an imbalance between the rate of cartilage loss and restoration, which may be due to failure of the body to replenish cartilage lost through normal use and ageing, an inadequate response to injury or inflammation, or both of these factors (Martel‐Pelletier 2016). It is possible that osteoarthritis occurs in the presence of altered stem cell function (the precursors of cells responsible for the repair of these tissues), which may contribute to disease progression. Thus, in theory, restoration of normal stem cell function could slow down or even reverse the osteoarthritis process (Murphy 2002). As such, it is plausible that the direct application of stem cells to the osteoarthritic joint is a potentially effective treatment.

The mechanism by which stem cell therapy may be effective in osteoarthritis remains unclear. While native articular cartilage has limited capacity for self‐renewal, it is thought that injection of a sufficient volume of stem cells directly into the affected joint may improve symptoms or joint structure and function in the osteoarthritic knee, either by restoration of lost cartilage volume (de Windt 2015; Horie 2012); enhancement of natural repair mechanisms through the secretion of growth factors and support of other repair cells (Haynesworth 1996); interference with the underlying pathological or inflammatory process via immune modulation (Le Blanc 2003; Ren 2008); or other unidentified mechanisms. The putative regenerative potential of stem cells may also provide benefits after surgical interventions designed to promote cartilage repair, but which have yet to demonstrate consistent effectiveness for the regeneration of hyaline cartilage (such as osteotomy or microfracturing) (Wong 2013).

Studies in animal models have been performed to test the putative cartilage‐regenerating capacity of stem cells in vivo (Wang 2022; Xing 2018a). Commonly used preclinical surgical models of osteoarthritis include the destabilisation of the medial meniscus (DMM) and the anterior cruciate ligament transection (ACLT) surgical model, often in mouse, rat or rabbit (Campbell 2024; Wang 2022). While improvements in cartilage morphology (Gupta 2016; Ozeki 2016), and radiographic appearance (Cheng 2019; Singh 2014), have been reported, animal studies to date have exhibited a high risk of bias and comparison across studies has proven difficult due to methodologic heterogeneity (e.g. animal species, modelling methods, stem cell origin, treatment timing, frequency of injections and dose of stem cells) (Wang 2022; Xing 2018a).

The potential regenerative effects of stem cells on damaged tissues in humans, including joint cartilage, is of particular interest in osteoarthritis because no treatments have yet been shown to reverse or stop the loss of cartilage. However, it is not known whether the injected cells function in vivo as precursors for articular chondrocytes, or the extent to which they can be manipulated to develop into effective cartilage‐producing cells, or whether they have potential therapeutic benefits via mechanisms unrelated to direct production of cartilage. For example, MSCs exhibit other biological functions, including immunomodulatory and anti‐inflammatory effects, which may be of value in the osteoarthritic joint, regardless of any potential for direct repair or regeneration of articular cartilage (van Buul 2012).

There is uncertainty regarding the extent to which injected stem cells are retained within the joint, or remain viable or capable of producing their putative biological effects, following intra‐articular injection (Delling 2015; Shim 2015). It is also unclear whether the behaviour of injected MSCs — including the extent and mechanism of any potential therapeutic effect in osteoarthritis — varies according to the source tissue, subsequent preparation techniques, implantation method, adjuvant therapies (such as exogenous growth factors), dose of cells, autologous or non‐autologous origin, or stage of disease.

Why it is important to do this review

Despite the apparent popularity of stem cell therapy as a potential therapeutic tool for knee osteoarthritis, there is uncertainty regarding the benefits and safety of this intervention. Early systematic reviews of therapeutic stem cell injection for osteoarthritis of the knee reported equivocal results despite considerable overlap of included studies (Jevotovsky 2018; Pas 2017; Xia 2015; Yubo 2017). Two of these reviews concluded that the benefits of mesenchymal stem cell injections were uncertain (Jevotovsky 2018; Xia 2015), while one concluded there may be benefits (Yubo 2017). The fourth review reported that, although some studies showed a benefit of stem cell injections, the evidence was likely to be biased (Pas 2017). The findings of these analyses are limited due to the inclusion of non‐randomised studies, considerable diversity in interventions and comparators, inclusion of different comparators in some analyses, and failure to account for biases in trials in some analyses.

Following publication of this systematic review, we will maintain it as a living systematic review. Literature searches will continue to be run monthly, and any new evidence that meets our inclusion criteria will be rapidly incorporated into the review. This topic lends itself to this framework for a number of reasons. First, osteoarthritis of the knee is a condition for which there is a high demand for new therapies, due to its prevalence, impact on function and quality of life, and paucity of highly effective non‐surgical treatments. This has led to a commensurate increase in the supply of treatment options, many of which have been instituted into practice before a robust evidence base for their effectiveness has been established. Non‐pharmacological therapies, including stem cell injections, have been well placed to fill this gap in the market as they are potentially subject to fewer regulatory restrictions than pharmaceutical products. Stem cell injections are now offered to patients with knee osteoarthritis, often at a substantial out‐of‐pocket cost, despite there being relatively little high‐quality evidence to date (Alcerro 2018). Second, the use of stem cell therapies for the treatment of osteoarthritis is an active area of research (Xing 2018), with a number of trials currently in progress. It is likely that the conclusions of this review, including estimates of the efficacy of the interventions, will change as new evidence is added in the near future. Finally, due to the large burden of disease attributable to knee osteoarthritis, it is important that consumers, healthcare providers and policy‐makers have the most up‐to‐date summary of the evidence for this intervention, so they can make informed decisions.

Objectives

To assess the benefits and harms of stem cell injections for people with osteoarthritis of the knee.

A secondary objective is to maintain the currency of the evidence, using a living systematic review approach.

Methods

Criteria for considering studies for this review

Types of studies

We included studies described as randomised controlled trials (RCTs), and trials using quasi‐randomised methods of participant allocation. We included data from studies reported as full text, while the characteristics of those published as abstract only, unpublished data and ongoing studies were also described, although no results were included in the data syntheses. There were no language or date restrictions.

Types of participants

We included participants with osteoarthritis of the knee (as defined by the study). In addition, we included trials that included participants with osteoarthritis in other joints, provided that the outcomes for people with osteoarthritis of the knee were presented separately or the majority (approximately more than 80%) of participants in the trial had osteoarthritis of the knee.

We excluded trials including participants with knee pain due to acute traumatic injuries.

Types of interventions

Experimental intervention

We included trials comparing stem cell injection, including, but not limited to: mesenchymal stem cells (MSCs); induced pluripotent stem cells (iPSCs); and aspirated autologous tissues enriched for stem cells, such as bone marrow aspirate concentrate and stromal vascular fraction.

We placed no restrictions on volume injected, frequency and total number of injections, injection approach, or use of local anaesthetic and imaging such as ultrasound.

Comparator interventions

Comparisons were grouped as follows.

1. Placebo injection.

2. No treatment, including control (described specifically as no intervention, or no other description provided by the trial authors); usual or normal care (participants could receive normal care, but this was not controlled by trial); wait list (no other description provided by the trial authors).

3. Other injections (including glucocorticoid injection, hyaluronic acid injection or cell‐based therapies such as autologous blood or platelet‐rich plasma injections).

4. Exercise therapies and other physical therapy interventions.

5. Drug therapy (including analgesics and non‐steroidal anti‐inflammatory drugs).

6. Surgical interventions (including arthroscopic debridement, meniscectomy or joint irrigation).

7. Supplements and complementary therapies.

8. Stem cell and comparison groups were offered, or received, the same additional injected intra‐articular therapy, allowing the effect of the stem cell treatment to be isolated.

Co‐interventions

Co‐interventions were allowed provided that they were applied equally in all treatment groups, and that they were not surgical interventions.

Exclusion criteria

We excluded studies comparing one type of stem cell injection to another type, or studies comparing different concentrations or doses of injected stem cells. Trials that assessed the additional benefit of stem cell therapies to a surgical procedure were also excluded.

Types of outcome measures

Major outcomes

1. Mean overall pain, measured on a visual analogue scale (VAS), numerical rating scale or other scales; or pain subscores of composite scores if overall pain scales are not reported.

2. Mean function, measured by global composite outcome scores, including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total scores (Bellamy 1988), Knee Injury and Osteoarthritis Outcome Score (KOOS) (Roos 1998), Lysholm Knee Scoring Scale (Lysholm 1982) or other composite scores; or function or disability subscores if composite scores are not reported.

3. Quality of life, measured by validated tools (e.g. the Short Form Health Survey (SF36) mental health component (Ware 1992), EuroQol 5D (EQ5D), EuroQol 15D) (Rabin 2001).

4. Participant‐reported global assessment of success, as measured by a participant‐reported global impression of clinical change (much or very much improved), or similar measure (e.g. proportion achieving 30% reduction in pain).

5. Radiographic joint progression.

6. Withdrawals due to adverse events.

7. Serious adverse events.

Minor outcomes

1. Total adverse events: proportion in each group experiencing any adverse event, mild or serious in nature.

2. Treatment failure, as measured by progression to a joint replacement or other surgical procedure.

3. Magnetic resonance imaging measure of joint pathology (e.g. cartilage volume, bone marrow lesions, synovitis).

Timing of outcome assessment

The analyses were reported at the following time periods for pain, function and quality of life: up to three months, over three months and up to six months (primary time point for the primary comparison); over six months and up to one year; over one year up to two years. We extracted data on participant‐reported global assessment of success, joint structure changes, adverse events, withdrawals and serious adverse events at the end of the trial period.

Search methods for identification of studies

The methods outlined in Appendix 1 are specific to maintaining the review as a living systematic review in the Cochrane Library (Brooker 2019). They will be implemented upon publication of the first version of the full review.

Electronic searches

We searched the following databases and registers on 15 September 2023:

• Cochrane Central Register of Controlled Trials (CENTRAL; 2023, Issue 9);

• Ovid MEDLINE ALL (1946 to 15 September 2023);

• Ovid Embase (1947 to 15 September 2023);

• ClinicalTrials.gov (www.clinicaltrials.gov); and

• WHO International Clinical Trials Registry Platform (ICTRP) (trialsearch.who.int).

Searches were not restricted by date, language or status of publication. See Appendix 2 for the database search strategies.

Searching other resources

We checked the reference lists of all primary studies and any relevant review articles for additional references.

Data collection and analysis

Selection of studies

For the first version of the review, two authors (SW, RJ) independently screened the search yield and identified any potentially eligible citations. We retrieved the full text of articles judged as being potentially eligible by at least one review author. Two review authors (SW, RJ) screened the full‐text articles for eligibility and resolved any disagreements by discussion or by consulting a third review author (RB). We recorded the selection process in sufficient detail to complete a study selection flow diagram (PRISMA Group 2020) and 'Characteristics of excluded studies' table.

Data extraction and management

We used a data collection form for study characteristics and outcome data, which we piloted on one study in the review. Various pairs of review authors (TB, JZ, SC) independently extracted the following study characteristics from the included studies at different times, and two other review authors (RJ, SW) spot‐checked study characteristics for accuracy against the trial report.

1. Methods: study design, total duration of study, number of study centres and location, study setting, withdrawals and date of study.

2. Participants: number (N), mean age and variance or age range, sex, disease duration, severity of condition, diagnostic criteria, inclusion criteria and exclusion criteria, affected knee compartment, baseline characteristics (e.g. height and weight).

3. Interventions: characteristics of the stem cell product preparation and injection protocols, including a description of the source of cells (autologous versus allogeneic; tissue of origin; method of harvest), in vitro expansion or processing and storage of cells, and injection characteristics (such as volume injected, frequency and total number of injections, injection approach, use of local anaesthetic and imaging such as ultrasound).

4. Comparisons, concomitant treatments and excluded co‐interventions.

5. Outcomes: primary and secondary outcomes specified and collected, and time points reported, withdrawals and adverse events.

6. Characteristics of the design of the trial, as outlined below in Assessment of risk of bias in included studies.

7. Notes: funding for trial, and notable declarations of interest of trial authors.

We extracted the number of events and number of participants per treatment group for dichotomous outcomes, and means and standard deviations and number of participants per treatment group for continuous outcomes. If outcome data were not reported in a usable way and/or when data were transformed or estimated from a graph, we noted this in the Characteristics of included studies table. We resolved disagreements by consensus or by involving a third person (RJ). One review author (SC) transferred data into the Review Manager 5 file (RevMan Web 2020). We double‐checked that data were entered correctly by comparing the data presented in the systematic review with the study reports.

We used freely available software (e.g. DigitizeIt: digitizeit.de/) to extract data from graphs or figures if means and measures of variance were not reported in the text of included studies. These data were also extracted in duplicate.

In the event of multiple measures of pain, function or radiographic joint structure changes reported in a single trial, we extracted the outcome measure that was highest on the following lists, based on hierarchies (Christensen 2015; Juhl 2012; Juni 2006).

If data on more than one pain scale were reported in a trial, we extracted data according to the following hierarchy.

1. Global pain, measured on a VAS, numeric rating scale or other pain scale.

2. Pain on walking.

3. Pain subscore of the WOMAC or KOOS.

4. Composite pain scores other than WOMAC or KOOS.

5. Pain on activities other than walking.

6. Rest pain or pain during the night.

7. WOMAC or KOOS global algofunctional score.

8. Lequesne osteoarthritis index global score.

9. Other algofunctional scale.

10. Participant's global assessment.

11. Physician's global assessment.

If data on more than one function scale was provided for a trial, we extracted data according to the following hierarchy.

1. Global disability score.

2. Walking disability.

3. WOMAC or KOOS disability subscore.

4. Composite disability scores other than WOMAC and KOOS.

5. Disability other than walking.

6. WOMAC or KOOS global scale.

7. Lequesne osteoarthritis index global score.

8. Other algofunctional scale.

9. Participant's global assessment.

10. Physician's global assessment.

If radiographic joint progression was presented more than once in a trial, we extracted data according to the following hierarchy.

1. Minimum joint space width.

2. Median joint space width.

3. Semi‐quantitative measurement.

We applied the following decision rules in the event of multiple outcome reporting.

1. If both final values and change from baseline values were reported for the same outcome, we extracted final values.

2. If both unadjusted and adjusted for baseline values for the same outcome were reported, we extracted adjusted values.

3. If data were analysed based on an intention‐to‐treat (ITT) sample and another sample (e.g. per‐protocol, as‐treated), we extracted ITT data preferentially.

Where studies reported outcomes at multiple follow‐up times, we extracted data at up to three months, six months, one year and two years for pain, function and quality of life. If multiple times were reported within each of these stratifications (such as at two months and three months), we extracted data at the latest time point.

Main planned comparisons

Our primary comparison was stem cell injection versus placebo injection.

Our other main comparisons were grouped as follows.

1. Stem cell injection versus no treatment including control (described specifically as no intervention, or no other description provided by the trial authors); usual or normal care (participants could receive normal care, but this was not controlled by the trial); wait list (no other description provided by the trial authors).

2. Stem cell injection versus other intra‐articular injections, including glucocorticoid injection, hyaluronic acid injection or cell‐based therapies such as autologous blood or platelet‐rich plasma injections. (Each comparison analysed separately.)

3. Stem cell injection versus exercise therapies and other physical therapy interventions.

4. Stem cell injection versus drug therapy (including analgesics and non‐steroidal anti‐inflammatory drugs). (We planned to analyse each comparison separately.)

5. Stem cell injection versus surgical interventions, including arthroscopic debridement, meniscectomy or joint irrigation. (We planned to analyse each comparison separately.)

6. Stem cell injection versus supplements and complementary therapies.

7. Stem cell injection plus another injected intra‐articular therapy versus the injected intra‐articular therapy alone.

Assessment of risk of bias in included studies

Pairs of review authors (SC, JZ, TB) independently assessed risk of bias for each study using the RoB 1 criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017) and two other authors (RJ, SW) checked the risk of bias assessment against the trial report and resolved any disagreements.

We assessed risk of bias according to the following domains.

1. Random sequence generation.

2. Allocation concealment.

3. Blinding of participants and personnel.

4. Blinding of outcome assessment.

5. Incomplete outcome data.

6. Selective outcome reporting.

7. Other bias, such as unequal application of co‐interventions across intervention groups, and whether the number of cross‐overs may bias the results, in particular if participants cross over from a more conservative intervention to a surgical intervention.

We judged each domain as being at high, low or unclear risk of bias, and provided a quote from the study report (if relevant) together with a justification for our judgement in the risk of bias table. We presented the figures generated by the risk of bias tool to provide summary assessments of the risk of bias.

We considered blinding separately for self‐reported and assessor‐reported outcomes (e.g. for unblinded outcome assessment, risk of bias may be low for radiographic joint progression, but high for participant‐reported pain and function). In addition, we considered the impact of missing data by key outcomes.

Where information on risk of bias relates to unpublished data or correspondence with a trialist, we noted this in the risk of bias table.

Assessment of bias in conducting the systematic review

We conducted the review according to a published protocol and have reported any deviations from it in the Differences between protocol and review section of the systematic review.

Measures of treatment effect

When possible, the analyses were based on ITT data (outcomes provided for every randomised participant) from the individual trials. For each trial, we presented outcome data as point estimates with mean and standard deviation for continuous outcomes (pain, function, quality of life, joint progression) and risk ratio (RR) with corresponding 95% confidence intervals (CIs) for dichotomous outcomes (withdrawals, adverse events, serious adverse events, participant‐reported success, treatment failure).

For continuous data, results are presented as mean differences (MDs) with corresponding 95% CIs if possible. However, where different scales were used to measure the same outcome or concept, we calculated the standardised mean difference (SMD).

Where trials used different measures for the same outcome or concept, we used the reported outcome measure that was the highest in our hierarchy as an index measure (Guyatt 2013). We transformed means and standard deviations (SDs) of other outcome measures to the scale of the index instrument and pooled the data using the MD as the summary estimate. For pain, we assumed the 0 to 10 visual analogue scale (zero represented no pain) as the index instrument. For function, we indexed the WOMAC disability subscale (normalised to 0 to 100, where 0 represents best function).

We re‐expressed the SMD as a mean difference on a typical scale (e.g. 0 to 100 for mean quality of life) by multiplying by a typical among‐person standard deviation (e.g. the standard deviation of the control group at baseline from the most representative trial) (Higgins 2022).

We used the minimal clinically important difference (MCID) in the interpretation of results; we assumed an MCID of 1.5 points on a 10‐point scale for pain and 10 points on a 100‐point scale for function or disability.

For each outcome, we reported the risks of events (for dichotomous data) or means (for continuous data) for all the intervention and comparison groups and the difference between groups in the summary of findings tables.

For dichotomous outcomes, we calculated the risk of events for the intervention and control group and the difference in the risks between the intervention and control group using GRADEpro GDT (GRADEpro GDT 2015).

For continuous outcomes, we estimated the control group risk using the mean value from a representative study (combination of the most representative study population and a large weighting in the overall result in RevMan). We calculated the corresponding intervention group risk by adding or subtracting the mean difference from the control group risk.

Unit of analysis issues

Where multiple trial arms were reported in a single trial, we included only the relevant arms, but reported that there were multiple trial arms in the Characteristics of included studies table. If two comparisons from a single trial (e.g. stem cell regimen 1 versus stem cell regimen 2 versus placebo) were combined in the same meta‐analysis, we combined the two treatment groups, as both regimens are relevant, and compared the combined treatment group to placebo in the usual way. For dichotomous outcomes, both the sample sizes and the numbers of people with events can be summed across groups. For continuous outcomes, means and standard deviations can be combined using the methods described in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022).

If we identified cross‐over trials, we extracted data from the first phase of the trial to avoid potential carry‐over effects. If we identified studies that injected both knees, or cluster‐randomised trials, we noted whether any unit of analysis issue had occurred during data analysis. We planned to assess the effect of including studies with potential unit of analysis issues in a sensitivity analysis.

Dealing with missing data

We contacted investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. for missing means and standard deviations for outcome data). Where this was not possible, and the missing or unpublished data were thought to introduce serious bias, we explored the impact of including such studies in the overall assessment of results by a sensitivity analysis. Any assumptions and imputations to handle missing data have been clearly described and the effect of imputation explored by sensitivity analyses.

For dichotomous outcomes that measure adverse events (e.g. number of withdrawals due to adverse events), we calculated the proportion using the number of participants that received treatment as the denominator.

For dichotomous outcomes that measure benefits (e.g. proportion of participants reporting treatment success), we calculated the proportion using the number of randomised participants as the denominator.

For continuous outcomes (e.g. mean pain), we calculated the MD or SMD based on the number of participants analysed at that time point. If the number of participants analysed was not presented for each time point, we used the number randomised to each group at baseline.

Where possible, we computed missing standard deviations from other statistics such as standard errors, confidence intervals (CIs) or P values (Deeks 2022). If standard deviations could not be calculated, they were imputed (e.g. from other studies in the meta‐analysis). Any assumptions and imputations to handle missing data have been clearly described and the effect of imputation was explored by sensitivity analyses.

Assessment of heterogeneity

We assessed clinical and methodological diversity in terms of participants, interventions, outcomes and study characteristics for the included studies, to determine whether a meta‐analysis was appropriate. When meta‐analysis was appropriate, we assessed and quantified the possible magnitude of inconsistency (i.e. heterogeneity) across studies, using the I² statistic with a guide for interpretation as follows: 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; and 75% to 100% represents considerable heterogeneity (Deeks 2022).

If we identified cases of considerable heterogeneity (defined as I² of 75% or greater), we explored the data further by comparing the characteristics of individual studies and performing subgroup analyses.

Assessment of reporting biases

In order to determine whether outcome reporting bias was present, we checked, a priori, trial protocols against published reports of trial results (i.e. checked if all planned outcomes had results reported). For studies published after 1 July 2005, we screened the International Clinical Trials Registry Platform of the WHO (apps.who.int/trialssearch) for the trial protocol.

We compared fixed‐effect estimates against the random‐effects model to assess the possible presence of small‐sample bias in the published literature (i.e. in which the intervention effect is more beneficial in smaller studies) for the primary comparison (stem cell versus placebo) at the six‐month time point. In the presence of small‐sample bias, the random‐effects estimate of the intervention is more beneficial than the fixed‐effect estimate (Sterne 2017). If we were able to pool more than 10 trials, we planned to undertake formal statistical tests to investigate funnel plot asymmetry to detect the possibility of publication bias, for the main comparison at the primary time point (Page 2022).

Data synthesis

We pooled outcomes from trials with similar characteristics (participants, interventions and common comparators, outcome measures and timing of outcome measurement) to provide estimates of benefit and harm.

We synthesised effect estimates using a random‐effects meta‐analysis model based on the assumption that clinical diversity is likely to exist, and that different studies are estimating different intervention effects.

Where we could not pool data, we presented the effect estimates and 95% CIs of each trial in tables, and summarised the results in the text.

Living systematic review approach

When we identify new evidence that meets the inclusion criteria, we plan to extract data, assess the risk of bias and incorporate it in the synthesis. We will update the 'What's new' section of the review monthly to indicate the search date and the status of the search results.

We will re‐publish the review in accordance with the evolving Cochrane guidance for living systematic reviews if the new evidence has an important impact on the findings of the review; for example, a change in one or more of the following components:

1. the findings of one or more major outcomes;

2. the credibility (e.g. GRADE rating) of one or more major outcomes; or

3. new settings, populations, interventions, comparisons or outcomes studied.

As recommended by the Cochrane Scientific Committee, Expert Panel in November 2018 (Schmid 2018), we will not apply error‐adjustment methods when conducting repeated meta‐analyses. We will make decisions about whether to stop updating when appropriate (e.g. if conclusions are unlikely to change with future updates; no meaningful effect is likely to be found; the review question is no longer a priority for decision‐making; or no new evidence is likely), and will be guided by ongoing work in this area (Elliott 2017).

Subgroup analysis and investigation of heterogeneity

We planned to carry out subgroup analyses, to assess whether effects on pain and function were modified by the following factors.

1. Mild to moderate osteoarthritis compared to more severe disease, as defined by imaging criteria such as Kellgren‐Lawrence grade 1, 2, 3 (mild to moderate) compared to Kellgren‐Lawrence grade 4 (severe) (Kellgren 1957).

2. Autologous versus allogeneic stem cells.

We planned to use the formal test for subgroup interactions in Review Manager 5 (RevMan Web 2020) and to use caution in the interpretation of subgroup analyses, as advised in Chapter 9 (section 9.6) of the Cochrane Handbook for Systematic Reviews of Interventions.

Sensitivity analysis

We assessed the robustness of the treatment effect (pain and function) to potential selection bias and potential detection bias by performing the following sensitivity analyses.

1. Selection bias: we removed the trials that reported inadequate or unclear allocation concealment from the meta‐analysis to see if this changed the overall treatment effect.

2. Detection bias: we removed the trials that reported inadequate or unclear participant blinding from the meta‐analysis to see if this changed the overall treatment effect.

We restricted these analyses to the primary comparison: stem cell injection versus placebo injection for pain and function at the primary time point (> three to six months).

Interpreting results and reaching conclusions

We followed the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 15 for interpreting results (Schünemann 2022), and distinguished a lack of evidence of effect from a lack of effect. We based our conclusions only on findings from the quantitative or narrative synthesis of included studies in this review. We avoided making recommendations for practice, and our implications for research suggest priorities for future research and outline what the remaining uncertainties are in the area.

Methods for future updates

We will review the scope and methods of this review approximately yearly (or more frequently, if appropriate) in light of potential changes in the topic area, or the evidence being included in the review (for example, additional comparisons, interventions or outcomes, or new review methods available).

Summary of findings and assessment of the certainty of the evidence

We created a summary of findings table using the following outcomes.

1. Mean overall pain, measured on a VAS, numerical rating scale or other scales; or pain subscores of composite scores if overall pain scales were not reported.

2. Mean function, measured by global composite outcome scores, including WOMAC total scores, KOOS disability subscore, Lysholm Knee Scoring Scale or other composite scores; or function or disability subscores if composite scores were not reported.

3. Quality of life, measured by validated tools (e.g. SF36, EQ5D, EuroQol, 15D).

4. Participant‐reported global assessment of success, as measured by a participant‐reported global impression of clinical change (much or very much improved), or similar measure (e.g. proportion achieving 30% reduction in pain).

5. Radiographic measures of joint structure change.

6. Withdrawals due to adverse events.

7. Serious adverse events.

We did not provide a summary of findings table for every possible comparison identified, but addressed the most relevant comparisons to inform current management. We produced a summary of findings table for the primary comparison (stem cell injection versus placebo injection); stem cell injection versus no treatment or usual care; and stem cell injection versus glucocorticoid injection, using six‐month follow‐up measures for pain, function, quality of life and last follow‐up for participant‐reported global assessment of success, joint structure changes, withdrawals due to adverse events and serious adverse events.

Two review authors (SW, RJ) independently assessed the certainty of the evidence. We resolved any disagreements by discussion or by involving another review author (RB). We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of the body of evidence as it related to the studies that contributed data to the meta‐analyses for the prespecified outcomes, and reported the certainty of evidence as high, moderate, low or very low. We prepared the summary of findings tables using the GRADEpro software version 3, which automatically shows the absolute percentage change for dichotomous outcomes (GRADEpro GDT 2015). We justified all decisions to downgrade the certainty of the evidence using footnotes, and we made comments to aid the reader's understanding of the review, where necessary.

Results

Description of studies

Results of the search

The searches conducted up to 15 September 2023 identified 2250 records (2248 from database searches and two from other sources). After removing 240 duplicates, we screened 2010 records, of which 1861 were excluded at title and abstract screening. We retrieved 149 unique studies for full‐text screening.

We excluded 35 unique studies (15 ineligible study designs, 17 ineligible interventions and 3 ineligible comparators), identified 77 ongoing trials from clinical trial registries, and listed 12 trials as awaiting classification. A flow diagram of the study selection process is presented in Figure.

1.

PRISMA study flow diagram

Twenty‐five trials met our criteria for inclusion (Anz 2020; Baria 2022; Bastos 2020; Chen 2021; Emadedin 2018; Freitag 2019; Garay‐Mendoza 2018; Garza 2020; Goncars 2017; Gupta 2016; Ho 2022; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Matas 2019; Ren 2023; Sadat‐Ali 2021; Sadri 2023; Shapiro 2017; Vega 2015; Zhang 2022).

Detailed descriptions of all unpublished trials that are completed, suspended or ongoing are provided in either the table of Characteristics of studies awaiting classification or the table of Characteristics of ongoing studies. A summary of the characteristics of these studies is provided in Table.

1. Study characteristics of unpublished or awaiting classification, ongoing and terminated trials.

Trial registration number and study reference	Principal investigator/s and country	Study arms	Main selection criteria	Primary outcome/s	Registration date	Recruitment commenced	Trial status to 24 March 2023	Planned sample size	Actual sample size	Planned follow‐up
Stem cell injection vs placebo injection (21 trials)
Liu 2021	Prof David Hunter, Australia	Mesenchymal stem cells vs placebo	Knee OA as defined by ACR criteria	Proportion of participants achieving patient‐acceptable symptom state (PASS) for knee pain	31 August 2020	15 March 2021	Recruiting (190 to date). Last updated on 9 November 2022	440	Not reported	3, 6, 9, 12, 15, 18, 21 and 24 months
ACTRN12617001095358	Julien Freitag Australia	Allogeneic human adipose‐derived mesenchymal stem cells vs placebo (isotonic solution)	BMI >19.0 kg/m2 and < 35.0 kg/m2; KL Grade 2 to 3	Adverse events and concomitant medication use	27 July 2017	02 July 2018	Recruiting. Last updated on 12 October 2021	Not reported	Not reported	3 months
CTRI/2009/091/000435	Jiji Abhraham India	Single‐dose allogeneic MSC vs plasmalyte A	KL Grade 1 to 3	Adverse events; VAS; Aggregated Locomotor Function scale	03 July 2009	23 June 2009	Terminated. Last updated on 24 November 2021	30	Not reported	1 week, 1, 3, 6, 9 and 12 months
CTRI/2011/07/001891	Dr Anoop CH India	Bone marrow derived mesenchymal stem cells vs placebo (Plasmalyte‐A)	KL grade 2 to 3	Safety and tolerability, assessed by adverse events	17 July 2011	18 July 2011	Recruitment completed (date unknown). No results available. Last update 24 November 2021	60	Not reported	6, 12 and 24 months
IRCT20080728001031N23	Shahedeh Karimi Torshizi Iran	Allogeneic adipose‐derived mesenchymal stromal cells	Osteoarthritis diagnosed by MRI	WOMAC and KOOS questionnaires; adverse events	24 April 2018	14 March 2017	Recruitment completed on 21 March 2019. No results available. Last update 26 August 2021	100	Not reported	3, 6 and 12 months
IRCT20210423051054N1	Najmeh Sadat Bolandnazar Iran	Stem cell injection plus exercise vs placebo injection plus exercise	VAS knee pain ≥ 4; KL grade 2 to 3	VAS pain; Lequesne Index; MRI of cartilage changes; WOMAC	11 May 2022	22 June 2022	Recruitment pending. Last update 11 May 2022	30	Not reported	2 and 6 months
KCT0001619	Dr Kim Kangil South Korea	Autologous adipose tissue‐derived mesenchymal stem cells vs placebo (saline)	Knee OA diagnosed by ACR criteria; KL grade 2 to 4	X‐ray and MRI scan for arthroscopy evaluation and histological evaluation; WOMAC, KOOS, SF‐36	8 September 2015	19 August 2015	Recruitment completed 18 December 2016. No results available. Last updated on 11 March 2019	24	Not reported	V2, V4, V5, details not reported
NCT01448434	Prof. Muhammad Ali Noor Muhd Abdul Ghani Malaysia	Ex‐ vivo cultured adult allogeneic MSC vs placebo (Plasmalyte‐A)	KL grade 2 to 3	VAS; WOMAC; KOOS; ICOAP; WORMS score of knee using MRI	7 October 2011	September 2011	Recruitment completed in September 2019. Last updated 12 May 2016. No results available	72	Not reported	12 months
NCT03164083	Dr Mohammad Nouri, Iran	Mesenchymal stem cell vs placebo	Knee OA diagnosed by MRI	WOMAC, VAS, joint swelling, adverse events	23 May 2017	No	Withdrawn. Last updated on 18 March 2020	0	0	2 weeks and 3 months
NCT03379168	Dr Dustin Richter USA	Mesenchymal stem cell vs placebo	Symptomatic knee OA; radiographic evidence of knee OA one or more of the following: osteophytes, joint space narrowing, loss of articular cartilage thickness, subchondral sclerosis or cysts	VAS, WOMAC, KOOS	20 December 2017	1 April 2018	Active, not recruiting. Last updated on 2 November 2022	75	Not reported	2 weeks, 6 weeks, 3, 6 and 12 months
Mikkelsen 2021	Kristoffer W Barfod Denmark	Autologous, micro‐fragmented adipose tissue vs placebo (saline)	KL grade 2 to 3	KOOS	11 December 2018	No	Active, not recruiting. Last updated on 5 April 2022	120	0	6, 12 and 24 months
NCT03990805	Dr Kim Kangil South Korea	MSC vs placebo	ACR class 1 to 3; KL grade 3	WOMAC; VAS; KOOS; IKDC, SF‐36, x‐ray changes in KL grade and joint space width	13 June 2019	19 June 2019	Recruitment completed on 15 December 2020, no results posted. Last updated in September 2022	260	Not reported	12 weeks and 24 weeks
NCT04208646	Chunde Bao China	Low‐dose mesenchymal progenitor cells vs high‐dose mesenchymal progenitor cells vs placebo	ARA clinical + radiology criteria; WOMAC pain score 7 to 17; KL grade 2 to 3	WOMAC, VAS, SF‐36, adverse events	23 December 2019	16 May 2020	Recruitment status unknown. Last updated 4 November 2020	108	Not reported	4, 8, 12, 24, 36 and 48 weeks
NCT04240873	Ji Hyeon Ju Korea	Bone marrow derived MSC vs placebo (saline)	ACR classification criteria for knee OA; KL grade 1 to 4	Adverse events, WOMAC, KOOS, IKDC, SF‐36, cartilage damage in MRI	27 January 2020	15 November 2019	Recruiting. Last updated on 27 January 2020	24	Not reported	12 months
NCT04368806	Hugh Lee USA	Autologous ADMSC vs placebo (saline with autologous serum)	ACR classification criteria for knee OA; ≥ 34 on WOMAC; ≥ 50 mm for one knee and ≤ 40 mm for the other knee on 100 mm VAS	WOMAC, VAS, IKDC, SF‐36, KL grade and cartilage defects on x‐ray	30 April 2020	26 May 2021	Recruiting. Last updated on 8 February 2023	140	Not reported	12, 24, 36, and 48 weeks
NCT04520945	Badrul Akmal Hisham Malaysia	MSC vs placebo (saline)	KL grade 1 to 3	VAS, WOMAC, IKDC, KOOS, PROMIS29, KL grade on x‐ray	20 August 2020	No	Not yet recruiting, status unknown. Last updated on 20 August 2020	100	Not reported	12 months
NCT04821102	Changmin Lee Korea	Autologous ADMSC vs placebo (saline)	Degenerative arthritis ACR class 1‐3; KL grade 1 to 3; > 50 mm on VAS; WOMAC score ≥ 1000	Change of damaged cartilage defects in arthroscopy, WOMAC, VAS, IKDC, KL grade on x‐ray	29 March 2021	No	Not yet recruiting. Last updated on 28 September 2022	21	Not reported	12, 24 and 48 weeks
NCT05182034	Eunyoung Lee Korea	Mid‐dose stem cell injection vs low‐dose stem cell injection vs placebo injection	ACR; KL grade 2 to 3	VAS, WOMAC, IKDC, MRI T2 mapping	24 February 2022	10 January 2022	Recruiting. Last updated on 15 March 2023	90	Not reported	1, 4, 8, 12, 24, and 52 weeks
NCT05526001	Yu‐Han Chang Taiwan	ADMSC vs placebo injection	WOMAC pain score of 7 to 17; KL grade 2 to 3	KOOS; VAS pain; KSS; MRI; WORMS; WOMAC	28 August 2022	Not yet recruiting	Not yet recruiting. Last updated on 19 May 2023	165	Not reported	2, 4, 12, 24, 36 and 48 weeks
NCT05933434	Rasmus Aabling Denmark	Allogenic MSC vs placebo (saline) injection	> 4 NRS; KL grade 2 to 3	KOOS; Adverse events; NRS; MRI; Range of motion	5 June 2023	October 2023	Not yet recruiting. Last updated on 6 July 2023	80	Not reported	3, 12 and 24 months, 3, 4 and 5 years
NCT05936060	Gustavo Salguero Colombia	Stem cell injection vs placebo (plasmalyte) injection.	KL grade 2 to 4	KOOS; VAS pain; MRI	16 June 2023	1 October 2023	Not yet recruiting. Last updated on 7 July 2023	32	Not reported	1, 3, 6, 12 and 24 months
Stem cell injection vs hyaluronic acid injection (29 trials)
ACTRN12611000274976	Kade Paterson Australia	Stromal vascular fraction containing ADMSC vs Hylan G‐F 20 (derivative of hyaluronic acid) knee injections	International Cartilage Repair Society OA guidelines and VAS > 50 out of 100	Pain on 100 mm VAS, KOOS	15 March 2011	May 2011	Withdrawn, no reason given. Last updated on 27 May 2014	60	Not reported	4 weeks, 8 weeks, 6 and 12 months
ChiCTR1800017713	Liangjing Lv China	Human umbilical cord MSC vs sodium hyaluronate	VAS score > 6 and < 8; KL score < Grade 4	X‐ray; Nuclear Magnetic Resonance Imaging (MRI); VAS and WOMAC scores	10 August 2018	Not yet recruiting	Not yet recruiting. Last updated on 20 August 2018	50	Not reported	Not reported
ChiCTR2000033408	Wang Ning China	Stem cell injection vs hyaluronic acid injection	KL scores of grades 2 to 3	MRI of the knee; VAS score; WOMAC score; Lequesne index; SF‐12 scale	31 May 2020	1 June 2020	Recruiting. Last updated on 1 June 2020	38	Not reported	Not reported
ChiCTR2000039017	Tong Wei China	Stem cell injection vs hyaluronic acid injection	KL scores of grades 1 to 3	Joint function ACR score; VAS pain; Radiograph of the knee joint; MRI of the knee joint; Articular cartilage score	13 October 2020	30 October 2020	Recruiting. Last updated on 11 January 2021	54	Not reported	Not reported
ChiCTR2100041683	Chuangran Wu China	Human umbilical cord MSC vs sodium hyaluronate	OA criteria as per COA Orthopedic Surgery Group; KL grade 2 to 3	WOMAC score; KSS score; VAS score	01 January 2021	31 December 2020	Recruitment ongoing. Last updated on 22 March 2021	20	Not reported	Not reported
ChiCTR‐INR‐17014226	Wenxue Jiang China	Stem cells vs sodium hyaluronate	Knee OA with < 6 months of conservative treatment; VAS score < 6; KL grade < 3	X‐ray; MRI; VAS; WOMAC scores	30 December 2017	1 March 2018	Recruitment pending. Last updated on 8 January 2018	40	Not reported	Not reported
ChiCTR‐IOR‐15006942	Prof. Kevin HO Ki Wai Hong Kong	Autologous BMMSC vs hyaluronic acid	ACR ‐ American College of Rheumatology ‐ classification of OA; pain ≥5.0 cm on a VAS scale of 10 cm	WOMAC, KSS and KSFS, SF‐36 and VAS pain scores MRI and X‐ray; adverse events	20 August 2015	01 December 2015	Recruitment pending. Last updated on 18 April 2017	30	Not reported	2 weeks, 3, 6, 9 and 12 months
EUCTR2019‐002446‐21	SCReN ‐ UICEC CAUSA/IBSAL Spain	Autologous MSC vs hyaluronic acid injection	KL grade 2 to 4	VAS pain scale; WOMAC; Lequesne scale;MRI T2 mapping	10 January 2020	20 April 2020	Recruitment ongoing. Last updated on 11 May 2020	120	Not reported	12 months
EUCTR2019‐005000‐17‐PL	Biuro Projektu BioMiStem, Poland	Autologous ADMSC vs hyaluronic acid	KL grade 2 to 3	NRS, KOOS, IKDC, SF‐36, adverse events, MRI cartilage structure changes	15 July 2021	20 September 2021	Recruitment status unknown. Last updated on 17 January 2022	200	Not reported	Follow‐up visit 1, visit 2, no other details given
IRCT2016021710507N4	Mashhad University of Medical Sciences, Iran	Autologous BMMSC vs hyaluronic acid	ACR criteria; KL grade 2 to 3	NRS, KOOS, ROM, cartilage changes Magnetic Resonance Observation of Cartilage Repair Tissue (Modified MOCART)	20 February 2016	23 September 2015	Recruitment complete on 23 September 2016. No results posted. Last updated on 22 February 2018	30	Not reported	1, 3, 6 and 12 months
ISRCTN88966184	Vilim Molnar Croatia	Autologous ADMSC vs hyaluronic acid	KL grade 2 to 3	VAS; WOMAC; IKDC; KOOS	1 August 2022	1 August 2022	Recruiting	80	Not reported	1‐month and 6‐month
IRCT20210103049925N1	Yunes Panahi Iran	Wharton’s jelly‐derived MSC vs hyaluronic acid	KL grade 2 to 3	VAS, ROM, IKDC, Lysholm, cartilage thickness in MRI	20 May 2021	23 August 2021	Recruitment pending. Last updated on 26 May 2021	40	Not reported	3 months
NCT01459640	Ya Mohammad Hassan Shukur Malaysia	Autologous BMMSC vs hyaluronic acid	KL grade 2 to 3	Change in cartilage thickness at 12 months by MRI; VAS; IKDC, x‐ray progression of OA	25 October 2011	March 2011	Was recruiting, now unknown. Last updated on 25 October 2011	50	Not reported	1, 3, 6, 9 and 12 months
NCT02674399	Nature Cell Co. Ltd. USA	Autologous ADMSC vs hyaluronic acid	KL grade 3 to 4	WOMAC, VAS, MRI, Lysholm, KOOS, IKDC, adverse events	16 February 2016	4 February 2016	Recruitment completed on 28 December 2018; results posted only for the stem cell group. Last updated on 10 August 2021	28	28	6 months
NCT02784964	Yu‐Han Chang Taiwan	ADMSC vs hyaluronic acid	KL grade 1 to 3; WOMAC pain score of 7 to 17	WOMAC, VAS, adverse events, Knee Society Clinical Rating System Score (KSCRS), analgesic consumption, cartilage thickness in MRI	27 May 2016	March 2016	Recruitment completed in June 2021; no results posted. Last updated on 15 July 2021.	57	Not reported	2, 4, 12, 24, 36, 48 weeks
NCT03028428	Yu Tang China	Placenta‐derived MSC vs hyaluronic acid	KL grade 3 to 4	Adverse events, MRI evidence of cartilage thickness, WOMAC, VAS, SF‐36	23 January 2017	December 2016	Active, not recruiting, status unknown. Last updated on 30 January 2018.	Not reported	Not reported	12 months
NCT03166865	Changhui Zhou China	Umbilical cord MSC vs hyaluronic acid	KL grade 1 to 3	VAS, WOMAC, KSS, SF‐36, cartilage thickness in MRI	25 May 2017	1 October 2018	Recruiting. Last updated on 4 June 2018	60	Not reported	1, 3, 6 and 12 weeks
NCT03357575	Ziyi Yang China	Autologous ADMSC vs hyaluronic acid	KL grade 2 to 3	Adverse events, VAS, WOMAC	30 November 2017	1 January 2018	Not yet recruiting, status unknown. Last updated on 30 November 2017	14	Not reported	2 years
NCT03800810	Ismail H Dilogo Indonesia	Umbilical cord MSC plus hyaluronic acid vs hyaluronic acid vs MSC plus hyaluronic acid plus recombinant human somatropin	KL grade 1 to 3 or KL grade 3 with corrective osteotomy according to knee x‐ray	MRI Cartilage T2 map score; IKDC; WOMAC; VAS	11 January 2019	May 2015	Recruiting. Last updated on 23 January 2019	9	Not reported	3 and 6 months
NCT03825133	Oliver Dulic Serbia	BMMSC vs hyaluronic acid	KL grade 2 to 4	WOMAC, KOOS, SF‐36, IKDC, VAS	31 January 2019	April 2016	Recruitment completed on 30 November 2017. No results posted. Last updated on 7 February 2019	180	Not reported	1, 3, 6, 9 and 12 months
NCT03943576	Chia‐Hsin Lee Taiwan	Allogeneic ADMSC vs hyaluronic acid	ACR criteria; KL grade 2‐4; WOMAC pain score of 7 to 17	WOMAC pain score; MRI; VAS; SF‐12	9 May 2019	December 2019	Recruiting. Last updated on January 4, 2023	30	Not reported	1, 4, 12, 24 weeks
NCT04130100	Guangrong Song China	Dental pulp MSC vs high‐dose sodium hyaluronate vs low‐dose sodium hyaluronate	ACR criteria; WOMAC score < 120; KL grade 1 to 3	KL grade x‐ray; Volume of femoral surface of knee joint on MRI; WOMAC score	4 April 2019	4 April 2019	Recruiting. Last updated on 17 October 2019	60	Not reported	12 months
NCT04326985	Ho Ki Wai Hong Kong	Autologous MSC vs hyaluronic acid	KL grade 2 to 3; > 5 VAS pain scale	Knee Society Score; MRI and X‐ray assessment of knee joint; WOMAC, VAS, SF‐36	31 January 2015	30 March 2020	Recruitment completed on 28 February 2019. No results. Last updated on 18 May 2020	20	Not reported	12 months
NCT05027581	Chun‐yao yang Taiwan	MSC vs hyaluronic acid	KL grade 2 to 4; WOMAC pain >7	WOMAC, VAS, SF‐36; MRI WORMS	15 September 2021	19 August 2021	Recruiting. Last updated on 4 October 2021	70	Not reported	4, 12, 24, 36 and 52 weeks
NCT05081921	Jolanta Rajca Poland	MSC vs hyaluronic acid	11‐point numerical rating scale ≥3; KL grade 2 to 3	VAS; SF‐36; KOOS; Adverse events	5 January 2022	23 August 2021	Recruiting. Last updated on 19 April 2022	200	Not reported	3 and 6 months
NCT05086939	Fermín Sánchez‐Guijo Spain	Allogeneic stem cell vs autologous stem cell vs hyaluronic acid	KL grade 2 to 4	Lequesne Algofunctional Index; VAS; WOMAC; range of motion; MRI T2 mapping; SF‐36	26 May 2021	7 July 2021	Recruiting. Last updated on 20 February 2023	120	Not reported	6, 12 and 24 months
NCT05579665	Radiyati U Partan Indonesia	Stem cell vs PRP vs hyaluronic acid	KL grade 2 to 3	VAS pain; WOMAC; Cartilage Oligomeric Matrix Protein	2 October 2022	2 October 2022	Recruitment completed on 31 May 2023. Last updated on 13 November 2023	45	Not reported	3 and 6 months
NCT05996224	Chunde Bao China	Stem cell vs sodium hyaluronate	KL grade 2 to 3; ACR criteria	WOMAC; VAS pain; minimum joint space width of the knee; MRI; adverse events	18 August 2023	01 October 2023	Recruiting. Last updated on 21 August 2023	488	Not reported	4, 12, 24, 36, 48, 60, 72, 84, 96 weeks
TCTR20230929002	Ponthep Tangkanjanavelukul Thailand	ADMSC vs hyaluronic acid	KL grade 2	WOMAC, MRI ultrasound	28 September 2023	12 October 2022	Recruitment completed on 27 May 2023. Last updated on 13 November 2023	44	Not reported	1,3 and 6 months
Stem cell injection vs platelet‐rich plasma (PRP) injection (4 trials)
ChiCTR‐OCN‐15006356	Tong Peijian China	Peripheral blood stem cells vs PRP and Chinese medicine vs PRP	X‐ray and MRI showed knee degenerative changes	WOMAC; The Lequesne Algofunctional Index score; VAS	6 June 2015	1 January 2015	Recruiting. Last updated on 18 April 2017	40	Not reported	Not reported
NCT03975101	Fuda Cancer Hospital Guangzhou China	Very small embryonic‐like stem cells (VSEL) mini‐dose injection vs VSEL medium‐dose vs VSEL maximum‐dose vs PRP	Moderate to severe osteoarthritis of both knees	VAS pain; MRI changes in knee joint	31 May 2019	31 May 2019	Withdrawn. Last updated in May 2020	0	0	1, 6 and 12 months
NCT03271229	Shane A. Shapiro USA	BMMSC vs PRP	KL grade 1 to 3	Adverse events	5 September 2017	September 2019	Withdrawn (Funding). Last updated on 24 December 2019	0	0	12 months
NCT06084637	Alexandre Rochwerge France	Stem cell vs PRP vs stem cell plus PRP	ICRS grade 2, 3 or 4 with VAS > 4	VAS, KOOS, proportion of treatment failures	10 October 2023	02 February 2024	Not yet recruiting. Last updated on 27 October 2023	180	Not reported	1,3,6 and 12 months
Stem cell injection vs glucocorticoid injection (6 trials)
IRCT20151017024572N19	Arash Babaei‐Ghazani Iran	MSC vs glucocorticoid injection	KL grade 1 to 3	VAS, WOMAC, ROM, adverse events	5 January 2019	23 October 2018	Recruiting. Last updated on 29 January 2019	30	Not reported	2 weeks, 1 and 6 months
NCT03467919	Ma Agnes Ith USA	Micro fragmented adipose tissue vs glucocorticoid (triamcinolone 40 mg) injection	KL grade 2 or 3	KOOS, Lysholm score, MRI Cartilage Scan	16 March 2018	1 April 2018	Recruiting. Last updated on 21 March 2023	40	Not reported	24 months
NCT03818737	Kenneth Mautner USA	Autologous BMMSC vs glucocorticoid; adipose‐derived SVF vs glucocorticoid; umbilical cord tissue vs glucocorticoid	KL grade 2 to 4	VAS, KOOS, EQ5D‐3L; PROMIS‐29	28 January 2019	March 2019	Recruitment completed on 31 May 2022, no results posted. Last updated on 15 March 2023	480	Not reported	1, 3, 6 and 12 months
NCT04230902	Asdghig Der‐Boghossian Lebanon	Micro‐fragmented adipose tissue transplant vs glucocorticoid	KL grade 2 or 3	Pain using numerical rating scale; MRI MOAKS (MRI Osteoarthritis Knee Score)	29 January 2019	18 January 2020	Recruiting. Last updated on 12 December 2020	48	Not reported	2weeks, 6weeks, 3 and 6 months
NCT04863183	Martha L Arango Colombia	MSC vs triamcinolone acetonide	KL grade 2 or 3; VAS pain > 40/100	VAS; WOMAC; SF‐36; nuclear magnetic resonance cartilage changes	28 April 2021	Not yet recruiting	Not yet recruiting. Last updated on 28 April 2021	30	Not reported	12 months
NCT05288725	Michael A Scarpone USA	Stem cell vs glucocorticoid	Kellgren‐Lawrence grade 2 to 4	VAS; WOMAC; Frailty Functional Testing; Fall Risk Functional Testing; MRI	01 August 2022	15 February 2022	Not yet recruiting. Last updated on 21 March 2022	120	Not reported	3, 6 and 12 months
Stem cell injection vs physical therapy (2 trials)
ChiCTR2100045261	Wang Fei China	Autologous stem cell vs physical therapy	OA diagnosis by ACR criteria	WOMAC; Global Rating of Change scale; timed "up and go" test; Alternate Step Test	10 April 2021	1 Oct 2021	Recruitment pending. Last updated on 16 November 2021	156	Not reported	Not reported
ChiCTR2100047124	Mohammed Nasb Syria	Stem cell injection vs rehabilitation therapy	ACR criteria; KL grading 2 to 3	International Knee Function Score; VAS pain	8 June 2021	1 July 2021	Recruiting. Last updated on 24 January 2022	70	Not reported	Not reported
Stem cell injection vs no treatment or usual care (5 trials)
NCT03383081	Hongbin Lu China	Low‐dose stem cells vs high‐dose stem cells vs no intervention	KL grade 2 to 3	Radiographic progression of knee OA; Assessment of Preoperative Cartilage Defect Severity (AMADEUS); IKDC; VAS; Lysholm	26 December 2017	1 October 2018	Recruiting. Last updated on 22 July 2022	60	Not reported	12 months
NCT03908827	Rob Durnham Canada	Bone marrow aspirate concentrate injection vs usual care	KL grade 3 to 4	NRS, WOMAC, 40 meter fast‐paced walk test, 30 second chair stand test, adverse events	9 April 2019	Not reported	Withdrawn (change of study design). Last updated on 6 May 2020	0	0	12 months
IRCT20210307050611N1	Naser Amini Iran	Stem cell vs knee care training in daily life activities	ACR criteria; KL grade 1 to 3	VAS; cartilage change in MRI; ROM	22 May 2021	22 May 2021	Recruiting. Last updated on 22 May 2021	80	Not reported	6 months
NCT05193877	Abdulmajeed Hammadi Iraq	Autologous bone marrow aspirate concentrate vs analgesics only	KL grade 2 to 3; 5/11 pain on NRS; MOAKS scoring	WOMAC; MRI of the knee join	18 January 2022	8 February 2022	Recruiting. Last updated on 30 January 2023	60	Not reported	6 and 12 months
NCT05783154	Moshiur Rahman Khasru Bangladesh	Stem cell injection vs standard conventional care	KL grade 2 to 4; ACR criteria	MRI Osteoarthritis Knee score (MOAK); WOMAC; VAS	3 February 2023	16 September 2022	Recruiting. Last updated on 3 April 2023	84	Not reported	1, 3, 6 and 12 months
Stem cell injection plus intra‐articular co‐intervention vs co‐intervention (10 trials)
ChiCTR1900025685	Fei Zhao China	Stem cells combined with PRP injection vs PRP injection	ACR criteria; KL grade 2 to 4	Knee cartilage volume; VAS; WOMAC; VascuQol; KL Grading Scale	5 September 2019	1 January 2020	Recruitment pending. Last updated on 9 September 2019	100	Not reported	Day 45, Day 90, Day 180, Day 360
ACTRN12614001044617	Prof David Hunter, Australia	SVF + PRP + placebo vs placebo	KL Grade > 2; WOMAC > 50	WOMAC; SF‐36; AQOL; X‐ray and MRI assessment; safety	29 September 2014	31 January 2015	Withdrawn. Last updated on 13 January 2020	64	Not reported	0, 28, 56, 112, 180, 365 days
ChiCTR1900025907	Chen Hong China	Stem cell injection with low‐intensity pulsed ultrasound vs saline injection with low‐intensity pulsed ultrasound	ACR criteria; KL grade 2 to 3	Pain; function; range of motion; cartilage thickness	14 September 2019	25 November 2019	Recruitment pending. Last updated on 16 September 2019	81	Not reported	1, 3, and 6 months
IRCT2012080510507N1	Zhaleh Shariati Sarabi Iran	Autologous stem cells plus dexamethasone vs stem cells plus PRP plus dexamethasone vs dexamethasone	ACR criteria; KL grade 2 to 3	NRS, KOOS, Range of motion, MRI Osteoarthritis Knee Score (MOAKS)	1 June 2014	23 August 2018	Recruitment completed on 23 August 2015. Last updated on 22 February 2018	60	Not reported	1, 3, 6 and 12 months
IRCT20211102052944N1	Mohsen Emadedin	Allogenic umbilical cord stem cells plus hyaluronic acid vs hyaluronic acid	KL grade 2 to 3	VAS; articular cartilage thickness via MRI; WOMAC; SF‐36	09 November 2021	22 November 2021	Recruiting. Last updated on 29 November 2021	30	Not reported	2, 4, 6, 9, and 12 months
NCT01985633	Aditya K Aggarwal India	Mesenchymal stem cell plus PRP vs PRP	Grade 1 to 2 on Ahlbacks radiographic staging	VAS, WOMAC, KOOS, cartilage changes on MRI	15 November 2013	January 2013	Recruiting, status unknown. Last updated on 18 November 2013	24	Not reported	6 months
NCT03969680	Peiwen Lian China	Autologous BMMSC plus PRP injection vs PRP injection	Pain score is 8 to 13 points (Lequesne's index); KL grade 2 to 4	WOMAC; VAS; MRI; SF‐36; Lequesne Index	29 May 2019	8 July 2019	Recruiting. Last updated on 15 August 2022	60	Not reported	3, 6, 9 and 12 months
NCT04212728	Peiwen Lian China	Autologous ADMSC plus PRP vs PRP alone	KL grade 2 to 4; pain score is 8 to 13 points (Lequesne's Index)	WOMAC 3 subscales, VAS, MRI cartilage changes	26 December 2019	29 December 2019	Recruiting. Last updated on 24 February 2022	60	Not reported	3, 6, and 12 months
NCT05660824	Adrien Schwitzguébel Switzerland	Stem cell injection plus PRP vs PRP injection	MRI diagnosis of OA	Low Extremity Functional Scale, Single Assessment Numeric Evaluation, VAS, WOMAC	24 January 2022	June 2023	Not yet recruiting. Last updated on 21 December 2022	195	Not reported	1, 2, 3, 6, and 12 months
RBR‐7qjcdd	Teresa Cristina Campos Mello Brazil	Stem cell injection plus PRP injection vs PRP injection vs hyaluronic acid injection	KL grade 2 to 3	Pain, stiffness, level of physical activity	07 June 2019	18 January 2019	Recruiting. Last updated on 29 May 2023	256	Not reported	12 months

ACR: American College of Rheumatology; ADMSC: adipose‐derived mesenchymal stem cell; AQOL: Assessment of Quality of life; ARA: Australian Rheumatology Association; BMI: body mass index; BMMSC: bone marrow‐derived mesenchymal stem cell; COA: Canadian Orthopaedic Association; EQ5D‐3L: European Quality of Life 5 Dimensions 3 Level Version; ICRS: International Cartilage Repair Society; IKDC: International Knee Documentation Committee; KL: Kellgren‐Lawrence; KOOS: Knee injury and Osteoarthritis Outcome Score; KSFS: Knee Society Function Score; KSS: Knee Society Score; MM: millimetres; MOAKS: MRI Osteoarthritis Knee Score; MRI: magnetic resonance imaging; MSC: mesenchymal stem cell; NRS: numerical rating scale; OA: osteoarthritis; PASS: Patient Acceptable Symptom State; PRP: platelet‐rich plasma; PROMIS‐29: patient reported outcome measures information system; ROM: range of motion; SF‐12: 12‐Item Short Form Health Survey; SF‐36: 36‐Item Short Form Health Survey; SVF: stromal vascular fraction; VAS: visual analogue scale; VascuQoL: Vascular Quality of Life Questionnaire; vs: versus; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; WORMS: Whole‐Organ magnetic resonance imaging Score

Twelve studies are awaiting classification as there was insufficient information to judge whether to include or exclude them (Aghdami 2014; Bakowski 2020; Dallo 2021; Fiolin 2020; Jones 2018; Khasru 2019; Liang 2015; March 2013; Maheswari 2022; Nasb 2020; Wang 2016; Zi‐Yi 2018). These are described in the Characteristics of studies awaiting classification table. They were available in abstract form only (Aghdami 2014; Dallo 2021; Fiolin 2020; Khasru 2019; March 2013; Maheswari 2022), as study protocol only (Bakowski 2020; Jones 2018; Nasb 2020) or the full‐text PDF could not be retrieved (Liang 2015), or inadequate translation was available at the time of publication (Wang 2016; Zi‐Yi 2018).

The 77 ongoing studies that did not have study results available at the time of submission of this review are described in the Characteristics of ongoing studies table. Twenty‐one studies are placebo‐controlled, out of which five are recruiting (ACTRN12617001095358; Liu 2021; NCT04240873; NCT04368806; NCT05182034); notably Liu 2021 has recruited 190 participants to date and is expecting to recruit a further 210 participants. Another five trials have completed the study but no results have been published as yet (CTRI/2011/07/001891; IRCT20080728001031N23; KCT0001619; NCT01448434; NCT03990805). A further eight trials have not yet commenced recruitment (IRCT20210423051054N1; Mikkelsen 2021; NCT03379168; NCT04520945; NCT04821102; NCT05526001; NCT05933434; NCT05936060), in one trial the recruitment status is unknown (NCT04208646), and two trials have been withdrawn (NCT03164083) or terminated (CTRI/2009/091/000435).

Included studies

A full description of the 25 included trials is provided in the Characteristics of included studies table and a summary of trial and participant characteristics is provided in Table. We contacted the authors of five trials (Gupta 2016; Khalifeh Soltani 2019; Kuah 2018; Lee 2019; Vega 2015) to retrieve (1) information about study design, participants, interventions and outcomes of the trial, (2) information required to complete the risk of bias assessments, and (3) missing data for unreported or partially reported outcomes. We received replies from the authors of three trials (Gupta 2016; Khalifeh Soltani 2019; Vega 2015).

2. Baseline demographic and clinical characteristics of the trial participants.

Trial (country)	Treatment groups	Sample size	Age	Gender (%)	Osteoarthritis criteria	Kellgren‐Lawrence grade	Duration of symptoms	Mean (SD) baseline paina	Mean (SD) baseline function (0 to 100 scale, 0 best functionb)	Follow‐up
Stem cell injection versus placebo injection (8 trials)
Emadedin 2018 (Iran)	Stem cell	19	Mean (SD) 51.7 (9.2) years	37 % female	KL grade 2 to 4, diagnosed using X‐ray but no severe joint involvement for grade 4	KL Grading: Grade 2:10.5%; Grade 3: 68.4%; Grade 4: 21.1%	12.5 months (mean)	Not reported	Not reported	1 week, 3 months and 6 months
	Placebo	24	Mean (SD) 54.7 (5.3) years	38% female		KL Grading: Grade 2: 4.2%; Grade 3: 83.3%; Grade 4: 12.5%	13.5 months (mean)
Garza 2020 (USA)	High‐dose stem cell	13	Mean (SD) 59.5 (11.7) years	46.2% female	KL grade 2 or 3, no full‐thickness lesion; WOMAC pain subscore > 6 and < 16 on a 20‐point scale in 1 knee and a WOMAC pain score < 6 for the contralateral knee	Not reported	Not reported	Not reported	Mean (SD) short‐form WOMAC (0 to 56, 0 is best function): 47.1 (SD not reported)	6 weeks, 3, 6 and 12 months
	Low‐dose stem cell	13	Mean (SD) 60.5 (7.9) years	69.2% female					Mean (SD) short‐form WOMAC (0 to 56, 0 is best function): 56.2 (SD not reported)
	Placebo	13	Mean (SD) 57.1 (9.1) years	53.8% female					Mean (SD) short‐form WOMAC (0 to 56, 0 is best function): 49.3 (SD not reported)
Khalifeh Soltani 2019 (Iran)	Stem cell	10	Mean 57.5 years (SD not reported)	90% female	KL grade 2 to 4; 35 to 75 years	Not reported	Not reported	Mean (SD) VAS (0 to 10, 0 is no pain): 7.2 (1.5)	Mean (SD) KOOS ADL subscale (0 to 100, 100 is best function): 33.2 (15.8)	2, 8 and 24 weeks
	Placebo	10	Mean 55.8 years (SD not reported)	90% female				Mean (SD) VAS (0 to 10, 0 is no pain): 6.6 (1.5)	Mean (SD) KOOS ADL subscale (0 to 100, 100 is best function): 38.4 (19.8)
Kim 2023 (Korea)	Stem cell	125	Mean (SD) 63.7 (7.1) years	68% female	> 20 years; KL grade 3; VAS 100mm ≥ 50; WOMAC total ≥ 40; symptomatic >12 weeks	KL Grading: Grade 3: 100%	84.1 (68.1) months	Mean (SD) VAS (0 to 100, 0 is no pain) pain: 57.7 (17.1)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function) function: 39.8 (9.4)	1, 3 and 6 months
	Placebo	127	Mean (SD) 63.8 (7.1) years	79% female		KL Grading: Grade 3: 100%	85.7 (66.5) months	Mean (SD) VAS (0 to 100, 0 is no pain) pain: 60.9 (16.6)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function) function: 41.8 (10.3)
Kuah 2018 (Australia)	Stem cell 3.9 M	8	Mean (SD) 50.8 (7.29) years	25% female	KL grade 1 to 3; 40 to 65 years	KL Grading: Grade 1: 0%; Grade 2: 25%; Grade 3: 75%	Not reported	Mean (SD) VAS (0 to 100, 0 is no pain): 57.0 (13.82)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 22.0 (9.80)	4 weeks; 3, 6, 9 and 12 months
	Stem cell 6.7 M	8	Mean (SD) 55 (5.15) years	38% female		KL Grading: Grade 1: 12.5%; Grade 2: 12.5%; Grade 3: 75%		Mean (SD) VAS (0 to 100, 0 is no pain): 60.8 (13.01)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 26.8 (10.20)
	Placebo	4	Mean (SD) 55 (10.42) years	75% female		KL Grading: Grade 1: 25%; Grade 2: 0%; Grade 3: 75%		Mean (SD) VAS (0 to 100, 0 is no pain): 43.8 (7.41)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 16.07 (10.69)
Lee 2019 (Korea)	Stem cell	12	Mean (SD) 62.2 (6.5) years	75% female	KL grade 2 to 4; 18 to 75 years; symptomatic for at least 12 weeks	KL Grading: Grade 2: 50%; Grade 3: 50%; Grade 4: 0%	Not reported	Mean VAS (0 to 10, 0 is no pain): 6.7 (SD not reported)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 60.0 (17.0)	1, 3 and 6 months
	Placebo	12	Mean (SD) 63.2 (4.2) years	75% female		KL Grading: Grade 2: 41.7%; Grade 3: 50%; Grade 4: 8.3%		Mean (SD) VAS (0 to 10, 0 is no pain): 5.7 (SD not reported)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 56.4 (16.3)
Sadri 2023 (Iran)	Stem cell	20	Mean (SD) 52.8 (7.2) years	90% female	Aged 18 to 65 years; KL grading II or III; VAS Index Score ≥ 3; knee joint alignment < 30 degrees	KL Grading: Grade 2: 55%; Grade 3: 45%	Not reported	Mean (SD) VAS pain: 7.40 (1.35)	Mean (SD) KOOS ADL subscale (0 to 100, 100 is best function): 32.80 (15.26)	3, 6 and 12 months
	Placebo	20	Mean (SD) 56.1 (7.2)	90% female				Mean (SD) VAS pain: 7.73 (1.14)	Mean (SD) KOOS ADL subscale (0 to 100, 100 is best function): 30.52 (14.43)
Shapiro 2017 (USA)	Stem cell	25 knees	60 years in overall sample	Overall 72% female	KL grade 1 to 3	Not reported	Longstanding	Median (min, max) VAS (0 to 10, 0 is no pain): 3.1 (0 to 8.1)	Not reported	6 months and 12 months
	Placebo	25 knees						Median (min, max) VAS (0 to 10, 0 is no pain): 2.9 (0 to 7.0)
Stem cell injection versus no treatment or usual care (2 trials)
Freitag 2019 (Australia)	Stem cell (1 injection)	10	Mean (SD) 54.6 (6.3) years	30% female	KL grade 2 to 3; 18 years or older; not reported	Not reported	Not reported	Mean (SD) NRS (0 to 10, 0 is no pain): 6.7 (1.7)	Mean (SD) KOOS ADL subscale (0 to 100, 100 is best function): 58.8 (19.8)	1, 3, 6 and 12 months
	Stem cell (2 injection)	10	Mean (SD) 54.7 (10.2) years	60% female				Mean (SD) pain on NRS (0 to 10, 0 is no pain): 6.5 (1.4)	Mean (SD) KOOS ADL subscale (0 to 100, 100 is best function): 53.8 (18.3)
	Usual care (analgesia, weight management and exercise)	10	Mean (SD) 51.5 (6.1) years	50% female				Mean (SD) pain on NRS (0 to 10, 0 is no pain): 6.5 (1.4)	Mean (SD) KOOS ADL subscale (0 to 100, 100 is best function): 59.4 (13.6)
Ren 2023 (China)	Stem cell	6 knees	Mean (SD) 62.17 (6.34 years)	83% female	35 to 70 years ; both knee joints with articular cartilage defect grades I/II	Not reported	Not reported	Not reported	Mean (SD) WOMAC total (0 to 96, 0 is best score): 85.33 (22.19)	Every 4 weeks till 24 weeks
	No treatment	6 knees	Mean (SD) 62.17 (6.34 years)	83% female					Mean (SD) WOMAC total (0 to 96, 0 is best score): 85.33 (22.19)
Stem cell injection versus glucocorticoid injection (1 trial)
Bastos 2020 (Portugal)	Stem cell	16	Mean (SD) 55.7 (7.8) years	37.5% female	Knee OA (based on American College of Rheumatology criteria) KL grade 1 to 4	KL Grading: Grade 1: 6.3%; Grade 2: 43.8%; Grade 3: 31.3%; Grade 4: 18.8%	Not reported	Mean (SD) KOOS pain (0 to 100, 0 is worst pain): 34.5 (11.4)	Mean (SD) KOOS ADL subscale (0 to 100, 100 is best function): 31.7 (19.1)	1,2, 3,6, 9 and 12 months
	Stem cell plus PRP (treatment group excluded from this review)	14	Mean (SD) 60.8 (9.9) years	64.3% female		KL Grading: Grade 1: 7.1%; Grade 2: 21.4%; Grade 3: 42.9%; Grade 4: 28.6%		Mean (SD) KOOS pain (0 to 100, 0 is worst pain): 42.3 (17.2)	Mean (SD) KOOS ADL subscale (0 to 100, 100 is best function): 41.2 (18.2)
	Glucocorticoid	17	Mean (SD) 55.9 (13.4) years	47.1% female		KL Grading: Grade 1: 5.8%; Grade 2: 23.5%; Grade 3: 41.1%; Grade 4: 29.4%		Mean (SD) KOOS pain (0 to 100, 0 is worst pain): 40.5 (19.6)	Mean (SD) KOOS ADL subscale (0 to 100, 100 is best function); 40.7 (21)
Stem cell injection versus hyaluronic acid injection (7 trials)
Chen 2021 (Taiwan)	Stem cell 64 M	15	Mean (SD) 64.9 (4.91) years	80% female	KL grade 1 to 3; aged 40 to 80 years; ACR criteria; WOMAC pain score 7–17	KL Grading: Grade 2: 80% Grade 3: 20%	2.4 years (mean)	Mean (SD) VAS pain (0 to 100, 0 is no pain): 55.27 (24.29)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 23.87 (14.06)	2, 4, 12 and 24 weeks
	Stem cell 32 M	17	Mean (SD) 68.6 (6.45) years	88.2% female		KL Grading: Grade 2:58.8% Grade 3: 41.2%	3.7 years (mean)	Mean (SD) VAS pain (0 to 100, 0 is no pain): 58.88 (22.04)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 32.65 (13.68)
	Stem cell 16 M	17	Mean (SD) 67.7 (6.84) years	82.4% female		KL Grading: Grade 2: 58.8% Grade 3: 41.2%	3 years (mean)	Mean (SD) VAS pain (0 to 100, 0 is no pain): 52 (19.44)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 30.24 (14.4)
	Hyaluronic acid	8	Mean (SD) 70.5 (8.37) years	62.5% female		KL Grading: Grade 2: 62.5% Grade 3: 37.5%	2.4 years (mean)	Mean (SD) VAS pain (0 to 100, 0 is no pain): 53.25 (18.80)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 29.5 (12.5)
Goncars 2017 (Latvia)	Stem cell	28	Mean (SD) 53.44 (15) years	46% female	KL grade 2 to 3; less than 75 years	KL Grading: Grade 2: 9% Grade 3: 19%	Not reported	Mean (SD) pain on KOOS pain (0 to 100, 100 is no pain): 54.09 (34)	Not reported	1, 3, 6 and 12 months
	Hyaluronic acid	28	Mean (SD) 58.55 (13) years	64% female		KL Grading: Grade 2: 7% Grade 3: 21%		Mean (SD) pain on KOOS pain (0 to 100, 100 is no pain): 50.18 (43)
Ho 2022 (China)	Stem cell	10	Mean (SD) 56.7 (4.83) years	40% female	50 to 65 years; KL grade 2 to 3	KL Grading: Grade 2: 80% Grade 3: 20%	Not reported	Median (IQR) VAS (0 to 10, 0 is no pain) at rest: 2.5 (1.00 to 3.75)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 28.7 (18.73)	3, 6, 9 and 12 months
	Hyaluronic acid	10	Mean (SD) 59.1 (4.04) years	80% female		KL Grading: Grade 2: 90% Grade 3: 10%		Median (IQR) VAS (0 to 10, 0 is no pain) at rest: 1.5 (0.75 to 3.25)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 32.9 (15.17)
Lu 2019 (China)	Stem cell	26	Mean (SD) 55.03 (9.19) years	89% female	KL grade 1 to 3; 18 to 70 years	KL grading: Grade 1: 3.8%, Grade 2: 34.6%, Grade 3: 61.5%	53.62 months (mean)	Mean (SD) VAS (0 to 10, 0 is no pain): 5.38 (2.37)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 23.65 (14.60)	1 week, 6 and 12 months
	Hyaluronic acid	27	Mean (SD) 59.64 (5.97) years	89% female		KL grading: Grade 1: 7.7%, Grade 2: 30.8%, Grade 3: 61.5%	63.81 months (mean)	Mean (SD) VAS (0 to 10, 0 is no pain): 4.94 (2.5)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 22.35 (13.29)
Matas 2019 (Chile)	Stem cell (high‐dose)	10	Mean (SD) 56.7 (4.1) years	60 % female	KL grade 1 to 3; 40 to 65 years; symptoms at least 3 months	KL grading: Grade 2: 60% Grade 3: 40%	Not reported	Mean (SD) VAS (0 to 100, 0 is no pain): 39.4 (21.4)	Mean (SE) WOMAC function subscale (0 to 68, 0 is best function): 23.8 (9.2)	2 weeks, 3 months, 6 months and 12 months
	Stem cell (low‐dose)	10	Mean (SD) 56.1 (6.8) years	50% female		KL grading: Grade 2: 50% Grade 3: 50%		Mean (SD) VAS (0 to 100, 0 is no pain): 44.8 (16.5)	Mean (SE) WOMAC function subscale (0 to 68, 0 is best function): 25.3 (8.5)
	Hyaluronic acid	9	Mean (SD) 54.8 (4.5) years	55% female		KL grading: Grade 2: 77% Grade 3: 23%		Mean (SD) VAS (0 to 100, 0 is no pain): 38.7 (19.4)	Mean (SE) WOMAC function subscale (0 to 68, 0 is best function): 18.7 (10.9)
Vega 2015 (Spain)	Stem cell	15	Mean 56.6 years (SD not reported)	60% female	KL grade 2 to 4, 18 to 75 years; symptomatic for at least 6 months	Not reported	Not reported	Mean (SE) VAS (0 to 100, 0 is no pain): 54 (7)	Mean (SE) WOMAC total normalised (0 to 100, 0 is best function): 41 (3)	8 days, and 3, 6 and 12 months
	Hyaluronic acid	15	Mean 53.3 years (SD not reported)	68% female				Mean (SE) VAS (0 to 100, 0 is no pain): 64 (7)	Mean (SE) WOMAC total normalised (0 to 100, 0 is best function): 45 (3)
Zhang 2022 (China)	Stem cell	56	Mean (SD) 53.98 (13.69) years	75% female	20 to 85 years; KL grade 2 to 3	KL Grading Grade 2: 73.2%; Grade 3: 26.8%	Not reported	Mean (SD) VAS (0 to 10, 0 is no pain) pain: 4.04 (1.46)	Mean (SD) WOMAC total (0 to 96, 0 is best score): 34.57 (22.85)	1, 2 and 3 years and every 2 years thereafter
	Hyaluronic acid	70	Mean (SD) 55.63 (12.18) years	77% female		KL Grading Grade 2: 66%; Grade 3: 34%		Mean (SD) VAS (0 to 10, 0 is no pain) pain: 3.64 (0.98)	Mean (SD) WOMAC total (0 to 96, 0 is best score): 29.97 (19.87)
Stem cell injection versus PRP injection (2 trials)
Anz 2020 (USA)	Stem cell	49	Mean (SD) 55.8 (11.3) years	40% female	KL grade 1 to 3; 18 to 80 years; symptomatic for at least 4 months	KL Grading 1 to 3 (mean (SD)): 1.8 (0.7)	Not reported	Mean (SD) WOMAC pain score (0 to 20, 0 is no pain): 7.0 (3.3)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 22.9 (13.2)	1, 3, 6, 9 and 12 months
	PRP	41	Mean (SD) 52.2 (12.4) years	44% female		KL Grading 1 to 3 (mean (SD)): 1.9 (0.7)		Mean (SD) WOMAC pain score (0 to 20, 0 is no pain): 6.2 (3.8)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 21.3 (12.5)
Baria 2022 (USA)	Stem cell	35	Mean (SD) 56.1 (1.7) years	71% female	KL grade 1 to 4; 25 to 75 years; symptomatic for at least 6 weeks	KL grading: Grade 1: 6% Grade 2: 14% Grade 3: 31% Grade 4: 28%	Not reported	Mean (SD) KOOS (0 to 100, 0 worst is pain) pain: 51.48 (9.78)	Mean (SD) KOOS ADL (0 to 100, 100 is best function): 62.11 (16.99)	1, 3, and 6 months
	PRP	36	Mean (SD) 51.9 (2.4) years	33% female		KL grading: Grade 1: 16% Grade 2: 22% Grade 3: 33% Grade 4: 11%		Mean (SD) KOOS (0 to 100, 0 is worst pain) pain: 50.9 (11.64)	Mean (SD) KOOS ADL (0 to 100, 100 is best function): 58.63 (15.20)
Stem cell injection versus oral acetaminophen (paracetamol) (1 trial)
Garay‐Mendoza 2018 (Mexico)	Stem cell	30	Mean (SD) 55.67 (12.02) years	77% female	Aged over 30 years; symptomatic for at least 6 months	Not reported	Not reported	Mean (SD) VAS (0 to 10, 0 is no pain) pain: 5.27 (2.2)	Mean (SD) WOMAC total score (0 to 100, 0 is best score): 62.61 (18.5)	1 week, 1 month, and 6 months
	Paracetamol	31	Mean (SD) 59.32 (10.85) years	71% female				Mean (SD) VAS (0 to 10, 0 is no pain) pain: 4.32 (2.35)	Mean (SD) WOMAC total score (0 to 100, 0 is best score): 69.93 (17.9)
Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection (1 trial)
Sadat‐Ali 2021 (Saudi Arabia)	Stem cell	30	Mean (SD) 56.18 (6.56) years	80% female	Aged between 45 and 70 years; symptomatic for 12 months	KL grading: Grade 2 and Grade 3: 60%	Not reported	Mean (SD) VAS pain: 6.65 (0.09)	Not reported	3, 12 and 24 months
	NSAIDs plus physical therapy plus hyaluronic acid injection	27	Mean (SD) 56.75 (5.77) years	53% female				Mean (SD) VAS pain: 6.96 (1.1)
Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone (3 trials)
Gupta 2016 (India)	Stem cell 25M plus hyaluronic acid injection	10	Mean (SD) 58.1 (8.23) years	70% female	KL grade 2 to 3; 40 to 70 years	KL Grading: Grade 2: 40%; Grade 3: 60%	Not reported	Mean (SD) VAS (0 to 100, 0 is no pain): 60.9 (19.7)	Mean (SD) WOMAC function subscale (0 to 1700, 0 is best function): 940.3 (409.9)	1, 3, 6 and 12 months
	Stem cell 50M plus hyaluronic acid injection	10	Mean (SD) 57.3 (9.45) years	80% female		KL Grading: Grade 2: 10%; Grade 3: 90%		Mean (SD) VAS (0 to 100, 0 is no pain): 73.7 (15.2)	Mean (SD) WOMAC function subscale (0 to 1700, 0 is best function): 1388.2 (307.4)
	Placebo 1 plus hyaluronic acid injection	10	Mean (SD) 54.9 (8.27) years	100% female		KL Grading: Grade 2: 30%; Grade 3: 70%		Mean (SD) VAS (0 to 100, 0 is no pain): 61.0 (23.8)	Mean (SD) WOMAC function subscale (0 to 1700, 0 is best function): 875.9 (344.7)
	Stem cell 75M plus hyaluronic acid injection	10	Mean (SD) 55 (6.72) years	80% female		KL Grading: Grade 2: 30%; Grade 3: 70%		Mean (SD) VAS (0 to 100, 0 is no pain): 57.4 (29.0)	Mean (SD) WOMAC function subscale (0 to 1700, 0 is best function): 1059.3 (317.8)
	Stem cell 150M plus hyaluronic acid injection	10	Mean (SD) 54 (6.73) years	50% female		KL Grading: Grade 2: 30%; Grade 3: 70%		Mean (SD) VAS (0 to 100, 0 is no pain): 46.6 (23.6)	Mean (SD) WOMAC physical function subscale (0 to 1700, 0 is best function): 987.8 (368)
	Placebo 2 plus hyaluronic acid injection	10	Mean (SD) 56.7 (5.19) years	70% female		KL Grading: Grade 2: 30%; Grade 3: 70%		Mean (SD) VAS (0 to 100, 0 is no pain): 65.3 (12.2)	Mean (SD) WOMAC physical function subscale (0 to 1700, 0 is best function): 1008.3 (358.5)
Lamo‐Espinosa 2016 (Spain)	High‐dose stem cell + hyaluronic acid	10	Median (IQR) 57.8 (55.0 to 60.8) years	20% female	KL grade 2 or above; 50 to 80 years; not reported	KL grading: Grade 2: 30% Grade 3: 30% Grade 4: 40%	10 years (median)	Median (IQR) VAS (0 to 10, 0 is no pain): 6 (4 to 8)	Median (IQR) WOMAC function subscale (0 to 68, 0 is best function): 19 (12 to 25)	3, 6 and 12 months
	Low dose stem cell + hyaluronic acid	10	Median (IQR) 65.9 (59.5 to 70.6) years	60% female		KL grading: Grade 2: 10% Grade 3: 20% Grade 4: 70%	9 years (median)	Median (IQR) VAS (0 to 10, 0 is no pain): 7 (5 to 8)	Median (IQR) WOMAC function subscale (0 to 68, 0 is best function): 26.5 (23 to 32)
	Hyaluronic acid alone	10	Median (IQR) 60.3 (55.1 to 61.1) years	30% female		KL grading: Grade 2: 40% Grade 3: 20% Grade 4: 40%	6 years (median)	Median (IQR) VAS (0 to 10, 0 is no pain): 5 (3 to 7)	Median (IQR) WOMAC function subscale (0 to 68, 0 is best function) 21 (13 to 24)
Lamo‐Espinosa 2020 (Spain)	Stem cell + PRP	30	Mean (range) 56 (40 to 62) years	43% female	ACR diagnosis, > 2.5 on 10 point VAS; KL grade ≥ 2	KL Grading: Grade 2: 20.8% Grade 3: 20% Grade 4: 50%	Not reported	Mean (SD) VAS pain score (0 to 10, 0 is no pain): 5.3 (1.9)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 23.5 (13.2)	3, 6 and 12 months
	PRP alone	30	Mean (range) 54.6 (33 to 70) years	46% female		KL Grading: Grade 2: 30.7% Grade 3: 19.2% Grade 4: 50%		Mean (SD) VAS pain score (0 to 10, 0 is no pain): 5 (1.8)	Mean (SD) WOMAC function subscale (0 to 68, 0 is best function): 22.3 (12.8)

Abbreviations
ACR: American College of Rheumatology; HA: hyaluronic acid; IQR: interquartile range; KL: Kellgren‐Lawrence; KOOS: Knee Injury and Osteoarthritis Outcome Score; M: million; Max: maximum; Min: minimum; NRS: numerical rating scale; NSAID: non‐steroidal anti‐inflammatory drug; PRP: platelet‐rich plasma; SD: standard deviation; SE: standard error; VAS: visual analogue scale; WOMAC: Western Ontario and McMaster Universities Arthritis Index

*calculated based upon individual participant data presented in the paper

Median age reported in Lamo‐Espinosa 2016 and Shapiro 2017.

^aMean pain at baseline measured using a visual analogue scale (VAS) 0 to 10 (0 is no pain) in Garay‐Mendoza 2018; Ho 2022 (median); Khalifeh Soltani 2019; Lamo‐Espinosa 2016 (median); Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Sadat‐Ali 2021; Sadri 2023; Shapiro 2017 (median); Zhang 2022; VAS 0 to 100 (0 is no pain) in Chen 2021; Gupta 2016; Kim 2023; Kuah 2018; Matas 2019; Vega 2015; numerical rating scale (NRS) 0 to 10 (0 no pain) in Freitag 2019; KOOS pain (0 to 100, 100 is no pain) in Baria 2022; Bastos 2020; Goncars 2017; WOMAC pain (0 to 20, 0 is no pain) in Anz 2020.

^bMean function at baseline measured using short‐form WOMAC (0 to 56, 0 is best function) in Garza 2020; KOOS ADL (0 to 100, 100 is best function) in Baria 2022; Bastos 2020; Freitag 2019; Khalifeh Soltani 2019; Sadri 2023; WOMAC function subscale (0 to 68, 0 is best function) in Anz 2020; Chen 2021; Ho 2022; Kim 2023; Kuah 2018; Lamo‐Espinosa 2016; Lee 2019; Lu 2019; Matas 2019; (median); Lamo‐Espinosa 2020; WOMAC total (0 to 96, 0 is best score) in Garay‐Mendoza 2018; Ren 2023; Vega 2015; Zhang 2022; WOMAC function (0 to 1700, 0 is best function) in Gupta 2016.

Study design and setting

Twenty‐three included trials were parallel‐group RCTs and a further two trials included participants with bilateral knee osteoarthritis and used participants as their own control. A total of 1341 participants contributed to analyses in this review. Five trials had three arms (Freitag 2019; Garza 2020; Kuah 2018; Lamo‐Espinosa 2016; Matas 2019), one trial had four arms (Chen 2021), one trial had six arms (Gupta 2016) and the remaining 18 trials had two arms. Two trials included participants with bilateral knee osteoarthritis and used participants as their own control (Ren 2023; Shapiro 2017). Trials were conducted in the USA (Anz 2020; Baria 2022; Garza 2020; Shapiro 2017), Iran (Emadedin 2018; Khalifeh Soltani 2019; Sadri 2023), Australia (Freitag 2019; Kuah 2018), India (Gupta 2016), Spain (Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Vega 2015), Portugal (Bastos 2020), Korea (Kim 2023; Lee 2019), Latvia (Goncars 2017), Taiwan (Chen 2021), China (Ho 2022; Lu 2019; Ren 2023; Zhang 2022), Saudi Arabia (Sadat‐Ali 2021), Mexico (Garay‐Mendoza 2018) and Chile (Matas 2019) (Table).

Seven trials were sponsored by stem cell manufacturers (Anz 2020; Freitag 2019; Garza 2020; Gupta 2016; Kim 2023; Kuah 2018; Lee 2019), two studies were supported by funding from stem cell manufacturers and a research grant (Chen 2021; Lu 2019), 13 studies received funding only from research grants (Baria 2022; Bastos 2020; Emadedin 2018; Garay‐Mendoza 2018; Khalifeh Soltani 2019; Ho 2022; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Ren 2023; Sadri 2023; Shapiro 2017; Vega 2015; Zhang 2022), and three studies did not report any funding (Goncars 2017; Matas 2019; Sadat‐Ali 2021).

Participant characteristics

Baseline demographic and clinical characteristics of participants are detailed in the Characteristics of included studies table and summarised in Table. A total of 1341 participants were included in the 25 trials. Most of the trials were small; the number of participants per trial ranged from six (Ren 2023) to 252 (Kim 2023), with only two trials having more than 100 participants (Kim 2023; Zhang 2022). Minimum and maximum age requirements varied from a minimum requirement of 18 years to 80 years. The mean age of participants ranged from 51 years to 66 years and 59.5% of participants were female. A summary description of symptom duration was only reported in five trials (mean in Chen 2021, Emadedin 2018, Kim 2023 and Lu 2019; median in Lamo‐Espinosa 2016) and ranged from 12.5 months to 10 years. Most trials included participants with moderate radiographic disease (Kellgren‐Lawrence grade II‐III), although six trials also included participants with more severe (grade IV) radiographic change (Baria 2022; Bastos 2020; Emadedin 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019) and six trials also included participants with grade I changes (Anz 2020; Baria 2022; Bastos 2020; Chen 2021; Kuah 2018; Lu 2019).

Intervention characteristics

The interventions are summarised in Table and grouped according to the comparator for stem cell injection. The source of stem cells varied across trials. Ten trials used autologous bone marrow‐derived mesenchymal stem cells (MSCs) (Anz 2020; Bastos 2020; Emadedin 2018; Garay‐Mendoza 2018; Goncars 2017; Ho 2022; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Sadat‐Ali 2021; Shapiro 2017), two trials used allogeneic bone‐marrow‐derived mesenchymal stem cells (Gupta 2016; Vega 2015), seven trials used autologous adipose cells (Baria 2022; Freitag 2019; Garza 2020; Kim 2023; Lee 2019; Lu 2019; Ren 2023), while the remaining trials used allogeneic placenta‐derived stem cells (Khalifeh Soltani 2019), allogeneic donor adipose cells (Chen 2021; Kuah 2018; Sadri 2023; Zhang 2022) and allogeneic umbilical‐derived stem cells (Matas 2019). The harvested stem cells underwent in vitro expansion in 17 of the 25 studies (Bastos 2020; Emadedin 2018; Freitag 2019; Garza 2020; Gupta 2016; Ho 2022; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Matas 2019; Sadat‐Ali 2021; Sadri 2023; Vega 2015). In 10 trials, the stem cell preparation underwent cryopreservation prior to injection (Chen 2021; Freitag 2019; Gupta 2016; Kim 2023; Kuah 2018; Lee 2019; Lu 2019; Matas 2019; Sadri 2023; Vega 2015), in five trials, stem cells were prepared in the laboratory without freezing (Bastos 2020; Emadedin 2018; Garza 2020; Goncars 2017; Khalifeh Soltani 2019), and in 10 trials they were injected immediately after harvest (Anz 2020; Baria 2022; Garay‐Mendoza 2018; Ho 2022; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Ren 2023; Sadat‐Ali 2021; Shapiro 2017; Zhang 2022). Most trials used a single injection of stem cells except for two trials that used two injections of stem cells (Lu 2019; Matas 2019). Knee injection was performed via ultrasound guidance in eight trials (Anz 2020; Freitag 2019; Garza 2020; Kuah 2018; Lee 2019; Lu 2019; Ren 2023; Shapiro 2017), via x‐ray guidance in one trial (Emadedin 2018) and via anatomical landmarks without image guidance in the remaining 16 trials.

3. Stem cells characteristics.

Study ID	Autologous vs allogeneic	Source tissue	Cell injectate	Cell characterisation	Addition of growth factors	In vitro expansion	Storage	Dosage regimen	Injection guidance method
Stem cell injection versus placebo injection (8 trials)
Emadedin 2018	Autologous	Bone marrow	MSC	ISCT criteria	None	Tissue culture	None	1 dose of 40 x 106 cells	X‐ray
Garza 2020	Autologous	Adipose	SVF	1) Cell yield and viability; 2) cultured sterility; 3) residual collagenase activity; 4) endotoxin contamination; 5) gram negative organism contamination; 6) phenotypical characterisation; 7) colony forming unit analysis; 8) cytokine/growth factor characterisation	None	Tissue culture	None	Low dose of 15 million cells or a high dose of 30 million cells	Ultrasound
Khalifeh Soltani 2019	Allogeneic	Placenta	MSC	None	None	Tissue culture	None	1 dose of 0.50 to 0.6 x 108	None
Kim 2023	Autologous	Adipose	MSC	Code of Federal Regulations, Title 21	None	Culture flask	Cryopreservation	1 dose of 108 AD‐MSCs	None
Kuah 2018	Allogeneic	Adipose	MSC	None	None	Tissue culture	Cryopreservation	1 dose of 3.9 million or 6.7 million	Ultrasound
Lee 2019	Autologous	Adipose	MSC	Code of Federal Regulations, Title 21	5 ng/mL recombinant epidermal growth factor	Tissue culture	Cryopreservation	1 dose 1 x 108 cells	Ultrasound
Sadri 2023	Allogeneic	Adipose	MSC	None	None	Culture flask	Cryopreservation	1 dose 100 × 106 cells	None
Shapiro 2017	Autologous	Bone marrow	Marrow concentrate	ISCT criteria	None	No	Immediate injection	1 injection, dose unclear	Ultrasound
Stem cell injection versus no treatment or usual care (2 trials)
Freitag 2019	Autologous	Adipose	MSC	ISCT criteria	None	Tissue culture under hypoxic conditions, passage x 2	Cryopreservation	1 dose of 100 x 106 cells	Ultrasound
Ren 2023	Autologous	Adipose	SVF	ISCT criteria	None	None	Immediate injection	1 dose of 108 SVF cell	Ultrasound
Stem cell injection versus glucocorticoid injection (1 trial)
Bastos 2020	Autologous	Bone marrow	MSC	None	None	Culture flask	None	1 dose of 40 × 106 cells	None
Stem cell injection versus hyaluronic acid injection (7 trials)
Chen 2021	Allogeneic	Adipose	MSC	None	None	No	Cryopreservation	1 dose of 64 × 106 cells or 32 × 106 cells or 16 × 106 cells	None
Goncars 2017	Autologous	Bone marrow	Bone marrow‐derived mononuclear cells	None	None	No	None	1 injection, dose unclear	None
Ho 2022	Autologous	Bone marrow	MSC	ISCT criteria	None	Culture flask	Immediate injection	6 mL BM‐MSCs (1 x 106 cells per mL)	None
Lu 2019	Autologous	Adipose	MSC	ISCT criteria	Not reported	Tissue culture	Cryopreservation	2 injections of 5 × 107	Ultrasound
Matas 2019	Allogeneic	Umbilical cord	MSC	ISCT criteria	None	Tissue culture	Cryopreservation	1 dose of 20 × 106 or 2 doses of 20 × 106	None
Vega 2015	Allogeneic	Bone marrow	MSC	ISCT criteria	None	Tissue culture	Cryopreservation	1 dose of 40 x 106 cells	None
Zhang 2022	Allogeneic	Adipose	SVF	None	None	No	Immediate injection	3 injections of 4.84 million viable SVF cells	None
Stem cell injection versus PRP injection (2 trials)
Anz 2020	Autologous	Bone marrow	Marrow concentrate	None	None	No	Immediate injection	1 injection, dose unclear	Ultrasound
Baria 2022	Autologous	Adipose	SVF	None	None	No	Immediate injection	1 injection, dose unclear	None
Stem cell injection versus oral acetaminophen (paracetamol) (1 trial)
Garay‐Mendoza 2018	Autologous	Bone marrow	Marrow concentrate	None	None	No	Immediate injection	1 injection, dose unclear	None
Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection (1 trial)
Sadat‐Ali 2021	Autologous	Bone marrow	Chondrocytes	None	None	Culture flask	Immediate injection	1 injection 5 million cells	None
Stem cell injection plus intra‐articular co‐intervention versus co‐intervention only (3 trials)
Gupta 2016	Allogeneic	Bone marrow	MSC	None	2 ng/mL basic fibroblast growth factor	Tissue culture	Cryopreservation	1 dose of 25 million or 50 million or 75 million or 150 million	None
Lamo‐Espinosa 2016	Autologous	Bone marrow	MSC	ISCT criteria	1 ng/mL human fibroblast growth factor	Tissue culture	Immediate injection	1 dose 10 x 106 cells	None
Lamo‐Espinosa 2020	Autologous	Bone marrow	MSC	ISCT criteria	1 ng/mL human fibroblast growth factor	Culture flask	Immediate injection	1 injection 100 × 106	None

AD‐MSC: adipose‐derived mesenchymal stem cell; BM‐MSC: bone marrow‐derived mesenchymal stem cell; ID: identifier; ISCT: International Society for Cellular Therapy; MSC: mesenchymal stem cell; ng: nanogram; NSAIDs: non‐steroidal anti‐inflammatory drugs; PRP: platelet‐rich plasma; SVF: stromal vascular fraction; vs: versus

Stem cell injection versus placebo injection

Eight trials compared a single injection of one or more stem cell doses to a single placebo injection (Emadedin 2018; Garza 2020; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lee 2019; Sadri 2023; Shapiro 2017). Kuah 2018 compared 3.9 million stem cell injection versus 6.7 million stem cell injection versus placebo injection. Garza 2020 compared high‐dose (30 million cells) and low‐dose (15 million cells) stem cell injections to placebo (lactated Ringer solution) injection. The other six trials compared a single stem cell injection to a single placebo (saline) injection (Emadedin 2018; Khalifeh Soltani 2019; Kim 2023; Lee 2019; Sadri 2023; Shapiro 2017).

Stem cell injection versus no treatment or usual care

Two trials compared stem cell injection to no treatment or usual care (Freitag 2019; Ren 2023). One trial, Freitag 2019, compared a single intra‐articular autologous adipose‐derived mesenchymal stem cell (100 × 10⁶ ADMSCs) injection versus two intra‐articular autologous adipose‐derived mesenchymal stem cell (100 × 10⁶ ADMSCs at baseline and six months) injections to usual care (analgesia, weight management and exercise). Another trial compared one injection of 10⁸ autologous adipose‐derived stromal vascular fraction cells to no treatment (Ren 2023).

Stem cell injection versus glucocorticoid injection

One trial compared a single intra‐articular injection of 40 × 10⁶ bone‐marrow‐derivedstem cells to a single intra‐articular injection of glucocorticoid (4 mg of dexamethasone) (Bastos 2020).

Stem cell injection versus hyaluronic acid injection

Seven trials compared stem cell injection to hyaluronic acid (Chen 2021; Goncars 2017; Ho 2022; Lu 2019; Matas 2019; Vega 2015; Zhang 2022).

Chen 2021 compared a single intra‐articular injection of allogeneic adipose‐derived stem cells (ADSCs) 64 × 10⁶ cells versus 32 × 10⁶ cells versus 16 × 10⁶ cells versus hyaluronic acid intra‐articular injection. Goncars 2017 compared a single intra‐articular injection of bone marrow‐derived mononuclear cells to three intra‐articular sodium hyaluronate injections at weekly intervals. Ho 2022 compared a single intra‐articular injection of 6 mL of bone marrow‐derived MSCs (1 x 10⁶ cells per mL) to 6 mL of hyaluronic acid (Synvisc‐One®: Hylan G‐F 20). One trial compared two intra‐articular injections of 5 × 10⁷ adipose‐derived MSCs to one intra‐articular injection of 1% sodium hyaluronic acid administered once per week for four weeks (Lu 2019). One trial compared a single intra‐articular injection of 20 × 10⁶ umbilical cord‐derived MSCs versus two intra‐articular injections of 20 × 10⁶ umbilical cord‐derived MSCs versus a single intra‐articular injection of hyaluronic acid (Durolane) (Matas 2019). Vega 2015 compared a single intra‐articular injection of 40 x 10⁶ bone marrow‐derived stem cells versus 60 mg of hyaluronic acid (Durolane). Zhang 2022 compared three monthly intra‐articular injections of 4.84 million stromal vascular fraction cells versus three monthly intra‐articular injections of hyaluronic acid.

Stem cell injection versus platelet‐rich plasma (PRP) injection

Two trials compared a single intra‐articular injection of bone marrow‐derived MSCs (Anz 2020) or adipose stromal vascular fraction (Baria 2022) to a single intra‐articular injection of PRP.

Stem cell injection versus oral acetaminophen (paracetamol)

One trial compared a single intra‐articular injection of bone marrow‐derived MSCs versus oral acetaminophen 500 mg every eight hours for six months (Garay‐Mendoza 2018).

Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection

One trial compared a single intra‐articular injection of autologous bone marrow‐derived chondrocytes (5 million cells) to non‐steroidal anti‐inflammatory drugs (NSAIDs), physical therapy and Durolane, a hyaluronic acid injection, as needed (Sadat‐Ali 2021).

Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone

One trial compared four arms of stem cell injections (25 million, 50 million, 75 million and 150 million) plus hyaluronic acid injection with two arms of placebo (plasmalyte) injections plus hyaluronic acid injection (Gupta 2016). One trial compared a single intra‐articular injection of 100 x 10⁶ bone marrow‐derived stem cells (high‐dose group) plus hyaluronic acid injection versus a single intra‐articular injection of 10 x 10⁶ bone marrow‐derived stem cells (low‐dose group) plus hyaluronic acid injection versus a single intra‐articular injection of hyaluronic acid injection (Lamo‐Espinosa 2016). Another trial compared three weekly intra‐articular injections of PRP versus three weekly intra‐articular injections of PRP plus a single intra‐articular injection of 100 x 10⁶ bone marrow‐derived stem cells in the first week (Lamo‐Espinosa 2020).

Outcomes

The outcome measures that were reported in each study are presented in Table.

4. Outcome Reporting Bias In Trials (ORBIT) matrix.

Study ID	Pain	Function	Quality of life	Participant‐reported treatment success	Radiographic joint progression	Withdrawals due to adverse events	Serious adverse events
Stem cell injection versus placebo injection (8 trials)
Emadedin 2018	VAS (0 to 100, 0 no pain)	WOMAC function subscale (0 to 68, 0 is best function) Change from baseline scores	Not measured	Minimum clinically important improvement in pain (threshold and scale undefined) at 6 months	Not measured	Not reporteda	Yes
Garza 2020	WOMAC short‐form pain subscale measured but only total score was reported	WOMAC short‐form total scores (0 to 56, 0 is best function)	Not measured	Proportion achieving greater than 33% change from baseline in total WOMAC score at 6 months	Not measured	0 events	0 events
Khalifeh Soltani 2019	VAS (0 to 10, 0 no pain)	KOOS ADL subscale (0 to 100, 100 is best function)	Not measured	Not measured	Not measured	0 events	0 events
Kim 2023	VAS (0 to 100, 0 no pain)	WOMAC function subscale (0 to 68, 0 best function)	SF‐36 (0 to 100, 100 best score)	Proportion achieving 20% improvement in VAS pain	Not measured	0 events	Yes
Kuah 2018	VAS (0 to 100, 0 no pain)	WOMAC function subscale (0 to 68, 0 is best function)	Measured but numerical data not reported	Proportion achieving 30% improvement from baseline in VAS pain score at 12 months	Not measured	0 events	Yes
Lee 2019	VAS (0 to 10, 0 no pain)	WOMAC function subscale (0 to 68, 0 is best function)	Not measured	Not measured	X‐ray assessment of joint‐space width, but results not reported	0 events	0 events
Sadri 2023	VAS (0 to 10 scale, 0 no pain)	KOOS ADL (0 to 100, 100 best function)	SF‐36 (0 to 100, 100 best score)	Not measured	Not measured	0 events	0 events
Shapiro 2017	VAS (0 to 10, 0 no pain)	Not measured	Not measured	Not measured	Not measured	0 events	0 events
Stem cell injection versus no treatment or usual care (2 trials)
Freitag 2019	NRS (0 to 10, 0 no pain)	KOOS ADL subscale (0 to 100, 100 is best function)	Not measured	Proportion achieving MCID in pain and function	Not measured	0 events	0 events
Ren 2023	WOMAC pain subscale measured but only WOMAC total score was reported	Mean (SD) WOMAC total (0 to 96, 0 best score) measured but scores were not reported separately for the stem cell and control groups	Not measured	Not measured	Not measured	0 events	0 events
Stem cell injection versus glucocorticoid injection (1 trial)
Bastos 2020b	KOOS pain subscale	KOOS ADL subscale (0 to 100, 100 is best function)	KOOS QoL	Proportion with KOOS global improvement	Not measured	Yes	Yes
Stem cell injection versus hyaluronic acid injection (7 trials)
Chen 2021	VAS (0 to 100, 0 no pain) change scores	WOMAC function subscale (0 to 68, 0 is best function) change scores	Not measured	Not measured	Not measured	Yes	Yes
Goncars 2017	KOOS pain (0 to 100, 100 no pain)	KOOS ADL (0 to 100, 100 is best function) partially reported 12 months only	Not measured	Not measured	Measured but results not reported	0 events	0 events
Ho 2022	VAS (0 to 10, 0 no pain)	WOMAC function subscale (0 to 68, 0 is best function)	SF‐36 MCS (0 to 100, 100 best quality of life)	Not measured	Not measured	0 events	0 events
Lu 2019	VAS (0 to 10, 0 no pain)	WOMAC function subscale (0 to 68, 0 is best function)	SF‐36 (0 to 100, 100 best quality of life)	50% improvement in WOMAC total score	Not measured	Yes	Yes
Matas 2019	VAS (0 to 100, 0 no pain)	WOMAC function subscale (0 to 68, 0 is best function)	Not measured	Not measured	Not measured	0 events	0 events
Vega 2015	VAS (0 to 100, 0 no pain)	WOMAC total score (0 to 100, 0 is best function)	SF‐12 (0 to 100, 100 best quality of life)	Not measured	Not measured	0 events	0 events
Zhang 2022	VAS (0 to 10, 0 no pain)	WOMAC total score (0 to 96, 0 is best function)	Not measured	Not measured	X‐ray assessment of KL grade	0 events	0 events
Stem cell injection versus PRP injection (2 trials)
Anz 2020	WOMAC pain subscale (0 to 20, 0 is no pain)	WOMAC function subscale (0 to 68, 0 is best function)	Not measured	Not measured	Not measured	Yes	Yes
Baria 2022	KOOS–Pain subscore (0 to 100, 0 worst pain)	KOOS ADL subscore (0 to 100, 0 is worst function)	Not measured	Proportion of PASS responders (cut‐off 84.5) on the KOOS ADL subscale	Not measured	Yes	Yes
Stem cell injection versus oral acetaminophen (paracetamol) (1 trial)
Garay‐Mendoza 2018	VAS pain (0 to 10)	WOMAC function subscale (0 to 100, 0 is best function)	Not measured	Not measured	Not measured	Reasons for withdrawals were not reported	0 events reported
Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection (1 trial)
Sadat‐Ali 2021	VAS pain (0 to 10)	Not measured	Not measured	Not measured	Not measured	Yes	0 events reported
Stem cell injection plus intra‐articular co‐intervention versus co‐intervention only (3 trials)
Gupta 2016	VAS (0 to 100, 0 no pain)	WOMAC function subscale (0 to 68, 0 is best function)	Not measured	Not measured	Measured, result not reported ("no difference")	0 events	Yes
Lamo‐Espinosa 2016	VAS (0 to 10, 0 no pain) change scores	WOMAC function subscale (0 to 68, 0 is best function)	Not measured	Measured but not reported	X‐ray assessment of joint‐space width	0 events	0 events
Lamo‐Espinosa 2020	VAS (0 to 10, 0 no pain)	WOMAC function subscale (0 to 68, 0 is best function)	Not measured	Measured but not reported	X‐ray assessment of joint‐space width	0 events	0 events

^aEmadedin 2018 reported 3/22 withdrawals from the stem cell group and 1/25 withdrawal from the placebo group; reasons not reported.
^bBastos 2020 measured KOOS subscale and total scores at 1, 3, 6, 9 and 12 months, but reported KOOS data only at 12 months.

Abbreviations
ADL: activities of daily living; ID: identifier; KL: Kellgren‐Lawrence; KOOS: Knee Injury and Osteoarthritis Outcome Score; MCID: minimal clinically important difference; MCS: mental component summary; NRS: numerical rating scale; NSAIDs: non‐steroidal anti‐inflammatory drugs; PASS: Patient Acceptable Symptom State; PRP: platelet‐rich plasma; QoL: quality of life; SD: standard deviation; SF‐12: 12‐Item Short Form Health Survey; SF‐36: 36‐Item Short Form Health Survey; WOMAC: Western Ontario and McMaster Universities Arthritis Index; VAS: visual analogue scale.

Major outcomes

Mean pain

All included trials measured pain, but two trials did not report the pain scores (Garza 2020; Ren 2023). Eighteen trials measured and reported pain using a visual analogue scale (VAS): 11 trials used a VAS on a 0 to 10 scale where 0 is no pain (Garay‐Mendoza 2018; Ho 2022; Khalifeh Soltani 2019; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Sadat‐Ali 2021; Sadri 2023; Shapiro 2017; Zhang 2022) and seven trials used a VAS on a scale of 0 to 100 where 0 is no pain (Chen 2021; Emadedin 2018; Gupta 2016; Kim 2023; Kuah 2018; Matas 2019; Vega 2015). One trial measured and reported pain using a numerical rating scale (NRS, 0 to 10) (Freitag 2019), and another using the WOMAC pain scale (Anz 2020). Three trials measured and reported pain using the KOOS pain subscale (Baria 2022; Bastos 2020; Goncars 2017). Two trials measured pain as part of the WOMAC total score, but did not explicitly report pain subscale scores (Garza 2020; Ren 2023).

Mean function

Twenty‐three trials measured function. Thirteen trials measured and reported function using the WOMAC function subscale (Anz 2020; Chen 2021; Emadedin 2018; Garay‐Mendoza 2018; Gupta 2016; Ho 2022; Kim 2023; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Matas 2019). Three trials measured function on the WOMAC total score (Ren 2023; Vega 2015; Zhang 2022) but one trial, Ren 2023, did not report results for the stem cell and control groups separately. One trial, Garza 2020, measured and reported function using the WOMAC short‐form total scale. WOMAC is a validated score that quantitatively assesses pain, stiffness and physical function in patients with symptomatic osteoarthritis. The total score is out of 96 and lower scores indicate a better outcome.

Six trials measured and reported function using the KOOS activities of daily living (ADL) subscale (Baria 2022; Bastos 2020; Freitag 2019; Goncars 2017; Khalifeh Soltani 2019; Sadri 2023). KOOS is a validated score that consists of five subscales, namely pain improvement, symptom improvement, activities of daily living, function in sport and recreation and knee‐related quality of life. A normalised score is calculated for each subscale with 100 indicating no symptoms and 0 indicating maximal symptoms.

Two trials did not measure function (Sadat‐Ali 2021; Shapiro 2017).

Mean quality of life

Seven trials measured quality of life. One trial used AQoL‐4D but did not report numerical data (Kuah 2018), one trial used the KOOS quality of life (QOL) subscale (Bastos 2020), four trials used the SF‐36 (Ho 2022; Kim 2023; Lu 2019; Sadri 2023) and one trial used the SF‐12 (Vega 2015).

Participant‐reported global assessment of success

Eight trials reported improvement in pain and function as measures of treatment success. One trial reported 30% improvement from baseline in VAS pain score (Kuah 2018); another reported 20% improvement in VAS pain score (Kim 2023). One trial used the proportion achieving greater than 33% change from baseline in total WOMAC score (Garza 2020) and another trial reported 50% improvement in WOMAC total score (Lu 2019). One trial used the proportion with KOOS global improvement (Bastos 2020) and one trial reported the proportion achieving MCID in pain and function (Freitag 2019). Baria 2022 used the proportion achieving 84.5 cut‐off on the KOOS ADL subscale. One trial, Emadedin 2018, used a minimal clinically important improvement in pain. However, these data were not included in the analyses, as the threshold and scale were not defined.

Radiographic progression

Five studies reported progression in radiographic change in the affected joint using x‐ray projections for assessment of joint‐space width (Gupta 2016; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Zhang 2022). One study measured radiographic progression but did not report the results (Goncars 2017).

Withdrawals due to adverse events

Six trials reported withdrawals due to adverse events (Anz 2020; Baria 2022; Bastos 2020; Chen 2021; Lu 2019; Sadat‐Ali 2021); the rest reported zero withdrawals due to adverse events.

Serious adverse events

Ten trials reported serious adverse events (Anz 2020; Baria 2022; Bastos 2020; Chen 2021; Emadedin 2018; Gupta 2016; Kim 2023; Kuah 2018; Lu 2019; Sadat‐Ali 2021) and the rest of the trials reported zero events (Table).

5. Description of adverse events.

Study ID	Study arms(n)	Withdrawals due toadverse events	Serious adverse events	Non‐seriousadverse events
Stem cell injection versus placebo injection (8 trials)
Emadedin 2018	Stem cell: 22	3 (not reported if due to adverse events)	2 participants: 1 infection (Grade 3), 1 musculoskeletal‐related (Grade 3)a	20 events: injection site and general disorders (n = 3); musculoskeletal‐related (n = 17)b
	Placebo: 25	1 (not reported if due to adverse events)	2 participants: musculoskeletal‐related (Grade 3)	6 events: musculoskeletal‐related (n = 5); skin/subcutaneous tissue disorder (n = 1)
Garza 2020	Stem cell (high‐dose): 13	0 withdrawals	0 events recorded	3 participants: < Grade 1 (CTCAE criteria) (knee swelling (n = 1) bacterial growth in SVF sample (n = 2)
	Stem cell (low‐dose): 13	0 withdrawals	0 events recorded	0 events recorded
	Placebo: 13	0 withdrawals	0 events recorded	0 events recorded
Khalifeh Soltani 2019	Stem cell: 10	0 withdrawals	0 events recorded	4 participants: increased local pain and mild effusion self‐limited within 48 to 72 hours
	Placebo: 10	0 withdrawals	0 events recorded	0 events recorded
Kim 2023	Stem cell: 125	0 withdrawals	1 participant: pneumonia	48 participants: musculoskeletal including arthralgia, joint swelling, back pain, musculoskeletal pain, pain in extremity (n = 30 events); infections (n = 5 events); injection site pain and swelling (n = 5 events); nervous system disorders (n = 2 events); gastrointestinal disorders (n = 2 events); skin and subcutaneous tissue disorders (n = 2 events); injury, poisoning and procedural complications (n = 1 event); metabolism and nutrition disorders (n = 1 event); renal and urinary disorders (n = 2 events); respiratory, thoracic and mediastinal disorders (n = 1 event); neoplasms (n = 1 event); congenital, familial and genetic disorders (n = 1 event); reproductive system (n = 1 event)
	Placebo: 127	0 withdrawals	3 participants: COVID‐19, herpes zoster and spondylolisthesis	41 participants: musculoskeletal including arthralgia, joint swelling, back pain, musculoskeletal pain, pain in extremity (n = 23 events); infections (n = 9 events); injection site pain and swelling (n = 2 events); nervous system disorders (n = 2 events); gastrointestinal disorders (n = 1 event); cataract (n = 2 events); injury, poisoning and procedural complications (n = 1 event); metabolism and nutrition disorders (n = 1 event); neoplasms (n = 1 event); ear and labyrinth (n = 1 event); vascular disorders (n = 1 event)
Kuah 2018	Stem cell 6.7 M: 8	0 withdrawals	0 events recorded	8 participants: arthralgia (n = 8 events), joint effusion (n = 3 events), joint stiffness (n = 1 event), joint lock (n = 1 event), upper respiratory infection (n = 3 events), supra‐patella bursitis possibly related to the IP injection technique, occurred 2 weeks after administration of the IP (n = 1 event)
	Stem cell 3.9 M: 8	0 withdrawals	1 participant: prepatellar bursitis	8 participants: arthralgia (n = 6 events), joint effusion (n = 6 events), joint stiffness (n = 2 events), joint lock (n = 2 events)
	Placebo: 4	0 withdrawals	0 events recorded	4 participants: arthralgia (n = 4 events), joint effusion (n = 3 events), joint stiffness (n = 3 events), joint lock (n = 1 event)
Lee 2019	Stem cell: 12	0 withdrawals	0 events recorded	10 participants: arthralgia (n = 6), joint effusion (n = 2) and undefined (n = 2)c CTCAE Grade 1 (n = 22 events), Grade 2 (n = 9 events), Grade 3 (n = 3 arthralgia events)
	Placebo: 12	0 withdrawals	0 events recorded	7 participants: joint effusion (n = 1) and undefined (n = 6)d CTCAE Grade 1 (n = 11 events), Grade 2 (n = 1 event)
Sadri 2023	Stem cell: 20	0 withdrawals	0 events recorded	2 participants: swelling and pain in injection site, self‐limited
	Placebo: 20	0 withdrawals	0 events recorded	0 events recorded
Shapiro 2017	Stem cell: 25	0 withdrawals	0 events recorded	12 knees: effusions (n = 2 knees), joint line tenderness (n = 10 knees)
	Placebo: 25	0 withdrawals	0 events recorded	9 knees: effusions (n = 1 knee), joint line tenderness (n = 8 knees)
Stem cell injection versus no treatment or usual care (2 trials)
Freitag 2019	Stem cell (one injection): 10	0 withdrawals	0 events recorded	8 participants: mild swelling and pain post‐injection (n = 6), moderate swelling and pain post‐injection (n = 1), severe (n = 1) pain and swelling for 4 weeks affecting daily activities
	Stem cell (two injections): 10	0 withdrawals	0 events recorded	After first injection: 9 participants: mild grade** (n = 5) post‐injection swelling and pain; moderate grade** (n = 3) post‐injection swelling and pain; severe grade** (n = 1) pain and swelling for 4 weeks, affecting daily activities After second injection: 10 participants: mild grade** (n = 4) post‐injection swelling and pain; moderate grade** (n = 6) post‐injection swelling and pain
	No injection (usual care): 10	0 withdrawals	0 events recorded	0 events recorded
Ren 2023	Stem cell: 6 knees	0 withdrawals	0 events recorded	0 events recorded
	No treatment: 6 knees	0 withdrawals	0 events recorded	0 events recorded
Stem cell injection versus glucocorticoid injection (1 trial)
Bastos 2020	Stem cell: 16	1 participant: total knee arthroplasty	1 participant: total knee arthroplasty	0 events recorded
	Stem cell + PRP: 14	0 withdrawals	0 events recorded	0 events recorded
	Glucocorticoid: 17	1 participant died; the reason for death is not given	1 participant died; the reason for death is not given	0 events recorded
Stem cell injection versus hyaluronic acid injection (7 trials)
Chen 2021	Stem cell 64 M: 15	1 participant withdrew due to severe pain treated with analgesics	2 (nature of events was not specified)	8 participants: injection site joint pain (n = 4), swelling (n = 2), effusion (n = 1), joint stiffness (n = 1)
	Stem cell 32 M: 17	1 participant withdrew due to severe pain treated with analgesics	2 (nature of events was not specified)	10 participants: injection site joint pain (n = 5), swelling (n = 3), erythema (n = 1), joint stiffness (n = 1)
	Stem cell 16 M: 17	2 participants withdrew due to severe pain treated with analgesics	0 events recorded	6 participants: injection site joint pain (n = 3), swelling (n = 2), inflammation (n = 1)
	Hyaluronic acid: 8	0 withdrawals	0 events recorded	1 participant: injection site joint pain
Goncars 2017	Stem cell: 28	0 withdrawals	0 events recorded	0 events recorded
	Hyaluronic acid: 28	0 withdrawals	0 events recorded	0 events recorded
Ho 2022	Stem cell: 10	0 withdrawals	0 events recorded	0 events recorded
	Hyaluronic acid: 10	0 withdrawals	0 events recorded	0 events recorded
Lu 2019	Stem cell: 26	Stem cell: 0	0 events recorded	19 participants: the most common adverse events were transient pain and swelling of injection site joint, all of which were mild to moderate and were spontaneously relieved within 7 days without special treatment.
	Hyaluronic acid: 26	1 withdrawal due to knee infection treated with articular cavity flushing operation	1 participant: infection of the right knee after 2 months from first injection. This was relieved after the articular cavity flushing operation and the patient withdrew from the study.	14 participants: the most common adverse events were transient pain and swelling of injection site joint, all of which were mild to moderate and were spontaneously relieved within 7 days without special treatment.
Matas 2019	Stem cell (high‐dose): 10	0 withdrawals	0 events recorded	10 participants: synovitis (n = 7), pain after injection (n = 3)
	Stem cell (low‐dose): 10	0 withdrawals	0 events recorded	4 participants: synovitis (n = 3), pain after injection (n = 1)
	Hyaluronic acid: 9	0 withdrawals	0 events recorded	7 participants: synovitis (n = 5), pain after injection = 2)
Vega 2015	Stem cell: 15	0 withdrawals	0 events recorded	14 participants: post‐implantation pain and synovial fluid effusion with articular swelling up to 1 week (8 events); unexpected osteoarticular pain and inflammation (knee, shoulder, hip, ankle, lumbar; 7 events); other, including menstrual disorders, influenza, migraine, toothache, restlessness, memory loss, testicular pain, rhinitis, sensitive hand alteration, sleepiness, allergic reaction, tinnitus, dental implant, lipoma, skin tumour (8 events)
	Hyaluronic acid: 15	0 withdrawals	0 events recorded	13 participants: post‐implantation pain and/or synovial fluid effusion with articular swelling up to 1 week (9 events), unexpected osteoarticular pain and inflammation (knee, shoulder, hip, ankle, lumbar; 5 events); other, including menstrual disorders, influenza, migraine, toothache, restlessness, memory loss, testicular pain, rhinitis, sensitive hand alteration, sleepiness, allergic reaction, tinnitus, dental implant, lipoma, skin tumour (11 events)
Zhang 2022	Stem cell: 56	0 withdrawals	0 events recorded	0 events recorded
	Hyaluronic acid: 70	0 withdrawals	0 events recorded	0 events recorded
Stem cell injection versus PRP injection (2 trials)
Anz 2020	Stem cell: 49	3 participants: total knee replacement (n = 2), cancer(n = 1)	3 participants: total knee replacement (n = 2), cancer (n = 1)	0 events recorded
	PRP: 41	1 participant: knee surgery	1 participant: knee surgery	0 events recorded
Baria 2022	Stem cell: 35	2 participants discontinued intervention and underwent either surgery or injection post‐intervention	2 participants discontinued intervention and underwent either surgery or injection post‐intervention	0 events recorded
	PRP: 36	3 participants discontinued intervention and underwent either surgery or injection post‐intervention	3 participants discontinued intervention and underwent either surgery or injection post‐intervention	0 events recorded
Stem cell injection versus oral acetaminophen (paracetamol) (1 trial)
Garay‐Mendoza 2018	Stem cell: 30	Reasons for withdrawals not reported	0 events recorded	Swelling and pain in the knee the day after the stem cell injection in 1 patient. Infection was ruled out and the patient recovered without further complications; 12 patients had bone pain during the stimulation with G‐CSF. Some patients had slight pain and stiffness during the first 48 hr after the injection.
	Oral acetaminophen: 31	0 withdrawals	0 events recorded	0 events recorded
Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection (1 trial)
Sadat‐Ali 2021	Stem cell: 30	0 withdrawals	0 events recorded	0 events recorded
	NSAIDs plus physical therapy plus HA injection: 27	3 withdrawals: 3 participants underwent joint replacement	3 participants underwent joint replacement	1 participant had local cellulitis, which was treated with oral antibiotics.
Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone (3 trials)
Gupta 2016	Stem cell 25 M plus HA: 10	0 withdrawals	2 participants: hysterectomy for menorrhagia (n = 1) dyslipidaemia (n = 1)c	7 participants: injection‐related arthralgia (n = 7)
	Stem cell 50 M plus HA: 10	0 withdrawals	1 participant: anaemiac	7 participants: injection‐related arthralgia (n = 7)
	Stem cell 75 M plus HA: 10	0 withdrawals	0 events recorded	7 participants: injection site pain and arthralgia (n = 4); arthralgia due to OA (n = 2); joint swelling due to hypersensitivity to injection (n = 1)
	Stem cell 150 M plus HA: 10	0 withdrawals	2 participants: injection‐related synovial effusion requiring hospitalisation for one additional day of observation (n = 1) muscle haemorrhage (n = 1)	6 participants: joint swelling due to hypersensitivity to injection (n = 3) events for the other 3 participants were not clearly specified
	Placebo 1 plus HA: 10	0 withdrawals	1 participant: suture‐related complication and varicose veinc	7 participants: injection‐related arthralgia (n = 7)
	Placebo 2 plus HA: 10	0 withdrawals	2 participants: haemorrhoidal haemorrhage (n = 1) umbilical hernia (n = 1)c	6 participants: reasons were not clearly specified
Lamo‐Espinosa 2016	Stem cell (high‐dose) plus HA: 10	0 withdrawals	0 events recorded	6 participants: articular pain requiring anti‐inflammatory treatment during the first 24 hr after infiltration
	Stem cell (low‐dose) plus HA: 10	0 withdrawals	0 events recorded	3 participants: articular pain requiring anti‐inflammatory treatment during the first 24 hr after infiltration
	HA: 10	0 withdrawals	0 events recorded	1 participant: articular pain requiring anti‐inflammatory treatment during the first 24 hr after infiltration
Lamo‐Espinosa 2020	Stem cell + PRP: 24	0 withdrawals	0 events recorded	6 participants: articular pain requiring anti‐inflammatory treatment during the first 24 hr after infiltration, all of whom recovered completely without sequelae
	PRP: 26	0 withdrawals	0 events recorded	0 events recorded

Abbreviations
ADL: activities of daily living; AE: adverse events; COVID‐19: coronavirus disease 2019; CTCAE: Common Terminology Criteria for Adverse Events; G‐CSF: granulocyte colony stimulating factor; HA: hyaluronic acid; hr: hour; ID: identifier; IP: investigational product; n: number; NSAIDs: non‐steroidal anti‐inflammatory drug; M: million; OA: osteoarthritis; PRP: platelet rich plasma; SAE: serious adverse events; SVF: stromal vascular fraction

^aCTCAE classification of AE Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or non‐invasive intervention indicated; limiting age‐appropriate instrumental ADL*. Grade 3 Severe or medically significant but not immediately life‐threatening; hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self‐care ADL**. Grade 4 Life‐threatening consequences; urgent intervention indicated. Grade 5 death related to AE. We classified Grade 3 and 4 as SAEs.

**AE grading:

• Mild: awareness of a sign or symptom which does not interfere with the participants’ usual daily activity and is transient, resolving with use of simple interventions including simple analgesia.
• Moderate: interferes with the participants’ usual daily activity and/or requires symptomatic treatment including regular analgesia (i.e., opiate analgesia).
• Severe: symptom(s) causing severe discomfort with significant impact of the participants’ usual daily activity.
• Serious: any unexpected medical incident which requires hospitalisation, results in long‐term disability, is life‐threatening or results in death.

^bFor serious adverse events, we assumed each event occurred in one person, and for total adverse events, we assumed the most frequently reported event as the number of people with an event.

^cGupta 2016 categorised these events as 'severe' but the authors did not report if they resulted in hospitalisation or other serious sequelae, hence we classified them as serious adverse events.

^dUndefined: Lee 2019 reported that these events were not related to treatment, but as they did not describe the nature of these events, we included them in our analysis.

Minor outcomes

Total adverse events

Twenty studies reported the proportion of participants with total adverse events (both serious and non‐serious adverse events) (Table) (Anz 2020; Baria 2022; Bastos 2020; Chen 2021; Emadedin 2018; Freitag 2019; Garza 2020; Gupta 2016; Kim 2023; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Matas 2019; Sadat‐Ali 2021; Sadri 2023; Shapiro 2017; Vega 2015; Zhang 2022). In one study, Garay‐Mendoza 2018, non‐serious adverse events were reported only in the stem cell group, but the proportion of participants with adverse events was not clearly reported.

Treatment failure

Treatment failure was measured by progression to a joint replacement or other surgical procedure (Table). Three trials reported knee replacements only in the stem cell injection group (Bastos 2020; Garza 2020; Lu 2019). Four trials also reported knee replacements/surgery in the control group (Anz 2020; Baria 2022; Sadat‐Ali 2021; Zhang 2022).

6. Reporting of minor outcomes.

Study ID	Treatment failure	Magnetic resonance imaging measure of joint pathology (e.g. cartilage volume, bone marrow lesions, synovitis)
Stem cell injection versus placebo injection (8 trials)
Emadedin 2018	No events in any arm	Not measured
Garza 2020	High‐dose stem cell: 1/13 total knee replacement Low‐dose stem cell: 0/13 Placebo: 0/13	Cartilage degeneration was rated with the modified Outerbridge classification. No measures of variance given
Khalifeh Soltani 2019	No events in any arm	The cartilage thickness was described in millimetres at 14 sites; the minimum and maximum thickness was determined (totalling 28 points of thickness evaluated per patient), and presence (yes/no) of synovial hypertrophy in sagittal views; spur in coronal and sagittal views and erosion in coronal, sagittal and axial views. The medial and lateral meniscus was evaluated using the Crues and Stroller classification. Data not extracted as only available as percentage of qualitative parameters defined as stable, progress or regress.
Kim 2023	No events in any arm	Whole‐Organ Magnetic Resonance Imaging Score (WORMS) of knee using MRI
Kuah 2018	No events in any arm	Quantitative MRI assessment of cartilage volume, tibial bone area, bone marrow lesions and cartilage defects
Lee 2019	No events in any arm	Size and change of cartilage defect; depth of cartilage defect assessed using the modified Noyes grading system
Sadri 2023	No events in any arm	Cartilage thickness in millimetres
Shapiro 2017	No events in any arm	T2 quantitative mapping data to clarify the regenerative potential of stem cells
Stem cell injection versus no treatment or usual care (2 trials)
Freitag 2019	No events in any arm	MRI Osteoarthritis Knee Score (MOAK): MOAKs scores were used to describe OA progression over time. Bone marrow lesions (BMLs) and cysts ‐ each region is graded for the percentage of volume of each BML and whether there is an associated cyst. Articular cartilage: Each region is graded on the percentage area of cartilage with partial to full thickness loss and also separately on area with full thickness loss. Synovitis: volume of effusion‐synovitis is graded as Grade 0 (none), Grade 1 (small), Grade 2 (medium) and Grade 3 (large).
Ren 2023	No events in any arm	Qualitative and quantitative evaluation of cartilage degeneration and regeneration via a novel 3D MRI imaging protocol
Stem cell injection versus glucocorticoid injection (1 trial)
Bastos 2020	Stem cell: 1/16 total knee replacement Glucocorticoid: none	Not measured
Stem cell injection versus hyaluronic acid injection (7 trials)
Chen 2021	No events in any group	Not measured
Goncars 2017	No events in any arm	Not measured
Ho 2022	No events in any arm	T2‐mapped sagittal MR images
Lu 2019	1 knee replacement in the stem cell group	Articular cartilage volume. Data were presented separately for right and left knees and hence not extracted
Matas 2019	No events in any arm	Whole‐Organ Magnetic Resonance Imaging Score (WORMS) of knee using MRI
Vega 2015	No events in any arm	T2 mapping using the GE CartiGram for assessing cartilage changes. Data only in figures and not extracted
Zhang 2022	Stem cell: 3/56 had knee surgery HA: 6/70 had knee surgery	T2 mapping of cartilage change
Stem cell injection versus PRP injection (2 trials)
Anz 2020	Stem cell: 2/49 total knee replacement PRP: 1/41 knee surgery	Not measured
Baria 2022	Stem cell: 2/35 discontinued intervention and underwent either surgery or injection post‐intervention PRP: 3/36 discontinued intervention and underwent either surgery or injection post‐intervention	Not measured
Stem cell injection versus oral acetaminophen (paracetamol) (1 trial)
Garay‐Mendoza 2018	No events in any arm	Not measured
Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection (1 trial)
Sadat‐Ali 2021	Stem cell: no events NSAIDs plus physical therapy plus hyaluronic acid injection: 3 underwent joint replacement	Not measured
Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone (3 trials)
Gupta 2016	No events in any arm	Whole‐Organ Magnetic Resonance Imaging Score (WORMS) of knee using MRI
Lamo‐Espinosa 2016	No events in any arm	Whole‐Organ Magnetic Resonance Imaging Score (WORMS) of knee using MRI
Lamo‐Espinosa 2020	No events in any arm	Whole‐Organ Magnetic Resonance Imaging Score (WORMS) of knee using MRI

ID: identifier; HA: hyaluronic acid; MRI: magnetic resonance imaging; NSAID: non‐steroidal anti‐inflammatory drug; OA: osteoarthritis; PRP: platelet‐rich plasma

Magnetic resonance imaging measure of joint pathology

Seventeen trials measured joint pathology using magnetic resonance imaging (MRI) (Freitag 2019; Garza 2020; Gupta 2016; Ho 2022; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Matas 2019; Ren 2023; Sadri 2023; Shapiro 2017; Vega 2015; Zhang 2022).

Freitag 2019 did an MRI analysis on articular cartilage thickness, size of osteophytes, volume of effusion‐synovitis and meniscal tears, and also used the MRI Osteoarthritis Knee Score (MOAK) score to describe osteoarthritis progression over time. Garza 2020 used the modified Outerbridge classification to assess cartilage changes. Five trials measured Whole‐Organ Magnetic Resonance Imaging Score (WORMS) of knee (Gupta 2016; Kim 2023; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Matas 2019). Khalifeh Soltani 2019 evaluated cartilage thickness, synovial hypertrophy, spurs and integrity of the medial and lateral meniscus (using the Crues and Stroller classification). Kuah 2018 performed MRI assessments of cartilage volume, tibial bone area, bone marrow lesions and cartilage defects. Lee 2019 assessed cartilage defects using the modified Noyes grading system. Ren 2023 used a novel 3D MRI imaging protocol to qualitatively and quantitatively evaluate knee cartilage. Sadri 2023 used a fast spoiled gradient‐echo MRI protocol to measure cartilage thickness. Four trials used T2 quantitative MRI mapping to detect cartilage changes (Ho 2022; Shapiro 2017; Vega 2015; Zhang 2022). One trial, Lu 2019, measured articular cartilage volume; however, as data were presented separately for right and left knees, it could not be extracted (Table).

Excluded studies

A full description of the 35 excluded trials is provided in the Characteristics of excluded studies. Fifteen were not RCTs (Anonymous 2021; Bhattacharya 2011; ChiCTR‐ONN‐16009932; CTRI/2010/091/000270; ISRCTN13337022 2017; JPRN‐UMIN000026732; NCT02963727; NCT02966951; NCT03308006; NCT03337243; NCT03602872; NCT03790189; NCT03956719; Saris 2022; Sekiya 2021); 17 examined interventions other than stem cell injections (ACTRN12616001259437; Brittberg 2018; Centeno 2018; Conaghan 2023; EUCTR2010‐022072‐31‐GB; Ha 2018; Hernigou 2021; Hong 2019; Khasru 2023; NCT02776943; NCT02958267; NCT04314661; NCT04448106; Olufade 2022; Pham 2016; Turajane 2017) or included stem cells combined with another intervention (Ruane 2021) and thus did not provide information on the effect of stem cell injection alone; and three did not include an appropriate comparator (Bastos 2018; JPRN‐jRCTb032220282; Zhao 2019).

Risk of bias in included studies

While the eight placebo‐controlled trials were largely free from performance and detection bias, most trials without a placebo control were susceptible to these biases. However, of the placebo‐controlled trials, five (63%) were at risk of selective reporting bias. Overall, 14 (56%) trials were susceptible to selection bias, 13 (52%) trials were at risk of performance bias, 13 (52%) trials were at risk of detection bias and 15 (60%) at risk of selective reporting bias (Figure).

2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Only 11 of the 25 included trials used adequate methods to both generate and conceal their random sequence and were at low risk of selection bias (Bastos 2020; Freitag 2019; Garza 2020; Gupta 2016; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lu 2019; Shapiro 2017). Eight trials did not clearly report the method of generating or concealing their random sequence (Emadedin 2018; Garay‐Mendoza 2018; Goncars 2017; Ho 2022; Lee 2019; Matas 2019; Ren 2023; Sadri 2023) and five trials adequately generated their random sequence, but did not report their method of allocation concealment (Anz 2020; Baria 2022; Chen 2021; Vega 2015; Zhang 2022). Therefore, the risk of selection bias in these trials is unclear. One trial used inadequate methods of generating and concealing their random sequence (appeared to allocate the first 30 participants to treatment and the second to control), and thus was at high risk of selection bias (Sadat‐Ali 2021).

Blinding

We judged 12 (49%) trials at low risk of performance bias because study participants and personnel were successfully blinded (Bastos 2020; Emadedin 2018; Garza 2020; Gupta 2016; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lee 2019; Lu 2019; Matas 2019; Sadri 2023; Vega 2015). We judged 11 trials to be at high risk of performance bias as participants and personnel were not successfully blinded to treatment arms (Anz 2020; Baria 2022; Freitag 2019; Garay‐Mendoza 2018; Goncars 2017; Ho 2022; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Ren 2023; Sadat‐Ali 2021; Zhang 2022). We judged two trials at unclear risk of performance bias as the study was single‐blinded, where only participants were blinded and study personnel were not (Chen 2021; Shapiro 2017).

Fourteen trials (56%) were at low risk of detection bias for self‐reported outcomes as participants were blinded in these trials (Bastos 2020; Chen 2021; Emadedin 2018; Garza 2020; Gupta 2016; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lee 2019; Lu 2019; Matas 2019; Sadri 2023; Shapiro 2017; Vega 2015). Eleven trials were at high risk of detection bias for self‐reported outcomes as participants were not blinded in these trials (Anz 2020; Baria 2022; Freitag 2019; Garay‐Mendoza 2018; Goncars 2017; Ho 2022; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Ren 2023; Sadat‐Ali 2021; Zhang 2022).

Two trials were at high risk of detection bias for assessor‐reported outcomes as assessors were aware of treatment assignments (Baria 2022; Chen 2021). Two trials were at unclear risk of detection bias for assessor‐reported outcomes as the radiological outcomes were assessed by a single musculoskeletal radiologist, and it is unclear if the assessor was blinded to the treatment groups or not (Goncars 2017; Shapiro 2017). We judged all the other 21 studies as at low risk of detection bias for assessor‐reported outcomes: in three trials, no assessor‐reported outcomes were measured (Anz 2020; Garay‐Mendoza 2018; Sadat‐Ali 2021); in the remaining 18 studies, assessors were blinded to treatment groups (Bastos 2020; Emadedin 2018; Freitag 2019; Garza 2020; Gupta 2016; Ho 2022; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Matas 2019; Ren 2023; Sadri 2023; Vega 2015; Zhang 2022).

Incomplete outcome data

All the 25 included studies were at low risk of attrition bias, as either the number of withdrawals and reasons for withdrawals were balanced across groups (Anz 2020; Baria 2022; Bastos 2020; Chen 2021; Emadedin 2018; Freitag 2019; Garay‐Mendoza 2018; Garza 2020; Kim 2023; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lu 2019; Matas 2019; Sadat‐Ali 2021; Sadri 2023; Zhang 2022) or there were no withdrawals from study arms and all randomised participants completed the study (Goncars 2017; Gupta 2016; Ho 2022; Khalifeh Soltani 2019; Lee 2019; Ren 2023; Shapiro 2017; Vega 2015).

Selective reporting

Only 10 trials were at low risk of selective reporting bias (Anz 2020; Baria 2022; Chen 2021; Ho 2022; Khalifeh Soltani 2019; Kim 2023; Lu 2019; Sadri 2023; Vega 2015; Zhang 2022). Thirteen trials were at high risk of selective reporting bias (Bastos 2020; Emadedin 2018; Freitag 2019; Garza 2020; Goncars 2017; Gupta 2016; Kuah 2018; Lamo‐Espinosa 2016; Lee 2019; Matas 2019; Ren 2023; Sadat‐Ali 2021; Shapiro 2017), as either the trial was not registered and no study protocol was found (Bastos 2020; Sadat‐Ali 2021), there was selective reporting of outcomes (Emadedin 2018; Freitag 2019; Garza 2020; Goncars 2017; Gupta 2016; Kuah 2018; Lamo‐Espinosa 2016; Lee 2019; Matas 2019; Shapiro 2017), or study outcomes were measured but not reported per group (Ren 2023). Two trials had stated quality of life as a secondary outcome in the trial registry but did not measure it in the study (Garay‐Mendoza 2018; Lamo‐Espinosa 2020). We rated these trials at unclear risk of bias.

Other potential sources of bias

All trials were at low risk of other bias except for three studies. Freitag 2019 was considered to be at high risk as it had a deviation from protocol: a third treatment group to receive five injections of 40 × 10⁶ ADMSCs at baseline, one, two, three and six months, respectively, was intended, but ceased due to moderate adverse events (increasing self‐limiting pain with sequential injections) in a concurrently run study with the same treatment protocol. Baria 2022 was at unclear risk as the trial recruitment was prematurely stopped due to institution regulations, and the potential impact of this on the power of the study is unclear. It is also unclear if Ren 2023, which recruited participants with bilateral knee osteoarthritis and allocated one knee to treatment and the other to control, appropriately analysed the data (they seem not to have reported data for the control knee).

Effects of interventions

See: Summary of findings 1 Stem cell injection versus placebo injection; Summary of findings 2 Stem cell injection versus no treatment or usual care; Summary of findings 3 Stem cell injection versus glucocorticoid injection

The summary of findings for stem cell injection versus placebo injection is presented in Table, stem cell injection versus no treatment in Table and stem cell injection versus glucocortoid injection in Table.

1. Stem cell injection versus placebo injection

Eight studies with 459 participants contributed data to this comparison (Emadedin 2018; Garza 2020; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lee 2019; Sadri 2023; Shapiro 2017). There were too few studies to formally assess the presence of publication bias using funnel plots; however, we identified up to three larger trials that had been conducted but withdrawn prior to reporting of results.

Major outcomes

Pain

Seven of eight studies reported pain (Emadedin 2018; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lee 2019; Sadri 2023; Shapiro 2017).

Low‐certainty evidence indicates that stem cell injection may improve pain slightly (Analysis 1.1). We downgraded the evidence due to indirectness and suspected publication bias.

1.1. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 1: Mean overall pain (0 to 10, 0 is no pain)

At up to three months follow‐up, mean pain (0 to 10 scale, lower scores indicate less pain) was 4.8 points with placebo injection and 1.1 points better (95% CI 1.7 points better to 0.5 points better) with stem cell injection (I² = 33%; 7 studies, 443 participants). At > three months to six months follow‐up, mean pain was 4.5 points with placebo injection and 1.2 points better (2.5 points better to 0 points better) with stem cell injection (I² = 80%; 7 studies, 445 participants; Table). At > six months to one year, mean pain was 4.0 points with placebo injection and 1.7 points better (95% CI 5.3 points better to 1.9 points worse) with stem cell injection (I² = 93%; 3 studies, 106 participants).

The substantial heterogeneity seen at the > three months to six months time point (I² = 80%) was driven by the large effect reported with stem cell injection in Sadri 2023. Excluding the data from Sadri 2023 in a sensitivity analysis reduced the heterogeneity.

Assuming a reduction of 1.5 points on a 10‐point pain scale is clinically important, the 95% confidence intervals included both little to no effect and a clinically important effect at three, six and 12 months.

A subgroup analysis did not indicate a difference in the effect on pain at the primary time point (> three to six months) between stem cells of autologous or allogeneic origin (subgroup difference Chi² = 0.23, df = 1 (P = 0.63), I² = 0%; Analysis 1.2). We did not have separate data available for osteoarthritis severity, so this subgroup analysis could not be performed in this baseline review, but data may be available in future living updates to this review.

1.2. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 2: Mean overall pain by cell origin (0 to 10, 0 is no pain)

Sensitivity analyses (data not shown) conducted at the primary time point only (> three to six months) indicated the effect estimates were largely robust to selection bias. Removing data from three trials at risk of selection bias (Emadedin 2018; Lee 2019; Sadri 2023) did not substantially change the result, but did move the effect estimate closer to no effect, and narrowed the 95% CIs so that they no longer included any clinically important effect (MD 0.3 better, 95% CI 1.4 better to 0.8 points worse). No studies were at risk of detection bias, so a sensitivity analysis could not be performed. Similarly, the result at the primary time point appeared to be robust to the potential for small sample bias; switching to a fixed‐effect model (data not shown) had a minimal impact (MD 1.4 better, 95% CI 1.8 better to 0.9 better).

Function

Seven of eight studies reported function (Emadedin 2018; Garza 2020; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lee 2019; Sadri 2023).

Low‐certainty evidence indicates that stem cell injection may slightly improve function (Analysis 1.3). We downgraded the evidence due to indirectness and suspected publication bias.

1.3. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 3: Mean function (0 to 100, 0 is best function)

At up to three months follow‐up, mean function (0 to 100 scale, lower scores indicate better function) was 47.2 points with placebo injection and 8.9 points better (95% CI 15.7 points better to 2.2 points better) with stem cell injection (I² = 66%; 7 studies, 432 participants). At > three months to six months follow‐up, mean function was 46.3 points with placebo injection and 14.2 points better (25.3 points better to 3.1 points better) with stem cell injection (I² = 82%; 7 studies, 432 participants; Table). At > six months to one year, mean function was 42 points with placebo injection and 24.6 points better (95% CI 51.9 points better to 2.8 points worse) with stem cell injection (I² = 83%; 3 studies, 82 participants).

Assuming a reduction of 10 points on a 100‐point function scale is clinically important, the 95% confidence intervals included both little to no effect and a clinically important effect at three, six months and 12 months.

A subgroup analysis did not indicate a difference in the effect on function at the primary time point (> three to six months) between stem cells of autologous or allogeneic origin (subgroup difference Chi² = 0.02, df = 1 (P = 0.89), I² = 0%; Analysis 1.4). We did not have separate data available for osteoarthritis severity, so this subgroup analysis could not be performed in this baseline review, but data may be available in future living updates to this review.

1.4. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 4: Mean function by cell origin (0 to 100, 0 is best function)

Sensitivity analyses (data not shown) conducted at the primary time point only (> three to six months) indicated that the effect estimates were largely robust to selection bias. Removing data from three trials at risk of selection bias (Emadedin 2018; Lee 2019; Sadri 2023) did not substantially change the result (MD 6.2 points better, 95% CI 12.3 points better to 0.2 points better). No studies were at risk of detection bias, so sensitivity analysis could not be performed. Similarly, the result at the primary time point appeared to be robust to the potential for small sample bias; switching to the fixed‐effect model (data not shown) had little impact (MD 11.1 points better, 95% CI 14.9 points better to 7.3 points better).

Quality of life

Two studies reported quality of life using the SF‐36 MCS scores (Kim 2023; Sadri 2023).

We are uncertain whether stem cell injection improves quality of life (very low‐certainty evidence; Analysis 1.5). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At up to three months follow‐up, mean quality of life (0 to 100 scale, higher scores indicate better quality of life) was 48.7 points with placebo injection and 10.13 points better (95% CI 9 points worse to 29.28 points better) with stem cell injection (I² = 86%; 2 studies, 288 participants). At > three months to six months follow‐up, mean quality of life was 45.3 points with placebo injection and 22.8 points better (18.0 points worse to 63.7 points better) with stem cell injection (I² = 96%; 2 studies, 288 participants). At > six months to one year, mean quality of life was 25 points with placebo injection and 60 points better (95% CI 45.5 points better to 74.5 points better) with stem cell injection (1 study, 36 participants).

1.5. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 5: Mean quality of life (SF‐36 mental health)

Participant‐reported global assessment of success

Four studies reported participant‐reported global assessment of success (Emadedin 2018; Garza 2020; Kim 2023; Kuah 2018).

We are uncertain whether stem cell injection increases the number of people who report treatment success (Analysis 1.6). We downgraded the evidence due to indirectness, imprecision and suspected publication bias (Table). At the end of follow‐up, 89/168 participants (530 per 1000) in the placebo injection group reported treatment success compared with 126/180 participants (683 per 1000) in the stem cell injection group (RR 1.3, 95% CI 1.1 to 1.5; I² = 0%; 4 studies, 348 participants; very low‐certainty evidence).

1.6. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 6: Participant‐reported global assessment of success

Radiographic joint progression

Radiographic joint progression was measured in one study (Lee 2019), but numerical results were not reported (Analysis 1.7).

1.7. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 7: Radiographic joint progression (minimum JSW or median JSW in mm)

Withdrawals due to adverse events

No withdrawals due to adverse events were reported with stem cell injection or with placebo injection (5 studies, 153 participants; very low‐certainty evidence; Analysis 1.8).

1.8. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 8: Withdrawals due to adverse events

Serious adverse events

We are uncertain whether stem cell injection increases the number of people who experience serious adverse events (Analysis 1.9). We downgraded the evidence due to indirectness, imprecision and suspected publication bias (Table). At the end of follow‐up, 5/219 participants (23 per 1000) in the placebo injection group experienced serious adverse events compared with 4/242 participants (16 per 1000) in the stem cell injection group (RR 0.7, 95% CI 0.2 to 2.6; I² = 0%; 7 studies, 461 participants; very low‐certainty evidence). One trial reported Grade 3 infection following stem cell injection (CTCAE 2017) and musculoskeletal‐related Grade 3 events in both stem cell and placebo groups (Emadedin 2018). In another study (Kuah 2018), serious adverse events were reported only in the group that received a dose of 3.9 million stem cells (prepatellar bursitis) and not in the group that received 6.7 million stem cells or in the placebo group. Kim 2023 reported one serious adverse event (pneumonia) in the stem cell group and three events (COVID‐19, herpes zoster and spondylolisthesis) in the placebo group.

1.9. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 9: Serious adverse events

Minor outcomes

Total adverse events

Eight studies reported total adverse events (Emadedin 2018; Garza 2020; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lee 2019; Sadri 2023; Shapiro 2017).

At the end of follow‐up, 71/239 participants (336 per 1000) in the placebo injection group reported total adverse events compared with 115/262 participants (487 per 1000) in the stem cell injection group (RR 1.5, 95% CI 1.0 to 2.1; I² = 56%; 8 studies, 501 participants) (Analysis 1.10). Most of the non‐serious adverse events were injection‐related, including pain, swelling, effusion and stiffness in the injected joint and infection at the injection site. Most studies reported injection‐related adverse events in both stem cell injection and control group arms, except for two trials in which no adverse events were reported in the placebo group (Garza 2020; Sadri 2023).

1.10. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 10: Total adverse events

Treatment failure

One study reported treatment failure (Garza 2020).

At six months, 0/13 participants (0 per 1000) in the placebo injection group experienced treatment failure (total knee arthroplasty) compared with 1/26 participants (38 per 1000) in the stem cell injection group (RR 1.6, 95% CI 0.1 to 35.8; 1 study, 39 participants; Analysis 1.11).

1.11. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 11: Treatment failure

MRI measure of joint pathology

Seven studies reported MRI joint progression (Garza 2020; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lee 2019; Sadri 2023; Shapiro 2017). In one trial, cartilage degeneration was rated with the modified Outerbridge classification (Garza 2020). Another trial used the modified Noyes grading system to assess cartilage defects (Lee 2019). Kim 2023 reported the modified whole‐organ MRI score (WORMS). Khalifeh Soltani 2019 evaluated cartilage thickness, synovial hypertrophy, spurs and integrity of the medial and lateral meniscus using the Crues and Stroller classification. Kuah 2018 performed MRI assessments of cartilage volume, tibial bone area, bone marrow lesions and cartilage defects. Shapiro 2017 used T2 quantitative cartilage mapping. Sadri 2023 used a fast spoiled gradient‐echo MRI protocol to measure cartilage thickness. As all seven studies used different ways of reporting this outcome, we could not meta‐analyse the data.

Six of the seven studies reported results based on MRI assessments performed at baseline and either six months (Garza 2020; Khalifeh Soltani 2019; Kim 2023; Lee 2019) or 12 months (Kuah 2018; Sadri 2023) following the intervention. Shapiro 2017 performed MRI assessments at baseline and six months but did not report the results. Four studies reported between‐group comparisons (Garza 2020; Kim 2023; Kuah 2018; Lee 2019). Garza 2020 found no difference in Outerbridge scores or cartilage thickness and Kim 2023 found no difference in cartilage appearance as measured by WORMS in those who received stem cell injection versus those who received a placebo injection. Kuah 2018 reported a reduction in lateral cartilage volume loss in those who received a low dose of stem cells compared with placebo, but no difference compared to placebo in those who received a high dose of stem cells. Lee 2019 reported a slower rate of progression of medial femoral condyle cartilage defects in the stem cell injection group compared to the placebo injection group. Khalifeh Soltani 2019 reported an increase in cartilage thickness within the group that received stem cell injections but not in those who received a placebo injection; however, progression in structural changes in the knee was numerically higher in the stem cell group compared to the placebo group. Sadri 2023 reported an increase in cartilage thickness between baseline and 12 months in the stem cell injection group in two of 10 anatomical sites, but no difference in other sites, and did not perform between‐group analyses.

2. Stem cell injection versus no treatment or usual care (analgesia, weight loss and exercise)

Two studies compared stem cell injections to no treatment or usual care (analgesia, weight loss and exercise) (Freitag 2019; Ren 2023). The control group received analgesia, weight loss and exercise in Freitag 2019 and nothing in Ren 2023. Ren 2023 (six participants) did not provide data per group; hence, only data from Freitag 2019 were analysed in this comparison (Table). No studies measured quality of life or radiographic joint progression.

Major outcomes

Pain

One study with 30 participants provided data for this outcome (Freitag 2019).

We are uncertain whether stem cell injection improves pain at any time point due to very low‐certainty evidence (Analysis 2.1). We downgraded the evidence due to the potential for bias, imprecision, indirectness and suspected publication bias. At up to three months follow‐up, mean pain (0 to 10 scale, lower scores indicate less pain) was 6 points with no treatment or usual care and 2.5 points better (95% CI 1.3 points better to 3.7 points better) with stem cell injection. At > three months to six months follow‐up, mean pain was 6 points with no treatment or usual care and 2.3 points better (1 point better to 3.6 points better) with stem cell injection. At > six months to one year, mean pain was 6 points with no treatment or usual care and 3.7 points better (95% CI 1.7 points better to 5.6 points better) with stem cell injection. Assuming a reduction of 1.5 points on a 10‐point pain scale is clinically important, the 95% confidence intervals included both little to no effect and a clinically important effect at all time points except 12 months.

2.1. Analysis.

Comparison 2: Stem cell injection versus no treatment or usual care (analgesia, weight loss and exercise), Outcome 1: Mean overall pain (0 to 10, 0 is no pain)

Function

One study with 30 participants provided data for this outcome (Freitag 2019).

We are uncertain whether stem cell injection improves function at any time point due to very low‐certainty evidence (Analysis 2.2). We downgraded the evidence due to the potential for bias, imprecision, indirectness and suspected publication bias. At up to three months follow‐up, mean function (0 to 100 scale, lower scores indicate better function) was 33 points with no treatment or usual care and 14.2 points better (95% CI 4.2 points better to 24.2 points better) with stem cell injection. At > three months to six months follow‐up, mean function was 34.5 points with no treatment or usual care and 12.7 points better (28.5 points better to 3.1 points worse) with stem cell injection. At > six months to one year, mean function was 39 points with no treatment or usual care and 25.9 points better (95% CI 16 points better to 35.7 points better) with stem cell injection. Assuming a reduction of 10 points on a 100‐point function scale is clinically important, the 95% confidence intervals included both little to no effect and a clinically important effect at all time points except 12 months.

2.2. Analysis.

Comparison 2: Stem cell injection versus no treatment or usual care (analgesia, weight loss and exercise), Outcome 2: Mean function (0 to 100, 0 is best function)

Participant‐reported global assessment of success

Freitag 2019 reported the proportion of participants achieving a minimal clinically important difference when combining all pain and functional outcome measures.

We are uncertain whether stem cell injection increases the number of people who report treatment success due to very low‐certainty evidence (Analysis 2.3). We downgraded the evidence due to the potential for bias, imprecision, indirectness and suspected publication bias. At the end of follow‐up, 6/10 participants (600 per 1000) in the no treatment or usual care group reported treatment success compared with 17/20 participants (852 per 1000) in the stem cell injection group (RR 1.4, 95% CI 0.8 to 2.4; 1 study, 30 participants).

2.3. Analysis.

Comparison 2: Stem cell injection versus no treatment or usual care (analgesia, weight loss and exercise), Outcome 3: Participant‐reported global assessment of success

Withdrawals due to adverse events

No withdrawals due to adverse events were reported with stem cell injection or with no treatment (1 study, 30 participants; very low‐certainty evidence; Analysis 2.4).

2.4. Analysis.

Comparison 2: Stem cell injection versus no treatment or usual care (analgesia, weight loss and exercise), Outcome 4: Withdrawals due to adverse events

Serious adverse events

No serious adverse events were reported with stem cell injection or with no treatment (1 study, 30 participants; very low‐certainty evidence; Analysis 2.5).

2.5. Analysis.

Comparison 2: Stem cell injection versus no treatment or usual care (analgesia, weight loss and exercise), Outcome 5: Serious adverse events

Minor outcomes

Total adverse events

We are uncertain whether stem cell injection increases the number of people who report total adverse events. We downgraded the evidence due to the potential for bias, imprecision, indirectness and suspected publication bias. At the end of follow‐up, 0 participants (0 per 1000) in the no treatment or usual care group reported total adverse events compared with 10/20 participants (500 per 1000) in the stem cell injection group (RR 11, 95% CI 0.7 to 170.6). Events included swelling and pain post‐injection (Analysis 2.6).

2.6. Analysis.

Comparison 2: Stem cell injection versus no treatment or usual care (analgesia, weight loss and exercise), Outcome 6: Total adverse events

Treatment failure

No treatment failures were reported with stem cell injection or with no treatment.

MRI measure of joint pathology (Whole‐Organ Magnetic Resonance Imaging (WORMS score))

The proportion with progression of bone marrow lesion (Global MOAKS) at 12 months was 3/9 participants (333 per 1000) in the no treatment or usual care group and 8/19 participants (421 per 1000) in the stem cell injection group (RR 1.3, 95% CI 0.4 to 3.7; Analysis 2.7).

2.7. Analysis.

Comparison 2: Stem cell injection versus no treatment or usual care (analgesia, weight loss and exercise), Outcome 7: MRI joint progression (bone marrow lesions)

3. Stem cell injection versus glucocorticoid injection

One study with 33 participants, Bastos 2020, contributed data to this comparison (Table). No studies measured radiographic joint progression or MRI measures of joint pathology.

Major outcomes

Pain

One study reported pain at 12 months (Bastos 2020).

We are uncertain whether stem cell injection improves pain (Analysis 3.1). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At 12 months follow‐up, the mean pain KOOS pain subscale (0 to 100, scale reversed so 0 is no pain and scaled to 10‐point scale) was 4.1 points with glucocorticoid injection and 0.3 points worse (95% CI 2.0 points worse to 1.4 points better; 32 participants; very low‐certainty evidence) with stem cell injection.

3.1. Analysis.

Comparison 3: Stem cell injection versus glucocorticoid injection, Outcome 1: Mean pain (0 to 10, 0 is no pain)

Function

One study reported function at 12 months (Bastos 2020).

We are uncertain whether stem cell injection improves function (Analysis 3.2). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At 12 months follow‐up, mean function (0 to 100 scale, lower scores indicate better function) was 38.4 points with glucocorticoid injection and 3.2 points worse (95% CI 21.2 points worse to 14.8 points better; 32 participants; very low‐certainty evidence) with stem cell injection.

3.2. Analysis.

Comparison 3: Stem cell injection versus glucocorticoid injection, Outcome 2: Mean function (0 to 100, 0 is best function)

Quality of life

One study reported quality of life (KOOS quality of life subscale) at 12 months (Bastos 2020).

We are uncertain whether stem cell injection improves quality of life (Analysis 3.3). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At 12 months follow‐up, mean quality of life (0 to 100 scale, higher scores indicate better quality of life) was 32.0 points with glucocorticoid injection and 8.2 points better (95% CI 11 points worse to 27.4 points better; 32 participants; very low‐certainty evidence) with stem cell injection.

3.3. Analysis.

Comparison 3: Stem cell injection versus glucocorticoid injection, Outcome 3: Mean quality of life (0 to 100, 100 is best score)

Participant‐reported global assessment of success

One study reported participant‐reported global assessment of success (Bastos 2020).

We are uncertain whether stem cell injection increases the number of people who report treatment success (Analysis 3.4). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At the end of follow‐up, 3/16 participants (176 per 1000) in the glucocorticoid injection group reported treatment success compared with 5/16 participants (312 per 1000) in the stem cell injection group (RR 1.7, 95% CI 0.5 to 5.8; 32 participants; very low‐certainty evidence).

3.4. Analysis.

Comparison 3: Stem cell injection versus glucocorticoid injection, Outcome 4: Participant‐reported global assessment of success

Withdrawals due to adverse events

One study reported withdrawals due to adverse events (Bastos 2020).

We are uncertain whether stem cell injection results in more withdrawals due to adverse events (Analysis 3.5). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At the end of follow‐up, 1/16 participants (59 per 1000) in the stem cell injection group reported withdrawals due to adverse events compared with 1/17 participants (62 per 1000) in the glucocorticoid injection group (RR 1.1, 95% CI 0.1 to 15.6; 32 participants; very low‐certainty evidence).

3.5. Analysis.

Comparison 3: Stem cell injection versus glucocorticoid injection, Outcome 5: Withdrawals due to adverse events

Serious adverse events

One study reported serious adverse events (Bastos 2020).

We are uncertain whether stem cell injection results in more serious adverse events (Analysis 3.6). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At the end of follow‐up, 1/16 participants (59 per 1000) in the glucocorticoid injection group reported a serious adverse event (death due to an unknown reason) compared with 1/17 participants (62 per 1000) with a serious adverse event (total knee arthroplasty) in the stem cell injection group (RR 1.1, 95% CI 0.1 to 15.6; 32 participants; very low‐certainty evidence).

3.6. Analysis.

Comparison 3: Stem cell injection versus glucocorticoid injection, Outcome 6: Serious adverse events

Minor outcomes

Total adverse events

One study reported total adverse events (Bastos 2020).

At the end of follow‐up, 1/17 participants (58 per 1000) in the glucocorticoid injection group reported total adverse events compared with 1/16 participants (62 per 1000) in the stem cell injection group (RR 1.1, 95% CI 0.1 to 15.6). Events included death (unknown reason) and arthroplasty (Analysis 3.7).

3.7. Analysis.

Comparison 3: Stem cell injection versus glucocorticoid injection, Outcome 7: Total adverse events

Treatment failure

One study reported treatment failure (knee arthroplasty) (Bastos 2020).

At six months, 0/17 (0 per 1000) in the glucocorticoid injection group reported treatment failure compared with 1/16 participants (62 per 1000) in the stem cell injection group (RR 3.2, 95% CI 0.1 to 72.8) (Analysis 3.8).

3.8. Analysis.

Comparison 3: Stem cell injection versus glucocorticoid injection, Outcome 8: Treatment failure

4. Stem cell injection versus hyaluronic acid injection

Seven studies with 429 participants contributed data to this comparison (Chen 2021; Goncars 2017; Ho 2022; Lu 2019; Matas 2019; Vega 2015; Zhang 2022). No studies reported radiographic joint progression.

Major outcomes

Pain

All seven studies reported pain.

We are uncertain whether stem cell injection improves pain (Analysis 4.1). We downgraded the evidence due to indirectness, imprecision and suspected publication bias.

4.1. Analysis.

Comparison 4: Stem cell injection versus hyaluronic acid injection, Outcome 1: Mean overall pain (0 to 10, 0 is no pain)

At up to three months follow‐up, mean pain (0 to 10 scale, lower scores indicate less pain) was 5.6 points with hyaluronic acid injection and 1.7 points better (95% CI 0.9 points better to 2.5 points better) with stem cell injection (I² = 0%; 4 studies, 159 participants). At > three months to six months follow‐up, mean pain was 5.2 points with hyaluronic acid injection and 1.4 points better (0.7 points better to 2 points better) with stem cell injection (I² = 32%; 6 studies, 241 participants). At > six months to one year, mean pain was 5.1 points with hyaluronic acid injection and 1.5 points better (95% CI 1.1 points better to 1.9 points better) with stem cell injection (I² = 12%; 7 studies, 367 participants). At > one to two years, mean pain was 3.5 points with hyaluronic acid injection and 1.5 points better (95% CI 0.9 points better to 2 points better) with stem cell injection (1 study, 126 participants). At between two and five years, mean pain was 3.7 points with hyaluronic acid injection and 1.3 points better (95% CI 0.8 points better to 1.8 points better) with stem cell injection (1 study, 126 participants). At five years, mean pain was 4 points with hyaluronic acid injection and 1.1 points better (95% CI 0.5 points better to 1.7 points better) with stem cell injection (1 study, 126 participants).

Function

Seven studies reported function (Chen 2021; Goncars 2017; Ho 2022; Lu 2019; Matas 2019; Vega 2015; Zhang 2022).

We are uncertain whether stem cell injection improves function (Analysis 4.2). We downgraded the evidence due to indirectness, imprecision and suspected publication bias.

4.2. Analysis.

Comparison 4: Stem cell injection versus hyaluronic acid injection, Outcome 2: Mean function (0 to 100, 0 is best function)

At up to three months follow‐up, mean function (0 to 100 scale, lower scores indicate better function) was 40.7 points with hyaluronic acid injection and 7.4 points better (95% CI 14.8 points better to 0.1 points worse) with stem cell injection (I² = 0%; 3 studies, 103 participants). At > three months to six months follow‐up, mean function was 39.8 points with hyaluronic acid injection and 8.2 points better (2.8 points better to 13.6 points better) with stem cell injection (I² = 0%; 5 studies, 185 participants). At > six months to one year, mean function was 41.2 points with hyaluronic acid injection and 8.2 points better (95% CI 3.6 points better to 12.8 points better) with stem cell injection (I² = 0%; 7 studies, 356 participants). At > one year to < two years, mean function was 32.6 points with hyaluronic acid injection and 11.2 points better (95% CI 3.1 points better to 19.3 points better) with stem cell injection (1 study, 115 participants).

Quality of life

Three studies reported quality of life (Ho 2022; Lu 2019; Vega 2015).

We are uncertain whether stem cell injection improves quality of life (Analysis 4.3). We downgraded the evidence due to imprecision, indirectness and suspected publication bias. At up to three months follow‐up, mean quality of life (0 to 100 scale, higher scores indicate better quality of life) was 47 points with hyaluronic acid injection and 3.5 points better (95% CI 4.8 points worse to 11.8 points better) with stem cell injection (I² = 0%; 2 studies, 50 participants). At > three months to six months follow‐up, mean quality of life was 48 points with hyaluronic acid injection and 1.6 points better (16.6 points worse to 19.8 points better) with stem cell injection (I² = 83%; 3 studies, 102 participants). At > six months to one year, mean quality of life was 47 points with hyaluronic acid injection and 3 points worse (15.6 points worse to 9.5 points better) with stem cell injection (I² = 66%; 3 studies, 102 participants).

4.3. Analysis.

Comparison 4: Stem cell injection versus hyaluronic acid injection, Outcome 3: Mean quality of life (0 to 100, 100 is best quality of life)

Participant‐reported global assessment of success

One study reported participant global assessment of success (Lu 2019).

We are uncertain whether stem cell injection increases the number of people who report treatment success (Analysis 4.4). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At the end of follow‐up, 1/26 participants (38 per 1000) in the hyaluronic acid injection group reported treatment success compared with 9/26 participants (346 per 1000) in the stem cell injection group (RR 9.0, 95% CI 1.2 to 66.1; 1 study, 52 participants).

4.4. Analysis.

Comparison 4: Stem cell injection versus hyaluronic acid injection, Outcome 4: Participant‐reported global assessment of success

Withdrawals due to adverse events

Five studies reported withdrawals due to adverse events (Chen 2021; Goncars 2017; Lu 2019; Matas 2019; Vega 2015).

We are uncertain whether stem cell injection increases the number of people who withdraw due to adverse events (Analysis 4.5). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At the end of follow‐up, 1/85 participants (11 per 1000) in the hyaluronic acid injection group withdrew due to adverse events compared with 4/138 participants (28 per 1000) in the stem cell injection group (RR 0.8, 95% CI 0.1 to 6.6; I² = 0%; 5 studies, 223 participants).

4.5. Analysis.

Comparison 4: Stem cell injection versus hyaluronic acid injection, Outcome 5: Withdrawals due to adverse events

Serious adverse events

Five studies reported serious adverse events (Chen 2021; Goncars 2017; Lu 2019; Matas 2019; Vega 2015).

We are uncertain whether stem cell injection increases the number of people reporting serious adverse events (Analysis 4.6). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At the end of follow‐up, 1/85 participants (11 per 1000) in the hyaluronic acid injection group reported serious adverse events compared with 4/138 participants (29 per 1000) in the stem cell injection group (RR 0.8, 95% CI 0.1 to 6.6; I² = 0%; 5 studies, 223 participants).

4.6. Analysis.

Comparison 4: Stem cell injection versus hyaluronic acid injection, Outcome 6: Serious adverse events

Chen 2021 reported serious adverse events in two participants in the 32 million and 64 million stem cell injection groups; however, the nature of the events was not specified. One study, Lu 2019, reported one serious adverse event in the hyaluronic acid group (post‐injection knee infection requiring joint washout).

Minor outcomes

Total adverse events

Five studies reported total adverse events (Chen 2021; Goncars 2017; Lu 2019; Matas 2019; Vega 2015).

We are uncertain whether stem cell injection increases the number of people reporting total adverse events (Analysis 4.7). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At the end of follow‐up, 36/85 participants (423 per 1000) in the hyaluronic acid injection group reported total adverse events compared with 76/138 participants (550 per 1000) in the stem cell injection group (RR 1.1, 95% CI 0.8 to 1.6; I² = 66%; 5 studies, 223 participants). Events included post‐injection joint swelling, pain, effusion, stiffness and synovitis.

4.7. Analysis.

Comparison 4: Stem cell injection versus hyaluronic acid injection, Outcome 7: Total adverse events

Treatment failure

Two studies reported treatment failure (knee arthroplasty) (Lu 2019; Zhang 2022).

We are uncertain whether stem cell injection increases the number of people reporting treatment failure (Analysis 4.8). We downgraded the evidence due to indirectness, imprecision and suspected publication bias. At six months, 4/82 (49 per 1000) in the stem cell injection group reported treatment failure compared with 6/96 participants (62 per 1000) in the hyaluronic acid injection group (RR 0.8, 95% CI 0.2 to 2.7; 2 studies, 178 participants).

4.8. Analysis.

Comparison 4: Stem cell injection versus hyaluronic acid injection, Outcome 8: Treatment failure

MRI measure of joint pathology (Whole‐Organ Magnetic Resonance Imaging (WORMS score))

Five studies reported cartilage changes using MRI (Ho 2022; Lu 2019; Matas 2019; Vega 2015; Zhang 2022). Three studies used T2 mapping (Ho 2022; Vega 2015; Zhang 2022) and one study, Lu 2019, measured cartilage volume but presented data for right and left knees separately, which were not extracted. Only one study, Matas 2019, reported MRI cartilage loss using the WORMS score (lower score, lesser damage): WORMS was 33.6 points in the hyaluronic acid injection group and 7.4 points worse (95% CI 11 points lower to 25.8 points higher) in the stem cell injection group (1 study, 27 participants). As all five studies used different ways of reporting this outcome, we could not meta‐analyse the data (Analysis 4.9).

4.9. Analysis.

Comparison 4: Stem cell injection versus hyaluronic acid injection, Outcome 9: MRI measure of joint pathology (e.g. cartilage volume, bone marrow lesions, synovitis)

5. Stem cell injection versus PRP injection

Two studies with 142 participants contributed data to this comparison (Anz 2020; Baria 2022). Quality of life, radiographic joint progression and MRI measure of joint pathology were not measured.

Major outcomes

Pain

Two studies reported pain (Anz 2020; Baria 2022). Baria 2022 used VAS‐ADL (0 to 100 scale) and Anz 2020 reported change scores on the WOMAC pain subscale (0 to 20, 0 no score); hence, we did not pool the data.

We are uncertain whether stem cell injection has any effect on pain at any time point (Analysis 5.1). We downgraded the evidence due to risk of bias, indirectness and imprecision. Anz 2020 reported the mean change from baseline pain (WOMAC pain subscale normalised to 0 to 10, lower scores indicate less pain) was 1.7 points with PRP injection and 0.2 points better (95% CI 0.8 points better to 0.5 points worse) with stem cell injection at up to three months, 1.3 points with PRP injection and 0.8 points worse (0.03 points worse to 1.5 points worse) with stem cell injection at > three months to six months follow‐up, and 1.4 points with PRP injection and 0.3 points worse (95% CI 0.4 points better to 0.1 points worse) with stem cell injection at > six months to one year (1 study, 84 participants). Baria 2022 reported the mean pain on VAS‐ADL (0 to 100 scale transformed to a 10‐point scale) was 2.1 points with PRP injection and 0.5 points better (95% CI 1.5 points better to 0.5 points worse) with stem cell injection at up to three months and 2 points with PRP injection and 0.5 points better (95% CI 1.6 points better to 0.6 points worse) with stem cell injection at > three months to six months follow‐up (1 study, 58 participants).

5.1. Analysis.

Comparison 5: Stem cell injection versus PRP injection, Outcome 1: Mean overall pain (0 to 10, 0 is no pain)

Function

Two studies reported function (Anz 2020; Baria 2022). Baria 2022 used the KOOS ADL subscale (0 to 100, 0 worst function) and Anz 2020 reported change scores on the WOMAC function subscale (0 to 68, 0 best function); hence, we did not pool the data.

We are uncertain whether stem cell injection has any effect on function at any time point (Analysis 5.2). We downgraded the evidence due to risk of bias, indirectness and imprecision. Mean change from baseline function (0 to 100 scale, lower scores indicate better function) was 18 points with PRP injection and 4 points better (95% CI 10.6 points better to 2.6 points worse) with stem cell injection at up to three months, 16.5 points with PRP injection and 1.9 points worse (95% CI 5 points better to 9 points worse) with stem cell injection at > three months to six months follow‐up, and 16.6 points with PRP injection and 2.2 points worse (95% CI 5.3 points better to 9.7 points worse) with stem cell injection at > six months to one year (1 study, 84 participants) (Anz 2020). Mean function on the KOOS ADL subscale (0 to 100, 0 worst function; direction reversed to 0 best function) was 16 points with PRP injection and 4.6 points better (95% CI 12.2 points better to 3 points worse) with stem cell injection at up to three months, and 12.6 points with PRP injection and 1.4 points worse (95% CI 8.7 points better to 6 points worse) with stem cell injection at > three months to six months follow‐up (1 study, 58 participants) (Baria 2022).

5.2. Analysis.

Comparison 5: Stem cell injection versus PRP injection, Outcome 2: Mean function (0 to 100, 0 is best function)

Participant‐reported global assessment of success

Baria 2022 reported the proportion of participants achieving the Patient Acceptable Symptom State (PASS) on the KOOS ADL subscale.

We are uncertain whether stem cell injection increases the number of people who report treatment success due to very low‐certainty evidence (Analysis 5.3). We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 19/30 participants (633 per 1000) in the PRP injection group reported treatment success compared with 21/28 participants (750 per 1000) in the stem cell injection group (RR 1.2, 95% CI 0.8 to 1.7; 1 study, 58 participants).

5.3. Analysis.

Comparison 5: Stem cell injection versus PRP injection, Outcome 3: Participant‐reported global assessment of success

Withdrawals due to adverse events

Two studies with 161 participants reported withdrawals due to adverse events (Anz 2020; Baria 2022).

We are uncertain whether stem cell injection increases the number of people reporting withdrawals due to adverse events. We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 3/36 (83 per 1000) participants withdrew from the PRP injection group and 2/35 (57 per 1000) participants withdrew from the stem cell injection group (RR 0.7, 95%CI 0.1 to 3.9) (Analysis 5.4).

5.4. Analysis.

Comparison 5: Stem cell injection versus PRP injection, Outcome 4: Withdrawals due to adverse events

Serious adverse events

Two studies with 161 participants reported serious adverse events (Anz 2020; Baria 2022).

We are uncertain whether stem cell injection has any effect on the number of people who report serious adverse events (Analysis 5.5). We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 4/77 participants (52 per 1000) in the PRP injection group reported serious adverse events compared with 5/84 participants (59 per 1000) in the stem cell injection group (RR 1.1, 95% CI 0.3 to 4.4). In Anz 2020, two participants had total knee replacements and one had cancer in the stem cell injection group and one participant in the PRP group underwent knee surgery. Baria 2022 reported two and three participants discontinued intervention and underwent either surgery or injection in the stem cell group and PRP group, respectively.

5.5. Analysis.

Comparison 5: Stem cell injection versus PRP injection, Outcome 5: Serious adverse events

Minor outcomes

Total adverse events

Two studies with 161 participants reported total adverse events (Anz 2020; Baria 2022).

We are uncertain whether stem cell injection has any effect on the number of people who report total adverse events (Analysis 5.6). We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 4/77 participants (52 per 1000) in the PRP injection group reported adverse events compared with 5/84 participants (59 per 1000) in the stem cell injection group (RR 1.1, 95% CI 0.3 to 4.4). Events included knee surgery and knee replacement.

5.6. Analysis.

Comparison 5: Stem cell injection versus PRP injection, Outcome 6: Total adverse events

Treatment failure

Two studies with 161 participants reported treatment failure (knee arthroplasty) (Anz 2020; Baria 2022).

We are uncertain whether stem cell injection has any effect on the number of people who report treatment failure (Analysis 5.7). We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 4/77 participants (52 per 1000) in the PRP injection group reported treatment failure compared with 4/84 participants (48 per 1000) in the stem cell injection group (RR 0.9, 95% CI 0.2 to 3.8).

5.7. Analysis.

Comparison 5: Stem cell injection versus PRP injection, Outcome 7: Treatment failure

6. Stem cell injection versus oral acetaminophen (paracetamol)

One study with 51 participants contributed data to this comparison (Garay‐Mendoza 2018). Quality of life, participant‐reported global assessment of success, radiographic joint progression, treatment failure and MRI measure of joint pathology were not measured. The reasons for withdrawals were not reported, and it is unknown if any were due to adverse events.

Major outcomes

Pain

We are uncertain whether stem cell injection improves pain (Analysis 6.1). We downgraded the evidence due to risk of bias, indirectness and imprecision. Mean pain on VAS (0 to 10 scale, 0 no pain) was 4 points with oral acetaminophen and 2.6 points better (95% CI 1.3 points better to 3.9 points better) with stem cell injection at up to three months follow‐up, and 4.6 points with oral acetaminophen and 3.7 points better (95% CI 2.6 points better to 4.8 points better) with stem cell injection at > three months to six months follow‐up.

6.1. Analysis.

Comparison 6: Stem cell injection versus oral acetaminophen (paracetamol), Outcome 1: Mean overall pain (0 to 10, 0 is no pain)

Function

We are uncertain whether stem cell injection improves function (Analysis 6.2). We downgraded the evidence due to risk of bias, indirectness and imprecision. Mean function on the WOMAC function subscale (0 to 100, 0 best function) was 26.7 points with oral acetaminophen and 14.3 points better (95% CI 5 points better to 23.6 points better) with stem cell injection at up to three months follow‐up and 27.7 points with oral acetaminophen and 19.2 points better (95% CI 12.3 points better to 26.1 points better) with stem cell injection at > three months to six months follow‐up.

6.2. Analysis.

Comparison 6: Stem cell injection versus oral acetaminophen (paracetamol), Outcome 2: Mean function (0 to 100, 0 is best function)

Serious adverse events

There were no serious adverse events reported.

Minor outcomes

Total adverse events

Adverse events were reported for the participants receiving stem cell injections, but were not assessed for the acetaminophen group. One participant reported swelling and pain in the knee on the day after the stem cell injection; infection was ruled out and recovery was complete. Twelve participants had bone pain during the stimulation with granulocyte colony stimulating factor (G‐CSF). Some participants (exact numbers not given) had slight pain and stiffness during the first 48 hours after the injection.

7. Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection

One study with 57 participants contributed data to this comparison (Sadat‐Ali 2021). Function, quality of life, participant‐reported global assessment of success, radiographic joint progression and MRI measure of joint pathology were not measured.

Major outcomes

Pain

We are uncertain whether stem cell injection improves pain (Analysis 7.1). We downgraded the evidence due to risk of bias, indirectness and imprecision. Mean pain on VAS (0 to 10 scale, 0 no pain) was 6.7 points with NSAIDs plus physical therapy plus hyaluronic acid injection and 3.7 points better (95% CI 5.7 points better to 1.6 points better) with stem cell injection at up to three months follow‐up; 6.7 points with NSAIDs plus physical therapy plus hyaluronic acid injection and 4.1 points better (95% CI 6 points better to 2.3 points better) with stem cell injection at 12 months follow‐up; and 6.3 points with NSAIDs plus physical therapy plus hyaluronic acid injection and 4.5 points better (95% CI 6.1 points better to 2.9 points better) with stem cell injection, at 24 months follow‐up.

7.1. Analysis.

Comparison 7: Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection injection, Outcome 1: Mean overall pain (0 to 10, 0 is no pain)

Withdrawals due to adverse events

We are uncertain whether stem cell injection has any effect on the number of people who reported withdrawals due to adverse events (Analysis 7.2). We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 3/27 participants (111 per 1000) in the NSAIDs plus physical therapy plus hyaluronic acid injection group reported withdrawals due to adverse events compared with 0/30 participants (0 per 1000) in the stem cell injection group (RR 0.1, 95% CI 0.01 to 2.4).

7.2. Analysis.

Comparison 7: Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection injection, Outcome 2: Withdrawals due to adverse events

Serious adverse events

We are uncertain whether stem cell injection has any effect on the number of people who report serious adverse events (Analysis 7.3). We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 3/27 participants (111 per 1000) in the NSAIDs plus physical therapy plus hyaluronic acid injection group reported serious adverse events (knee arthroplasty) compared with 0/30 participants (0 per 1000) in the stem cell injection group (RR 0.1, 95% CI 0.01 to 2.4).

7.3. Analysis.

Comparison 7: Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection injection, Outcome 3: Serious adverse events

Minor outcomes

Total adverse events

We are uncertain whether stem cell injection has any effect on the number of people who report total adverse events (Analysis 7.4). We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 1/30 participants (33 per 1000) in the NSAIDs plus physical therapy plus hyaluronic acid injection group reported adverse events compared with 0/30 participants (0 per 1000) in the stem cell injection group (RR 0.3, 95% CI 0.01 to 7.9). One participant had local cellulitis, which was treated with oral antibiotics.

7.4. Analysis.

Comparison 7: Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection injection, Outcome 4: Total adverse events

Treatment failure

There were no events reported in the stem cell group. In those receiving NSAIDs plus physical therapy plus hyaluronic acid injection, three participants underwent joint replacement.

We are uncertain whether stem cell injection has any effect on the number of people who report serious adverse events (Analysis 7.5). We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 3/30 participants (111 per 1000) in the NSAIDs plus physical therapy plus hyaluronic acid injection group had knee arthroplasty compared with 0/30 participants (0 per 1000) in the stem cell injection group (RR 0.1, 95% CI 0.01 to 2.7).

7.5. Analysis.

Comparison 7: Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection injection, Outcome 5: Treatment failure

8. Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone

Three studies contributed data to this comparison (Gupta 2016; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020). Gupta 2016 (60 participants) compared stem cell injection plus hyaluronic acid injection to placebo (plasmalyte) injection plus hyaluronic acid injection. Lamo‐Espinosa 2016 (30 participants) compared stem cell injection plus hyaluronic acid injection to hyaluronic acid injection alone. Lamo‐Espinosa 2020 (50 participants) compared stem cell injection plus PRP injection to PRP injection alone. We did not pool data from these three studies due to the differences in interventions and comparators.

Quality of life was not measured in any of these studies. Participant‐reported treatment success was not measured in Gupta 2016, and not reported in Lamo‐Espinosa 2016 or Lamo‐Espinosa 2020. Radiographic joint progression was measured, but the results were not reported in Gupta 2016.

Pain

We are uncertain whether stem cell injection plus hyaluronic acid injection improves pain compared to placebo (plasmalyte) injection plus hyaluronic acid injection (Analysis 8.1). We downgraded the evidence due to risk of bias, indirectness and imprecision. At up to three months follow‐up, mean pain (0 to 10 scale, lower scores indicate less pain) was 4.4 points with placebo injection plus hyaluronic acid injection and 0.4 points better (95% CI 1.8 points better to 0.9 points worse) with stem cell injection plus hyaluronic acid injection. At > three months to six months follow‐up, mean pain was 4.4 points with placebo injection plus hyaluronic acid injection and 0.7 points better (2.1 points better to 0.8 points worse) with stem cell injection plus hyaluronic acid injection. At > six months to one year, mean pain was 4 points with placebo injection plus hyaluronic acid injection and 0.3 points better (95% CI 1.7 points better to 1.1 points worse) with stem cell injection plus hyaluronic acid injection (1 study, 60 participants; Gupta 2016).

8.1. Analysis.

Comparison 8: Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone, Outcome 1: Mean overall pain (0 to 10, 0 is no pain)

We are uncertain whether stem cell injection plus hyaluronic acid injection improves pain compared to hyaluronic acid injection (Analysis 8.1). We downgraded the evidence due to risk of bias, indirectness and imprecision. At up to three months follow‐up, mean pain (0 to 10 scale, lower scores indicate less pain) was 3 points with hyaluronic acid injection and 0.5 points better (95% CI 1.3 points better to 2.3 points worse) with stem cell injection plus hyaluronic acid injection. At > three months to six months follow‐up, mean pain was 5 points with hyaluronic acid injection and 2.5 points better (5.5 points better to 0.5 points worse) with stem cell injection plus hyaluronic acid injection. At > six months to one year, mean pain was 4 points with hyaluronic acid injection and 2 points better (95% CI 3.4 points better to 0.6 points better) with stem cell injection plus hyaluronic acid injection (1 study, 30 participants; Lamo‐Espinosa 2016).

We are uncertain whether stem cell injection plus PRP injection improves pain (Analysis 8.1). We downgraded the evidence due to risk of bias, indirectness and imprecision. At up to three months follow‐up, mean pain (0 to 10 scale, lower scores indicate less pain) was 3.8 points with PRP injection and 0 points better (95% CI 1.0 points better to 1.0 points worse) with stem cell injection plus PRP injection. At > three months to six months follow‐up, mean pain was 3.5 points with PRP injection and 0.2 points better (1.4 points better to 1 point worse) with stem cell injection plus PRP injection. At > six months to one year, mean pain was 4.5 points with PRP injection and 1 point better (95% CI 2.3 points better to 0.3 points worse) with stem cell injection plus PRP injection (1 study, 50 participants; Lamo‐Espinosa 2020).

Function

We are uncertain whether stem cell injection plus hyaluronic acid injection improves function compared to placebo (plasmalyte) injection plus hyaluronic acid injection (Analysis 8.2). We downgraded the evidence due to risk of bias, indirectness and imprecision. At up to three months follow‐up, mean function (WOMAC function subscale normalised to 0 to 100, 0 best function) was 45 points with placebo injection plus hyaluronic acid injection and 3.6 points better (95% CI 17.1 points better to 9.8 points worse) with stem cell injection plus hyaluronic acid injection. At > three months to six months follow‐up, mean function was 42 points with placebo injection plus hyaluronic acid injection and 1.2 points better (15 points better to 12.6 points worse) with stem cell injection plus hyaluronic acid injection. At > 6 months to one year, mean function was 40 points with placebo injection plus hyaluronic acid injection and 4.9 points better (95% CI 18.5 points better to 8.8 points worse) with stem cell injection plus hyaluronic acid injection (1 study, 60 participants; Gupta 2016).

8.2. Analysis.

Comparison 8: Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone, Outcome 2: Mean function (0 to 100, 0 is best function)

We are uncertain whether stem cell injection plus hyaluronic acid injection improves function (Analysis 8.2). We downgraded the evidence due to risk of bias, indirectness and imprecision. At up to three months follow‐up, mean function (WOMAC function subscale normalised to 0 to 100, 0 best function) was 13 points with hyaluronic acid injection and 7 points worse (95% CI 0.9 points better to 14.8 points worse) with stem cell injection plus hyaluronic acid injection. At > three months to six months follow‐up, mean function was 11 points with hyaluronic acid injection and 13 points worse (3.7 points worse to 22 points worse) with stem cell injection plus hyaluronic acid injection. At > six months to one year, mean function was 14 points with hyaluronic acid injection and 6.6 points worse (95% CI 6.2 points better to 19.5 points worse) with stem cell injection plus hyaluronic acid injection (1 study, 30 participants; Lamo‐Espinosa 2016).

We are uncertain whether stem cell injection plus PRP injection improves function (Analysis 8.2). We downgraded the evidence due to risk of bias, indirectness and imprecision. At up to three months follow‐up, mean function (WOMAC function subscale normalised to 0 to 100, 0 best function) was 22.8 points with PRP injection and 3.1 points worse (95% CI 7.2 points better to 13.4 points worse) with stem cell injection plus PRP injection. At > three months to six months follow‐up, mean function was 24 points with PRP injection and 2.1 points better (11.4 points better to 7.3 points worse) with stem cell injection plus PRP injection. At > six months to one year, mean function was 22.8 points with PRP injection and 1.8 points worse (95% CI 7.8 points better to 11.3 points worse) with stem cell injection plus PRP injection (1 study, 50 participants; Lamo‐Espinosa 2020).

Radiographic joint progression

Radiographic joint progression, measured as change in joint space width (mm) at 12 months, was reported in two studies (Lamo‐Espinosa 2016; Lamo‐Espinosa 2020).

We are uncertain whether stem cell injection plus hyaluronic acid injection slows down radiographic joint progression (Analysis 8.3). We downgraded the evidence due to risk of bias, indirectness and imprecision. Compared with hyaluronic acid injection, the change in joint space width was 4 mm (95% CI 4.3 worse to 12.3 better) with stem cell injection plus hyaluronic acid injection at 12 months (1 study, 30 participants; Lamo‐Espinosa 2016).

8.3. Analysis.

Comparison 8: Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone, Outcome 3: Radiographic joint progression

We are uncertain whether stem cell injection plus PRP injection slows down radiographic joint progression (Analysis 8.3). We downgraded the evidence due to risk of bias, indirectness and imprecision. Compared with PRP injection, the change in joint space width was 0.36 mm (95% CI 0.4 worse to 1.2 better) with stem cell injection plus PRP injection at 12 months (1 study, 50 participants; Lamo‐Espinosa 2020).

Withdrawals due to adverse events

No withdrawals due to adverse events were reported.

Serious adverse events

Serious adverse events were reported in one study (Gupta 2016).

We are uncertain whether stem cell injection plus hyaluronic acid injection has any effect on the number of people who report total adverse events compared to placebo (plasmalyte) injection plus hyaluronic acid injection (Analysis 8.4). We downgraded the evidence once for risk of bias and twice for imprecision. At the end of follow‐up, 3/20 participants (150 per 1000) in the placebo injection plus hyaluronic acid injection group reported serious adverse events compared with 5/40 participants (125 per 1000) in the stem cell injection plus hyaluronic acid injection group (RR 0.8, 95% CI 0.2 to 3.1). Serious adverse events were reported in both stem cell (injection‐related: muscle haemorrhage, synovial effusion; not injection‐related: anaemia, hysterectomy for menorrhagia, dyslipidaemia) and placebo groups (not injection‐related: haemorrhoidal haemorrhage, varicose veins, umbilical hernia).

8.4. Analysis.

Comparison 8: Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone, Outcome 4: Serious adverse events

Minor outcomes

No treatment failures were reported in either treatment group.

Total adverse events

We are uncertain whether stem cell injection plus hyaluronic acid injection has any effect on the number of people who report total adverse events compared to placebo (plasmalyte) injection plus hyaluronic acid injection (Analysis 8.5). We downgraded the evidence once for risk of bias and twice for imprecision. At the end of follow‐up, 16/20 participants (800 per 1000) in the placebo injection plus hyaluronic acid injection group reported adverse events compared with 32/40 participants (800 per 1000) in the stem cell injection plus hyaluronic acid injection group (RR 1.0, 95% CI 0.8 to 1.3). Events included injection‐related arthralgia and joint swelling due to hypersensitivity (1 study, 60 participants; Gupta 2016).

8.5. Analysis.

Comparison 8: Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone, Outcome 5: Total adverse events

We are uncertain whether stem cell injection plus hyaluronic acid injection has any effect on the number of people who report total adverse events (Analysis 8.5). We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 1/10 participants (100 per 1000) in the hyaluronic acid injection group reported adverse events compared with 9/20 participants (450 per 1000) in the stem cell injection plus hyaluronic acid injection group (RR 4.5, 95% CI 0.7 to 30.7). Events included articular pain requiring anti‐inflammatory treatment during the first 24 hours after injections (1 study, 30 participants; Lamo‐Espinosa 2016).

We are uncertain whether stem cell injection plus PRP injection has any effect on the number of people who report total adverse events (Analysis 8.5). We downgraded the evidence due to risk of bias, indirectness and imprecision. At the end of follow‐up, 0/26 participants (0 per 1000) in the PRP injection group reported adverse events compared with 6/24 participants (250 per 1000) in the stem cell injection plus PRP injection group (RR 14, 95% CI 0.8 to 236.6). Events included articular pain requiring anti‐inflammatory treatment during the first 24 hours after injections (1 study, 50 participants; Lamo‐Espinosa 2020).

MRI measure of joint pathology (Whole‐Organ Magnetic Resonance Imaging (WORMS score))

We are uncertain whether stem cell injection plus hyaluronic acid injection has any effect on MRI cartilage loss compared to placebo (plasmalyte) injection plus hyaluronic acid injection (Analysis 8.6). We downgraded the evidence due to risk of bias, indirectness and imprecision. At 12 months, the mean WORMS score (lower score indicates lesser damage) was 73 points in the hyaluronic acid injection group and 5.7 points better (95% CI 17.2 points better to 5.8 points worse) in the stem cell injection plus hyaluronic acid injection group (1 study, 60 participants; Gupta 2016).

8.6. Analysis.

Comparison 8: Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone, Outcome 6: MRI cartilage loss (Whole‐Organ Magnetic Resonance Imaging (WORMS score))

We are uncertain whether stem cell injection plus hyaluronic acid injection has any effect on MRI cartilage loss (Analysis 8.6). We downgraded the evidence due to risk of bias, indirectness and imprecision. At 12 months, the mean WORMS score (lower score indicates lesser damage) was 83 points in the hyaluronic acid injection group and 12 points better (95% CI 49 points better to 26.4 points worse) in the stem cell injection plus hyaluronic acid injection group (1 study, 30 participants; Lamo‐Espinosa 2016).

We are uncertain whether stem cell injection plus PRP injection has any effect on MRI cartilage loss (Analysis 8.6). We downgraded the evidence due to risk of bias, indirectness and imprecision. At 12 months, the mean WORMS score (lower score indicates lesser damage) was 77 points in the PRP injection group and 2.4 points worse (95% CI 14.4 points better to 19.2 points worse) in the stem cell injection plus PRP injection group (1 study, 50 participants; Lamo‐Espinosa 2020).

Discussion

Summary of main results

We found 25 randomised trials, including 1341 participants, which compared stem cell injections with placebo injection (8 trials, 459 participants), no treatment or usual care (analgesia, weight loss and exercise) (two trials, 30 participants), glucocorticoid injection (1 trial, 33 participants), hyaluronic acid injection (7 trials, 429 participants), platelet‐rich plasma injections (2 trials, 142 participants), oral acetaminophen (paracetamol) (1 trial, 51 participants), NSAIDs plus physical therapy plus hyaluronic acid injection (1 trial, 57 participants) and stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone (3 trials, 140 participants) in people with osteoarthritis of the knee. One trial (6 participants) that compared stem cell injection to no treatment was not included in the analysis as data were not provided per group.

Our findings demonstrate that, compared with placebo, there is low‐certainty evidence that stem cell injection may slightly improve pain and function up to six months after treatment (Table). We are uncertain whether stem cell injections improve quality of life or increase the number of people who report treatment success compared to placebo injections, because the certainty of the evidence is very low. We downgraded the evidence due to imprecision and indirectness (as the source, method of preparation and dose of stem cells varies across studies), and suspected publication bias (as up to three larger RCTs have been conducted but withdrawn prior to reporting of results). We are uncertain of the potential harms associated with treatment, due to very low event rates for serious adverse events, and no events reported for withdrawals due to adverse events. Radiographic progression was not reported in any of the included studies. Similar slight improvements in pain and function in participants receiving stem cells compared with placebo injections were seen at up to three months' follow‐up, but there were no differences in pain or function between stem cell injection and placebo at other time points (> 6 months up to 12 months).

It is uncertain whether stem cell injection improves pain, function or the number of people who report treatment success at six months compared to no treatment or usual care (analgesia, weight loss and exercise) because the certainty of the evidence is very low (Table). No trials that compared stem cell injection to no treatment or usual care reported quality of life outcomes or radiographic joint progression, and no serious adverse events or withdrawals due to adverse events were reported in the included trials.

It is uncertain whether stem cell injection improves pain, function, quality of life, the number of people who report treatment success, withdrawals due to adverse events or serious adverse events at 12 months compared to glucocorticoid injection, because the certainty of the evidence is very low (Table). The single trial that compared stem cell injection to glucocorticoid injection did not report radiographic outcomes.

It is uncertain whether stem cell injection improves pain, function, quality of life or the number of people who report treatment success compared to hyaluronic acid injection, because the certainty of evidence is very low. We are also uncertain whether there is a difference in the risk of serious adverse events or withdrawals due to adverse events between stem cell and hyaluronic acid injections due to a low event rate in the included trials. No studies that compared stem cell injection to hyaluronic acid injection reported radiographic outcomes.

It is uncertain whether stem cell injection improves pain, function or the number of people who report treatment success compared to platelet‐rich plasma injection, because the certainty of evidence is very low. It is also uncertain whether there is a difference in the risk of serious adverse events or withdrawals due to adverse events. Quality of life and radiographic outcomes were not assessed in the two trials comparing these treatments.

It is uncertain whether stem cell injection improves pain or function compared to oral acetaminophen (paracetamol) because the certainty of evidence is very low. Participant‐reported global assessment of success, quality of life, radiographic joint progression, serious adverse events and withdrawals due to adverse events were not reported in the single trial in this comparison.

It is uncertain whether stem cell injection improves pain compared to NSAIDs plus physical therapy plus hyaluronic acid injection, because the certainty of evidence is very low. It is also uncertain whether there is a difference in withdrawals due to adverse events or the risk of serious adverse events due to a low event rate in the single trial that compared these interventions. Function, participant‐reported global assessment of success, quality of life and radiographic joint progression were not reported in this trial.

Three trials compared stem cell injection plus an intra‐articular co‐intervention (hyaluronic acid or platelet‐rich plasma injections) to co‐intervention alone: all participants in Gupta 2016 received placebo (plasmalyte) injection plus hyaluronic acid injection, all participants in Lamo‐Espinosa 2016 received an intra‐articular hyaluronic acid injection and all participants in Lamo‐Espinosa 2020 received an intra‐articular platelet‐rich plasma injection. It is uncertain whether stem cell injection plus co‐intervention improves pain, function or radiographic joint progression compared to co‐intervention alone. It is also uncertain whether there is a difference in withdrawals due to adverse events or the risk of serious adverse events due to a low event rate in the three trials in this comparison. Quality of life and participant‐reported treatment success were not assessed in these trials.

Adverse events were infrequently reported across all comparisons. A total of 46 serious adverse events were reported across the 25 included trials, including injection‐related joint effusion, acute knee inflammation and septic arthritis. There were no reports of serious complications related to the donor site in participants who underwent donor tissue harvest. There remains uncertainty regarding the total physiological effects of different stem cell preparations, not only locally at the site of injection, but also potential systemic effects related to alteration of inflammatory pathways or cell growth. There was one cancer reported in the included trials, in a participant who received autologous bone marrow aspirate concentrate (Anz 2020), but no additional clinical details were provided.

Overall completeness and applicability of evidence

The 25 trials included in this review compared stem cell injection with placebo injection (eight trials), no treatment or usual care (two trials), glucocorticoid injection (one trial), hyaluronic acid injection (seven trials), platelet‐rich plasma injection (two trials), oral acetaminophen (paracetamol) (one trial), NSAIDs plus physical therapy plus hyaluronic acid injection (one trial), and stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone (three trials). Trials were conducted in 13 countries, including four in the USA, four in China, three in Spain, three in Iran, two in Australia, two in Korea and single trials in India, Portugal, Taiwan, Saudi Arabia, Mexico, Chile and Latvia. Eight trials followed participants up to six months (Baria 2022; Chen 2021; Emadedin 2018; Garay‐Mendoza 2018; Khalifeh Soltani 2019; Kim 2023; Lee 2019; Ren 2023), one trial followed participants up to 24 months (Sadat‐Ali 2021), another trial up to 5 years (Zhang 2022), and the remaining 15 trials followed participants up to 12 months. Eight trials used more than one intervention arm to test different doses of stem cells (Bastos 2020; Chen 2021; Freitag 2019; Garza 2020; Gupta 2016; Kuah 2018; Lamo‐Espinosa 2016; Matas 2019).

Participants in the included trials were generally representative of people with knee osteoarthritis seen in clinical practice. Participants were similar in terms of mean age and baseline pain. The mean duration of symptoms was only reported in five trials and ranged from 12.5 months to 10 years (Chen 2021; Emadedin 2018; Kim 2023; Lamo‐Espinosa 2016; Lu 2019). Most trials included participants with moderate radiographic disease (Kellgren‐Lawrence grade II‐III), although six trials also included participants with more severe (grade IV) radiographic change (Baria 2022; Bastos 2020; Emadedin 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019) and six trials also included participants with grade I changes (Anz 2020; Baria 2022; Bastos 2020; Chen 2021; Kuah 2018; Lu 2019). Gender ratio ranged from 37% female (Emadedin 2018; Lamo‐Espinosa 2016) to 90% female (Khalifeh Soltani 2019).

There is considerable variation in the methods used for stem cell preparation and injection in the existing literature, including the use of autologous versus allogeneic cells, the tissue of origin, expansion and isolation of cells, storage prior to injection, dose of cells and number of injections. Amongst the 25 trials included in this review, 16 used some form of mesenchymal stem cells (MSC), three trials used bone marrow aspirate concentrate, four trials used stromal vascular fraction, one trial used bone marrow‐derived mononuclear cells and one trial used chondrocytes. Eight of the included trials used allogeneic stem cells, either pooled from multiple donors (two trials), or from a single donor (six trials); the remainder used autologous cells. The stem cells were obtained from bone marrow in 12 trials, adipose tissue in 11 trials, or from umbilical cord or placental tissue (one trial each). The harvested stem cells underwent in vitro expansion in 17 of the 25 trials. In 10 trials, the stem cell preparation underwent cryopreservation prior to injection (Chen 2021; Freitag 2019; Gupta 2016; Kim 2023; Kuah 2018; Lee 2019; Lu 2019; Matas 2019; Sadri 2023; Vega 2015); in five trials, stem cells were prepared in the laboratory without freezing (Bastos 2020; Emadedin 2018; Garza 2020; Goncars 2017; Khalifeh Soltani 2019); in 10 trials they were injected immediately after harvest (Anz 2020; Baria 2022; Garay‐Mendoza 2018; Ho 2022; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Ren 2023; Sadat‐Ali 2021; Shapiro 2017; Zhang 2022). Knee injection was performed via ultrasound guidance in eight trials (Anz 2020; Freitag 2019; Garza 2020; Kuah 2018; Lee 2019; Lu 2019; Ren 2023; Shapiro 2017), via x‐ray guidance in one trial (Emadedin 2018), and via anatomical landmarks without imaging guidance in the remaining 16 trials.

While differences in cell source, harvest and preparation methods may result in differences in the concentration and function of stem cells within the injected product, we elected to include all interventions that are hypothesised to be potentially effective due to the action of stem cells. For the primary comparison (stem cell injection versus placebo injection), six of the eight included trials used injections of MSCs in a dose of at least 10⁶ cells (Emadedin 2018; Khalifeh Soltani 2019; Kim 2023; Kuah 2018; Lee 2019; Sadri 2023), and a further trial used stromal vascular fraction (characterised for cell yield) at a dose of at least 15 million cells (Garza 2020). Inclusion of Shapiro 2017, which used bone marrow concentrate injections as the intervention, and which may have therefore contained a lower concentration of stem cells than other interventions, is likely to have had little impact on the estimate of effect or confidence in the findings of this review. As this is a living review, subgroup analyses may become possible as further evidence is added in the future.

Knee pain was measured in all trials but not reported in one trial (Garza 2020). Function was measured via either WOMAC or KOOS in all but two trials (Sadat‐Ali 2021; Shapiro 2017). Other outcomes that are likely to be important to people with knee osteoarthritis were measured less frequently. Quality of life was measured in only seven trials (Bastos 2020; Ho 2022; Kim 2023; Kuah 2018; Lu 2019; Sadri 2023; Vega 2015), but results were not reported in two trials (Bastos 2020; Kuah 2018). A measure of participant‐reported treatment success was measured in 10 trials (Baria 2022; Bastos 2020; Emadedin 2018; Freitag 2019; Garza 2020; Kim 2023; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lu 2019), but results were not reported in two trials (Lamo‐Espinosa 2016; Lamo‐Espinosa 2020). Radiographic change in the knee was measured with x‐ray in six trials (Goncars 2017; Gupta 2016; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Zhang 2022), but only reported in two (Lamo‐Espinosa 2016; Lamo‐Espinosa 2020).

All interventions that involve intra‐articular injection carry a small risk of joint infection, a serious adverse outcome that is associated with substantial morbidity, including irreversible joint damage, and a risk of mortality. Overall, serious adverse events were rare in the included trials, so any differential risk of serious harm (including joint infection) between stem cell injections and other interventions cannot be estimated. Only one case of septic arthritis was reported, in a participant who received a hyaluronic acid injection (Lu 2019).

Although seven trials included in this review used hyaluronic acid as the comparator intervention, the utility of this comparison to clinicians is likely to be low. A systematic review found high‐certainty evidence from randomised trials of an association between viscosupplementation and potential serious harmful effects, and an absence of clinically relevant benefits (Pereira 2022).

Although intra‐articular glucocorticoid injection remains a common intervention for knee osteoarthritis in clinical practice, only one trial compared stem cell injection to intra‐articular glucocorticoids. Although outcome data, including pain, function and quality of life, were collected at 1, 2, 3, 6, 9 and 12 months after the intervention, only 12‐month data were provided. Given that this is longer than the expected period of symptomatic benefit from intra‐articular glucocorticoids, it is unlikely that a meaningful interpretation can be drawn for this comparison.

Quality of the evidence

Overall, the included studies were hampered by poor reporting, including failure to report major outcomes (including WOMAC function subscores), and many trials failed to fully report standard deviation or other measures of variance, requiring us to impute these from other studies. Furthermore, some purported SD values appear to be comparatively small for the number of participants, resulting in these small studies contributing substantial weight to the meta‐analysis for pain in particular (Lee 2019; Matas 2019). We cannot independently verify the accuracy of the SD values; the trialists may have inadvertently entered standard errors (SEs) (although the corresponding SDs seem too large when we made calculations of SD based on that assumption). In any case, removal of the studies with small SDs in post‐hoc sensitivity analyses did not alter the effect estimates substantially; there was little to no benefit in terms of pain at six months.

Stem cell injection versus placebo injection

We downgraded the certainty of the evidence for pain and function to low certainty due to indirectness (the tissue source, method of preparation, storage prior to injection and dose of cells varied across studies), and due to suspected publication bias, as up to three larger trials have been conducted but withdrawn prior to reporting of results. We downgraded the evidence for participant‐reported global assessment of success and quality of life to very low due to indirectness, imprecision and suspected publication bias. Radiographic outcomes were not reported in any of the included trials.

We downgraded the evidence for both serious adverse events and withdrawals due to adverse events to very low due to indirectness, suspected publication bias and imprecision. The trials were not large enough to detect many serious adverse events, and no withdrawals due to adverse events were reported in the five studies that measured this outcome.

Stem cell injection versus no treatment or usual care

We downgraded the evidence for all major outcomes (pain, function, participant‐reported global assessment of success) to very low certainty due to risk of bias, indirectness, imprecision and suspected publication bias. The included trials were likely to be at risk of performance and detection bias due to the lack of blinding of participants in all three trials that compared stem cell injection to no treatment or usual care. We downgraded due to indirectness as the tissue source, method of preparation, storage prior to injection and dose of cells varied across studies. We downgraded due to imprecision as the 95% confidence intervals for continuous outcomes do not rule in or rule out a clinically important change, and there were no events reported for the dichotomous outcomes (withdrawals due to adverse events and serious adverse events). We downgraded due to suspected publication bias as up to five trials have been conducted or are still ongoing, but no results are available yet.

Stem cell injection versus glucocorticoid injection

We downgraded the evidence for all major outcomes (pain, function, quality of life, participant‐reported global assessment of success, withdrawal due to adverse events, serious adverse events) to very low certainty due to indirectness, imprecision and suspected publication bias. We downgraded due to indirectness as it is unknown whether there is an optimal stem cell treatment regimen and the method of stem cell harvest and preparation, storage prior to injection and dose of cells used in the included study may differ from the methods used in other contexts. We downgraded due to imprecision as the 95% confidence intervals for continuous outcomes do not rule in or rule out a clinically important change, and few events were reported for the dichotomous outcomes (withdrawals due to adverse events and serious adverse events). We downgraded due to suspected publication bias as up to four trials have been conducted or are still ongoing, but no results are available yet.

Stem cell injection versus hyaluronic acid injection

We downgraded the evidence for all major outcomes (pain, function, quality of life, participant‐reported global assessment of success, withdrawal due to adverse events, serious adverse events) to very low certainty due to indirectness, imprecision and suspected publication bias. We downgraded due to indirectness as the tissue source, method of preparation, storage prior to injection and dose of cells varied across studies. We downgraded due to imprecision as the 95% confidence intervals for continuous outcomes do not rule in or rule out a clinically important change, and few events were reported for the dichotomous outcomes (withdrawals due to adverse events and serious adverse events). We downgraded due to suspected publication bias as there are up to 18 unpublished trials comparing stem cell with hyaluronic acid injection.

Stem cell injection versus platelet‐rich plasma injection

We downgraded the evidence for all major reported outcomes (pain, function, participant‐reported global assessment of success, withdrawal due to adverse events, serious adverse events) to very low certainty due to risk of bias, indirectness and imprecision. We downgraded due to risk of bias as the participants and investigators in the included trial were not blinded and the method of allocation concealment was not described. We downgraded due to indirectness as it is unknown whether there is an optimal stem cell treatment regimen and the method of stem cell harvest and preparation, storage prior to injection and dose of cells used in the included study may differ from the methods used in other contexts. We downgraded due to imprecision as the 95% confidence intervals for continuous outcomes do not rule in or rule out a clinically important change, and few events were reported for the dichotomous outcomes (withdrawals due to adverse events and serious adverse events).

Stem cell injection versus oral acetaminophen (paracetamol)

We downgraded the evidence for pain and function to very low certainty due to risk of bias, indirectness and imprecision. We downgraded due to risk of bias as the participants and investigators in the included trial were not blinded and the methods of randomisation and allocation concealment were not described. We downgraded due to indirectness as it is unknown whether there is an optimal stem cell treatment regimen and the method of stem cell harvest and preparation, storage prior to injection and dose of cells used in the included study may differ from the methods used in other contexts. We downgraded due to imprecision as the 95% confidence intervals for continuous outcomes do not rule in or rule out a clinically important change.

Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection

We downgraded the evidence for pain, withdrawal due to adverse events and serious adverse events to very low certainty due to risk of bias, indirectness and imprecision. We downgraded due to risk of bias as the participants and investigators in the included trial were not blinded and the methods of randomisation and allocation concealment were not described. We downgraded due to indirectness as it is unknown whether there is an optimal stem cell treatment regimen and the method of stem cell harvest and preparation, storage prior to injection and dose of cells used in the included study may differ from the methods used in other contexts. We downgraded due to imprecision as the 95% confidence intervals for continuous outcomes do not rule in or rule out a clinically important change, and few events were reported for the dichotomous outcomes (withdrawals due to adverse events and serious adverse events).

Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone

We downgraded the evidence for pain, function, radiographic joint progression and serious adverse events to very low certainty due to risk of bias, indirectness and/or imprecision. We downgraded due to risk of bias as all participants and investigators in the included trials were not blinded. We downgraded due to indirectness as it is unknown whether there is an optimal stem cell treatment regimen and the method of stem cell harvest and preparation, storage prior to injection and dose of cells used in the included study may differ from the methods used in other contexts. We downgraded due to imprecision as the 95% confidence intervals for continuous outcomes do not rule in or rule out a clinically important change.

Potential biases in the review process

To the best of our knowledge, we identified all relevant trials meeting the review's eligibility criteria through a comprehensive search of major electronic databases and trial registries without language restrictions. We used at least two independent assessors to screen and select studies, perform risk of bias judgements and rate the certainty of the evidence. None of the review authors have been involved in the conduct of the included trials.

There were too few studies to formally assess the presence of publication bias using funnel plots. However, there are 21 ongoing studies comparing stem cell injection with placebo. There were two trials that were registered, but have since been withdrawn (Table). One large ongoing trial is likely to increase our confidence in the findings once published, including providing data for radiographic progression (Liu 2021).

We identified six ongoing trials comparing stem cell injection to glucocorticoid injection (Table). As the results from these trials will increase the certainty of the evidence, this may change the conclusions for this comparison.

There are 29 unpublished trials comparing stem cell with hyaluronic acid injection and, of these, it seems one trial has been withdrawn. As there does not appear to be a benefit of one intervention over the other, it is unclear if subsequent publication of these results will alter the conclusions. Of note, a large systematic review indicates that there is high‐certainty evidence of an association between viscosupplementation and potential serious harmful effects, and an absence of clinically relevant benefits (Pereira 2022). Thus, it is doubtful that further comparison of stem cell injections with hyaluronic acid injections will be of any clinical value.

Agreements and disagreements with other studies or reviews

We identified 42 other systematic reviews of stem cell injections for knee osteoarthritis (Agarwal 2021; Aletto 2022; Álvarez 2022; Anil 2021; Anzillotti 2022; Boada‐Pladellorens 2022; Chahla 2016; Cui 2016; Dai 2021; Delanois 2019; Delanois 2022; Dhillon 2022; Di Matteo 2019; Ding 2021; Gadelkarim 2022; Gong 2020; Ha 2019; Hall 2020; Iijima 2018; Jiang 2021; Jevotovsky 2018; Kim 2019; Kim 2020; Kim 2023; Long 2022; Ma 2020; Maheshwer 2021; Migliorini 2020; Naja 2021; Pas 2017; Prodromos 2020; Ranmuthu 2018; Shang 2023; Shanmugasundaram 2021; Shoukrie 2022; Song 2020; Tan 2021; Wei 2021; Xia 2015; Yubo 2017; Zhang 2022; Zhao 2021). None of the reviews included more than 13 of the 25 trials included in this review. The most common difference from this review was the inclusion of trials in which stem cells were used as an adjunct to a surgical procedure, which occurred in 21 systematic reviews. Six systematic reviews included a network meta‐analysis (Anil 2021; Ding 2021; Naja 2021; Wei 2021; Zhang 2022; Zhao 2021).

There was considerable heterogeneity in the interventions that were included in these systematic reviews. The majority of reviews included trials of mesenchymal stromal cells (MSCs), of which one review was limited to autologous MSCs (Prodromos 2020), one review was limited to MSCs of adipose or bone marrow origin (Zhao 2021), and one review included only hyaluronic acid as the comparator (Jiang 2021). Several reviews included a broader definition of stem cell interventions, of which two restricted the intervention to stem cells of bone marrow, adipose or amnion origin (Delanois 2022, which was an update of Delanois 2019) and one review that excluded trials in which the intervention was stromal vascular fraction or bone marrow aspirate concentrate (Ding 2021). Seven reviews were limited to trials of stem cells of adipose origin (Agarwal 2021; Aletto 2022; Boada‐Pladellorens 2022; Gadelkarim 2022; Kim 2023; Ranmuthu 2018; Shanmugasundaram 2021), of which three included trials of any adipose‐derived stem cells (Agarwal 2021; Gadelkarim 2022; Ranmuthu 2018), one included trials of autologous adipose‐derived stem cells (Kim 2023), and three included trials of stromal vascular fraction (Aletto 2022; Boada‐Pladellorens 2022; Shanmugasundaram 2021). One review was limited to trials of bone marrow aspirate concentrate (Chahla 2016), one review included trials of either bone marrow aspirate concentrate or stromal vascular fraction (Di Matteo 2019), and one review was limited to trials of umbilical cord‐derived stem cells (Dhillon 2022).

Several trials included in this review were infrequently included in other systematic reviews, including the one trial in our review that compared a stem cell intervention (bone marrow aspirate concentrate) to injection with platelet‐rich plasma (Anz 2020), which was included in three of the nine reviews for which it was potentially eligible. Similarly, a trial that compared autologous bone marrow‐derived mononuclear cell injection with hyaluronic acid injection (Goncars 2017) was included in only three reviews, and the only trial that compared MSC injection with glucocorticoid injection (Bastos 2020) was included in four reviews. The earliest trial included in our review (Vega 2015), which compared injection with allogeneic pooled MSCs to hyaluronic acid injection, was included in the highest number of reviews, 27 of the 31 reviews for which it was potentially eligible.

There was also considerable heterogeneity in the conclusions of the reviews. Only five reviews concluded that the efficacy of stem cell injections had not been demonstrated. Potential harms, particularly serious adverse events, were variably reported in the reviews, and 12 of the 42 reviews did not include adverse events as an outcome (Anil 2021; Anzillotti 2022; Delanois 2022; Gong 2020; Ha 2019; Kim 2019; Kim 2020; Maheshwer 2021; Naja 2021; Tan 2021; Wei 2021; Xia 2015).

Shang 2023 included 13 trials that are included in this review (Bastos 2020; Chen 2021; Emadedin 2018; Freitag 2019; Garay‐Mendoza 2018; Khalifeh Soltani 2019; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Matas 2019; Vega 2015), and also included prospective observational studies. They did not undertake meta‐analysis; however, their descriptive conclusions are largely in agreement with this review. They did not include nine trials that were included in this review (Anz 2020; Baria 2022; Garza 2020; Goncars 2017; Gupta 2016; Ho 2022; Sadat‐Ali 2021; Shapiro 2017; Zhang 2022) and included three trials that were not included in this review, two of which used stem cells as an adjunct to surgery (Kim 2022; Lim 2021), and one of which compared different doses of stem cells (Lu 2020).

Long 2022 included 28 trials of MSC injections for osteoarthritis, including 12 trials that appear in this review (Bastos 2020; Freitag 2019; Garza 2020; Gupta 2016; Khalifeh Soltani 2019; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Matas 2019; Vega 2015). They did not include several trials of MSCs that were included in this review, including trials of autologous bone marrow‐derived MSCs (Emadedin 2018; Garay‐Mendoza 2018; Ho 2022; Sadat‐Ali 2021), allogeneic adipose‐derived stem cells (Chen 2021), bone‐marrow derived mononuclear cells (Goncars 2017), stromal vascular fraction (Baria 2022; Zhang 2022), and bone marrow aspirate concentrate (Anz 2020; Shapiro 2017). They included a further 16 trials that were not included in our review, including 10 trials published in Chinese (Chengzhi 2018; Hao‐Lin 2021; Jianji 2015; Jingzhao 2016; Meng 2020; Wang 2016; Xiaoxia 2015; Xu 2009; Yang 2017; Zhang 2018), one trial quoted in the review text but not in the reference list (Gan), a trial of subchondral injections in osteonecrosis (Hernigou 2018), and four trials in which stem cell injections were an adjunct to a surgical procedure (Hong 2019; Tan 2013; Vangsness 2014; Wong 2013). Of the 10 trials published in Chinese language publications, two were identified in our search: one categorised as awaiting classification (Wang 2016) and another as excluded (Hong 2019). One of the Chinese language publications appears to be a thesis (Meng 2020). They reported an improvement in pain and function in those receiving intra‐articular MSCs compared to non‐MSC interventions from three months and up to 12 months after the intervention.

Anzillotti 2022 included trials of MSCs in people with grade IV osteoarthritis of the knee. They identified only one trial that met their inclusion criteria (Hernigou 2018), which was not included in our review as it was a trial of subchondral stem cell injection for osteonecrosis.

Shoukrie 2022 included trials of MSC injections, including four trials that appear in this review (Freitag 2019; Kuah 2018; Lee 2019; Lu 2019), but did not include eight other trials of MSC injections (Bastos 2020; Emadedin 2018; Gupta 2016; Khalifeh Soltani 2019; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Matas 2019; Vega 2015). They also included observational studies, an RCT protocol (Liu 2021) and a trial that compared different doses of MSCs (Lu 2020). They performed a narrative review and reported MSC injections to be beneficial in terms of pain and function.

Delanois 2022 was an update of Delanois 2019 that included trials of stem cells derived from bone marrow, adipose tissue and amniotic tissue. They performed a narrative review that included 11 trials that appear in this review (Anz 2020; Emadedin 2018; Freitag 2019; Garza 2020; Gupta 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Matas 2019; Shapiro 2017; Vega 2015), plus two trials in which the intervention was amniotic suspension (Farr 2019; Gomoll 2021) and one trial in which the intervention was a combination of stem cells and other potentially active treatments including PRP and other platelet products (Centeno 2018), in addition to observational studies. They did not include five other trials of stem cells of bone marrow (Bastos 2020; Goncars 2017; Lamo‐Espinosa 2016) or adipose (Chen 2021; Kuah 2018) origin. They concluded that the evidence for the benefits of stem cell injections remains uncertain.

Gadelkarim 2022 was a review of adipose‐derived MSCs that included four trials that were included in this review (Freitag 2019; Kuah 2018; Lee 2019; Lu 2019), in addition to two trials that compared different doses of stem cells (Lu 2020; Song 2018), and nine observational studies. A meta‐analysis of two included RCTs (Kuah 2018; Lu 2019) did not demonstrate an improvement in pain at six months in those receiving stem cells compared with a control injection (placebo or hyaluronic acid).

Aletto 2022 was a review of stromal vascular fraction (SVF) that included two trials, one of which (Garza 2020) was also included in this review, in addition to one trial (Hong 2019) in which SVF injections were an adjuvant to surgery, and 22 observational studies. The authors provided a narrative review of the 24 included studies and concluded that SVF injection improves pain, function and radiographic outcomes and was not associated with serious adverse events.

Boada‐Pladellorens 2022 was also a review of SVF injections that included the same two trials as Aletto 2022 (Garza 2020, included in this review, and Hong 2019), plus seven observational studies. The authors provided a narrative review and concluded that SVF injection is associated with improvement in pain, function and structural outcomes measured by MRI.

Zhang 2022 was a network meta‐analysis of intra‐articular injections for knee osteoarthritis that included MSCs of bone‐marrow, adipose or umbilical origin as an intervention. It included 12 trials that are included in this review (Emadedin 2018; Freitag 2019; Garay‐Mendoza 2018; Gupta 2016; Khalifeh Soltani 2019; Kuah 2018; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019; Matas 2019; Vega 2015), but did not include one further trial of intra‐articular MSCs that was included in this review (Bastos 2020). The network meta‐analysis also included placebo, conservative treatment, platelet‐rich plasma and hyaluronic acid as nodes in the network. They reported that MSC injections had a superior ranking to other interventions for pain and function. The authors concluded that stem cell injections are effective and that cells of adipose and umbilical origin have superior efficacy to cells of bone marrow origin.

Dhillon 2022 was a review of umbilical cord‐derived stem cells that included one trial that also appears in this review (Matas 2019) plus six observational studies. The authors performed a narrative review and concluded that umbilical cord‐derived stem cell injections improve pain and function in the short term.

Álvarez 2022 included only three trials that appear in this review (Gupta 2016; Lamo‐Espinosa 2016; Vega 2015), however, the literature search date was February 2018. They performed a narrative review that also included six observational studies. The authors concluded that there was insufficient evidence to determine the efficacy of MSC injections.

Prodromos 2020 reviewed autologous MSCs and included nine trials included in this review (Anz 2020; Emadedin 2018; Freitag 2019; Garay‐Mendoza 2018; Garza 2020; Lamo‐Espinosa 2016; Lamo‐Espinosa 2020; Lee 2019; Lu 2019). The search date was not reported; however, some other trials of autologous MSCs were not included (Bastos 2020; Matas 2019). Observational studies were also included in the review. The method of pooling results is unclear. The authors reported that the results of their review demonstrate clinically important efficacy associated with autologous MSC injection.

Kim 2023 was a review of autologous adipose‐derived stem cells that included five RCTs, four of which appear in this review (Freitag 2019; Garza 2020; Lee 2019; Lu 2019), plus one trial where stem cell injections were an adjuvant to surgery (Hong 2019). They reported a benefit in pain (SMD 1.06, 95% CI 1.19 to2.02) and function (SMD 0.75, 95% CI 0.39 to 1.11) at six months with adipose‐derived stem cell injection compared to placebo or hyaluronic acid injection. They did not identify any serious adverse effects. The authors concluded that adipose‐derived stem cell injections are a safe and effective intervention.

Agarwal 2021 was also a review of adipose‐derived stem cells that included five RCTs, three of which appear in this review (Freitag 2019; Garza 2020; Lee 2019), plus one trial where stem cell injections were an adjuvant to surgery (Hong 2019), one trial that compared different doses of stem cells (Song 2018) and 13 observational studies. They did not include one eligible RCT (Lu 2019). They performed a pooled analysis of pre‐ and post‐intervention total WOMAC scores. The authors concluded that the improvement in WOMAC scores following the intervention demonstrates the efficacy of stem cell injections.

Hall 2020 included 11 trials of MSC injections, including nine that appear in this review (Emadedin 2018; Freitag 2019; Gupta 2016; Lamo‐Espinosa 2016; Lee 2019; Lu 2019; Matas 2019; Shapiro 2017; Vega 2015), plus one trial protocol (Jones 2018) and one trial in which stem cell injections were an adjuvant to surgery (Hong 2019). Two potentially eligible trials of MSC injections were not included (Khalifeh Soltani 2019; Kuah 2018). The authors provided a narrative summary of individual trial findings (no synthesis) and concluded that MSC injections are a safe and effective intervention for knee osteoarthritis. Three adverse events (knee pain and swelling post‐injection) that required hospitalisation were identified, but these were not categorised as serious adverse events.

Dai 2021 included 13 trials of MSC injections, including 12 that appear in this review (Emadedin 2018; Freitag 2019; Garza 2020; Gupta 2016; Khalifeh Soltani 2019; Kuah 2018; Lamo‐Espinosa 2016; Lee 2019; Lu 2019; Matas 2019; Shapiro 2017; Vega 2015), plus one trial in which stem cell injections were an adjuvant to surgery (Hong 2019). They reported no significant difference in pain for MSC injections compared to placebo injection (10 cm pain VAS mean difference 1.62, 95% CI ‐0.60 to 3.85) but an improvement in pain compared to hyaluronic acid injection (10 cm pain VAS mean difference 2.0, 95% CI 0.94 to 3.07). They reported no difference between MSC injections and the comparator for WOMAC function score (MD ‐0.67, 95% CI ‐6.54 to 5.19 compared to placebo; MD 4.64, 95% CI ‐0.31 to 9.59 compared to hyaluronic acid). They reported no evidence of a difference in total adverse events for MSC injections compared to control injections (RR 0.75, 95% CI 0.54 to 1.03). The authors concluded that MSC injections are not superior to placebo for pain or function in people with knee osteoarthritis.

Zhao 2021 was a network meta‐analysis of intra‐articular injections for knee osteoarthritis that included MSCs of bone‐marrow or adipose origin as an intervention. It included five trials that were included in this review (Emadedin 2018; Lamo‐Espinosa 2016; Lee 2019; Lu 2019; Vega 2015). The network meta‐analysis also included placebo, platelet‐rich plasma and hyaluronic acid as nodes in the network. They reported that adipose‐derived MSC injections (but not bone marrow‐derived MSC injections) were associated with improvements in pain and function compared to placebo at six and 12 months of follow‐up.

Shanmugasundaram 2021 was a review of stromal vascular fraction injections for knee osteoarthritis. No RCTs were identified, and 11 observational studies were included in the review. The authors performed a narrative review and concluded that SVF injections are safe and effective.

Gong 2020 included 13 trials that evaluated the effect of MSC injections on structural outcomes in people with knee osteoarthritis, including nine that appear in this review (Freitag 2019; Gupta 2016; Khalifeh Soltani 2019; Kuah 2018; Lamo‐Espinosa 2016; Lee 2019; Lu 2019; Matas 2019; Vega 2015), plus four trials in which MSCs were an adjuvant to surgery (Saw 2013; Vangsness 2014; Wang 2017; Wong 2013). The authors provided a narrative summary of individual trial findings (no synthesis) and concluded that there was evidence in favour of a beneficial effect of intra‐articular MSC injections on articular cartilage and subchondral bone.

Tan 2021 included 10 trials that appear in this review (Bastos 2020; Emadedin 2018; Freitag 2019; Garay‐Mendoza 2018; Garza 2020; Goncars 2017; Kuah 2018; Lee 2019; Lu 2019; Vega 2015). They also included nine observational studies in their review and performed a meta‐analysis of pre‐ and post‐intervention outcomes across all study types. Pain and function scores improved following MSC injection, so the authors concluded that MSC injections are an effective intervention for knee osteoarthritis.

Ding 2021 was a systematic review and network meta‐analysis of cell‐based injection therapies for knee osteoarthritis, including stem cells but excluding stromal vascular fraction and bone marrow aspirate concentrate. They included 10 trials that appear in this review (Bastos 2020; Emadedin 2018; Freitag 2019; Gupta 2016; Kuah 2018; Lamo‐Espinosa 2016; Lee 2019; Lu 2019; Matas 2019; Vega 2015), but did not include two potentially eligible trials (Goncars 2017; Khalifeh Soltani 2019). They reported a benefit of stem cell therapy for pain compared to non‐stem cell interventions at 12 months (SMD ‐1.05, 95% CI ‐1.46 to ‐0.64) but no evidence of a difference in total WOMAC score at six months (SMD ‐3.6, 95% CI ‐0.90 to 0.18).

Naja 2021 was a systematic review and network meta‐analysis of non‐surgical interventions for knee osteoarthritis, including MSCs, bone marrow aspirate concentrate and stromal vascular fraction. They included three trials that appear in this review (Freitag 2019; Matas 2019; Shapiro 2017), plus one trial in which stem cell injections were an adjuvant to surgery (Hong 2019), but did not identify seven potentially eligible trials at the time of their search (Emadedin 2018; Garay‐Mendoza 2018; Goncars 2017; Khalifeh Soltani 2019; Kuah 2018; Lee 2019; Lu 2019). The network meta‐analysis included 19 trials of 16 different non‐surgical interventions. The authors reported that MSC injection had the highest‐ranked probability of being the most effective intervention for pain and function.

Anil 2021 was a systematic review and network meta‐analysis of intra‐articular injection therapies for knee osteoarthritis, including bone marrow aspirate concentrate, MSCs and stromal vascular fraction. They included six trials that appear in this review (Anz 2020; Garza 2020; Kuah 2018; Lamo‐Espinosa 2020; Lu 2019; Vega 2015), but did not include 11 potentially eligible trials (Bastos 2020; Emadedin 2018; Freitag 2019; Garay‐Mendoza 2018; Goncars 2017; Gupta 2016; Khalifeh Soltani 2019; Lamo‐Espinosa 2016; Lee 2019; Matas 2019; Shapiro 2017). They reported a benefit of stromal vascular fraction for pain compared to saline injection at six months (pain VAS MD ‐38.98, 95% CI ‐54.65 to ‐23.31) but no evidence of a benefit of MSCs (pain VAS MD ‐1.40, 95% CI ‐15.83 to 13.03). A network map was not provided, but the authors reported that stromal vascular fraction was the intervention with the highest probability of benefit for both pain and function at up to one year in the network meta‐analysis.

Ma 2020 included 10 trials that evaluated the effect of MSC injections that were included in our review (Emadedin 2018; Freitag 2019; Gupta 2016; Khalifeh Soltani 2019; Kuah 2018; Lamo‐Espinosa 2016; Lee 2019; Lu 2019; Matas 2019; Vega 2015). They excluded trials in which bone marrow aspirate concentrate or stromal vascular fraction was the intervention, and trials in which MSCs were an adjuvant to surgery. They reported a benefit of stem cell therapy for pain (VAS MD ‐19.24, 95% CI ‐26.31 to ‐12.18) and function (WOMAC SMD ‐0.36, 95% CI ‐0.69 to ‐0.04) compared to non‐stem cell interventions at six to 12 months, but a higher proportion of participants who experienced adverse events among those who received MSCs compared to controls (odds ratio (OR) 3.2, 95% CI 1.5 to 6.8). The authors concluded that MSC injections are an effective and safe intervention.

Jiang 2021 included nine trials that compared MSCs to hyaluronic acid, including five trials that appear in this review (Goncars 2017; Lamo‐Espinosa 2016; Lu 2019; Matas 2019; Vega 2015), in addition to three trials where the intervention was an adjuvant to surgery (Saw 2013; Turajane 2017; Wong 2013) and one Chinese language trial categorised in this review as awaiting classification (Wang 2016). The authors concluded that MSC injections significantly improve symptoms in knee osteoarthritis compared to hyaluronic acid but found little difference in structural outcomes.

Maheshwer 2021 included RCTs and observational studies that evaluated the effect of stem cell injections in people with osteoarthritis or chondral defects in the knee. They included six trials that appear in this review (Goncars 2017; Gupta 2016; Kuah 2018; Lee 2019; Lu 2019; Vega 2015) plus seven other controlled trials, one of which was not randomised (Wakitani 2002), and six RCTs in which stem cells were an adjuvant to surgery (Akgun 2015; Hashimoto 2019; Koh 2014; Koh 2016; Turajane 2017; Wong 2013). They did not include four additional eligible trials (Emadedin 2018; Freitag 2019; Khalifeh Soltani 2019; Lamo‐Espinosa 2016). The authors reported a benefit of MSCs for function but not pain.

Wei 2021 was a systematic review and network meta‐analysis that investigated the effectiveness of injections of MSCs from different tissue sources. They included seven trials that appear in this review (Emadedin 2018; Gupta 2016; Kuah 2018; Lamo‐Espinosa 2016; Lee 2019; Matas 2019; Vega 2015). The authors reported that the pooled analysis demonstrated a benefit of MSC injection compared to placebo injection for pain (VAS weighted MD ‐20.31, 95% CI ‐26.81 to ‐13.80) and function (SMD ‐0.47, 95% CI ‐0.76 to ‐0.17). They reported that the network meta‐analysis indicated that adipose‐derived stem cells were the highest‐ranked intervention for pain. Adverse events were not reported.

Song 2020 was a systematic review of MSC injections that included nine trials that appear in this review (Emadedin 2018; Freitag 2019; Gupta 2016; Khalifeh Soltani 2019; Kuah 2018; Lee 2019; Matas 2019; Shapiro 2017; Vega 2015), but did not identify two other trials (Lamo‐Espinosa 2016; Lu 2019). Observational studies were also included in the pooled analyses. The authors reported that no serious adverse events were reported in the included studies but also reported adverse events, including joint infection, myocardial infarction and intestinal obstruction. The authors concluded that MSC injections are a safe and effective intervention.

Kim 2020 included six trials that appear in this review (Emadedin 2018; Gupta 2016; Khalifeh Soltani 2019; Kuah 2018; Lamo‐Espinosa 2016; Vega 2015). They reported a benefit of MSC injection compared to comparator (placebo, usual care or hyaluronic acid) at six to 12 months for pain (MD ‐13.6, 95% CI ‐22.2 to ‐4.9) but not function (WOMAC SMD ‐0.37, 95% CI ‐0.91 to 0.18). A similar systematic review from the same group (Kim 2019) included three trials that appear in this review (Gupta 2016; Lamo‐Espinosa 2016; Vega 2015), in addition to two trials in which MSCs were an adjuvant to surgery (Koh 2014; Wong 2013). The authors of Kim 2019 also reported a benefit of MSCs compared to a control intervention (placebo, usual care or hyaluronic acid) for pain but not function.

Migliorini 2020 included two trials that appear in this review (Lamo‐Espinosa 2016; Vega 2015), in addition to one trial that was not randomised (Orozco 2013), and 15 observational studies. They did not identify six other trials of MSC injection (Emadedin 2018; Freitag 2019; Gupta 2016; Kuah 2018; Lee 2019; Lu 2019). The authors concluded that the within‐group change in pain and function measures indicated the effectiveness of MSC injections.

Di Matteo 2019 was a systematic review of minimally manipulated stem cell preparations, including bone marrow aspirate concentrate and stromal vascular fraction. They included one trial included in this review (Shapiro 2017) plus three other trials, one of which was a trial protocol without data (Jones 2018), one in which the intervention was subchondral injection in osteonecrosis (Hernigou 2018) and one in which stem cell injection was an adjuvant to surgery (Hong 2019). Observational studies were also included. The authors performed a narrative review and concluded that the effect of minimally manipulated stem cell injections is unclear.

Ha 2019 included three trials that appear in this review (Gupta 2016; Lamo‐Espinosa 2016; Vega 2015), in addition to two trials in which MSCs were an adjuvant to surgery (Koh 2014; Wong 2013), one that was not randomised (Wakitani 2002), and 11 other observational studies. The authors reported a count of the number of included studies that reported a benefit and concluded that MSC injections may improve pain and function.

Iijima 2018 included three trials that appear in this review (Gupta 2016; Lamo‐Espinosa 2016; Vega 2015), in addition to four other controlled trials, three in which MSCs were an adjuvant to surgery (Koh 2014; Varma 2010; Wong 2013) and one that was not randomised (Wakitani 2002), and 28 observational studies. The authors reported that their pooled analyses suggested a benefit of MSC injections for pain and function compared to control interventions. They did not identify any serious adverse events.

Ranmuthu 2018 was a systematic review of adipose‐derived stem cell injections for osteoarthritis. No RCTs were identified. The authors performed a narrative review of 12 observational studies.

Jevotovsky 2018 was a systematic review of MSC injections for osteoarthritis that included five trials of MSCs for knee osteoarthritis, four of which appear in this review (Garay‐Mendoza 2018; Gupta 2016; Lamo‐Espinosa 2016; Vega 2015), plus one trial in which MSCs were an adjuvant to surgery (Turajane 2017). The authors performed a narrative review of both RCTs and observational studies.

Yubo 2017 included one trial that appears in this review (Vega 2015) in addition to trials in which MSCs were an adjuvant to surgery, and observational studies. The authors performed pooled analyses of within‐group change that included data from observational studies. Based on these analyses, they concluded that MSC injections are safe and potentially effective.

Pas 2017 included one trial that appears in this review (Vega 2015) and four trials in which stem cells were an adjuvant to surgery (Koh 2014; Saw 2013; Tan 2013; Wong 2013). The authors performed a narrative review and concluded that there was no high‐quality evidence regarding the effects of stem cell therapy in people with knee osteoarthritis.

Xia 2015 included one trial that appears in this review (Vega 2015), in addition to four trials in which stem cells were an adjuvant to surgery (Koh 2014; Tan 2013; Varma 2010; Wong 2013) and two trials that were not randomised (Gan 2014; Koh 2012). The authors included both RCTs and observational studies in their pooled analyses. They reported a benefit of MSCs compared to control interventions for function but not pain.

Two systematic reviews performed literature searches that predated the earliest trial in our review (Chahla 2016; Cui 2016). Chahla 2016 performed a narrative review of observational studies of bone marrow aspirate concentrate. Cui 2016 reported a pooled analysis of data from RCTs in which stem cells were an adjuvant to surgery and from observational studies, and concluded that MSCs improve pain and function.

Authors' conclusions

Implications for practice.

The findings of this review demonstrate that stem cell injection for people with knee osteoarthritis may provide a small improvement in pain and function, but not quality of life or treatment success, compared with placebo injection. The clinical significance of the improvement in pain and function remains unclear. The benefits and risks of stem cell injection compared with no treatment, routine care or glucocorticoid injection remain unclear. Although the putative benefits of stem cell therapies for osteoarthritis include potential regenerative effects on damaged tissues, particularly articular cartilage, we remain uncertain of the effect of stem cell injections on structural progression in the knee (measured by radiographic appearance). There is also uncertainty regarding the safety of stem cell injections. Serious adverse events were infrequently reported, although all invasive joint procedures (including injections) carry a small risk of septic arthritis. The risk of other important harms, including potential concerns related to the use of a therapy with the theoretical capacity to promote cell growth, or to the use of allogeneic cells, remains unknown.

It remains unknown whether any of the diverse methods of stem cell harvest, isolation, expansion, pooling, storage, injection technique, cell dose or use of biologically active carriers are more likely to achieve the putative beneficial effects on symptoms or disease progression. A wide array of techniques was identified in this review.

People contemplating stem cell injections for knee osteoarthritis should be informed about the findings of this evidence synthesis to help them make an evidence‐informed decision. They should also be informed that their symptoms may vary over time irrespective of treatment and that invasive procedures, including stem cell harvest and knee injection, carry a risk of harms. Furthermore, non‐pharmacological therapies, including stem cell procedures, may be subject to fewer regulatory restrictions than pharmacological interventions, and may be offered to people living with persistent pain due to osteoarthritis, often at a substantial out‐of‐pocket cost, despite the uncertainty about the benefits or harms of this intervention.

Implications for research.

Our conclusions regarding the comparison of stem cell injection versus placebo are based on low‐certainty evidence for pain and function, and very low‐certainty evidence for participant‐reported global assessment, withdrawal due to adverse events and serious adverse events. There were no radiographic data available for this comparison. The evidence for stem cell injections compared with no treatment or other interventions, including injection with glucocorticoids, hyaluronic acid or platelet‐rich plasma, was all of very low certainty.

Further trials to establish the efficacy and safety of stem cell injections are most likely to be of value if they have a sufficient sample size to increase the certainty of our effect estimates, use a placebo control and include both patient‐reported efficacy outcomes (pain, function, quality of life) and a measure of structural change (such as plain radiography or magnetic resonance imaging). The latter is important due to the putative regenerative benefits of stem cells on structural progression in osteoarthritis, including articular cartilage thickness. Longer‐term follow‐up of participants in placebo‐controlled trials or data from prospectively designed registries is also important to provide more precise estimates of the risk of adverse events. Given the variation in stem cell harvest and preparation techniques, careful performance and reporting of trials using a standard protocol and dose remains particularly important.

Future living updates of this review will be published when ongoing placebo‐controlled trials are published, as well as ongoing glucocorticoid‐controlled trials, as these represent the most relevant comparisons in clinical practice. Further trials comparing stem cell injection with hyaluronic acid and platelet‐rich plasma are likely to be of limited value, and we are unlikely to include such studies in future updates.

What's new

Date	Event	Description
23 May 2025	Amended	Correction to statement on the effect of stem cell injections on quality of life in the Plain language Summary. Amended from stating that quality of life is better with stem cell injections to 'It is unclear if stem cell injections improve quality of life.

History

Protocol first published: Issue 5, 2019
Review first published: Issue 4, 2025

Appendices

Appendix 1. Cochrane living systematic reviews

Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available (Brooker 2019; Elliott 2017). Searching is conducted quarterly, and new relevant evidence (studies, data or other information) is incorporated into the review in a timely manner so that the findings of the review remain current.

Living systematic review approach

Searching

Database searches will be run quarterly (January, April, July and October). Any studies identified in the period from the baseline searches to the publication of the review will be incorporated in the review or noted in the 'What’s new' section and included in the first update. For the searches of CENTRAL, MEDLINE and Embase, we use auto‐alerts in the Cochrane Library and Ovid to receive the quarterly search yield by email. We manually searched ClinicalTrials.gov and the WHO ICTRP trials portal for the first iteration of the review, but expect any new or ongoing trials will be available via CENTRAL. We will review search methods (sources, search terms and frequency) approximately yearly to ensure they reflect any changes in subject headings or text words and any changes in the review's eligibility criteria.

For the quarterly searches following the baseline search, we will immediately screen any new citations retrieved. We intend to screen all records using the RCT classifier available in Covidence; other automation techniques may be employed over time if they become available and are found to improve efficiency.

For the most up‐to‐date information about the review, the results of the searches and any new evidence being incorporated, readers are encouraged to check the update status information. The update status information will be updated whenever the searches are re‐run.

We will republish the review as a new citation version when new evidence has an important impact on the findings of the review, for example a change in one or more of the following components.

1. The findings for one or more major outcomes.

2. The credibility (e.g. GRADE rating) of one or more major outcomes.

3. New settings, populations, interventions, comparisons or outcomes studied. For example, as different methods for harvesting and preparation of stem cells evolve, this may impact the types of interventions to be included in future updates. Also, if stem cell injections are shown to have a benefit over placebo injections, in future updates, we will consider including studies comparing one type of stem cell injection to another type, or studies comparing different concentrations or doses of stem cells.

Future updates may include additional subgroup or secondary analyses as the technologies become more advanced and there is more consensus about the importance of the type and preparation of stem cells. This may include subgroup analysis comparing:

1. stem cell tissue origin (e.g. bone marrow versus adipose tissue versus synovial); and

2. direct injection after centrifuge versus lab‐based cellular expansion of injected cells.

If no new studies are identified, the review will remain the same, but the 'What's new' section will be amended to reflect the status, 'No new studies identified with search'.

If new evidence is identified but the authors and the editorial team judge that it is unlikely to have an important impact on the findings of the review, the 'What's new' section will be amended to reflect the status, 'New information identified, but unlikely to change conclusions'.

The review will be maintained as a living review until the topic is no longer a priority, or we judge that the conclusions of the review will no longer change with the addition of new evidence (Brooker 2019).

Appendix 2. Database search strategies

Cochrane Central Register of Controlled Trials (CENTRAL)

1. MeSH descriptor: [Osteoarthritis] explode all trees
2. MeSH descriptor: [Knee Joint] explode all trees
3. (osteoarthr* or arthrosis or (degenerative near/2 arthritis) or (degeneration near/3 (knee* or menisc*)))
4. #1 or #2 or #3
5. MeSH descriptor: [Cell‐ and Tissue‐Based Therapy] this term only
6. MeSH descriptor: [Stem Cell Transplantation] explode all trees
7. Stem Cell Transplantation:kw
8. "stem cell" or "stem cells" or "stemcell" or "cell therapy" or "cell therapies"
9. #5 or #6 or #7 or #8
10. #4 and #9

MEDLINE Ovid

1. exp Osteoarthritis/
2. exp Knee Joint/
3. (osteoarthr$ or arthrosis or (degenerative adj2 arthritis) or (degeneration adj3 (knee$ or menisc$))).tw.
4. or/1‐3
5. "Cell‐ and Tissue‐Based Therapy"/
6. exp Stem Cell Transplantation/
7. (stem cell$ or stemcell$ or cell therap$).tw.
8. or/5‐7
9. 4 and 8
10. Animals/ not Humans/
11. 9 not 10
12. Randomized Controlled Trial.pt.
13. Controlled Clinical Trial.pt.
14. randomized.ab.
15. placebo.ab.
16. drug therapy.fs.
17. randomly.ab.
18. trial.ab.
19. groups.ab.
20. or/12‐19
21. 11 and 20

Embase Ovid

1. exp Osteoarthritis/
2. exp Knee/
3. (osteoarthr$ or arthrosis or (degenerative adj2 arthritis) or (degeneration adj3 (knee$ or menisc$))).tw.
4. or/1‐3
5. exp Cell Therapy/
6. (stem cell$ or stemcell$ or cell therap$).tw.
7. or/5‐6
8. 4 and 7
9. Animals/ not Humans/
10. 8 not 9
11. exp Controlled Clinical Trial/
12. random$.ti,ab.
13. placebo.ti,ab.
14. or/11‐13
15. 10 and 14

ClinicalTrials.gov

Osteoarthritis, Knee (Condition) and Stem cells (Intervention)

WHO ICTRP

Osteoarthritis (Condition) and Stem cells (Intervention)

Data and analyses

Comparison 1. Stem cell injection versus placebo injection.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Mean overall pain (0 to 10, 0 is no pain)	7		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.1.1 Up to 3 months	7	443	Mean Difference (IV, Random, 95% CI)	‐1.07 [‐1.67, ‐0.48]
1.1.2 > 3 months to 6 months	7	445	Mean Difference (IV, Random, 95% CI)	‐1.24 [‐2.49, 0.00]
1.1.3 > 6 months to 1 year	3	106	Mean Difference (IV, Random, 95% CI)	‐1.71 [‐5.35, 1.92]
1.2 Mean overall pain by cell origin (0 to 10, 0 is no pain)	7		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.2.1 Autologous (> 3 months to 6 months)	4	369	Mean Difference (IV, Random, 95% CI)	‐0.89 [‐2.01, 0.22]
1.2.2 Allogeneic (> 3 months to 6 months)	3	76	Mean Difference (IV, Random, 95% CI)	‐1.72 [‐4.93, 1.50]
1.3 Mean function (0 to 100, 0 is best function)	7		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.3.1 Up to 3 months	7	432	Mean Difference (IV, Random, 95% CI)	‐8.93 [‐15.67, ‐2.20]
1.3.2 > 3 months to 6 months	7	432	Mean Difference (IV, Random, 95% CI)	‐14.19 [‐25.28, ‐3.10]
1.3.3 > 6 months to 1 year	3	82	Mean Difference (IV, Random, 95% CI)	‐24.55 [‐51.87, 2.77]
1.4 Mean function by cell origin (0 to 100, 0 is best function)	7		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.4.1 Autologous	4	356	Mean Difference (IV, Random, 95% CI)	‐9.73 [‐14.25, ‐5.21]
1.4.2 Allogeneic	3	76	Mean Difference (IV, Random, 95% CI)	‐11.95 [‐41.92, 18.03]
1.5 Mean quality of life (SF‐36 mental health)	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.5.1 Up to 3 months	2	288	Mean Difference (IV, Random, 95% CI)	10.13 [‐9.02, 29.28]
1.5.2 > 3 months to 6 months	2	288	Mean Difference (IV, Random, 95% CI)	22.84 [‐18.02, 63.69]
1.5.3 > 6 months to 1 year	1	36	Mean Difference (IV, Random, 95% CI)	60.00 [45.51, 74.49]
1.6 Participant‐reported global assessment of success	4	348	Risk Ratio (M‐H, Random, 95% CI)	1.29 [1.10, 1.53]
1.7 Radiographic joint progression (minimum JSW or median JSW in mm)	0	0	Mean Difference (IV, Random, 95% CI)	Not estimable
1.8 Withdrawals due to adverse events	5	153	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.9 Serious adverse events	7	461	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.20, 2.64]
1.10 Total adverse events	8	501	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.02, 2.07]
1.11 Treatment failure	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.12 Mean overall pain (0 to 10 points, 0 is no pain)	7	445	Mean Difference (IV, Random, 95% CI)	‐1.25 [‐2.53, 0.02]

1.12. Analysis.

Comparison 1: Stem cell injection versus placebo injection, Outcome 12: Mean overall pain (0 to 10 points, 0 is no pain)

Comparison 2. Stem cell injection versus no treatment or usual care (analgesia, weight loss and exercise).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Mean overall pain (0 to 10, 0 is no pain)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1.1 Up to 3 months	1	30	Mean Difference (IV, Random, 95% CI)	‐2.50 [‐3.71, ‐1.29]
2.1.2 > 3 months to 6 months	1	30	Mean Difference (IV, Random, 95% CI)	‐2.30 [‐3.63, ‐0.97]
2.1.3 > 6 months to 1 year	1	30	Mean Difference (IV, Random, 95% CI)	‐3.65 [‐5.60, ‐1.70]
2.2 Mean function (0 to 100, 0 is best function)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.2.1 Up to 3 months	1	30	Mean Difference (IV, Random, 95% CI)	‐14.15 [‐24.15, ‐4.15]
2.2.2 > 3 months to 6 months	1	30	Mean Difference (IV, Random, 95% CI)	‐12.70 [‐28.50, 3.10]
2.2.3 > 6 months to 1 year	1	30	Mean Difference (IV, Random, 95% CI)	‐25.85 [‐35.72, ‐15.98]
2.3 Participant‐reported global assessment of success	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.4 Withdrawals due to adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.5 Serious adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.6 Total adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.7 MRI joint progression (bone marrow lesions)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 3. Stem cell injection versus glucocorticoid injection.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Mean pain (0 to 10, 0 is no pain)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
3.1.1 12 months	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
3.2 Mean function (0 to 100, 0 is best function)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
3.2.1 12 months	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
3.3 Mean quality of life (0 to 100, 100 is best score)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
3.4 Participant‐reported global assessment of success	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.5 Withdrawals due to adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.6 Serious adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.7 Total adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.8 Treatment failure	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 4. Stem cell injection versus hyaluronic acid injection.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Mean overall pain (0 to 10, 0 is no pain)	7		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.1.1 Up to 3 months	4	159	Mean Difference (IV, Random, 95% CI)	‐1.68 [‐2.46, ‐0.91]
4.1.2 > 3 months to 6 months	6	241	Mean Difference (IV, Random, 95% CI)	‐1.37 [‐2.03, ‐0.71]
4.1.3 > 6 months to 1 year	7	367	Mean Difference (IV, Random, 95% CI)	‐1.46 [‐1.88, ‐1.05]
4.1.4 > 1 year to 2 years	1	126	Mean Difference (IV, Random, 95% CI)	‐1.46 [‐2.03, ‐0.89]
4.1.5 > 2 years to < 5 years	1	126	Mean Difference (IV, Random, 95% CI)	‐1.30 [‐1.83, ‐0.77]
4.1.6 5 years	1	126	Mean Difference (IV, Random, 95% CI)	‐1.09 [‐1.65, ‐0.53]
4.2 Mean function (0 to 100, 0 is best function)	7		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.2.1 Up to 3 months	3	103	Mean Difference (IV, Random, 95% CI)	‐7.35 [‐14.82, 0.12]
4.2.2 > 3 months to 6 months	5	185	Mean Difference (IV, Random, 95% CI)	‐8.20 [‐13.56, ‐2.83]
4.2.3 > 6 months to 1 year	7	356	Mean Difference (IV, Random, 95% CI)	‐8.16 [‐12.76, ‐3.56]
4.2.4 > 1 year to < 2 years	1	115	Mean Difference (IV, Random, 95% CI)	‐11.15 [‐19.25, ‐3.05]
4.3 Mean quality of life (0 to 100, 100 is best quality of life)	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.3.1 Up to 3 months	2	50	Mean Difference (IV, Random, 95% CI)	3.51 [‐4.76, 11.78]
4.3.2 > 3 months to 6 months	3	102	Mean Difference (IV, Random, 95% CI)	1.61 [‐16.61, 19.83]
4.3.3 > 6 months to 12 months	3	102	Mean Difference (IV, Random, 95% CI)	‐3.02 [‐15.56, 9.53]
4.4 Participant‐reported global assessment of success	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.4.1 12 months	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.5 Withdrawals due to adverse events	5	223	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.10, 6.59]
4.6 Serious adverse events	5	223	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.10, 6.59]
4.7 Total adverse events	5	223	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.76, 1.60]
4.8 Treatment failure	2	178	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.23, 2.73]
4.9 MRI measure of joint pathology (e.g. cartilage volume, bone marrow lesions, synovitis)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 5. Stem cell injection versus PRP injection.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Mean overall pain (0 to 10, 0 is no pain)	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1.1 Up to 3 months	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1.2 > 3 months to 6 months	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1.3 > 6 months to 1 year	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.2 Mean function (0 to 100, 0 is best function)	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.2.1 Up to 3 months	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.2.2 > 3 months to 6 months	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.2.3 > 6 months to 1 year	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.3 Participant‐reported global assessment of success	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.3.1 6 months	1	58	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.84, 1.67]
5.4 Withdrawals due to adverse events	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.5 Serious adverse events	2	161	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.29, 4.37]
5.6 Total adverse events	2	161	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.29, 4.37]
5.7 Treatment failure	2	161	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.23, 3.77]

Comparison 6. Stem cell injection versus oral acetaminophen (paracetamol).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Mean overall pain (0 to 10, 0 is no pain)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.1.1 Up to 3 months	1	51	Mean Difference (IV, Random, 95% CI)	‐2.62 [‐3.94, ‐1.30]
6.1.2 > 3 months to 6 months	1	51	Mean Difference (IV, Random, 95% CI)	‐3.72 [‐4.80, ‐2.64]
6.2 Mean function (0 to 100, 0 is best function)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
6.2.1 Up to 3 months	1	51	Mean Difference (IV, Fixed, 95% CI)	‐14.28 [‐23.56, ‐5.00]
6.2.2 > 3 months to 6 months	1	51	Mean Difference (IV, Fixed, 95% CI)	‐19.19 [‐26.12, ‐12.26]

Comparison 7. Stem cell injection versus NSAIDs plus physical therapy plus hyaluronic acid injection injection.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Mean overall pain (0 to 10, 0 is no pain)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
7.1.1 3 months	1	57	Mean Difference (IV, Fixed, 95% CI)	‐3.66 [‐5.73, ‐1.59]
7.1.2 12 months	1	57	Mean Difference (IV, Fixed, 95% CI)	‐4.12 [‐5.96, ‐2.28]
7.1.3 24 months	1	57	Mean Difference (IV, Fixed, 95% CI)	‐4.47 [‐6.07, ‐2.87]
7.2 Withdrawals due to adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.3 Serious adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.4 Total adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5 Treatment failure	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 8. Stem cell injection plus intra‐articular co‐intervention versus co‐intervention alone.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Mean overall pain (0 to 10, 0 is no pain)	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
8.1.1 Up to 3 months	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
8.1.2 > 3 months to 6 months	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
8.1.3 > 6 months to 1 year	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
8.2 Mean function (0 to 100, 0 is best function)	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
8.2.1 Up to 3 months	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
8.2.2 > 3 months to 6 months	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
8.2.3 > 6 months to 1 year	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
8.3 Radiographic joint progression	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
8.4 Serious adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8.5 Total adverse events	3		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8.6 MRI cartilage loss (Whole‐Organ Magnetic Resonance Imaging (WORMS score))	3		Mean Difference (IV, Random, 95% CI)	Totals not selected

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anz 2020.

Study characteristics
Methods	Study design: single‐centre, parallel, 2‐arm randomised controlled trial Setting: Andrews Research & Education Foundation, Gulf Breeze, Florida, USA Trial time period: not specified, but recruitment took place over a 4‐year period Interventions: autologous bone marrow aspirate concentrate (BMC) injection versus autologous platelet‐rich plasma (PRP) injection Sample size calculation: sample size of 25 and 50 patients in each group to detect 'large effects' (exact difference not specified) in WOMAC and IKDC respectively based upon power of 0.8 and alpha of 0.05. Analysis: completers analysis
Participants	Number of participants Number screened for eligibility: 110 Number excluded: 20 (19 not meeting inclusion criteria, 1 declined to participate) Number randomised: 90 (49 to the BMC group and 41 to the PRP group) Number included in analyses: 84 (45 in the BMC group and 39 in the PRP group) Inclusion criteria Male or female age 18 to 80 years Knee osteoarthritis Pain or swelling of target knee for at least 4 months Kellgren‐Lawrence score between 1 and 3 Willing and able to provide informed consent Willing and able to return for scheduled follow‐up visits Exclusion criteria Major mechanical axis deviation of more than 50% into either compartment (varus or valgus) Glucocorticoid injection within 3 months or hyaluronic acid injection within 6 months History of diabetes Autoimmune disorders Disorders requiring immunosuppression Rheumatoid arthritis Haemophilic arthropathy Infectious arthritis Charcot's knee Paget's disease of the femur or tibia Cancer Ongoing infectious disease Significant cardiovascular, renal or hepatic disease Baseline characteristics Stem cell injection group (45 participants): Mean (SD) age: 55.8 (11.3) years; 18 female, 27 male Mean (SD) BMI: 27.7 (5.0) Mean (SD) Kellgren‐Lawrence grade: 1.8 (0.7) Mean (SD) IKDC: 45.0 (14.2) Mean (SD) WOMAC total score: 35.3 (18.1) Mean (SD) WOMAC pain score: 7.0 (3.3) Mean (SD) WOMAC stiffness score: 3.8 (1.6) Mean (SD) WOMAC function score: 22.9 (13.2) Platelet‐rich plasma injection group (39 participants) Mean (SD) age: 52.2 (12.4) years No. male/female: 22/17 Mean(SD) BMI: 27.9 (5.8) Mean (SD) Kellgren‐Lawrence grade: 1.9 (0.7) Mean (SD) IKDC: 47.4 (16.6) Mean (SD) WOMAC total score: 32.1 (17.9) Mean (SD) WOMAC pain score: 6.2 (3.8) Mean (SD) WOMAC stiffness score: 3.4 (1.5) Mean (SD) WOMAC function score: 21.3 (12.5) Pretreatment group differences: none
Interventions	Stem cell preparation Bone marrow was harvested autologously under local anaesthesia (1% lidocaine) using ultrasound‐guided bone puncture at the posterior superior iliac spine with a traditional 11‐gauge, 11 cm Jamshidi needle (Ranfac) pre‐rinsed with heparin. Two 30 ‐mL syringes were pre‐loaded with 5 mL of sodium citrate anticoagulant and aspiration was performed until the 30 mL mark was reached on the first syringe, and then the needle was advanced a second time in a divergent trajectory and aspiration repeated with the second 30 mL syringe while withdrawing and rotating the needle. Bone marrow was processed at the point of care with a dual‐spin protocol/disposable (PureBMC; EmCyte) and centrifuged for 2.5 minutes at 3800 rpm, producing a 3‐layer hard stack: platelet plasma suspension, early buffy coat and red cell layer. The top plasma layer and 2 mL buffy coat were aspirated off and loaded into a concentrating accessory disposable. A second centrifuge was performed for 7 minutes at 3800 rpm, creating a platelet‐poor plasma (PPP) layer above a BMC buffy coat. The PPP was aspirated off, leaving approximately 7 mL of plasma and the BMC buffy coat, which was reconstituted into the plasma by swirling, and the final BMC, approximately 7 mL, was loaded into the injection syringe. Stem cell injection The stem cell group received a single intra‐articular injection (7 mL) of autologous bone marrow aspirate concentrate (BMC) with ultrasound guidance through a superolateral, parapatellar approach. Autologous platelet‐rich plasma (PRP) preparation Autologous blood for PRP production involved standard, antecubital venipuncture with a 60 mL syringe pre‐loaded with 10 mL of sodium citrate anticoagulant. Blood was processed at the point of care with a dual‐spin protocol/ disposable (PurePRP; EmCyte) to make leukocyte‐rich(LR‐PRP), which is monocyte/lymphocyte rich and neutrophil poor. The blood was loaded into a first cylinder disposable and centrifuged for 1.5 minutes at 3800 rpm to produce a platelet plasma suspension and a red blood cell layer. The top platelet plasma suspension was aspirated off until red blood cells filled the aspiration pipe and was then loaded into a second disposable and centrifuged for 5 minutes at 3800 rpm, creating a platelet‐poor plasma (PPP) top layer and platelet buffy coat at the bottom of the disposable. PPP was aspirated off, leaving approximately 7 mL of pure PRP. The plasma and platelet buffy coat were resuspended into the remaining plasma by swirling, and the final PRP, approximately 7 mL, was aspirated into the injection syringe. Platelet‐rich plasma injection The PRP group received a single intra‐articular injection (7 mL) of PRP with ultrasound guidance through a superolateral, parapatellar approach. Post‐intervention All participants were instructed not to take any NSAIDs for 7 days and to partial weightbearing for 2 to 3 days. All were instructed to perform a standard physical therapy programme from 1 week after the injection for 4 weeks.
Outcomes	Outcomes measured at baseline, and at 1, 3, 6, 9 and 12 months of follow‐up. Outcomes Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total, pain, stiffness and function change form baseline scores International Knee Documentation Committee (IKDC) questionnaire total score Withdrawals Adverse events ‐ total and serious Outcomes included in this review at 3, 6 and 12 months Pain measured on WOMAC pain (0 to 20, 0 no pain) change scores Function measured on WOMAC function sub‐scale scores (0 to 68, 0 is best function) change scores Withdrawals due to adverse events Serious adverse events Total adverse events
Notes	Funding: The Andrews Research & Education Foundation received funding and material support from EmCyte to support this study. Trial registration: NCT03289416 (ClinicalTrials.gov) Data analysis: We extracted the WOMAC pain score for mean pain and reported WOMAC function sub‐scale scores for mean function. We normalised the pain scores to 0 to 10 (divided by 20 and multiplied by 10) and function scores to 0 to 100 (divided by 68 and multiplied by 100). Withdrawals: 4/49 (8%) in the stem cell group (1 withdrew consent, 2 total knee replacement, 1 cancer) and 2/41 (5%) in the PRP group (1 knee surgery, 1 lost to follow‐up) Adverse events: Stem cell group: Serious adverse events: 3/49 participants: 2 total knee replacement, 1 cancer Non‐serious adverse events: 0/49 Platelet‐rich plasma group: Serious adverse events: 1/41 participants: 1 knee surgery Non‐serious adverse events: 0/41
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Performed using a computer‐generated random list.
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and investigators were aware of the treatment group assignment.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of their treatment group.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	No assessor‐reported outcomes were measured in this study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups: 4/49 in the BMC group (1 withdrawal, 2 total knee replacements, 1 cancer) and 2/41 in the PRP group (1 knee surgery, 1 lost to follow‐up).
Selective reporting (reporting bias)	Low risk	Trial was registered, and all pre‐specified outcomes were reported.
Other bias	Low risk	None apparent.

Baria 2022.

Study characteristics
Methods	Study design: single‐centre, 2‐arm, parallel, randomised controlled trial Setting: sports medicine clinic, The Ohio State University, Columbus, Ohio, USA Trial time period: between June 2020 and July 2021 Interventions: intra‐articular stem cell injection versus PRP injection Sample size calculation: An a priori power analysis was undertaken based on the minimal clinically important difference (MCID) for the KOOS–Pain of 9 points between baseline and final follow‐up. With an alpha error of.05 and an anticipated SD of 15 points for the KOOS–Pain subscore, a total of 88 patients (44 per treatment group) would be required to detect a 9‐point difference between treatment groups with 80% power. The initial study design was to enrol 110 patients (55 per group) to account for up to 20% loss to follow‐up. Owing to a change in regulatory requirements during the study, enrolment was halted after 71 patients. A repeated power calculation demonstrated that the study achieved 56% power to detect a between‐group difference in excess of the 9‐point MCID for the KOOS–Pain. Analysis: completers analysis
Participants	Number of participants Number screened for eligibility: 79 Number excluded: 8 not meeting eligibility criteria Number randomised: 71 (35 to the stem cell group and 36 to the PRP group) Number analysed: 58 (28 in the stem cell group and 30 to the PRP group) Inclusion criteria Age of 25 to 75 years Body mass index < 40 kg/m2 Symptomatic knee OA (primary and posttraumatic) Radiographic evidence of OA in the target knee (Kellgren‐Lawrence grades 1‐4) Continued pain in the target knee despite at least 6 weeks of one of the following nonoperative treatment options: activity modification, weight loss, physical therapy or NSAID/acetaminophen KOOS–Pain subscore of 20 to 65 Working knowledge of the English language Exclusion criteria Isolated patellofemoral OA 3+ effusion in the target knee (stroke test grading system) Valgus or varus deformities > 10 degrees Steroid injection in the target knee in the past 3 months Viscosupplementation in the target knee in the past 6 months PRP in the target knee in the past 1 year Other cellular/orthobiologic treatment in the index knee (bone marrow, amniotic suspension, etc) at any previous time Participation in any experimental device or drug study within 1 year before the screening visitOral or intramuscular steroids for the past 3 months Medical condition that may affect outcomes of the procedure, including anaemia, thrombocytopenia, bleeding disorders, systemic inflammatory disorders (rheumatoid arthritis, lupus, etc), diabetes, history of cancer (other than non‐melanoma skin malignancies), anticoagulant therapy (that could not be held 1 week before the procedure), and immunosuppression Previous cartilage repair procedure on the injured cartilage surface Previous surgery in the target knee within the past 1 year Any degree of cognitive impairment Symptomatic OA in either hip Symptomatic OA in the contralateral knee Pregnancy, lactation or intent to become pregnant during the treatment period History of gout History of infections or current infections in the affected joint Smoking Baseline characteristics Stem cell injection (35 participants) Mean (SD) age, years: 56.1 (1.7) No.% female: 20 (71.4) No. K‐L Grading: grade 1: 2; grade 2: 5; grade 3: 11; grade 4: 10 Mean (SD) KOOS Pain: 51.48 (9.78) Mean (SD) KOOS ADL: 62.11 (16.99) Mean (SD) VAS ADL: 48.97 (22.46) PRP injection (36 participants) Mean (SD) age, years: 51.9 (2.4) No.% female: 10 (33.3) No.% K‐L Grading: grade 1: 6; grade 2: 8; grade 3: 12; grade 4: 4 Mean (SD) KOOS Pain: 50.90 (11.64) Mean (SD) KOOS ADL: 58.63 (15.20) Mean (SD) VAS ADL: 50.10 (21.73)
Interventions	All patients were instructed to avoid non‐steroidal anti‐inflammatory drugs (NSAIDs) and aspirin 7 days before the procedure, avoid exercise the day before and the day of the procedure, and arrive for the procedure well hydrated. Stem cell preparation "MFAT (microfragmented adipose tissue) samples were processed for stromal vascular fraction (SVF) isolation to ensure accurate quantification of the total nucleated cell count. The samples were washed twice with phosphate‐buffered saline for the removal of residual blood via centrifugation at 250g for 3 minutes. The liquid phases were removed between washes. The MFAT samples were digested in collagenase A (1 mg/mL) solution under gentle agitation for 1 hour at 37C. The collagenase digest was neutralized by the addition of an equal volume of Dulbecco’s modified Eagle medium (DMEM) containing 10% fetal bovine serum and centrifuging at 800g for 5 minutes to separate the SVF pellet from the adipocytes. The SVF was washed twice with phosphate‐buffered saline and centrifuged at 800g for 5 minutes after each wash. The cell suspension was filtered through a 40‐mm cell strainer. The supernatant was discarded, and the cell pellet termed the SVF was resuspended in 5 mL of DMEM containing 10% fetal bovine serum." Stem cell injection "For the MFAT procedure, adipose tissue was aspirated from subcutaneous tissue of the abdomen or flank (depending on the ease of harvest determined by the patient’s body habitus). Under sterile precautions, the aspiration site was injected with 10 mL of 1% lidocaine. A small incision was made with a No. 11 scalpel blade, and 120 mL of Klein solution was injected into the adipose layer bilaterally. The solution was allowed to sit for 15 minutes to achieve proper anesthesia and vasoconstriction. Then, 30 mL of adipose tissue was aspirated (15 mL from each side) using a 13‐gauge cannula. The lipoaspirate was rinsed with sterile saline and resized via mechanical agitation using the Lipogems system. Once all adipose tissue had been processed according to manufacturer guidelines and in accordance with minimal manipulation, up to 8 mL was transferred into a syringe for the injection. The knee injection was carried out using the same approach described for the PRP group, except that a 21‐gauge needle was used because of higher viscosity. Any remaining MFAT that was not injected was sent for a total nucleated cell count." PRP injection "For the PRP procedure, 156 mL of whole blood was harvested by venipuncture from the antecubital fossa and mixed with 24 mL of Anticoagulant Citrate Dextrose Solution, Solution A (Citra Labs). This solution was concentrated using double‐spin centrifugation (Angel cPRP system using the 2% hematocrit setting; Arthrex). For both whole blood and the final PRP, 0.5 mL was analyzed immediately for complete blood counts using a hemoanalyzer (XN‐350; Sysmex). The aliquot of PRP that underwent cell counts was then frozen at –80C. At the conclusion of the study, all PRP samples underwent growth factor analysis by enzyme‐linked immunosorbent assay. After the aliquot of 0.5 mL was taken for analysis, the remaining PRP (up to a maximum volume of 8 mL) was injected using an ultrasound‐guided superolateral approach with a 25‐gauge, 1.5‐inch needle." Co‐intervention "For pain control, patients were permitted to ice and use acetaminophen and NSAIDs as needed. Patients were allowed to bear weight as tolerated. They were instructed to avoid high‐impact and sporting activity for 1 week and then were allowed to resume activities as tolerated."
Outcomes	Outcomes were assessed at 1, 3 and 6 months Primary outcome: KOOS–Pain subscore (0 to 100, 0 worst pain) Secondary outcomes: Knee injury and Osteoarthritis Outcome Score (KOOS, 0 to 100, 0 worst score) subscales (Pain, Symptoms, Activities of Daily Living, Sport and Recreation, and Quality of Life) Visual analogue scale for pain with Activities of Daily Living (VAS‐ADL; 100‐point scale) Tegner activity scale Adverse events The responder rate was also reported using the Patient Acceptable Symptom State (PASS) for each KOOS subscale (Pain, 73.6; Symptoms, 71.2; ADL, 84.5; Sport/Rec, 47.5; and QoL, 47.0) Outcomes used in this review Mean pain on VAS‐ADL (100‐point scale 0 no pain) Mean function using the KOOS ADL subscale (0 to 100, 0 worst function) Participant‐reported treatment success: proportion of PASS responders (cut‐off 84.5) on the KOOS ADL subscale Adverse events Withdrawals due to adverse events
Notes	Trial registration: NCT04351087 Funding: Research grant from the Lisa Dean Moseley Foundation. Data analysis: The direction of KOOS ADL scores (0 to 100, 0 worst function) for function was reversed so 0 is best function. Withdrawals: 7/35 in the stem cell group (4 voluntary withdrawal, 1 loss to follow‐up, 2 discontinued intervention and underwent either surgery or injection post‐intervention); 6/36 in the PRP group (3 voluntary withdrawal, 3 discontinued intervention and underwent either surgery or injection post‐intervention) Adverse events Stem cell injection Serious adverse events: 2/35. 2 participants discontinued intervention and underwent either surgery or injection post‐intervention Non‐serious adverse events: 0/35 PRP injection Serious adverse events: 3/36. 3 participants discontinued intervention and underwent either surgery or injection post‐intervention Non‐serious adverse events: 0/36
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random sequence.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and investigators were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	High risk	Outcome assessors were aware of treatment assignments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and balanced across groups: 7/35 in the stem cell group (4 voluntary withdrawal, 1 loss to follow‐up, 2 discontinued intervention); 6/36 in the PRP group (3 voluntary withdrawal, 3 discontinued intervention).
Selective reporting (reporting bias)	Low risk	Trial was registered and results for all outcomes were reported.
Other bias	Unclear risk	Due to institution regulations, the trial recruitment was prematurely stopped, potentially impacting the power.

Bastos 2020.

Study characteristics
Methods	Study design: single‐centre, parallel, 3‐arm randomised controlled trial Setting: Portugal Trial time period: not reported Interventions: stem cell injection versus stem cell injection plus PRP injection versus glucocorticoid injection Sample size calculation: not described Analysis: per protocol analysis
Participants	Number of participants Number screened for eligibility: 50 Number excluded: 3 (1 not meeting inclusion criteria, 2 declined to participate) Number randomised: 47 (16 to the stem cell group; 14 to the stem cell plus PRP group; 17 to the glucocorticoid group) Number included in analyses: 45 (16 in the stem cell group; 14 in the stem cell plus PRP group; 16 in the glucocorticoid group) Inclusion criteria Patients aged over 35 years with knee OA (based on the American College of Rheumatology criteria) and confirmatory radiographs (Kellgren‐Lawrence grade 1 to 4). Exclusion criteria History of untreated diabetes mellitus, glaucoma, immunodeficiency Chronic use of oral corticosteroid or immunosuppressive therapies History or presence of malignant disorders and use of chemotherapy Infection or active wound in the knee area History of severe trauma to the knee (post‐traumatic OA) Presence of systemic inflammation Body mass index (BMI) higher than 40 kg/m2 Pregnancy Any other comorbidity that prevented the bone marrow aspiration surgical procedure. Baseline characteristics: Stem cell injection group (16 participants) Mean (SD) age: 55.7 (7.8) years; 6 female, 10 male Mean (SD) BMI: 30.6 (4.5) No. (%) Kellgren‐Lawrence grade: Grade I: 1 (6.3); Grade II: 7(43.8); Grade III: 5 (31.3); Grade IV: 3 (18.8) Mean (SD) range of motion: hyperextension 2.2 (4.1); flexion 2.5 (5.8); total flexion 104.4 (39.4) Mean (SD) KOOS subscales (0 to 100, 100 best score): KOOS symptoms 41.5 (18.4); KOOS pain 34.5 (11.4); KOOS function 31.7 (19.1); KOOS sports/recreation 13.1 (21); KOOS QOL 16.8 (12.4); KOOS global score (0 to 100, 100 best score) 30.3 (13.1) Stem cell injection plus PRP injection group (14 participants) Mean (SD) age: 60.8 (9.9) years; 9 female, 5 male Mean (SD) BMI: 28.9 (4.9) No. (%) Kellgren‐Lawrence grade: Grade I: 1 (7.1); Grade II: 3 (21.4); Grade III: 6 (42.9); Grade IV: 4 (28.6) Mean (SD) range of motion: hyperextension 0.7 (2.7); flexion 3.2 (4.6); total flexion 115.2 (26.6) Mean (SD) KOOS subscales (0 to 100, 100 best score): KOOS symptoms 44.6 (14.9); KOOS pain 42.3 (17.2); KOOS function 41.2 (18.2); KOOS sports/recreation 18.9 (23.5); KOOS QOL 19.2 (20.3); KOOS global score (0 to 100, 100 best score) 37.3 (16.4) Glucocorticoid group (17 participants) Mean (SD) age: 55.9 (13.4) years; 8 female, 9 male Mean (SD) BMI: 31 (4.7) No. (%) Kellgren‐Lawrence grade: Grade I: 1 (5.8); Grade II 4 (23.5); Grade III 7 (41.1); Grade IV 5 (29.4) Mean (SD) range of motion: hyperextension 1 (2.1); flexion 3.9 (6.3); total flexion 118.3 (18.3) Mean (SD) KOOS subscales (0 to 100, 100 best score): KOOS symptoms 47.4 (17.9); KOOS pain 40.5 (19.6); KOOS function 40.7 (21); KOOS sports/recreation 18.2 (28.3); KOOS QOL 16.5 (16.5); KOOS global score (0 to 100, 100 best score) 36.9 (17.8) Pre‐treatment group differences: KOOS total and subscale scores were lower in the stem cell group compared to the stem cell plus PRP and glucocorticoid groups.
Interventions	Stem cell preparation "Bone marrow aspirate was obtained percutaneously from both posterior iliac crests with a Jamshidi needle (11G × 10 cm; Ecomed, Rio de Janeiro, Brazil) after spinal nerve block and sedation. Approximately 80 to 100 mL of bone marrow was aspirated through 10 mL EDTA‐coated syringes (ten syringes used on the left posterior iliac crest side and ten syringes used on the right side). Each syringe was filled with 4 to 5 mL of bone marrow aspiration and the Jamshidi needle was introduced to different iliac crest sites to prevent the aspiration of venous blood. The syringes were previously rinsed with anticoagulant Mononuclear cells from bone marrow samples were separated using the Sepax automated closed system (Biosafe, Eysins, Switzerland), according to manufacturer’s instructions. After isolation, cells were seeded at a density of 4 × 105 cells/cm2 in minimum essential medium eagle alpha modification (alpha MEM) (Cultilab, Campinas, SP, Brazil) supplemented with 10% foetal bovine serum (FBS) (Gibco) and incubated for 5 days in a humidified atmosphere of 5% CO2 at 37 °C. Non‐adherent cells were then discarded after cell culture medium exchange. Medium exchange was performed every 3 to 4 days. Once the cells reached 70 to 80% confluence, they were detached from culture flasks using 0.05% trypsin solution and re‐seeded onto new culture flasks characterising one passage. Cultures were maintained for no more than two passages. When reaching the desired number of 40 × 106, cells were suspended in 10 mL phosphate buffer solution supplemented with 2% human albumin in the stem cell group or in PRP in the stem cell plus PRP group." Stem cell injection Intra‐articular injection of stem cells was performed between 2 and 3 weeks after the bone marrow aspiration procedure. After adequate antisepsis, an intra‐articular injection with a 20G needle was performed in the superolateral region of the patella, with the patient in the supine position and the knee in extension. Stem cell injection plus PRP injection Intra‐articular injection of stem cells enriched with PRP was performed between 2 and 3 weeks after the bone marrow aspiration procedure. The injection procedure as described above. Only autologous PRP was used. Peripheral blood (54 mL) was collected by venipuncture from each donor using six blood collection tubes containing anticoagulant citrate dextrose (ACD) solution. Under sterile conditions, the blood collected in one ACD tube was divided into three polypropylene tubes containing no anticoagulant to enhance platelet recovery. After two centrifugation steps, platelets were re‐suspended in phosphate buffer solution at a concentration of 106/ μL, namely PRP, of which 10 mL was used to resuspend stem cells in the stem cell plus PRP group. Glucocorticoid injection 4 mg of dexamethasone was administered as an intra‐articular injection using the same process as above. Post‐intervention Immediately after injection, patients were instructed to initiate daily prophylactic exercises for preventing deep venous thrombosis in all study groups. All patients were instructed to remain non‐weight bearing with two Canadian‐type crutches for 2 weeks to favour cell adhesion to chondral lesions. Patients were recommended to continue their mild to moderate level of activities and to increase their activity level gradually as tolerated. All activities, including moderate sports, were allowed after 2 weeks. During the 12 months of follow‐up, other therapies such as anti‐inflammatory medications (steroid or non‐steroidal), physical therapy or acupuncture were not allowed. The use of dipyrone 1 g every 6 hours (analgesic non‐anti‐inflammatory) was allowed in case of severe pain.
Outcomes	Outcomes were measured at 1, 2, 3,6, 9 and 12 months Primary outcome KOOS total and sub‐scores (pain, symptoms, ADL, sports/recreation, QoL); scores range from 0 to 100 where higher scores indicate better knee function (Portuguese version) Secondary outcome Treatment success: KOOS subscales and global score, the expected improvement (IE=100−initial score), the improvement observed (IO=final score−initial score) and the percentage achieved of the improvement expected (CIE=IO/IE) from baseline to 12‐month follow‐up Knee range of motion using Goniômetro Pro for iPhone software Cytokine analysis performed by synovial fluid aspiration Withdrawals due to adverse events Adverse events Outcomes used in this review at 12 months Mean pain on KOOS pain subscale (0 to 100, 0 worst pain) Mean function on KOOS ADL subscale (0 to 100, 100 best function) Mean quality of life on KOOS QoL subscale (0 to 100, 100 best quality of life) Treatment success Withdrawals due to adverse events Serious adverse events
Notes	Trial registration: not reported Funding: This study was funded by ESHO Empresa de Serviços Hospitalares S.A. Data analysis: we compared the stem cell arm to the glucocorticoid arm. Although data were collected at 1, 2, 3, 6, 9 and 12 months, only 12‐month data were provided for the KOOS total and subscale scores. We emailed authors requesting the missing data, however no response was received. We reversed KOOS pain and function scores so that 0 is no pain and 0 is best function. Withdrawals: 1/16 (6%) in the stem cell group (total knee arthroplasty 6 months post‐intervention); 0/14 in the stem cell plus PRP group; 1/17 died in the glucocorticoid group 9 months post‐intervention; reason for death not given. Adverse events Stem cell injection group Serious adverse events: 1/16 total knee arthroplasty Non‐serious adverse events: 0/16 Stem cell injection plus PRP injection group Serious adverse events: 0/14 Non‐serious adverse events: 0/14 Glucocorticoid injection group Serious adverse events: 1/17 participants: 1 death at 9 months post‐intervention, reason for death not given. Non‐serious adverse events: 0/17
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised in a 1:1 ratio using central and permuted‐block randomisation. Size of the blocks not reported.
Allocation concealment (selection bias)	Low risk	Not explicitly reported, but as participants were randomised just before the procedure, we assume allocation of the random sequence was concealed.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The orthopaedic surgeon and participants were unaware of group assignment, as the therapeutic solutions were packed in a standard syringe and covered with a blank protector to ensure blinding.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	The authors state that "trial staff" were unaware of treatment group assignment; we assume this included the outcome assessor for range of motion and cytokine analysis.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups: 1/16 in the MSC group and 1/17 in the glucocorticoid group.
Selective reporting (reporting bias)	High risk	Trial was not registered, and no study protocol was found. Results for all outcomes were presented only at 12 months, but were also measured at 1, 2, 3, 6 and 9 months.
Other bias	Low risk	None apparent.

Chen 2021.

Study characteristics
Methods	Study design: single‐blind, parallel, 4‐arm randomised controlled trial Setting: Taiwan Trial time period: 2016‐2018 Interventions: intra‐articular injection of allogeneic adipose‐derived stem cells (ADSCs) ELIXCYTE 64 M versus stem cells ELIXCYTE® 32 M injection versus stem cells ELIXCYTE 16 M injection versus hyaluronic acid (HA) intra‐articular injection Sample size calculation: not described Analysis: intention‐to‐treat
Participants	Number of participants Number screened for eligibility: 64 Number excluded: 7 (screening failure = 7) Number randomised: 57 (15 in the stem cell ELIXCYTE® 64 M group; 17 in the stem cell ELIXCYTE® 32 M group; 17 in the stem cell ELIXCYTE® 16 M group and 8 in the hyaluronic acid group) Number included in analyses: 57 (15 in the stem cell ELIXCYTE® 64 M group; 17 in the stem cell ELIXCYTE® 32 M group; 17 in the stem cell ELIXCYTE® 32 M group and 8 in the hyaluronic acid group) Inclusion criteria Patients aged 40 to 80 years (inclusive) with Kellgren‐Lawrence (KL) grading I to III, as determined by American College of Rheumatology (ACR) criteria for knee osteoarthritis and WOMAC pain score 7 to 17. Exclusion criteria Those with surgery history on the target knee joint Previous intra‐articular intervention on the target knee joint within past 3 months Hypersensitivity to any component used in the study Inadequate haematologic and hepatic function Human immunodeficiency virus (HIV) infection Body mass index (BMI) greater than 35 kg/m2 Those already participating in any other interventional study before 4 weeks of entering the study. Baseline characteristics Stem cell ELIXCYTE® 64 M group (15 participants) Mean (SD) age: 64.9 (4.91) years; 12 female, 3 male Mean (SD) BMI: 25.66 (3.782) No. (%) Kellgren‐Lawrence Grade: Grade II: 12 (80.0%); Grade III: 3 (20.0%) Mean (SD) disease duration (years): 2.4 (1.6) Mean (SD) VAS (0 to 100, 0 no pain): 55.27 (24.29) Mean (SD) WOMAC function subscale (0 to 68, 0 best function): 23.87 (14.06) Stem cell ELIXCYTE® 32 M group (17 participants) Mean (SD) age: 68.6 (6.45) years; 15 female, 2 male Mean (SD) BMI: 26.72 (4.192) No. (%) Kellgren‐Lawrence Grade: Grade II: 10 (58.8%); Grade III: 7 (41.2%) Mean (SD) disease duration (years): 3.7 (7.2) Mean (SD) VAS (0 to 100, 0 no pain): 58.88 (22.04) Mean (SD) WOMAC function subscale (0 to 68, 0 best function): 32.65 (13.68) Stem cell ELIXCYTE® 16 M group (17 participants) Mean (SD) age: 67.7 (6.84); 14 female, 3 male Mean (SD) BMI: 27.65 (3.026) No. (%)Kellgren‐Lawrence Grade: Grade II: 10 (58.8%) Grade III: 7 (41.2%) Mean (SD) disease duration (years): 3.0 (1.7) Mean (SD) VAS (0 to 100, 0 no pain): 52 (19.44) Mean (SD) WOMAC function subscale (0 to 68, 0 best function): 30.24 (14.4) Hyaluronic acid group (8 participants) Mean (SD) age: 70.5 (8.37); 5 female, 3 male Mean (SD) BMI: 25.47 (3.494) Kellgren‐Lawrence Grade: Grade II: 5 (62.5%) Grade III: 3 (37.5%) Mean (SD) disease duration (years): 2.4 (2.4) Mean (SD) VAS (0 to 100, 0 no pain): 53.25 (18.80) Mean (SD) WOMAC function subscale (0 to 68, 0 best function): 29.5 (12.5) Pre‐treatment group differences: no differences found between groups
Interventions	Stem cell preparation "The adipose tissue was collected from eligible donor via ultrasonic‐assisted liposuction and was transferred to UnicoCell BioMed Company under hypothermal condition within 6 h. The stromal vascular fraction (SVF) was isolated by digesting the adipose tissue with type I collagenase, centrifuged, and cultured at 37 °C in a humidified carbon dioxide incubator for primary culture. The adherent and highly proliferated cells termed ADSCs were detached and propagated to the passage 7 and within predefined population doubling level. The ADSCs were then harvested and formulated at a density of 8 × 106 cells/mL with cryoprotectant CryoStor® CS10 (BioLife Solutions). Release testing of ELIXCYTE® for microbiological evaluation (including mycoplasma, sterility, and endotoxin tests) was employed to ensure safety. The product characteristics such as identity (including MSC markers, viable cell count, and cell viability), and tri‐lineage differentiation properties were also assessed." Stem cell injection ELIXCYTE® 64 M group: single intra‐articular injection of ELIXCYTE® 64 × 106 cells into the affected knee joint. Each eligible patient would have exactly one “target knee” for efficacy evaluation for this study. The target knee would be the knee meeting entry criteria and be administered on day 1 with the treatment upon the patient was randomly assigned. ELIXCYTE® 32 M group: single intra‐articular injection of ELIXCYTE® 32 × 106 cells into the affected knee joint ELIXCYTE® 16 M group: single intra‐articular injection of ELIXCYTE® 16 × 106 cells into the affected knee joint Hyaluronic acid injection Intra‐articular injection of hyaluronic acid (Hya Joint Plus synovial fluid supplement 3 mL, SciVision Biotech Inc) into the affected knee joint Post‐intervention None reported
Outcomes	Outcomes were measured at weeks 2, 4, 12, 24 (main study), 36, 48 (extension study), 72 and 96 (structural study). Primary outcome Pain: change in WOMAC pain score (0 to 20, 0 no pain) from baseline to week 24 after treatment Secondary outcomes Change from baseline to post‐treatment visit in WOMAC stiffness, physical function and total score Change from baseline VAS (0 to 100, 0 no pain) for pain Knee Society Clinical Rating System (KSCRS) score Incidence of adverse events and serious adverse events Outcomes included in the review at 3, 6 and 12 months: Pain on VAS (0 to 100, pain) change scores Function on WOMAC function subscale (0 to 68, 0 best function) change scores Withdrawals due to adverse events Adverse events
Notes	Trial registration: ClinicalTrials.gov Identifier: NCT02784964. Retrospectively registered Funding: This study was funded by UnicoCell BioMed Co. Ltd. and the A+Industrial Innovative R&D Program, Ministry of Economic Affairs, R.O.C (Grant No.105‐EC‐17‐A‐22‐I5‐0007). Data analysis: We extracted outcome data from supplement file, table S6 for pain and table S5 for function. We combined the 3 treatment arms and compared them to the HA group. We normalised VAS for pain to 0 to 10 scale (divided by 10). We normalised the function scores to 0 to 100 (divided by 68 and multiplied by 100). Withdrawals: 1/15 (6.6%) in the ELIXCYTE® 64 M group (severe pain treated with analgesics); 1/17 (5.8%) in the ELIXCYTE® 32 M group (severe pain treated with analgesics); 2/17 (11.7%) in the ELIXCYTE® 16 M group (severe pain treated with analgesics); 0/8 in the HA group Adverse events Stem cell ELIXCYTE® 64 M group: Serious adverse events: 2/15 participants; the nature of events was not specified. Non‐serious adverse events: 8/15 participants: 4 injection site joint pain, 2 swelling, 1 effusion, 1 joint stiffness Stem cell ELIXCYTE® 32 M group: Serious adverse events: 2/17 participants, the nature of events was not specified. Non‐serious adverse events: 10/17 participants: 5 injection site joint pain, 3 swelling, 1 erythema, 1 joint stiffness Stem cell ELIXCYTE® 16 M group: Serious adverse events: 0/17 Non‐serious adverse events: 6/17 participants: 3 injection site joint pain, 2 swelling, 1 inflammation Hyaluronic acid group: Serious adverse events: 0/17 Non‐serious adverse events: 1/8 participants: injection site joint pain
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Statistician from contract research organization (CRO) generated the random allocation sequence"
Allocation concealment (selection bias)	Unclear risk	The method of allocation concealment was not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Participants were unaware of treatment assignment, however study personnel were aware of treatment assignment.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	High risk	Outcome assessors were aware of treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups: 1/15 in the ELIXCYTE® 64 M group (withdrew due to severe pain treated with analgesics); 1/17 in the ELIXCYTE® 32 M group (withdrew due to severe pain treated with analgesics); 2/17 in the ELIXCYTE® 16 M group (withdrew due to severe pain treated with analgesics); 0/8 in the HA group.
Selective reporting (reporting bias)	Low risk	All outcomes planned in the trial registration were reported.
Other bias	Low risk	None apparent.

Emadedin 2018.

Study characteristics
Methods	Study design: single‐centre, 2‐arm, triple‐blind (participant, investigator and outcome assessor), parallel, randomised placebo‐controlled trial Setting: Orthopedic Clinic at Royan Cell Therapy Center, Iran Trial time period: between Jan 2012 and Feb 2016 Interventions: intra‐articular stem cell injection versus placebo (5 mL normal saline) injection Sample size calculation: sample size of 52 (26 per group) with 80% power, α risk of 0.05 but to detect what difference in ability to alleviate pain (primary outcome) was not specified. Analysis: not intention‐to‐treat
Participants	Number of participants Number screened for eligibility: 250 Number excluded: 203 (149 not meeting inclusion criteria, 44 declined to participate) Number randomised: 47 (22 to the stem cell group and 25 to the placebo group) Number analysed: 43 (19 in the stem cell group and 24 to the placebo group) Inclusion criteria Age 18 to 65 years Kellgren‐Lawrence grades 2, 3 and 4 OA diagnosed using X‐ray No severe joint involvement for grade 4 OA Angle of parenthesis feet not > 20° WOMAC pain score > 25 Exclusion criteria Malignancy Organ failure Uncontrolled chronic disease other than OA Allergic reaction to anaesthesia Positive viral markers (human immunodeficiency virus, hepatitis B virus, hepatitis C virus and human T‐cell leukaemia virus type 1) Allergic reaction to components of study treatment and study implantation procedure Pregnancy or lactation Baseline characteristics Stem cell group (19 participants) Mean (SD) age: 51.7 (9.2) years; 7 female, 12 male Mean (SD) duration of disease in months: 12.5 (8.5) Mean (SD) BMI: 30.2 (4.4) No. (%) Kellgren‐Lawrence grading: Grade 2: 2 (10.5); Grade 3: 13 (68.4); Grade 4: 4 (21.1) Placebo group (24 participants) Mean (SD) age: 54.7 (5.3) years; 9 female, 15 male Mean (SD) duration of disease in months: 13.5 (7.4) Mean (SD) BMI: 31.5 (5.4) No. (%) Kellgren‐Lawrence grading: Grade 2: 1 (4.2); Grade 3: 20 (83.3); Grade 4: 3 (12.5) Pre‐treatment group differences: no differences found between groups at baseline
Interventions	Stem cell preparation "All patients underwent bone marrow aspiration from their iliac crests. MSCs were isolated and cultured, and prepared using 10ml identical covered syringes with 22‐gauge needles that contained either MSCs or normal saline. MSCs obtained from patients were relatively homogenous and had a fibroblast‐like appearance 7 to 10 days after culturing; this morphology did not change until use. MSCs were characterized according to the International Society for Cellular Therapy (ISCT) criteria. Patients in the MSC group underwent the implantation of MSCs as soon as the cells were prepared. For the placebo group, MSCs were frozen and the same amount of saline was injected instead." Both MSCs and placebo were supplemented with 2% human serum albumin. Stem cell injection The stem cell group received one intra‐articular implantation of autologous bone marrow derived mesenchymal stromal cells (40 x 106 cells) in 5 mL saline supplemented with 2% human serum albumin. The implantation was blinded and performed according to each patient’s anatomy, which was shown in the knee radiography. Placebo injection The placebo group received a single intra‐articular implantation of placebo (5 mL normal saline) in the knee joint. Post‐intervention None reported
Outcomes	Outcomes were measured at 1 week, 3 months and 6 months. Study outcomes Pain measured on VAS (0 to 100, 0 no pain), change from baseline scores Function measured on WOMAC total score and pain, stiffness and function subscales, change from baseline scores, higher scores on the WOMAC indicate worse pain, stiffness and functional limitations Minimum Clinically Important Improvement (MCII) and Patient Acceptable Symptom State (PASS) were evaluated VAS, the WOMAC pain subscale and the WOMAC physical function subscale (MCII and PASS thresholds were not defined) Walking distance, painless walking distance, standing time with weightbearing, time to induction of stiffness (time to gelling) and degree of knee flexion Adverse events Outcomes included in this review at 3 months and 6 months Pain measured on VAS (0 to 100, 0 no pain) change from baseline scores Function measured on WOMAC function subscale (0 to 68, 0 best function) change from baseline scores Participant‐reported global assessment of success: measured by the proportion of participants reporting an MCII in pain (threshold and scale undefined). Adverse events
Notes	Funding: grant from the Royan Institute Trial registration: ClinicalTrials.gov (National Institutes of Health number: NCT01504464) Data analysis: Authors reported change scores from baseline to follow‐up for all outcomes. We calculated SDs from 95% confidence intervals. We normalised WOMAC function subscale to 0 to 100 (divided by 68 and multiplied by 100). Baseline data for pain and function were not provided in the paper. For serious adverse events, we assumed each event occurred in one person, and for total adverse events, we assumed the most frequently reported event as the number of people with an event. Withdrawals: 3/22 (14%) in the MSC group (lost to follow‐up); 1/25 (4%) in the placebo group (lost to follow‐up) Adverse events CTCAE classification of AE Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or non‐invasive intervention indicated; limiting age appropriate instrumental ADL*. Grade 3 Severe or medically significant but not immediately life‐threatening; hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self‐care ADL**. Grade 4 Life‐threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. We classified Grade 3 and 4 as SAEs. Stem cell group Serious adverse events: 2 events: 1 infection (Grade 3), 1 musculoskeletal‐related (Grade 3) Non‐serious adverse events: 20 events: 3 related to injection site and general disorders; 17 musculoskeletal‐related Placebo group Serious adverse events: 2 events: musculoskeletal‐related (Grade 3) Non‐serious adverse events: 6 events: 5 musculoskeletal‐related; 1 skin/subcutaneous tissue disorder‐related
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Blocked randomisation (block size 4) was used, but the method of sequence generation was not explicitly reported.
Allocation concealment (selection bias)	Unclear risk	The trial authors implied that a laboratory staff member was responsible for allocating participants to treatment groups, but it is not explicitly reported how they generated and concealed the random sequence.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The participants and investigators were unaware of treatment assignments as a laboratory staff member provided the treating orthopaedic surgeon with similar vials that contained either MSCs or placebo and labelled with the participant name and registration code.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	As participants were blinded to treatment allocation, there is low risk of bias in the measurement of self‐reported outcomes.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	The outcome assessor (knee flexion, walking distance) was blinded to group assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups: 3/22 (13%) in the MSC group and 1/25 (4%) in the placebo group.
Selective reporting (reporting bias)	High risk	Trial was registered. Joint swelling and erythema post‐injection were listed as secondary outcomes in the trial registration but results were not reported. Other outcomes, including participant‐reported global assessment of success measures such as MCII and PASS, appear to have been added after the registration.
Other bias	Low risk	None apparent.

Freitag 2019.

Study characteristics
Methods	Study design: single‐centre, parallel, 3‐arm randomised controlled trial Setting: Australia Trial time period: not specified Interventions: Single intra‐articular autologous adipose‐derived mesenchymal stem cell (100 × 106 ADMSCs) injection versus two intra‐articular autologous adipose‐derived mesenchymal stem cell (100 × 106 ADMSCs at baseline and 6 months) injections versus no treatment (usual care ‐ analgesia, weight management and exercise). A third treatment arm to receive five injections of 40 × 106 ADMSCs at baseline, 1, 2, 3 and 6 months, respectively, was abandoned. Sample size calculation: not performed due to insufficient published data on the effects of autologous MSC therapy in OA. This trial was stated to be a pilot RCT to assess treatment protocols for safety and efficacy prior to development of a larger RCT. Analysis: completers analysis
Participants	Number of participants Number screened for eligibility: not reported Number excluded: not reported Number randomised: 30 (10 to the single stem cell injection group, 10 to the 2 stem cell injections group and 10 to no treatment) Number included in analyses: 27 (9 in the single stem cell injection group, 9 in the 2 stem cell injections group and 9 in the no treatment group) Inclusion criteria Radiological diagnosis of osteoarthritis using the American College of Rheumatology criteria Radiological grading of Grade II–III osteoarthritis (OA) of the knee as determined by a qualified radiologist using the Kellgren and Lawrence system Medial or lateral compartment OA as determined above Conservative OA treatment already undertaken defined as: analgesia/anti‐inflammatory medication, supplements approved by the treating clinician (e.g. glucosamine sulphate), an attempted exercise programme prescribed by a physiotherapist or medical practitioner for at least 8 weeks, weight loss and nutritional management as prescribed by a dietitian or medical practitioner for at least 8 weeks, and biomechanical management including bracing if appropriate as prescribed by a physiotherapist, podiatrist or medical practitioner. Autologous MSC is an invasive treatment and guidelines recommend trialing conservative measures as the first line of treatment in knee OA A minimum pain score of 5 on an 11‐point numerical rating scale Single knee osteoarthritis Less than 5 degrees varus or valgus knee deformity as measured by the long mechanical axis of the knee on x‐ray Sufficient English skills to complete the questionnaires required for the study, as well as to understand the instructions given by the study doctors Exclusion criteria Pregnancy (accepted contra‐indication as no safety data on this population) Breastfeeding (accepted contra‐indication as no safety data on this population) Have other causes of their knee symptoms suspected to be due to serious pathology such as tumours or referral from the hip or lumbar spine. These conditions are not under investigation within the current project Bleeding disorder – i.e. haemophilia (accepted contra‐indication as no safety data on this population) MRI confirmed displaced meniscal tear MRI confirmed Grade IV chondral loss Previous meniscectomy/significant partial meniscectomy or other knee related surgery within the last 12 months Previous intra‐articular injectable therapies within the last 6 months History of cancer History of atypical chronic pain syndrome – i.e. chronic regional pain History of systemic illness or significant organ impairment/failure (i.e. renal failure) History of allergy to any substances used within the treatments Plans at the time of enrolment to undergo surgery in the following 12 months. This criterion is aimed at avoiding co‐interventions that may confound the results of the study. While involvement in the project will not strictly prevent participants from undertaking such interventions if required, we will exclude volunteers who already have such procedures scheduled. Baseline characteristics Single stem cell injection group (10 participants) Mean (SD) age: 54.6 (6.3) years; 3 female; 7 male Mean (SD) BMI: 31.6 (5.9) Mean (SD) pain on NRS (0 to 10, 0 no pain): 6.7 (1.7) Mean (SD) KOOS Pain scores: 53 (14.5) Mean (SD) KOOS Symptom scores: 63.6 (21.3) Mean (SD) KOOS ADL scores (0 to 100,100 is best function): 58.8 (19.8) Mean (SD) KOOS Sport scores: 39 (26.2) Mean (SD) KOOS QOL scores: 29.4 (20.5) Mean (SD) WOMAC global (0 to 100, 0 is best score): 59.6 (17.9) No. (%) bone marrow lesion: 8 (80) No. (%) articular cartilage pathology: 10 (100) No. (%) osteophytes: 9 (90) No. (%) meniscus pathology: 10 (100) Two stem cell injections group (10 participants): Mean (SD) age: 54.7 (10.2) years; 6 female, 4 male Mean (SD) BMI: 30.4 (5.6) Mean (SD) pain on NRS (0 to 10, 0 no pain): 6.5 (1.4) Mean (SD) KOOS Pain: 52.1 (15.1) Mean (SD) KOOS Symptom: 56.5 (19.7) Mean (SD) KOOS ADL (0 to 100,100 is best function): 53.8 (18.3) Mean (SD) KOOS Sport: 18 (12.7) Mean (SD) KOOS QOL : 19.4 (13.1) Mean (SD) WOMAC global (0 to 100, 0 is best score): 54.4 (18.2) No. (%) bone marrow lesion: 8 (89) No. (%) articular cartilage pathology: 9 (100) No. (%) osteophytes: 8 (89) No. (%) meniscus pathology: 9 (90) No treatment group(10 participants) Mean (SD) age: 51.5 (6.1) years; 5 female, 5 male Mean (SD) BMI: 25.2 (3.4) Mean (SD) pain on NRS (0 to 10, 0 no pain): 6.5 (1.4) Mean (SD) KOOS Pain scores: 52.8 (10.8) Mean (SD) KOOS Symptom scores: 46.1 (11) Mean (SD) KOOS ADL scores (0 to 100,100 is best function): 59.4 (13.6) Mean (SD) KOOS Sport scores: 26 (20.4) Mean (SD) KOOS QOL scores: 30.1 (15.9) Mean (SD) WOMAC global (0 to 100, 0 is best score): 58.8 (12.8) No. (%) bone marrow lesion: 8 (89) No. (%) articular cartilage pathology: 9 (100) No. (%) osteophytes: 9 (100) No. (%) meniscus pathology: 9 (100) Pretreatment group differences: none
Interventions	Stem cell preparation "Adipose tissue was chosen as the source of autologous MSCs due to the relative ease of harvest, abundance of MSCs and shared chondrogenic potential in comparison to other source sites such as bone marrow. Participants randomly allocated to a treatment group underwent an abdominal lipoharvest procedure. Using a lateral abdominal approach, the subcutaneous fat was infiltrated with up to 300 ml of tumescent fluid (comprising of 30 ml of 2% lidocaine, 1 ml of 1:1000 adrenaline and 1 ml of 8.4% bicarbonate suspended in a normal saline solution to a total 1000 ml). Following this, up to 60 ml of adipose tissue and tumescent fluid was aspirated through a 4mm lipo‐aspirate cannula and collected within a sterile medical grade single use Shippert Tissu‐Trans Collection filter (Shippert Medical, CO, USA)." "The lipoaspirate was transferred directly to an onsite clean room laboratory facility for later isolation and expansion of autologous ADMSCs (Magellan Stem Cells, Melbourne, Australia). All tissue processing was performed within a Biological Safety Cabinet (BSC) Class II and within a clean room with ISO 5 equivalent or above air quality. In summary, lipoaspirate was separated into stromal vascular fraction using enzymatic digestion and centrifugation and later cell culturing performed under hypoxic conditions within standard growth media containing 10% fetal bovine serum (FBS). Cells were cultured until 80% confluency was reached and further cultured until passage 2 (P2). At completion of P2, cells were washed three times to remove FBS and cryopreserved using a validated control rate freezing method. Characterization of isolated ADMSCs was confirmed using international established standards as published by the International Society of Cellular Therapy. Flow Cytometry Fluorescent Activated Cell Sorting (FACS) analysis was completed independently on all isolated ADMSC samples at Monash University. Samples were tested for the presence ofMSC surface markers CD90, CD73 and CD 105 and absence of hematopoietic surface markers CD14, CD19, CD34 and CD45. All isolated ADMSC samples underwent additional independent sterility testing for microbial growth/contamination. On the day of injection stored cells were thawed using a sterile water bath with cyroprotectant removed under centrifugation and washed in chilled phosphate buffered saline (PBS). The resultant cell pellet was resuspended in injectable sterile isotonic (0.9%) normal saline to a total of 3 ml. Cell count and viability was confirmed using a Muse Cell Analyzer (Merck Millipore, USA)." Stem cell injection Single stem cell injection "At the time of injection, the knee of the participants allocated to an active treatment group was prepped using standard sterile protocols. All injections were performed under direct visualisation using ultrasound guidance to ensure accuracy. Local anaesthetic (2 ml of 1% lidocaine) was infiltrated superficial to the knee joint capsule. Under aseptic conditions, and using a superolateral patella approach, the re‐suspended autologous stem cells were injected into the intra‐articular knee space." Two stem cell injections The procedure described above was done in the exact manner in this group as well and repeated at 6 months post‐baseline. No treatment The control group was not prescribed a trial‐specific conservative programme but were advised to continue their pre‐existing conventional conservative programme consisting of simple analgesia, weight management and exercise. Post‐intervention "Participants in the stem cell injection groups were provided with post‐injection analgesia as required. They were advised to remain non‐weight bearing with the use of crutches for 4 weeks, but were not required to be non‐weight bearing after the second injection at 6 months. Education regarding range of motion and quadriceps activation exercises was provided." The control group did not receive any of these.
Outcomes	Outcomes were measured at baseline 1, 3, 6 and 12 months Primary outcomes Mean pain: Numeric Pain Rating Scale (0 to 10, where 0 is no pain) Mean function: Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales (0, worst score). Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) global scores (0 to 100, 0 is best score) Secondary outcomes MRI analysis: bone marrow lesions (BMLs) and cysts graded for the percentage of volume of each BML and whether there is an associated cyst; articular cartilage graded on the percentage area of cartilage with partial to full thickness loss and also separately on area with full thickness loss; size of osteophytes in 14 sub‐regions graded as Grade 0 (none), Grade 1 (small), Grade 2 (medium) and Grade 3 (large); volume of effusion‐synovitis graded as Grade 0 (none), Grade 1 (small), Grade 2 (medium) and Grade 3 (large); medial and lateral menisci are assessed for signal and morphology of the tear including vertical, radial, horizontal, complex, root tear, partial or complete maceration; popliteal cyst scored as present or not present. MRI Osteoarthritis Knee Score (MOAK): MOAK scores were used to describe OA progression over time. Subregional scores were collated into the broader regions of medial, lateral and patella‐femoral compartments. Percentage of participants achieving a minimal clinically important difference, when combining all pain and functional outcome measures. All data are in percentages and expressed as the percentage of subjects who registered a MCID at 12 months when compared with their baseline value. Note that an MCID equates to a decrease of 1 point or more on a 10 point Numeric Pain Rating Scale and an increase of 8 points or more on a 100 point Knee Injury and Osteoarthritis Outcome Score or Western Ontario and McMaster Universities Arthritis Index score (outcome added post‐hoc). Outcomes used in this review at 3, 6 and 12 months Mean pain measured with Numeric Pain Rating Scale (0 to 10, 0 no pain) Mean function measured with KOOS ADL sub scale scores (0 to 100, 100 is best function, we reversed this scale) Participant‐reported global assessment of success measured as percentage of participants achieving a minimal clinically important difference, when combining all pain and functional outcome measures Adverse events
Notes	Funding: this study was funded jointly by both Magellan Stem Cells and Melbourne Stem Cell Centre. Members of their Medical and Scientific Advisory board are co‐authors of this paper. The authors received no payment for their involvement in the study. Interpretation of results, and subsequent submission and publication decisions were made independent of the sponsors. Trial registration: Australian and New Zealand Clinical Trial Registry (Trial ID: ACTRN12614000814673) Protocol variation: A third treatment group to receive five injections of 40 × 106 ADMSCs at baseline, 1, 2, 3 and 6 months, respectively, was intended. This arm was ceased due to moderate adverse events in a concurrently run study with the same treatment protocol (documented as increasing self‐limiting pain with sequential injections at monthly intervals). Participants that were already randomly allocated to this treatment group and yet to commence the trial were re‐randomised to another trial. Data analysis: As indicated in the methods, we reported outcome data for the intervention group by combining the single and double injection groups. Mean pain and function were extracted from supplement table 3, but the SDs in the table did not correspond to the 95% confidence intervals from the figure in the main paper, thus we calculated the SDs from the 95% CIs in the main paper. We used KOOS ADL subscale scores for function and reversed the direction so 0 is best function. Withdrawals: 1/10 (10%) in the single stem cell injection group (excluded from analysis due to incomplete questionnaire data); 1/10 (10%) in the two injection group (excluded from radiological analysis due to late follow‐up); 1/10 (10%); 1/10 (10%) in the no treatment group (excluded from radiological analysis due to late follow‐up). Adverse events: AE grading: Mild: awareness of a sign or symptom which does not interfere with the participants’ usual daily activity and is transient, resolving with use of simple interventions including simple analgesia. Moderate: interferes with the participants’ usual daily activity and/or requires symptomatic treatment including regular analgesia (i.e., opiate analgesia). Severe: symptom(s) causing severe discomfort with significant impact of the participants’ usual daily activity. Serious: any unexpected medical incident which requires hospitalisation, results in long term disability, is life‐threatening or results in death. Single stem cell injection group: Serious adverse events: 0/10 Non‐serious adverse events: 8/10 participants: 6 mild swelling and pain post‐injection, 1 moderate swelling and pain post‐injection, 1 severe pain and swelling for 4 weeks affecting daily activities Two stem cell injections group: Serious adverse events: 0/10 Non‐serious adverse events: After first injection: 9/10 participants: 5 mild post‐injection swelling and pain, 3 moderate post‐injection swelling and pain, 1 severe pain and swelling for 4 weeks affecting daily activities. After second injection: 10/10 participants: 4 mild post‐injection swelling and pain, 6 moderate post‐injection swelling and pain No treatment group: Serious adverse events: 0/10 Total adverse events: 0/10
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random sequence was generated by a web‐based automated random number generator (www.randomizer.org).
Allocation concealment (selection bias)	Low risk	Performed by an independent researcher not otherwise involved in the study.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Researchers and treating clinicians were unaware of treatment allocation, but participants were not blinded to their treatment allocation.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of treatment assignment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	MRI assessment was conducted by a physician who was unaware of treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups: 1/10 excluded from final analysis from all 3 groups due to either incomplete questionnaire data or late MRI follow‐up.
Selective reporting (reporting bias)	High risk	Trial was registered. Some pre‐specified outcomes were not reported, including global perceived effect scale, the Orebro Musculoskeletal Pain Questionnaire and the Pain Treatment Satisfaction Scale, and one outcome (WOMAC) was added.
Other bias	High risk	Protocol variation: A third treatment group to receive 5 injections of 40 × 106 ADMSCs at baseline, 1, 2, 3 and 6 months, respectively, was intended, but ceased due to moderate adverse events (increasing self‐limiting pain with sequential injections) in a concurrently run study with the same treatment protocol.

Garay‐Mendoza 2018.

Study characteristics
Methods	Study design: single‐centre, 2‐arm, open‐label, parallel, randomised controlled trial Setting: Hospital Universitario Dr. Jose E. Gonzalez, Mexico Trial time period: August 2011 to May 2014 Interventions: intra‐articular stem cell injection versus oral acetaminophen Sample size calculation: not reported Analysis: completers' analysis
Participants	Number of participants Number screened for eligibility: not reported Number excluded: not reported Number randomised: 61 (30 to the stem cell group and 31 to the acetaminophen group) Number analysed: 51 (26 in the stem cell group and 25 in the acetaminophen group) Inclusion criteria Individuals of both genders aged over 30 years and with a confirmed diagnosis of knee OA made by clinical and radiological evaluation, with unilateral affection, and at least 6 months of progression. They were classified as OA grades II and III according to the Kellgren and Lawrence radiological classification system. Exclusion criteria Systemic arthritis Knee infection or surgery in the last 6 months Intra‐articular injection in the past 3 months Neurodegenerative, autoimmune, malignant or traumatic lesions (joint fracture, meniscal or ligament injury) Baseline characteristics Stem cell group (30 participants) Mean (SD) age, years: 55.67 (12.02) No. (%) female: 23 (77%) Mean (SD) VAS (0 to 10, 0 no pain) pain: 5.27 (2.2) Mean (SD) WOMAC total score (0 to 100, 100 best score): 62.61 (18.5) Acetaminophen group (31 participants) Mean (SD) age, years: 59.32 (10.85) No. (%) female: 22 (71%) Mean (SD) VAS (0 to 10, 0 no pain) pain: 4.32 (2.35) Mean (SD) WOMAC total score (0 to 100, 100 best score): 69.93 (17.9)
Interventions	Stem cell preparation "Autologous stem cell stimulation was started with the subcutaneous administration of 600 lg per day of granulocyte colony stimulating factor (G‐CSF) (Biofilgran, Landsteiner Scientific, Mexico City, Mexico) for 3 consecutive days on an outpatient basis, before the procedure. A complete blood count (CBC) was performed to determine the increase in cell concentration in peripheral blood on the day of BM harvesting (white blood cell count: pre‐G‐CSF 8.22 9 103 lL, post‐G‐CSF: 36.60 9 103 lL). Bone marrow aspiration was performed using local anesthesia with xylocaine at 2% and with the patient under sedation with intravenous midazolam at 0.1 mg/kg. Patients were placed in the prone position, and after aseptic manoeuvres, Jamshidi needles (Carefusion Corporation, Chicago, IL, USA) were inserted in both posterior iliac crests to aspirate a BM volume of 75 mL from each iliac crest. The harvested BM aspirate was collected in three sterile 50‐ mL Corning tubes (Corning Incorporated, Corning, NY, USA) with a previously added anticoagulant solution composed of a 1 : 100 dilution of 1000 units of heparin and citrate dextrose." "BM‐derived SC isolation was set to obtain a final volume of 10 mL for intra‐articular administration. After harvesting, BM contained in the Corning tubes was filtered in a laminar flow cabinet using a 180‐l blood filter. A sample of 0.5 mL was taken to perform BM‐CBC. BM was centrifuged at 26009 g for 15 min at 6°C and returned to the flow cabinet. Plasma was removed with a 16‐gauge needle 2 mm above the buffy coat and discarded. The buffy coat was obtained manually with the use of a 10‐mL syringe, in approximately 3.3 mL of volume for each of the BM harvest tubes. This process was performed while attempting to obtain a rich‐cell buffy coat with as few red blood cells as possible. A 0.5‐mL sample of the collected buffy coat was used to perform a CBC, bacterial cultures, and flow cytometry for CD45+, CD34+ and viability determination." Stem cell injection "Intra‐articular stem cell (IA‐SC) injection was made on the same day, 90 min after the bone marrow harvesting. The patient was placed in a supine position with the affected knee flexed at 70°. After surgical cleaning and local anesthesia with 3 mL of 1% xylocaine at the puncture site, a 10 mL concentrate of BM SCs was injected with an 18 G 9 1" needle infra‐patellar immediately lateral to the patellar tendon into the lateral compartment intra‐articular space of the affected knee. All patients were injected by the same orthopedic surgeon. The intra‐articular injection was made on an outpatient basis." Control group Patients enrolled in the control group underwent treatment with oral acetaminophen, 500 mg every 8 hours for 6 months. Co‐interventions None reported
Outcomes	Outcomes were assessed at 1 week, 1 month and at 6 months. Primary outcomes VAS pain (0 to 10, 0 no pain) WOMAC total score, and pain, stiffness and function subscale scores, all reported as 0 to 100 scales, where 100 is the best score Adverse events Outcomes used in this review Pain measured on VAS (0 to 10, 0 no pain) Function measured on WOMAC function subscale (0 to 100, 0 best function). We reversed the direction of function scores so 0 is best function.
Notes	Trial registration: NCT01485198 Funding: Hospital Universitario Dr. Jose E. Gonzalez Withdrawals: 4/30 (lost to follow‐up 4) in the stem cell group; 6/31 (lost to follow‐up 6) in the control group Data analysis: For function, we reversed the direction of the scale so 0 is best function, for consistent reporting of function scores across trials. Adverse events Stem cell injection group Serious adverse events: none Non‐serious adverse events: exact numbers not given. Swelling and pain in the knee the day after the stem cell injection in one patient. Infection was ruled out and the patient recovered without further complications; 12 patients had bone pain during the stimulation with G‐CSF. Some patients had slight pain and stiffness during the first 48 hours after the injection. Control group No adverse events were reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random sequence generation was not described.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and investigators were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	No assessor‐reported outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups: 4/30 (lost to follow‐up 4) in the stem cell group; 6/31 (lost to follow‐up 6) in the control group.
Selective reporting (reporting bias)	Unclear risk	Trial registered, few outcomes not measured or reported (SF‐36, KSS); adverse events not reported clearly.
Other bias	Low risk	None apparent.

Garza 2020.

Study characteristics
Methods	Study design: multicentre, double‐blinded, parallel, 3‐arm, randomised, placebo‐controlled trial Setting: Cooper University Hospital, Rothman Institute, Texas Plastic Surgery, USA Trial time period: July 2016 and September 2017 Interventions: high‐dose stem cell injection versus low‐dose stem cell injection versus placebo injection Sample size calculation: The sample size determination was based on a difference to detect at least 17 points (representing a 33% change relative to baseline for a median baseline score of 50 points on the WOMAC scale [100 points, full scale]), a 1‐sided superiority test, a standard deviation of 14 points, a value of 0.05, and a power of 80%, resulting in 11 participants per group. To account for possible losses to follow‐up, a loss rate of 20% was assumed, and an additional 2 participants per treatment group were added for a total sample size of 13 per group and a total enroled sample size of 39. Analysis: intention‐to‐treat
Participants	Number of participants Number screened for eligibility: 329 Number randomised: 39 (13 in the high‐dose stem cell group, 13 in the low‐dose stem cell group, 13 in the placebo group) Number analysed: 39 (13 in the high‐dose stem cell group, 13 in the low‐dose stem cell group, 13 in the placebo group) Inclusion criteria Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore > 6 and ≤ 16 on a 20‐point scale in 1 knee and a WOMAC pain score < 6 for the contralateral knee Grade 2 or 3 Kellgren‐Lawrence OA on radiograph with no full‐thickness lesion 1 cm in any dimension by MRI assessment Failure of a minimum of 2 nonoperative therapies (oral pain medications, physical therapy, corticosteroid injection, or viscosupplementation injection) Exclusion criteria Body mass index ≥ 35 American Society of Anesthesiologists score ≥ 3 History of symptomatic OA (hips, spine, or ankle) Rheumatologic disease, avascular necrosis, severe bone deformity, previous infection of the knee joint, pes anserine bursitis, pain attributed to diffuse oedema, pain attributed to displaced meniscal tear or osteochondritis dissecans, neurogenic or vascular claudication Bleeding disorders, chemotherapy, radiation therapy to treatment leg or adipose harvest site, and tobacco use Patients were also excluded if their target knee had an injection within 3 months before screening, surgery within 6 months before screening Major injury within 12 months before enrolment Those who could not discontinue use of the following drugs 7 days before injection have also excluded prescription pain medication, chronic oral steroids, anticoagulants, thrombolytics or antiplatelet medication Baseline characteristics High‐dose stem cell injection group (13 participants) Mean (SD) age: 59.5 (11.7) years; 6 female, 7 male Mean (SD) BMI: 28.8 (4.3) Mean (SD) short‐form WOMAC (0 to 56, 0 best function): 47.1 (not reported) Low‐dose stem cell injection group (13 participants) Mean (SD) age: 60.5 (7.9) years; 9 female, 4 male Mean (SD) BMI: 27.6 (4.1) Mean short‐form WOMAC (0 to 56, 0 best function): 56.2 (not reported) Placebo group (13 participants) Mean (SD) age: 57.1 (9.1) years; 7 female, 6 male Mean (SD) BMI: 27.1 (2.7) Mean (SD) short‐form WOMAC (0 to 56, 0 best function): 49.3 (not reported) Pretreatment group differences: none
Interventions	Stem cell preparation "Adipose was harvested from the abdomen with patients under local anaesthetic. A mean 75 mL of adipose was aspirated directly into a sterile GID SVF‐2 tissue‐processing device (GID Group). The GID SVF‐2 device is designed to produce a standardised and fully characterised dose of stromal vascular cells. The filled device was handed to a technician for tissue processing and cell characterisation. All tissue processing was done under sterile conditions within the single‐use GID SVF‐2 device. The appropriate dose (per treatment group) was created in a blinded 5‐mL syringe, and the total volume was brought to 3 to 4 mL with lactated Ringer solution." Stem cell injections "Both high and low dose stem cells in a 5‐mL syringe, with the total volume brought to 3 to 4 mL with lactated Ringer solution were injected into the knee joint via a superior‐lateral approach under sterile conditions. Verification of the joint space location of the needle was done by ultrasound imaging or by aspiration of visible synovial fluid into the syringe." Placebo injection 5 mL lactated Ringer solution with zero stem cells were injected using the same approach as described above. Post‐intervention All participants were advised to maintain minimal weightbearing for 2 days. Full range of motion (nonweightbearing) was encouraged. "Participants were advised to maintain only light activity and to avoid previously painful activities for the first 3 weeks after injection."
Outcomes	Outcomes were measured at 6 weeks, 3, 6 and 12 months. Study outcomes WOMAC short form total score 0 to 56 point scale (lowest score is no pain and stiffness and best function). The total score was normalised to 100 points. MRI: changes in cartilage from baseline to 6 months (mm) using the modified Outerbridge classification. Proportion achieving greater than 33% change from baseline in total WOMAC score was set as the minimal clinically important difference (MCID). Serious adverse events Total adverse events Withdrawals due to adverse events Outcomes included in this review at 3, 6 and 12 months Function measured with short‐form WOMAC total scores (0 to 56, lower score = better function normalised to 100 points scale by authors). Participant‐reported global assessment of success: proportion achieving greater than 33% change from baseline in total WOMAC score. Serious adverse events Total adverse events Withdrawals due to adverse events MRI: changes in cartilage from baseline to 6 months (mm). No measures of variance provided.
Notes	Trial registration: NCT02726945. Trial protocol available. Funding: GID Bio Inc. The GID Group provided funding for all supplies related to the clinical trial. The GID Group also provided funding for data collection personnel. Data analysis: We combined data from high‐ and low‐dose groups and compared versus placebo. We used WOMAC short‐form total scores for function (0 to 56, 0 best function, normalised to a 100‐point scale by review authors) and calculated SD from the interquartile range (IQR divided by 1.35). Data were unblinded at 12 months. We contacted study authors requesting WOMAC pain and function subscale scores. Withdrawals: 3/13 (23%) in the high‐dose stem cell group (1 total knee arthroplasty, 1 use of prescription pain medication, 1 alternative treatment); 3/13 (23%) in the low‐dose stem cell group (1 use of prescription pain medication, 2 alternative treatment); 7/13 (54%) in the placebo group (3 declined to participate, 3 alternative treatment, 1 not eligible) Adverse events High‐dose stem cell group Serious adverse events: 0/13 Non‐serious adverse events: 3/13 participants: 1 knee swelling, 2 bacterial growth in SVF sample, 3 events < Grade 1 (CTCAE criteria) Low‐dose stem cell group Serious adverse events: 0/13 Non‐serious adverse events: 0/13 Placebo group Serious adverse events: 0/13 Non‐serious adverse events: 0/13
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised 1:1:1 by use of opaque folders containing one of the three treatment groups.
Allocation concealment (selection bias)	Low risk	To ensure concealment, an opaque folder containing the treatment group assignment was randomly selected and delivered to the site technician just prior to the procedure.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and investigators were unaware of treatment assignments until the 6‐month follow‐up as the dose syringe and tip were wrapped in sterile white labels to mask the contents.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignment until 6 months follow‐up.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	MRI assessments were performed by a blinded outcome assessor.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups at 3 and 6 months: 1/13 in the high‐dose group, 0/13 in the low‐dose group and 1/13 in the placebo group. But at 12 months, there were more losses in the placebo group: 3/13 in the high‐dose group, 3/13 in the low‐dose group and 7/13 in the placebo group.
Selective reporting (reporting bias)	High risk	Authors planned to collect WOMAC pain, function and stiffness subscales and WOMAC total score, and VAS pain according to the original trial registration and protocol, but have only reported WOMAC total score. The primary outcome was changed from safety to change in WOMAC score subsequent to the trial registration.
Other bias	Low risk	None apparent.

Goncars 2017.

Study characteristics
Methods	Study design: single‐centre, parallel, 2‐arm randomised controlled trial Setting: outpatient setting, Latvia Trial time period: between 2012 and 2015 Interventions: stem cell (mononuclear cells) injection versus hyaluronic acid (HA) injection Sample size calculation: a priori sample size calculation not reported Analysis: intention‐to‐treat analysis
Participants	Number of participants: Number screened for eligibility: 72 Number excluded: 16 (not meeting inclusion criteria) Number randomised: 56 (28 to the stem cell group and 28 to the HA group) Number included in analyses: 56 (28 in the stem cell group and 28 in the HA group) Inclusion criteria Degenerative osteoarthritis of the knee Grade 2 to 3 Kellgren‐Lawrence classification At least 6 months of persisting OA symptoms Exclusion criteria Age over 75 Oncologic diseases Severe kidney, lungs or liver function disorder Haematologic diseases including anaemia and thrombocytopenia First type diabetes mellitus Severe effusion, contracture and axial deformities in the knee joint Septic arthritis or skin disorders Use of NSAID medication for more than 1 week during observation period Previous injection in target knee within 2 months before and during observation period Use of corticosteroids and immunosuppressive agents Baseline characteristics Stem cell group (28 participants) Mean (SD) age: 53.44 (15) years; 13 female, 15 male No. (%) Kellgren‐Lawrence grading: Grade 2: 9 (32%); Grade 3: 19 (68%) Mean (SD) pain on KOOS pain (0 to 100, 100 no pain): 54.09 (34) Hyaluronic acid group (28 participants) Mean (SD) age: 58.55 (13) years; 18 female, 10 male No. (%) Kellgren‐Lawrence grading: Grade 2: 7 (25%); Grade 3: 21(75) Mean (SD) pain on KOOS pain (0 to 100, 100 no pain): 50.18 (43)
Interventions	Stem cell preparation "Cells were harvested from the patient's own red bone marrow during Iliac crest puncture under local anaesthesia. Up to 45 ml of bone marrow was aspirated into heparin‐treated syringes, shipped at room temperature to a central cell‐processing laboratory and diluted with sterile 0.9% NaCl (1:5), filtrated through 70 μm cell strainer (BD Biosciences). Bone marrow mononuclear cells (BM‐MNCs) were isolated and enriched by density gradient with the use of Ficoll–Paque Premium (GE Healthcare Ltd) and washed 3 times with 45 ml 0.9% NaCl containing 10 U/mL heparin and re‐suspended in saline with 10,000 U/L heparin. The cell count in all samples was made using the flow cytometry analysis. During gradient centrifugation, plasma factors, red blood cells and platelets where removed so that the final cell suspension used for injection contained only the mononuclear cell fraction resuspended in 0.9% NaCl solution in 5‐mL syringes." Stem cell injection "A single intra‐articular injection of bone marrow‐derived mononuclear cells without using local anaesthesia was injected into the knee joint cavity, following 5 to 10 mL saline injection to ensure correct needle placement." Hyaluronic acid injection "Three intra‐articular sodium hyaluronate intra‐articular injections with an interval of one week, starting at week 1 and finishing at week 3. The GO‐ON 25 mg/2.5 mL pre‐filled syringe containing Na hyaluronate 1% gel, average molecular weight 800–1500 kDa was used." Post‐intervention "Participants had an hour of bed rest before going home and were advised to avoid excessive physical activity. Short‐term use of pain reliever drugs were allowed. The use of glucosamine, chondroitin sulfate, the avocado soybean oil were not explicitly recommended or prohibited."
Outcomes	Outcomes were measured at 1, 3, 6 and 12 months. Study outcomes KOOS subscales ‐ pain, symptoms, activities of daily living (ADL), sport and recreation function (Sport/Rec), and knee‐related quality of life (QOL). A KOOS score of 100 indicates no symptoms and 0 indicates extreme symptoms. Knee Society Score (KSS) 0 to 100, 100 best score Radiological assessment using digital calibrated X‐rays Adverse events Outcomes used in this review at 3, 6 and 12 months Pain on KOOS pain subscale (0 to 100, 100 no pain) Function on KOOS ADL subscale (0 to 100, 100 best function) Adverse events
Notes	Trial registration: not reported Funding: not reported Data analysis: We transformed KOOS pain to a 0 to 10 scale and reversed the direction so that 0 is no pain. For function, we extracted the KOOS ADL 0 to 100 subscale and reversed the direction so 0 is best function. We extracted SDs for both groups from Figure 4 for pain. Function was reported at all time points for the stem cell group but only at 12 months for the HA group (with no SD), thus we imputed SD for HA from the stem cell SD reported in Figure 2. Authors did not report the results of the radiological assessments. Adverse events: 0 events in both groups Withdrawals: 0 events in both groups
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The method used for generating the random sequence was not reported.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and investigators were aware of treatment group assignment.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of their treatment group.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Unclear risk	Radiologists from the department not otherwise involved in the study performed radiological assessment, but it is not stated if they were aware of the treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were no losses to follow‐up in either treatment group.
Selective reporting (reporting bias)	High risk	Function was incompletely reported ‐ only 12‐month data for HA group with no measure of variance, and radiographic assessment was measured, but no results were reported.
Other bias	Low risk	None apparent.

Gupta 2016.

Study characteristics
Methods	Study design: multi‐centre, parallel, double‐blind, placebo‐controlled, randomised controlled trial Setting: orthopaedic departments in 5 different hospitals and research institutes in India Timing: November 2011 to November 2013 Interventions: stem cell injection (bone marrow‐derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel)) 25 million (M) plus hyaluronic acid injection versus stem cell 50 million injection plus hyaluronic acid injection versus stem cell 75 million injection plus hyaluronic acid injection versus stem cell 150 million injection plus hyaluronic acid injection versus placebo injection plus hyaluronic acid injection Sample size calculation: none Analysis: modified intention‐to‐treat
Participants	Number of participants Number screened for eligibility: 82 Number excluded: 22 (20 no reasons given; 2 dropped out of the study before intervention) Number randomised: 60 (cohort 1:10 to the stem cell 25 M group; 10 to the stem cell 50 M group; 10 to the placebo 1 group; cohort 2: 10 to the stem cell 75 M group; 10 to the stem cell 150 M group; 10 to the placebo 2 group) Number included in analyses: 60 (cohort 1:10 to the stem cell 25 M group; 10 to the stem cell 50 M group; 10 to the placebo 1 group; cohort 2: 10 to the stem cell 75 M group; 10 to the stem cell 150 M group; 10 to the placebo 2 group) Inclusion criteria Males or females aged 40 to 70 years Radiographic evidence of grade 2 to 3 osteoarthritis based on the Kellgren and Lawrence radiographic entry criteria History of primary idiopathic osteoarthritis of the knee characterised by pain which requires intake of analgesics Self‐reported difficulty in at least one of the following activities attributed to knee pain: lifting and carrying groceries, walking 400 metres, getting in and out of a chair, or going up and down the stairs Patients who have been on stable medication, which may be NSAIDs/opioid or opiate analgesics, for the past 3 months Female patients of childbearing age must be willing to use accepted methods of contraception during the course of the study Ability to provide written informed consent Exclusion criteria Prior or ongoing medical conditions (e.g. concomitant illness, psychiatric condition, alcoholism, drug abuse), medical history, physical findings, electrocardiogram (ECG) findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow‐up would be completed, or could impair the assessment of study results History of surgery, or major trauma to the study joint Arthroscopy on the study joint in the previous 12 months Signs of active study joint inflammation including redness, warmth, and/or, if qualifying with osteoarthritis of the knee, a large, bulging effusion of the study knee joint with the loss of normal contour of the joint at the screening visit or at the baseline examination Patients who had received intraarticular steroids or hyaluronan within the last three months Infections in or around the knee Patients awaiting a replacement knee or hip joint Patients with other conditions that cause pain Patients with deformity of the knee joint Significantly incapacitated or disabled and would be categorised as ACR Functional Class IV (largely or wholly incapacitated), or unable to walk without assistive devices Patients with other known rheumatic or inflammatory disease such as rheumatoid arthritis Other pathologic lesions on X‐rays of knee Positive hepatitis B surface antigen, hepatitis C antibody test, anti‐human immunodeficiency virus (HIV) antibody test, or Rapid Plasma Reagin (RPR) History of bleeding disorders Known hypersensitivity to hyaluronan products or animal sera For women of child‐bearing potential: positive pregnancy test or lactating Baseline characteristics Stem cell injection 25 M plus hyaluronic acid injection (10 participants) Mean (SD) age: 58.10 (8.23) years; 7 female/3 male Mean (SD) BMI: 29.73 (6.09) Mean (SD) VAS (0 to 100, 0 no pain): 60.9 (19.7) Mean (SD) WOMAC total (0 to 2400, 0 best outcome): 1315.8 (444.8) Mean (SD) WOMAC function subscale (0 to 1700, 0 best function): 940.3 (409.9) Mean (SD) Intermittent and Constant Osteoarthritis Pain (ICOAP) score: 45.7 (19.2) Mean (SD) WORMS total score: 67.0 (19.8) No. (%) Kellgren‐Lawrence grading: Grade 2: 4 (40); Grade 3: 6 (60%) Stem cell injection 50 M plus hyaluronic acid injection (10 participants) Mean (SD) age, years: 57.30 (9.45) years; 8 female, 2 male Mean (SD) BMI: 27.74 (4.16) Mean (SD) WOMAC total (0 to 2400, 0 best outcome): 1498.4 (407.4) Mean (SD) WOMAC function subscale (0 to 1700, 0 best function): 1388.2 (307.4) Mean (SD) ICOAP score: 59.3 (21.7) Mean (SD) VAS (0 to 100, 0 no pain): 73.7 (15.2) Mean (SD) WORMS total score: 78.8 (40.9) No. (%) Kellgren‐Lawrence grading: Grade 2: 1 (10); Grade 3: 9 (90%) Placebo 1 injection plus hyaluronic acid injection (10 participants) Mean (SD) age, years: 54.90 (8.27) years; 10 female, 0 male Mean (SD) BMI: 28.84 (4.91) Mean (SD) WOMAC total (0 to 2400, 0 best outcome): 1239.6 (472.2) Mean (SD) WOMAC function subscale (0 to 1700, 0 best function): 875.9 (344.7) Mean (SD) ICOAP score: 49.3 (18.7) Mean (SD) VAS (0 to 100, 0 no pain): 61.0 (23.8) Mean (SD) WORMS total score: 76.5 (23.5) No. (%) Kellgren‐Lawrence grading: Grade 2: 3 (30); Grade 3: 7 (70%) Stem cell injection 75 M plus hyaluronic acid injection (10 participants) Mean (SD) age, years: 55.00 (6.72) years; 8 female/2 male Mean (SD) BMI: 28.38 (2.38) Mean (SD) WOMAC total (0 to 2400, 0 best outcome): 1470.6 (471.0) Mean (SD) WOMAC function subscale (0 to 1700, 0 best function):1059.3 (317.8) Mean (SD) ICOAP total: 58.4 (20.7) Mean (SD) VAS (0 to 100, 0 no pain): 57.4 (29.0) Mean (SD) WORMS total score: 71.3 (21.4) No. (%) Kellgren‐Lawrence grading: Grade 2: 1(10); Grade 3: 9 (90) Stem cell injection 150 M plus hyaluronic acid injection (10 participants) Mean (SD) age: 54.00 (6.73) years; 5 female, 5 male Mean (SD) BMI: 26.33 (4.48) Mean (SD) WOMAC total (0 to 2400, 0 best outcome): 1388.1 (508.8) Mean (SD) WOMAC physical function subscale (0 to 1700, 0 best function): 987.8 (368) Mean (SD) ICOAP total: 46.4 (22.0) Mean (SD) VAS (0 to 100, 0 no pain): 46.6 (23.6) Mean (SD) WORMS total score: 62.0 (17.9) No. (%) Kellgren‐Lawrence grading: Grade 2: 3 (30); Grade 3: 7 (70) Placebo 2 injection plus hyaluronic acid injection (10 participants) Mean (SD) age: 56.70 (5.19) years; 7 female, 3 male Mean (SD) BMI: 26.40 (3.99) Mean (SD) WOMAC total (0 to 2400, 0 best outcome): 1382.0 (324.7) Mean (SD) WOMAC physical function subscale (0 to 1700, 0 best function): 1008.3 (358.5) Mean (SD) ICOAP total: 54.8 (17.8) Mean (SD) VAS (0 to 100, 0 no pain): 65.3 (12.2) Mean (SD) WORMS total score: 70.8 (14.7) No. (%) Kellgren‐Lawrence grading: Grade 2: 2 (20); Grade 3: 8 (80) Number of participants with K‐L Pretreatment group differences: none
Interventions	Stem cell preparation "Preparation was performed under a validated biosafety cabinet by a trained person independent of the investigator’s team. A cryobag containing the stem cell was thawed at 37 °C in a water bath. The cell suspension was diluted to 100 ml using PLASMA‐LYTE A using two 50‐ml centrifuge tubes. The cell pellet was re‐suspended in 2 mL PLASMA‐LYTE A (for the 25‐ and 50‐million‐cell dose groups) and in 4 mlL PLASMA‐LYTE A (for the 75‐ and 150‐million‐cell dose groups) based on the viable cell count and was loaded to a blinded syringe. Patients were hospitalized for the procedure, and were monitored for 24 h after the injection. Patients were discharged after inspection of the target joint, a general physical examination, and vital signs evaluation. The intra‐articular injections were performed by qualified and experienced investigators (either orthopaedician or rheumatologist) using a 2.0‐inch (5.1‐cm) 20‐gauge needle as a lateral midpatellar injection (an injection into the patellofemoral joint)." Stem cell injection plus hyaluronic acid injection Stem cell injection 25M: The cell suspension was diluted to 100 mL using PLASMA‐LYTE A using two 50 mL centrifuge tubes. The cell pellet was re‐suspended in 2 mL PLASMA‐LYTE A based on the viable cell count and was loaded to a blinded syringe. Stem cell injection 50M: The cell pellet was re‐suspended in 2 mL PLASMA‐LYTE A based on the viable cell count and was loaded to a blinded syringe. Stem cell injection 75M: The cell pellet was re‐suspended in 4 mL PLASMA‐LYTE A based on the viable cell count and was loaded to a blinded syringe. Stem cell injection 150M: The cell pellet was re‐suspended in 4 mL PLASMA‐LYTE A based on the viable cell count and was loaded to a blinded syringe. All groups received a single injection of 2 mL hyaluronic acid (20 mg; Hyalgan, Fidia Farmaceutici S.p.A., Italy) after the stem cell injection. Placebo (plasmalyte) injection plus hyaluronic acid injection "For the placebo preparation, a similar amount of PLASMA‐LYTE A was loaded to a blinded syringe and participants also received a single injection of 2 mL hyaluronic acid (20 mg; Hyalgan, Fidia Farmaceutici S.p.A., Italy) after the placebo injection." Post‐intervention "All groups received pre‐medication (hydrocortisone 100 mg IV and pheniramine maleate 45.5 mg IV) administered 15 to 30 minutes before the injections."
Outcomes	Outcomes were measured at baseline, 1, 3, 6 and 12 months (and 2 years; 2‐year results are as yet unreported). Primary outcomes Number and percentage of patients with adverse events as a measure of safety and tolerability Safety: physical examination, periodic monitoring of vital signs (heart rate, respiratory rate, blood pressure and temperature), clinical laboratory investigations (including haematology tests for complete blood count and erythrocyte sedimentation rate, serum chemistry, liver function test, urine‐analysis) and 12‐lead electrocardiogram recording Tolerability: adverse events identified by participants or investigator and reported as total number of adverse events and compared between study arms Secondary outcomes Change from baseline in the WOMAC pain subscale score (0 to 500) Change from baseline in WOMAC OA stiffness index (0 to 200) Change from baseline in the WOMAC function subscale score (0 to 1700) Change from baseline in WOMAC OA composite index (0 to 2400) Change from baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) Questionnaire Change from baseline in radiographic (X‐ray) findings of knee Change from baseline in the Whole‐Organ Magnetic Resonance Imaging Score (WORMS) of knee using MRI Change from baseline in arthritis pain scores on VAS (0 to 100, 0 no pain) Reduction in the intake of analgesic tablets from baseline Outcomes used in this review at 3, 6 and 12 months Pain measured with VAS pain (0 to 100, 0 no pain) change from baseline scores Function measured with WOMAC function subscale (0 to 1700, 0 best function) change from baseline scores normalised to 0 to 100 Adverse events MRI WORMS scores
Notes	Trial registration: ClinicalTrials.gov NCT01453738. Registered 13 October 2011. CTRI/2018/09/015785 Data analysis: The study was unblinded after 6 months. Authors stated there were no clinically meaningful changes in the X‐ray parameters at follow‐up visits compared to baseline (data not presented). Authors provided numerical data for VAS and WOMAC total and subscores. We transformed VAS from 0 to 100 scale to 0 to 10 scale. We normalised mean WOMAC function subscale scores to a 0 to 100 scale. We combined the 4 intervention groups (25M, 50M, 75M, 150M) and compared the combined treatment group to the combined placebo groups (placebo 1 and placebo 2). Funding: This study was funded by Stempeutics Research Pvt. Ltd., Bangalore, India. PKG, AC, MR, PKV, CT, SB, DD, PV, and ASM are employees of Stempeutics Research Pvt. Ltd. The remaining authors declared no competing interests. Withdrawals: none in any arm Adverse events Stem cell injection 25 M plus hyaluronic acid injection Serious adverse event: 2/10 participants: 1 hysterectomy for menorrhagia, 1 dyslipidaemia Non‐serious adverse event: 7/10 participants: injection‐related arthralgia Stem cell injection 50M plus hyaluronic acid injection Serious adverse event: 1/10 participant: anaemia Non‐serious adverse event: 7/10 participants: injection‐related arthralgia Placebo 1 injection plus hyaluronic acid injection Serious adverse event: 1/10 participant: suture‐related complication and varicose vein Non‐serious adverse event: 7/10 participants: injection‐related arthralgia Stem cell injection 75M plus hyaluronic acid injection Serious adverse event: 0/10 Non‐serious adverse event: 7/10 participants: 4 injection site pain and arthralgia; 2 arthralgia due to OA; 1 joint swelling due to hypersensitivity to injection Stem cell injection 150M plus hyaluronic acid injection Serious adverse event: 2/10 participants: 1 injection‐related synovial effusion requiring hospitalisation for one additional day of observation; 1 muscle haemorrhage Non‐serious adverse event: 6/10 participants: 3 joint swelling due to hypersensitivity to injection; reasons for the other 3 participants not specified Placebo 2 injection plus hyaluronic acid injection Serious adverse event: 2/10 participants: 1 haemorrhoidal haemorrhage; 1 umbilical hernia Non‐serious adverse event: 6/10 participants: reasons not specified
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised centrally in a 2:1 ratio using a computer‐generated randomisation in blocks of 5.
Allocation concealment (selection bias)	Low risk	Performed centrally.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, study personnel and investigators were unaware of treatment as syringes containing stem cells or placebo were prepared independently of the investigators and the syringes were covered with semitransparent tape, so the contents were indistinguishable.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignment at 3 months and 6 months follow‐up. At the 12‐month follow‐up, the participants were unblinded, so this time point may be subject to bias.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	X‐ray and MRI, blood tests and ECG results were assessed by blinded outcome assessors at 6 months follow‐up. MRI and ECG were assessed unblinded at 12 months.
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were no losses to follow‐up from any treatment groups.
Selective reporting (reporting bias)	High risk	Trial was registered. Results were not reported for all planned outcomes at all time points (2‐year data not presented). X‐ray progression was measured, but data were not presented.
Other bias	Low risk	None apparent.

Ho 2022.

Study characteristics
Methods	Study design: single‐centre, parallel, single‐blind, 2‐arm randomised controlled trial Setting: Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China Trial time period: between 2015 and 2020 Interventions: autologous bone marrow‐derived mesenchymal stem cell injection versus hyaluronic acid injection Sample size calculation: According to the VAS score reported in relevant clinical trials at the time of protocol preparation, a sample size of 10 would allow for a mean difference of 2.76 and population variance of 7.46 with 80% power and significance level of 0.05 to detect a difference between the two groups. Analysis: intention‐to‐treat
Participants	Number of participants Number screened for eligibility: 100 Number excluded: 80 (not meeting eligibility criteria) Number randomised: 20 (10 to the stem cell group and 10 to the HA group) Number included in the analysis: 20 (10 in the stem cell group and 10 in the HA group) Inclusion criteria 50 to 65 years Primary OA of the knee of Kellgren‐Lawrence (K‐L) grade 2–3 Pain level equal to or higher than 5 on a Visual Analogue Scale (VAS) scale of 10 for at least 2 months No restriction on medication or any other treatment or daily activity Exclusion criteria Alcoholism or drug abuse Pregnancy and breast‐feeding Serious pathologies such as carcinoma or autoimmune disease Hypersensitivity towards HA Ongoing or recent (1 month) steroid‐based systemic therapy Significant haematologic disease Mechanical knee instability, ligamentous laxity or deficiency or gross knee deformity Prior knee surgery Baseline characteristics Stem cell injection (10 participants) Mean (SD) age, years: 56.7 (4.83) No. (%) female: 4 (40%) No. (%) K‐L grading: Grade 2: 8; Grade 3: 2 Mean (SD) WOMAC (0 to 68, 0 best function) function subscale: 28.7 (18.73) Mean (SD) SF‐36 MCS: 39.0 (11.38) Median (IQR) VAS (0 to 10, 0 no pain) at rest: 2.5 (1.00, 3.75) Hyaluronic acid injection (10 participants) Mean (SD) age, years: 59.1 (4.04) No. (%) female: 8 (80%) No. (%) K‐L grading: Grade 2: 9; Grade 3: 1 Mean (SD) WOMAC (0 to 68, 0 best function) function subscale: 32.9 (15.17) Mean (SD) SF‐36 MCS: 35.2 (8.01) Median (IQR) VAS (0 to 10, 0 no pain) at rest: 1.5 (0.75, 3.25)
Interventions	Stem cell preparation "Human bone marrow (10 ml) was harvested from the posterior iliac crest under local anaesthesia at least 1‐month before injection. Bone marrow nucleated cells were isolated and cultured with standard protocol in a clean room facility. In brief, 20 ml bone marrow solution diluted in Dulbecco's phosphate‐buffered saline (DPBS; 1:1 ratio) was layered on Ficoll‐Paque PREMIUM (GE Healthcare, Chicago, USA) before centrifugation at 400g for 30 min at 20 degrees C. The layer of buffy coat was collected and washed twice with 3 times the volume of DPBS. The nucleated cells were seeded at a density of 2.5 x 105 cells/cm2 in culture medium (KO‐DMEM supplemented with 1% Glutamax and 10% fetal bovine serum) which was changed twice a week. At 70% confluent, the cells were collected with Tryple, then resuspended in the culture medium, and seeded at a density of 5000 cells/cm2 in culture flask. Cell culture with viability above 86% as determined by trypan blue exclusion test was used. International Society for Cellular Therapy (ISCT) recommendations were adopted for MSC characterization. In passage 3, BM‐MSCs cell suspension was washed twice with DPBS, re‐suspended in 200 μl stain buffer (BD, 1 x 106 cells/ml) and incubated for 15 min at 4 degrees C. Primary antibodies against CD14, CD19, CD29, CD34, CD44, CD45, CD73, CD90, HLA‐DR or corresponding isotype controls were added to each suspension and incubated for 15 min at 4C with gentle intermittent shaking before subjecting to flow cytometry. In addition, the multi‐differentiation potential and clonogenicity of the BM‐MSCs were evaluated by standard staining protocols. One hundred BM‐MSCs were seeded per 10 cm diameter culture dish and stained with 0.5% crystal violet (Sigma‐Aldrich, Missouri, USA) at day 14. The BM‐MSCs at passage 3 were subjected to iosteogenic, adipogenic or chondrogenic induction using commercially available differentiation kits (StemPro, Gibco, Massachusetts, USA), followed by staining of calcium deposits by 0.5% alizarin red S (pH 4.1 adjusted with ammonia, Sigma‐Aldrich, Missouri, USA), intracellular oil droplets by 0.3% freshly filtered oil red O (Sigma‐Aldrich, Missouri, USA), or type II collagen in micromass culture by immunohistochemical staining with anti‐type II collagen (Santa Cruz, California, USA) respectively. BM‐MSCs in passage 5 were used for intra‐articular injection." Stem cell injection In the BM‐MSCs group, 6 mL of BM‐MSCs (1 x 106 cells per mL) was injected intra‐articularly into the knee joint. Hyaluronic acid injection 6 mL of HA (Synvisc‐One®: Hylan G‐F 20) was injected intra‐articularly into the knee joint. Co‐intervention No restriction on medication or any other treatment or daily activity by the recruited patients before or after intervention
Outcomes	Outcomes were assessed at 3, 6, 9 and 12 months. Primary outcome: VAS (0 to 10, 0 no pain) for pain evaluation at rest, with a burden, and during physical activity Secondary outcomes: Knee Society Score (KSS) Knee Society Function Score (KSFS) MRI assessment of cartilage changes: T2‐mapped sagittal MR images WOMAC total and subscales (pain, stiffness, function) 36‐Item Short Form Survey (SF‐36) Outcomes used in this review Mean pain at rest on VAS (0 to 10, 0 no pain) change from baseline score Mean function on WOMAC function subscale (0 to 68, 0 best function) change from baseline score Mean quality of life SF‐36 MCS (0 to 100, 100 best quality of life) change from baseline score
Notes	Trial registration: CUHK_CCT00469 Funding: Sports Medicine and Regenerative Technology (SMART) of Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong Withdrawals: none in either arm Adverse events: none in either arm
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The method of random sequence generation was not described.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and investigators were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	Radiologist was not aware of treatment assignments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals from either group.
Selective reporting (reporting bias)	Low risk	Trial registered and results for all outcomes reported.
Other bias	Low risk	None apparent.

Khalifeh Soltani 2019.

Study characteristics
Methods	Study design: single‐centre, double‐blind, parallel, 2‐arm randomised placebo controlled trial Setting: University of Medical Sciences, Tehran, Iran Trial time period: November 2015 to December 2016. Interventions: stem cell injection versus placebo (normal saline) injection Sample size calculation: not performed Analysis: completers analysis
Participants	Number of participants Number screened for eligibility: 66 Number excluded: 44 (20 did not meet the criteria, 24 refused to participate) Number randomised: 20 (10 to the stem cell group, 10 to the placebo group) Number included in analyses: 20 (10 in the stem cell group, 10 in the placebo group) Inclusion criteria Age between 35 and 75 years Knee OA (grades 2 to 4 based on the KL criteria in knee standing anteroposterior and lateral radiographs) Exclusion criteria Age < 35 or > 75 years Any acute or chronic infection Visible knee deformity (varus > 10°; valgus > 20°) Pregnant or lactating women Any sort of neoplasia BMI > 35 Conditions along with impaired immune system Any inflammation in the joints or secondary OA Intra‐articular injections during the last 3 months History of knee surgery Kidney malfunction (creatinine > 2.0 mg/dL) Liver malfunction (bilirubin > 2.0 mg/dL; AST and ALT > 100 IU/L) Uncontrolled diabetes mellitus Baseline characteristics Stem cell injection group (10 participants) Mean age: 57.5 (SD not reported) years; 9 female, 1 male Mean BMI: 29.6 Mean (SD) VAS (0 to 10, 0 no pain): 7.2 (1.5) Mean KOOS Pain: 34.8 Mean (SD provided by author) KOOS ADL: 33.2 (15.8) Mean KOOS Symptom: 41.1 Mean KOOS Sport/Rec: 0 Mean KOOS QOL: 18.2 Mean ROM: 81 deg Placebo injection group (10 participants) Mean age: 55.8 (SD not reported) years; 9 female, 1 male Mean BMI: 28.9 Mean (SD) VAS (0 to 10, 0 no pain): 6.6 (1.5) Mean KOOS Pain: 40.1 Mean (SD provided by author) KOOS ADL: 38.4 (19.8) Mean KOOS Symptom: 38.8 Mean KOOS Sport/Rec: 3 Mean KOOS QOL: 41.3 Mean ROM: 111.8 deg Pretreatment group differences: none
Interventions	Stem cell preparation "The donors of placenta were selected from full‐term healthy mothers who had normal vaginal delivery without complication. The individual donor blood samples were tested for reactive transmissible infectious agents. All procedures were performed in a Good Manufacturing Practice (GMP) facility (clean room) according to current GMP guidelines. Placenta (34 g) was selected picked, rinsed and minced into minute pieces. The minced tissue was washed three times with 9% sodium chloride solution to remove the remaining blood, before being incubated with 1mg/mL GMP‐grade collagenase NB6 (SERVA Electrophoresis GmbH) at 37°C for 3 h, with shaking every 30 min. Then, 9% sodium chloride solution was added, and the mixture was shaken and centrifuged. The supernatant was discarded, and the cell pellet was cultivated in MSC complete medium containing Dulbecco’s Modified Eagle’s Medium (ATOCEL) supplemented with 10% pharmaceutical grade Australian‐origin foetal bovine serum (ATOCEL). Primary cultures were maintained for 1 week in a 37°C humidified 5% CO2 incubator in small digested residues; non‐adherent cells were removed by changing the culture medium. New medium was added twice‐weekly. Upon approximately 80% confluence, adherent mesenchymal stem cells (MSCs) were passaged via animal origin‐free TrypLE Express enzyme to reach a sufficient number of MSCs for further clinical applications. Each donor placenta was used for two to three patients. Average passage of cells was 12 passages. The cells were injected via 10‐mL syringe. The MSC group received intra‐articular injection of MSCs (10 mL; 0.50‐0.6 x 108). This concentration was chosen considering the average amount of cells that had been used in the previous reported studies on MSC injection for knee OA trials." Stem cell injection Single intra‐articular injection of 10 mL of 0.5 to 0.6 x 108 allogenic placenta‐derived MSCs was administered to 10 participants. Placebo injection Single intra‐articular injection of 10 mL of normal saline was given to 10 participants. Post‐intervention Participants in both groups were allowed to use acetaminophen to alleviate pain if needed. Their routine activities of daily living were continued early after intervention and only heavy activities or prolonged walking were restricted for 1‐week post‐injection.
Outcomes	Outcomes were measured at baseline 2, 8 and 24 weeks. Study outcomes Range of motion determined with a standard goniometer Pain on VAS (0 to 10, 0 no pain) Knee OA Outcome Score (KOOS) questionnaire on 5 subscales (ADL, Symptom, Sport, QOL and Pain); change from baseline scores were reported Knee magnetic resonance arthrography (MRA) cartilage thickness in millimetres at 14 sites; the minimum and maximum thickness was determined (totalling 28 points of thickness evaluated per patient), and presence (yes/no) of synovial hypertrophy in sagittal views; spur in coronal and sagittal views and erosion in coronal, sagittal and axial views. The medial and lateral meniscus was evaluated using the Crues and Stroller classification. Adverse events Outcomes used in this review at 8 weeks and 6 months Pain on VAS (0 to 10, 0 no pain) Knee OA Outcome Score (KOOS) questionnaire KOOS ADL subscale (0 to 100, 100 best function) Adverse events
Notes	Funding: This study was supported by a grant from the National Institute For Medical Research Development (NIMAD) granted to M. Vasei. Trial registration: IRCT2015101823298N2 Withdrawals: zero events in either group Data analysis: individual participant data for pain on VAS and KOOS ADL subscale were provided by the author upon request. We reversed the direction of KOOS ADL subscale so 0 is best function (0 to 100, 0 is best function). Adverse events Stem cell injection Serious adverse events: 0/10 Non‐serious adverse events: 4 participants: increased local pain and mild effusion self‐limited within 48 to 72 hours Placebo injection Serious adverse events: 0/10 Non‐serious adverse events: 0/10
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised using a random number table.
Allocation concealment (selection bias)	Low risk	The authors reported using a "sealed envelope method". No further details were provided, but it seems likely the sequence was concealed.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, interventionists and outcome assessors were unaware of treatment assignment as the injection syringes were covered to mask the contents.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	The radiologist interpreting the MRI was unaware of treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were no losses to follow‐up in either treatment group.
Selective reporting (reporting bias)	Low risk	Trial was registered and results for all outcomes were reported.
Other bias	Low risk	None apparent.

Kim 2023.

Study characteristics
Methods	Study design: multi‐centre, parallel, 2‐arm, randomised, placebo‐controlled trial Setting: Kyung‐Hee University Hospital, Korea Trial time period: June 2019 to February 2021 Interventions: adipose‐derived mesenchymal stem cells (ADMSCs) injection versus placebo injection Sample size calculation: A priori sample size calculation was determined according to previous studies to detect a 15.2‐point difference in total WOMAC score based on a 1‐tailed test, an SD of 30.2, and a value of.025, and a power (ß) of 0.90, resulting in 104 participants required per group. Accordingly, the current trial was designed to include 130 participants per group to account for a potential dropout rate of approximately 20%. Analysis: completers analysis
Participants	Number of participants Number screened for eligibility: 334 Number excluded: 73 (19 not meeting inclusion criteria, 1 declined to participate) Number randomised: 261 (131 to the BMC group and 130 to the placebo group) Number included in analyses: 252 (125 in the BMC group and 127 in the placebo group) Inclusion criteria: Age older than 20 years old Diagnosis of primary osteoarthritis of the knee, according to the American College of Rheumatology criteria Kellgren‐Lawrence grade 3 At least one focal or diffuse 3‐4 International Cartilage Repair Society grade on baseline magnetic resonance imaging Patients with 100 mm VAS ≥ 50 at the screening point Patients with total Western Ontario and McMaster Universities Osteoarthritis score ≥ 40 at the screening point Patients who had persistent knee pain despite conservative treatment for more than 12 weeks Patient is able to understand the instructions from doctors and to complete the questionnaires required for the study Exclusion criteria: Female who are planning to be pregnant and agreed to use contraception during study period Female who are pregnant, lactating or planning pregnancy Body mass index > 35 kg/m2 Patients with a positive screening test for human immunodeficiency, hepatitis B or hepatitis C Patients with other disease (no matter the length of time) including systemic or rheumatoidal or inflammatory cartilage disease, crystalline disease (gout or pseudogout), haemochromatosis, inflammatory joint disease, femoral head necrosis, Paget disease in the joint of femur or tibia, or related knee joint disease, ochronosis, haemophilia arthropathy, joint infections, joint sarcoidosis, villonodular synovitis, or solitary synovial chondromatosis History of liposarcoma or other cancer diagnosed Patients with serious condition which can affect this study, such as cardiovascular diseases, renal diseases, liver diseases, endocrine diseases, cancer or diabetes Patients with measures twice or more than normal in lab test or with any condition that the principal investigator considers clinically important Patient who had an intra‐articular injection (hyaluronic acid or steroid) within 6 months before the investigational drug injection Any knee around injection of any drugs (platelet‐rich plasma, stem cells, or prolotherapy) before the screening Patients who had received any anti‐inflammatory drugs, glucosamine, chondroitin sulfate, diacerhein, any oriental drugs, acetaminophen, oral corticosteroid, or physical therapy within 14 days before the investigational drug injection Patients with a history of hypersensitivity or allergy to any substances used within the treatments Patients who had skin problems or infectious sign at the injection site Patients who had 2 or more than grade 2 instability of anterior‐posterior or medial‐lateral stability of the knee joint Patients who have difficulty with MRI because they have inserted metal materials (pacemakers, cerebral aneurysm clips, etc.) or have claustrophobia Patients who are not able to have lipo‐aspiration or local anaesthesia Patients with known, current substance abuse (ex: alcohol, illegal drugs, etc.) or urine‐tested positivity for those substances Patients who are legally incompetent, have active mental illness, or have serious neurological and psychiatric problems that affect the conduct of clinical trials Patients who had participated in other clinical trials within 12 weeks prior to this study Patients who the principal investigator considers inappropriate for the clinical trial due to any other reasons than those listed above (i.e. cognitive dysfunction, lack of will) Baseline characteristics: Stem cell injection group (125 participants): Mean (SD) age: 63.7 (7.1) years; 86 female, 39 male Mean (SD) BMI: 26.3 (3.2) Mean (SD) osteoarthritis duration, months: 84.1 (68.1) No. (%) Kellgren‐Lawrence grading: Grade 3:125 (100) Mean (SD) joint space width, mm: 3.5 (1.3) Mean (SD) VAS (0 to 100, 0 no pain) pain: 57.7 (17.1) Mean (SD) WOMAC pain: 10.7 (3.3) Mean (SD) WOMAC (0 to 68, 0 best function) function: 39.8 (9.4) Mean (SD) WOMAC stiffness: 4.5 (1.3) Mean (SD) WOMAC total: 55 (13.4) Mean (SD) SF‐36 MCS: 46.6 (10.1) Placebo injection group (127 participants): Mean (SD) age: 63.8 (7.1) years; 101 female, 26 male Mean (SD) BMI: 25.9 (3.1) Mean (SD) osteoarthritis duration, months: 85.7 (66.5) No. (%) Kellgren‐Lawrence grading 1:2:3:4: 0:0:127 (100):0 Mean (SD) joint space width, mm: 3.6 (1.5) Mean (SD) VAS (0 to 100, 0 no pain) pain: 60.9 (16.6) Mean (SD) WOMAC pain: 11.3 (3.2) Mean (SD) WOMAC (0 to 68, 0 best function) function: 41.8 (10.3) Mean (SD) WOMAC stiffness: 4.9 (1.5) Mean (SD) WOMAC total: 58 (14.4) Mean (SD) SF‐36 MCS: 45.9 (9.6)
Interventions	Stem cell preparation "Autologous adipose tissue was obtained in both groups from abdominal subcutaneous fat by lipoaspiration via the tumescent technique. ADMSCs were isolated from this tissue and cultured under good manufacturing practice conditions. All adipose tissues collected from multiple institutions were transported to a single manufacturer (Jointstem; R‐Bio) for the preparation of ADMSCs under strict and homogeneous conditions per good manufacturing practices. All ADMSCs were collected at passage 3 (mean, 4‐5 days per passage) and tested for cell number, viability, purity (CD31, CD34, and CD45), identity (CD73 and CD90), sterility, and endotoxin and mycoplasma contamination, as recommended by the Code of Federal Regulations, title 21, before being injected." Stem cell injection: Three weeks after lipoaspiration, an intra‐articular autologous adipose‐derived mesenchymal stem cell (ADMSCs) injection (1 x 108 ADMSCs) in 3 mL of saline (normal saline, 2.1 mL; autologous serum, 0.9 mL) was administered in the outpatient clinic. "Ice pack application and limited physical activity were recommended on the day after the injection." Placebo injection: Three weeks after lipoaspiration, an intra‐articular saline injection (normal saline, 2.1 mL; autologous serum, 0.9 mL) was administered in the outpatient clinic. "Ice pack application and limited physical activity were recommended on the day after the injection." Co‐interventions: "Rescue medicine (acetaminophen, 3000 mg/d) was allowed when the participants required analgesics for knee pain. Other analgesics and nonoperative treatments, including physical therapy and injections were not allowed."
Outcomes	Outcomes were assessed at 1, 3 and 6 months Primary outcome: Pain on VAS (0 to 100, 0 no pain) change from baseline WOMAC total score for function change from baseline Secondary outcomes: WOMAC pain, function, stiffness subscales change from baseline scores KOOS total and subscale change from baseline scores 36‐Item Short Form Health Survey change from baseline scores Proportions of patients achieving improvement on VAS (20%) and total WOMAC (33%) International Knee Documentation Committee subjective knee change from baseline score Adverse events Radiologic evaluation of change in K‐L grade, joint space width of the medial and lateral compartments, and hip‐knee‐ankle angle with simple radiographs (results not reported). MRI evaluations ‐ modified whole‐organ MRI score (WORMS) was used to evaluate MRI changes in cartilage status, including cartilage defect depth, defect surface area and signal intensity Outcomes used in this review: Mean pain measured on VAS (0 to 100, 0 no pain); change from baseline Mean function measured on WOMAC function subscale (0 to 68, 0 best function); change from baseline score Mean quality of life SF‐36 (0 to 100, 100 best score); change from baseline score Participant‐reported treatment success recorded as the proportion of participants achieving 20% improvement in VAS pain Serious adverse events Total adverse events
Notes	Trial registration: NCT03990805 Funding: R‐Bio Co, Ltd. Withdrawals: 6/131 (4.6%) in the stem cell group due to loss to follow‐up (1) and failure to collect an adequate amount of adipose tissue (5); 3/130 (2%) in the placebo group due to failure to collect an adequate amount of adipose tissue (3) Data analysis: We transformed VAS pain score to a 10‐point scale and WOMAC function subscale to a 100‐point scale. Adverse events Stem cell injection: Non‐serious adverse events: 48/131 events include: musculoskeletal including arthralgia, joint swelling, back pain, musculoskeletal pain, pain in extremity (30); infections (5); injection‐site pain and swelling (5); nervous system disorders (2); gastrointestinal disorders (2); skin and subcutaneous tissue disorders (2); injury, poisoning and procedural complications (1); metabolism and nutrition disorders (1); renal and urinary disorders (2); respiratory, thoracic and mediastinal disorders (1); neoplasms (1); congenital, familial and genetic disorders (1); reproductive system (1) Serious adverse events: 1/131 pneumonia Placebo injection: Non‐serious adverse events: 41/130 events include: musculoskeletal including arthralgia, joint swelling, back pain, musculoskeletal pain, pain in extremity (23); infections (9); injection‐site pain and swelling (2); nervous system disorders (2); gastrointestinal disorders (1); cataract (2); injury, poisoning and procedural complications (1); metabolism and nutrition disorders (1); neoplasms (1); ear and labyrinth (1); vascular disorders (1) Serious adverse events: 3/130 COVID‐19, herpes zoster and spondylolisthesis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random sequence generation performed using permuted block randomisation.
Allocation concealment (selection bias)	Low risk	Not explicitly described, but it was likely concealed given that this was a multi‐centre trial with a central randomisation process.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and investigators were unaware of treatment assignments.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignments.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	Outcome assessors were unaware of treatment assignments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and similar across groups: 6/131 (4.6%) in the stem cell group (loss to follow‐up 1, failure to collect an adequate amount of adipose tissue 5); 3/130 (2%) in the placebo group due to failure to collect an adequate amount of adipose tissue.
Selective reporting (reporting bias)	Low risk	Trail registered and results for all outcomes reported except for radiographic evaluations of joint space width.
Other bias	Low risk	None apparent.

Kuah 2018.

Study characteristics
Methods	Study design: single‐centre, randomised, parallel, double‐blind, placebo‐controlled trial Setting: Sydney Sportsmed Specialists and Sydney Sports Medicine Centre, Sydney, Australia Trial time period: between April 2015 and March 2017 Interventions: stem cell injection (Progenza) 3.9 million cells versus stem cell injection (Progenza) 6.7 million cells versus placebo (cell culture media and cryopreservative) injection Sample size calculation: This was a first‐in‐human study with a primary objective of safety and tolerability; no formal sample size calculation was performed but available regulatory and industry guidance for first‐in‐human studies was referenced. Analysis: intention‐to‐treat
Participants	Number of participants Number screened for eligibility: 32 Number excluded: 11 not meeting inclusion criteria Number randomised: 21 (cohort 1: 8 to the stem cell 3.9M group; 2 to the placebo group; cohort 2: 8 to the stem cell 6.7M group; 2 to the placebo group); 1 withdrew from cohort 1 prior to investigational product administration and did not receive treatment (patient decision) Number included in analyses: 20 (cohort 1: 8 to the stem cell 3.9M group; 2 to the placebo group; cohort 2: 8 to the stem cell 6.7M group; 2 to the placebo group) Inclusion criteria Provide written informed consent Males or females aged 40 to 65 years, inclusive Body mass index (BMI) of 20 to 30 km/m2,inclusive Diagnosed Kellgren‐Lawrence (KL) grade 1, 2 or 3 knee OA in the study knee Moderate to severe pain in the study knee at screening as measured by a visual analogue scale (VAS score of 35 to 90 mm, inclusive, out of 100 mm) Negative results for the virus antibody tests from samples taken at the screening visit: (i) HIV1 and HIV2 antibody test, (ii) HCV antibody test, and (iii) HBV antibody test Able to read and write in English A female patient is eligible to enter the study if she meets the following criteria: (i) not pregnant or breastfeeding/lactating (ii) females of non‐childbearing potential (i.e. women who had a hysterectomy, had both ovaries surgically removed or have current documentation of tubal ligation, or are postmenopausal which is defined as 1 year without menses) Females of childbearing potential must agree to use adequate and highly effective methods of contraception throughout the study Male patients with female partners of childbearing potential must use adequate and highly effective methods of contraception such as double‐barrier form for the entire duration of the study Exclusion criteria Inability or unwillingness to comply with protocol requirement Evidence, or diagnosis, of OA in the non‐study knee that is of a worse screening visit VAS score than the study knee Joint surgery in the study knee, including arthroscopy, within the last 3 years Consistently occurring major mechanical issues in the study knee including locking, catching and giving way Intra‐articular injections into either knee within the last 3 months Current evidence of infection in either knee Diagnosed or symptomatic OA in other major joints (feet, hips, shoulders or spine) that is of greater clinical significance than the study knee Planned hip, knee, ankle or foot surgery including joint replacement within the expected study duration History or current evidence of other joint diseases (such as gout, rheumatoid arthritis and ankylosing spondylitis), or disease or medication affecting the bone or cartilage metabolism, including systemic corticosteroids and osteoporosis medication Unable to undergo an MRI scan for any reason including severe claustrophobia and metal implants such as hip, knee or aortic valve prosthetics Current smoker, or have been a regular (daily) smoker in the past 3 months Planned or current participation in any other interventional clinical trials Patients who require use of systemic immunosuppressants Any clinically significant condition(s) that in the opinion of the principal investigator may compromise safety or compliance, interfere with evaluation or preclude completion of the study Baseline characteristics Stem cell 3.9M group (8 participants) Mean (SD) age: 50.8 (7.29) years; 2 female, 6 male Mean (SD) BMI (kg/m2): 27.7 (2.05) No. (%) Kellgren‐Lawrence OA grading: Grade 1: 0 (0%); Grade 2: 2 (25%); Grade 3: 6 (75%) Mean (SD) VAS (0 to 100, 0 no pain): 57.0 (13.82) Mean (SD) WOMAC pain score (0 to 20, 0 no pain): 6.6 (2.07) Mean (SD) WOMAC stiffness score (0 to 8, 0 no stiffness): 3.4 (1.19) Mean (SD) WOMAC function (0 to 68, 0 best function): 22.0 (9.80) Mean (SD) AQoL‐4D utility score: 0.80 (0.140) Stem cell 6.7M group (8 participants) Mean (SD) age: 55.0 (5.15) years; 3 female, 5 male Mean (SD) BMI (kg/m2): 26.8 (2.98) No. (%) Kellgren‐Lawrence OA grading: Grade 1: 1 (12.5%); Grade 2: 1 (12.5%); Grade 3: 6 (75%) Mean (SD) VAS (0 to 100, 0 no pain): 60.8 (13.01) Mean (SD) WOMAC pain (0 to 20, 0 no pain): 7.9 (3.04) Mean (SD) WOMAC stiffness (0 to 8, 0 no stiffness): 4.1 (1.89) Mean (SD) WOMAC function (0 to 68, 0 best function): 26.8 (10.20) Mean (SD) AQoL‐4D utility score: 0.76 (0.183) Placebo group (4 participants) Mean (SD) age: 55.0 (10.42) years; 3 female, 1 male Mean (SD) BMI (kg/m2): 25.5 (2.84) No. (%) Kellgren‐Lawrence OA grading: Grade 1: 1 (25%); Grade 2: 0 (0%); Grade 3: 3 (75%) Mean (SD) VAS (0 to 100, 0 no pain): 43.8 (7.41) Mean (SD) WOMAC pain (0 to 20, 0 no pain): 6.3 (3.86) Mean (SD) WOMAC stiffness (0 to 8, 0 no stiffness): 3.3 (2.06) Mean (SD) WOMAC function (0 to 68, 0 best function): 16.07 (10.69) Mean (SD) AQoL‐4D utility score: 0.75 (0.213) Pre‐treatment group differences: none
Interventions	Stem cell preparation "The stem cells used for this study were derived from a single human donor, who was qualified according to TGA requirements. Cells were isolated and culture‐expanded in a good manufacturing practice accredited facility. 2 mL of Progenza (PRG) in vitro expanded mesenchymal stem cells 3.9M was provided by Regeneus Ltd, Australia and stored in a CryoVial® and maintained at or below ‐150 °C prior to administration." Stem cell injection Progenza (PRG) in vitro expanded Mesenchymal stem cells 3.9M "The stem cells were thawed prior to being drawn up into a sterile syringe and administered via ultrasound guided intra‐articular injection into the study knee either by an independent, unblinded radiologist or sports and exercise medicine physician trained in this technique. A screen was used to ensure the patient remained blinded to the treatment allocation." Progenza (PRG) in vitro expanded Mesenchymal stem cells 6.7M 2 mL of Progenza (PRG) in vitro expanded mesenchymal stem cells PRG 6.7M using the same procedures described above. Placebo injection The placebo (vehicle control of cell culture media) was administered as a single, 2 mL, once only, intra‐articular injection into the knee using the same procedures described above. Post‐intervention None reported
Outcomes	Outcomes measured at baseline, day 28, months 3, 6, 9 and 12. Outcomes Safety assessments involved AE monitoring, vital signs, clinical laboratory parameters, physical examinations, ECG and documentation of concomitant medication use Visual analogue scale (VAS) pain (0 to 100, 0 no pain) change from baseline scores Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for pain (0 to 20), stiffness (0 to 8) and physical functioning (0 to 68) AQoL‐4D utility score 30% improvement from baseline in VAS score were classified as pain responders Activity level (as measured by FitBit® for average number of daily steps) Quantitative MRI assessment of cartilage volume, tibial bone area, bone marrow lesions and cartilage defects Urine biomarkers (CTX‐II and C2C) Blood biomarkers (serum HA, MIF and CTX‐I) Outcomes included in this review at 3, 6 and 12 months VAS pain change from baseline score (0 to 100, 0 no pain) transformed to 0 to 10 Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function subscale change from baseline scores (0 to 68, 0 best function), normalised to 0 to 100 Participant‐reported treatment success assessed as 30% improvement from baseline in VAS pain score Adverse events
Notes	Funding: This study was sponsored by Regeneus Ltd. The authors were responsible for all content, interpretation of the data and the decision to publish the results; they received no honoraria related to the development of this manuscript. The sponsor funded statistical and editorial assistance and reviewed the final draft before submission. Kuah, D: Receipt of payment from Regeneus Ltd via a Clinical Trial Research Agreement; Sivell, S: Employee of Regeneus Ltd, sponsor of the trial; Longworth, T: Receipt of payment from Regeneus Ltd via a Clinical Trial Research Agreement; James, K: Receipt of payment from Regeneus Ltd via a Clinical Trial Research Agreement; Guermazi, A: Fee for service for MRI analyses from Regeneus Ltd. President of Boston Imaging Core Lab, LLC. Consultant to Merck Serono, OrthoTrophix, Genzyme, Sanofi, TissueGene, Astra Zeneca; Cicuttini, F: Fee for service for MRI analyses from Regeneus Ltd. Other consultancy roles: Mesoblast LTD, Paradigm Biopharmaceuticals LTD; Wang, Y: Fee for service for MRI analyses from Regeneus Ltd. Y.W is the recipient of National Health and Medical Research Council (NHMRC) Career Development Fellowship (Clinical Level 1, APP1065464). Other consultancy roles: Mesoblast LTD, Paradigm Biopharmaceuticals LTD; Craig, S: Employee of Regeneus Ltd, sponsor of the trial; Comin, J: No competing interests to disclose; Robinson, D: Fee for service for providing ultrasound‐guided injection from Regeneus Ltd; Wilson, J: Employee of Regeneus Ltd, Sponsor of the trial. Trial registration: ANZCTR, ACTRN12615000439549. Date registered: 7th May 2015. Data analysis: We emailed trial authors to request QOL data and X‐ray data but have not received a response to date. We combined PRG 3.9M and 6.7M groups as a single intervention group vs placebo, and used plot digitizer to extract mean change and SD for pain (Figure 2) and WOMAC function (Figure 3). Withdrawals: 1/8 (12.5%) in the stem cell 3.9M group (total knee arthroplasty); 0/8 in the stem cell 6.7M group; 0/4 in the placebo group Adverse events Stem cell 3.9M group Serious adverse events: 1/8 participant: severe prepatellar bursitis 13 days after injection and was considered by the investigator as possibly related to the intra‐articular injection technique. A clear straw‐coloured fluid (17 mL) aspirated from the bursa showed no growth on microbiology testing, and the condition resolved with treatment within 2 weeks. Non‐serious adverse events: 8/8 participants; events included: 6 arthralgia, 6 joint effusion, 2 joint stiffness, 2 joint lock Stem cell 6.7M group Serious adverse events: 0/8 Non‐serious adverse events: 8/8 participants; events included: 8 arthralgia, 3 joint effusion, 1 joint stiffness, 1 joint lock; 1 bursitis; 3 upper respiratory infection, 1 moderate supra‐patellar bursitis, possibly related to the injection technique at 2 weeks post‐injection Placebo group Serious adverse events: 0/4 Non‐serious adverse events: 4/4 participants; events included: 4 arthralgia, 3 joint effusion, 3 joint stiffness, 1 joint lock
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random sequence generated by a computer.
Allocation concealment (selection bias)	Low risk	Randomisation and allocations were done via a secure customised central website.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, investigators and study team were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	Outcome assessors for MRI and blood markers were unaware of treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Two participants were lost to follow‐up; this was unlikely to have affected results.
Selective reporting (reporting bias)	High risk	The trial was registered. Numerical results were not reported for one of the pre‐specified outcomes (quality of life).
Other bias	Low risk	None apparent.

Lamo‐Espinosa 2016.

Study characteristics
Methods	Study design: multi‐centre, 3‐arm, parallel randomised controlled trial Setting: 2 centres, the Clínica Universidad de Navarra (Pamplona, Spain) and IBSAL‐Hospital Universitario de Salamanca (Salamanca, Spain) Trial time period: between August 2012 and October 2014 Interventions: high‐dose stem cell injection plus hyaluronic acid (HA) versus low‐dose stem cell injection plus hyaluronic acid versus hyaluronic acid injection Sample size calculation: A sample size of 10 patients per group was required to detect an effect size of 0.6 with a power of 80%, assuming a balanced allocation to treatment groups, and a 5% type I error probability, but it was unclear which outcome this referred to. Analysis: intention‐to‐treat
Participants	Number of participants Number screened for eligibility: 32 participants Number excluded: 0 Number randomised: 32 (10 to the high‐dose stem cell group, 10 to the low‐dose stem cell group and 12 to the hyaluronic acid group) Number included in analyses: 30 (10 to the high‐dose stem cell group, 10 to the low‐dose stem cell group and 10 to the hyaluronic acid group) Inclusion criteria Males and females aged 50 to 80 years Diagnosis of knee OA according to American College of Rheumatology criteria Visual Analogue Scale (VAS) for joint pain of ≥ 2.5 Kellgren and Lawrence grades ≥ 2 Body mass index between 20 and 35 kg/m Availability to be followed through the study period Exclusion criteria Previous diagnosis of polyarticular disease Severe mechanical extra‐articular deformation (> 15° varus/15° valgus) Systemic rheumatoid arthritis disease Arthroscopy or intra‐articular infiltration in the last 6 months Chronic treatment with immunosuppressive or anticoagulation drugs Corticosteroid treatment in the last 3 months Non‐steroidal anti‐inflammatory drugs in the last 15 days Bilateral knee OA requiring treatment in both knees Poorly controlled diabetes mellitus Blood dyscrasias Allergy to hyaluronic acid (HA) or bird proteins Baseline characteristics High‐dose stem cell injection plus hyaluronic acid injection (10 participants) Median (IQR) age: 57.8 (55.0, 60.8) years; 2 female, 8 male Median (IQR) duration of disease: 10 (7, 15) Median (IQR) BMI, in kg/m2: 28.5 (25.8, 31.0) No. (%) Kellgren‐Lawrence grading: Grade 2: 3 (30); Grade 3: 3 (30); Grade 4: 4 (40) Median (IQR) VAS (0 to 10, 0 no pain): 6 (4, 8) Median (IQR) WOMAC pain subscale (0 to 20, 0 no pain): 4.5 (4,5) Median (IQR) WOMAC stiffness subscale (0 to 8, 0 no stiffness): 2.5 (2,4) Median (IQR) WOMAC function subscale (0 to 68, 0 best function): 19 (12,25) Median (IQR) WOMAC total scores: 28 (16,34) Low‐dose stem cell injection plus hyaluronic acid injection (10 participants) Median (IQR) age: 65.9 (59.5, 70.6) years; 6 female, 4 male Median (IQR) duration of disease: 9 (4, 12) Median (IQR) BMI, in kg/m2: 27.1 (24.4, 31.2) No. (%) Kellgren‐Lawrence grading: Grade 2: 1 (10); Grade 3: 2 (20); Grade 4: 7 (70) Median (IQR) VAS (0 to 10, 0 no pain): 7 (5, 8) Median (IQR) WOMAC pain subscale: 7.5 (5,9) Median (IQR) WOMAC stiffness subscale: 4 (2,5) Median (IQR) WOMAC function subscale (0 to 68, 0 best function): 26.5 (23,32) Median (IQR) WOMAC total scores: 37 (32,42) Hyaluronic acid injection (12 participants) Median (IQR) age: 60.3 (55.1, 61.1) years; female 3, male 7 Median (IQR) duration of disease: 6 (2, 8) Median (IQR) BMI, in kg/m2: 29.6 (26.2, 30.8) No. (%) Kellgren‐Lawrence grading: Grade 2: 4 (40); Grade 3: 2 (20); Grade 4: 4 (40) Median (IQR) VAS (0 to 10, 0 no pain): 5 (3, 7) Median (IQR) WOMAC pain subscale: 5.5 (5,6) Median (IQR) WOMAC stiffness subscale: 2 (1,3) Median (IQR) WOMAC function subscale (0 to 68, 0 best function): 21 (13,24) Median (IQR) WOMAC total scores: 29 (19,38) Pre‐treatment group differences: No differences found between groups at baseline.
Interventions	Stem cell preparation "Bone marrow mesenchymal stromal cells (BM‐MSCs) were generated under good manufacturing practice conditions (GMP) with standard operating procedures. Briefly, bone marrow (100 ml) was harvested from the pelvic bone (iliac crest) under sterile conditions. The mononuclear cell fraction was isolated by Ficoll density gradient centrifugation (Ficoll‐Paque, GE Healthcare Bio‐Sciences AB, Uppsala, Sweden). Cells, ranging between 20 × 106 and 60 × 106, were subsequently seeded in 175 cm2 flasks with growth medium, which consisted of αMEM without ribonucleosides (Gibco, Life Technologies, Carlsbad, CA, USA) supplemented with 5% platelet lysate, 2 units/ml heparin, penicillin–streptomycin at 1% (Gibco) and 1 ng/ml human fibroblast growth factor (bFGF) (Sigma‐Aldrich, St. Louis, MO, USA). The flasks were maintained in culture at 37°C in 5% CO2 atmosphere. The growth medium was changed every 3–4 days. About 10–15 days later, colonies were formed, and the cells were split with TrypLE SelectÔ (Life Technologies) and seeded at 3000–5000 cells/cm2. Once 70–80 % confluence was reached, cells were split again and cultured until they were available at the amounts required to be administered to patients. Finally, cells were harvested with TrypLE Select™, washed three times with PBS and resuspended in Ringer’s lactate buffer (Grifols, Barcelona, Spain) containing 1% human albumin (Grifols), to be administered within 24 h of harvesting of the cells. Cells were characterised according to ISCT criteria. Cells were then analysed by flow cytometry (FACSCalibur, BD Biosciences, San José, CA, USA) with the appropriate antibodies (BD Biosciences) to confirm expression of surface markers CD90, CD73 and CD44, as well as absence of CD34 and CD45." Stem cell injection plus hyaluronic acid injection "The injection was performed without radiographic guidance through a lateral patellar approach by three different orthopaedic surgeons from both involved centres, 3 to 4 weeks after the iliac crest biopsy had been performed. In 90% of the patients, cells were administered within the first hour after being harvested. For this purpose, a 19 G needle was used in two consecutive intraarticular injections." High‐dose stem cell injection plus hyaluronic acid injection Participants received a single intra‐articular injection of 100 × 106 autologous cultured BM‐MSCs in 3 mL Ringer’s lactate solution, followed by an intraarticular injection of 4 mL HA. Low‐dose stem cell injection plus hyaluronic acid injection Participants received a single intra‐articular injection of 10 × 106 autologous cultured BM‐MSC in 1.5 mL Ringer’s lactate solution, followed by an intra‐articular injection of 4 mL HA. Hyaluronic acid injection Participants received a single intra‐articular injection of 60 mg HA (Hyalone®) in a final volume of 4 mL. Post‐intervention None reported
Outcomes	Outcomes were measured at baseline, 3, 6, 12 months and 4 years after treatment. Outcomes VAS (0 to 10, 0 no pain) WOMAC (Likert‐scale version): comprised of three sub‐scores: (i) pain (5‐items), (ii) stiffness (2‐items) and (iii) physical function (17‐items). Patients were considered WOMAC responders when they reported an improvement of 20% in at least two items together with an improvement of ten points in the overall scale. Knee range of motion: measured using a goniometer in degrees Rosenberg X‐ray projections (radiographic assessment of joint‐space width). MRI study: assessing the number and location of OA lesions, cartilage thickness, signal intensity, and subchondral bone alteration and volume, following the Whole‐Organ Magnetic Resonance Imaging Score (WORMS) protocol, in which higher score values indicate more damage. Adverse events Outcomes used in this review at 3, 6 and 12 months VAS (0 to 10, 0 no pain) WOMAC function subscale (0 to 68, 0 best function) Radiographic assessment of joint‐space width (change scores from baseline) WORMS score Total adverse events
Notes	Funding: Partially supported by grants PI17/00163 (MINECO through Instituto de Salud Carlos III to FG‐M) and RD12/0019/0017 and RD12/0019/0031 from Instituto de Salud Carlos III (Red TerCel) and RD16/0011/0005 to FP. EMV is supported by Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Consejería de Sanidad, Junta de Castilla y León. Trial registration: No. EudraCT: 2009‐017624‐ 72, Clinical Trials.gov identifier: NCT02123368 Data analysis: Authors reported median and IQR change scores from baseline to follow‐up for all outcomes (except X‐ray measurement and WORMS protocol score, which did not have a comparison at the 3‐month follow‐up). We reported the medians and calculated the SDs from IQR (SD = IQR/1.35). As noted in the methods, we combined the two intervention groups and compared the combined treatment group to placebo in the usual way. We transformed function scores to a 0 to 100 scale. Withdrawals: 0/10 in high‐dose stem cell group, 0/10 in low‐dose stem cell group, 2/12 (17%) in the HA group (withdrew consent and were excluded from the trial) Adverse events Low‐dose stem cell injection plus HA injection Serious adverse events: 0/10 Non‐serious adverse events: 3/10 participants: articular pain requiring anti‐inflammatory treatment during the first 24 hours after infiltration High dose stem cell injection plus HA injection Serious adverse events: 0/10 Non‐serious adverse events: 6/10 participants: articular pain requiring anti‐inflammatory treatment during the first 24 hours after infiltration HA group Serious adverse events: 0/12 Non‐serious adverse events: 1/10 participants: articular pain requiring anti‐inflammatory treatment during the first 24 hours after infiltration
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants assigned to comparison groups by an unblinded computer‐generated list, based on unrestricted randomisation.
Allocation concealment (selection bias)	Low risk	Allocation to comparison groups was carried out by centrally located staff with no clinical involvement in the trial.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and investigators were aware of treatment assignment.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of treatment assignment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	Radiologists evaluating the MRI images were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups: 2/10 in the control group (withdrew consent and excluded from the trial), 0/10 in high‐dose BM‐MSC and 0/10 in low‐dose BM‐MSC groups.
Selective reporting (reporting bias)	High risk	This trial was registered with ClinicalTrials.gov. The trial registry listed 9 unique primary outcome measures, however it did not provide results on 4 of them (knee injury and osteoarthritis outcome score (KOOS), SF‐36, Euroquol 5D and Lequesne index).
Other bias	Low risk	None apparent.

Lamo‐Espinosa 2020.

Study characteristics
Methods	Study design: multicentre, phase II, parallel, 2‐arm randomised controlled trial Setting: Clínica Universidad de Navarra (Pamplona, Spain); IBSAL‐Hospital Universitario de Salamanca (Salamanca, Spain) and Hospital Vithas San José (Vitoria, Spain) Timing: August 2016 and July 2018 Interventions: stem cell injection plus platelet‐rich plasma injection (PRP) versus PRP injection Sample size: A sample size of 60 patients (30 patients per group) was required to achieve a 95% power to detect a Cohen’s effect size of 1, assuming a standard deviation for both groups of 10, an alpha value of 0.05 (two‐sided test), and an expected dropout rate of 10%. Analysis: per protocol analysis
Participants	Number of participants Number screened: 60 Number excluded: not reported Number randomised: 60 (30 to the stem cell plus PRP group and 30 to the PRP group) Number included in analyses: 50 (24 in the stem cell plus PRP group and 26 in the PRP group) Inclusion criteria Males and females between 40 and 80 years old Bad results with previous hyaluronic acid injection Diagnosis of knee OA according to the criteria of osteoarthritis of the ACR (American College of Rheumatology) Joint pain equal or greater than 2.5 points on the visual analogue scale (VAS) Radiological classification: Kellgren‐Lawrence scale greater or equal to 2 Body mass index between 20 and 35 kg/m2 Ability to follow during the study period Exclusion criteria Bilateral osteoarthritis of the knee requiring treatment in both knees Previous diagnosis of polyarticular disease Severe mechanical deformation Arthroscopy during the previous 6 months Intraarticular infiltration of hyaluronic acid in the last 6 months Systemic autoimmune rheumatic disease Poorly controlled diabetes mellitus Blood dyscrasias Immunosuppressive or anticoagulant treatments Treatment with corticosteroids in the 3 months prior to inclusion in the study NSAID therapy within 15 days prior to inclusion in the study Patients with a history of allergy to penicillin or streptomycin Baseline characteristics Stem cell plus PRP injection (24 participants) Mean (SD) age: 56 (40, 62) years; 13 female, 11 male No. (%) Kellgren‐Lawrence grading: Grade 2: 5 (20.83); Grade 3: 2 (20); Grade 4: 12 (50) Mean (SD) VAS pain (0 to 100, 0 no pain): 5.3 (1.9) Mean (SD) WOMAC pain subscale (0 to 20, 0 no pain): 6.6 (4.4) Mean (SD) WOMAC stiffness subscale (0 to 8, 0 no stiffness): 3.3 (2.1) Mean (SD) WOMAC function subscale (0 to 68, 0 best function): 23.5 (13.2) PRP injection (26 participants) Mean (SD) age: 54.6 (33,70) years; 14 female; 12 male No. (%) Kellgren‐Lawrence grading: Grade 2: 8 (30.77); Grade 3: 5 (19.23); Grade 4: 13 (50) Mean (SD) VAS pain score (0 to 100, 0 no pain): 5 (1.8) Mean (SD) WOMAC pain subscale (0 to 20, 0 no pain): 6.6 (2.9) Mean (SD) WOMAC stiffness subscale (0 to 8, 0 no stiffness): 3 (1.6) Mean (SD) WOMAC function subscale (0 to 68, 0 best function): 22.3 (12.8) Pre‐treatment group differences: none
Interventions	Stem cell preparation "BM‐MSCs were generated under good manufacturing practice conditions (GMP) with standard operating procedures. Briefly, bone marrow (100 ml) was harvested from the pelvic bone (iliac crest) under sterile conditions. The mononuclear cell fraction was isolated by Ficoll density gradient centrifugation (Ficoll‐Paque, GE Healthcare Bio‐Sciences AB, Uppsala, Sweden). Mononuclear cells, ranging between 20 × 106 and 60 × 106, were subsequently seeded in 175cm2 flasks with growth medium, which consisted of αMEM without ribonucleosides (Gibco, Life Technologies, Carlsbad, CA, USA) supplemented with 5% platelet lysate, 2 units/ml heparin, penicillin–streptomycin at 1% (Gibco, Life Technologies) and 1 ng/ml human fibroblast growth factor (bFGF) (Sigma‐Aldrich, St. Louis, MO, USA). The flasks were maintained in culture at 37ºC in 5% CO2 atmosphere. The growth medium was changed every 3–4 days. About 10–15 days later, colonies were formed, and the cells were split with TrypLE Select™ (Life Technologies) and seeded at 3000–5000 cells/cm2. Once 70–80% confluence was reached, cells were split again and cultured until they were available in the amounts required to be administered to patients. Finally, cells were harvested with TrypLE Select™, washed three times with PBS and resuspended in Ringer’s lactate buffer (Grifols, Barcelona, Spain) containing 1% human albumin (Grifols), to be administered within 24 h of harvesting of the cells. Cells were characterised according to ISCT criteria. Cells were then analysed by flow cytometry (FACSCalibur, BD Biosciences, San José, CA, USA) with the appropriate antibodies (BD Biosciences) to confirm expression of surface markers CD90, CD73 and CD44, as well as absence of CD34 and CD45." Stem cell injection plus PRP injection "BM‐MSC injection was performed through a lateral patellar approach. The BM‐MSC injection was applied 3–4 weeks after the iliac crest biopsy had been performed and within the first hour after harvesting. For this purpose, a 19 G needle was used in two consecutive intraarticular injections. In the first injection, 100 × 106 BM‐MSCs were administered in 3 ml of Ringer lactate. Subsequently, 8 ml of PRP were injected using the same route. A weekly single intra‐articular injection of PRP, in a final volume of 8 ml, was applied for 2 additional weeks." Participants received 3 weekly intra‐articular injections of PRP plus a single intra‐articular injection of 100 × 106 cultured autologous BM‐MSCs in the first week. Injections were performed through a lateral patellar approach. PRP injection "Participants received 3 weekly intra‐articular injections of 8 mL of PRP in three separate doses at one‐week intervals. PRP was obtained with PRGF‐Endoret (BTI System II; BTI Biotechnology Institute, Vitoria, Spain) by centrifugation at 580×g for 8 min at room temperature. The top volume of plasma, with a platelet count similar to peripheral blood, was not used. The plasma fraction, located just above the sedimented red blood cells but not including the buffy coat, was collected in another tube. This plasma contains a moderate enrichment in platelets (two to threefold the platelet count of the peripheral blood) with no leukocytes. Thereafter, in the injection room 10% calcium chloride was added to activate platelets (0.05 ml of calcium chloride per ml PRP). Injections were performed through a lateral patellar approach." Post‐intervention None reported
Outcomes	Outcomes were measured at 3 months, 6 months and 12 months. Outcomes VAS (0 to 10, 0 no pain) Knee injury and osteoarthritis outcome score (KOOS) Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC) Likert version comprises three sub‐scores: pain, which includes 5 items; stiffness, with 2 items; and physical function, with 17 items. According to Osteoarthritis Research Society International (OARSI), patients were considered WOMAC responders when they reported an improvement of 20% on at least 2 items together with an improvement of 10 points in the overall scale Femoritibial distance on Rosenberg x‐ray view ‐ to provide a radiographic assessment of the joint space width, Rosenberg X‐ray projections were taken at baseline and 12 months afterwards. A custom methacrylate patient positioner was used to achieve a comparative view as previously described. Serious and non‐serious adverse events An MRI study was carried out at baseline and 12 months after treatment Outcomes included in this review at 3 months, 6 months and 12 months Mean pain on VAS (0 to 10, 0 no pain) Mean function on WOMAC function subscale (0 to 68, 0 best function) scores, we transformed function scores to a 0 to 100 scale, where 0 is best function Participant‐reported global assessment of success: WOMAC responders when they reported an improvement of 20% on at least 2 items together with an improvement of 10 points in the overall scale Radiological progression change scores (median, IQR) ‐ For each group of treatment, variation for knee joint space width, which was measured in mm, was calculated by subtracting, for each patient in the group, the value at 6 or 12 months from the baseline value.
Notes	Trial registration: Clinical Trials.gov identifier NCT02365142. EudraCT: 2011‐006036‐23 Funding: This work was supported by grants from ISCIII RETIC Program TerCel (RD16/0011/0005, RD16/0011/0015), PI17/00136 and EC11‐070 supported in part by FEDER Funds and the Spanish Ministry of Health Withdrawals: 6/24 (25%) in the stem cell plus PRP group (4 loss to follow up, 1 withdrawal of consent, 1 detection of trisomy in the culture); 4/26 (15%) in the PRP group (2 lost to follow up, 2 withdrawal of consent) Adverse events Stem cell plus PRP injection Serious adverse events: 0/24 Non‐serious adverse events: 6/24 participants: articular pain requiring anti‐inflammatory treatment during the first 24 hours after infiltration in 6 participants, all of whom recovered completely without sequelae. PRP injection Non‐serious adverse events: 0/26 Serious adverse events: 0/26
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random sequence was generated by a computer.
Allocation concealment (selection bias)	Low risk	This allocation procedure was centralised to ensure that no centre knew the treatment allocation of any patient until the patient had been recruited into the trial.
Blinding of participants and personnel (performance bias) All outcomes	High risk	The biopsy linked to the use of autologous cells did not allow any blinding procedure for patients or clinicians for ethical reasons.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of treatment assignment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	Radiologists who assessed radiographs and MRIs were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups: 6/24 in the BM‐MSC group and 4/26 in the PRP group.
Selective reporting (reporting bias)	Unclear risk	This trial was registered with ClinicalTrials.gov. Quality of life was stated in the trial registry but not measured in the study.
Other bias	Low risk	None apparent.

Lee 2019.

Study characteristics
Methods	Study design: 2‐centre, double‐blind, parallel, randomised, placebo‐controlled trial Setting: 2 orthopaedic centres (outpatient setting), Korea Trial time period: between June 2015 and December 2016 Interventions: stem cell injection versus placebo (saline) injection Sample size calculation: Because the primary outcome was the difference in WOMAC score between baseline and 6 months, sample size was set based on the results of the previous study (α risk 0.05, power 0.8, changes in WOMAC score 21.3, and SD 19.12). The required number of patients was determined to be five. Considering the representative clinical trial and dropout rate, 12 participants were recruited in each group. Analysis: intention‐to‐treat
Participants	Number of participants Number screened for eligibility: 33 Number excluded: 9 (8 not meeting inclusion criteria, 1 declined to participate) Number randomised: 24 (12 to the stem cell group and 12 to the placebo group) Number included in analyses: 24 (12 in the stem cell group and 12 in the placebo group) Inclusion criteria Male or female aged 18 to 75 years Healthy patients with no major history of illness Diagnosis of osteoarthritis of the knee (Kellgren‐Lawrence grades 2‐4) Mean pain intensity of > 4 on a 10‐point visual analogue scale (VAS) for at least 12 weeks Patient signed informed consent document prior to screening Exclusion Criteria Patients with measures twice or more than normal in lab test or with any condition that principal investigator considers clinically important Pregnant women or lactating mothers Patients who have received any anti‐inflammatory drugs, including herb‐drug within 14 days prior to the investigational drug injection Patients with a known, current substance abuse (Ex: alcohol, illegal drugs, etc.) or urine‐tested positively for those substances within one year prior to the study Patients who received any drug by intra‐articular injection for treatment within 2 months prior to enrolment Patients with other disease (no matter the length of time) including systemic or rheumatoidal or inflammatory cartilage disease, crystalline disease (gout or pseudogout), haemochromatosis, inflammatory joint disease, femoral head necrosis, Paget disease in the joint of femur or tibia, or related knee joint disease, ochronosis, haemophilia arthropathy, joint infections, joint sarcoidosis, villonodular synovitis, or solitary synovial chondromatosis Patients with positive human immunodeficiency (HIV), hepatitis B (HBV) or hepatitis C (HCV) at screening indicative of current or past infection Patients with a serious condition which can affect the study, such as cardiovascular diseases, renal diseases, liver diseases, endocrine diseases, cancer or diabetes Patients with BMI > 30 Patients who had participated in other clinical trials within 12 weeks prior to this study Patients who the principal investigator considered inappropriate for the clinical trial due to any other reasons than those listed above Baseline characteristics Stem cell injection group (12 participants) Mean (SD) age: 62.2 (6.5) years; 9 female, 3 male Mean (SD) BMI: 25.3 (4.9) No. (%) Kellgren‐Lawrence grading: Grade 2: 6 (50); Grade 3: 6 (50); Grade 4: 0 (0) Mean (SD) Mechanical axis (degrees): Varus 1.4° (5.7°) Mean (SD) WOMAC total score: 60.0 (17.0) Mean (SD) VAS (0 to 10, 0 no pain): 6.7 (SD not reported) Mean (SD) cartilage defect (femoral condyle), mm: 312.4 (271.0) Placebo group (12 participants) Mean (SD) age: 63.2 (4.2); 9 female, 3 male Mean (SD) BMI: 25.4 (3.0) No. (%) Kellgren‐Lawrence grading: Grade 2: 5 (41.7); Grade 3: 6 (50); Grade 4: 1 (8.3) Mean (SD) Mechanical axis (degrees): Varus 0.4° (3.6°) Mean (SD) WOMAC total score: 56.4 (16.3) Mean (SD) VAS (0 to 10, 0 no pain): 5.7 (SD not reported) Mean (SD) cartilage defect (femoral condyle), mm: 389.9 (273.0) Pre‐treatment group differences: Participants in each group had similar demographic characteristics.
Interventions	Stem cell preparation "Adipose‐derived mesenchymal stem cells (AD‐MSCs) (JOINTSTEM; R‐Bio, Seoul, Korea) used in the current study were isolated and cultured based on a previously reported study. Adipose tissues of patients were obtained by lipoaspiration from abdominal subcutaneous fat under Good Manufacturing Practices conditions. Lipoaspiration was per‐ formed using the tumescent technique, which was defined as 3–5 cc of infiltrate per 1 cc of aspirate at 3 weeks before injection. The process of lipoaspiration was as follows: (a) sterile skin preparation; (b) local anesthesia using 2% lidocaine; (c) stab incision (2 mm) using number 11 mass; (d) injection of tumescent solution into the subcutaneous fat layer of the harvesting site; (e) after 10–15 minutes, approximately 20 mL of adipose tissue was collected using an metal cannula connected to a 10 cc syringe; (f) the collected fat‐tumescent solution was kept at 2°C–8°C in a sterile bag and transported to the laboratory; and (g) wound suture (number 5 blue nylon) and dressing. Aspirated tissues were digested with collagenase I (1 mg/mL) under gentle agitation for 60 minutes at 37°C. The digested tissues were filtered through a 100‐mm nylon sieve to remove cellular debris and were centrifuged to obtain a pellet. The pellet was resuspended in Dulbecco’s modified Eagle’s medium (Invitrogen, USA)‐based media containing 0.2 mM ascorbic acid and 10% fetal bovine serum (FBS). The cell suspension was recentrifuged. The supernatant was removed and the pellet was collected. The cell fraction was cultured for 4–5 days in Keratinocyte‐SFM (Invitrogen, USA)‐based media containing 0.2 mM ascorbic acid, 0.09 mM calcium, 5 ng/mL recombinant epidermal growth factor (rEGF), and 5% FBS until confluent (passage 0). When the cells reached 90% confluency, they were passaged. AD‐MSCs from the control group were also cultured until passage 1. The cells were then frozen and stored at liquid nitrogen cell storage (−196°C), which might be the most common method of storing cells safely for a long period in most laboratories. All of the AD‐MSCs used in this study were collected at passage 3. Culture‐expanded cells were then tested for cell number, viability, purity (CD31, CD34, CD45), identity (CD 73, CD 90), sterility (bacterial and fungal), and endotoxin and mycoplasma contamination as recommended by the Code of Federal Regulations, Title 21 (21CFR), before shipping. Cultured AD‐MSCs maintained a survival rate of more than 80% for 72 hours at 2°C–8°C. This high level of purity was demonstrated by the consistent expression of positive or negative surface antigen for MSC up to 72 hours. Thus, the cells were made and shipped on the day of injection, with a survival rate of at least 87% (average 92.8%) for 72 hours. And the MSCs were injected into the knee joint in the outpatient clinic within an hour after being delivered to the hospital. Three weeks after lipo aspiration, the intra‐articular injections were administered in the two groups." Stem cell injection Participants received one "intra‐articular implantation of 1 × 108 cells of AD‐MSCs in 3 mL of saline in the knee joint under the ultrasound guidance. Intra‐articular injection was performed by a specialized physician who was not involved in the entire evaluations of the participants." Placebo injection Participants in the control group received a single "intra‐articular injection of placebo (5 ml normal saline) in the knee joint under ultrasound guidance. Intra‐articular injection was performed by a specialized physician who was not involved in the entire evaluations of the participants." Post‐intervention "The rescue analgesic was defined as an approved medication for pain control. The rescue medication that was permitted was acetaminophen at a dose of 4,000 mg or less per day. Other analgesics were not permitted, and any medications that patients were taking were recorded. If the participant had an osteoarthritis medication, the drug was discontinued for 2 weeks as a wash‐out period."
Outcomes	Outcomes were measured at 1, 3, and 6 months follow‐up. Primary outcome WOMAC index score Secondary outcomes VAS (0 to 10) to measure knee pain change from baseline scores Knee Injury and Osteoarthritis Outcome Scores (KOOS) WOMAC pain, stiffness and function subscales change from baseline scores Knee range of motion (degrees), quadriceps power, presence of joint effusion, presence of joint crepitus, presence of medial joint line tenderness, and presence of pes anserine tenderness. Radiographic assessments: Kellgren‐Lawrence grade, joint space width (medial and lateral compartments) Hip‐knee‐ankle (HKA) angle MRI assessment: size and change of cartilage defect; depth of cartilage defect assessed using the modified Noyes grading system Adverse events: severity of adverse events was based on the National Cancer Institute‐Common Terminology Criteria for Adverse Events (NCI‐CTCAE). When adverse events occurred, the cause‐and‐relationship between injection and adverse events was recorded according to the WHO‐Uppsala Monitoring Centre causality assessment system. Outcomes used in this review at 3 and 6 months VAS pain (0 to 10, 0 no pain) WOMAC function sub‐scale change from baseline scores (0 to 68, 0 best function) AEs
Notes	Funding: This study was supported by the R‐Bio Co., Ltd. Trial registration: ClinicalTrials.gov (National Institutes of Health number: NCT02658344) Data analysis: Authors reported change scores from baseline to 6 months for the stem cell group but not the control group, however results for joint space width were not provided either in the figure or text. We extracted mean pain (VAS 0 to 10 from figure 3A) and function (WOMAC function sub‐scale 0 to 68 figure 2D) using Plotdigitizer. We transformed function scores to a 0 to 100 scale. For WOMAC function, we imputed SDs from baseline as no SDs were reported at follow‐up. For pain, the only variance reported at follow‐up was the SD in the stem cell group at 3 months (1.5) and we used it at all follow‐ups for both stem cell and placebo groups. Withdrawals: zero events in both groups Adverse events Stem cell injection Serious adverse events: 0/12 Non‐serious adverse events: 10/12 participants: 6 arthralgia, 2 joint effusion, 2 undefined. CTCAE criteria: Grade 1 (22 events), Grade 2 (9 events), Grade 3 (3 events, arthralgia). All treatment‐related adverse events were recovered by the use of intermittent acetaminophen. Placebo group: Serious adverse events: 0/12 Non‐serious adverse events: 7/12 participants: 1 joint effusion, 6 undefined. Grade 1 (11 events), Grade 2 (1 event). All treatment‐related adverse events were recovered by the use of intermittent acetaminophen.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Trial was reported to be randomised but method of random sequence generation not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not explicitly reported.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both physician and participants were unaware whether the injection was ADMSCs or saline.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	As participants were blinded, there is low risk of bias in the measurement of self‐reported outcomes.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	Clinical evaluation was performed by a blinded physician; radiological evaluations were performed by a blinded musculoskeletal radiologist.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No patients were lost to follow‐up at 6 months.
Selective reporting (reporting bias)	High risk	Some outcomes listed with ClinicalTrials.gov Registry were not reported in the published paper, including SF‐36 questionnaire (health survey), arthroscopy evaluation data to evaluate change in cartilage defect at the time of injection (baseline) and 24 weeks, International Documentation Committee (IKDC) tool and knee ligament laxity at 12 and 24 weeks. Measures of variance were not reported for most outcomes.
Other bias	Low risk	None apparent.

Lu 2019.

Study characteristics
Methods	Study design: 2‐centre, double‐blind, parallel, randomised, active‐controlled, phase IIb clinical trial Setting: 2 clinical centres in the People’s Republic of China: Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University and The General Hospital of Chinese Armed Police Trial time period: between Nov 2013 and Nov 2016 Interventions: intra‐articular injection of human adipose‐derived mesenchymal progenitor cells (haMPCs) (5 x 107cells, approx. 2.5 mL) versus hyaluronic acid (HA) (1% sodium hyaluronic acid; 25 mg/2.5 mL) Sample size calculation: Given the lack of safety and efficacy data of intra‐articular human adipose‐derived mesenchymal progenitor cells (haMPCs) with other active comparators in patients with OA at the time of study design, the sample size was based on other mesenchymal progenitor cell (MPC) clinical trials for other indications. Analysis: intention‐to‐treat (ITT). All data presented are on an ITT/last observation carried forward basis.
Participants	Number of participants: No. screened for eligibility: 61 No. excluded: 8 (not meeting inclusion criteria = 6, declined to participate = 2) No. randomised: 53 (26 to the haMPCs group and 27 to the HA group) No. included in analyses: 47 (23 in the haMPCs group and 24 in the HA group) Inclusion criteria: Patients aged between 18 and 70 years Definite diagnosis of knee OA according to ACR clinical classification criteria for knee OA Pain in knee joint Below grade 4 on Kellgren and Lawrence criteria Exclusion Criteria: History of allergy or allergic constitution Concomitant severe infection, malignant tumour, coagulation disorder, or uncontrolled or unmanageable systemic diseases Presence of other types of arthritis except OA Intra‐articular injection of hyaluronic acid (HA) or corticosteroid in the preceding 2 months Pregnant or breastfeeding women Baseline characteristics: haMPC (Rejoin®) group (26 participants): Mean (SD) age: 55.03 (9.19) No. male/female: 3/23 Mean (SD) duration of symptoms in months: 53.62 (41.24) Mean (SD) BMI: 24.27 (3.04) No. (%) Kellgren‐Lawrence grading: Grade 1: 1 (3.85), Grade 2: 9 (34.62), Grade 3: 16 (61.54) Mean(SD) VAS left knee: 5.27 (2.27) Mean(SD) VAS right knee: 5.50 (2.48) Mean(SD) VAS both knees (calculated): 5.38 (2.37) Mean (SD) WOMAC pain sub‐scale: 7.69 (4.08) Mean (SD) WOMAC stiffness sub‐scale: 2.42 (1.94) Mean (SD) WOMAC function sub‐scale: 23.65 (14.60) Mean (SD) WOMAC total scores: 33.77 (19.99) Mean (SD) SF‐36: 81.35 (17.16) HA group (27 participants): Mean (SD) age: 59.64 (5.97) No. male/female: 3/23 Mean (SD) duration of symptoms in months: 63.81 (34.14) Mean (SD) BMI: 24.26 (2.59) No. (%) Kellgren‐Lawrence grading: Grade 1: 2 (7.69), Grade 2: 8 (30.77), Grade 3: 16 (61.54) Mean(SD) VAS left knee: 4.92 (2.56) Mean(SD) VAS right knee: 4.96 (2.46) Mean(SD) VAS both knees (calculated): 4.94 (2.5) Mean (SD) WOMAC pain sub‐scale: 7.23 (3.68) Mean (SD) WOMAC stiffness sub‐scale: 2.58 (1.79) Mean (SD) WOMAC function sub‐scale: 22.35 (13.29) Mean (SD) WOMAC total scores: 32.15 (18.07) Mean (SD) SF‐36: 87.04 (16.66) Pre‐treatment group differences: Participants were similar at baseline in terms of height, weight, body mass index, radiographic grade of osteoarthritis, cartilage volume of both knees by MRI, previous treatment history, and concomitant disease, with a slightly younger age in the stem cell group.
Interventions	Stem cell preparation Adipose tissue was obtained from abdominal subcutaneous by liposuction with local anaesthetic. Isolation and culture of haMPCs were performed under Good Manufacturing Practice (GMP) conditions. Stem cell injection Intra‐articular injection of Re‐Join® (in‐vitro expanded haMPCs) 5 x 107 haMPCs (around 2.5 mL) administered at weeks 0 and 3. Sham injection was performed at weeks 1 and 2 (no details provided). Hyaluronic acid injection Intra‐articular injection of 1% sodium hyaluronic acid (ARTZ Dispo; 25mg/2.5mL; Seikagaku Corporation, Japan), administrated once per week for 4 weeks (week 0, 1, 2 and 3) Post‐intervention Patients were advised to rest for 24 hours following each injection.
Outcomes	Outcomes were measured at baseline (prior to first injection), 1 week after injection, and follow‐up visits at 6 months and 12 months Outcomes: WOMAC total and pain, stiffness and function subscale scores VAS of left and right knees (0 to 100) SF‐36 Questionnaire (36‐item health survey, consisting of 8 scaled scores to measure health‐related quality of life) Improvement rate (20%, 50% and 70% improvement) was calculated for WOMAC, VAS and SF‐36, which was reported as the percentage of change of score in each time point of follow‐up MRI of knees Safety profiles Outcomes used in this review: WOMAC function sub‐scale scores Improvement (50%) of WOMAC total score VAS (0 to 10) to measure pain SF‐36 scores (baseline, 6 months, 12 months) Adverse events Serious adverse events Time points used in this review: Assessments were performed at screening, at baseline (prior to the first injection), 1 week after injection, and at follow‐up visits after 6 and 12 months.
Notes	Funding: Provided by the Cellular Biomedicine Group and the National Key Research and Development Program of China (Grant No. 2017YFC1103900 and 2018YFB1105600). Cellular Biomedicine Group did not in any way try to suppress information or influence the conclusions of the study authors. Chengxiang Dai, Suke Li, and Li Zhang are current employees and stock option holders of the Cellular Biomedicine Group (Nasdaq: CBMG). The other authors declare that they have no competing interests. Data analysis: Authors presented VAS data separately for right and left knees; we assumed only one knee was treated, and we do not know which one it was. This may invalidate the reporting of pain, as we think the authors pooled the scores for a treated and untreated knee. Thus, we extracted WOMAC pain instead based on the assumption that the authors assessed the outcome in relation to the treated knee. We transformed function scores to a 0 to 100 scale and transformed pain scores to 0 to 10. Trial registration: ClinicalTrials.gov (National Institutes of Health number: NCT02162693) Withdrawals: 3/26 in the haMPC (Re‐Join®) group were lost to follow‐up (unknown reasons 2, joint arthroplasty 1) and 2/27 in the HA group (withdrawal due to knee infection treated with articular cavity flushing operation = 1; unknown reason = 1) Adverse events haMPC (Rejoin®) group: Serious adverse events: 0 Total adverse events: 19 (73.07%) (the most common adverse events were transient pain and swelling of the injection site joint, all of which were mild to moderate and were spontaneously relieved within 7 days without special treatment). HA group: Serious adverse events: 1 (infection of right knee after 2 months of first injection. This was relieved after articular cavity flushing operation and the patient withdrew from the study). Total adverse events: 14 (53.85%) (most common adverse events were transient pain and swelling of the injection site joint, all of which were mild to moderate and were spontaneously relieved within 7 days without special treatment).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random sequence using PROC PLAN in SAS by a biostatistician.
Allocation concealment (selection bias)	Low risk	Allocation was performed centrally by a biostatistician.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote "Preparation for injection and the intra‐articular injection was performed in two different clean rooms by a trained investigator (separate from the evaluator). A curtain was used to prevent patients from seeing the injection procedures". Participants and investigators were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	Radiologists assessing knee cartilage volume were unaware of treatment assignments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups: 3/26 in the stem cell group (unknown reasons 2, joint arthroplasty 1); 2/27 in the HA group (withdrawal due to knee infection treated with articular cavity flushing operation 1; unknown reason 1).
Selective reporting (reporting bias)	Low risk	All outcomes planned in the trial registration were reported.
Other bias	Low risk	None apparent.

Matas 2019.

Study characteristics
Methods	Study design: single‐centre, 3‐arm, parallel, double‐blind, randomised controlled trial Setting: University of Los Andes Clinical Centre, Santiago, Chile Trial time period: between November 2015 and January 2016 Interventions: single‐dose stem cell injection versus double‐dose stem cell injection versus hyaluronic acid (HA) injection Sample size calculation: not reported Analysis: not reported
Participants	Number of participants Number screened for eligibility: 40 Number excluded: 11 (10 not meeting inclusion criteria, 1 declined to participate) Number randomised: 29 (10 to the single‐dose stem cell group, 10 to the double‐dose stem cell group, 9 to the HA group) Number included in analyses: 26 (9 in the single‐dose stem cell group, 9 in the double‐dose stem cell group, 8 in the HA group) Inclusion criteria 40 to 65 years of age Symptomatic knee OA (defined by daily pain at the affected joint for at least 3 months before inclusion) Grade 1 to 3 Kellgren‐Lawrence radiographic changes in the targeted knee, without meniscal rupture Exclusion criteria Bilateral symptomatic knee OA Condylar or tibial‐plateau generalised bone marrow oedema on MRI Major axial deviation defined by valgus (> 10°) or varus (5°) deformity of the involved leg Use of oral or intra‐articular steroids or hyaluronic acid in the past 6 months Ipsilateral hip or ankle pain Local or systemic infection Any form of secondary arthritis Previous malignancy Body mass index ≥ 30 Baseline characteristics Double‐dose stem cell injection group (10 participants) Mean (SD) age: 56.7 (4.1) years; 5 female, 5 male Mean (SD) BMI (kg/m2): 27.4 (2.6) No. (%) Kellgren‐Lawrence grading: Grade 2: 6 (60); Grade 3: 4 (40) Mean (SEM) WOMAC total (0 to 96, 0 best score): 35.6 (10.1) Mean (SEM) WOMAC pain (0 to 20, 0 no pain): 8.1 (2.1) Mean (SEM) WOMAC stiffness (0 to 8, 0 no stiffness): 2.8 (1.2) Mean (SEM) WOMAC function (0 to 68, 0 best function): 23.8 (9.2) Mean (SD) VAS (0 to 100, 0 no pain): 39.4 (21.4) Mean (SD) SF‐36 physical (0 to 100, 100 best quality of life): 60 (18.4) Mean (SD) SF‐36 pain (0 to 100, 100 no pain): 57.8 (19) Mean (SD) WORMS (0 to 332 points): 40.1 (25.7) Single‐dose stem cell injection group (10 participants) Mean (SD) age: 56.1 (6.8) years; 4 male, 6 female Mean (SD) BMI (kg/m2): 27.6 (2.6) No. (%) Kellgren‐Lawrence grading: Grade 2: 5 (50); Grade 3: 5 (50) Mean (SEM) WOMAC total (0 to 96, 0 best score): 37.4 (12.8) Mean (SEM) WOMAC pain (0 to 20, 0 no pain): 9.3 (3.0) Mean (SEM) WOMAC stiffness (0 to 8, 0 no stiffness): 2.9 (1.1) Mean (SEM) WOMAC function (0 to 68, 0 best function): 25.3 (8.5) Mean (SD) VAS (0 to 100, 0 no pain): 44.8 (16.5) Mean (SD) SF‐36 physical (0 to 100, 100 best quality of life): 46.9 (16.5) Mean (SD) SF‐36 pain (0 to 100, 100 no pain): 48.9 (24) Mean (SD) WORMS (0 to 332 points): 46.1 (18.1) Hyaluronic acid injection group (9 participants) Mean (SD) age: 54.8 (4.5) years; 5 female, 4 male Mean (SD) BMI (kg/m2): 27.9 (3.4) No. (%) Kellgren‐Lawrence grading: Grade 2: 7 (77); Grade 3: 2 (23) Mean (SEM) WOMAC total (0 to 96, 0 best score): 28.9 (13.3) Mean (SEM) WOMAC pain (0 to 20, 0 no pain): 7.0 (2.7) Mean (SEM) WOMAC stiffness (0 to 8, 0 no stiffness): 3.2 (1.2) Mean (SEM) WOMAC function (0 to 68, 0 best function): 18.7 (10.9) Mean (SD) VAS (0 to 100, 0 no pain): 38.7 (19.4) Mean (SD) SF‐36 physical (0 to 100, 100 best quality of life): 51.3 (20.8) Mean (SD) SF‐36 pain (0 to 100, 100 no pain): 48.4 (19.4) Mean (SD) WORMS (0 to 332 points): 30.9 (25.1) Pre‐treatment group differences: Stem cell‐treated groups tended to have more severe baseline disease as gauged by the total WOMAC score and the K‐L grading in the single‐dose and double‐dose stem cell groups (50% and 40%) as opposed to the HA group (23%).
Interventions	Stem cell preparation "Umbilical cords were obtained from full‐term human placentas and aseptically stored in sterile phosphate‐buffered saline (PBS) supplemented with 100 U/mL penicillin and 100 μg/mL streptomycin (Gibco, Grand Island, NY, U.S.). Within 3 hours of birth, the umbilical cord was sectioned and washed with PBS and antibiotics. Wharton’s jelly was dissected into small fragments (1 to 2 mm), seeded in 100‐mm culture plates, and maintained in Minimum Essential Medium Eagle (MEM) Alpha Modifications (Alfa‐MEM) high glucose (Gibco, Grand Island, NY, U.S.) supplemented with 10% heat‐inactivated foetal bovine serum (Gibco, U.S.), 1% penicillin/streptomycin, and 2 mM L‐glutamine (Gibco, Grand Island, NY, U.S.). At 48 hours, nonadherent cells were removed and washed with PBS, and culture medium was replaced with fresh medium every 3 days. When the cell culture reached 70% to 80% confluence, cells were detached by treatment with TrypLETM Express (Gibco, Grand Island, NY, U.S.) and reseeded at a density of 2,500 cells per cm2 into 500‐cm2 flasks (Nunc, Denmark). At passage 3, umbilical cord mesenchymal stem cells (UC‐MSC) were characterised according to the International Society for Cellular Therapy Guidelines, harvested, and cryopreserved in Profreeze (Lonza, Walkersville, MD) following the manufacturer’s instruction. For the trial, cells were thawed and expanded until passage 5 using Alfa‐MEM supplemented with 10% AB plasma. Cells were detached by treatment with TrypLETM Express and washed twice with PBS prior to final suspension and packaging. The release criteria for clinical use of UC‐MSC comprised the absence of macroscopic clumps, contaminating pathogenic microorganisms (bacteria, mycoplasma, syphilis, hepatitis B virus, hepatitis C virus, HIV, cytomegalovirus, and fungi), or endotoxin (≤0.5 EU/mL); and a viability >80%, with an identity and purity pattern characterized by ≥95% positivity for CD73, CD90, and CD105, and negativity (≤2%) for the expression of CD45, CD34, CD14, and Human Leukocyte Antigen‐DR isotype (HLA‐DR). Cells (20 × 106) were suspended in a final volume of 3 mL (saline solution, 5% AB plasma) and dispensed in masked 5‐mL syringes to treat individual patients accordingly with the study design." Stem cell injections Single stem cell injection Intra‐articular UC‐MSCs injection containing 20 × 106 UC‐MSCs in 3 cc of saline with 5% AB plasma given only at baseline, followed by placebo injection at 6 months Two stem cell injections Intra‐articular UC‐MSCs injections containing 20 × 106 UC‐MSCs in 3 cc of saline with 5% AB plasma given at baseline and 6 months Hyaluronic acid injection HA injections contained 3 cc of Durolane and placebo injections contained 5% AB plasma in 3 cc of saline Post‐intervention "Patients were encouraged to avoid physical activity for 48 hours after the procedure. Acetaminophen (1 g every 8 hours) was allowed as needed in case of pain."
Outcomes	Outcomes were measured at 1, 4, 8, 12, 24, 36 and 52 weeks Primary Outcome Safety of UC‐MSC treatment, according to the number of treatment‐related adverse events (AEs) reported for each study group as coded by the Common Terminology Criteria for Adverse Event classification Secondary Outcomes Efficacy, as assessed by the following validated clinical outcome scales: Western Ontario and Mc Master Universities Arthritis Index (WOMAC) Spanish validated Likert version. WOMAC was registered according to Likert Scale version using the following descriptors for each item: none (0), mild (1), moderate (2), severe (3) and extreme (4). Final scores are the sum of items in each sub‐scale, ranging 0 to 20 for pain, 0 to 8 for stiffness, and 0 to 68 for physical function. Pain VAS Quality of life by the Short‐form‐36 (SF‐36) questionnaire ‐ Physical scale and pain scale Patient Global Assessment Outcome Measures in Rheumatology Committee (OMERACT) ‐ Osteoarthritis Research Society International (OARSI) Responder Index Criteria Knee MRI assessments were performed and assessed blindly by a single radiologist at baseline, at 6 months, and at 12 months, according to the Whole‐Organ Magnetic Resonance Imaging Score Outcomes included in the review at 6 and 12 months Mean overall pain, on VAS (0 to 100, 0 no pain) Mean function on WOMAC function subscale (0 to 68, 0 best function)
Notes	Funding: unclear Trial registration: NCT02580695 (ClinicalTrials.gov) Data analysis: Authors reported results for outcomes only at 6 and 12 months. As noted in the methods, we combined the two intervention groups (MSC‐1 and MSC‐2) and compared the combined treatment group to the HA group in the usual way. We transformed the WOMAC function subscale (0 to 68, 0 best function) to a 0 to 100 scale. We transformed VAS scores (0 to 100) to 0 to 10, 0 no pain. Withdrawals: 1/10 in the single‐dose stem cell group (discontinued intervention); 1/10 in the double‐dose stem cell group (discontinued intervention); 1/9 in the HA group (spontaneous withdrawal) Adverse events Single‐dose stem cell group Serious adverse events: 0/10 Non‐serious adverse events: 4/10 participants: 3 synovitis, 1 pain after injection Double‐dose stem cell group Serious adverse events: 0/10 Non‐serious adverse events: 10/10 participants: 7 synovitis, 3 pain after injection HA group Serious adverse events: 0/10 Non‐serious adverse events: 7/10 participants: 5 synovitis, 2 pain after injection
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The method of random sequence generation was not described.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not clearly reported.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and investigators were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	The radiologist conducting the knee MRI assessments was unaware of treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups: 1/10 in the MSC‐1 group (discontinued intervention); 1/10 in the MSC‐2 group (discontinued intervention); 1/9 in the control group withdrew from the study.
Selective reporting (reporting bias)	High risk	Trial was registered with ClinicalTrials.gov. Outcomes that were not listed in the ClinicalTrials.gov registry, but published in this paper include Patient Global Assessment, and the Outcome Measures in Rheumatology Committee (OMERACT)‐Osteoarthritis Research Society International (OARSI) Responder Index Criteria. Authors conducted outcome assessments at 1, 4, 8, 12, 24, 36 and 52 weeks but reported results only at 24 and 52 weeks.
Other bias	Low risk	None apparent.

Ren 2023.

Study characteristics
Methods	Study design: single‐centre, within‐participant, randomised, open‐label trial: one knee received active treatment and one no treatment Setting: Wuhan, China Trial time period: December 2016 to January 2019 Interventions: autologous stromal vascular fraction therapy injection versus no treatment Sample size calculation: not reported Analysis: completers analysis
Participants	Number of participants Number screened for eligibility: not reported Number excluded: not reported Number randomised: 6 (6 knees to the BMC group and 6 knees to the no treatment group) Number included in the analysis: 6 (6 knees in the BMC group and 6 knees in the no treatment group) Inclusion criteria: Aged 35 to 70 years Both knee joints with articular cartilage defect grades I/II Body mass index (BMI) less than 35 kg/m2 Exclusion criteria: Serious medical disorders Previous major knee trauma Mechanical pain caused by severe meniscus injury Autoimmune or inflammatory arthritis Intra‐articular hyaluronic acid or corticosteroid injection in the preceding 3 months Previous arthroscopic or open surgery treatment for knee OA in the past 6 months Inability to provide informed consent Baseline characteristics Stem cell injection group (6 knees) Mean (SD) age, years: 62.17 (6.34 years) No. (%) female: 5 (83.3) Mean (SD) WOMAC total (0 to 96, 0 best score): 85.33 (22.19) Mean (SD) Lysholm score: 42.50 (15.76) No treatment group (6 knees) Mean (SD) age, years: 62.17 (6.34 years) No. (%) female: 5 (83.3) Mean (SD) WOMAC total (0 to 96, 0 best score): 85.33 (22.19) Mean (SD) Lysholm score: 42.50 (15.76)
Interventions	Stem cell preparation "The adipose tissue harvest and subsequent stromal vascular fraction (SVF) cells processing protocols were followed within the guidelines of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). On the day of SVF injection, subcutaneous adipose tissue was harvested from the patients’ abdomen by liposuction with tumescent technique. Through a small incision, a 3.7 mm hollow blunt‐tipped cannula was inserted into the abdominal subcutaneous tissue of the subject, and tumescent solution (0.9% saline solution supplemented with 2% lidocaine, 8.4% sodium hydrogen carbonate, and 0.1% epinephrine) was administered into adipose tissue through infiltration before aspiration. Liposuction with a target volume of about 200–250 mL was collected directly into a sterile tissue‐processing container to produce SVF. After the liposuction procedure, pressure bandages were applied around the abdomen for 48 h. The adipose tissue was then transported to the certified cell therapy laboratory. The adipose tissue was washed twice in PBS and digested through mixing with collagenase Type I (Washington Biochemical Corp., NJ, USA) at 37° C for 30 min with agitation at 5‐min intervals. Afterwards PBS‐EDTA was added to stop collagenase activity. The solution was then centrifuged at 800 g for 10 min to collect the cell pellet. The supernatant, including all debris, floating cells and the aqueous phase, was removed and discarded. The pellet was resuspended with normal saline 0.9% to obtain 3 mL of cell solution containing 108 SVF cells for injection into each knee joint." The SVF cells processing time from the end of adipose tissue harvest to prepared SVF cells in syringe for injection was 120 to 150 min. The aliquot SVF cells were sent to a national certified laboratory for quality control testing. "The two knees of each patient were randomly assigned to an autologous SVF (108 cells) treatment group or non‐treatment control group." Stem cell injection The SVF injections were completed in the operating room. The patient was kept in a supine position on the operating table. Under local anaesthesia with 1% lidocaine and ultrasound guidance, 2 mL of 108 SVF cell suspension was injected into the medial side of the knee joint. The injection site was disinfected with povidone‐iodine solution and covered with a sterile bandage. After injection, the participant's knee was kept in zero load state for 48 hours. No treatment The 6 control knees did not receive any treatment. Co‐interventions None reported
Outcomes	Outcomes were assessed every 4 weeks until 24 weeks. Study outcomes: Knee pain, functional mobility and physical disability were assessed using the WOMAC patient questionnaire and the Lysholm knee scale. MRI evaluation of cartilage thickness Adverse events Outcomes used in this review Mean change from baseline in WOMAC and Lysholm scores are reported at 12 and 24 weeks, but it is unclear if the results are reported for the knees receiving stem cell injections or if participants reported the score for both knees. No control values appear to be reported.
Notes	Funding: Wuhan University Zhongnan Hospital Research Fund (No. RCKY20150101), National Natural Science Foundation of China Grant (Nos. 81571558 and 81870162) and Fundamental Research Funds for the Central Universities (Grant No. 413000333). Trial registration: NCT05019378 Withdrawals: none in either group Adverse events: none occurred in both groups
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not described.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and investigators were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	The outcome assessor was unaware of treatment assignments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals.
Selective reporting (reporting bias)	High risk	Trial registered, however results for knee function were reported for the whole sample and not reported per group.
Other bias	Unclear risk	Each participant acted as their own control, with one knee receiving active treatment and one control, but it is unclear if data from the control knee were analysed.

Sadat‐Ali 2021.

Study characteristics
Methods	Study design: single‐centre, parallel, 2‐arm, open‐label randomised controlled trial Setting: King Fahd Hospital, University AlKhobar, Saudi Arabia Trial time period: not reported Interventions: autologous bone marrow‐derived chondrocytes (ABMDC) versus conservative therapy (NSAIDs, physical therapy, HA injection) Sample size calculation: not described Analysis: completers analysis
Participants	Number of participants Number screened for eligibility: 6 Number excluded: 0 Number randomised: 60 (30 in the stem cell group; 30 in the conservative therapy group) Number included in analyses: 57 (30 in the stem cell group; 27 in the conservative therapy group) Inclusion criteria Aged between 45 and 70 years of age Diagnosed with knee OA for at least 12 months based on American College of Rheumatology (ACR) criteria Unsatisfied with conservative therapy of NSAIDs and physiotherapy Exclusion criteria Past knee intra‐articular steroid or hyaluronic acid injection within the last 3 months Any knee surgery within the last 6 months Pregnancy and breast‐feeding (women of childbearing age need the pregnancy test) Mental disorders Drug dependency Baseline characteristics Stem cell injection group (30 participants) Mean (SD) age, years: 56.18 (6.56) No. (%) female: 24 (80) No. K‐L grades II and III: 18 Mean (SD) VAS pain: 6.65 (0.09) Mean (SD) Modified Knee Scoring Score‐Short Form: 37.40 (6.46) Mean (SD) daily living (0 to 10, scoring not reported): 4.49 (0.75) Mean (SD) quality of life (0 to 10, scoring not reported): 4.87 ± 1.09 Conservative therapy group (27 participants) Mean (SD) age, years: 56.75 (5.77) No. (%) female: 16 (53) No. K‐L grades II and III: 16 Mean (SD) VAS pain: 6.96 (1.1) Mean (SD) Modified Knee Scoring Score‐Short Form: 39.34 (6.83) Mean (SD) daily living (0 to 10, scoring not reported): 4.34 (0.97) Mean (SD) quality of life (0 to 10, scoring not reported): 5.25 (1.13)
Interventions	Stem cell preparation "Under general anaesthesia, 20 cc of bone marrow was aspirated from the patients’ iliac crest following standard procedures. (The aspirate was added to a sterile bone marrow transplantation medium (Hanks’ Balanced Salt Solution with 10,000 units/mL of penicillin, 10,000 μg/mL of streptomycin, and 25 μg/mL of amphotericin B). The samples were properly labelled and were immediately transported to the stem cell laboratory under ice‐cold conditions. Bone marrow in the transportation medium was overlaid on approximately 20 ml of sterile Ficoll‐Paque Plus (Merck KGaA, Darmstadt, Germany) taken in a conical centrifuge tube (Sarstedt AG & Co, Numbrecht, Germany) and centrifuged in a swing bucket centrifuge (Sorvall ST8, (ermo Fisher Scientific, Massachusetts, USA) at 2000 rpm for 5 minutes at 4°C. (the resultant layer containing mononuclear cells were siphoned out and seeded onto a T75 tissue culture flask (Greiner BioOne GmbH, Frickenhausen, Germany) at the rate of 5000 cells/cm. Approximately 20 ml of the MSC culture medium (CTS™ StemPro™ MSC SFM, Thermo Fisher, Massachusetts, USA) was added, and the flask was incubated at 37 C, with 5% CO2 and 95% RH in a CO2 incubator. Adherent cells were cultured, and the process was continued with change of the medium every second day till cells became confluent. (e cells were trypsinised, harvested, and used for chondrocyte differentiation. A portion of the cells was used for cell characterization using MSC specific antibodies in a flow cytometer (Human MSC Phenotyping Kit from Miltenyi Biotec (Auburn, CA, USA)). Positive expression of CD73, CD90, and CD105 and negative for CD45 were confirmed." Stem cell injection Participants received a single intra‐articular injection of ABMDC of 5 million cells. Participants did not receive any further treatment, including physical therapy. Conservative therapy Participants received NSAIDs, physical therapy and Durolane, a hyaluronic acid injection, as needed.
Outcomes	Outcomes were assessed at 3, 12 and 24 months Study outcomes VAS 10‐point for pain Short Knee Society score (100‐point scale), pain at rest (10‐point scale), pain on movement (10‐point scale), satisfaction with daily life (10‐point scale) and quality of life (10‐point scale) Adverse events Outcomes used in this review VAS 10‐point for pain Adverse events
Notes	Trial registration: not reported Funding: not reported Withdrawals: 0/30 in the stem cell group; 3/30 in the standard care group (3 underwent joint replacement) Adverse events Stem cell injection Non‐serious adverse events: 0/30 Serious adverse events: 0/30 Conservative therapy Non‐serious adverse events: 1/30; 1 participant had local cellulitis which was treated by oral antibiotics Serious adverse events: 3/30; 3 participants underwent joint replacement
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Random sequence generation was described as follows, and is not truly random: "the first 30 patients who agreed to be part of the chondrocyte treatment were part of Group I, and all second patients (30) who were being treated conservatively were Group II patients"
Allocation concealment (selection bias)	High risk	Allocation concealment was unlikely, given the quasi‐random allocation of participants to the treatment groups.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and investigators were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	No assessor‐reported outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small across groups (0/30 in the stem cell group; 3/30 in the conservative therapy group (3 underwent joint replacement)).
Selective reporting (reporting bias)	High risk	Trial does not appear to be registered and no study protocol was found.
Other bias	Low risk	None apparent.

Sadri 2023.

Study characteristics
Methods	Study design: single‐centre, 2‐arm, triple‐blind (participant, investigator and outcome assessor), parallel, randomised, placebo‐controlled trial Setting: Shafa Yahyaian Hospital, Iran University of Medical Science, Iran Trial time period: between June 2019 and September 2021 Interventions: intra‐articular stem cell injection versus placebo (5 mL normal saline) injection Sample size calculation: An α risk of 0.05, power of 80%, mean difference in WOMAC score of 0.5, standard deviation of 0.5 were considered in this study, which resulted in the sample size of 16 participants per group, increased to 20 patients per group. Analysis: Completers' analysis
Participants	Number of participants Number screened for eligibility: 52 Number excluded: 12 (reasons not reported) Number randomised: 40 (20 to the stem cell group and 20 to the placebo group) Number analysed: 36 (18 in the stem cell group and 18 in the placebo group) Inclusion criteria Aged 18 to 65 years Kellgren‐Lawrence grading: II or III VAS Index Score ≥ 3 Knee joint alignment < 30 degrees Exclusion criteria BMI > 35 kg/m2 Immune deficiency Renal failure (Cr > 2 mg/dL) Hepatitis B, C, HIV, HTLV1‐2, CMV infections Coagulopathy or using anticoagulant agents Liver malfunction (ALT or AST > 100 IU/L) Uncontrolled diabetes (HbA1c > 8.5%) Heart diseases (EF < 45%) Allergy to proteins or cultured substances Pregnancy or lactation Malignancy Addiction Concurrent corticosteroid therapy Baseline characteristics Stem cell group (20 participants) Mean (SD) age, years: 52.8 (7.2) No. % female: 18 (90) No. % K‐L Grade 2: 11 (55); K‐L Grade 3: 9 (45) Mean (SD) VAS pain: 7.40 (1.35) Mean (SD) KOOS ADL: 32.80 (15.26) Mean (SD) WOMAC total: 58.35 (13.25) Mean (SD) SF‐36 MCS: 22.50 (19.70) Placebo group (20 participants) Mean (SD) age, years: 56.1 (7.2) No. % female: 18 (90) No. % K‐L Grade 2: 10 (50); K‐L Grade 3: 10 (50) Mean (SD) VAS pain: 7.73 (1.14) Mean (SD) KOOS ADL: 30.52 (14.43) Mean (SD) WOMAC total: 65.42 (14.63) Mean (SD) SF‐36 MCS: 15.78 (19.02)
Interventions	Stem cell preparation "Allogeneic AD‐MSCs were provided from GMP‐certifed allogeneic biobank by CellTech Pharmed Co. AD‐MSCs were isolated and cultured in IR‐FDA‐certifed clean room facility at CellTech Pharmed Co under PICS/GMP and ISO9001 regulations. The standard operating procedure for allogeneic AD‐MSCs isolation, preparation, and characterization was applied according to GMP regulation at CellTech Pharmed Co., an IR‐FDA certified cell production facility." A healthy donor (30 year‐old female), whose health was confirmed after physical exam and laboratory tests, underwent liposuction surgery under local anaesthesia and sterile conditions after signing informed consent. AD‐MSCs were isolated and cultured in the IR‐FDA GMP‐certified clean room facility, CellTech Pharmed Co. All procedures followed good manufacturing practice (GMP) conditions. The harvested abdominal subcutaneous tissue (250 to 300 mL) was washed with phosphate‐buffered saline (PBS) which contained antibiotics and was cut into 1 to 2 mm sections afterward. In the first stage, a combination of collagenase enzyme 0.2% and dispase protease was added to the adipose tissue with the same volume. The mixture was incubated for 15 to 30 min while being shaken every 5 min, then neutralised with fetal bovine serum (FBS) 10% culture media with 1:1 ratio. After centrifugation at 2000 rpm, the cells of the stromal vascular fraction (SVF) were collected in a conical tube and passed through a 0.7 µm mesh filter. In the next stage, the number of mononuclear cells (MNCs) in SVF was counted by a nucleocounter and 10 million MNCs were transferred into T‐175 flasks containing Dulbecco’s modified eagle’s medium (DMEM)‐F12 and FBS 10% culture media. The flasks were then kept for 3 days in the CO2 incubator at 37 ºC. Three days later, the supernatant was removed. Then, 25 mL of the culture media was added to the flasks. Culture media of the flasks was changed every 4 days for 3 weeks. At the end of the third passage, AD‐MSCs were harvested and cryopreserved in liquid nitrogen. Then, the cryopreserved AD‐MSCs were thawed before each transplantation. AD‐MSCs were thawed and suspended in NS solution 0.9% with a density of 100 × 106106 cells/5 mL and transported in a standard cool box at a temperature of 2 to 4 °C to the Shafa Yahyaian hospital for intra‐articular application. These allogeneic AD‐MSCs were received from a GMP certified biobank in Celltech Pharmed Co. Stem cell injection Participants received an intra‐articular single dose of 100 × 106 AD‐MSCs suspended in 5 mL normal saline under sterile conditions by an experienced orthopaedic surgeon. Placebo injection Participants received an intra‐articular single dose of 5 mL normal saline under sterile conditions by an experienced orthopaedic surgeon. Co‐interventions: Participants were "only allowed to take acetaminophen to alleviate the potential upcoming pain during this time."
Outcomes	Outcomes assessed at 3, 6 and 12 months Primary outcome: Change in WOMAC total score between baseline and 12 months Secondary outcomes: VAS (0 to 10 scale, 0 no pain) pain KOOS (0 to 100, 100 best function) total and 5 subscales: pain, symptoms, daily function, sport and recreation, and quality of life. Each item was scored on a Likert scale ranging from 0 to 4, where 0 represents no difficulty or symptom, and 4 represents extreme difficulty or severe symptoms. The KOOS score was calculated by summing the scores for each subscale and averaging them, which higher scores indicate better knee function and less severe OA symptoms. SF‐36 (0 to 100, 100 best quality of life) under 8 different subcategories, including physical functioning (PF), role physical (RP), body pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), mental health (MH) Adverse events evaluated by common terminology criteria for adverse events (CTCAE) version 4.0 Inflammatory biomarkers including cartilage oligomeric matrix protein (COMP), hyaluronic acid (HA), matrix metalloproteinase‐3 (MMP‐3), IL‐6, and IL‐10 in blood serum MRI assessment of cartilage thickness Outcomes used in this review: Mean function on KOOS ADL (0 to 100, 100 best function) Mean pain on VAS (0 to 10 scale, 0 no pain) SF‐36 mental health scores Adverse events
Notes	Trial registration: IRCT20080728001031N23 Funding: This work has received grants from Iran Ministry of Health and Medical Education and Royan Institute for Stem Cell Biology and Technology. The funding sources had no responsibilities in the study design; data collection, analysis, interpretation and manuscript writing. Data analysis: Function was extracted on the KOOS ADL subscale (0 to 100, 100 best function) and direction reversed so 0 is best function. Withdrawals: 2/20 in the stem cell injection group (1 death due to COVID‐19, 1 withdrew due to personal decision); 2/20 in the placebo injection group (1 refused to have final MRI due to claustrophobia, 1 withdrew due to personal decision) Adverse events Stem cell group Serious adverse events: 0/20 Non‐serious adverse events: 2/20 swelling and pain at the injection site, self‐limited Placebo group Serious adverse events: 0/20 Non‐serious adverse events: 0/20
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Permuted block randomisation, unclear how the random sequence was generated.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and investigators were unaware of treatment assignments.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignments.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	Outcome assessors were unaware of treatment assignments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across groups: 2/20 in the stem cell injection group (1 death due to COVID‐19, 1 withdrew due to personal decision), 2/20 in the placebo injection group (1 refused to have final MRI due to claustrophobia, 1 withdrew due to personal decision).
Selective reporting (reporting bias)	Low risk	Trial was registered and results for all outcomes reported.
Other bias	Low risk	None apparent.

Shapiro 2017.

Study characteristics
Methods	Study design: single‐centre, within‐participant randomised controlled trial (different interventions applied to each knee) Setting: Mayo Clinic, Jacksonville, Florida, USA Trial time period: November 2013 to February 2015 Interventions: stem cell injection into one knee versus placebo (saline) injection into the other knee Sample size calculation: The sample size of 25 patients was chosen primarily based on feasibility rather than on formal power calculations. Analysis: intention‐to‐treat
Participants	Number of participants Number screened for eligibility: not reported Number randomised: 25 (13 had BMAC to right knee, placebo to left knee and 12 had BMAC to left knee, placebo to right knee) Number included in analyses: 25 participants (50 knees) (25 knees in BMAC and 25 knees in placebo groups) Inclusion criteria Long‐standing, mild‐to‐moderate knee pain (Kellgren‐Lawrence Grades 1‐3) due to bilateral osteoarthritis, despite conventional medical therapy or arthroscopic intervention 'for a clinically appropriate period of time' (not defined in paper) Exclusion criteria Not reported Baseline characteristics Overall cohort (25 participants) Median (min, max) age: 60 (42, 68) years; 18 female, 7 male Median (min, max) BMI: 27.1 (18.4, 37.5) No. (%) prior knee surgery: 11 (44) No. (%) prior surgery on knee treated with BMAC: 9 (75) No. (%) prior surgery on knee treated with placebo: 3 (25) Stem cell injection group(25 knees) Median (min, max) VAS pain (0 to 10, 0 no pain): 3.1 (0, 8.1) Placebo injection group(25 knees) Median (min, max) VAS pain (0 to 10, 0 no pain): 2.9 (0, 7.0) Pre‐treatment group differences: none reported
Interventions	Stem cell preparation "Bone marrow was harvested from each superior iliac crest using a standard technique. After a 1‐cm stab wound with an 11‐blade scalpel, 26 mL of bone marrow from 3 sites on each iliac crest was harvested using a 11‐gauge Jamshidi bone marrow aspiration needle for a total of 52 mL of bone marrow aspirate. Aspirated marrow and anticoagulant citrate dextrose solution A were then passed through a sterile 170‐μm filter into a separate 60‐mL syringe to remove particulate matter. The resulting filtered marrow was transferred to a Magellan Autologous Platelet Separator System (Arteriocyte) for automated centrifugation in a dual spin technique (2800 rpm initial soft spin followed by 3800 rpm hard spin) for resulting marrow cell concentration. The concentration process yielded 6 mL of cellular product; 1 mL of concentrated cells was reserved for analysis that characterised a BMAC product containing a median of 56% mononuclear cells containing 150×106 white blood cells, 80×106 mononuclear cells, 4.4×106 haematopoietic stem cells (HSCs), and 34,000 MSCs in accordance with the minimal criteria for defining MSC set forth by the International Society for Cellular Therapy. These numbers are consistent with other published reports of BMAC (known to have only small numbers of MSCs). A median cell viability of 97% was determined for all samples by flow cytometry using 7‐AAD staining. No activating agent was added to the BMAC. Patients were blinded to the contents of each injection by a curtain hung just proximal to the patients’ thighs. Both knees were aspirated prior to injection. Treatment cells were combined with 10 mL of previously separated platelet‐poor bone marrow plasma to increase the volume of injectate to 15 mL within the knee to distribute the volume of injectate as best as possible throughout the suprapatellar pouch and knee compartments." Stem cell injection "Intraarticular injection of BMAC was performed into the randomly assigned knee through a superolateral approach under continuous ultrasound guidance. Every patient received an intra‐articular injection of BMAC into one knee, while a saline placebo was injected into the contralateral knee." Placebo injection "The contralateral knee was injected with 15 mL of sterile saline through a superolateral approach under continuous ultrasound guidance". Post‐intervention None reported
Outcomes	Outcomes measured at baseline, 1 week, 3 months, 6 months and 12 months Study outcomes Pre‐ and post‐injection magnetic resonance imaging (MRI) T2 quantitative mapping data to clarify the regenerative potential of BMAC VAS pain score (0 to 10, 0 no pain) Osteoarthritis Research Society International Intermittent and Constant Osteoarthritis Pain (ICOAP) questionnaire, measuring 5 outcomes of interest: Constant pain score Intermittent pain score Total pain score How much constant knee pain has affected quality of life How much intermittent knee pain has affected quality of life Algometry measures Radiographic K‐L score Quantitative T2 cartilage mapping using MRI at 6 months and radiographs at 12 months Adverse events (recorded at 12 months only) Outcomes included in the review at 3 months, 6 months and 12 months Median overall pain, measured on VAS (0 to 10, 0 no pain) Adverse events
Notes	Funding: Funding provided by Mayo Clinic Center for Regenerative Medicine. Trial registration: NCT01931007 Data analysis: Authors have reported medians, the measures of variance were minimum and maximum values, which they have named as range. We assumed the median approximates the mean and as we could not estimate SD from the data provided, we imputed it from Gupta 2016. The unit of analysis was the knee. The 12‐month data were taken from Shapiro 2018. Withdrawals: zero events in both groups Adverse events Stem cell injection group Serious adverse events: 0/25 knees Non‐serious adverse events: 12/25 knees: 2 effusions, 10 joint line tenderness Placebo injection group Serious adverse events: 0/25 knees Non‐serious adverse events: 9/25 knees: 1 effusion, 8 joint line tenderness
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐based randomisation.
Allocation concealment (selection bias)	Low risk	Allocation of one knee to stem cell and the other knee to placebo occurred simultaneously in each participant.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Participants were blinded, the physician giving the injection was unblinded, and it is likely the other personnel were unblinded, although this is not explicitly reported.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were shielded from the contents of each injection by a large curtain hung just proximal to their thighs such that they did not have knowledge of which knee was injected with stem cells or saline.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Unclear risk	Radiological outcomes were assessed by a single, fellowship‐trained, musculoskeletal radiologist and it is likely that they were not blinded, although this is not explicitly reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete data were reported for all participants at follow‐up.
Selective reporting (reporting bias)	High risk	Trial was registered with two outcome measures (adverse events and cartilage); but additional outcomes were reported (partially) in the results.
Other bias	Low risk	None apparent. Each participant acted as their own control and the between‐group analysis used paired tests, which was appropriate.

Vega 2015.

Study characteristics
Methods	Study design: multi‐centre, 2‐arm, parallel randomised controlled trial Setting: Valladolid University Hospital and Barcelona Teknon Medical Centre Trial time period: between April and September 2012 Interventions: stem cell injection versus hyaluronic acid injection Sample size calculation: sample size was determined based on the results from the previous trial for α risk = 0.05 and β risk = 0.20 Analysis: not reported
Participants	Number of participants Number screened for eligibility: not reported Number randomised: 30 (15 to the stem cell group and 15 to the HA group) Number included in analyses: 30 (15 in the stem cell group and 15 in the HA group) Inclusion criteria Grade II‐IV osteoarthritis, identified by two different observers, according to the Kellgren‐Lawrence grading scale Chronic knee pain of mechanical origin Absence of local or general infection Haematological and biochemical analyses with no significant alterations that contraindicate intervention Exclusion criteria Age under 18 or over 75 years, or legally dependent Signs of infection or positive serology for HIV, hepatitis or syphilis Congenital or acquired diseases leading to significant knee deformities that may interfere with cell application or the interpretation of results Obesity with a body mass index > 30 (calculated as mass in kg/height in m2) Pregnancy or breastfeeding Neoplasia Immunosuppression Intra‐articular injection of any drug during the previous 3 months Participation in another clinical trial or treatment with another investigational product within 30 days prior to inclusion in the study Other conditions that may, according to medical criteria, discourage participation in the study Baseline characteristics Stem cell injection group (15 participants) Mean (SD) age: 56.6 (SD not reported) years; 9 female, 6 male Mean (SE) VAS (0 to 100, 0 no pain): 54 (7) Mean (SE) WOMAC pain (0 to 20, 0 no pain): 46 (4) Mean (SE) WOMAC total (0 to 100, 0 best function): 41 (3) Mean (SE) SF‐12 physical (0 to 100, 100 best quality of life): 40 (9) Mean (SE) SF‐12 mental (0 to 100, 100 best quality of life): 54 (10) Hyaluronic acid group (15 participants) Mean (SD) age: 53.3 (SD not reported) years ; 10 female, 5 male Mean (SE) VAS (0 to 100, 0 no pain): 64 (7) Mean (SE) WOMAC pain (0 to 20, 0 no pain): 50 (4) Mean (SE) WOMAC total (0 to 100, 0 best function): 45 (3) Mean (SE) SF‐12 physical (0 to 100, 100 best quality of life): 35 (8) Mean (SE) SF‐12 mental (0 to 100, 100 best quality of life): 49 (9) Pre‐treatment group differences: none
Interventions	Stem cell preparation "Bone marrow mesenchymal stromal cells, were obtained from 3 healthy donors that were subjected to autologous MSC transplantation. Isolations were carried out with the following parameters (mean ± SD; n = 3): BM volume = 103 ± 8 mL, number of mononuclear cells obtained = 1.1 ± 0.5109, expansion time= 22 ± 2 days, number of MSC injected into the knee = 40x106 while suspended in Ringer‐lactate at 5x106 cells/mL, and viability greater than 98%. A serum sample from each donor was obtained to screen for human immunodeficiency, hepatitis B, and hepatitis C virus by Nucleic Acid Amplification Technology. Puncture and bone marrow (BM) aspiration were performed with the patient in a prone position. After local anaesthesia (20 mL of 1% lidocaine without epinephrine diluted v/v with saline) and under sterile conditions, several punctures with an 11‐G trocar under the iliac spine, aiming towards the posterior sacroiliac joint were performed. The aspirate was injected into a heparinised bag for transport, refrigerated to 4°C, conditioned, and transported to the cell production unit at 4 to 12°C within 24 hours of harvesting. The mononuclear cell fraction was isolated by density gradient centrifugation, resuspended, and cultured in MSC expansion culture medium in 175‐cm2 tissue culture flasks, with periodic washing to remove nonadherent cells. When cells reached 80% confluence, they were trypsinised and replated, and the process was repeated for 2 more passages. At the end of this period (21 to 24 days), cells were harvested, resuspended in Ringer lactate solution containing 0.5% human albumin (CSL Behring GmbH, Marburg, Germany) and 5mM glucose, and transported at 4 to 20°C to the hospital application. In addition to quality control tests, viability and flow cytometric immunophenotypic profiles were determined at this stage." Stem cell injection Intra‐articular injection of allogeneic bone marrow mesenchymal stromal cells (MSCs) 40 x 106 cells per knee from a 5 x 106 cell/mL suspension via a parapatellar approach was administered. Hyaluronic acid injection Intra‐articular injection of 60 mg of hyaluronic acid (Durolane) in a 3 mL single dose was administered. Post‐intervention None reported
Outcomes	Outcomes measured at baseline, 8 days, and 3, 6 and 12 months after implantation of either MSCs or HA. Outcomes Visual analogue scale (VAS) on a 0 to 100 scale Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scale from 0 to 100 where 0 is the least pain, stiffness or difficulty and 100 is the greatest pain, stiffness or difficulty Lequesne algofunctional indices Short form‐12 life quality (SF‐12) questionnaire scores Quantitative MRI exploration (T2 Relaxation Measurements) Adverse events (as measured by clinical review and using questionnaires for pain, disability and QOL) Outcomes included in the review at 3, 6 and 12 months Mean overall pain, measured on VAS Mean function ‐ WOMAC total scores Quality of life, measured by Short Form Health Survey (SF‐12) Adverse events
Notes	Funding: Financial support was provided by the Program for Support of Independent Clinical Research of the Spanish Ministerio de Sanidad (EC11‐309), Red de Terapia Celular (RD06/0010/0000 and RD12/0019/0036) of the Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, and the Centro en Red de Medicina Regenerativa de Castilla y León. Trial registration: Clinical trial registries: EudraCT 2011‐005321‐51, ClinicalTrials.gov: NCT01586312 Data analysis: Numerical data for VAS, WOMAC for 3 and 6 months were requested from the authors. We received the data from them for 100‐point VAS pain and WOMAC total scores (0 to 100, 0 best function). Mean age calculated by review authors from individual participant data. Withdrawals: zero events in both groups Adverse events Stem cell injection Serious adverse events: 0/15 Non‐serious adverse events: 14 participants: 23 events: 8 post‐implantation pain and synovial fluid effusion with articular swelling up to 1 week; 7 unexpected osteoarticular pain and inflammation (knee, shoulder, hip, ankle, lumbar); 8 miscellaneous ‐ menstrual disorders, influenza, migraine, toothache, restlessness, memory loss, testicular pain, rhinitis, sensitive hand alteration, sleepiness, allergic reaction, tinnitus, dental implant, lipoma, skin tumour Hyaluronic acid injection Serious adverse events: 0/15 Non‐serious adverse events: 13 participants: 25 events: 9 post‐implantation pain and synovial fluid effusion with articular swelling up to 1 week; 5 unexpected osteoarticular pain and inflammation (knee, shoulder, hip, ankle, lumbar); 11 miscellaneous ‐ menstrual disorders, influenza, migraine, toothache, restlessness, memory loss, testicular pain, rhinitis, sensitive hand alteration, sleepiness, allergic reaction, tinnitus, dental implant, lipoma, skin tumour
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisation in 1:1 ratio performed by the quality control manager of the cell production facility, who was blinded; however, the method of random sequence generation was not described.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not clearly described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and investigators were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	Low risk	Participants were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	The radiologist was unaware of treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals were reported.
Selective reporting (reporting bias)	Low risk	All outcomes planned in the trial registration were reported.
Other bias	Low risk	None apparent.

Zhang 2022.

Study characteristics
Methods	Study design: single‐centre, 2‐arm, parallel, single‐blinded randomised controlled trial Setting: Zhejiang Provincial Hospital of Chinese Medicine, China Trial time period: between 2013 and 2019 Interventions: intra‐articular stem cell injection versus hyaluronic acid injection Sample size calculation: not described Analysis: completers analysis
Participants	Number of participants Number screened for eligibility: 144 Number excluded: 18 declined to participate, preferring other treatment Number randomised: 126 (56 to the stem cell group and 70 to the HA group) Number analysed: 115 (51 in the stem cell group and 64 in the HA group) Inclusion criteria OA diagnosis met the diagnostic criteria in the American Rheumatism Association Revised Classification Criteria for Knee Osteoarthritis Kellgren‐Lawrence (K‐L) grade 2–3 Age 20 to 85 years No history of significant trauma Exclusion criteria Local infection of the knee joint Systemic diseases such as blood disorders or diabetes Rheumatoid arthritis, gout, autoimmune disease or malignancy in the past 5 years Prior injection or use of oral steroids within 3 weeks before screening Knee surgery within 6 months before screening Pain attributed to displaced meniscal tear and torn ligaments Baseline characteristics Stem cell group (56 participants) Mean (SD) age, years: 53.98 (13.69) No. (%) female: 42 (75%) No. (%) K‐L Grade: Grade 2: 41 (73.2%); Grade 3: 15 (26.8%) Mean (SD) VAS (0 to 10, 0 no pain) pain: 4.04 (1.46) Mean (SD) WOMAC total (0 to 96, 0 best score): 34.57 (22.85) HA group (70 participants) Mean (SD) age, years: 55.63 (12.18) No. (%) female: 54 (77.1%) No. (%) K‐L Grade: Grade 2: 46 (65.7%); Grade 3: 24 (34.3%) Mean (SD) VAS (0 to 10, 0 no pain) pain: 3.64 (0.98) Mean (SD) WOMAC total (0 to 96, 0 best score): 29.97 (19.87)
Interventions	Stem cell preparation "Adipose tissues of patients in SVF group were obtained from the abdomen by liposuction surgery performed by a skilled orthopaedic surgeon. The patient lay supine with full exposure of the abdomen. Routine sterilization and drape operation were performed. Local anaesthesia was applied to the abdomen with 10 mg/ml lidocaine (10 ml), two small incisions of approximately 5 mm were created around the umbilicus, and approximately 40 ml of abdominal subcutaneous adipose tissue was aspirated through a sterile syringe. The incisions were closed with sutures, and the abdomen was wrapped with pressure. Harvested adipose tissue was stored in a small freezer and transported to the laboratory. The adipose tissue was washed 3–5 times with PBS containing penicillin at a 2% concentration and then centrifuged at 1000 rpm for 5 min. The upper layer of adipose tissue was removed and cut to chyme with sterilization scissors. The chylomicron adipose tissue was collected in a clean 15 ml centrifuge tube with the addition of an appropriate amount of 1% collagenase type IV at 400 rpm and 37 °C for digestion. After that, the filtrate was collected through a 100‐mesh cell sieve and centrifuged at 1200 rpm for 5 min, and the supernatant was removed. The residual SVF pellet at the bottom was resuspended in PBS to a volume of 6 ml, in which 1 ml of the sample was retained for cell counting. The SVF was characterized by flow cytometry, and the constituent cell subpopulations of live nucleated SVF cells were shown as a percentage of the total number of live nucleated cells, without counting RBCs. The remaining 5 ml, with an average count of 4.84 million viable SVF cells according to the counting result, was used for injection. SVF was injected into the knee joint within one hour after successful preparation." Stem cell injection "The patient was placed in a supine position with the knee straight. Local sterilization was performed. 5 ml of SVF was injected into the joint cavity via a superior‐lateral approach under sterile technique by percutaneous puncture with a disposable syringe once a month for a total of three times. After the injection, a local sterile dressing was applied, and the patient was instructed to bend and extend the knee joint several times." Hyaluronic acid injection "HA was injected in patients of control group as described above at a dose of 5 ml once a month for a total of three times." Post‐injection protocol "Patients were instructed to be non‐weight bearing for two days and to undertake only light activity and avoid previously painful activities for the first 3 weeks after the injection. Patients were informed of the possibility of adverse reactions, including fever, swelling, or skin rash, after the injection and were asked to contact their physician immediately if any adverse reactions occurred during the follow‐up period. Patients should inform their physician if they suffer from knee pain and take pain medication during the follow‐up period."
Outcomes	Outcomes were assessed at 1, 2 and 3 years after treatment and every 2 years thereafter. Primary outcomes: Pain on VAS (0 to 10, 0 no pain) Function on WOMAC total score (0 to 96, 0 best score) Secondary outcomes: Radiographs to assess K‐L grading MRI assessment of cartilage change Adverse events Outcomes used in this review Pain on VAS (0 to 10, 0 no pain) Function on WOMAC total score (0 to 96, 0 best score)
Notes	Trial registration: ChiCTR2100052818 Funding: Zhejiang Provincial Natural Science Foundation of China under Grant No. LQ16H270007, National Natural Science Foundation of China under Grant No. 81873324 and National Natural Science Foundation of China under Grant No. 81603639. Data analysis: WOMAC total scores (0 to 96, 0 best score) were used for function after transforming to a 0 to 100 scale. Withdrawals: 5/56 (3 knee surgeries, 2 lost to follow‐up) in the stem cell group and 6/70 (6 knee surgeries) in the HA group Adverse events Stem cell injection Serious adverse events: 0/56 Non‐serious adverse events: 0/56 Hyaluronic acid injection Serious adverse events: 0/70 Non‐serious adverse events: 0/70
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random sequence.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and investigators were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, function, quality of life, treatment success, withdrawals due to adverse events, adverse events)	High risk	Participants were aware of treatment assignments.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (radiographic joint progression)	Low risk	Outcome assessors were not aware of treatment assignments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and balanced across groups: 5/56 (3 knee surgeries, 2 lost to follow‐up) in the stem cell group and 6/70 (6 knee surgeries) in the HA group.
Selective reporting (reporting bias)	Low risk	Trial registered and results for all pre‐specified outcomes reported.
Other bias	Low risk	None apparent.

Abbreviations: ABMDC: autologous bone marrow‐derived chondrocytes; ACR: American College of Rheumatology; ADL: activities of daily living; ADMSC: adipose‐derived mesenchymal stem cell; AE: adverse events; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMAC: bone marrow aspirate concentrate; BMC: bone marrow concentrate; BMI: body mass index; BML: bone marrow lesion; CMV: cytomegalovirus; CTCAE: Common Terminology Criteria for Adverse Events (CTCAE) classification of AE; ECG: electrocardiogram; EF: ejection fraction; G‐CSF: granulocyte colony stimulating factor; HA: hyaluronic acid; haMPC: human adipose‐derived mesenchymal progenitor cells; HTLV1‐2: human T‐cell leukaemia virus type 1 and 2; ICOAP: Intermittent and Constant Osteoarthritis Pain; IKDC: International Knee Documentation Committee; IQR: interquartile range; K‐L: Kellgren‐Lawrence (grade); KOOS: Knee Injury and Osteoarthritis Outcome Score; KSS: Knee Society Score; MCII: minimum clinically important improvement; MRI: magnetic resonance imaging; NRS: numerical rating scale; NSAID: non‐steroidal anti‐inflammatory drug; OA: osteoarthritis; PASS: Patient Acceptable Symptom State; PPP: platelet‐poor plasma; PRP: platelet‐rich plasma; QOL: quality of life; ROM: range of motion; SAE: serious adverse events; SD: standard deviation; SVF: stromal vascular fraction; UC‐MSC: umbilical cord mesenchymal stem cells; VAS: visual analogue scale; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; WORMS: Whole‐Organ Magnetic Resonance Imaging Score

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
ACTRN12616001259437	Ineligible intervention
Anonymous 2021	Ineligible study design
Bastos 2018	Ineligible comparator
Bhattacharya 2011	Ineligible study design
Brittberg 2018	Ineligible intervention
Centeno 2018	Ineligible intervention
ChiCTR‐ONN‐16009932	Ineligible study design
Conaghan 2023	Ineligible intervention
CTRI/2010/091/000270	Ineligible study design
EUCTR2010‐022072‐31‐GB	Ineligible intervention
Ha 2018	Ineligible intervention
Hernigou 2021	Ineligible intervention
Hong 2019	Ineligible intervention
ISRCTN13337022 2017	Ineligible study design
JPRN‐jRCTb032220282	Ineligible comparator
JPRN‐UMIN000026732	Ineligible study design
Khasru 2023	Ineligible intervention
NCT02776943	Ineligible intervention
NCT02958267	Ineligible intervention
NCT02963727	Ineligible study design
NCT02966951	Ineligible study design
NCT03308006	Ineligible study design
NCT03337243	Ineligible study design
NCT03602872	Ineligible study design
NCT03790189	Ineligible study design
NCT03956719	Ineligible study design
NCT04314661	Ineligible intervention
NCT04448106	Ineligible intervention
Olufade 2022	Ineligible intervention
Pham 2016	Ineligible intervention
Ruane 2021	Ineligible intervention
Saris 2022	Ineligible study design
Sekiya 2021	Ineligible study design
Turajane 2017	Ineligible intervention
Zhao 2019	Ineligible comparator

Characteristics of studies awaiting classification [ordered by study ID]

Aghdami 2014.

Methods	Study design: double‐blind, randomised, placebo‐controlled trial Setting: not reported Timing: not reported Interventions: intra‐articular injection of autologous bone marrow‐derived mesenchymal stem cells (BM‐MSC) vs placebo Sample size: not reported Analysis: not reported
Participants	Number of participants: No. screened for eligibility: not reported No. excluded: not reported No. randomised: 46 patients No. included in analyses: not reported Inclusion criteria: moderate to severe knee osteoarthritis Exclusion criteria: not specified
Interventions	Intervention: This group received intra‐articular injection of autologous bone marrow‐derived mesenchymal stem cells (BM‐MSC) (20 million cells, twice at day 0 and week 12) Control: This group received carrier media as placebo.
Outcomes	Primary outcomes: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)‐Total score, WOMAC‐Physical Function sub score, WOMAC‐pain sub score and VAS for pain at baseline and at the end of weeks 12, 24 and 36 Secondary outcomes: Pain‐free walking distance, cartilage thickness, subchondral oedema and tumour formation at 24 and 36 weeks
Notes	Abstract only. Full‐text publication not available. Funding: not reported Trial registration: not reported

Bakowski 2020.

Methods	Study design: double‐blind, randomised, placebo‐controlled trial Setting: Department of Spine Disorders and Pediatric Orthopedic Surgery, Poznan University of Medical Sciences and Rehasport Clinic in Poznan, Poland Timing: not reported Interventions: intra‐articular injection of autologous adipose‐derived mesenchymal stem cells vs PRP Sample size: not reported Analysis: not reported
Participants	Inclusion criteria: Symptomatic knee OA Age between 45 and 65 years Kellgren‐Lawrence grades I – III OA No or minimal positive effects of previous conservative treatment (rehabilitation, hyaluronic acid injections, steroid injections) VAS pain level minimum 4 in one knee, VAS pain < 2 in the contralateral knee Exclusion criteria: Use of local corticosteroids up to 3 months or hyaluronic acid injections up to 6 months prior to the study, past or present joint infection Previous knee arthroscopy surgery up to 1 year prior to examination Peripheral inflammatory diseases (rheumatoid arthritis, spondyloarthropathies, etc.) Total arthroplasty and osteotomy Ankylosis of the joint Dermatitis or dermatological disease at the intended injection site Coexistence of degenerative changes in other limb joints (hip, foot) Cancer Oral corticosteroid therapy Use of medicines that affect blood clotting Pregnancy or breast‐feeding
Interventions	Autologous adipose‐derived mesenchymal stem cell injection Platelet‐rich plasma injection
Outcomes	Outcomes will be measured at 1, 3, 6 and 12 months after the treatment. Study outcomes: Knee injury and Osteoarthritis Outcome Score (KOOS) International Knee Documentation Committee 2000 (IKDC 2000) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Health Questionnaire EQ‐ 5D‐ 5 L Timed Up and Go Test, 5 Times Sit to Stand Test, 10 m Walk Test
Notes	Study protocol Funding: Rehasport clinic, Poland Trial registration: NCT04321629

Dallo 2021.

Methods	Study design: single‐centre, 2‐arm, triple‐blind, parallel, randomised placebo‐controlled trial Setting: Bioresearch Foundation, Italy Trial time period: not reported Interventions: autologous microfragmented adipose tissue vs autologous leukoctye‐poor PRP+HA Sample size calculation: 50 Analysis: not reported
Participants	Early osteoarthritis (OA) symptoms
Interventions	Group 1 received 3 intra‐articular injections (1 month apart) using autologous LP‐PRP+HA Group 2 received a single dose of autologous microfragmented adipose tissue injection
Outcomes	Outcomes were measured by PROMs Tegner, Marx, VAS and Knee Injury and Osteoarthritis Outcome Score (KOOS) at 6 and 12 months.
Notes	Trial registration: not reported Funding: not reported Abstract only. Full‐text publication not available.

Fiolin 2020.

Methods	Study design: 3‐arm, parallel, randomised, placebo‐controlled trial Setting: Cipto Mangunkusumo General Hospital, Indonesia Timing: January 2016 to April 2018 Interventions: umbilical cord‐mesenchymal stem cells plus HA vs somatotropin plus HA vs control Sample size: 28 knees from 15 patients Analysis: not reported
Participants	Inclusion criteria: Early knee osteoarthritis Kellgren‐Lawrence I‐II Exclusion criteria: not reported
Interventions	Group A was treated with 1 x 106 units of intra‐articular UC‐MSCs + 2 ml HA followed with 2 consecutive weeks of HA injection. Group B was treated with the same dose of HA with additional 8 IU of Somatotropin. Group C was treated as control.
Outcomes	Outcomes measured at 1st and 3rd month, then every 3rd month until 12 months. The International Knee Documentation Committee (IKDC) score, WOMAC, VAS, cartilage evaluation using MRI cartigram
Notes	Trial registration: not reported Funding: not reported Abstract only. Full‐text publication not available.

Jones 2018.

Methods	Study design: single‐centre, parallel, 2‐arm, randomised clinical trial Setting: USA Timing: not reported (study protocol) Interventions: single intra‐articular, ultrasound‐guided injection of autologous adipose tissue vs a single intra‐articular, ultrasound‐guided injection of hyaluronic acid Sample size: 54 participants
Participants	Inclusion Criteria: Age 45 to 75, inclusive Normal axial alignment X‐ray, Kellgren‐Lawrence OA grade 2 to 3, inclusive WOMAC‐pain: between 9 and 19, inclusive Willingness to participate all scheduled follow‐ups Willingness to refrain from taking NSAIDs, level 2 analgesics, and opioids for the course of the study BMI < 40 Exclusion Criteria: Pregnant or lactating Intra‐articular injection within 3 months of treatment Inflammatory arthritis Any disease or active drug use that significantly compromises coagulation Significant damage and/or tears of the ACL or other supporting tissues Prior knee surgery in the last 6 months in the knee that will be injected Active tobacco use Active alcohol or substance abuse within 6 months of study entry Known hypersensitivity (allergy) to hyaluronan (sodium hyaluronate) preparations Knee joint infections, skin diseases or infections in the area of the injection site Diabetes Active inhaler use Any medical condition, which in the opinion of the clinical investigator, would interfere with the treatment or outcome evaluation
Interventions	Intervention: autologous adipose tissue 20 mL to 40 mL of subcutaneous adipose tissue will be aspirated from the abdomen. Adipose tissue will be processed using the Lipogems device, a closed‐loop processing device used in medical procedures involving the harvesting, concentrating and transferring of autologous adipose tissue. The resulting fat product will be delivered locally via ultrasound‐guided, intra‐articular injection. Approximately 5 mL of the microfragmented fat product will be injected into the knee joint. Control: HA acid Hyaluronic acid ‐ Synvisc‐One®: a high molecular weight sodium hyaluronate (HA). HA is an FDA‐approved, standard of care treatment.
Outcomes	Outcomes will be measured at 6 weeks and 6 months. Primary outcome: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain domain Secondary outcomes: WOMAC (full) Clinical anchors (pain, function and stiffness) 29‐point Patient‐Reported Outcomes Measurement Information System (PROMIS®) profile Other Outcome Measures: Synovial fluid analysis (time frame: baseline, 6 weeks and 6 months). Selected OA biomarker profiles that define different OA phenotypes predict the responses to autologous adipose tissue injections. Short‐term clinical evaluation ‐ WOMAC (time frame: change from baseline at 6 weeks). WOMAC questionnaire will be administered at the 6‐week follow‐up. Short‐term clinical evaluation ‐ PROMIS (time frame: change from baseline at 6 weeks). PROMIS questionnaire will be administered at the 6‐week follow‐up. Force Plate Analysis (time frame: assessment and change from baseline to 6 weeks and 6 months)
Notes	Trial registration: NCT03242707, registered on 8 August 2018 Funding: University of Southern California

Khasru 2019.

Methods	Study design: single‐centre, parallel, 2‐arm, randomised clinical trial Setting: PM&R department of BSMMU, Bangladesh Timing: not reported Interventions: single‐dose autologous peripheral blood‐derived stem cells vs standard care Sample size calculation: not reported
Participants	Number of participants: No. screened for eligibility: not reported No. excluded: not reported No. randomised: 12 (6 per arm) No. included in analyses: 12 (6 per arm) Inclusion criteria: All the patients attending PM&R department having primary OA Knee (Kellgren‐Lawrence grade III and IV) are being considered as the sample. Exclusion criteria: not reported
Interventions	Intervention: peripheral blood‐derived stem cells Stem cells are being harvested using granulocyte colony stimulating factor (G‐CSF) 30 MU for consecutive 05 days and CD34, CD145 stem cells are being collected through apheresis. Quality is being ensured measuring cell surface antigen. Control: standard care for knee OA
Outcomes	Outcomes measured at weeks of 0, 4, 12 and 24 Study outcomes: VAS pain Function on WOMAC (Western Ontario and McMaster Universities Arthritis Index) Ultrasonography at 3 and 6 months
Notes	Trial registration: not reported Funding: not reported

Liang 2015.

Methods	Study design: parallel, 2‐arm, randomised, placebo‐controlled trial Setting: China Trial time period: not reported Interventions: intra‐articular injection of autologous bone marrow mesenchymal stem cells (2 × 107 cells) vs ‘control medium’ without bone marrow mesenchymal stem cells Sample size calculation: not reported Analysis: not reported
Participants	Number of participants: No. screened for eligibility: not reported No. excluded: not reported No. randomised: 26 No. included in analyses: not reported Inclusion criteria: not reported Exclusion Criteria: not reported
Interventions	About 15 mL bone marrow was aspired from 26 patients with mild‐to‐moderate OA and taken to the laboratory, where bone marrow mesenchymal stem cells were isolated and characterised in terms of some surface markers by a flow cytometer, and the ability of osteogenic and adipogenic differentiation was analysed. Bilateral knees of each patient were divided into two groups at random. Intra‐articular implantation of autologous bone marrow mesenchymal stem cells in the knee joint: The experimental group were treated with autologous bone marrow mesenchymal stem cells by intra‐articular injection (2 × 107 cells). Single intra‐articular implantation of placebo in the knee joint: The control group injected the same volume of control medium without bone marrow mesenchymal stem cells.
Outcomes	Outcomes were measured at 2 and 4 weeks post‐treatment. WOMAC scores used to estimate knee joint function, before and after treatment Production of interleukin‐1, interleukin‐10, tumour necrosis factor‐alpha, cartilage oligomeric matrix protein
Notes	Abstract only. Full‐text publication not available. Funding: not reported Trial registration: not reported

Maheswari 2022.

Methods	Study design: 2‐arm, parallel, randomised, placebo‐controlled trial Setting: India Timing: not reported Interventions: intra‐articular injection of autologous bone marrow‐derived mesenchymal stem cells (BM‐MSC) vs placebo Sample size: 146 Analysis: not reported
Participants	Number of participants: No. screened for eligibility: not reported No. excluded: not reported No. randomised: 146 patients (73 to stem cell group; 73 to placebo group) No. included in analyses: 133 patients (65 in the stem cell group; 68 in the placebo group) Inclusion criteria: Primary osteoarthritis having Grade II and III OA based on Kellgren and Lawrence radiographic criteria. Exclusion criteria: Patients having subchondral sclerosis (by X ray), complete tear of ACL/PCL, grade 3 meniscal tears and exclusive patellofemoral arthritis (by MRI) were excluded from the study.
Interventions	Intervention: a single intra‐articular injection of Stempeucel ® (25 million cells) followed by 20 mg hyaluronan Control: placebo (saline) followed by 20 mg hyaluronan under ultrasound guidance.
Outcomes	Outcomes measured up to 12 months with 7 visits. Primary outcome: Evaluation of WOMAC Composite Index score (score range 0 to 2400) Secondary outcomes: WOMAC sub‐scores (pain (0 to 500), stiffness (0 to 200) and physical function (0 to 1700)) VAS (0 to 100) MRI assessment (by 3T imaging) of the articular cartilage (T2 mapping (assessment of hydration and cartilage quality), volume (measured using dicom reader and calculated at midportion of medial and lateral tibiofemoral compartment) and thickness (measured at mid points of 20 predetermined sub‐regions of two compartments))
Notes	Abstract only. Full‐text publication not available. Trial registration: CTRI/2018/09/015785 Funding: not reported

March 2013.

Methods	Study design: randomised controlled trial Setting: Australia Trial time period: 25 February 2011 to 1 April 2013 Interventions: autologous adipose‐derived stem cells versus placebo (sterile normal saline) Sample size calculations: 40 participants (this target was reached and recruitment completed)
Participants	Number of participants: No. screened for eligibility: not reported No. excluded: not reported No. randomised: 40 No. included in analyses: 10 Inclusion criteria: Aged over 40 years Knee pain on most days of the last month OARSI Grade 1 or 2 with joint space narrowing in either medial or lateral compartments Osteophyte grade 2 or 3 in medial or lateral compartment without Joint Space Narrowing Symptomatic Knee Osteoarthritis as measured by a pain score of at least 42 on the Numerical Rating Scale Exclusion criteria: Dementia or inability to give informed consent Pregnancy or lactation OARSI Grade 3 or above changes in either knee Planned knee or hip joint replacement surgery Positive blood test to HIV, HBV or HCV at screening visit Positive nasal or groin swab for MRSA at screening visit More than 2 mm space in the knee joint on X‐Ray at screening visit Subjects with metal implants such as knee, hip or aortic valve prosthetics Any clinically significant condition(s) that in the opinion of the investigator may compromise safety or compliance, interfere with evaluation or preclude completion of the study
Interventions	Intervention: Adipose (fat) tissue is removed by lipo‐aspiration (this may take up to 80 minutes). The fat is processed on‐site to isolate the cells (this process takes up to 2 hours). The suspension of stem cells is injected into the knee joint under ultrasound guidance (about 20 minutes). A single 5 mL injection into the knee joint space of cell suspension, which includes autologous adipose‐derived stem cells and sterile normal saline. On average, 50 million cells are injected. Comparator: Placebo. A single 5 mL injection into the knee joint space of sterile normal saline
Outcomes	Outcomes measured at 1, 4, 12 and 24 weeks Primary outcome: Change in Intermittent and Constant Osteoarthritis Pain (ICOAP) scale Percentage of patients achieving OMERACT‐OARSI responder criteria Secondary outcome: Analgesic use. A daily diary is completed by the patient to record analgesic use. Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) disability scale Australian Assessment of Quality of Life Index
Notes	Clinical trial registration: Retrospectively registered with ANZCTR on 5 October 2011 (ACTRN12611001046998). Trial status: recruitment completed (1 April 2013) Estimated study completion date: not reported

Nasb 2020.

Methods	Study design: double‐blind, randomised, placebo‐controlled trial Setting: Tongji University Hospital, China Timing: not reported Interventions: intra‐articular HADMSCs injection with LIPUS, intra‐articular HADMSCs injection with shame LIPUS, or normal saline with LIPUS Sample size: The current study was designed to achieve 80% power overall to detect a 10‐point change on the WOMAC between groups after 6 months (the significance level was set at 0.05). Based on an earlier study using a similar outcome measuring method with adding around 20% for the overall attrition rate. Thus, a sample size of 96 (32 per group) will be used for estimating a two‐sided 95% confidence interval. Analysis: not reported
Participants	Inclusion criteria Males and females aged 18 to 70 years old Radiological diagnosis of osteoarthritis using the American College of Rheumatology criteria Radiological grading of Grade II–III osteoarthritis (OA) of the knee as determined by a qualified radiologist using the Kellgren and Lawrence system Medial or lateral compartment OA Less than 5 degrees varus or valgus knee deformity as measured by the long mechanical axis of the knee on x‐ray A minimum pain score of equal or greater than 5/10 on a visual analogue scale (VAS) Exclusion criteria Previous meniscectomy/significant partial meniscectomy or other knee‐related surgery within the last 12 months Previous intra‐articular injectable therapies within the last 6 months Patients who have meniscus injury of knee joint need surgical repair Patients who have severe coagulation disorders or cardiopulmonary conditions Women who are pregnant or nursing Electronic implants such as pacemakers in the body Patients who are infected with HIV, hepatitis or syphilis, or with bleeding disorders Patients with severe cognitive impairment who cannot follow instructions to complete the treatment History of cancer Immunodeficient patients History of systemic illness or significant organ impairment/failure (i.e. renal failure) Patients who have congenital or acquired knee malformation
Interventions	Group 1: single intra‐articular injection of 10* 106 HADMSCs with low‐intensity pulsed ultrasound treatment for 20 min daily, 5 days a week, for up to 8 weeks Group 2: single intra‐articular injection of 10* 106 HADMSCs with shame ultrasound irradiation for 20 min daily, 5 days a week, for up to 8 weeks Group 3: normal saline with low‐intensity pulsed ultrasound treatment for 20 min daily, 5 days a week, for up to 8 weeks
Outcomes	Outcomes will be measured at baseline (1 month prior to treatment), 1 month, 3 months and 6 months following the interventions. Primary outcome: Western Ontario and McMaster Universities Index of OA (WOMAC) score Secondary outcomes: Cartilage thickness measurement (MRI), visual analogue scale (0 to 100 mm) for pain (VAS), a quality of life index (QLI), range of knee motion, muscle strength, global posture analysis system (GPS) and Likert scale
Notes	Trial registration: ChiCTR1900025907 Funding: National Natural Science Foundation

Wang 2016.

Methods	Study design: parallel, 2‐arm randomised controlled trial Setting: China Trial time period: between January 2015 and January 2016 Interventions: intra‐articular injection of human umbilical cord MSCs suspension vs sodium hyaluronate Sample size calculations: not reported
Participants	Number of participants: No. screened for eligibility: not reported No. excluded: not reported No. randomised: 36 (18 in the MSC group and 18 in the control group) No. included in analyses: not reported Inclusion criteria: Moderate or severe degenerative knee osteoarthritis Exclusion criteria: not reported
Interventions	Intervention: MSC injection Intra‐articular injection of 2.5 to 3.0 mL human umbilical cord MSCs suspension containing (2‐3) × 107 cells was performed once a month for 2 times as a course of treatment in the cell treatment group. Control: sodium hyaluronate Sodium hyaluronate by intra‐articular injection was used once a week for 5 times as a course of treatment in the control group.
Outcomes	The clinical efficacy was evaluated by SF‐36 scale score, Lysholm score and WOMAC score at 6 months. Adverse events: After injection, the incidences of pain and swelling in the cell treatment group were significantly higher than those in the control group.
Notes	Full text in Chinese awaiting translation into English Trial registration: not reported Funding: not reported

Zi‐Yi 2018.

Methods	Study design: double‐blind randomised controlled trial Setting: Arthritis Clinic & Research Center, Beijing, China Timing: Jan 2018 to Dec 2020 Interventions: umbilical cord‐derived mesenchymal stem cells (UC‐MSCs) vs hyaluronic acid Sample size: 14 Analysis: not reported
Participants	—
Interventions	—
Outcomes	—
Notes	Trial registration: NCT03357770; NCT03358654 Full text in Chinese

Abbreviations: EQ‐ 5D‐ 5 L: European quality of life measure; ACL: anterior cruciate ligament; ANZCTR: Australian New Zealand Clinical Trials Registry; BMI: body mass index; BSMMU: Bangabandhu Sheikh Mujib Medical University; FDA: Food and Drug Administration; HA: hyaluronic acid; HADMSCs: human adipose‐derived mesenchymal stem cells; HBV: hepatitis B virus; HCV: hepatitis C virus; IU: international unit; LIPUS: low‐intensity pulsed ultrasound; LP: leukocyte‐poor; m: minute; mL: millilitre; MRI: magnetic resonance imaging; MRSA: methicillin‐resistant staphylococcus aureus; MSCs: mesenchymal stem cells; No.: number; NSAIDs: nonsteroidal anti‐inflammatory drugs; OA: osteoarthritis; OARSI: Osteoarthritis Research Society International; OMERACT: outcome measures in rheumatoid arthritis clinical trials; PCL: posterior cruciate ligament; PM&R: Physical Medicine & Rehabilitation; PROM: patient‐reported outcome measures in osteoarthritis; PROMIS: Patient‐Reported Outcomes Measurement Information System; PRP: platelet‐rich plasma; SF‐36: 36‐item Short‐Form Health Survey; UC‐MSCs: umbilical cord‐derived mesenchymal stem cells; VAS: visual analogue scale; vs: versus; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index.

Characteristics of ongoing studies [ordered by study ID]

ACTRN12611000274976.

Study name	Adipose‐derived stem cells in patients with knee osteoarthritis: a randomised controlled trial evaluating pain, function and cartilage repair
Methods	Study design: randomised controlled trial (Phase 2/3). Likely double‐blind study, but this was not clearly reported. Setting: sports medicine clinic, Australia Trial time period: not reported Interventions: stromal vascular fraction containing adipose‐derived stem cells versus Hylan G‐F 20 (derivative of hyaluronic acid) knee injections Sample size calculations: sample size target = 60
Participants	Inclusion criteria: A diagnosis of OA assessed via the International Cartilage Repair Society guidelines and a visual analogue pain score of greater than 50 out of 100 Adult aged 18 to 80 years Exclusion criteria: No systemic or inflammatory joint disease, no history of crystalline or neuropathic arthropathy, no cancer or other tumour‐like lesions, not pregnant or lactating, not drug abusing, no other intra‐articular lesion in the previous 6 months, no allergy to any test substance and not immunosuppressed
Interventions	Intervention: Three injections each of 5 mL stromal vascular fraction containing adipose‐derived stem cells 2 months apart. Time points for injections: 1) initial injection, 2) 2 months following initial injection and 3) 4 months following initial injection. This results in a total treatment duration of 5 months. Comparator: Three injections each of 2 mL (16 mg) of Hylan G‐F 20 two months apart. Time‐points for injections: 1) initial injection, 2) 2 months following initial injection and 3) 4 months following initial injection. This results in a total treatment duration of 5 months.
Outcomes	Outcomes measured at 3 time points; time point 1: baseline, daily for the first 2 weeks, weekly for the subsequent 2 weeks and 4 and 8 weeks, and 6 and 12 months, following the final injection, time point 2: baseline, 4 and 8 weeks, and 6 and 12 months, following the final injection and time point 3: baseline, 6 and 12 months, following the final injection Primary outcomes: Pain measured using 100 mm VAS, measured at time point 1 Knee Injury and Osteoarthritis Outcome Score, measured at time point 2 Secondary outcomes: Maximum single leg hop for distance. Participant hops as far as possible and the distance (in cm) from the toe in starting position to heel in landing position is measured by the researcher using a tape measure. The best of three hops is recorded. Measured at time point 1. Maximum number of knee bends performed in 30 seconds. Participant bends the knee without bending forward from the hip (until they cannot see a line along the toes, equivalent to about 30 degrees of knee flexion) as many times as possible in 30 seconds. Time is recorded using a stopwatch and number of bends are counted by the researcher. Measured at time point 2 Whole Organ Magnetic Resonance Imaging Score. Measured at time point 3.
Starting date	May 2011
Contact information	Principal investigator: Kade Paterson Centre for Health, Exercise & Sports Medicine Department of Physiotherapy, Melbourne School of Health Sciences The University of Melbourne, Victoria, Australia 3010 P: +61 3 8344 0425 E: kade.paterson@unimelb.edu.au
Notes	Clinical trial registration: Prospectively registered with ANZCTR on 15 March 2011 (ACTRN12611000274976). Trial status: Recruitment status listed as withdrawn and ethics application not yet submitted. Estimated study completion date: not reported

ACTRN12614001044617.

Study name	A Randomised, Stratified, Placebo‐Controlled, Observer Double‐Blind Multicentre Proof of Concept Study of the Safety and Efficacy of Autologous Stromal Vascular Fraction (SVF) With or Without Platelet Rich Plasma (PRP) and Hyaluronic Acid (HA) in Patients with Osteoarthritis of the Knee.
Methods	Study design: randomised controlled trial Setting: sports medicine clinic, Australia Trial time period: 31 January 2015 to 31 January 2016 Interventions: stromal vascular fraction (SVF) stem cells with PRP plus placebo versus placebo injections Sample size calculations: 64
Participants	Inclusion criteria: X‐ray reporting grade 2 or more osteoarthritis of the knee Kellgren and Lawrence scale WOMAC score greater than 50 Greater than 6 months knee pain with the index side (left or right) predominately on one side Pain worse with activity An improvement in pain score (>1 0%) as measured by Numerical Rating scale (NRS, 0‐10) within 2 weeks after PRP injection Sufficient fat present for liposuction Adequate blood chemistry and haematopoietic, renal, cardiovascular, respiratory, immunological function Exclusion criteria: Participants who have received investigational agents within 4 weeks (or 5 half‐lives) of treatment Subjects with significant concurrent or intercurrent illness, psychiatric disorders or alcohol or chemical dependence that would, in the opinion of the Investigator, compromise their safety or compliance or interfere with interpretation of the study Presence of clinically significant acute or unstable cardiovascular, cerebrovascular (stroke), renal, gastrointestinal, pulmonary, immunological (viral hepatitis, or cirrhosis), endocrine or central nervous system disorders Participants who have had active neoplastic disease (cancer) in the previous 3 years. Presence of active infection (except for colds or minor URTI) History of human immunodeficiency virus or acquired immune deficiency syndrome. Significant peripheral vascular disease Participants who are pregnant or lactating Female participants who have positive serum beta HCG pregnancy test taken within 7 days before treatment Fertile participants who are not using effective contraception (e.g. oral contraceptives, intrauterine devices, double barrier methods such as condoms and diaphragms, abstinence or equivalent measures) Previous treatment with SVF
Interventions	Group 1: Placebo Day 0 (Intravenous (IV) + Intra‐articular (IA)) and placebo IA at Days 7, 14 and 21 Group 2: SVF + PRP (IA) + placebo (IV) at Day 0, and placebo IA at Days (7, 14 and 21) Group 3: SVF (IV + IA) + PRP (IA) at Day 0, and placebo (IA Days 7, 14 and 21) Group 4: SVF (IV +IA) + PRP/HA (IA) at Day 0, and PRP (IA) at Days 7, 14 and 21
Outcomes	Outcomes measured at 0, 28, 56, 112, 180, 365 days Primary outcome Safety will be assessed by monitoring for adverse events (including abnormal laboratory test results) over the study interval. Adverse events will be graded by the Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) Secondary outcomes WOMAC; SF‐36; AQOL; X‐ray and MRI assessment of cartilage and joint space width
Starting date	31 January 2015
Contact information	Dr David Mathers Hunter Regenerative medicine 71 Georgetown Rd Georgetown NSW 2298
Notes	Registered on 29 September 2014 Withdrawn trial

ACTRN12617001095358.

Study name	A Phase I, single centre, randomised, double blind, placebo‐controlled, single ascending dose (SAD) study to evaluate the safety and tolerability of allogeneic adipose‐derived mesenchymal stem cells (MAG200) administered by intra‐articular injection to patients with symptomatic osteoarthritis of the knee.
Methods	Study design: randomised, double‐blind, placebo‐controlled, single ascending dose (SAD) study (Phase 1 study) Setting: single centre, Melbourne Stem Cell Centre, Australia Trial time period: 2 July 2018 to unknown (still recruiting) Interventions: allogeneic human adipose‐derived mesenchymal stem cells (MSCs) versus placebo (sterile, clinical grade injectable isotonic solution) Sample size calculations: No formal sample size calculation will be performed for this study. The sample sizes chosen for this study are based on clinical and regulatory considerations and precedence for first‐in‐human studies, and have no formal statistical basis. The number of subjects proposed is considered sufficient for this initial study to explore the safety and tolerability of MAG200 in patients with OA of the knee.
Participants	Inclusion criteria: Adults aged 18 to 65 years Body mass index BMI must be 'greater than or equal' to 19.0 kg/m2 and 'less than or equal to' 35.0 kg/m2 A documented diagnosis of osteoarthritis (Grade 2 or Grade 3) of the study knee Exclusion criteria: MRI‐confirmed displaced meniscal tear, ligament deficiency or generalised Grade 4 chondral loss in the study knee History of or suspected infective or inflammatory joint disorders Joint surgery within 3 years prior to study start Females who are pregnant or planning a pregnancy during the following 12 months Any contraindication to intra‐articular injection Any contraindication to an X‐ray or MRI of the study knee
Interventions	Intervention: The Investigational Product MAG200 is a preparation of allogeneic human adipose‐derived mesenchymal stem cells (MSCs) in sterile, clinical grade injectable isotonic solution. Participants will receive a single dose of Investigational Product (MAG200 / placebo) which will be administered by intra‐articular injection into the study knee. Up to 40 eligible subjects will be randomised into the study in four sequential cohorts. Each cohort will comprise 10 subjects, who will be randomised in a 4 to 1 ratio to active or placebo treatment arms (i.e. 8 active: 2 placebo). Dosing will commence at the lowest dose level of MAG200. An internal Safety Review Team (SRT) will be established to review safety data of the previous cohort to determine if dose escalation to the next dose level is recommended. A maximum of 4 dose levels of MAG200 will be studied: 10 million cells, 20 million cells, 50 million cells and 100 million cells. Comparator: Placebo. The Placebo solution will contain sterile, clinical grade injectable isotonic solution. Placebo will be administered as a single dose via intra‐articular injection into the study knee. Due to differences in appearance between the MAG200 suspension and Placebo solution, two unblinded laboratory technicians, independent of the study conduct, will prepare the syringes of study treatment. The syringes will be covered with black plastic to prevent the identification of the injectable material. Syringes will be over‐labelled, with each syringe identifiable by the unique Subject Randomisation Number only.
Outcomes	Outcomes measure time points: Changes from baseline to end of study (Month 3/Day 84) Physical exam and vital signs will be assessed at Days 0, 7, 14, 28 and month 3 ECG will be performed at Days 0, 28 and month 3 Clinical laboratory testing will be assessed at Days 0, 7, 28 and month 3 Adverse events and concomitant medication use will be captured and assessed from Day 0 to month 3) Primary outcome: Safety and tolerability of MAG200 is the primary outcome. It will be assessed by monitoring adverse events, conducting physical examination, vital signs, ECG, clinical laboratory data and concomitant medication usage. Secondary outcome: No secondary outcome was reported.
Starting date	2 July 2018
Contact information	Principal investigator: A/Prof Julien Freitag Melbourne Stem Cell Centre 116‐118 Thames St Box Hill North, Victoria, Australia 3128 P: +61 3 9270 8000, E: info@mscc.com.au
Notes	Clinical trial registration: Prospectively registered with ANZCTR on 27 July 2017 (ACTRN12617001095358). Trial status: recruiting (date of first participant enrolment was 2 July 2018) Estimated study completion date: not reported

ChiCTR1800017713.

Study name	A multicentre, randomized, double blind, controlled trial for safety and efficacy of BL173‐hUMSCs in the treatment of osteoarthritis
Methods	Study design: double‐blind randomised controlled trial Setting: multi‐centre (5 tertiary hospitals in China) Trial time period: 31 October 2018 to 31 March 2020 Interventions: human umbilical cord mesenchymal stem cells (MSCs) versus sodium hyaluronate Sample size calculations: not reported; 25 participants per group were reported for sample size on registry
Participants	Inclusion criteria: Adults aged 18 to 70 years The subjects or his/her legal representative voluntarily accepts the treatment and signs the informed consent According to the diagnostic criteria, the patient was clearly diagnosed with osteoarthritis of the knee Subjects are aged from 18 to 70 years old, male and female The clinical course of knee arthritis was more than 6 months and less than 10 years The VAS score was more than 6 and less than 8 The K‐L score was lower than Grade 4 Subjects are able to walk autonomously Exclusion criteria: Subjects are allergic to one or more medicines or to two or more foods Subjects' height and weight index (BMI) was more than 30 The subject suffers from uncontrollable or uncontrollable cardiovascular and cerebrovascular, liver, kidney, lung, endocrine and other systematic diseases The subject has a history of malignancy Subjects were associated with systemic or rheumatic arthritis chondrosis, articular cartilage calcinosis, haemochromatosis, inflammatory arthropathy, ischaemic necrosis of femoral head, Paget's disease, haemophilic arthropathy, infectious arthritis, Charcot's disease, villous synovitis, synovial chondromatosis Within 3 months before the start of the study, the subject has a relatively serious systemic or local knee infection (including skin and lumen infection) Subjects have lower limb diseases that can interfere with knee assessment, such as fibromyalgia, more obvious lower back pain, and lumbar disc herniation The subject has coagulation disorder Subjects received knee arthroscopic surgery or other open surgery related to knee joint operation within 6 months before the study begins Subjects received intra‐articular drug injection for knee osteoarthritis within 6 months before the start of the study, including but not limited to hyaluronic acid, hormone, PRP, BMP, etc. Subjects received glucosamine and/or chondroitin sulfate treatment within 4 weeks prior to the start of the study Subjects will undergo knee replacement during the observation period Subjects had contraindications for MRI examination The subjects were infected with HIV, hepatitis virus and syphilis Subjects had alcoholism, drug abuse or mental illness within 3 years before the study Subjects will participate in any other clinical study within 3 months before the study The subject is gestation or nursing or intends to conceive for the last six months Other conditions considered inappropriate for the study were determined by the researchers
Interventions	Intervention: human umbilical cord mesenchymal stem cells (MSCs) Comparator: sodium hyaluronate
Outcomes	Timebpoints for data collection of outcomes measures not reported. Outcome 1: X‐ray Outcome 2: nuclear magnetic resonance imaging (MRI) Outcome 3: visual analogue scale (VAS) score Outcome 4: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score
Starting date	31 October 2018
Contact information	Principal investigator: Liangjing Lv 160 Pujian Road, Pudong New District Shanghai, China 200127 P: +86 13661472001, E: Lu_liangjing@medmail.com.cn Fax: +86 021‐63260477
Notes	Clinical trial registration: Prospectively registered with the Chinese Clinical Trial Registry (ChiCTR) on 10 August 2018 (ChiCTR1800017713). Trial status: Not yet recruiting Estimated study completion date: 31 March 2020

ChiCTR1900025685.

Study name	The clinical research for efficacy and safety of intra‐articular injection of autologous adipose‐derived stem cell combined with platelet rich plasma for the treatment of degenerative osteoarthritis articular cartilage defects of the knee
Methods	Study design: single‐centre, 2‐arm randomised controlled trial Setting: Taihe Hospital, Hubei University of Medicine, China Timing: not reported Interventions: intra‐articular injection of mesenchymal stem cells combined with platelet‐rich plasma versus intra‐articular injection of platelet‐rich plasma Sample size: 100
Participants	Inclusion criteria: 1. Diagnosis of Knee Osteoarthritis according to the criteria of osteoarthritis of the ACR (American College of Rheumatology) 2. Radiographic evidence of grade 2 to 4 osteoarthritis based on the Kellgren‐Lawrence radiographic entry criteria 3. Confirm with cartilage injury, articular cartilage part or full‐thickness injury, via MRI 4. Males or females age >18 years and the ability to understand the treatment plan 5. Over 6 months/2 years knee pain and lack of effective with conservative treatments 6. Knee pain of VAS score is 4 or higher 7. Normal hepatic and renal function, no history of gout, rheumatoid arthritis, and autoimmune diseases, and no serious organ dysfunction 8. Patients willing to participate and follow up in this clinical trial; understand and sign the consent form of this study 9. Ability to tolerate liposuction 10. There was no obvious abnormality in tumour marker detection, or patient was evaluated and has no risk of cancer Exclusion criteria: 1. Pregnant or considering pregnancy in the next 6 months, lactating 2. Positive tests for HIV, HCV, HBV and syphilis 3. Uncontrollable or difficult to control/uncontrolled/poorly controlled cardiovascular and cerebrovascular, liver, kidney, lung, endocrine and other systematic diseases with a life expectancy of less than 1 year 4. History of malignancy 5. Serious systemic or local knee infection (including skin and lumen infection) within 3 months prior to this study 6. Underwent arthroscopy or knee related surgery within half year 7. Subjects received intra‐articular drug injection for knee osteoarthritis within 6 months before the start of the study, including but not limited to corticosteroid, hyaluronic acid, hormone, PRP, BMP, etc. 8. Subjects had alcoholism, drug abuse or mental illness within 3 years prior to this study 9. Body Mass Index (BMI) of 30 kg/m2 or greater./Overweight expressed as body mass index (BMI) > 35 10. Patient participating in another clinical study within 3 months of this study
Interventions	Stem cell injection plus PRP injection: intra‐articular injection of mesenchymal stem cells combined with platelet rich plasma PRP injection: intra‐articular injection of platelet‐rich plasma
Outcomes	Primary outcomes Adverse effects Knee cartilage volume Secondary outcomes WOMAC score; VAS; VascuQol; Kellgren‐Lawrence Grading Scale
Starting date	1 January 2020
Contact information	Fei Zhao Taihe Hospital, Hubei University of Medicine Email: 75960987@qq.com
Notes	Trial registration: ChiCTR1900025685 registered on 2019‐09‐05 Funding: Renmin Hospital, Hubei University of Medicine Status: recruitment pending Estimated completion date: none reported

ChiCTR1900025907.

Study name	Stem cells, low intensity pulsed ultrasound or their combination for the treatment of knee osteoarthritis
Methods	Study design: quasi‐randomised, controlled 3‐arm trial Setting: Tongji Hospital, Huazhong University of Science and Technology, China Trial time period: trial has not commenced Sample size: 81
Participants	Inclusion criteria: 1. Males or females aged 18 Years to 70 Years old 2. Radiological diagnosis of osteoarthritis using the American College of Rheumatology criteria 3. Radiological grading of Grade II–III osteoarthritis (OA) of the knee as determined by a qualified radiologist using the Kellgren and Lawrence system 4. Medial or lateral compartment OA as determined above 5. Less than 5 degrees varus or valgus knee deformity as measured by the long mechanical axis of the knee on x‐ray 6. A minimum pain score of equal or greater than 5/10 on a visual analogue scale (VAS) Exclusion criteria: 1. Previous meniscectomy/significant partial meniscectomy or other knee‐related surgery within the last 12 months 2. Previous intra‐articular injectable therapies within the last 6 months: (1) Patients who have meniscus injury of knee joint need surgical repair (2) Patients who have severe coagulation disorders, cardiopulmonary failure and so on (3) The women who are pregnant or nursing (4) There are electronic implants such as pacemakers in the body (5) Patients who are infected with HIV, the virus of hepatitis or syphilis or bleeding disorders (6) Patients with severe cognitive impairment who cannot follow instructions to complete the treatment (7) History of cancer (8) Immunodeficiency patients (9) History of systemic illness or significant organ impairment/failure (i.e. renal failure) (10) Patients who have congenital or acquired knee malformation (11) Patients or researchers who are participating in other clinical trials believe that other reasons are not appropriate for clinical trials
Interventions	Group 1: Intraarticular stem cell injection with shame low‐intensity pulsed ultrasound Group 2: Receive Intraarticular stem cell injection with low‐intensity pulsed ultrasound Group 3: Normal saline with low‐intensity pulsed ultrasound
Outcomes	Primary outcome: Osteoarthritis function assessment Secondary outcomes: Pain assessment Global posture analysis Range of knee motion Cartilage thickness
Starting date	14 September 2019
Contact information	Prof. Chen Hong +86 13296508243 chenhong1129@hotmail.com
Notes	Trial registration: ChiCTR1900025907 Status: recruitment pending

ChiCTR2000033408.

Study name	Clinical study on the efficacy and safety of human umbilical cord mesenchymal stem cells in the treatment of osteoarthritis
Methods	Study design: 2‐arm, parallel randomised controlled trial Setting: Chinese PLA General Hospital, China Trial time period: June 2020 to March 2023 Interventions: stem cell injection versus hyaluronic acid injection Sample size calculations: 38
Participants	Inclusion criteria: 1. Diagnosed as osteoarthritis of the knee 2. K/L scores of grades 2 to 3 3. Chronic knee joint pain 4. No local or systemic infection 5. No contraindications for joint injection by haematological and biochemical tests 6. Subjects and their families understand and agree to participate in the trial of the clinical trial protocol, and sign a written "informed consent" Exclusion criteria: 1. Age greater than 75 years old or less than 18 years old, or do not have full civil capacity 2. HIV, hepatitis virus or syphilis virus infection or serological test positive 3. BMI greater than 30kg/m2 4. Congenital or acquired knee joint deformities 5. Pregnant or lactating women 6. Tumour patients 7. Immunodeficiency patients 8. A history of intra‐articular drug injection within 3 months
Interventions	Stem cell injection Hyaluronic acid injection
Outcomes	Blood routine; blood chemistry; lymphocyte subsets; MRI of the knee; VAS score; WOMAC score; Lequesne index; SF‐12 scale
Starting date	1 June 2020
Contact information	Wang Ning Chinese PLA General Hospital wangningmd@163.com
Notes	Trial registration: registered on 31 May 2020 Funding: China Zhongguancun Precision Medicine science and technology foundation Status: recruiting Estimated completion date: 31 March 2023

ChiCTR2000039017.

Study name	Clinical study of human umbilical cord mesenchymal stem cells (UC‐MSCs) in the treatment of knee osteoarthritis
Methods	Study design: Randomised controlled trial (Phase 2/3). Likely double‐blind study, but this was not clearly reported. Setting: Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan, China Trial time period: Not reported Interventions: Stromal vascular fraction containing adipose‐derived stem cells versus Hylan G‐F 20 (derivative of hyaluronic acid) knee injections. Sample size calculations: 54
Participants	Inclusion criteria 1. Aged 40‐75 years 2. Diagnosed as knee osteoarthritis 3. KL scores of I‐III grades 4. Duration of KOA is more than 6 months 5. Traditional treatment is invalid Exclusion criteria 1. Those who have recently (within the past 1 year) undergone arthroscopy and/or surgery, or intra‐articular injection of hormones and/or sodium hyaluronate treatment 2. Pregnant or lactating women, or those who plan to become pregnant during the experiment 3. Patients with positive serology tests for pathogens (AIDS, hepatitis B, syphilis) 4. Body mass index (BMI) greater than 30 5. Severe past diseases, such as cardiovascular disease, kidney disease, liver disease, endocrine disease and cancer 6. Patients who are still participating in other clinical trials 7. Bilateral knee osteoarthritis 8. Severe varus and varus deformity of the knee joint, with varus and varus greater than 10°
Interventions	Stem cell injection (intra‐articular injection of human umbilical cord mesenchymal stem cells) Hyaluronic acid injection (intra‐articular injection) Placebo injection (intra‐articular saline injection)
Outcomes	Study outcomes Joint function ACR score VAS pain Radiograph of the knee joint MRI of the knee joint Articular cartilage score Adverse events
Starting date	30 October 2020
Contact information	Tong Wei Union Hospital Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China tongwei312@126.com
Notes	Trial registration: ChiCTR2000039017 registered on 13 October 2020 Funding: Union Hospital Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Status: recruiting

ChiCTR2100041683.

Study name	Human umbilical cord mesenchymal stem cells treating knee osteoarthritis: a randomized, double‐blind, controlled trial
Methods	Study design: double‐blind randomised controlled trial Setting: Sun Yat‐Sen Memorial Hospital, Sun Yat‐Sen University Trial time period: 2020 ‐ current, recruitment ongoing Interventions: human umbilical cord mesenchymal stem cells vs sodium hyaluronate Sample size calculations: hUC‐MSCs: n = 10; sodium hyaluronate: n = 10
Participants	Inclusion criteria: 1. Subjects understood the research procedures and methods, volunteered to participate in the trial, signed the informed consent, and able to communicate with the researchers and complete the study in accordance with the protocol 2. The clinical diagnosis of the patient complied with the knee osteoarthritis diagnostic criteria prescribed by the Orthopedic Surgery Group of the COA (2018 version): 1) Repeated knee pain in the past month 2) X‐ray (standing or weight‐bearing) show narrowing of the joint space, hardening of subchondral bone and/or cystic degeneration, and formation of osteophytes at the edge of the joint 3) Aged ≥ 50 years 4) Morning stiffness ≤ 30 minutes 5) Bone fricative (sense) during activity Note: Meeting the diagnostic criteria 1+ (any 2 of 2, 3, 4, 5) can diagnose knee osteoarthritis 3. The patient's clinical diagnosis complies with grades I‐II in the Kellgren & Lawrence classification: Class I: slight osteophyte Grade II: obvious osteophytes, with slight narrowing of joint space Class iii: moderately narrow joint space Grade iv: significant narrowing of the joint space and subchondral bone hardening 4. When randomised, age is ≤ 70 years, gender is not limited Exclusion criteria: 1. Patient's clinical diagnosis complies with Kellgren‐Lawrence classification III‐IV 2. Have other diseases that can cause knee pain, such as anterior cruciate ligament tear, meniscal tear, villous nodular synovitis, synovial chondromatosis, traumatic arthritis, infectious diseases, etc. MRI examination should be done if necessary 3. Received any of the following treatments within 4 weeks before the first treatment: opioid analgesics, non‐steroidal antipyretic analgesics or oral proprietary Chinese medicines; unilateral or bilateral knee joint physical therapy or exercise therapy; unilateral or bilateral Traditional Chinese medicine for external use or acupuncture and moxibustion, etc. 4. Received any of the following treatments within 8 weeks before the first treatment: glucocorticoids injections, anaesthetic injections in unilateral or bilateral knee joint cavity, or external glucocorticoids; glucocorticoids for any reason at any location, such as oral, external, suppositories, etc. 5. Received any of the following treatments within 24 weeks before the first treatment: unilateral or bilateral knee joint biotherapy, including stem cell therapy, platelet‐rich plasma (PRP) injection therapy, etc.; unilateral or bilateral knee joint cavity sodium hyaluronate injection treatment 6. Those who have had a high tibial osteotomy, or those who underwent knee surgery within 12 months before screening 7. Complicated with systemic or rheumatic diseases 8. Patients who are unable to understand the content of the study materials or who cannot undergo clinical, imaging, and laboratory evaluations 9. Patients who have a skin disease or infection in the area of the injection site and who are at risk for infection by the injection 10. Patients with severe malnutrition (MNA‐SF score ≤ 11), heart, lung, liver, kidney and other important organs and endocrine system disease history, or patients with syphilis and HIV test positive 11. Those who are known to be allergic to the components of this treatment 12. Pregnant, suspicious pregnancy, lactating female patients or patients (including men and women) who refused to use contraception during the study 13. Currently have or have a history of malignancy within 5 years prior to signing the informed consent 14. Those who have participated in any drug or medical device clinical trial within 3 months before screening 15. Other subjects determined by the investigator to be inappropriate
Interventions	Intervention: human umbilical cord mesenchymal stem cells (hUC‐MSCs) Local injection in the knee joint. The total number of cells is 5 × 10^7 and the volume is 2.5 mL each time. The injection frequency is 2 times. The second injection is 3 weeks after the first injection. Control: sodium hyaluronate Local injection in the knee joint. The total amount of sodium hyaluronate is 2.5 mg and the volume is 2.5 mL each time. The injection frequency is 2 times. The second injection is 3 weeks after the first injection.
Outcomes	Primary outcomes: WOMAC score; KSS score; VAS score Secondary outcomes: EQ‐5D score; MRI and X‐ray
Starting date	31 Dec 2020
Contact information	Chuangran Wu 547018789@qq.com
Notes	Recruitment ongoing

ChiCTR2100045261.

Study name	Short‐term clinical efficacy of autologous stem cell injection versus physical therapy for inflammatory knee osteoarthritis: a randomized controlled trial
Methods	Study design: parallel randomised controlled trial Setting: The Third Hospital of Hebei Medical University, China Trial time period: trial has not commenced Sample size: 156
Participants	Inclusion criteria: 1. Age: 45 to 75 2. Diagnosis of knee osteoarthritis according to clinical and radiographic criteria defined by the American Society of Rheumatology (standing anterophotograph) 3. Positive floating patellar test 4. Ultrasound or NMR showed synovial thickening ≥ 1 mm, or synovial thickness ≥ 2 mm 5. Imaging showed joint space stenosis (JSN) score ≥ 1 6. VAS score ≥ 4 7. IL‐6 concentration ≥7 pg/mL in the articular fluid detected by ELISA Exclusion criteria: 1. A history of knee surgery or arthroscopic surgery 2. Body mass index (BMI) ≥ 35 kg/m2 3. Knee injection history within the previous month 4. A history of knee infection 5. Take opioids daily 6. The illness is serious enough to prevent participation in activities, such as attendance at scheduled examinations, etc.
Interventions	Intra‐articular injections of autologous stem cells Physical therapy
Outcomes	Primary outcome: Bone and Joint Index (WOMAC) score Secondary outcome: The score on the Global Rating of Change scale; timed "up and go" test; Alternate Step Test
Starting date	10 April 2021
Contact information	Wang Fei +86 311 88602613 doctorwf@yeah.net
Notes	Trial registration: ChiCTR2100045261 Status: recruitment pending

ChiCTR2100047124.

Study name	Comparing the effects of human adipose‐derived mesenchymal stem cells, and rehabilitation therapy for the treatment of knee osteoarthritis
Methods	Study design: 2‐arm parallel randomised controlled trial Setting: Damascus, Syria Trial time period: 1 July 2021 to 1 September 2021 Interventions: stem cell injection versus rehabilitation therapy Sample size: 70
Participants	Inclusion criteria: 1. Males and females aged 18 to 70 years 2. Radiological diagnosis of osteoarthritis using the American College of Rheumatology criteria 3. Radiological grading of Grade II–III osteoarthritis (OA) of the knee as determined by a qualified radiologist using the Kellgren and Lawrence system 4. Medial or lateral compartment OA 5. Less than 5 degrees varus or valgus knee deformity as measured by the long mechanical axis of the knee on X‐ray 6. A minimum pain score of equal or greater than 4/10 on a visual analogue scale (VAS) Exclusion criteria: 1. Previous meniscectomy/significant partial meniscectomy or other knee‐related surgery within the last 12 months 2. Previous intra‐articular injectable therapies within the last 6 months 3. Patients who have meniscus injury of knee joint need surgical repair 4. Patients who have severe coagulation disorders or cardiopulmonary conditions 5. Women who are pregnant or nursing 6. Electronic implants such as pacemakers in the body 7. Patients who are infected the HIV, the virus of hepatitis or syphilis or bleeding disorders 8. Patients with severe cognitive impairment who cannot follow instructions to complete the treatment 9. History of cancer 10. Immunodeficiency patients 11. History of systemic illness or significant organ impairment/failure (i.e. renal failure) 12. Patients who have congenital or acquired knee malformation
Interventions	Stem cell injection: single intra‐articular injection of human adipose‐derived MSCs Rehabilitation therapy daily, 5 days a week, for up to 8 weeks
Outcomes	International Knee Function Score; VAS pain
Starting date	1 July 2021
Contact information	Mohammad Nasb Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology mmn87@yahoo.com
Notes	Trial registration: ChiCTR2100047124 registered on 8 June 2021 Status: recruiting

ChiCTR‐INR‐17014226.

Study name	A randomized, single blind clinical study of human umbilical cord mesenchymal stem cells compare sodium hyaluronate to treatment of early osteoarthritis of the knee
Methods	Study design: single‐blinded randomised controlled trial Setting: a tertiary hospital (Tianjin First Center Hospital), China Trial time period: 1 March 2018 to 30 November 2019 Interventions: sodium hyaluronate versus human umbilical cord mesenchymal stem cells (MSCs) Sample size: 20 participants were recruited for each study arm (40 total)
Participants	Inclusion criteria: Knee osteoarthritis not more than 6 months of conservative treatment VAS score was less than 6 Knee joint activity decreased The K‐L score was lower than grade 3 Patient aged under 65 years Patients with primary osteoarthritis of the knee Exclusion criteria: Autoimmune arthropathy Unstable or damaged ligaments There was infection, surgery and radioactivity of the knee joint within 6 weeks The immunosuppressant was made in 6 weeks Glucocorticoids or sodium hyaluronate were injected within 3 months Pregnant or lactating women Abnormal coagulation function Infection in the skin of the injection area The investigator considered the patient unsuitable for the study
Interventions	Intervention: sodium hyaluronate Comparator: human umbilical cord mesenchymal stem cells (MSCs)
Outcomes	Outcomes: X‐ray Nuclear magnetic resonance imaging (MRI) Visual analogue score (VAS) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores
Starting date	1 March 2018
Contact information	Principal investigator: Wenxue Jiang Department of Orthopedics Tianjin First Central Hospital 24 Fukang Road, Nankai District, Tianjin, China P: +86 13752002876, E: jiangwenxue1920@163.com
Notes	Clinical trial registration: Prospectively registered with the Chinese Clinical Trial Registry (ChiCTR) on 30 December 2017 (ChiCTR‐INR‐17014226). Trial status: completed Study completion date: 30 November 2019

ChiCTR‐IOR‐15006942.

Study name	RCT mesenchymal stem cells versus hyaluronic acid in OA knee
Methods	Study design: 2‐arm, parallel randomised controlled trial Setting: not reported Trial time period: unclear. Clinical trials registry reports as “not yet recruiting”, while the principal investigator’s website reports “recruitment status complete”. Interventions: autologous bone marrow derived mesenchymal stem cells versus hyaluronic acid Sample size calculations: not reported; 30 participants were listed for sample size on registry
Participants	Inclusion criteria: Male and female subjects aged between 18 and < 65 All patients must provide their written consent All patients must be affected by primary osteoarthritis of the knee (according to ACR ‐ American College of Rheumatology ‐ classification); in case a patient shows a bilateral OA, they will be included and treated for both knees All patients must have pain symptoms for at least 2 months All patients must experience, during the inclusion visit (T0), a pain level higher than or equal to 5.0 cm on a VAS of 10 cm All patients should have at least 8 years of school education Radiological evidence of osteoarthritis with Kellgren and Lawrence grade 2 and 3 Exclusion criteria: Patients with previous cases of alcoholism or drug abuse Pregnancy and breastfeeding Presence of serious pathologies Hypersensitivity towards hyaluronic acid Intra‐articular infiltrations of hyaluronic acid or steroids that are in the process of being administered or that have been interrupted within less than 3 months Steroid‐based systemic therapy in progress or interrupted within less than 1 month and/or anti‐clotting drugs History of fractures and/or severe traumas of the knee bone Significant haematologic diseases Non‐consenting patients who have not provided written informed consent Mechanical instability, ligamentous laxity/deficiency and gross deformity Isolated meniscal tear without evidence of osteoarthritis
Interventions	Intervention: autologous bone marrow‐derived mesenchymal stem cells 6 mL knee injection Comparator: hyaluronic acid 6 mL knee injection
Outcomes	Primary outcomes: Functional osteoarthritis scores including WOMAC, KSS and KSFS, SF‐36 and VAS pain scores will be assessed at 2 weeks, 3 months, 6 months, 9 months and 12 months post‐operation Radiologic knee osteoarthritis will be assessed by MRI and X‐ray before operation, 3 months and 12 months post‐operation Adverse event will be monitored during the study Secondary outcomes: Analgesic/NSAIDs consumption Crackling sounds with movement (subjective evaluation) Per‐articular swelling (thigh and knee circumference evaluation)
Starting date	Not reported (not yet recruiting)
Contact information	Principal investigator: Prof. Kevin HO Ki Wai Department of Orthopaedics and Traumatology The Chinese University of Hong Kong P +852 26322715, E: kevinho@cuhk.edu.hk
Notes	Prospectively registered with the Chinese Clinical Trial Registry (ChiCTR) on 20 August 2015 (ChiCTR‐IOR‐15006942). Trial status: recruitment complete (according to principal investigator’s website. This has not been updated on the clinical trial registry). Estimated study completion date: unknown

ChiCTR‐OCN‐15006356.

Study name	The Effect of Injecting the Peripheral Blood Stem Cell and Platelet Rich Plasma into Articular Cavity combined Oral Chinese Medicine to Treat Knee Osteoarthritis
Methods	Study design: parallel, single‐blind randomised controlled trial Setting: a tertiary hospital (Chinese medicine hospital of Zhejiang province) Trial time period: 1 January 2015 to 30 June 2016 Interventions: intra‐articular knee injection of platelet‐rich plasma (PRP) versus peripheral blood stem cells (PBSC), PRP and 中药 (Chinese medicine) Sample size calculations: not reported; 20 participants per group were reported for sample size on registry
Participants	Inclusion criteria: Adults aged 40 to 80 years, inclusive Recurrent knee pain No significant injury history X‐ray and MRI showed knee degenerative changes Exclusion criteria: Rheumatoid arthritis, ankylosing spondylitis, haemophilia sex arthritis, gouty arthritis Acute knee joint infection, or systemic infection Within 1 week of oral antiplatelet or against the use of fibrinolytic drugs, non‐steroidal anti‐inflammatory drugs or corticosteroids and immunosuppressive drugs Knee joint cavity injected drugs within 3 months Underwent knee related surgery within half year Blood system diseases, cardiovascular disease, diabetes, immune deficiency diseases, tumour etc. Haemoglobin is less than 11 g/dL, platelet count is less than 100 x 109/L white blood cell count is less than 3 x 109/L
Interventions	Intervention: intra‐articular injection of platelet‐rich plasma (PRP) into articular cavity of knee Comparator: intra‐articular injection of peripheral blood stem cells (PBSC), PRP and 中药 (Chinese medicine)
Outcomes	Time points for data collection of outcomes measures not reported (except outcome 4). Outcome 1: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score Outcome 2: Lequesne Algofunctional Index score Outcome 3: VAS score Outcome 4: MRI cartilage lesion score (before treatment and 6‐months post treatment) Outcome 5: knee x‐ray (before treatment) Outcome 6: body mass index (BMI) score
Starting date	1 January 2015
Contact information	Principal investigator: Tong Peijian 54 Youdian Road, Hangzhou, Zhejiang, China P: +86 13906503677, E: tongpeijian@163.com
Notes	Clinical trial registration: Retrospectively registered with the Chinese Clinical Trial Registry (ChiCTR) on 6 June 2015 (ChiCTR‐OCN‐15006356). Trial status: recruiting (but status may be outdated, as ‘study execute time’ is 01 January 2015 to 30 June 2016) Estimated study completion date: 30 June 2016

CTRI/2009/091/000435.

Study name	A controlled study with allogenic mesenchymal stem cells in patients with osteoarthritis
Methods	Study design: double‐blind randomised controlled trial (Phase 1 study) Setting: not reported Trial time period: not reported Interventions: single dose of allogenic MSCs suspended in plasmalyte A given as intra‐articular knee injection versus Plasmalyte A: intra‐articular Sample size calculations: not reported; target sample size was 30 participants
Participants	Inclusion criteria: History of primary idiopathic osteoarthritis of the knee characterised by pain of moderate intensity which requires intake of analgesics at least 3 days a week Self‐reported difficulty in at least one of the following activities attributed to knee pain: lifting and carrying groceries, walking 400 metres, getting in and out of a chair, or going up and down stairs Radiographic evidence of grade 1 to 3 osteoarthritis based on the Kellgren and Lawrence radiographic entry criteria Patients who have been on stable medication for the past 3 months Able to complete a 1‐week washout period during which NSAIDs are prohibited Patients who have not received intraarticular steroids or hyaluronan within the last 3 months Ability to provide written informed consent Exclusion criteria: Prior or ongoing medical conditions (e.g. concomitant illness, psychiatric condition, alcoholism, drug abuse), medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow‐up would be completed, or could impair the assessment of study results History of surgery, including arthroscopy, or major trauma to the study joint in the previous 12 months Signs of active study joint inflammation including redness, warmth, and/or, if qualifying with osteoarthritis of the knee, a large, bulging effusion of the study knee joint with the loss of normal contour of the joint at the screening visit or at the baseline examination after the washout period Infections in or around the knee Patients awaiting a replacement knee or hip joint Patients with other conditions that cause pain Patients taking corticosteroid medication or hyaluronan injection within last 3 months Significantly incapacitated or disabled and would be categorised as ACR Functional Class IV (largely or wholly incapacitated), or unable to walk without assistive devices Patients with other known rheumatic or inflammatory disease such as rheumatoid arthritis Other pathologic lesions on x‐rays of knee Positive hepatitis B surface antigen, hepatitis C antibody test, anti‐human immunodeficiency virus (HIV) antibody test, or VDRL Bleeding disorders Known hypersensitivity to hyaluronan products or animal sera For women of child‐bearing potential: positive pregnancy test or lactating
Interventions	Intervention: ex vivo cultured adult allogenic MSCs: single dose of allogenic MSCs (either 75 million or 150 million cells) suspended in plasmalyte A given as intra‐articular injection Control intervention: Plasmalyte A: intra‐articular
Outcomes	Outcomes measured at baseline, Day 7 and Months 1, 3, 6, 9, 12 Primary outcomes: Safety and tolerability, assessed by adverse events. The type of AE(s), number of AE(s) and proportion of patients with AE(s) Patients Assessment of Arthritis Pain (Osteoarthritis‐Pain VAS) Aggregated Locomotor Function (ALF) scale Secondary outcomes: Change from baseline in the WOMAC OA (Western Ontario and McMaster Universities Osteoarthritis) Index ‐pain subscale score Reduction in intake of analgesic tablets 6‐minute walking test WOMAC Osteoarthritis Stiffness Index WOMAC Osteoarthritis Composite Index Joint space width WORMS scoring system using MRI of the knee (time point: baseline, 1st month, 3rd month, 6th month, 9th month, 12th month)
Starting date	Not reported
Contact information	Principal investigator: Jiji Abhraham Stempeutics Research Pvt. Ltd. Akshay Tech Park, No. 72 & 73 2nd Floor, EPIP Zone, Phase I‐Area Whitefield 560066 Bangalore, KARNATAKA India P: 91‐80‐39992405, E: pawan.kumarg@manipal.edu
Notes	Clinical trial registration: Registered on 03‐07‐2009 with the Clinical Trials Registry India (CTRI/2009/091/000435). Trial status: study terminated

CTRI/2011/07/001891.

Study name	A Randomized, Double Blind, Multicentric, Placebo Controlled, Phase II Study Assessing The Safety And Efficacy Of Intraarticular Ex‐Vivo Cultured Adult Allogeneic Mesenchymal Stem Cells In Patients With Osteoarthritis Of Knee
Methods	Study design: double‐blind randomised controlled trial (Phase 2 study) Setting: multicentre Trial time period: not reported Interventions: bone marrow‐derived mesenchymal stem cells versus placebo (Plasmalyte‐A) Sample size calculations: not reported; target sample size was 60 participants
Participants	Inclusion criteria: Males or females in the age 40 to 70 years (both inclusive) Radiographic evidence of grade 2 to 3 osteoarthritis based on the Kellgren and Lawrence radiographic entry criteria History of primary idiopathic osteoarthritis of the knee characterised by pain which requires intake of analgesics Self‐reported difficulty in at least one of the following activities attributed to knee pain: lifting and carrying groceries, walking 400 metres, getting in and out of a chair, or going up and down stairs Patients who have been on stable medication, which may be NSAIDs/opioid or opiate analgesics, for the past 3 months Female patients of childbearing age must be willing to use accepted methods of contraception during the course of the study Ability to provide written informed consent Exclusion criteria: Prior or ongoing medical conditions (e.g. concomitant illness, psychiatric condition, alcoholism, drug abuse), medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow‐up would be completed, or could impair the assessment of study results History of surgery, or major trauma to the study joint Arthroscopy on the study joint in the previous 12 months Signs of active study joint inflammation including redness, warmth, and/or, if qualifying with osteoarthritis of the knee, a large, bulging effusion of the study knee joint with the loss of normal contour of the joint at the screening visit or at the baseline examination Patients who had received intra‐articular steroids or hyaluronan within the last 3 months Infections in or around the knee Patients awaiting a replacement knee or hip joint Patients with other conditions that cause pain Patients with deformity of the knee joint Significantly incapacitated or disabled and would be categorised as ACR Functional Class IV (largely or wholly incapacitated), or unable to walk without assistive devices Patients with other known rheumatic or inflammatory disease such as rheumatoid arthritis Other pathologic lesions on x‐rays of knee Positive hepatitis B surface antigen, hepatitis C antibody test, anti‐human immunodeficiency virus (HIV) antibody test, or VDRL History of bleeding disorders Known hypersensitivity to hyaluronan products or animal sera For women of child‐bearing potential: positive pregnancy test or lactating
Interventions	Intervention: allogeneic mesenchymal stem cells: bone marrow‐derived mesenchymal stem cells, 2 to 4 mL, single dose, intraarticular Comparator: placebo: Plasmalyte‐A, 2 to 4 mL, single dose, intra‐articular
Outcomes	Primary outcome: safety and tolerability, assessed by adverse events (time point: 2 years) Secondary outcomes: Change from baseline in the WOMAC OA Index ‐pain subscale score WOMAC Osteoarthritis stiffness Index WOMAC Osteoarthritis Composite Index ICOAP (Intermittent and Constant Osteoarthritis Pain) Radiograph of knee WORMS scoring system using MRI of the knee after 6 and 12 months Patient assessment of arthritis pain (Osteoarthritis‐Pain VAS) Reduction in intake of analgesic tablets (time point: 2 years)
Starting date	not reported
Contact information	Principal investigator: Dr Anoop CH Stempeutics Research Pvt. Ltd. Akshay Tech Park, No. 72 & 73 2nd Floor, EPIP Zone, Phase I‐Area Whitefield 560066 Bangalore, KARNATAKA India P: 91‐80‐39992430, E: anoop.ch@stempeutics.com
Notes	Clinical trial registration: Prospectively registered on 17‐07‐2011 with the Clinical Trials Registry India (CTRI/2011/07/001891). Trial status: recruitment completed Estimated study completion date: not reported

EUCTR2019‐002446‐21.

Study name	Phase III, multicentre, randomized, open clinical trial comparing treatment with allogenic mesenchymal cells against autologous mesenchymal cells and against active control with hyaluronic acid in patients with knee osteoarthritis
Methods	Study design: phase III, multicentre, open‐label, randomised controlled trial Setting: Spain Trial time period: Jan 2020 to current Interventions: autologous mesenchymal stem cell injection versus hyaluronic acid injection Sample size calculations: 120, numbers per group not given
Participants	Inclusion criteria: 1. Kellgren and Lawrence grade 2, 3 or 4 gonarthrosis 2. Chronic painful knee of mechanical characteristics 3. Absence of local or systemic septic process 4. Haematological and biochemical analysis without significant alterations that contraindicate the treatment 5. Informed written consent of the patient 6. The patient is able to understand the nature of the study 7. NEGATIVE Serologies: RPR, HIV, HBV, HCV and HCV PCR, in the 30 days prior to bone marrow extraction 8. BMI 20 to 35 kg/m2 Exclusion criteria: 1. Patient < 18 years, or legally dependent 2. Patient > 75 years 3. Present infection (to be included in the study, no infectious signs should be evidenced) 4. Congenital or evolutionary diseases that translate malformation and/or significant deformations of the knee (varus < 10º; valgus < 20º) and condition difficulties of application and evaluation of the results 5. Weight overload expressed in body mass index (BMI) greater than 30.5 (grade II obesity), being BMI = mass (kg): (height (m)) 2 6. Women who are pregnant or pretend to be pregnant or breastfeeding 7. Neoplastic disease 8. Primary or secondary immunosuppression 9. Intra‐articular infiltration of any drug in the 3 months prior to inclusion in the study 10. Simultaneous participation in another clinical trial or treatment with another product under investigation in the 30 days prior to inclusion in the study 11. Other pathologies or circumstances that compromise participation in the study according to medical criteria
Interventions	Autologous mesenchymal stem cell injection Allogeneic mesenchymal stem cell injection Hyaluronic acid injection
Outcomes	Primary outcomes Measurement of pain intensity according to the VAS pain scale at 12 months Assessment of functional capacity and pain according to the Lequesne scale at 12 months Measurement of symptomatology and perceived physical disability according to the WOMAC scale at 12 months Estimation of the improvement or stabilisation of the lesions in the MR images in T2‐mapping at 12 months Secondary outcomes Assessment of perceived quality of life on the SF‐12 scale at 6 and 12 months Rate of products that do not comply with the validation criteria in each branch of experimental treatment Rate of adverse effects in each of the treatment branches
Starting date	10 January 2020
Contact information	SCReN ‐ UICEC CAUSA/IBSAL esperanza.lopez@scren.es
Notes	Registered on: Status:

EUCTR2019‐005000‐17‐PL.

Study name	A Randomized, Double Blind, Two Arms, Controlled Phase I/II Safety and Efficacy Study on MesoCellA‐Ortho Tissue Engineered Product Intraarticularly Administrated in Adult Patients with Osteoarthrosis
Methods	Study design: randomised, double‐blind, 2‐arm, parallel‐group, controlled trial Setting: not reported Trial time period: not reported Interventions: MesoCellA‐Ortho (autologous adipose‐derived mesenchymal stem cells in vitro expanded) versus hyaluronic acid therapy Sample size calculations: target sample size = 200
Participants	Inclusion criteria: 1. Knee cartilage lesions (osteoarthritis II/III grade in Kellgren‐Lawrence scale confirmed in X‐ray) 2. Age between 40 and 70 years (inclusive) 3. No contraindications for liposuction 4. No contraindications for the general use of biological treatment, stem cells, PRP and whole autologous blood 5. Availability to take part into all study visits, barring unforeseen circumstances 6. Able and willing to perform exercises at home given by a physiotherapist 7. Contraceptive (birth control pills, injection, pessary or intrauterine device (IUD), spermicide condoms) 8. The pain intensity in treated knee not lower than grade 3 (on 11‐point Numerical Rating Scale) Exclusion criteria: 1. A history of cancer for 2 years before screening. In case of history of cancer medical above 2 years, consultation with oncologist and her/his permission for participation in clinical trial will be obligatory. 2. Pregnant or breastfeeding women 3. Allergy or poor tolerance of hyaluronic acid 4. Diabetes mellitus type 1, diabetes mellitus type 2 on insulin treatment 5. Lack of medical consultation in case of patients with diabetes group 6. Comorbidities significantly affecting overall health (e.g. history of myocardial infarction, heart failure, thrombophlebitis, arterial hypertension (hypertensive crises), chronic obstructive pulmonary disease, renal failure, liver failure, advanced atherosclerosis, psycho‐organic syndrome, hemiparesis, history of stroke) 7. Current or medical history of the patient: inflammatory diseases of the joints (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative arthritis involving the spine joints, septic arthritis, prior diagnosis of target arthrosis with crystal precipitation or elevated CRP in the condition, inflammation), osteonecrosis, osteoporotic fractures or other painful joint diseases other than osteoarthritis; secondary causes of osteoarthritis (e.g. rheumatoid arthritis, fibromyalgia, birth defects) 8. Current or medical history of the patient concerning carrier state or diseases: i) HIV, syphilis, HBV, HCV ii) CMV, mycoplasmas (only subjects with positive results for IgM antibodies will be excluded) iii) Medical history or diagnosed during anamnesis/medical examination: EBV, malaria, Toxoplasma gondii, Trypanosoma cruzi, HTLV 9. Symptomatic sciatica with radiation of pain to the examined limb 10. Symptomatic osteoarthritis of the hip of both limbs 11. Significant knee injuries within 6 months such as: ligament injuries, distal femur fracture or proximal tibia fracture, arthrofibrosis or cyclops lesions 12. Endoprosthesis of the hip or knee joints 13. Partial/total knee or hip joints replacement planned during the study 14. Surgical operation of the lower limbs (including arthroscopy) within 6 months before screening visit or planned during the study 15. Constant use of orthopaedic aids 16. Intolerance or hypersensitivity to any component of the preparation 17. Use of alternative treatment methods i.e. acupuncture within 4 weeks before screening visit or planning their use during the study 18. Use in the treatment of osteoarthritis: Hyaluronates (injections ‐ test knee) within 3 months Corticosteroids (injections) within 3 months Oral corticosteroids within 3 months 19. At screening: Blood test result outside of the allowable ranges (e.g. morphology, electrolytes, blood clotting APTT, INR, fibrinogen, CRP, glucose) Positive results of laboratory blood test (HIV, syphilis, HBV, HCV, CMV‐IgM, mycoplasmas‐IgM) 20. Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study or unable to comply with the study requirements. 21. Known allergic reactions to antibiotics used in cell culture: penicillin, streptomycin, amphotericin B 22. Intolerance or hypersensitivity to any of the anaesthetics (including lignocaine)
Interventions	Intervention: MesoCellA‐Ortho (Autologous adipose‐derived mesenchymal stem cells in vitro expanded) Comparator: Hyaluronic acid therapy
Outcomes	Primary Outcome(s) Secondary Objective: Clinical efficacy: • To evaluate efficacy of treatment of osteoarthritis (OA) with autologous AT‐MSCs (MesoCellA‐Ortho) when compared to treatment method employing hyaluronic acid intraarticular injection in non‐obese patients and patients burdened with T2DM and obesity, considering changes in cartilage structure observed in MRI, as well as objective improvement of knee joint function assessed by dynamographic platform and ROM. Main Objective: Safety: • To establish the safety of hyaluronic acid supplemented with AT‐MSCs (MesoCellA‐Ortho) injected intraarticular at a dose of 20 mln cells over 6 months by monitoring adverse reactions in three group of patients with osteoarthritis, additionally burdened with obesity and type 2 diabetes. Clinical efficacy: • To evaluate efficacy of treatment of osteoarthritis (OA) with autologous AT‐MSCs (MesoCellA‐Ortho) when compared to treatment method employing hyaluronic acid intraarticular injection in non‐obese patients and in patients burdened with T2DM and obesity, considering patient’s subjective pain level and evaluation of the improvement of knee joint function. osteoarthrosis treatment, through subjective patient assessment of knee function and pain level. Timepoint(s) of evaluation of this end point: during whole study Primary end point(s): Safety Endpoints The primary endpoint of this study is to measure the number and frequency of adverse event(s) including serious adverse event(s) throughout the study duration. Therefore, the following data will be collected: Primary: • Nature, incidence and severity of adverse events and serious adverse events, • Numerical Rating Scale (NRS) – evaluation of changes in pain level under the influence of intraarticular injection of MesoCellA‐Ortho (according to Table 1) • Joint swelling (physical examination) ‐ evaluation the joint swelling by physical examination after intraarticular injection • Allergic reactions Efficacy Endpoints The efficacy endpoint of this study is to measure positive effect of the proposed therapy in knee osteoarthritis, both in patient’s subjective assessment of knee function and pain and in cartilage regeneration. Therefore, clinical efficacy data will be collected during 6 months after intraarticular administration: Primary: • KOOS ‐ subjective assessment of knee function using the Knee injury and Osteoarthritis Outcome Score • IKDC 2000 ‐ subjective assessment of knee function using the International Knee Documentation Committee • SF‐36 ‐ subjective assessment of quality of life using the The The Short Form (36) Health Survey • Numerical Rating Scale (NRS) ‐ evaluation of changes in pain level under the influence of intraarticular injection of MesoCellA‐Ortho Secondary Outcome(s) Secondary end point(s): • MRI – qualitative and quantitative assessment of cartilage: ‐ evaluation of the cartilage by modified Outerbridge (Modified Outerbridge classification of cartilage defects), ‐ cartilage mapping: measurement of relaxation time (measured in milliseconds, ms) in selected ROIs (Region of Interest) in both medial and lateral femoral and tibial condyle, ‐ subchondral bone evaluation: observation of bone marrow edema‐like lesions (BMLs) in medial and lateral femoral and tibial condyle; if present then measurement of width and length of BMLs in sagittal cross‐sections. • Dynamographic platform – weight distribution on stable platform for objective evaluation of lower limb loading symmetry during clinical study during 5 exercises: standing, standing with eyes closed, calf raises, squat, jump. Minimum, maximum and average weight‐bearing value (measured in kilograms, kg) of the left and right lower extremity will be recorded. • Range of motion (ROM) ‐ measurement of knee flexion and extension angles. Normal ROM at the knee is considered to be 0 degrees of extension (completely straight knee joint) to 135 degrees of flexion (fully bent knee joint). Timepoint(s) of evaluation of this end point: pre‐rehabilitation visit 1, intraarticular administration visit, rehabilitation visit 4, follow‐up visit 1, follow‐up visit 2
Starting date	20/09/2021
Contact information	Name: Biuro Projektu BioMiStem Address: Gronostajowa 7 30‐387 Cracow Poland Telephone: +4812664 61 80 Email: biomistem@uj.edu.pl Affiliation: Ewa Zuba‐Surma
Notes

IRCT20080728001031N23.

Study name	Evaluation of safety and efficacy of intra‐articular transplantation of allogeneic adipose derived mesenchymal stromal cells in patients with knee joint osteoarthritis. An interventional randomized triple‐blind placebo controlled clinical trial phase I/II
Methods	Study design: randomised, triple‐blind, placebo‐controlled trial Setting: Royan Institute, Iran Trial time period: March 2017 to March 2019 Interventions: stem cell injection versus placebo injection Sample size calculations: 100
Participants	Inclusion criteria Patients in the range of 18 to 65 years old Osteoarthritis diagnosed by MRI Exclusion criteria Pregnancy or lactating Positive tests for HIV, HCV, HBV Active central or peripheral neurologic disorder End organ damage or uncontrolled endocrine disorder Active respiratory disorder and reaction to sedative drugs History of cancer
Interventions	Stem cell injection Intraarticular transplantation of a single dose of 100 million allogeneic adipose‐derived mesenchymal stem cells Placebo injection Intra‐articular transplantation of a single dose of 3 to 5 mL normal saline as placebo
Outcomes	Outcome assessment at 3, 6 and 12 months Primary outcome WOMAC and KOOS questionnaires for osteoarthritis Adverse events Secondary outcomes MRI assessment of new cartilage formation and cartilage thickness, joint effusion and oedema Molecular and cellular indexes (IL‐6, IL‐10, TNF‐a, IFN‐?, COMP, CTX‐II, HA, CS846, CD4, CD3, CD8, CD25)
Starting date	14 March 2017
Contact information	Shahedeh Karimi Torshizi Royan Institute, Iran karimi58shah@gmail.com
Notes	Trial registration: 24 April 2018 Funding: Royan Institute, Iran Trial status: recruitment complete Estimated completion date: 21 March 2019

IRCT2012080510507N1.

Study name	Evaluation of efficacy of treatment with stem cells (SCs) and platelet‐rich plasma (PRP) in patients with knee arthrosis
Methods	Study design: randomised, 4‐arm, parallel, controlled trial Setting: Iran Trial time period: August 2013 to August 2015 Interventions: stem cell injection versus placebo injection Sample size calculations: 60
Participants	Inclusion criteria: Female or male patient with knee osteoarthritis based on the ACR criteria and knee radiography Grade 2 or 3 osteoarthritis according to Kellgren and Lawrence grading scale Patient’s age < 75 No consumption of glucocorticoids, anti‐inflammatory and immunomodulatory medications one week prior to the treatment No history of previous participation in clinical trials on treatment of osteoarthritis No intra‐articular injection of hyaluronic acid in the past 6 months Exclusion criteria: Secondary osteoarthritis Concurrent connective tissue disorder Active neurological disease Severe cardiac disease Debilitating respiratory disease requiring constant treatment Any endocrinopathy Malignancies Current infectious disease Psychologic diseases (especially major depression) requiring treatment with antidepressants or related medications Being under treatment with immunosuppressive or cytotoxic medications Being under constant treatment with antithrombotic medications History of allergy to biologic products Hb < 11 g/dL; Plt < 120*103/µL
Interventions	Intervention 1: Intra‐articular injection of 2 mL hyaluronan (scaffold) + 2 mL autologous mesenchymal stem cell (2‐3 million) + 0.2 mL dexamethasone Intervention 2: Intra‐articular injection of 2 mL hyaluronan (scaffold) + 2 mL autologous platelet rich plasma + 0.2 mL dexamethasone Intervention 3: Intra‐articular injection of 2 mL hyaluronan (scaffold) + 2 mL autologous mesenchymal stem cell (2‐3 million) + 2 mL autologous platelet‐rich plasma + 0.2 mL dexamethasone Intervention 4: Intra‐articular injection of 2 mL hyaluronan + 0.2 mL dexamethasone
Outcomes	Measured 1, 3, 6 and 12 months post‐intervention Range of motion Morphological characteristics of articular cartilage: MRI Osteoarthritis Knee Score (MOAKS) Pain: pain numerical rating scale Symptoms and function of the affected knee: Knee injury and Osteoarthritis Outcome Score (KOOS)
Starting date	23 August 2013
Contact information	Dr. Zhaleh Shariati Sarabi shariatij@mums.ac.ir
Notes	Trial registered on 01 June 2014 Status: recruitment completed

IRCT20151017024572N19.

Study name	The effects of ultrasound‐guided corticosteroid injection compared to mesenchimal stem cell injection in patients with knee osteoarthritis: a randomized controlled trial
Methods	Study design: randomised controlled trial Setting: physical medicine clinics (Iran University of Medical Sciences) Timing: 2019 Interventions: ultrasound‐guided corticosteroid injection vs mesenchymal stem cell injection Sample size: 30
Participants	Inclusion criteria: Patients with mild to moderate OA of the knee (Kellgren Lawrence grade I, II and III); the absence of any acute or chronic infection; no history of any intra‐articular injection of the knee in 3 months; the absence of inflammatory articular diseases Exclusion criteria: Willingness of patients to exit from the study
Interventions	1 cc lidocaine 2% will be used for local anaesthesia (skin) in both groups. Intervention: Mesenchymal stem cell injection will be performed under ultrasound guidance in the knee joint, which will be done by an experienced physical medicine and rehabilitation specialist, using supra patellar approach. Under sterile conditions, 30 ×(8)10 mesenchymal stem cells with fat source ultrasound‐guided (in suprapatellar pouch), will be injected into the joint. Control: Corticosteroid injection will be performed under ultrasound guidance in the knee joint, which will be done by an experienced physical medicine and rehabilitation specialist, using supra patellar approach. Under sterile conditions, 40 mg triamcinolone (1 cc) will be injected into the knee joint (ultrasound‐guided in suprapatellar pouch).
Outcomes	Outcomes were measured at 2 weeks, 1 month and 6 months Study outcomes: Pain intensity (VAS) WOMAC score Clinical assessment (range of motion) Maximum depth cartilage of distal femur joint surface Adverse events
Starting date	5 Jan 2019
Contact information	Arash Babaei‐Ghazani Email: babaei‐ghazani.a@iums.ac.ir
Notes	Trial registration: IRCT20151017024572 Trial status: recruitment complete Estimated study completion date:

IRCT2016021710507N4.

Study name	Evaluation of Effectiveness of Intra‐Articular Injection of Bone Marrow Derived Stem Cells for Treatment of Degenerative Knee Osteoarthritis
Methods	Study design: randomised controlled trial Setting: Imam Reza Hospital Timing: 23 September 2015 to 23 September 2016 Interventions: 1) intra‐articular injection of bone marrow‐derived mesenchymal cells or MSCs (treatment group), 2) intra‐articular injection of commercially available hyaluronic acid gel (control group) Sample size: 30
Participants	Inclusion criteria: Female or male patients with knee osteoarthritis based on the ACR criteria and knee radiography; Grade 2 or 3 osteoarthritis according to Kellgren and Lawrence grading scale; Patient’s age < 75; signed informed consent; no consumption of glucocorticoids, anti‐inflammatory and immunomodulatory medications one week prior to the treatment; no history of previous participating in clinical trials on treatment of osteoarthritis; no intra‐articular injection of hyaluronic acid in the past 6 months Exclusion criteria: Secondary osteoarthritis; concurrent connective tissue disorder; active neurological disease; severe cardiac disease; debilitating respiratory disease requiring constant treatment; any endocrinopathy; malignancies; current infectious disease; psychologic diseases (especially major depression) requiring treatment with antidepressants or related medications; being under treatment with immunosuppressive or cytotoxic medications; being under constant treatment with antithrombotic medications; history of allergy
Interventions	Intervention Intra‐articular injection of 2 mL hyaluronan (scaffold) + 2 mL autologous bone‐marrow derived mesenchymal stem cell (2‐3 million) + 0.2 mL dexamethasone Comparator Intra‐articular injection of 2 mL hyaluronan + 0.2 mL dexamethasone
Outcomes	Outcomes were measured at 1, 3, 6 and 12 months follow‐up. Primary outcomes: Modified version of "Magnetic Resonance Observation of Cartilage Repair Tissue" (Modified MOCART) for assessing the morphological characteristics of articular cartilage Pain numerical rating scale Function on Knee injury and Osteoarthritis Outcome Score (KOOS) Range of motion
Starting date	20 Feb 2016
Contact information	Mashhad University of Medical Sciences shariatij@mums.ac.ir
Notes	Trial registration: IRCT2016021710507N4 Trial status: Recruitment complete Estimated study completion date: 23 September 2016

IRCT20210103049925N1.

Study name	The effect of mesenchymal stem cells on osteoarthritis recovery
Methods	Study design: randomised, double‐blind, placebo‐controlled clinical trial, phase I Setting: Baqiyatallah University of Medical Sciences, Tehran, Iran Trial time period: trial has not commenced Intervention: Wharton’s jelly‐derived mesenchymal stem cells vs hyaluronic acid Sample size: 40
Participants	Inclusion criteria: Knee osteoarthritis (OA) (grade 2 and 3 Kellgren Lawrence scale) Radiography indicative of knee and femur malalignment of less than 30 degrees Pain level of 4‐7 measured on VAS 24 hours prior to referral Age range of 40 to 65 years Exclusion criteria: Inflammatory disorders Metabolic disorders (e.g. diabetes mellitus) Autoimmune diseases Immunodeficiency Cancer or other severe diseases Contagious viral infections Psychological disorders History of renal or hepatic failure Body mass index (BMI) > 30 Fever Oral corticosteroids in the last 4 weeks Injection of corticosteroids in the last 6 months History of protein or other related allergies Coagulation disorders Pregnancy or planning for pregnancy in the last 12 months Participating in other clinical trials at the same time Septic arthritis Addiction to opium, alcohol, painkillers and/or anaesthetics
Interventions	Intervention group: receiving 40 million Wharton’s jelly‐derived mesenchymal stem cells loaded on 5CC hyaluronic acid via injection into knee joint (20 patients). All the required elements and ingredients such as cells are provided by Celltech Pharmed company. Control group: receiving 5CC hyaluronic acid via injection into knee joint (20 patients). All the required elements and ingredients are provided by Celltech Pharmed company.
Outcomes	Primary outcomes: Pain index. Time point: 3 months post injection. Method of measurement: VAS questionnaire. Cartilage thickness. Time point: 3 months post injection. Method of measurement: magnetic resonance imaging. Walking distance in 6 minutes. Time point: 3 months post injection. Method of measurement: Metre. Disability index. Time point: 3 months post injection. Method of measurement: Health Assessment Questionnaire. Lysholm score. Time point: 3 months post injection. Method of measurement: Lysholm questionnaire. International Knee Documentation Committee score. Time point: 3 months post injection. Method of measurement: International Knee Documentation Committee (IKDC) Questionnaire. Range of motion. Time point: 3 months post injection. Method of measurement: Goniometer. Secondary outcomes: Adverse events
Starting date	20 May 2021
Contact information	Yunes Panahi Baqiyatallah University of Medical Sciences, Mollasadra Ave., Vanak Square, Tehran, Iran 1435916471 Tehran Iran (Islamic Republic of) +98 21 8821 1524 yunespanahi@yahoo.com
Notes	Trial registration: IRCT20210103049925N1 Status: Recruitment pending

IRCT20210307050611N1.

Study name	Mesenchymal stem cell injection in patients with knee osteoarthritis compared to a randomized controlled trial
Methods	Study design: double‐blinded, 2‐arm, parallel randomised controlled trial Setting: Iran Timing: not reported Interventions: mesenchymal stem cell injection vs control (knee care training in daily life activities) Sample size: 80
Participants	Inclusion criteria: Knee Osteoarthritis Based on American College of Rheumatology Criteria in Grades 1, 2 and 3: Lowrence ‐ Kellergan Knee pain for at least 6 months Proper liver function Proper renal function Exclusion criteria: Any acute or chronic infection Pregnancy or decision to become pregnant Any intra‐articular injection during the last 3 months Inflammatory joint disease or secondary osteoarthritis History of knee surgery Severe underlying disease such as uncontrolled diabetes, taking anticoagulants Daily use of opioid and non‐opioid analgesics
Interventions	Mesenchymal stem cell injection: 8 million adipose‐derived stem cells in two millilitres of normal saline were injected into each patient's knee under an ultrasound guide. Before the stem cell injection, a two‐hour session is considered to explain and teach the patient the treatment method, satisfaction as well as post‐injection care. After selecting the patient to study, the time required for patient availability is eight months. Adipose‐derived stem cells after isolation, culture, characterisation and quality control tests are performed in a clean room with grade A and B clean room of Motahhari Hospital and under sterile conditions, by experts in this field. Control group (knee care training in daily life activities): These patients will be given knee care training in daily life activities and they will not receive any other therapeutic intervention.
Outcomes	Outcomes will be measured at 6 months. Primary outcome: Pain: The pain assessment scale is performed by the VAS (0‐10). Secondary outcomes: Knee cartilage formation using MRI Pain due to inflammation in the knee joint in the last 6 months on VAS The range of motion of the knee joint from the extent position to 140 degrees is measured in both active and passive forms on goniometer
Starting date	22 May 2021
Contact information	Naser Amini amini_ot@yahoo.com Iran University of Medical Sciences
Notes	Trial registration: IRCT20210307050611N1 Trial status: recruiting

IRCT20210423051054N1.

Study name	Evaluation of therapeutic effect of placental mesenchymal stem cell exosome injection in improving clinical symptoms and MRI changes in patients with knee osteoarthritis
Methods	Study design: 2‐arm, parallel, double‐blind randomised controlled trial Setting: physical medicine and rehabilitation clinic of Taleghani Hospital, Tehran, Iran Trial time period: Not reported Interventions: stem cell injection plus exercise versus placebo injection plus exercise Sample size calculations: 30
Participants	Inclusion criteria: Pain in both knees over the past 6 months, which is related to the degenerative process of the knee, requires pain medication and has lasted for more than a month Graphical confirmation of bilateral knee osteoarthritis with grade 2 or 3 based on the Kellgren‐Lawrence classification The knee pain intensity should be greater than or equal to 4 according to the VAS Exclusion criteria Younger than 45 years or older than 65 years Rheumatic or collagen vascular disease History of malignancy Coagulopathy or taking anticoagulant drug Any injection into the knee joint during the last 3 months A history of recent severe knee trauma in the past 1 month Septic arthritis of the knee or active wound of the knee joint Genovarum or genovalgum greater than 20 degrees Total knee replacement Cardiac pacemaker Cochlear implantation Existence of fragments or foreign metal object in the knee or around the arteries, nerves and brain
Interventions	Stem cell injection plus exercise Injection of 5 cc of placental mesenchymal stem cell exosome into the knee with anterolateral approach in the flexed position, isometric strengthening exercises for quadriceps, adductor and abductor muscles of the thigh (10 times and each time for 10 seconds), 2 times a day, and stretching of hamstrings (3 times and each time for 30 seconds), 2 times a day Placebo injection plus exercise Injection of 5 cc of normal saline into the knee with anterolateral approach in the flexed position, isometric strengthening exercises for quadriceps, adductor and abductor muscles of the thigh (10 times and each time for 10 seconds), 2 times a day, and stretching of hamstrings (3 times and each time for 30 seconds), 2 times a day
Outcomes	Timepoints: 2 and 6 months Pain intensity on VAS Pain or discomfort, maximum distance walked, and activities of daily living on Lequesne Index MRI of cartilage changes Pain intensity, stiffness, and physical activity on WOMAC
Starting date	11 May 2022
Contact information	Najmeh Sadat Bolandnazar Taleghani Hospital, Yaman St, Shahid Chamran Hwy 1115119857 Tehran Iran (Islamic Republic of) Email: n.sadat.bolandnazar@gmail.com
Notes	Trial registration: IRCT20210423051054N1 Funding: Shahid Beheshti University of Medical Sciences Estimated completion date: not reported Status: recruitment pending

IRCT20211102052944N1.

Study name	Evaluation of safety and efficacy of intra‐articular knee transplantation of three consecutive doses of allogenic umbilical cord mesenchymal stromal cells in patients with knee osteoarthritis: interventional clinical trial, phase I/II
Methods	Study design: double‐blinded, 2‐arm, parallel randomised controlled trial Setting: Iran Timing: not reported Interventions: mesenchymal stem cell injection vs hyaluronic acid Sample size: 30
Participants	Inclusion criteria: 40‐70 years Unilateral knee osteoarthritis Kellgren and Lawrence grade of both knees between 2 and 3 Evidence of x‐ray imaging findings compatible with knee osteoarthritis Knee pain for at least 4 months that has not responded to common medical and physical therapies Visual analogue score = 4 Informed consent Exclusion criteria: Pregnancy or lactation Inflammatory or infectious arthritis Intra‐articular injection during the last 2 months BMI = 35 Haematological and biochemical analysis with significant alterations that contraindicates intervention Known and uncontrolled chronic disease (including diabetes (HbA1c = 8), heart failure (EF < 45%), renal failure (Cr > 2), liver failure (AST, ALT > 100) History of any type of neoplasm Take aspirin one week before the cell injection History of coagulopathy or use of anticoagulants Positive viral tests (HIV, CMV, HTLV1 and 2, HBV, HCV) Having a movement disorder Having serious illnesses with a life expectancy of less than 1 year
Interventions	Intervention group: patients receiving 3 doses of normal saline containing 20 million mesenchymal cells derived from allogenic umbilical cord tissue + hyaluronic acid at intervals of 0, 2 and 4 months Control group: patients receiving 3 doses of normal saline + hyaluronic acid injected intra‐articularly at 0, 2 and 4 months intervals
Outcomes	VAS; articular cartilage thickness via MRI; WOMAC; SF‐36 at 2, 4, 6, 9 and 12 months after intervention
Starting date	09 November 2021
Contact information	Mohsen Emadedin Email: mohsen.emadedin@royaninstitute.org
Notes	Trial registration: Irct20211102052944N1 Status: recruiting

ISRCTN88966184.

Study name	Personalized treatment of knee osteoarthritis with fat tissue containing stem cells
Methods	Study design: multicentre, interventional, double‐blinded randomised controlled trial Setting: Zagreb, Croatia Trial time period: not reported Interventions: stem cell injection versus hyaluronic acid (HA) injection Sample size calculations: 80
Participants	Inclusion criteria 1. Patients with osteoarthritis of the knee who are aged 30‐75 years old 2. Osteoarthritis grade 2‐3 based on Kellgren‐Lawrence classification 3. Patellofemoral osteoarthritis Iwano grade 2‐3 4. Presence of knee pain for at least six months 5. Patients who have lower limb axis deviation less than 5° 6. The possibility of following research instructions and responding to control examinations 7. Signed informed consent for participation in the research Exclusion criteria: 1. Malignant diseases, systemic inflammatory diseases (e.g. rheumatoid arthritis, psoriatic arthritis) or other systemic diseases that can result in knee pain or cause systemic inflammation 2. A body mass index (BMI) greater than 30 or diabetes 3. Six or more painful points on the body, distributed above and below the waist, on both sides of the body and in the axilla 4. Depression (determined according to the CESD‐R questionnaire) 5. Stage 4 of the Kellgren‐Lawrence classification for knee osteoarthritis, stage 4 of the Iwano classification of patellofemoral arthrosis 6. A MOAKS score for synovitis or effusion less than 2 (patients without knee effusion) 7. Post‐traumatic osteoarthritis 8. A history of surgery on the affected knee 9. A deviation of the mechanical axis (valgus/varus) of the lower extremities greater than 5° 10. An injury of the affected knee in the last 3 months
Interventions	Stem cell injection (microfragmented adipose tissue (MFAT)) Both groups will undergo the lipoaspiration procedure to ensure proper blinding. The collected adipose tissue of the participants who will receive HA will be cryopreserved until the end of the study, when they will be offered to receive their MFAT, after viability analysis. The lipoaspiration procedure will be performed under sterile conditions in the operating room. The participant will be placed lying supine on the operating table. Local anesthesia (2% lidocaine) will be applied to the area from which adipose tissue is taken and a small incision (6‐8 mm) will be made. Approximately 500 ml of saline containing 50 ml of 2% lidocaine and 1 ampoule of adrenaline will be injected to reduce bleeding. A thin cannula will then be inserted through the incision and the adipose tissue will be pulled into the syringe in a controlled back and forth motion. After waiting several minutes, using a 17‐G cannula connected to a negative pressure syringe, 60 ml of subcutaneous adipose tissue will be collected. After taking the adipose tissue, an elastic band will be put on the participants to avoid the formation of subcutaneous haematomas. The lipoaspirate will then be put into the Lipogems System (Lipogems, Milan, Italy) from which the MFAT will be obtained. Hyaluronic acid injection The same injection procedure will be used for both treatments.
Outcomes	Knee symptoms, pain and function measured by patient‐reported outcomes measures (PROMs) using a visual analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC), Oxford Knee Score and Tegner/Lysholm knee score at baseline, 1‐month and 6‐month follow‐up
Starting date	1 August 2022
Contact information	Vilim Molnar Branimirova 71E 10000 Zagreb Croatia Email:vilim.molnar@svkatarina.hr
Notes	Trial registration: registered on 1 August 2022 Funding: St Catherine Specialty Hospital Status: recruiting Completion date: not known

KCT0001619.

Study name	Multicenter, Randomized, Double‐Blind, Placebo Controlled Phase IIb/III Clinical Trial to Evaluate Efficacy and Safety of JOINTSTEM in Patients with Degenerative Arthritis
Methods	Study design: multicentre, randomised, double‐blind, placebo controlled phase IIb/III clinical trial Setting: Kyung Hee University Hospital at Gangdong and Yonsei University Health System, Gangnam Severance Hospital Timing: 30 March 2016 to 30 June 2016 Interventions: experimental (Jointstem): autologous adipose tissue‐derived MSCs Placebo comparator (saline solution): sodium chloride 9 mg/mL Sample size: 24
Participants	Inclusion criteria: Age 18 or older, male and female Patients must consent in writing to participate in the study by signing and dating an informed consent document Diagnosis of osteoarthritis by ACR (American College of Rheumatology Criteria) osteoarthritis of the knee Diagnosis of osteoarthritis by radiographic criteria of Kellgren and Lawrence grade 2‐4 More than Grade 4 (0 to 10‐point numeric scale) pain at least for 12 weeks Diagnosis of osteoarthritis of class Ⅰ‐Ⅲ by ACR global functional criteria Patients who agree with contraception Exclusion criteria: Preparing for pregnancy or pregnant women or lactating mothers Patients with BMI > 35 Patients with other disease including septic arthritis, rheumatoidal or inflammatory joint disease, crystalline disease (gout or pseudogout), Paget disease, articular fractures, ochronosis, acromegaly, haemochromatosis, Wilson's disease, osteochondromatosis, hereditary disorder Patients with serious condition (internal medicine disease) Patients with positive human immunodeficiency (HIV), hepatitis B (HBV), hepatitis C (HCV), syphilis at screening indicative of current of past infection Patient with behavioural disorders, cognitive disorders and chronic mental symptoms Patient with significant neurologic or psychiatric disorders Patients with alcohol, drug abuse history Patients who had participated in other clinical trials within 12 weeks prior to this study. Patients who received any drug by intra‐articular injection for treatment within 2 months prior to this enrolment Patients who have experienced knee joint cartilage and stem cell therapy Patients who the principal investigator considers inappropriate for the clinical trial due to any other reasons than those listed above Patients with penicillin hypersensitivity reactions
Interventions	Intervention Jointstem (autologous adipose tissue‐derived MSCs 1 x 108 cells/3 mL), 1 time injection Comparator Saline solution (sodium chloride 9 mg/mL), 1 time injection
Outcomes	Primary outcomes: WOMAC (Western Ontario and McMaster Universities) total scores Secondary outcomes: KOOS (Knee Injury and Osteoarthritis Outcome Score) WOMAC (Western Ontario and McMaster Universities) subscale scores SF‐36 Global assessment of disease activity Overall satisfaction X‐ray and MRI scan for arthroscopy evaluation and histological evaluation
Starting date	2015
Contact information	Name of organisation/entity R‐bio
Notes	Trial registration: KCT0001619 2015 Trial status: recruitment completed on 18 Dec 2016. No results available (https://adisinsight.springer.com/trials/700267365).

Liu 2021.

Study name	Evaluating the efficacy and cost‐effectiveness of stem cell injections in people with mild to moderate knee osteoarthritis: a randomised placebo‐controlled trial (The SCUlpTOR trial)
Methods	Study design: randomised, double‐blind, placebo‐controlled trial Setting: New South Wales, Tasmania, Australia Trial time period: 2 July 2018 to unknown (still recruiting) Interventions: allogeneic human adipose‐derived mesenchymal stem cells (MSCs) versus placebo (sterile, clinical grade injectable isotonic solution) Sample size: 440
Participants	Inclusion criteria: People ≥ 40 years of age Knee OA as defined by the clinical and radiographic American College of Rheumatology (ACR) criteria Presence of pain in the study knee for at least half of the days in the previous month Average pain intensity ≥ 40 and ≤ 90 on a 0‐100 visual analogue scale (VAS) over the past week before the Online Screening and Baseline surveys Kellgren‐Lawrence grade (KLG) 2 or 3 of the study knee based on knee radiographs Medial or lateral minimal joint space width (mJSW) between 0.5 and 4 mm of the study knee based on radiographs Willingness to undergo a new knee X‐ray and MRI Willingness to stop or maintain a routine (on the same dosage and frequency) of conservative treatments Willingness to stop or minimise the use of anti‐inflammatory drugs and other analgesics (except paracetamol for rescue pain relief) for the duration of the study Willingness to undergo a 1‐week medication wash‐out (for all pain medications) before each pain assessment (baseline, 3, 6, 9, 12, 15, 18, 21 and 24‐months) Willingness to avoid a new treatment for knee OA during the study Willingness and ability to travel for study visits according to their site Exclusion criteria: Incomplete online screening surveys Participants that are non‐responders after completing the screening survey but before being enrolled Women who are pregnant or breastfeeding, or women of childbearing potential not willing to use contraceptive methods for the duration of the study Bilateral symptomatic knee OA if the patient‐reported pain intensity in the contralateral knee is ≥ 30 on a 0‐100 VAS Significant injury in the study knee that led to substantial loss of function or surgeries within the past 6 months Prior knee joint replacement or high tibial osteotomy in the study knee Surgery on the study knee within the past 12 months Planned surgery for the study knee in the next 24 months History of crystalline arthropathy, autoimmune arthritis, haemochromatosis or fibromyalgia. Except for the following conditions: participants diagnosed with gout are eligible for the study as long as the condition is being appropriately treated and they have not experienced flare‐ups for at least 12 months participants diagnosed with haemochromatosis but with normal iron levels for at least 12 months are eligible for the study Signs of acute knee joint inflammation (i.e. red, swollen and hot) and/or abnormal synovial fluid suggestive of either crystal or infection Any painful muscular or neurological condition of the lower limb that, in the opinion of the investigators, is the main contributor to the pain and/or loss of function in the study knee which may interfere with the self‐reported assessment Immunosuppression or acute infective processes Cancer or other tumour‐like lesions, except for non‐melanoma skin cancer which has been removed and not active within the past 3 years Hyaluronic acid (HA) injection within the past 6 months Autologous blood product or stem cell injection in the study knee within the past 12 months Steroid injections in any joint within the past 6 months Regularly taking centrally acting analgesics (e.g. opioid analgesics, duloxetine and pregabalin) Participation in another clinical trial and/or treatment received with any investigational agent within 30 days before enrolment Any unstable concurrent clinically significant acute, chronic medical conditions or abnormal laboratory findings that, in the judgment of the Investigator, would jeopardise the safety of the participant, interfere with study objectives or affect the participant’s compliance Needle phobia Contraindications to MRI Inability to fit into the MRI knee coil
Interventions	Stem cell injection: The dose administered: 2.5 x 10^7 cell culture‐expanded mesenchymo angioblast‐derived mesenchymal stem cells (MSCs) suspended in 5 mL excipient solution. Frequency and duration of administration: 3 knee intra‐articular injections of allogeneic MSCs performed at baseline, week 3 and 52 (12 months) Mode of administration: ultrasound‐guided intra‐articular injections applied to the study knee delivered by an experienced radiologist Placebo injection: Saline solution containing 0.9% sodium chloride
Outcomes	Outcomes measured at 3, 6, 12 and 24 months post‐treatment Primary outcomes: The proportion of participants achieving patient‐acceptable symptom state (PASS) for knee pain. Central medial femorotibial (cMFT) cartilage thickness loss in µm. The cMFT cartilage thickness will be measured by drawing disarticulation contours around the cartilage edges, section by section in all MRI slices of the study knee. Secondary outcomes: Knee pain intensity measured by VAS Knee pain intensity measured by the Wong‐Baker FACES Pain Rating Scale Physical activity levels measured by the Physical Activity Scale for the Elderly (PASE) Health‐related quality of life measured using the total score of the Assessment of Quality of Life ‐ 8 domains (AQoL‐8D) instrument Knee pain intensity measured by the Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain subscale Knee function in daily living measured by the KOOS Function in daily living subscale Sport‐ and recreation‐related knee function measured by the KOOS' Function in sport and recreation subscale Knee‐related quality of life measured by the KOOS knee‐related quality of life subscale KOOS total score using all 5 subscales: pain, other symptoms, function in daily living, function in sport and recreation and knee‐related quality of life Perceived overall improvement assessed by the global rating of change Treatment satisfaction to be assessed using a "yes/no" question
Starting date	Date registered: 31 August 2020 Date of first enrolment: 15 March 2021
Contact information	Prof David Hunter Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney. Rheumatology Department, Lv 10 Kolling Building, Reserve Road, St Leonards, NSW 2065, Australia. Australia +61 02 9463 1855 sculptor.trial@sydney.edu.au
Notes	Trial registration: ACTRN12620000870954 https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000870954 Status: recruiting Published protocol: doi:10.1136/bmjopen‐2021‐056382

Mikkelsen 2021.

Study name	Treatment of Osteoarthritis With Autologous, Microfragmented Adipose Tissue.
Methods	Study design: parallel, triple‐blind, 2‐arm randomised controlled trial Setting: Copenhagen University Hospital Hvidovre, Denmark Timing: Jan 2019 to June 2022 Interventions: intra‐articular knee injection of autologous micro‐fragmented adipose tissue vs intra‐articular injection of saline Sample size: 120 participants
Participants	Inclusion criteria Age 18 to 70 years Kellgren‐Lawrence grade 2 to 3 in the tibiofemoral joint The patient must be expected to be able to attend follow‐up examinations The patient must be able to speak and understand Danish The patient must be able to give informed consent Exclusion criteria Smoking (the patient must consent to being non‐smoking 6 weeks pre and post the procedure) Varus or valgus malalignment of the knee > 5 degrees Laxity of the MCL or LCL of 10 degrees or more compared to the opposite knee Knee instability and anterior‐posterior laxity of 3mm or above Preceding open surgery to the knee or fracture in the proximal tibia or distal femur Extension deficit of the knee Kellgren‐Lawrence grade 4 in any of the three compartments BMI > 40 Terminal illness or severe medical illness: ASA score higher than or equal to 3
Interventions	Intervention: Patients are treated with an intra‐articular injection with autologous, micro‐fragmented adipose tissue. Control: Patients are treated with an intra‐articular injection with saline (placebo).
Outcomes	Primary outcome measures: KOOS4 (time frame: 6 months) The Knee injury and Osteoarthritis Outcome Score Secondary outcome measures: KOOS (time frame: 6 months, 12 months and 24 months). The Knee injury and Osteoarthritis Outcome Score (including all five subscales): KOOS Pain, KOOS Symptoms, Function in daily living (KOOS ADL), Function in Sport and Recreation (KOOS Sport/Rec) and knee‐related Quality of Life (KOOS QOL) Failure (time frame: 6 months, 12 months and 24 months). If the patients do not experience a clinically relevant improvement in KOOS4 the treatment is considered a failure. A clinical relevant difference is estimated to be 10 points. The number of patients experiencing failure of the treatment is recorded at each follow‐up.
Starting date	1 January 2019
Contact information	Kristoffer W Barfod +45 38621703 kristofferbarfod@gmail.com
Notes	Trial registration: NCT03771989 Trial status: recruiting Estimated study completion date: 30 June 2022

NCT01448434.

Study name	Allogeneic Mesenchymal Stem Cells for Osteoarthritis
Methods	Study design: randomised, double‐blind, 2‐arm parallel trial Setting: KPJ Ampang Puteri Specialist Hospital, Malaysia Timing: September 2011 to September 2013 Interventions: allogeneic MSCs injection plus hyaluronic acid injection versus placebo plus hyaluronic acid injection Sample size: 72
Participants	Inclusion criteria: 1. Males or females aged 20 ‐ 70 years (both inclusive) 2. Radiographic evidence of grade 2 to 3 osteoarthritis based on the Kellgren and Lawrence radiographic entry criteria. 3. History of primary idiopathic osteoarthritis of the knee characterised by pain which requires intake of analgesics 4. Self‐reported difficulty in at least one of the following activities attributed to knee pain: lifting and carrying groceries, walking 400 metres, getting in and out of a chair, or going up and down stairs 5. Patients who have been on stable medication for the past 3 months 6. Patients who have not received intra‐articular steroids or hyaluronan within the last 3 months 7. Female patients of childbearing age must be willing to use accepted methods of contraception during the course of the study 8. Ability to provide written informed consent Exclusion criteria: 1. Prior or ongoing medical conditions (e.g. concomitant illness, psychiatric condition, alcoholism, drug abuse), medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow‐up would be completed, or could impair the assessment of study results. 2. History of surgery, including arthroscopy, or major trauma to the study joint in the previous 12 months 3. Signs of active study joint inflammation including redness, warmth, and/or, if qualifying with osteoarthritis of the knee, a large, bulging effusion of the study knee joint with the loss of normal contour of the joint at the screening visit or at the baseline examination 4. Infections in or around the knee. 5. Patients awaiting a replacement knee or hip joint 6. Patients with other conditions that cause pain 7. Significantly incapacitated or disabled and would be categorised as ACR Functional Class IV (largely or wholly incapacitated), or unable to walk without assistive devices 8. Patients with other known rheumatic or inflammatory disease such as rheumatoid arthritis 9. Other pathologic lesions on x‐rays of knee 10. Positive hepatitis B surface antigen, hepatitis C antibody test, anti‐human immunodeficiency virus (HIV) antibody test, or VDRL 11. History of bleeding disorders 12. Known hypersensitivity to hyaluronan products or animal sera 13. For women of child‐bearing potential: positive pregnancy test or lactating
Interventions	Intervention Ex‐ vivo cultured adult allogeneic MSCs: single intraarticular dose of allogeneic MSCs suspended in 2 mL Plasmalyte followed by 2 mL of hyaluronan Comparator Plasmalyte‐A: single intraarticular dose of 2 mL Plasmalyte followed by 2 mL hyaluronan
Outcomes	Outcomes were measured at 1 year. Primary: Adverse events Secondary outcomes: Change from baseline in the WOMAC OA (Western Ontario and McMaster Universities Osteoarthritis) Index ‐ pain subscale score Change from baseline in WOMAC OA stiffness index Change from baseline in WOMAC OA composite index Change from baseline in ICOAP (Intermittent and Constant Osteoarthritis Pain) Change from baseline in radiographic (X‐ray) findings of knee Change from baseline in the WORMS score of knee using MRI Change from baseline in arthritis pain scores on the visual analogue scale Reduction in the intake of analgesic tablets from baseline
Starting date	Sep 2011
Contact information	Prof. Dr. Muhammad Ali Noor Muhd Abdul Ghani, FRCS KPJ Ampang Puteri Specialist Hospital Kuala Lumpur, Selangor, Malaysia, 68000
Notes	Trial registration: NCT01448434 Trial status: completed Estimated study completion date: September 2013

NCT01459640.

Study name	Intra‐Articular Autologous Bone Marrow Mesenchymal Stem Cells Transplantation to Treat Mild to Moderate Osteoarthritis
Methods	Study design: randomised, open‐label study Setting: Malaysia Timing: March 2011 to March 2014 Interventions: autologous bone marrow‐derived mesenchymal stem cells versus hyaluronic acid Sample size: 50
Participants	Inclusion Criteria: Diagnosed with mild to moderate osteoarthritis based on Kellgren‐Lawrence radiographic classification Has a history of joint swelling, pain, stiffness, altered gait and loss of motion due to degenerative cartilage Exclusion Criteria: Has systemic bone or cartilage disorders Has significant vascular impairment proximal to implant site Has substantial joint destabilisation including extensive osteophyte formation Has substantial surface erosion of the weight‐bearing articular cartilage Evidence of infection or fractures in or around the joint Contraindication to bone marrow aspiration Any acute or chronic communicable diseases including Hepatitis B, Hepatitis C and HIV Any past history of neoplasia and primary haematological disease Renal impairment indicated by serum creatinine greater than 200mM Liver impairment indicated by serum aspartate transaminase and serum alanine transaminase greater than 120 IU Any other co‐morbidity which the physician deems as a contraindication to stem cell transplantation and bone marrow biopsy
Interventions	Intervention Single intra‐articular implantation of autologous bone marrow‐derived mesenchymal stem cells in hyaluronic acid "Orthovisc" (3rd injection in a 3‐weekly injection regimen) Comparator Intra‐articular injection of 30 mg/2 mL of hyaluronic acid in a 3‐weekly injection regimen
Outcomes	Outcomes were measured at 1, 3, 6, 9 and 12 months. Primary outcome: Change from baseline in cartilage thickness at 12 months by MRI Secondary outcome: VAS IKDC Subjective Knee Evaluation Form (2000) Change from baseline in progression of osteoarthritis at 12 months by plain radiograph (X‐ray)
Starting date	March 2011
Contact information	Ya Mohammad Hassan Shukur, MD UKM Medical Centre Kuala Lumpur, Malaysia, 56000
Notes	Trial registration: NCT01459640 Trial status: unknown Estimated study completion date: March 2014

NCT01985633.

Study name	Mesenchymal Stem Cells Enhanced With PRP Versus PRP In OA Knee (MSCPRPOAK)
Methods	Study design: interventional (randomised parallel clinical trial) Setting: Department of Orthopaedics Postgraduate Institute of Medical Education & Research Timing: January 2013 to June 2014 Interventions: mesenchymal stem cells (MSCs) plus PRP versus PRP Sample size: 24
Participants	Inclusion criteria: Grade 1 or Grade 2 osteoarthritis of the knee as per Ahlbacks radiographic staging Patients willing to give consent Exclusion criteria: Osteoarthritis secondary to joint inflammatory diseases (e.g. rheumatoid arthritis, ankylosing spondylitis etc) Patients with other diseases affecting the knee joint like crystal arthropathy, symptomatic chondrocalcinosis, acute synovitis, excessive joint effusion(> 100 mL), cystic disease around the knee joint (e.g. popliteal cyst) Advanced stage of osteoarthritis Bone marrow suppression Co‐morbidities like pregnancy, cancer, immunosuppression Osteoarthritis secondary to trauma
Interventions	Intervention: mesenchymal stem cell plus PRP Comparator: platelet‐rich plasma
Outcomes	Outcomes were measured at 6 weeks and 6 months Primary: Pain on 1‐10 VAS Secondary: Function on Western Ontario and McMaster Universities score (WOMAC) and Knee Injury and Osteoarthritis Outcome Scores (KOOS) Quantitative articular cartilage volume analysis using MRI
Starting date	Jan 2013
Contact information	Aditya K Aggarwal Postgraduate Institute of Medical Education and Research Email: agg_adityadoc@yahoo.co.in
Notes	Trial registration: NCT01985633 Trial status: unknown Estimated study completion date: June 2014

NCT02674399.

Study name	A Phase 2 Study to Evaluate the Efficacy and Safety of JointStem in Treatment of Osteoarthritis
Methods	Study design: double‐blind, parallel, 2‐arm randomised controlled trial Setting: California, USA Timing: Feb 2016 to Dec 2018 Interventions: autologous adipose tissue‐derived mesenchymal stem cells (AdMSC) vs hyaluronic acid Sample size: not reported
Participants	Inclusion criteria: Subject who can give written informed consent Male or female of any race, aged 22 to 60 Subject who had osteoarthritis of knee diagnosed at least 6 months prior to screening Subject who has joint pain ≥ 40 mm on VAS at screening Subject who has swelling, tenderness and active range of motion ≥ Grade I at screening Subject who seeks invasive interventions of intra‐articular injections Subject who is willing to discontinue all pain medications for osteoarthritis except rescue medication (< acetaminophen 3.25 g per day) at least 72 hours prior to screening and throughout the duration of study Subject who has radiographic evidence of grade 3 to 4 osteoarthritis based on the Kellgren and Lawrence radiographic criteria Female subject who is neither pregnant nor lactating Subject who is able to comply with lifestyle guidelines, scheduled visits, treatment plan, laboratory tests and other study procedures Exclusion criteria: Subject who has BMI > 35 kg/m2 Subject who has unstable knees Subject who took any NSAID within 2 weeks from screening Subject who had any intra‐articular injection therapy in any joint within 2 months from screening Subject who has any clinically significant disease, which is judged by the investigator to affect this clinical trial Subject who has inflammatory arthropathy (rheumatoid, psoriatic, or avascular necrosis), and post‐traumatic or septic arthritis Subject who has chondrocalcinosis, Paget's disease, Villonodular synovitis, and other non‐OA joint diseases Subject who has HIV/viral hepatitis Subject who had knee surgery or radiation therapy in the affected joint within 6 months from screening Subject who had CVA attack within 6 months from screening Subject for whom the investigator judges the liposuction can cause any problem Subject who has significant lab abnormalities Subject who has history of local anaesthetic allergy Subject who took immunosuppressants such as Cyclosporin A or azathioprine within 6 weeks from screening (If a subject uses aspirin or plavix) Subject for whom it is determined that it would not be safe to stop the aspirin/plavix therapy for 2 weeks prior to Visit 2 Subject who uses anticoagulants which cannot be stopped or corrected Subject who had oral or intra‐muscular corticosteroids within 30 days from Visit 2 Subject who had intra‐articular corticosteroid injection in any joint within 30 days from Visit 2 Subject who had intra‐articular hyaluronic acid injection within 30 days from Visit 2 Subject who has known hypersensitivity (allergy) to hyaluronan (sodium hyaluronate) preparations or gram‐positive proteins Subject who has knee joint infections or skin diseases or infections in the area of the injection site Subject who has known systemic bleeding disorders Subject who is an active drug/EtOH abuser Subject who was enrolled in any other clinical trials within 2 months from screening Subject who the principal investigator considers inappropriate for the study for any other reasons than those listed above Subject whose MRI scan results at screening do not demonstrate any sign of cartilage damage
Interventions	Intervention: JointStem ‐ autologous adipose tissue‐derived mesenchymal stem cells (AdMSC) Control: Synvisc‐One ‐ hyaluronic acid
Outcomes	Primary outcomes: Change from baseline on Western Ontario and McMaster Universities Arthritis Index (WOMAC) score in JointStem group (time frame: baseline and 6 months). Comparing the baseline and 6‐month WOMAC scores in JointStem group Change from baseline on Visual Analog Scale (VAS) in JointStem group (time frame: baseline and 6 months). Comparing the baseline and 6‐month VAS scores in JointStem group MRI Improvement Evaluation in JointStem group (time frame: 6 months). Comparing the baseline and 6‐month MRI improvement values in JointStem group Secondary outcomes: Change from baseline on WOMAC between JointStem and positive control groups (time frame: baseline and 6 months). Comparing the changes of WOMAC scores between JointStem and positive control groups at 6 months Change from baseline on VAS between JointStem and positive control groups (time frame: baseline and 6 months). Comparing the changes of VAS scores between JointStem and positive control groups at 6 months Change from baseline on Knee Injury & Osteoarthritis Outcome Score (KOOS) between JointStem and positive control groups (time frame: baseline and 6 months). Comparing the changes of KOOS values between JointStem and positive control groups at 6 months Change from baseline on Lysholm Knee Scoring Scale between JointStem and positive control groups (time frame: baseline and 6 months). Comparing the changes of Lysholm Knee Scoring Scales between JointStem and positive control groups at 6 months Change from baseline on International Knee Documentation Committee (IKDC) between JointStem and positive control groups (time frame: baseline and 6 months). Comparing the changes of IKDC scores between JointStem and positive control groups at 6 months Change from baseline on RAND‐36 Score between JointStem and positive control groups (time frame: baseline and 6 months) Comparing the changes of RAND‐36 scores between JointStem and positive control groups at 6 months Change from baseline on WOMAC in JointStem group (time frame: baseline, 9 months and 12 months). Comparing the baseline and 9‐month/12‐month WOMAC scores in JointStem group Change from baseline on VAS in JointStem group (time frame: baseline, 9 months and 12 months). Comparing the baseline and 9‐month/12‐month VAS scores in JointStem group Comparison of MRI improvement evaluation in JointStem group (time frame: baseline, 6 months and 12 months). Comparing the baseline and 9‐month/12‐month MRI improvement values in JointStem group Incidence of adverse events and laboratory abnormalities (time frame: baseline, 1 month, 3 months, 6 months, 9 months and 12 months) Comparing safety values between JointStem and positive groups Other Outcome Measures: Analysis of all efficacy scales and MRI results and the history of treatments and medications (time frame: 24 months). Analysing efficacy and safety variables at 24 months
Starting date	16 February 2016
Contact information	Nature Cell Co. Ltd. Santa Monica, California, United States
Notes	Trial registration: NCT02674399 Trial status: recruitment completed Actual study completion date: 28 December 2018

NCT02784964.

Study name	Adipose‐derived Stem Cells (ADSCs) for Knee Osteoarthritis
Methods	Study design: single‐blind parallel, 4‐arm randomised controlled trial Setting: Taipei Veterans General Hospital and Chang Gung Memorial Hospital, Taiwan Timing: Mar 2016 to Dec 2020 Interventions: adipose‐derived stem cells (ADSCs) vs Hya Joint Plus synovial fluid supplement Sample size: 57 participants
Participants	Inclusion criteria: Aged 40 to 80 years (inclusive) Kellgren‐Lawrence grading I‐III, as determined by American College of Rheumatology (ACR) criteria for osteoarthritis of the knee Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score of 7‐17 in the study knee even if treated with chronic doses of non‐steroidal anti‐inflammatory drugs Having provided informed consent Exclusion criteria: With previous surgery of articular fracture, ligament reconstruction, meniscal reconstruction and knee arthroplasty on the target knee joint With previous intra‐articular intervention on the target knee joint within past 3 months (e.g. steroid, anaesthetic, sodium hyaluronate) Known or suspected infection of the target knee joint Ascertained hypersensitivity to any component used in the study Administered with systemic anti‐inflammatory drugs (e.g. non‐steroidal anti‐inflammatory drug or steroid) or topical anti‐inflammatory drugs on target knee within 7 days prior to administration in the study With serious prior or ongoing medical conditions (e.g. concomitant illness such as cardiovascular (e.g. New York Heart Association grade III or IV), hepatic (e.g. Child‐Pugh Class C), psychiatric condition, alcoholism, drug abuse), medical history, physical findings, or laboratory abnormality that in the investigators' opinion could interfere with the results of the trial or adversely affect the safety of the patient With any evidence of malignant disease with life expectancy of less than 1 year Pregnant or lactating women or planning to be pregnant during the study period With body mass index (BMI) greater or equal to 35 kg/m2 With joint diseases except knee osteoarthritis considered by investigator not eligible to enter the study With known history of human immunodeficiency virus (HIV) infection Judged to be not applicable to this study by investigator such as difficulty of follow‐up observation With any other serious diseases/medical history considered by the investigator not in the condition to enter the trial Having participated other investigational study within 4 weeks of entering this study With known history of claustrophobia Having any existing active/inactive implanted medical devices, such as cardiac pacemaker, cochlear, intracranial vascular clips or neurostimulator, etc. Having any existing metallic intraocular foreign body
Interventions	Intervention 1: Elixcyte 8mL ‐ ADSC 6.4*10^7 cells, allogeneic injection, one‐time injection on Day 1 Intervention 2: Elixcyte 4mL ‐ ADSC 3.2*10^7 cells, allogeneic injection, one‐time injection on Day 1 Intervention 3: Elixcyte 2mL ‐ ADSC 1.6*10^7 cells, allogeneic injection, one‐time injection on Day 1 Active Comparator: Hya Joint Plus synovial fluid supplement 3mL, SciVision Biotech Inc., one‐time injection on Day 1
Outcomes	Primary Outcome Measures: Changes from baseline to post‐treatment visit of WOMAC pain score at week 24 after treatment (time frame: weeks 0, 24) Incidence of adverse events (AEs) and serious adverse events (SAEs) (time frame: week 48) Secondary Outcome Measures: Changes from baseline to post‐treatment visits of Visual Analogue Scale (VAS) to measure pain levels (time frame: weeks 0, 2, 4, 12, 24, 36, 48) Changes from baseline to post‐treatment visits of scores of sections in Knee Society Clinical Rating System (KSCRS) Score (time frame: weeks 0, 2, 4, 12, 24, 36, 48) Changes from baseline to post‐treatment visits of MRI examination results (time frame: weeks 0, 24, 48, 72, 96) Changes from baseline to post‐treatment visits of total score, and sub‐scores of all sections in WOMAC (time frame: weeks 0, 2, 4, 12, 36, 48) Total acetaminophen consumption during the first 48 weeks and week 48 to week 96 (time frame: week 0, 2, 4, 12, 24, 48, 96) Total non‐steroidal anti‐inflammatory drug (NSAID) consumption amount during the first 48 weeks and week 48 to week 96 (time frame: weeks 0, 2, 4, 12, 24) Time to subject first‐time consumes acetaminophen (time frame: weeks 0, 2, 4, 12, 24) Time to subject first‐time consumes non‐steroidal anti‐inflammatory drug (NSAID) (time frame: weeks 0, 2, 4, 12, 24) Number of patients with clinically abnormal laboratory values and/or adverse events that are related to treatment (time frame: weeks 0, 2, 4, 12, 24, 36, 48, 72, 96) Number of patients with clinically abnormal vital signs and/or adverse events that are related to treatment (time frame: weeks 0, 2, 4, 12, 24, 36, 48, 72, 96) Changes from baseline to week 96 visit in cartilage thickness in the total femorotibial joint by centralised (independent) imaging interpretation (time frame: weeks 0, 24, 48, 72, 96)
Starting date	March 2016
Contact information	Yu‐Han Chang, MD Chang Gung Memorial Hospital Taoyuan City, Taiwan, 333
Notes	Trial registration: NCT02784964 Trial status: active, not recruiting Estimated study completion date: December 2020

NCT03028428.

Study name	Intra‐articular Injection of MSCs in Treatment of Knee OA
Methods	Study design: double‐blind parallel, 2‐arm randomised controlled trial Setting: Affiliated Hospital of Jiangsu University, China Timing: Dec 2016 to Dec 2019 Interventions: intra‐articular injection of mesenchymal stem cell vs sodium hyaluronate Sample size: not reported
Participants	Inclusion criteria: Patients between 40 and 75 years of age with symptomatic moderate to severe (Kellgren‐Lawrence III or IV) primary osteoarthritis of the knee Idiopathic or secondary osteoarthritis of the knee with grade 2, 3 or 4 radiographic severity, as defined by the modified Kellgren‐Lawrence classification No history of prior intra‐articular cortisone, hyaluronic acid or platelet‐rich plasma injection within the previous 6 months No history of prior arthroscopic knee surgery or open knee surgery on the ipsilateral side within the past year Adequate bone marrow, liver, and renal functions Body weight > 40 kg Body Mass Index < 40 Negative for (HIV, HTLV1&2, Hep A, B, C, syphilis) infection as determined by approved serological testing Negative for pregnancy as determined by a serum pregnancy test. Females of childbearing potential will be required to practice abstinence or use an effective form of contraception for 12 months following their MSC injection. Ability to provide written informed consent. Exclusion criteria: Patients with clinically unstable knee due to the presence of a complete anterior cruciate ligament, posterior cruciate ligament, medial collateral ligament and/or posterolateral corner tear Patients with varus or valgus malalignment > 5 degrees as measured by 4 foot standing antero‐posterior radiographs Patients with a history of a previous subtotal medial or lateral meniscectomy Patients with a history of septic arthritis in the affected joint Patients with a history of a prior intra‐articular knee fracture Severe bleeding diathesis Contraindication to bone marrow aspiration and/or biopsy Active infection Bone marrow failure Cytopenia Patients who have previously received radiotherapy to the pelvis Patients who have been on chemotherapy from within a year of the date of informed Patients with positive serological test for (HIV, HTLV1&2, Hep A, B, C, syphilis) Pregnancy or risk of pregnancy (this includes participants that are not willing to practice active contraception for the duration of the study) Patients with unforeseen conditions that are deemed unsafe or inappropriate for the study (e.g. patients who are claustrophobic and cannot undergo an MRI) as per the discretion of the principal investigator
Interventions	Intervention: Placenta derived mesenchymal stem cell (1ml 1*10^7) administered into the knee joint once Control: Sodium hyaluronate administered into the knee joint once
Outcomes	Primary Outcome Measures: Adverse events (time frame: 1 year). Number of participants with adverse events as measure of safety and tolerability Secondary Outcome Measures: Radiographic evidence (time frame: 1 year). Number of participants with a change in cartilage thickness of knee OA using MRI WOMAC assessment (time frame: 1 year). Number of participants with a change in joint function from baseline WOMAC assessment VAS (time frame: 1 year). Number of participants with a change in arthritis pain scores on the visual analogue scale SF‐36 (time frame: 1 year). Number of participants with a change in SF‐36
Starting date	Dec 2016
Contact information	Dr Yu Tang Affiliated Hospital of Jiangsu University
Notes	Trial registration: NCT03028428 Trial status: active, not recruiting Estimated study completion date: Dec 2019

NCT03164083.

Study name	The Effects of Stromal Vascular Fraction and Mesenchymal Stem Cells as Intra‐articular Injection in Knee Joint Osteoarthritis
Methods	Study design: triple‐blind, parallel, 2‐arm randomised controlled trial Setting: Iran Timing: not reported Interventions: intra‐articular injection of mesenchymal stem cell vs placebo injection Sample size: not reported
Participants	Inclusion criteria: Osteoarthritis diagnosed by MRI Exclusion criteria: Pregnancy or lactating Positive tests for HIV, hepatitis C virus (HCV), hepatitis C virus (HBV) Active neurologic disorder End organ damage Uncontrolled endocrine disorder
Interventions	Intervention: Patients with knee joint osteoarthritis who underwent intra‐articular mesenchymal stem cell injection Control: Control group patients underwent placebo injection
Outcomes	Primary outcome measures: Physical function improvement (time frame: 2 weeks). Evaluation of physical function improvement. Measured by WOMAC osteoarthritis index after cell injection Change in pain density (time frame: 2 weeks). Evaluation of the change in pain density measured by VAS after cell injection Secondary outcome measures: Joint swelling (time frame: 3 months). Evaluation of joint swelling by physical examination after intra‐articular cell injection Joint erythema (time frame: 3 months). Evaluation of joint erythema by physical examination after cell injection Deterioration of joint function (time frame: 3 months). Evaluation of deterioration of joint function by physical examination after intra‐articular cell injection Allergic reactions (time frame: 3 months). Evaluation of allergic reactions like skin rash, skin erythema, dyspnoea by physical examination after cell injection
Starting date	10 November 2019
Contact information	Neda Keyhanvar SCARM Institute Tabriz, Islamic Republic of Iran
Notes	Trial registration: NCT03164083 Trial status: withdrawn (not approved by sponsor) Estimated study completion date: Dec 2020

NCT03166865.

Study name	Clinical Study of Umbilical Cord Mesenchymal Stem Cells (UC‐MSC) for Treatment of Knee Osteoarthritis
Methods	Study design: double‐blind, parallel, 2‐arm randomised controlled trial Setting: Liaocheng People's Hospital, China Timing: Oct 2018 to Oct 2020 Interventions: intra‐articular injection of umbilical cord mesenchymal stem cell vs HA acid injection Sample size: 60 participants
Participants	Inclusion criteria: 30 to 70 years old. No serious infection, chronic diseases, diabetes and tuberculosis Osteoarthritis of the knee with grade 1‐3 defined by the modified Kellgren‐Lawrence classification Written informed consent obtained from all subjects Exclusion criteria: Pregnant women or cognitively impaired adults Inflammatory or post‐infectious arthritis Intra‐articular drug injection within the previous 2 months Serious medical illness with a life expectancy of less than 1 year Prior admission for substance abuse Arthroscopy during the previous 6 months Systemic autoimmune rheumatic disease Poorly controlled diabetes mellitus Immunosuppressive or anticoagulant treatments Treatment with corticosteroids in the 3 months prior to inclusion in the study NSAID therapy within 15 days prior to inclusion in the study
Interventions	Intervention: Intra‐articular injection of 2×10~7 umbilical cord mesenchymal stem cells with platelet‐rich plasma (5 mL) Control: Intra‐articular injection of hyaluronic acid
Outcomes	Primary outcome measures: Change from baseline in Visual Analogue Scale (VAS) (time frame: baseline, 1, 3, 6 and 12 weeks) Change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index score (time frame: baseline, 1, 3, 6 and 12 weeks) WOMAC Change from baseline in knee society score (KSS) (time frame: baseline, 1, 3, 6 and 12 weeks), Knee Society Score (KSS) Change from baseline in MOS item short from health survey (SF‐36) (time frame: baseline, 1, 3, 6 and 12 weeks). The MOS item short from health survey (SF‐36) Secondary outcome measures: The number of cartilage defects, thickness of cartilage evaluated by X‐ray and MRI (time frame: baseline, 1, 3, 6 and 12 weeks) The IL‐1β, IL‐6, PGE‐2, TGF‐β, TNF‐α and IGF‐1 of articular cavity fluid (time frame: baseline, 1, 3, 6 and 12 weeks) The IL‐1β, IL‐6, PGE‐2, TGF‐β, TNF‐α and IGF‐1 of articular cavity fluid
Starting date	25 May 2017
Contact information	Changhui Zhou, PhD Liaocheng People's Hospital 86‐0635‐8272202 zhouchanghui008@163.com
Notes	Trial registration: NCT03166865 Trial status: recruiting Estimated study completion date: 1 October 2020

NCT03271229.

Study name	Conventional Platelet‐Rich Plasma Versus Concentrated Bone Marrow Stem Cell Injections for Osteoarthritis of the Knee
Methods	Study design: single‐blind, parallel, 2‐arm randomised controlled trial Setting: Mayo Clinic, Florida, USA Timing: Sep 2019 to Jan 2021 Interventions: intra‐articular injection of bone marrow aspirate (BMAC) vs PRP injection Sample size: none (trial withdrawn)
Participants	Inclusion criteria: Subjects must have bilateral OA and pain in one knee Osteoarthritis may be primary or secondary. Knees must have Kellgren‐Lawrence Grades 1‐3. Subjects must have previously tried 6 weeks of one of the following conservative treatments: activity modification, weight loss, physical therapy, anti‐inflammatory or injection therapy Patients must be able to provide written informed consent after the nature of the study is fully explained Exclusion criteria: Patients with abnormal haematology, serum chemistry, or screening laboratory results. Patients taking anti‐inflammatory medications (prescription or over‐the‐counter), including herbal therapies, within 14 days of baseline visit Patients taking anti‐rheumatic disease medication (including methotrexate or other antimetabolites) within the 3 months prior to study entry Patients receiving injections to the treated knee within 3 months prior to study entry Patients who are pregnant or currently breast‐feeding Patients with systemic, rheumatic, or inflammatory disease of the knee or chondrocalcinosis, haemochromatosis, inflammatory arthritis, arthropathy of the knee associated with juxta‐articular Paget's disease of the femur or tibia, ochronosis, haemophilic arthropathy, infectious arthritis, Charcot's knee joint, villonodular synovitis, and synovial chondromatosis Patients with ongoing known infectious disease Patients with clinically significant cardiovascular, renal, hepatic, endocrine disease or cancer Patients participating in a study of an experimental drug or medical device within 30 days of study entry
Interventions	Intervention: Participants will have concentrated bone marrow aspirate (BMAC) injections into symptomatic knee Control: Participants will have platelet‐rich plasma (PRP) injections into symptomatic knee
Outcomes	Primary Outcome Measures: Occurrence of Adverse Events (time frame: approximately 12 months). The number of adverse events Morbidity (time frame: approximately 12 months). The number of deceased participants
Starting date	September 2019
Contact information	Shane A. Shapiro Mayo Clinic Florida, USA
Notes	Trial registration: NCT03271229 Trial status: withdrawn (Funding) Estimated study completion date: January 2021

NCT03357575.

Study name	The Comparison of Efficacy and Safety of the Mesenchymal Stem Cells From Adipose and Hyaluronic Acid
Methods	Study design: quadruple‐blind, parallel, 2‐arm randomised controlled trial Setting: Peking University People's Hospital, China Timing: Jan 2018 to Dec 2020 Interventions: intra‐articular injection of mesenchymal stem cells from adipose vs hyaluronic acid injection Sample size: 14 participants
Participants	Inclusion criteria: K‐L score of 2‐3 Chronic knee pain No local or systemic infection Without obvious contraindication of the joint puncture from haematology and biochemical tests Informed consent Exclusion criteria: Older than 75 years old or less than 18 years old, or without full capacity for civil conduct HIV, hepatitis virus or syphilis virus infection or their serology is positive BMI index is greater than 30 Congenital or acquired knee deformity Pregnant or lactating women Tumour patients Immunodeficiency patients Intra‐articular drug injection history within 3 months Participating in other clinical trials Other patients who researchers believe are not eligible for inclusion, such as suffering from other concomitant diseases
Interventions	Intervention: Mesenchymal stem cells from adipose will be injected Control: Hyaluronic acid will be injected
Outcomes	Primary outcome measures: Unexplained local and systemic symptoms or death (time frame: 2 years). The severity of AE must be recorded and graded according to the CTCAE criteria, and its relationship to therapy must be assessed according to the following definition: 1) not related: there is evidence that the cause of adverse events is not due to intra‐articular injection therapy (such as previous conditions, potential diseases, concurrent diseases); 2) related: AE and intra‐articular injection are time‐related and it is known or suspected that intra‐articular injection of drugs can cause the AE; 3) it can't be assessed. Secondary outcome measures: VAS score (time frame: 2 years). VAS score decrease 3 points or more. WOMAC score (time frame: 2 years). Two or more terms of WOMAC score have improvement.
Starting date	1 January 2018
Contact information	Ziyi Yang, MD 18810335110 bjmuyangziyi@163.com
Notes	Trial registration: NCT03357575 Trial status: not yet recruiting Estimated study completion date: 1 December 2020

NCT03379168.

Study name	Efficacy of Micro‐fragmented Adipose Tissue Injection for Knee Osteoarthritis.
Methods	Study design: single‐blind, parallel, 3‐arm randomised controlled trial Setting: UNM Hospital, New Mexico, USA Timing: April 2018 to July 2019 Interventions: intra‐articular Injection of Lipogems vs intra‐articular corticosteroid injection vs placebo injection of saline Sample size: 100 participants
Participants	Inclusion criteria: Age 18 or older Diagnosis of symptomatic knee osteoarthritis Radiographic evidence of knee osteoarthritis. Note: For the purposes of this study, radiographic evidence of knee osteoarthritis is defined as any one or more of the following: osteophytes, joint space narrowing, loss of articular cartilage thickness, subchondral sclerosis or cysts. Exclusion criteria: History of treatment with any intra‐articular knee injection Current ligament instability as demonstrated by a positive Lachman Test, Anterior or Posterior Drawer Test, or positive Valgus or Varus Stress Test Known allergy to lidocaine Under 18 years of age Pregnant women Prisoners
Interventions	Intervention: micro‐fragmented adipose tissue (Lipogems) Patients who are randomised to the Lipogems treatment group will undergo a lipoaspiration from their abdomen and autologous injection of the harvested adipocytes into their knee. It is standard to harvest three to four times more adipose tissue than is planned to be injected to account for tissue processing by the Lipogems device. The investigators plan to inject 7 cc of autologous adipose tissue. Thus, the investigators will harvest between 25 and 30 cc of adipose tissue from each patient. The tissue will be processed immediately and 7 cc will be injected. Any remaining adipose tissue will be disposed of immediately in biohazardous waste. Control: corticosteroid injection Patients who are randomised to the corticosteroid group will receive an injection of 2 cc (80 mg) of triamcinalone acetonide injectable suspension mixed with 5 cc of 1% plain lidocaine for a total of 7 cc of fluid injected in the affected knee. Control: placebo injection Patients who are randomised to the placebo group will receive an injection of 7 cc of sterile saline in the affected knee.
Outcomes	Primary outcome measures: Change in pain VAS over time (time frame: prior to procedure then post‐procedure: 2 weeks, 6 weeks, 3 months, 6 months, 1 year). Scaled pain score to assess change in a patient's knee pain over time. Pain level is marked on a 100 mm line with the 0 mm corresponding to "no pain" and the 100 mm corresponding to 10/10 pain. Using a ruler, the score is determined by measuring the distance (mm) on the 100 mm line between the "no pain" anchor and the patient's mark, providing a range of scores from 0‐100. The following cut points on the pain VAS have been recommended: no pain (0‐4 mm), mild pain (5‐44 mm), moderate pain (45‐74 mm), and severe pain (75‐100 mm). Secondary outcome measures: Change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Over Time (time frame: prior to procedure then post‐procedure: 2 weeks, 6 weeks, 3 months, 6 months, 1 year). Patient self‐reported outcome measure to assess pain, stiffness, and physical function in patients with knee osteoarthritis. The WOMAC consists of 24 items divided into 3 subscales: Pain (5 items), Stiffness (2 items), and Physical Function (17 items). The following descriptors are used for all items: none, mild, moderate, severe, and extreme. These correspond to an ordinal scale of 0‐4. The scores are summed for items in each subscale, with possible ranges as follows: pain = 0‐20, stiffness = 0‐8, physical function = 0‐68. A total WOMAC score is created by summing the items for all three subscales. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations. The score can range from 0 to 96; however, this score is typically reported as a percentage of 100 for normalisation. Change in Knee Injury and Osteoarthritis Outcomes Score (KOOS) over time (time frame: prior to procedure then post‐procedure: 2 weeks, 6 weeks, 3 months, 6 months, 1 year). Patient self‐reported outcome measure to assess the patient's opinion about their knee and associated issues. KOOS consists of 5 subscales: Pain, Other symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and Knee‐related quality of life (QOL). Standardised answer options are given (5 Likert boxes) and each question gets a score from 0 to 4. A normalised score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated by adding the subscales together.
Starting date	April 2018
Contact information	Dustin L. Richter UNM Health Sciences Center Dept of Orthopaedic Surgery 505‐272‐1209 DLRichter@salud.unm.edu
Notes	Trial registration: NCT03379168 Trial status: unknown Estimated study completion date: July 2019

NCT03383081.

Study name	A Clinical Research on the Safety/Efficacy of Human Umbilical Cord Mesenchymal Stem Cells（19#iSCLife®‐OA） Therapy for Patients With Osteoarthritis
Methods	Study design: parallel, open‐label, 3‐arm randomised controlled trial Setting: Xiangya Hospital Central South University, Hunan, China Timing: February 2019 to January 2020 Interventions: umbilical cord mesenchymal stem cell plus hyaluronic acid vs hyaluronic acid vs mesenchymal stem cell plus hyaluronic acid plus recombinant human somatropin Sample size: 60 participants
Participants	Inclusion criteria: Diagnosis of knee osteoarthritis by Kellgren and Lawrence Grading Scale, classified with Grade 2‐3 Confirm with cartilage injury, articular cartilage part or full‐thickness injury, by MR (magnetic resonance) Age < 70, no serious organ dysfunction Over 2 years knee pain or conservative treatments not very effective Knee pain on VAS (visual analogue scale score) is 4 or higher Normal hepatic and renal function, no history of gout, rheumatoid arthritis and autoimmune diseases, etc. Understand and sign the consent form of this study Exclusion criteria: Refuse to sign the consent form, or cannot keep follow‐up visit Age > 70; age < 70, but with multiple organ failure Unstable vital signs (breath, blood pressure, pulse) Combined with knee ligament (anterior and the posterior cruciate ligament, medial and lateral collateral ligament) rupture, laxity, etc. Serious bleeding tendency, poor coagulation function (PTA < 35%) Pregnant or breastfeeding women, or positive pregnancy test in 7 days before treatment Participate other clinical experiments in 3 months With progressing malignant tumour Combined with shock and critically ill patients Without mental disease With history of knee joint infection, surgery and radiotherapy With immunosuppressive agents treatment in 6 weeks Injection with hormones and sodium hyaluronate in joint in 3 months Overweight expressed as body mass index (BMI) > 35 With skin disease around knee joint With immunodeficiency disease, including long‐term use immunosuppressive agents patients Combined with serious infection With some other conditions that doctor propose not to participate
Interventions	Intervention: low‐dose MSC Intra‐articular injection with human umbilical cord mesenchymal stem cells: group A, 1 * 10^7 cells (5 mL) Intervention: high‐dose MSC Intra‐articular injection with human umbilical cord mesenchymal stem cells group B, 2 * 10^7 cells (5 mL) Control: No intervention
Outcomes	Primary outcome measures: Kellgren‐Lawrence Grading Scale (time frame: 12 months). Using Magnetic Resonance Imaging (MRI) examination, and based on the images of bilateral knee joint, grade by Kellgren‐Lawrence Grading Scale. Kellgren‐Lawrence Grading Scale is a method of classifying the severity of knee osteoarthritis (OA). Grade 0: No radiographic features of osteoarthritis; Grade 1: Possible joint space narrowing (normal joint space is at least 2 mm at the superior acetabulum) and osteophyte formation; Grade 2: Definite osteophyte formation with possible joint space narrowing; Grade 3: Multiple osteophytes, definite joint space narrowing, sclerosis and possible bony deformity; Grade 4: Large osteophytes, marked joint space narrowing, severe sclerosis and definite bony deformity. Secondary outcome measures: Assessment of Preoperative Cartilage Defect Severity (AMADEUS) (time frame: 12 months). Using MRI examination to diagnose patients by Assessment of Preoperative Cartilage Defect Severity (AMADEUS). Lysholm scoring (time frame: 12 months). Using Lysholm Knee Scoring Scale to grade the knee function of patients, and examine the changes or improvement compare to baseline. The international knee documentation committee (IKDC) knee evaluation form (time frame: 12 months). The international knee documentation committee knee evaluation form is used to assess the knee function of patients, examine the changes or improvement compare to baseline. VAS score (time frame: 12 months). Using VAS/score for pain to examine the change/improvement of knee joint function.
Starting date	Feb 2019
Contact information	Hongbin Lv Xiangya Hospital of Central South University Changsha, Hunan, China, 410008
Notes	Trial registration: NCT03383081 Trial status: recruiting Estimated study completion date: January 2020

NCT03467919.

Study name	The Effect of Micro Fragmented Adipose Tissue (MFAT) on Knee Osteoarthritis
Methods	Study design: parallel, double‐blind, 2‐arm randomised controlled trial Setting: Stanford University USA Timing: April 2018 to June 2022 Interventions: intra‐articular knee injection of autologous micro‐fragmented adipose tissue vs intra‐articular injection of corticosteroid Sample size: 40 participants
Participants	Inclusion criteria: Age between 35 and 75 years old Diagnosis of pre‐existing osteoarthritis of the joint by Kellgren‐Lawrence Grade 2 or 3. Working understanding of the English language and able to fully understand the procedure Capable of providing informed consent Able to complete online, in‐person or phone surveys for the purposes of follow‐up Capable of understanding pre‐ and post‐procedure care instructions Ambulatory at baseline Previous trial and failure of conservative therapy consisting of a minimum of 6 weeks of physical therapy and trial of anti‐inflammatory medications if not contraindicated, with or without concomitant bracing and/or injections. Exclusion criteria: Age < 35 or > 75 years old Radiographs demonstrating either no, little or severe osteoarthritis (Kellgren‐Lawrence Grade 0, 1) Prior total or partial joint replacement surgery or a surgery involving cartilage regeneration (microfracture, ACI, etc) Previous cortisone and/or Hyaluronic acid intra‐articular injection within the last 3 months Co‐morbidity with rheumatologic condition, inflammatory arthritis Currently undergoing immunomodulatory therapy Uncontrolled endocrine disorder BMI > 35 Current diagnosis of osteomyelitis, human immunodeficiency virus (HIV‐1, ‐2) and/or hepatitis C (HCV), infection and poorly controlled diabetes (HgA1C > 7.0) Pregnancy or planned pregnancy Previous stem cell injection into treatment joint Patient scheduled to undergo any concomitant surgical procedures. Coagulopathy or anticoagulant treatment Chronic pain involving multiple body parts or opioid medication management
Interventions	Intervention: Intra‐articular knee injection of autologous micro‐fragmented adipose tissue harvested from the thigh using tumescent lipoaspiration and processing with minimal manipulation. This harvested tissue will then be injected into the patient's knee. Control: Intra‐articular injection of corticosteroid (triamcinolone 40 mg)
Outcomes	Primary outcome measures: Knee Injury and Osteoarthritis Outcomes Score (KOOS) score (time frame: 24 months). Patient‐reported outcome measure that reports a normalised score (100 indicating no symptoms and 0 indicating extreme symptoms Secondary outcome measures: Lysholm score (time frame: 24 months). Patient reported activity outcome measure on a scale of 0‐100 (100 is best activity score) Veterans RAND 12 (VR‐12) score (time frame: 24 months). Patient reported quality of life outcome measure on a scale of 0‐50 with 50 being healthy. Other outcome measures: MRI cartilage scan (time frame: 12 month). Cartilage thickness on MRI using T2‐weighted cartilage mapping
Starting date	1 April2018
Contact information	Ma Agnes Ith (650) 721‐7600 mith@stanford.edu
Notes	Trial registration: NCT03467919 Trial status: recruiting Estimated study completion date: June 2022

NCT03800810.

Study name	Implantation of Allogenic Mesenchymal Stem Cell From Umbilical Cord Blood for Osteoarthritis Management
Methods	Study design: parallel, triple‐blind, quadruple‐arm randomised controlled trial Setting: Indonesia University, Jakarta, Indonesia Timing: May 2015 to May 2019 Interventions: intra‐articular knee injection of umbilical cord mesenchymal stem cell plus hyaluronic acid versus hyaluronic acid Sample size: 9 participants
Participants	Inclusion criteria: Patients aged 30‐80 years old Kellgren‐Lawrence grade I, II, and III, or KL grade III with corrective osteotomy according to knee x‐ray examination Minimal VAS: 2 Unresponsive with pharmacological therapy Signed the informed consent Exclusion criteria: Osteoarthritis KL grade IV Secondary osteoarthritis due to trauma, infection, rheumatoid arthritis, congenital diseases, autoimmune diseases Hypersensitivity to hyaluronic acid Malignancies (previously or currently diagnosed) Pregnancy
Interventions	Intervention 1: Week 1: Intra‐articular injection of 10x10^6 unit of umbilical cord mesenchymal stem cells in 2 mL conditioned medium, 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis). Week 2: Intra‐articular injection of 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis), 8 IU recombinant human somatropin (Novell‐Eutropin®, Novell Pharmaceutical Laboratories) Week 3: Intra‐articular injection of 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis), 8 IU recombinant human somatropin (Novell‐Eutropin®, Novell Pharmaceutical Laboratories) Intervention 2: Week 1: Intra‐articular injection of 10x10^6 unit of umbilical cord mesenchymal stem cells in 2 mL conditioned medium, 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis). Week 2: Intra‐articular injection of 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis) Week 3: Intra‐articular injection of 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis) Intervention 3: Week 1: Intra‐articular injection of 10x10^6 unit of umbilical cord mesenchymal stem cells in 2 mL conditioned medium, 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis). Week 2: Intra‐articular injection of 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis), 8 IU recombinant human somatropin (Novell‐Eutropin®, Novell Pharmaceutical Laboratories) Week 3: Intra‐articular injection of 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis), 8 IU recombinant human somatropin (Novell‐Eutropin®, Novell Pharmaceutical Laboratories) Control: Week 1: Intra‐articular injection of 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis). Week 2: Intra‐articular injection of 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis) Week 3: Intra‐articular injection of 2 mL hyaluronic acid (Synvisc‐One® Hylan G‐F 20, Sanofi‐Aventis)
Outcomes	Primary outcome measures: Cartilage T2 map score (time frame: 6 months). MRI examination of the knee with additional T2 mapping software CartiGram (GE Healthcare, USA). T2 map sequence are obtained from the medial and lateral aspect of both femoral and tibial cartilage. IKDC score (time frame: 3 months). Subjective assessment of knee function using the International Knee Documentation Committee Subjective Knee Evaluation form.Scale ranges from 1 to 100, higher value indicates higher function. WOMAC score (time frame: 3 months). Subjective assessment of knee function using the the Western Ontario and McMaster Universities Osteoarthritis Index. Scale ranges from 100% to 1%, lower value indicates higher function. VAS score (time frame: 3 months). VAS score is used to assess knee pain experienced by subjects.
Starting date	May 2015
Contact information	Ismail H Dilog +622144539917 ismailorthofkui@yahoo.co.id
Notes	Trial registration: NCT03800810 Trial status: recruiting Estimated study completion date: May 2019

NCT03818737.

Study name	Multicenter Trial of Stem Cell Therapy for Osteoarthritis (MILES) (MILES)
Methods	Study design: multi‐centre parallel, single‐blind, triple‐arm randomised controlled trial Setting: 4 sites in USA Timing: March 2019 to Dec 2021 Interventions: intra‐articular knee injection of autologous BMAC versus adipose‐derived SVF vs umbilical cord tissue vs corticosteroid Sample size: 480 participants
Participants	Inclusion criteria: Age > 40 but < 70 years old Males and females Recent knee radiograph of the targeted knee (standing anteroposterior (AP) lateral and sunrise view) Diagnosis of OA in the targeted knee (radiographic evidence of OA in the medial and/or lateral tibiofemoral compartment, which would include one or more osteophytes on a standard radiograph taken within 3 months) Continued OA pain in the targeted knee despite conservative measures (per treating provider's discretion) Average daily VAS ≥ 3 Kellgren‐Lawrence system of Grade II, III, or IV Subjects may have concomitant patellofemoral but they must have stage II or higher generalised knee OA Females of childbearing potential only, must have a negative pregnancy test done ≤ 7 days prior to enrolment in the study Women and men of child‐producing potential must agree to use acceptable contraception methods for the duration of the trial such as birth control pills or condoms with spermicide Exclusion criteria: Clinically apparent tense effusion of the targeted knee Significant valgus/varus deformities (+/‐ 5 degrees) Viscosupplementation within 6 months in the targeted knee Other biologic injection (PRP or stem cell) within 1 year in the targeted knee Surgery in the targeted knee within the past 6 months (either open or scope) Systemic or intra‐articular injection of corticosteroids in any joint within 3 months before screening Daily opioid use for the past three months History of malignancy in the previous 5 years prior to study entry, with the exception of in‐situ cancers treated only by local excision with curative intent History of, or ongoing, autoimmune disorder that requires treatment with an immunosuppressive medication Active, suspected, or prior infection to the joint in the targeted knee Part of a vulnerable population per Office for Human Research Protections (OHRP) definition (pregnant women and breast‐feeding women, cognitively impaired, prisoners, etc.) Use of NSAIDS within 1 week of the procedure Unwilling to discontinue use of NSAIDS for 5 calendar days after procedure History of bleeding disorders or inflammatory joint disease Inability to hold anti‐platelet therapy according to treating provider prior to procedure If deemed medically inappropriate or noncompliant by the treating investigator Uncontrolled diabetes Subject has an active workers' compensation case in progress Subject with insufficient amount of subcutaneous tissue to allow recovery of a minimum of 100 mL of lipoaspirate Haemoglobin less than 10 g/dL at the time of screening Leukocytes < 3000/μL; neutrophils < 1500/μL; lymphocytes < 800/μL; platelets < 100,000/μL at the time of screening Diagnosis of liver disease as defined by alanine aminotransferase (ALT) >3x the upper limit of age‐determined normal (ULN) or total bilirubin > 1.5 x ULN Subjects who have had greater than 3 corticosteroid injections in the targeted knee in the 12 months prior to screening and at the physician's discretion Subjects with a known diagnosis of osteoporosis Subjects with anticipated use of systemic corticosteroids during the study period for treatment of a chronic medical condition
Interventions	Intervention 1: Autologous BMAC versus corticosteroid Forty subjects will be randomised to this arm at each site. They will be further randomised within the arm in a 3:1 ratio to receive either bone marrow‐derived mesenchymal stem cells (MSCs) or corticosteroid (CS) injection (30:10). All subjects randomised to this arm will undergo bone marrow aspiration, but will only receive one of the injections. At each site, 30 subjects in this arm will receive a standard Orthobiologic injection of Bone Marrow Concentrate (BMAC) and 10 will receive the CS injection. All injections will be made into the knee joint via ultrasound guidance using a standard approach. Bone Marrow Concentrate (BMAC) is a standard Orthobiologic injection for knee osteoarthritis. The procedure involves harvesting of bone marrow aspirate (BMA) from the posterior superior iliac spine (PSIS) and then following centrifugation in an FDA‐approved device (EmCyte GenesisCS Pure BMAC®‐60 ml) will be injected back into the knee joint. All injections will be made via ultrasound guidance using a standard approach. Drug: Depomedrol and normal saline (corticosteroid injection) 7cc of the corticosteroid injection prepared by mixing 1 cc of 40 mg/dL depomedrol and 6 cc of normal saline in a 10 cc syringe will be made into the knee joint. All injections will be made via ultrasound guidance using a standard approach. Intervention 2: adipose‐derived SVF versus corticosteroid Forty subjects will be randomised to this arm at each site. They will be further randomised within the arm in a 3:1 ratio to receive either an injection of Adipose‐derived Stromal Vascular Fraction (SVF) or corticosteroid (CS) (30:10). All subjects randomised to this arm will undergo small volume lipoplasty, but will only receive one of the injections. At each site, 30 subjects in this arm will receive the Adipose‐derived Stromal Vascular Fraction (SVF) and 10 subjects will receive the CS injection. All injections will be made into the knee joint via ultrasound guidance using a standard approach. Adipose‐derived Stromal Vascular Fraction will be obtained from a mini lipoaspirate. The lipoaspirate will then be enzymatically digested to produce a stromal vascular fraction (SVF) that will be injected into the knee joint. All injections will be made via ultrasound guidance using a standard approach. Intervention 3: umbilical cord tissue (UCT) versus corticosteroid Forty subjects will be randomised to this arm at each site. They will be further randomised within the arm in a 3:1 ratio to receive either an injection of cryopreserved doses of cord tissue MSCs or corticosteroid (30:10) injected into the knee. At each site, 30 subjects in this arm will receive the umbilical cord tissue MSCs and 10 subjects will receive the CS injection. All injections will be made into the knee joint via ultrasound guidance using a standard approach. Cryopreserved doses of cord tissue MSCs will be used. These MSCs were cryopreserved at P2 culture in plasmalyte A + 5% human serum albumin in 5 finger cryobags containing 20 million cells in 4 mL and stored under liquid nitrogen until shipment. Cells will be transported in a dry shipper and thawed at the study sites. The dose of MSCs will be aspirated from the cryobag into a sterile syringe and directly injected into the knee. All injections will be made via ultrasound guidance using a standard approach.
Outcomes	Primary outcome measures: Change in Visual Analog Pain Scale (VAS pain) scores (time frame: baseline, 1 month, 3 months, 6 months, 9 months, 12 months). Pain assessment will be done using the VAS‐pain scale at baseline and at 1 month, 3 months, 6 months, 9 months and at 12 months using the Visual Analog Pain Scale (VAS‐pain). The VAS‐pain is self‐completed by the participant. The respondent is asked to place a line perpendicular to the VAS line at the point that represents their pain intensity. Using a ruler, the score is determined by measuring the distance (mm) on the 10‐cm line between the "no pain" anchor and the participant's mark, providing a range of scores from 0‐100. Pain will be assessed at rest and active movement of the affected joint. The recommended cut points for VAS are: no pain (0‐4 mm), mild pain (5‐44 mm), moderate pain (45‐74 mm), and severe pain (75‐100 mm). Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) (time frame: baseline, 1 month, 3 months, 6 months, 9 months, 12 months). The KOOS questionnaire is an instrument to assess the participant's opinion about their osteoarthritis and associated problems. It consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee‐related Quality of life (QOL). Standardised answer options are given (5 Likert boxes) and each question is assigned a score from 0 to 4. A normalised score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale. A total lower score indicates more problems. The assessment will be done at baseline and at 1 month, 3 months, 6 months, 9 months and at 12 months. Secondary outcome measures: Change in EuroQuality of Life (EQ5D‐3L) scores (time frame: baseline, 1 month, 3 months, 6 months, 9 months, 12 months). The EQ5D 3L survey measures five dimensions ‐ mobility, self‐care, usual activities, pain/discomfort, and anxiety/depression. The participants will be asked to answer questions regarding these measures and to indicate their current experience on a scale from 1 to 3 (1 being "no problem" and 3 being "most extreme problem"). The answers to these question are put together to create a 5 digit composite score.This composite score will be indexed to a lookup table which produces a single summary score from 0 to 100. The respondents self‐rate their level of severity for each dimension using three levels. The assessment will be done at baseline and at 1 month, 3 months, 6 months, 9 months and at 12 months. Change in Patient‐Reported Outcomes Measurement Information System (PROMIS‐29 scales) (time frame: baseline, 1 month, 3 months, 6 months, 9 months, 12 months). The PROMIS‐29 assesses seven health domains: physical function, anxiety, depression, fatigue, sleep disturbance, pain interference, and ability to participate in social roles and activities. Each of the seven domains has four questions which are scored on a five‐point Likert scale. The PROMIS‐29 scales will be scored using a T‐score metric method available at the Assessment Center website (http://assessmentcenter.net). A score of 50 points represents the population average for each scale, and 10 points represent one standard deviation. Higher scores mean more of the specific scale's construct, which may indicate a desirable or an undesirable outcome. The assessment will be done at baseline and at 1 month, 3 months, 6 months, 9 months and at 12 months.
Starting date	March 2019
Contact information	Kenneth Mautne 404‐778‐7142 aakard@emory.edu
Notes	Trial registration: NCT03818737 Trial status: recruitment completed Estimated study completion date: 31 December 2021

NCT03825133.

Study name	The Comparison of Knee Osteoarthritis Treatment With Bone Marrow Aspirate Concentrate , Leukocyte Rich Platelet Rich Plasma and Hyaluronic Acid
Methods	Study design: open‐label, parallel, triple‐arm randomised controlled trial Setting: Clinical Center of Vojvodina, Serbia Timing: April 2016 to Nov 2017 Interventions: single‐dose of bone marrow aspirate concentrate vs single‐dose of leukocyte‐rich platelet‐rich plasma vs 3 injection of high molecular weight hyaluronic acid Sample size: 180 participants
Participants	Inclusion criteria: History of complaints of knee pain because of knee osteoarthritis with no relief using anti‐inflammatory agents even after 3 months, Kellgren‐Lawrence (KL) grade 2‐4 Normal blood results and coagulation profile (platelets 150,000 to 450,000/L) Patients who had not undergone any surgery on the affected knee within 2 years prior to the first injection and Mentally fit for clinical study Exclusion criteria: Severe knee instability Severe misalignment Unicompartmental OA BMI more than 35 Inflammatory arthritis such as rheumatoid arthritis and ankylosing spondylitis Presenting muscle pain underlying diseases such as haematologic disorders, septicaemia, coagulopathy, neoplasm, active infection and immune deficiency
Interventions	Intervention: bone marrow aspirate concentrate Patients treated with single injection of BMAC in the knee. Bone marrow (100 mL) is aspirated from proximal tibia, concentrated in Arthrex Angel Centrifuge, and after concentration 6 ml of BMAC is injected in the knee Intervention: leukocyte‐rich platelet‐rich plasma Patients treated with single injection of LR‐PRP in the knee. Blood sample is taken (100 mL), centrifuged in Arthrex Angel Centrifuge and after double spinning process about 6 ml of PRP is injected in the knee Control: hyaluronic acid Patients treated with 3 single injection of high molecular HA in the knee (one injection weekly)
Outcomes	Outcomes measured at 1, 3, 6, 9 and 12 months Primary outcome measures: Change of WOMAC Change of KOOS Secondary outcome measures: Change of SF‐36 Change of IKDC Change of VAS pain VAS pain injection VAS score after injection of fluid
Starting date	April 2016
Contact information	Oliver Dulic Clinical Center of Vojvodina Novi Sad, Vojvodina, Serbia, 21137
Notes	Trial registration: NCT03825133 Trial status: completed Estimated study completion date: Nov 2017

NCT03908827.

Study name	BMAC in Severe Hip or Knee Osteoarthritis Awaiting Arthroplasty
Methods	Study design: single‐blind parallel, 2‐arm randomised controlled trial Setting: Capri Clinic, Alberta, Canada Timing: Dec 2019 to Dec 2022 Interventions: single‐dose of bone marrow aspirate concentrate injection vs usual care Sample size: 0 (withdrawn trial)
Participants	Inclusion criteria: Symptomatic advanced unilateral knee or hip osteoarthritis (Kellgren‐Lawrence grade 3 or 4) that is inadequately controlled with conservative management including physical therapy, bracing and/or oral anti‐inflammatory medications Completed an intake assessment by a Hip and Knee Clinic of the Alberta Bone and Joint Health Institute with the musculoskeletal physician and have been deemed to be a candidate for a knee or hip arthroplasty Exclusion criteria: Unable to provide informed consent Have religious or other objections to the use of blood or blood products Will not be available for the projected 1‐year follow‐up period At the time of treatment have a systemic infection or a localised infection at the area of injection Have thrombocytopenia or are on antiplatelet, anti‐inflammatory or statin medications that cannot be stopped for 1 week prior to and for 1 month following the treatment.
Interventions	Intervention: Active BMAC treatment ‐ 60 mL of bone marrow will be aspirated from the iliac crest of each subject in the active treatment group. The bone marrow aspirate (BMA) will be centrifuged using a single spin protocol such that the red blood cells are minimised and the total nucleated and platelet cells are concentrated into a 12 mL volume of bone marrow aspirate concentrate (BMAC). Control: Wait list ‐ participants will continue with their usual treatment, inclusive of medications or conservative treatments and will continue with activity guidelines as previously provided by clinical staff whilst awaiting joint arthroplasty
Outcomes	Primary outcome measures: Numeric Pain Rating Scale (time frame: up to 12 months). Participants will be asked to rate the average pain severity for the prior week of the affected joint using a Numeric Pain Rating Scale (McCaffery & Beebe, 1989). Participants will be asked to select the number that best represents their pain during the previous 24‐hours on a scale of 0 to 10; with 0 indicating no pain and 10 indicating worst possible pain. Secondary outcome measures: Western Ontario and McMaster University Arthritis Index (WOMAC) (time frame: up to 12 months). The WOMAC measures five items for pain (score range 0‐20), two for stiffness (score range 0‐8), and 17 for functional limitation (score range 0‐68). Physical functioning questions cover everyday activities such as stair use, standing up from a sitting or lying position, standing, bending, walking, getting in and out of a car, shopping, putting on or taking off socks, lying in bed, getting in or out of a bath, sitting, and heavy and light household duties. 40 meter fast‐paced walk test (time frame: up to 12 months). A fast‐paced walking test that is timed over 4 x 10m (33 ft) for a total 40 m (132 ft) 30 second chair stand test (time frame: up to 12 months). The maximum number of chair stand repetitions possible in a 30 second period Other outcome measures: Healthcare utilisation (time frame: up to 12 months). The number of physician and allied health professional visits relating to the treatment of joint pain in the prior month Medication utilisation (time frame: up to 12 months). Medications used to control symptoms of the arthritic joint in the prior week Perceived need for joint arthroplasty: YES/NO (time frame: up to 12 months). "Given the problems you're having with your hip/knee at present, do you still want to have joint replacement surgery?" Reported complications/adverse events (time frame: up to 12 months). Descriptive list of any complications or adverse events
Starting date	December 2019
Contact information	Rob Durnham CAPRI Clinic Canada
Notes	Trial registration: NCT03908827 Trial status: withdrawn (change of study design) Estimated study completion date: March 2023

NCT03943576.

Study name	Allogeneic Adipose Tissue‐Derived Mesenchymal Stem Cells (GXCPC1) for Knee Osteoarthritis
Methods	Study design: single‐blind, parallel, 2‐arm randomised controlled trial Setting: Taiwan Timing: Dec 2019 to Oct 2022 Interventions: intra‐articular injection of allogeneic adipose tissue‐derived mesenchymal stem cells vs hyaluronic acid Sample size: 30 participants
Participants	Inclusion criteria: Provision of signed and dated informed consent form Aged 40 to 80 years old (inclusive) Kellgren‐Lawrence grading II‐IV, as determined by American College ofRheumatology (ACR) criteria for osteoarthritis of the knee Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score of 7‐17 (inclusive) in the target knee despite use of NSAID Contraindicated to long‐term systemic NSAID (e.g. suffer from severe gastrointestinal side effects upon systemic NSAID administration, or due to underlying increased gastrointestinal, cardiovascular, or renal risk) and not able to receive or wish to delay knee arthroplasty Exclusion criteria: With previous surgery of articular fracture, ligament reconstruction, meniscal reconstruction, and knee arthroplasty on the target knee joint With previous intra‐articular intervention (e.g. steroid, anaesthetics, hyaluronate, arthroscopic surgery) on the target knee joint 12 weeks prior to screening Administered or required systemic or local on the target knee joint immunosuppressive agent, anti‐inflammatory drug, steroid, analgesics, opioid, or duloxetine for OA knee except for acetaminophen and NSAID within 1 week prior to screening With joint diseases other than knee osteoarthritis considered by investigator not eligible to enter the study Unable to receive MRI examination, including allergic to the contrast medium for MRI used in the study, with known history of claustrophobia, having any existing metallic intraocular foreign body or active/inactive implanted medical devices, such as cardiac pacemaker, cochlear, intracranial vascular clips or neurostimulator Active or suspected infection of the target knee joint History of human immunodeficiency virus (HIV) infection History of malignancy within 2 years prior to screening With body mass index (BMI) greater or equal to 35 kg/m2 Known hypersensitivity to any component of the investigational product or the active control Participated other investigational study within 4 weeks prior to screening With ongoing or within the past 2 years serious medical conditions (e.g. concomitant illness) such as cardiovascular (e.g. New York Heart Association grade III or IV), hepatic (e.g. Child‐Pugh Class C), psychiatric condition (e.g. alcoholism, drug abuse), medical history, physical findings, or laboratory abnormality that in the investigators' opinion could interfere with the results of the trial or adversely affect the safety of the subject Female subject with childbearing potential who is lactating or has positive serum or urine pregnancy test at screening Subject with childbearing potential refuses to use highly effective contraceptives from signing informed consent until Final/Early Termination Visit. At least two forms of birth control must be adopted and one of which must be a barrier method. Acceptable forms include: established use of oral, injected or implanted hormonal methods of contraception;placement of an intrauterine device (IUD) or intrauterine system (IUS); barrier methods of contraception: condom, or occlusive cap (diaphragm or cervical/vault caps)
Interventions	Intervention:GXCPC1 (Allogeneic Adipose Tissue‐Derived Mesenchymal Stem Cells) Single intra‐articular injection of GXCPC1 containing 6.7×10^6 or 4×10^7 allogeneic adipose‐derived stem cells (ADSCs) in 3 mL saline Control: hyaluronic acid Hya Joint Plus synovial fluid supplement 3 mL
Outcomes	Primary outcome measures: WOMAC pain score (time frame: week 24) Change from baseline in WOMAC pain score at Week 24 Secondary outcome measures: MRI (time frame: week 0, 24, 48). Change from baseline to post‐treatment visits on the target knee in MRI examination results Visual Analogue Scale (VAS) (time frame: week 0, 1, 4, 12, 24). Changes from baseline to post‐treatment visits on the target knee in Visual Analogue Scale (VAS) for pain 12‐item Short Form (SF‐12) (time frame: week 0, 1, 4, 12, 24). Change from baseline to post‐treatment visits in total score of 12‐item Short Form (SF‐12) health survey questionnaire
Starting date	1 December 2019
Contact information	Chia‐Hsin Lee +886 6585959 ext 341 jessie.lee@gwoxi.com
Notes	Trial registration: NCT03943576 Trial status: recruiting Estimated study completion date: 31 October 2022

NCT03969680.

Study name	Autologous Mesenchymal Stem Cell Transplantation for the Treatment of Knee Osteoarthritis
Methods	Study design: single‐centre, randomised, single‐blind, phase II clinical study Setting: Yantai Yuhuangding Hospital, China Trial time period: not reported Interventions: stem cell injection plus PRP injection versus PRP injection Sample size calculations: 60
Participants	Inclusion criteria: Subject has Kellgren and Lawrence grade II‐IV primary osteoarthritis as determined by X‐ray Subject's pain score is 8‐13 points (Lequesne's index) Ages between 40‐70 years Signed informed consent from the subject Exclusion criteria: Subject infected with hepatitis B, hepatitis C, HIV, syphilis or HTLV Subject not suitable for bone marrow suction surgery Subject with hypersensitivity/allergy to anaesthetic Subject's creatinine values higher than 1.6 mg/dL Subject with body mass index, BMI over 30 Subject's studied knee treated with intra‐articular injection therapy within 6 months prior to screen Subject has undergone surgery on studied knee, including fracture surgery, arthroscopic surgery, meniscus repair surgery, or cruciate ligament reconstruction surgery Subject enrolled in any other cell therapy studies within the past 30 days Subject who the investigator considers inappropriate for the clinical trial for any other reasons than those listed above Subject has a history of gouty arthritis, septic arthritis, rheumatoid arthritis and any other autoimmune arthritis of the knee joint Subject has had major medical problems in vital organs, such as; heart, liver, kidney, or lung
Interventions	BMSCs plus PRP injection Three intra‐articular injections in total and autologous bone marrow‐derived mesenchymal stem cells (BMSCs) suspended in 3 mL autologous platelet rich plasma (PRP) for each injection. Time points for intervention: 1) initial injection; 2) 3 months following initial injection; 3) 6 months following initial injection. PRP injection Three intra‐articular injections in total and 3 mL autologous platelet rich plasma (PRP) for each injection. Time points for intervention: 1) initial injection; 2) 3 months following initial injection; 3) 6 months following initial injection.
Outcomes	Outcomes will be assessed at 3, 6, 9 and 12 months Primary outcomes: Function on WOMAC Pain on VAS 10‐point scale Secondary outcomes: MRI cartilage assessment Change in Lequesne Index SF‐36 quality of life score Change in Knee society score
Starting date	8 July 2019
Contact information	Peiwen Lian, PhD Yantai Yuhuangding Hospital, China Phone Number:+0086 5356691999 ext 82708
Notes	Clinical trial registration: Prospectively registered on 29 May 2019 Trial status: recruiting Estimated study completion date: 31 Dec 2023

NCT03975101.

Study name	Autologous Very Small Embryonic‐like Stem Cells (VSELs) for Knee Osteoarthritis
Methods	Study design: single‐centre, randomised, 3‐arm, parallel, controlled trial Setting: China Trial time period: May 2019 to May 2020 Interventions: VSEL injection (mini dose) versus VSEL injection (medium dose) VSEL injection (maximum dose) versus PRP injection Sample size calculations: 0
Participants	Inclusion criteria: Patients had moderate to severe osteoarthritis of both knees Those had mechanical pain of knee joints, which was aggravated by walking or stair climbing Those complained of gelling pain of knee joint Those who have crepitus and limitation of the joint range of motion with joint bony hypertrophy on physical examination, X‐rays showed narrowing of joint space and osteophyte formation Exclusion criteria: Diabetic foot and patients with obvious oedema in the legs of various causes Blood disease patients, thrombocytopenia or dysfunction, hypofibrinemia or anticoagulant therapy, long‐term use of aspirin
Interventions	VSEL injection (mini dose) versus VSEL injection (medium dose) VSEL injection (maximum dose) versus PRP injection
Outcomes	Outcomes measured at 1, 6 and 12 months VAS pain; MRI changes in knee joint
Starting date	31 May 2019
Contact information	Fuda Cancer Hospital, Guangzhou
Notes	Trial registered on 31 May 2019 Status: withdrawn

NCT03990805.

Study name	A Phase 3 Study to Evaluate the Efficacy and Safety of JointStem in Treatment of Osteoarthritis
Methods	Study design: double‐blind parallel, two‐arm randomised controlled trial Setting: Korea Timing: June 2019 to Dec 2020 Interventions: intra‐articular injection of Mesenchymal Stem Cells JointStem vs placebo Sample size: 260
Participants	Inclusion criteria: Age 20 and older, male and female Patients must consent in writing to participate in the study by signing and dating an informed consent document Diagnosis of degenerative arthritis of class 1‐3 by ACR (American College of Rheumatology Criteria) global functional criteria Diagnosis of Kellgren and Lawrence grade 3 by radiographic criteria Patients suitable for one of three conditions of 'diagnostic criteria for osteoarthritis of knee' based on ACR guideline Clinical and inspectional opinion Clinical and radiographic opinion Clinical opinion Patients who have joint pain ≥ 50 mm on 100 mm VAS at screening Patient who has WOMAC score ≥ 1000 at screening No improvement with persisting knee pain at least for 12 weeks (3 months) by non‐operational therapy before screening Exclusion criteria: Pregnant women or lactating mothers Patients with Body Mass Index (BMI) > 35 Patients with positive human immunodeficiency (HIV), hepatitis B (HBV), hepatitis C (HCV), syphilis at screening indicative of current of pass infection Patients with other disease including septic arthritis, rheumatoid or inflammatory joint disease, gout, recurrent pseudogout, paget disease, articular fractures, ochronosis, acromegaly, haemochromatosis, wilson's disease, osteochondromatosis, hereditary disorder, genetic disorder of collagen Patients who are diagnosed with malignant tumour in the past or present Patients who have clinically significant diseases including Cardiac disorder (myocardial infarction, coronary artery bypass graft, arrhythmia and other severe cardiac disorders etc.) Resistant hypertension (systolic blood pressure > 160 mmHg or diastolic pressure > 100 mmHg at screening) Kidney disease (chronic renal failure, glomerulonephritis etc.) Liver disease (hepatocirrhosis, fatty liver, acute or chronic liver disease etc.) Endocrinopathy (thyroiditis, diabetes insipidus, Cushing disease etc.)
Interventions	JOINTSTEM Autologous Adipose Tissue derived MSCs 1x10^8 cells/(saline), 1‐time injection Saline, 1‐time injection
Outcomes	Outcomes will be measured at 12 weeks and 24 weeks Primary outcomes: WOMAC and VAS Secondary outcomes: KOOS; IKDC, SF‐36, x‐ray changes KL grade and joint space width
Starting date	19 June 2019
Contact information	Dr Kangil Kim KyungHee University Gangdong Hospital, South Korea
Notes	Trial registration: NCT03990805 Status: completed, no results posted

NCT04130100.

Study name	Clinical Study of Pulp Mesenchymal Stem Cells in the Treatment of Primary Mild to Moderate Knee Osteoarthritis
Methods	Study design: randomised, 3‐arm, parallel‐group, controlled trial Setting: Changhai Hospital, Shanghai, China Trial time period: 4 April 2019 to 30 December 2021 (estimated) Interventions: dental pulp mesenchymal stem cells versus high dose sodium hyaluronate versus low dose sodium hyaluronate Sample size calculations: target sample size = 60
Participants	Inclusion criteria: Complying with the diagnostic criteria for primary knee osteoarthritis revised by the American Rheumatological Association (1995), age 40‐70 years, gender‐free For patients with mild to moderate knee arthritis, the WOMAC score of knee joint was less than 120 X‐ray Kellgren‐Lawrence was used to evaluate the grade I, II and III of osteoarthritis Fertility patients should take effective contraceptive measures until the end of follow‐up. Fertility women should exclude the possibility of early pregnancy, that is, HCG negative test in early pregnancy Voluntary participation in this clinical study, can cooperate with doctors to carry out research, stop all medical measures for knee arthritis for more than 2 weeks, and sign the informed consent of patients Exclusion criteria: (Those with other diseases that may affect the knee joint, such as rheumatoid arthritis, ankylosing spondylitis, rheumatoid arthritis, gout and other rheumatic diseases, bone tumours, osteoporosis, bone tuberculosis or obvious history of acute trauma, resulting in meniscus injury, ligament rupture and vascular nerve injury; those with previous history of femur, tibial plateau, tibia and fibula fracture. The patients with gonarthritis, the patients with knee joint and surrounding skin infection were not cured. Patients who have undergone surgery and other factors affecting the efficacy of the treatment. Patients with severe deformities or even deformities of the knee joint, who need surgical treatment. Patients who have received knee joint irrigation or arthroscopic examination within one year. Patients with systemic cancer tendency or cancer and patients with systemic infection in active stage. Patients with severe heart, lung, liver, kidney, blood system, endocrine system and immune deficiency, or abnormal laboratory biochemical indicators, namely: haemoglobin (Hb) < 9 g/dL, white blood cell (WBC) > 15 x 109/L, platelet (Pt) < 100 x 109/L, glutamic oxalate transaminase (AST) and alanine aminotransferase (ALT) > 1.5 times normal upper limit; serum creatinine > 1.5 times normal upper limit. Physical history or clinical manifestations with bleeding tendency, including patients currently using anticoagulants. Patients with uncontrollable epileptic seizures, psychosis or Alzheimer's disease who are unable to complete the scale. Pregnant or lactating women, legal disabled patients (blind, deaf, dumb, mentally retarded, physically disabled), drug addiction and other adverse drug addiction. Patients with contraindications or allergies were examined and treated in this study. Those who have participated in other clinical studies within one month. Researchers consider it inappropriate for patients to participate in this clinical study.
Interventions	Dental pulp mesenchymal stem cells versus high‐dose sodium hyaluronate versus low‐dose sodium hyaluronate
Outcomes	Primary outcomes: 1. Kellgren and Lawrence's rating (time frame: 12 months) X‐ray imaging was used to evaluate the degree of improvement in knee joint structure 2. WOMAC score (time frame: 12 months). WOMAC score decreased Secondary outcomes: 1. Volume of femoral surface of knee joint on MRI (time frame: 12 months) Changes of volume of lateral femoral condylar, medial femoral condylar, lateral tibial condylar, medial tibial condylar and posterior patellar articular surfaces on MRI 2. Relaxation time of femoral surface of knee joint on MRI (time frame: 12 months) Changes of relaxation time (T1 condylar, T2 condylar, T2*) of lateral femoral condylar, medial femoral condylar, lateral tibial condylar, medial tibial condylar and posterior patellar articular surfaces on MRI
Starting date	4 April 2019
Contact information	Contact: Dr Guangrong Song +86‐13918384480 songguangrong@cart‐sh.com
Notes

NCT04208646.

Study name	Allogenic Adipose Tissue‐Derived Mesenchymal Progenitor Cells for the Treatment of Knee Osteoarthritis
Methods	Study design: multicentre, randomised, 3‐arm, double‐blind, controlled trial Setting: multicentre, China Trial time period: 16 May 2020 to January 2022 (estimated) Interventions: low‐dose mesenchymal progenitor cells versus high‐dose mesenchymal progenitor cells versus placebo Sample size calculations: target sample size = 108
Participants	Inclusion criteria: 1. Subjects who understand and voluntarily sign the consent form before this study 2. According to the diagnostic criteria (American Rheumatology Association, clinical + radiology criteria), patients with knee osteoarthritis are definitely diagnosed 3. Age: 40‐75, males and females 4. The course of knee osteoarthritis was more than 6 months and less than 10 years 5. The subjects' WOMAC score was 24‐72, and the WOMAC pain score 7 to 17 (the WOMAC score at least 48 hours after discontinuation of all painkillers) 6. The Kellgren Lawrence grade (X‐ray axial position of knee joint) of subjects was grade II/III 7. Subjects are generally in good condition and can walk autonomously, except for those who use wheelchairs, walking aids or crutches Exclusion criteria: 1. The subject may be allergic to the main cell preparation components (B vitamins, amino acids and so on) 2. The subject received systemic and/or local treatment with autologous and/or allogeneic mesenchymal progenitor cells. 3. The subject has a BMI of over 30 4. Laboratory test (any item meets): neutrophil absolute number < 1.0 × 10^9/L, platelet count < 50 × 10^9/L, serum albumin < 30g/L, serum creatinine > upper limit of normal value range, total bilirubin, alanine aminotransferase, aspartate aminotransferase > upper limit of 2 times of normal value range 5. The subject has diseases or symptoms may affect VAS, WOMAC and so on 6. The subject has serious and poorly controlled concomitant diseases, such as (but not limited to) nervous system, cardiovascular, liver, kidney, gastrointestinal and endocrine diseases, which may prevent the subjects from participating in the study according to the judgment of the researchers 7. The subject has a history of malignant tumour 8. The subject has connective tissue disease or rheumatoid arthritis, chondropathy, chondrocalcinosis articularis, haemochromatosis, inflammatory arthropathy, avascular necrosis of femoral head, Paget's disease, haemophilic arthropathy, infectional arthritis, Charcot's disease, villonodular synovitis or synovial chondromatosis 9. The subject has severe generalised infectious diseases or local knee infection (including skin and intra‐articular infection) in the 3 months prior to this trial 10. According to the researchers, the subject has disease of lower limbs which may be interfered knee evaluation, for example fibromyalgia, osphyalgia, lumbar disc protrusion and so on 11. The subject had any other coagulation dysfunction caused by acute or chronic diseases, according to the judgment of the researchers, this coagulation dysfunction may endanger the safety of patients and/or affect the judgment of knee joint evaluation indicators 12. The subject has received arthroscopic surgery or other open surgery related to knee joint operation in the 6 months prior to this trial 13. The subject has received other intra‐articular injections, including but not limited to hyaluronic acid, hormone, PRP, BMP (bone morphogenetic protein) , hypertonic glucose and so on for KOA in the 3 months preceding the trial 14. The subject has received aminoglucose or chondroitin sulfate within 1 month before the treatment 15. The subject has used dexamethasone, prednisone, hydrocortisone and other hormones orally/intravenously within 1 month before the treatment 16. The subject has undergone knee prosthesis or a plan of knee prosthesis within the trial 17. The subject has contraindication of MRI, included but not only: the subject installed heart pacemaker, defibrillator, heart bracket, heart valve prosthesis, metal clip after aneurysm surgery, drug infusion device implanted in vivo, any electronic device implanted in the body (nerve stimulator, bone growth stimulator) endovascular coil, strainer, ECG monitor, metal suture, shrapnel or sand of body, plate fixation and steel nail after fracture surgery, artificial cochlea, middle ear shift plant, metallic intraocular foreign body etc; the subject is a claustrophobia, critical ill patient and so on 18. The subject tests positive for: HIV, HBV, HCV and treponema pallidum 19. The subject has history of alcoholism, drug abuse, or mental illness in the 3 years prior to this trial 20. The subject has participated in any other clinical trial in the 3 months prior to this trial 21. The subject (including male subjects) has fertility, sperm donation or egg donation plans during the trial period; the female subject is pregnant, lactating or having a positive pregnancy test 22. The subject is legally disabled by reference to the law of the People's Republic of China on the protection of disabled persons (April 2008) 23. The subject has any other unsuitable condition (such as factors reducing the follow‐up compliance) to be determined by the investigator 24. The Kellgren Lawrence grade (X‐ray axial position of knee joint) of any knee joint of the subjects was grade IV
Interventions	Intervention 1: Low‐dose mesenchymal progenitor cell injection. Adipose tissue‐derived mesenchymal progenitor cells administrated for intra‐articular use. Intervention 2: High‐dose mesenchymal progenitor cell injection. Adipose tissue‐derived mesenchymal progenitor cells administrated for intra‐articular use. Comparator: Placebo injection
Outcomes	Primary outcomes: 1. WOMAC Score (time frame: 24 weeks) The Western Ontario and McMaster Universities Osteoarthritis Index, 0‐96 points; 96 points means a worse outcome, will be tested at 24 weeks after the first injection Secondary outcomes: Magnetic resonance imaging analysis of articular cartilage, will be tested at 24, 48 weeks after the first injection WOMAC score (time frame: 4, 8, 12, 36, 48 weeks). The Western Ontario and McMaster Universities Osteoarthritis Index;0‐96 points; 96 points means a worse outcome, will be tested at 4, 8, 12, 36, 48 weeks after the first injection VAS score (time frame: 4, 8, 12, 24, 36, 48 weeks) Visual Analogue Scale/score; 0‐10 points; 10 points means a worse outcome, will be tested at 4, 8, 12, 24, 36, 48 weeks after the first injection SF‐36 (time frame: 4, 8, 12, 24, 36, 48 weeks). The Medical Outcomes Study 36‐Item Short‐Form Health Survey;0‐100 points;100 points means a better outcome, will be tested at 4, 8, 12, 24, 36, 48 weeks after the first injection Adverse events and serious adverse events (time frame: 0d, 1, 3, 4, 8, 12, 24, 25, 27, 28, 36, 48 weeks). AE and SAE, will be assessed at 0d, 1, 3, 4, 8, 12, 24, 25, 27, 28, 36, 48 weeks. Changes of laboratory test indexes and vital signs (time frame: 0 d, 1, 3, 4, 8, 12, 24, 25, 27, 28, 36, 48 weeks) Vital signs, physical examination, clinical laboratory tests:infectious disease check, blood coagulation test , blood check, urine check, blood biochemical test, immunological examination, tumour screening, will be tested at 0d, 1, 3, 4, 8, 12, 24, 25, 27, 28, 36, 48 weeks Metabolic index detection (time frame: 0, 4, 8, 12, 24, 36, 48 weeks) Levels of cartilage metabolism and inflammatory biomarkers in serum and urine will be tested at 0, 4, 8, 12, 24, 36, 48 weeks
Starting date	16 May 2020
Contact information	Contact: Chunde Bao, M.D. & Ph.D. 021‐587523545 xck@renji.com
Notes	Locations: China‐Japan Friendship Hospital Beijing, China, 100029 Principal Investigator: Guochun Wang The Second Affiliated hospital of Zhejiang University School of Medicine Hangzhou, China, 310009 Principal Investigator: Shigui Yan Huashan Hospital Affiliated to Fudan University Shanghai, China, 200040 Contact: Weiguo Wan Principal Investigator: Weiguo Wan Shanghai General Hospital Shanghai, China, 200080 Principal Investigator: Chengqing Yi Shanghai Jiaotong University School of Medicine, Renji Hospital Shanghai, China, 200127 Principal Investigator: Chunde Bao, MD Shanghai Sixth People's Hospital Shanghai, China, 200233 Principal Investigator: Changqing Zhang Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine Shanghai, China Principal Investigator: Jinwu Wang

NCT04212728.

Study name	Treatment of Knee Osteoarthritis With Autologous Adipose‐derived Mesenchymal Stem Cells
Methods	Study design: single‐centre, randomised, single‐blind, controlled trial Setting: Yantai Yuhuangding Hospital, Shangdong, China Trial time period: 29 December 2019 to December 2023 (estimated) Interventions: autologous adipose‐derived mesenchymal stem cells with PRP versus PRP alone Sample size: 60 participants
Participants	Inclusion criteria: 1. Subject has Kellgren and Lawrence grade II‐IV primary osteoarthritis as determined by X‐ray 2. Subject's pain score is 8‐13 points (Lequesne's index) 3. Ages between 40‐70 years 4. Signed informed consent from the subject Exclusion criteria: 1. Subject infected with hepatitis B, hepatitis C, HIV, syphilis or HTLV 2. Subject not suitable for liposuction surgery 3. Subject with hypersensitivity/allergy to anaesthetic 4. Subject's creatinine values higher than 1.6 mg/dL 5. Subject with body mass index, BMI over 30 6. Subject's studied knee treated with intra‐articular injection therapy within 6 months prior to screen 7. Subject has undergone surgery on studied knee, including fracture surgery, arthroscopic surgery, meniscus repair surgery, or cruciate ligament reconstruction surgery 8. Subject enrolled in any other cell therapy studies within the past 30 days 9. Subject who the investigator considers inappropriate for the clinical trial due to any reasons other than those listed above 10. Subject has a history of gouty arthritis, septic arthritis, rheumatoid arthritis and any other autoimmune arthritis of the knee joint 11. Subject has had major medical problems in vital organs, such as; heart, liver, kidney, or lung
Interventions	Intervention: Autologous adipose‐derived mesenchymal stem cells with PRP. 150 mL subcutaneous abdominal adipose tissue will be harvested via liposuction. AMSCs will be isolated and cultured from adipose tissue. Before injection, 30 mL of blood will be collected from each patient to produce 3 mL PRP by cenrifugation. Cultured AMSCs will be collected and suspended by 3 mL autologous PRP. Three intra‐articular injections in total and autologous adipose‐derived mesenchymal stem cells (AMSCs) suspended in 3 mL autologous platelet rich plasma (PRP) for each injection. Time points for intervention: 1) initial injection; 2) 3 months following initial injection; 3) 6 months following initial injection. Comparator: Autologous PRP injection. 30 mL of blood will be collected from each patient to produce 3ml PRP by cenrifugation. Three intra‐articular injections in total and 3 mL autologous platelet rich plasma (PRP) for each injection. Time points for intervention: 1) initial injection; 2) 3 months following initial injection; 3) 6 months following initial injection.
Outcomes	Primary outcomes: 1. Physical function change (time frame: from before randomisation until 3, 6, and 12 months after treatment start.) Evaluation of the physical function change measured by the Western Ontario and McMaster Universities Arthritis Index (WOMAC). The WOMAC consists of three subscales: pain (five questions), stiffness (two questions), and physical function (17 questions). The subscale scores can vary, with pain ranging from 0 to 20 points; stiffness, 0 to 8 points; and physical function, 0 to 68 points. Higher scores represent worse pain, stiffness, and functional limitations. 2. Change in pain density (time frame: from before randomisation until 3, 6, and 12 months after treatment start.) Evaluation of the changing of pain density measured by Visual Analogue Scale. Draw a 10 cm horizontal line on the paper. One end of the line is 0, indicating no pain; the other end is 10, indicating severe pain; and the middle part indicates varying degrees of pain. The patient selects a point from the horizontal line and the length from 0 to this point is the Visual Analogue Scale score. Secondary outcomes: 1. Cartilage repair (time frame: from before randomisation until 3, 6, and 12 months after treatment start.) Evaluation of cartilage repair under MRI. Recht criterion was used for grading articular cartilage injury of knee joint, including 0‐IV grade, in which: 0 grade, normal articular cartilage, no obvious abnormal signal was found; 1 grade, the layered structure of cartilage disappeared, and there were focal low signal areas, but the surface was smooth; 2 grade, the surface of cartilage was irregular, the depth of cartilage injury was less than 50% cartilage thickness; 3 grade, the surface of cartilage was heavy. The degree of injury is irregular, the depth of injury is more than 50% of the thickness of cartilage or through the whole layer, but the surface of cartilage is not completely exfoliated; Grade IV, full‐thickness cartilage defect, articular cartilage injury deep to the cortex, subchondral bone exposed. 2. Change in MOS item short from health survey(SF‐36) (time frame: from before randomisation until 3, 6, and 12 months after treatment start.) Evaluation of the health‐related quality of life change Measured by MOS item short from health survey(SF‐36) after each cell injection. SF‐36 is a self‐administered questionnaire comprising 36‐ items measuring eight dimensions of general HRQOL: physical functioning (10 items), role limitation due to physical health problems (4 items), bodily pain (2 items), general health perceptions (5 items), vitality (4 items), social functioning (2 items), role limitations due to emotional problems (3 items), and general mental health (5 items).These outcomes will be grouped as physical component summary and mental component summary. The norm data is 0‐100, the health related quality of life is increases as the scores are increased. The average score is 50. 3. Change in Lequesne Index (time frame: from before randomisation until 3, 6, and 12 months after treatment start.) Evaluation of severity of knee symptoms Lequesne Index includes the measurement of pain (5 items), walking distance (2 items), and activities of daily living (4 items). Maximal score is 24 and higher scores represent worse function 4. Change in knee society score (KSS) (time frame: from before randomisation until 3, 6, and 12 months after treatment start.) The knee society score is divided into four parts: it consists of "Symptoms"(25 points), "Patient satisfaction"(40 points), "Patient expectation"(15 points) and "Functional activities"(100 points). Each part will be evaluated separately. Higher scores indicate better knee score/satisfaction/functioning or higher expectations.
Starting date	29 December 2019
Contact information	Contact: Peiwen Lian, PhD +0086 5356691999 ext 81511 peiwen.lian@hotmail.com Contact: Jian Chen, PhD +0086 5356691999 ext 82708 chenjianyt@163.com
Notes

NCT04230902.

Study name	Effects of α MAT Versus Steroid Injection in Knee Osteoarthritis (STα MAT‐knee Study)
Methods	Study design: single‐blind, parallel, 2‐arm randomised controlled trial Setting: Lebanon Timing: Jan 2020 to Mar 2021 Interventions: intra‐articular injection of micro‐fragmented adipose tissue transplant vs corticosteroid injection Sample size: 48
Participants	Inclusion criteria: Patients who are ≥ 45 years old Symptomatic knee OA defined as symptoms of knee pain and/or decreased range of motion (ROM) Classified radiographically as having Grade 2 or 3 Knee OA Failure of 3 months conservative management (NSAIDs and p Exclusion criteria: Patients < 45 years old Pregnant or breastfeeding women Cancer patients Rheumatoid arthritis patients Patients having any autoimmune disease affecting the joint Patients who have had hyaluronic acid injection < 1 year ago Patients who have undergone lower extremity surgery or trauma on the same side Hypersensitivity to methylprednisolone (Depo‐Medrol®) or any of its components, lidocaine/xylocaine or any of its components, and any of the ingredients of Lipogems® injection kit Patients with acute systemic or local infection Patients on anticoagulants (warfarin, coumadin, heparin, Xeralto, or Plavix)
Interventions	Intervention ‐ Lipogems: The cases assigned to this group will be injected intra‐articularly with Lipogems®. The patients will undergo harvesting of their own adipose tissue for aMAT then this aMAT will be injected intra‐articularly in the knee. It will be administered once at the baseline visit of the study. Control ‐ Corticosteroid injection: The cases assigned to this group will be injected intra‐articularly in the knee with corticosteroids. No extra preparation of any type is necessary in this case. It will be administered once at the baseline visit of the study.
Outcomes	Primary outcomes: The difference in total pain scores (using numerical rating scale) between the baseline visit (prior to injection) and 6 months after injection will be obtained for each arm The difference in MOAKS values (MRI Osteoarthritis Knee Score) between the baseline visit (prior to injection) and 6 months after injection will be obtained for each arm Secondary outcomes: ROM Cartilage thickness The difference scores of patient‐based outcome questionnaires (Lipogems® Questionnaire‐Knee, and Knee injury and Osteoarthritis Outcome Score or KOOS) Pain score‐other follow‐ups ‐ time frame: 3 months
Starting date	18 Jan 2020
Contact information	Asdghig Der‐Boghossian Email: ad24@aub.edu.lb
Notes	Trial registration: NCT04230902 Trial status: recruiting Estimated study completion date: 31 March 2021

NCT04240873.

Study name	Clinical Study of Intra Articular Injection of Catholic MASTER Cell (Bone Marrow Derived Mesenchymal Stem Cell) in Knee Osteoarthritis (MSC‐OA)
Methods	Study design: single‐centre, randomised, double‐blind, controlled trial Setting: Seoul St. Mary's Hospital, Republic of Korea Trial time period: 15 November 2019 to 31 March 2022 (estimated) Interventions: Catholic MASTER Cell injection versus saline injection Sample size calculations: sample size target = 24
Participants	Inclusion criteria: 1. Age 20‐80 2. Diagnosed with knee osteoarthritis (OA) according to ACR classification criteria for knee OA 3. Symptomatic OA that lasted for at least 3 months before screening 4. Baseline pain VAS ≥ 50 mm 5. treated with medication such as acetaminophen, tramadol, NSAID for at least 1 month due to OA pain 6. X‐ray Kellgren‐Lawrence grade 1~4 7. voluntarily enrolled with informed consent 8. no improvement with medical treatment for at least 3 months Exclusion criteria: 1. Disease in spine or lower extremities that can affect the outcome of index knee 2. Surgery on lower extremities within 6month before injection or planned 3. Joint symptoms that can affect the interpretation of the trial data or prevent the subject from enrolment including but not limited to symptomatic fracture, fibromyalgia, rheumatoid arthritis, reactive arthritis 4. Steroid injection to the index knee within previous 3 months 5. Hyaluronic acid injection to the index knee within previous 6 months 6. Underwent cell therapy or gene therapy in the past 7. More than 3 times upper normal limit in one or more of the followings: serum creatinine, bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or more than 3 times upper normal limit in two or more of the followings: bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 8. Participation in a different clinical trial other than this within 4 weeks after initiation of the current study 9. Use (recurrent use or addiction) of substances that can affect pain sensation such as narcotics 10. Females of childbearing age who do not consent to effective contraceptive methods during the study period 11. Pregnant or lactating woman 12. Malignancy 13. Considered to be inappropriate for the trial by investigators
Interventions	Intervention: Single intra‐articular injection of Catholic MASTER cell, 1 x 10^8 cells/DMEM 5 cc, into knee joint of patients with osteoarthritis. Control: Single intra‐articular injection of saline, 1 time, 5 cc, into knee joint of patients with osteoarthritis
Outcomes	Outcomes measured at two time points: baseline and 12 months Primary outcomes: 1. Adverse event according to CTCAE 5.0, clinically meaningful abnormalities in laboratory tests 2. Western Ontario and McMaster Universities Arthritis Index (WOMAC) score 3. Knee injury and Osteoarthritis Outcome Score (KOOS) 4. International knee documentation committee (IKDC) 5. Cartilage damage evaluation through knee MRI 6. SF‐36 questionnaire 7. Serum inflammatory cytokine, acute phase reactant, bone turnover marker 8. Cartilage damage evaluation through knee x‐ray
Starting date	15 November 2019
Contact information	Contact: Ji Hyeon Ju, MD, PhD 82‐2‐2258‐6893 juji@catholic.ac.kr Contact: Jennifer Lee, MD, PhD 82‐2‐2258‐6893 poohish@naver.com
Notes

NCT04326985.

Study name	A Randomized Control Clinical Trial to Evaluate the Efficacy of Intra‐articular Injections of Mesenchymal Stem Cells Versus Hyaluronic Acid in Patients Affected by Osteoarthritis of the Knee
Methods	Study design: 3‐arm, parallel randomised controlled trial Setting: Department of Orthopaedics & Traumatology, Chinese University of Hong Kong, Hong Kong Trial time period: Jan 2015 to Feb 2019 Intervention: mesenchymal stem cells versus hyaluronic acid Sample size: 20
Participants	Inclusion criteria: Male and female subjects aged between 18 and < 65 Radiological evidence of osteoarthritis with Kellgren and Lawrence grade 2 and 3 Patients on a pain level equal to or higher than 5 on a VAS scale of 10 Exclusion criteria: Previous cases of alcoholism or drug abuse Pregnancy and breast‐feeding Serious pathologies such as carcinoma or autoimmune disease Hypersensitivity toward hyaluronic acid Undergoing steroid‐based systemic therapy or interrupted since less than 1 month Significant haematologic diseases Mechanical instability, ligamentous laxity/deficiency or gross deformity
Interventions	Autologous mesenchymal stem cells treatment (MSCs): The MSCs treatment group patients will receive an intra‐articular injection of a mesenchymal stem cell (MSCs) suspension in the affected knee. Hyaluronic acid (HA): The HA group patients will be given a single intra‐articular injection of hyaluronic acid sodium salt, Synvisc‐One (TRB Chemedica Ltd.) No injection: This group will not receive any injections.
Outcomes	Primary outcomes: Knee Society Score (time frame: one year), Clinical Questionnaire Assessment Tool. Score 80‐100 = Excellent, Score 70‐79 = Good, Score 60‐69 = Fair, Score below 60 = Poor Knee Society Function Score (time frame: one year), Clinical Questionnaire Assessment Tool. Score from 100 to ‐20. The higher the score, the better the knee function outcome. Magnetic resonance image (MRI) and X‐ray assessment of knee joint (time frame: one year) Secondary outcomes: WOMAC, VAS, SF‐36 at one year
Starting date	31 January 2015
Contact information	Dr. Ho Ki Wai, Clinical Professional Consultant, Chinese University of Hong Kong
Notes	Trial registration: NCT04326985 Status: recruitment completed, no results posted

NCT04368806.

Study name	A 48‐Weeks, Phase 2b/3a, Double‐Blind, Randomized, Placebo Controlled, Multi‐center, Superiority Study to Evaluate the Efficacy and Safety of JointStem, Autologous Adipose Tissue Derived Mesenchymal Stem Cells in Patients Diagnosed as Knee Osteoarthritis
Methods	Study design: double‐blind, randomised, placebo‐controlled, multi‐centre trial Setting: multicentre (medical clinics), USA Trial time period: May 2021 to Dec 2023 Intervention: autologous adipose tissue‐derived mesenchymal stem cells (AdMSC) versus placebo injection Sample size: 140
Participants	Inclusion criteria: Subject who had osteoarthritis of knee diagnosed (according to the clinical and American College of Rheumatology Criteria) Subject who has ≥ 34 on WOMAC function score at screening and baseline Subject who has knee pain ≥ 50 mm for one knee and ≤ 40 mm for the other knee out of 100 mm on VAS (Visual Analog Scale) at screening and baseline Subject who has radiographic evidence of grade 3 osteoarthritis in one knee and grade 1 or 2 in the other knee based on the Kellgren and Lawrence radiographic criteria. Subjects whose knee pain persists for at least 12 weeks (about 3 months) prior to screening and do not improve symptoms with non‐operative treatment options Subject who is willing to discontinue all pain medications for osteoarthritis except rescue medication (< acetaminophen 3.25 g per day) at least 72 hours prior to screening and throughout the duration of study Subject who is willing and able to give written informed consent for participation in the study Exclusion criteria: Subject who has Body Mass Index (BMI) > 35 kg/m2 Subject judged by the investigator to have a history of clinically significant disease Subject who has any of the following clinically significant disease Autoimmune diseases Paget's disease, ochronosis, acromegaly, haemochromatosis, or Wilson's disease Genetic diseases (hyperkinesia, collagen gene abnormality, etc.) Inflammatory joint disorders (e.g. rheumatoid inflammation) Infectious joint disorders (e.g. septic arthritis) Other joint disorders (e.g. gout, recurrent pseudogout, articular fracture, primary osteochondrosis, villonodular synovitis) Subject who has any history of cancer or currently receiving treatment for a current cancer diagnosis Subject who has a positive pathogenic test (HIV, viral hepatitis, or syphilis) Subject who has heart diseases (myocardial infarction, coronary artery bypass graft surgery, arrhythmia, or other serious heart diseases) or history of heart diseases within 6 months prior to screening Subjects who have received any intra‐articular therapy in any joint within 6 months prior to screening, or surgery on the relevant knee, including articular endoscopic procedures within 6 months prior to screening Subject with history of prolotherapy, or platelet rich plasma injection within 6 months prior to screening Subject who have received long‐acting hyaluronic acid injection (e.g. Synvisc‐One®, etc.) within 12 months prior to screening Subject who has a history of stem cell therapy Subject who have significant lab abnormalities for the following parameters (If the value is within 10% of the listed laboratory exclusion criterion value and the value is considered not to be clinically significant by the investigator, the subject can be considered for enrolment): Serum ALT and AST > 2 x upper limit of normal Serum creatinine out of normal range PT/INR out of normal range Haemoglobin < 10 g/dL for female subject and haemoglobin < 11 g/dL for male subject Platelets out of normal range Subject for whom the investigator judges the lipoaspiration can cause any problem Subject who has history of local anaesthetic allergy Subject who has taken anti‐inflammatory drugs (prescription and non‐prescription NSAIDs), symptomatic slow acting drugs (glucosamine, chondroitin sulfate, diacerhein etc.), or oral steroids (prednisone etc.) within 14 days prior to screening (however, those who undergo a 14‐day wash‐out period can participate.) Subject who is an active drug/alcohol abuser Pregnant or breast‐feeding women, or women or men who are not using appropriate method of contraception (appropriate method includes hormones, bilateral tubal ligation, and barrier method with spermicide, and intra‐uterine device for women and vasectomy and barrier method with spermicide for men; subjects should agree to use appropriate method) Subject who is enroled in any other clinical trials within 3 months from screening Subject who received the COVID‐19 vaccines within 1 week from Visit 2 (lipoaspiration, baseline)
Interventions	Autologous adipose tissue derived mesenchymal stem cells (AdMSC) Placebo: normal saline with autologous serum
Outcomes	Primary outcome measures : Change from baseline in WOMAC function subscale at Week 48 Change from baseline on Visual Analog Scale (VAS) score at Week 48 Secondary outcome measures : Change from baseline in WOMAC subscale (Function) score at Week 12, 24, and 36 Change from baseline in WOMAC subscale (Pain) score at Week 12, 24, 36, and 48 Change from baseline in total WOMAC score at Week 12, 24, 36, and 48 Change from baseline in VAS score at Week 12, 24 and 36 Change from baseline in IKDC score at Week 12, 24, 36, and 48 Change from baseline in SF‐36 score at Week 12, 24, 36, and 48 Change from baseline in cartilage defect area changes to the knee joint determined by MRI at Week 48 Change from baseline in Kellgren‐Lawrence grade of knee osteoarthritis determined by X‐ray at Week 48 The number and amount of rescue medication use at Week 12, 24, 36 and 48
Starting date	30 April 2020
Contact information	Hugh Lee 301‐540‐2600 hughlee@kcrnresearch.com
Notes	Trial registration: NCT04368806 Status: recruiting Estimated completion: Dec 2023

NCT04520945.

Study name	Phase 2B: Randomized Double‐Blinded Clinical Study of Chondrogen for Treatment of Knee Osteoarthritis
Methods	Study design: randomised controlled trial (phase 2 study) Setting: Department of Orthopedic & Traumatology, Faculty of Medicine, Hospital Canselor Tuanku Mukhriz, KL, Malaysia Trial time period: October 2020 to September 2022 Intervention: stem cell injection plus hyaluronic acid versus hyaluronic acid injection Sample size: 100
Participants	Inclusion criteria: 30‐70 years old No serious infection, chronic diseases, diabetes and tuberculosis Idiopathic or secondary osteoarthritis of the knee with grade 1‐3 defined by the modified Kellgren‐Lawrence classification Written informed consents were obtained from all subjects. Exclusion criteria: Pregnant or lactating women Women of childbearing potential unwilling to use two forms of contraception Cognitively impaired adults Presence of large meniscal tears Inflammatory or post‐infectious arthritis More than 5 degrees of varus or valgus deformity Kellgren Lawrence grade 4 osteoarthritis in two compartments in persons over 60 years of age Intra‐articular corticosteroid injection within the 3 previous months Major neurologic deficit Arthroscopy during the previous 6 months Poorly controlled diabetes mellitus Immunosuppressive or anticoagulant treatment NSAID therapy within 15 days prior to inclusion in the study Serious medical illness with a life expectancy of less than 1 year Prior admission for substance abuse Body Mass Index (BMI) of 40 kg/m2 or greater
Interventions	Chondrogen: mesenchymal stem cell‐derived from umbilical cord Wharton Jelly and hyaluronic acid Placebo: saline and hyaluronic acid
Outcomes	Primary outcome measures : VAS score (time frame: 12 months). Change from Baseline in VAS WOMAC score (time frame: 12 months). Change from Baseline in WOMAC IKDC score (time frame: 12 months). Change from Baseline in knee function change and improvement (IKDC) KOOS score (time frame: 12 months). Change from Baseline in KOOS Secondary outcome measures : PROMIS29 score (time frame: 12 months). Change in Patient‐Reported Outcomes Measurement Information System (PROMIS29) scores Kellegren‐Lawrence grading (time frame: 12 months). Number of participants evaluated by X‐ray and MRI of knee OA from baseline Kellegren‐Lawrence grading system. Interleukins (time frame: 12 months). Changes of interleukins (IL‐1b, IL‐6, PGE‐2, TGF‐b, TNF‐a, IGF‐1) of articular cavity fluid from baseline to week 12
Starting date	31 October 2020
Contact information	Prakash Nathan, MBA 03‐88902968 research@meluhalifesciences.com
Notes	Trial registration: NCT04520945 Status: not yet recruiting Estimated completion: September 2022

NCT04821102.

Study name	Investigator Initiated Trial to Evaluate Cartilage Regeneration by Arthroscopy in Patients With K‐L Grade III Knee Osteoarthritis After JOINTSTEM Administration
Methods	Study design: double‐blinded, 2‐arm, parallel randomised controlled trial Setting: Bethesda Hospital, Korea Trial time period: July 2023 to December 2024 Intervention: stem cell injection versus placebo injection Sample size: 21
Participants	Inclusion criteria: Age 20 and older, male and female Patients must consent in writing to participate in the study by signing and dating an informed consent document Diagnosis of degenerative arthritis of class 1‐3 by ACR (American College of Rheumatology Criteria) global functional criteria Diagnosis of Kellgren and Lawrence grade 3 by radiographic criteria Patients suitable for one of three conditions of 'diagnostic criteria for osteoarthritis of knee' based on ACR guideline Clinical and inspectional opinion Clinical and radiographic opinion Clinical opinion Patients who has joint pain ≥ 50 mm on 100 mm VAS at screening Patient who has WOMAC score ≥ 1000 at screening No improvement with persisting knee pain at least for 12 weeks (3 months) by non‐operational therapy before screening Exclusion criteria: Pregnant women or lactating mothers Patients with Body Mass Index (BMI) > 35 Patients with positive human immunodeficiency (HIV), hepatitis B (HBV), hepatitis C (HCV), syphilis at screening indicative of current of pass infection Patients with other disease including Septic arthritis, rheumatoid or inflammatory joint disease, gout, recurrent pseudogout, Paget disease, articular fractures, ochronosis, acromegaly, haemochromatosis, Wilson's disease, osteochondromatosis, hereditary disorder, genetic disorder of collagen Patients who are diagnosed with malignant tumour in the past or present Cardiac disorder (myocardial infarction, coronary artery bypass graft, arrhythmia and other severe cardiac disorder etc.) Resistant hypertension (systolic blood pressure > 160 mmHg or diastolic pressure > 100 mmHg at screening) Kidney disease (chronic renal failure, gomerulonephritis etc.) Liver disease (hepatocirrhosis, fatty liver, acute or chronic liver disease etc.) Endocrinopathy (thyroiditis, diabetes insipidus, Cushing disease etc.)
Interventions	JOINTSTEM autologous adipose tissue‐derived MSCs 1x10^8 cells/(saline), 1 time injection under ultrasonic guided Placebo: saline
Outcomes	Primary outcome measures: Arthroscopy (time frame: 48 Weeks). Change of damaged cartilage defects after 48 weeks from IP administration, compared to Baseline Secondary outcome measures WOMAC total score (time frame: 12 weeks, 24 weeks, 48 weeks). Change of WOMAC total scores from baseline WOMAC subscale score (time frame: 12 weeks, 24 weeks, 48 weeks). Change of WOMAC subscale score (3 sub‐scales: Pain, stiffness, and physical function of the knee) from baseline VAS score (time frame: 12 weeks, 24 weeks, 48 weeks). Change of VAS from baseline. Pain will be measured by the 100mm VAS Score range is from 0mm(no pain) to 100mm(severe pain) RAND‐36 (time frame: 12 weeks, 24 weeks, 48 weeks). Change of The RAND‐36 Measure of Health‐Related Quality of Life (RAND‐36) score from baseline, a high score defines a more favourable health state. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. The items in the same scale are averaged together to create the 8 scale scores. IKDC (time frame: 12 weeks, 24 weeks, 48 weeks). Change of International Knee Documentation Committee (IKDC) score from baseline. The IKDC is a patient‐completed tool, which contains sections on knee symptoms (7 items), function (2 items), and sports activities (2 items). Scores range from 0 points (lowest level of function or highest level of symptoms) to 100 points (highest level of function and lowest level of symptoms). Biopsy (time frame: 48 weeks). Change from baseline Use of rescue medication (time frame: 4 weeks, 12 weeks, 24 weeks, 48 weeks). Frequency and total amount of rescue medication administration will be measured. Kellgren‐Lawrence grade (time frame: 24 weeks, 48 weeks). Change from baseline in Kellgren‐Lawrence grade of knee osteoarthritis determined by X‐ray at Week 48
Starting date	29 March 2021
Contact information	CHANGMIN LEE, M.D., Ph.D. 055‐781‐9722 oschangmin@naver.com
Notes	Trial registration: NCT04821102 Status: not yet recruiting Estimated completion: December 2024

NCT04863183.

Study name	Cell Therapy for Patients With Symptomatic Knee Osteoarthritis: Phase I / II, Controlled, Randomized and Double‐blind Clinical Trial
Methods	Study design: 2‐arm, parallel randomised controlled trial Setting: Centro de Terapias Avanzadas Fundación Ofalmológica de Santander, Colombia Trial time period: June 2021 to June 2022 Intervention: stem cell injection versus triamcinolone acetonide injection Sample size: 30
Participants	Inclusion criteria: Osteoarthritis of the knee Kellgren II or III to knee radiography 30 to 75 years inclusive Pain scale greater than 40 over 100 mm MRI with G I, II or III chondral knee injury with or without stable degenerative meniscal injury Stable knee Examination of the rest of the normal limb Willingness to participate in the study for 1 year Ability to understand and willingness to sign the informed consent Exclusion criteria: Symptomatic contralateral knee osteoarthritis Significant knee trauma in the preceding 3 months Wound or skin lesion in the knee studied Anatomical valgus greater than 10º Anatomical varus greater than 5º Clinically significant joint effusion Oedema greater than 20% of the surface of the plateau or condyle in NMR Previously known alterations in the hip and / or spine Predominant patellofemoral pathology (radiographs with IWANO II osteoarthritis or more) Any type of inflammatory arthritis History of active infections including HIV, HBV and HCV Results of laboratory tests (haemogram and CRP) outside the normal ranges Presence of fever on day ‐1 or day 0 Use of oral corticosteroids Use of anticoagulants Immunosuppression, uncontrolled diabetes mellitus, hyperthyroidism, psychiatric illnesses Active neoplasia or during the preceding 5 years Pregnancy or breastfeeding (b‐Hcg positive) Use of drugs or alcoholism IA injections or knee surgeries in the last 180 days BMI > 35 Any type of metallic implant susceptible to displacement with MRI Use of pacemakers History of severe allergy or anaphylactic shock
Interventions	CELLISTEM‐OA: CELLISTEM‐OA via intra‐articular, doses of 2 x 106 mesenchymal stem cells in 5 cc of saline solution, one dose (zero time) Triamcinolone acetonide: triamcinolone acetonide (10 mg/mL) via intra‐articular, 5 cc, one dose (zero time)
Outcomes	Primary Outcome Measures : Decrease in joint pain (time frame: 12 months). Pain will be measured through visual analogue scale (VAS). Increased joint functionality (time frame: 12 months). Joint functionality will be measured through the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Improvement in the quality of life (time frame: 12 months). Quality of life will be measured through the Short Form 36 Health Survey Questionnaire (SF‐36). Imaging improvement of articular cartilage (time frame: 12 months). The improvement of articular cartilage will be evaluated by nuclear magnetic resonance (NMR).
Starting date	28 April 2021
Contact information	Martha L Arango, PhD (57) 3226816547 martha.arango@foscal.com.co
Notes	Trial registration: NCT04863183 Status: not yet recruiting Estimated completion: June 2022

NCT05027581.

Study name	A Phase IIb Study to Evaluate the Efficacy and Safety of Chondrochymal® for Subjects With Knee Osteoarthritis (Knee OA)
Methods	Study design: single‐centre, 2‐arm randomised controlled trial Setting: Taipei Veterans General Hospital, Taiwan Timing: September 2021 to September 2024 Interventions: intra‐articular injection of bone marrow‐derived mesenchymal cells versus hyaluronic acid injection Sample size: 70
Participants	Inclusion criteria: All genders aged 40 to 80 (inclusive) WOMAC pain score equals to or higher than 7 in the target knee Subject with unilateral/bilateral OA knee(s) of Kellgren‐Lawrence grading II‐IV, who is not suitable for or unwilling to undergo knee surgery (including total knee replacement) Pain of the target knee as assessed by Visual Analogue Scale (VAS) equals to or higher than 4 Body mass index (BMI) between 20 and 35 kg/m2 Has received conventional therapies for knee OA (e.g. analgesic administration or physical therapy) for more than 3 months but the symptoms have not relieved Exclusion criteria: With congenital or acquired bone hypoplasia (Varus more than 10° or Valgus more than 20°) Had any intra‐articular (IA) injection or surgery of the target knee within 3 months prior to screening, or had received any prior cell therapy on the target knee With severe knee osteoarthritis on the target knee who has decided to receive surgery (including total knee replacement) per surgeon's advice before screening With coagulation or haematological disorder not suitable for IA injection Administered or requiring systemic or topical on the target knee joint immunosuppressive agent, anti‐inflammatory drug, steroid, analgesics, opioid, or duloxetine for knee OA, except for acetaminophen (oral daily dose ≤ 2000 mg or topical use at any dose level), Etoricoxib (oral daily dose ≤ 120 mg or topical use at any dose level), and Celebrex (oral daily dose ≤ 200 mg or topical use at any dose level), within 1 week prior to screening. For long‐acting steroids (e.g., dexamethasone), a subject received systemic treatment within 2 weeks before screening will be excluded. A subject requiring routine use of low‐dose aspirin for preventing thrombosis (≤ 100 mg/day) will not be excluded from this study. With spontaneous knee osteonecrosis on either knee With crippled lower limb(s) rated ACR functional class IV (Largely or Wholly Incapacitated) or cannot walk without one/two arm(s)‐operated walking assisting device (defined by CNS15390) With effusion, bleeding, ligament instability, arthrochalasis, muscular or neurological diseases causing deformity of the knee joint, or any joint diseases other than OA on the target knee Active systemic infection or acute infection around the target knee joint
Interventions	Stem cell injection: Chondrochymal® group Subjects will be injected intra‐articularly at the target knee with 3 mL of Chondrochymal® containing 5.0 x 107 BM‐MSCs in lactated Ringer's solution at Day 1. HA injection: Hya‐Joint Plus Synovial Fluid Supplement Hya‐Joint Plus Synovial Fluid Supplement containing 60 mg/3 mL of hyaluronic acid will be IA administrated into the subject's target knee at Day 1.
Outcomes	Timepoints: 4, 12, 24, 36 and 52 weeks Primary outcome Change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score on the target knee at Week 24. For ease of interpretation, WOMAC scores (including total scores and sub‐scores) will be linearly transformed to a 0 to 100 scale. Secondary outcomes Change from baseline at each post‐treatment visit in total scores and sub‐scores of each section of WOMAC Change from baseline at each post‐treatment visit in VAS 0 to 10 pain scale Change from baseline at each post‐treatment visit in SF‐36 Change from baseline in MRI WORMS score assessment Change from baseline in joint space width Percentage of subjects using the rescue medication(s) during Visit 3 to Visit 7 and Visit 3 to Visit 8. Adverse events
Starting date	15 September 2021
Contact information	chun‐yao yang, PhD Taipei Veterans General Hospital, Taiwan Email: Cyrusyang@twbio‐thera.com
Notes	Trial registration: NCT05027581 registered on 19 August 2021 Funding: Taiwan Bio Therapeutics Co., Ltd. Status: recruiting Estimated completion date: 10 September 2024

NCT05081921.

Study name	A Randomized, Double Blind, Two Arms, Controlled Phase I/II Safety and Efficacy Study on MesoCellA‐Ortho Tissue Engineered Product Intraarticularly Administrated in Adult Patients With Osteoarthrosis
Methods	Study design: double‐blind, 2‐arm randomised controlled trial Setting: Poland Trial time period: May 2022 to December 2023 Interventions: human umbilical cord mesenchymal stem cells (MSCs) versus hyaluronic acid Sample size calculations: 200
Participants	Inclusion criteria: Knee cartilage lesions (osteoarthritis II/III grade in Kellgren‐Lawrence scale confirmed in X‐ray) Age between 40‐70 years (inclusive) No contraindications for liposuction No contraindications for the general use of biological treatment, stem cells, PRP and whole autologous blood Availability to take part into all study visits, barring unforeseen circumstances Able and willing to perform exercises at home given by a physiotherapist Contraceptive (birth control pills, injection, pessary or intrauterine device (IUD), spermicide condoms) The pain intensity in treated knee not lower than grade 3 (on 11‐point Numerical Rating Scale) Exclusion criteria: A history of cancer for 2 years before screening. In case of history of cancer medical above 2 years, consultation with oncologist and her/his permission for participation in clinical trial will be obligatory Pregnant or breastfeeding women Allergy or poor tolerance of hyaluronic acid Diabetes mellitus type 1, diabetes mellitus type 2 on insulin treatment Lack of medical consultation in case of patients with diabetes group Comorbidities significantly affecting overall health (e.g. history of myocardial infarction, heart failure, thrombophlebitis, arterial hypertension (hypertensive crises), chronic obstructive pulmonary disease, renal failure, liver failure, advanced atherosclerosis, psycho‐organic syndrome, hemiparesis, history of stroke) Current or medical history of the patient: inflammatory diseases of the joints (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative arthritis involving the spine joints, septic arthritis, prior diagnosis of target arthrosis with crystal precipitation or elevated CRP in the condition, inflammation), osteonecrosis, osteoporotic fractures or other painful joint diseases other than osteoarthritis; secondary causes of osteoarthritis (e.g. rheumatoid arthritis, fibromyalgia, birth defects)
Interventions	Experimental: MesoCellA‐Ortho ‐ treated Patients with type 2 diabetes and with obesity The patients with osteoarthritis of knee, suffering also with type 2 diabetes and obesity (BMI > 30) will be enrolled into this group and will be treated with MesoCellA‐Ortho (single intra‐articular application of 20 mL of AT‐MSCs resuspended in carrier solution mixed with hyaluronic acid) Active comparator: control patients with type 2 diabetes and obesity Patients with osteoarthritis of knee, suffering also with type 2 diabetes and obesity (BMI > 30) will be enrolled into this group and will be injected with hyaluronic acid (single intra‐articular application of HA) Experimental: MesoCellA‐Ortho ‐ treated patients without type 2 diabetes and with obesity The patients with osteoarthritis of knee, suffering also with obesity (BMI > 30), but with no type 2 diabetes will be enrolled into this group and will be treated with MesoCellA‐Ortho (single intra‐articular application of 20 mL of AT‐MSCs resuspended in carrier solution mixed with hyaluronic acid) Active comparator: control patients without type 2 diabetes and with obesity The patients with osteoarthritis of knee, suffering also with obesity (BMI > 30), but with no type 2 diabetes will be enrolled into this group and will be injected with hyaluronic acid (single intra‐articular application of HA) Experimental: MesoCellA‐Ortho ‐ treated patients without type 2 diabetes and without obesity The patients with osteoarthritis of knee, with no obesity (BMI < 30) nor type 2 diabetes will be enrolled into this group and will be treated with MesoCellA‐Ortho (single intra‐articular application of 20 mlL of AT‐MSCs resuspended in carrier solution mixed with hyaluronic acid) Active comparator: control patients without type 2 diabetes and without obesity The patients with osteoarthritis of knee, with no obesity (BMI < 30) nor type 2 diabetes will be enrolled into this group and will be injected with hyaluronic acid (single intra‐articular application of HA)
Outcomes	Primary outcomes VAS pain on 10‐point scale Evaluation the joint swelling during physical examination by a 4‐item scale: none, mild, moderate, severe Adverse events SF‐36 scores KOOS total and subscale (Pain, other Symptoms, Function in daily living (ADL), Function in Sport and Recreation (Sport/Rec), and knee‐related Quality of Life (QOL)) International Knee Documentation Committee (IKDC 2000) scale Secondary outcomes Cartilage morphology on MRI; T2 mapping; bone marrow oedema‐like lesions Range of motion Ultrasound of knee joint
Starting date	5 January 2022
Contact information	Jolanta Rajca, MS Galen Ortopedia, Poland Email: jolanta.rajca@galen.pl
Notes	Trial registration: NCT05081921 registered on 23 August 2021 Funding: Jagiellonian University, Poland Status: Recruiting Estimated completion date: December 2023

NCT05086939.

Study name	Multicenter Clinical Trial Comparing Treatment With Allogeneic Mesenchymal Cells Versus Autologous Mesenchymal Cells and Versus Active Control With Hyaluronic Acid in Patients With Knee Osteoarthritis. (ARTROCELL)
Methods	Study design: multicentre, randomised, open‐label clinical trial Setting: 3 centres in Spain Timing: May 2021 to December 2025 Interventions: allogeneic stem cell injection versus autologous stem cell injection versus hyaluronic acid injection Sample size: 120
Participants	Inclusion criteria: Gonarthrosis grade 2, 3 or 4 of Kellgren and Lawrence (Kellgren & Lawrence, 1957) assessed by two observers Chronic painful knee of mechanical characteristics Absence of local or systemic septic process Hematimetric and biochemical analysis without significant alterations that contraindicate the treatment Written informed consent of the patient The patient is able to understand the nature of the study Body Mass Index 20‐35 kg/m2 Exclusion criteria: Patient < 18 years old, or legally dependent Patient > 75 years old Congenital or developmental diseases that translate malformation and/or significant deformations of the knee (varus > 10º; valgus > 20º) and condition difficulties of application and evaluation of the results Pregnant or breastfeeding women Neoplastic disease Intra‐articular infiltration of any drug in the 3 months prior to study inclusion Concurrent participation in another clinical trial or treatment with another investigational product within 30 days prior to study enrolment Allergy to gentamicin (antibiotic used in the cell culture process) Other diseases or circumstances that compromise participation in the study according to medical criteria
Interventions	Stem cell injection: autologous mesenchymal stromal cells (MSC) Treatment with 40 millions of autologous autologous adult mesenchymal stem cells from expanded bone marrow administered intra‐articularly Stem cell injection: allogenic mesenchymal stromal cells (MSC) Treatment with 40 millions of adult allogeneic expanded bone marrow mesenchymal stem cells administered intra‐articularly HA injection: Hyaluronic acid 60 mg/3 mL administered intra‐articularly
Outcomes	Primary outcomes VAS pain on a 10‐point scale Functional response using Lequesne Algofunctional Index WOMAC total and subscale sores Range of motion X‐ray changes of osteoarthritis using K‐L classification MRI T2 mapping Secondary outcomes SF‐36 quality of life Adverse events Feasibility assessment of a multicentre strategy production of both cell types with several Cell Production Units Evaluation of cell populations (NK cells, B cells, regulatory T cells, myeloid suppressor cells, T cell populations) by flow cytometry, prior to administration of cell therapy, at 7 days and 30 days
Starting date	26 May 2021
Contact information	Fermín Sánchez‐Guijo Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León
Notes	Trial registration: NCT05086939 registered on 7 July 2021 Status: recruiting Estimated completion date: December 2025

NCT05182034.

Study name	A Multi‐center, Randomized, Double‐Blinded, Active‐Controlled, Phase II Clinical Trial to Evaluate Efficacy and Safety of SMUP‐IA‐01 in Patients With Knee Osteoarthritis
Methods	Study design: multicentre, 3‐arm, parallel, placebo‐controlled randomised trial Setting: Seoul National University Bandung Hospital, Korea Trial time period: February 2022 to August 2023 Interventions: mid‐dose stem cell injection versus low‐dose stem cell injection versus placebo injection Sample size calculations: 90
Participants	Inclusion criteria: Patients who are ≥ 19 years of age on the date on which the consent form was signed Patients diagnosed with knee osteoarthritis in at least one knee according to the clinical and radiological definition criteria of American College of Rheumatology (ACR) guideline at screening visit Patients with knee OA corresponding to K&L Grade 2 or 3 on radiographic examination at screening visit Patients with less than 35 of BMI at screening visit Patients who voluntarily decide to participate and sign the consent form Patients who have persistent symptoms despite having undergone a reasonable trial of standard therapy (i.e. for a minimum of 3 months) Exclusion criteria: Patients with any of the following diseases: infectious arthritis, autoimmune or inflammatory joint diseases, gout, recurrent pseudogout, Paget's disease, intra‐articular displaced fracture, ochronosis, acromegaly, haemochromatosis, Wilson's disease, genetic disease (hyperkinesia etc.), genetic collagen disorder, etc. Patients who have ever undergone surgery or radiotherapy in the knee joint area within the 12 weeks prior to the screening visit date, or who have not been recovered from its side effect yet Patients with SIF (Subchondral insufficiency fracture) corresponding to type II of the RPOA (rapidly progressive osteoarthritis) Patients whose physical examination results show severe degree of ligament instability Patients who have ever been given any intra‐articular drug injection (i.e. hyaluronic acid injection, etc.) in to‐be‐treated (index) knee within the 6 months, prior to the screening visit date Patients who have ever been given steroids via intra‐articular injection in to‐be‐treated (index) knee within the 12 weeks prior to the screening visit date Patients who have ever taken medications or given therapy below within the past 2 weeks on the basis of screening visit date. However, if patients have 14 days of wash‐out period, the patient is allowed to participate drugs containing the ingredient of glucosamine, chondroitin sulfate or diacerein drugs containing herbal ingredient or herbal drugs for knee OA pain relief anti‐inflammatory analgesics or NSAIDs (prescription/non‐prescription drugs). (However, patients who take acetaminophen and have 3 days of wash‐out period are allowed to participate.) oral steroids hospital physiotherapy or oriental medicine treatment (buhang, acupuncture, moxibustion etc.) Patients who have skin disease on injection site or who are judged inappropriate for intra‐articular injection on to‐be‐treated knee
Interventions	Stem cell injection (low dose) Investigational Product ‐ 4.0×10^6 cells/2 mL of SMUP‐IA‐01 (2 ml of 1% sodium hyaluronate injection is administered before administration of SMUP‐IA‐01) Stem cell injection (mid dose) Investigational Product ‐ 1.0×10^7 cells/2 mL of SMUP‐IA‐01 (2 ml of 1% sodium hyaluronate injection is administered before administration of SMUP‐IA‐01) HA injection Investigational Product ‐ 2 ml of 1% sodium hyaluronate (2 ml of sodium chloride injection is administered before administration of 1% sodium hyaluronate)
Outcomes	Time points: 1, 4, 8, 12, 24 and 52 weeks Primary outcome Change in the WOMAC (Western Ontario and McMaster University Osteoarthritis Index) total score at post‐dose 52 weeks Secondary outcomes Change from baseline in WOMAC total score at 24 weeks Change from baseline in WOMAC pain, stiffness, physical function subscale scores Change from baseline in VAS 100 mm pain scale Change from baseline in IKDC score Change in KL grade, joint space width in X‐rays Change in T2 mapping MRI assessment
Starting date	24 February 2022
Contact information	Name: Eunyoung Lee Seoul National University Bandung Hospital, Korea Email: ley0113@medi‐post.co.kr
Notes	Trial registration: NCT05182034 registered on 10 January 2022 Funding: Medipost Co Ltd. Status: recruiting Estimated study completion date: 30 August 2023

NCT05193877.

Study name	Autologous Bone Marrow Aspirate Concentrate Injection for the Treatment of Early Osteoarthritis: a Randomized Controlled Trial, Ibn‐Sina Hospital, Baghdad 2022
Methods	Study design: 2‐arm, parallel randomised controlled trial Setting: Ministry of Health, Baghdad, Iraq Trial time period: February 2022 to August 2023 Intervention: stem cell injection versus analgesics Sample size: 60
Participants	Inclusion criteria: Radiological diagnosis of osteoarthritis according to Kellgren and Lawrence criteria stage II‐III Radiological grading of osteoarthritis of the knee determined by qualified radiologist using MOAKS scoring system Primary osteoarthritis not responsive to conventional treatment and physiotherapy A minimum pain score of 5 on an 11‐point numerical scale Age > 55 year Exclusion criteria: Pregnancy and breastfeeding. Knee symptom due to other condition like tumours or referred pain from lumbar spine MRI confirmed displaced meniscal tear MRI confirmed Grade IV chondral loss. Previous knee surgery within the last 12 months Previous intra‐articular injectable therapies within the last 6 months History of severe systemic illness Active neoplasm under treatment in the last 12 months Health conditions including known allergy to local Bleeding tendency
Interventions	Autologous bone marrow aspirate concentrate Control group given analgesics only
Outcomes	Primary outcome: Clinical (time frame: 6 months): improvement in pain scale WOMAC Secondary outcome: Radiological proof (timeframe: 6 months to 1 year): MRI of the knee joint to monitor effect
Starting date	18 January 2022
Contact information	Dr Abdulmajeed hammadi +9647902268105 majeed51578@yahoo.co.uk
Notes	Trial registered: on 24 December 2021 Status: recruiting Estimated completion: August 2023

NCT05288725.

Study name	A Study to Evaluate the Safety, and Efficacy of Minimally Manipulated Autologous Bone Marrow Aspirate to Treat Knee Osteoarthritis in Patients
Methods	Study design: multicentre, double‐blinded, randomised controlled trial Setting: 3 centres in USA Trial time period: not reported Interventions: stem cell injection versus corticosteroid injections Sample size calculations: 120
Participants	Inclusion criteria: Individuals 18 to 80 years old with knee osteoarthritis X‐rays that demonstrate OA with the Kellgren‐Lawrence grading scale of 2, 3 or 4 in at least one compartment of the knee either or both knees. Only subjects that have a single symptomatic knee will be enroled. No significant Medial Collateral Ligament (MCL) or Lateral Collateral Ligament (LCL) tear or laxity No significant meniscal tear. (i.e. bucket handle) Exclusion criteria: Tibia on femur subluxation greater than 1 mm. Varus or valgus number greater than 9°. Intra‐articular injection to affected knee within 6 weeks of BMA injection Subjects who have had recent administration of intra‐articular injection (e.g. corticosteroid, viscosupplement, platelet‐rich plasma (PRP), or any other stem cell therapy) within the last 3 months prior to the experimental therapy Subjects who have had recent systemic (oral (PO), intravenous (IV) and/or intramuscular (IM) within 6 weeks of treatment) administration of corticosteroids; including subjects who are likely to need or who are currently on systemic steroids (e.g. asthma) Subjects with a BMI of > 40 and < 18 will be excluded Fever, active infection and ongoing infectious diseases, including HIV and hepatitis
Interventions	Stem cell injection: bone marrow‐derived MSCs Autologous bone marrow aspirate (BMA) is an orthobiologic injection used in knee osteoarthritis therapy. Bone marrow aspirate is harvested from the posterior superior iliac crest (PSIS) of the spine using the Marrow Cellutions kit. BMA will be injected into the knee using ultrasound guidance. Corticosteroid injection The corticosteroid is prepared in a 10 mL syringe by combining 1 to 2 mL Kenalog (40 mg/dL), 6 to 8 mL sterile normal saline, 3 to 4 mL ropivicaine 1%.
Outcomes	Timepoints: 3, 6 and 12 months Primary outcomes Change from baseline Western Ontario McMaster University Osteoarthritis Index (WOMAC) Change from baseline Visual Analog Score (VAS) MRI assessment of cartilage changes Secondary outcomes Change from baseline measure of Frailty Functional Testing Change from baseline measure of Fall Risk Functional Testing Change from baseline measure of Joint Specific Range of Motion Functional Testing Change from baseline measure of Obesity Functional Testing
Starting date	August 2022
Contact information	Michael A Scarpone, D.O. Next Generation Regenerative Medicine LLC
Notes	Trial registration: NCT05288725 registered on 15 February 2022 Status: not yet recruiting Estimated completion: June 2024

NCT05526001.

Study name	A Phase III, Randomized, Parallel, Double‐blinding, 2‐Arm Study to Investigate the Efficacy and Safety of Intra‐articular ELIXCYTE (Adipose‐Derived Stem Cells) Injection Compared With Placebo in Subjects With Knee Osteoarthritis
Methods	Study design: multicentre, double‐blinded, randomised placebo‐controlled trial Setting: Chang Gung Memorial Hospital, Taiwan Trial time period: not reported Interventions: stem cell injection versus placebo (saline) injection Sample size calculations: 165
Participants	Inclusion criteria Either gender, aged 40 to 80 With unilateral/bilateral knee OA of Kellgren‐Lawrence grading II‐III (determined by American College of Rheumatology criteria of knee OA) WOMAC pain score of 7 to 17 in the target knee even if treated with chronic doses of NSAID Has received conventional therapies for knee OA (e.g. analgesic administration or physical therapy) for more than 3 months but the symptoms have not relieved Unwilling or not suitable to undergo knee surgery (including total knee replacement and knee arthroplasty) Understands and has signed the informed consent form Exclusion criteria With previous surgery of articular fracture, ligament reconstruction, meniscal reconstruction and knee arthroplasty on the target knee joint With any IA intervention of the target knee within 3 months prior to screening (e.g. steroid, anaesthetic). But, sodium hyaluronate by IA intervention of the target knee within 6 months prior to screening. Administered systemic anti‐inflammatory drugs (e.g. non‐steroidal anti‐inflammatory drug or steroid) or topical anti‐inflammatory drugs on the target knee within 7 days prior to screening. A subject requiring routine use of low‐dose aspirin for preventing thrombosis (≤ 100 mg/day) will not be excluded from this study. Administered local immunosuppressive agent, local anti‐inflammatory drug, local steroid, local analgesics, over‐the‐counter medications contain analgesics, herbal, homeopathic, or naturopathic remedies for knee OA within 2 weeks prior to screening. Has participated in other investigational studies within 4 weeks prior to screening Administered monoamine oxidase inhibitor, selective serotonin reuptake inhibitor, serotonin‐norepinephrine reuptake inhibitors, benzodiazepine, or tricyclic antidepressants within 4 weeks prior to screening With joint diseases expect knee OA that is considered not eligible to enter the study by the investigator Systemic diseases that may affect joints, including but not limited to inflammatory joint diseases, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis Known or suspected infection around the target knee joint Has serious medical conditions or ongoing disease (e.g. concomitant illness such as cardiovascular (e.g. New York Heart Association grade III or IV), hepatic (e.g. Child‐Pugh Class C), psychiatric condition, alcoholism, drug abuse), medical history, physical findings, or laboratory abnormality that in the investigators' opinion could interfere with the results of the trial or adversely affect the safety of the subject With any evidence of malignant disease with a life expectancy less than 1 year
Interventions	Stem cell injection Subjects will be intra‐articular (IA) injected with 4 mL of ELIXCYTE (containing 32×10^6 ADSCs) at the target knee once Placebo injection Subjects will be intra‐articular (IA) injected with 4 mL of saline at the target knee once
Outcomes	Primary outcome Change of WOMAC pain score on the target knee Secondary outcome Percentage of pain responders (WOMAC pain score) WOMAC total and pain, stiffness, function subscale scores KOOS VAS pain KSS MRI WORMS Percentage of subjects using the rescue medication(s) Adverse events
Starting date	28 August 2022
Contact information	Yu‐Han Chang, MD Email: yhchang@cloud.cgmh.org.tw
Notes	Trial registration: NCT05526001 Funding: UnicoCell Biomed CO. LTD Estimated completion date: June 2026 Status: not yet recruiting

NCT05579665.

Study name	Effectiveness of PRP, Conditioned Medium UC‐MSCs Secretome and Hyaluronic Acid for the Treatment of Knee Osteoarthritis
Methods	Study design: single‐centre, parallel, 3‐arm, open‐label randomised controlled trial Setting: Dr. Moh Hoesin Central Hospital, Palembang, Indonesia Trial time period: October 2022 to March 2023 Interventions: stem cell injection versus hyaluronic acid injection versus PRP injection Sample size calculations: 45
Participants	Inclusion criteria Patients aged 30‐60 years Suffering from grade 2 and 3 osteoarthritis (OA) was identified by two observers who differed accordingly the Kellgren and Lawrence research scale Patient with knee pain that had been continuing for at least 12 months with no relief using anti‐inflammatory medications and that deteriorated with weight‐bearing Patients can understand the nature of the study and written informed consent is given to patients Exclusion criteria Age > 60 years Acute knee osteoarthritis effusions Patients are not willing to obey the study protocol There are signs of infection local or general infection or positive serology for HIV, hepatitis and syphilis There is a congenital disease that causes significant deformity of the knee can interfere with cell applications and interpret results Articular injection of the knee by any drug during the previous 3 months Participate in any clinical trial or treatment 30 days before the study Other conditions may, according to medical criteria, not support participation in this research (recent history of knee trauma, autoimmune rheumatic diseases, uncontrolled systemic diseases such as diabetes or hypertension, patient with immunosuppressive or anticoagulant treatment and cancer)
Interventions	Stem cell injection Conditioned medium from umbilical cord mesenchymal stem cell culture (MSCs) Secretome administered 5 times as an intra‐articular injection under ultrasound guidance as a series of once‐weekly injections to the affected knee. 1 weekly injections are conditioned medium from umbilical cord mesenchymal stem cell culture (MSCs) Secretome averaging 2 mL in volume. Platelet‐rich plasma (PRP) injection Platelet‐rich plasma administered 5 times as an intra‐articular injection under ultrasound guidance as a series of once‐weekly injections to the affected knee. 1 weekly injections are of leukocyte poor, buffer/additive free, singe spin, platelet‐rich plasma averaging 3 mL in volume. Hyaluronic acid (HA) injection Hyaluronic acid administered 5 times as an intra‐articular injection under ultrasound guidance as a series of once‐weekly injections to the affected knee. 1 weekly injections are of low molecular weight hyaluronan in a 2mL injection.
Outcomes	Timepoints: 3 and 6 months Primary outcomes VAS pain WOMAC total score and pain, stiffness, and physical functioning subscales Secondary outcome Cartilage oligomeric matrix protein (COMP)
Starting date	2 October 2022
Contact information	Radiyati U Partan, MD, Universitas Sriwijaya
Notes	Trial registration: NCT05579665 registered on 2 October 2022 Study completion date: 31 May 2023 Status: recruitment completed

NCT05660824.

Study name	Effectiveness of Stromal Vascular Fraction (SVF) and Platelets Rich Plasma (PRP) in Osteoarthritis and Tendinopathy (SPOT)
Methods	Study design: single‐centre, parallel, 2‐arm randomised controlled trial Setting: Hôpital de La Providence, Switzerland Trial time period: 2023 to 2025 Interventions: stem cell injection plus PRP versus PRP injection Sample size calculations: 195
Participants	Inclusion criteria: Informed consent as documented by signature (Appendix Informed Consent Form) Age older than 16 years old Symptomatic osteoarthritis of the hip, knee, ankle, elbow, shoulder confirmed by MRI or symptomatic tendinopathy confirmed by ultrasonography Failure of first‐line conservative management in the last 3 months, including medical or infiltrative treatment, orthotics use, active rehabilitation plan, adaptation of sports and work habits Exclusion criteria: Patient is familiar with the lipoaspiration process In case of tendinopathy: significant impingement according to investigator's judgement Subacromial impingement of the supraspinatus tendon, Haglund disease with erosion of the anterior part of Achilles tendon Significant disease of the contralateral member with a function evaluated with SANE score below 80% In case of osteoarthritis: microcristalline disease (i.e. gout, pseudogout) Active inflammatory rheumatic disorders Need of regular anti‐inflammatory treatment (either NSAIDs or corticosteroids) Allergy to local anaesthetics or epinephrine Bleeding disorders or current anticoagulation therapy Patients with decompensated renal failure, hepatic dysfunction, or severe pulmonary or cardiovascular disease Patients with an immunocompromised status Women who are pregnant or intend to become pregnant during the study
Interventions	Stem cell injection plus PRP injection PRP injection
Outcomes	Quick DASH, Low Extremity Functional Scale, Single Assessment Numeric Evaluation (SANE), VAS, WOMAC at 1, 2, 3, 6, and 12 months
Starting date	June 2023
Contact information	Adrien Schwitzguébel adrien.schwitzguebel@gmail.com
Notes	Trial registered on 24 January 2022. Last verified 21 December 2022 Status: not yet recruiting

NCT05783154.

Study name	Effect of Mesenchymal Stem Cells in Primary Knee Osteoarthritis
Methods	Study design: single‐blinded, parallel, 2‐arm randomised controlled trial Setting: Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh Trial time period: September 2022 to September 2024 Interventions: stem cell injection versus standard conventional care Sample size calculations: 84
Participants	Inclusion criteria Primary osteoarthritis of the target knee refractory to conventional treatment only Age between 40‐70 years All the genders Participants with knee pain who fulfil 2016 revised American College of Rheumatology (ACR) criteria for OA knee The Kellgren and Lawrence Grade ≥ 2 patients Pain score > 3 on VAS (0‐10 cm scale) Exclusion criteria Previous diagnosis of poly‐articular disease Severe mechanical extra‐articular deformation (>15° varus/15° valgus) Systemic auto‐immune rheumatic disease Arthroscopy or intra‐articular infiltration in the last 6 months Chronic treatment with Immunosuppressive or anticoagulant drugs Corticosteroids treatment in the 3 last months Non‐steroidal anti‐inflammatory drugs therapy in the last 15 days Poorly controlled diabetes mellitus, blood dyscrasias Septic or tubercular arthritis Recent trauma, fracture, and unstable knee joint
Interventions	Experimental: Stem cell injection In the interventional group, another 42 patients with primary KOA will receive adipose tissue‐derived mesenchymal stem cells (AT‐MSCs) injection intra‐articularly (Group‐2). However, group‐2 (Interventional group) will be subdivided into two subgroups, namely group‐2a, and group‐2b. A total of 21 participants of group‐2a will receive single doses of autologous adipose tissue‐derived stem cell (AT‐MSCs) and standard conservative care including rehabilitation for KOA. Whereas, group‐2b, 21 respondents will receive two doses of autologous adipose tissue‐derived stem cell (AT‐MSCs) at 3 months intervals along with standard conservative care including rehabilitation for KOA. Control group: standard conventional care 42 patients with primary KOA will receive standard conventional care including rehabilitation for knee osteoarthritis.
Outcomes	Timepoints: 1, 3, 6 and 12 months Primary outcomes Changes in the articular cartilage defect: MRI Osteoarthritis Knee score (MOAKS) Changes in femoral cartilage thickness using ultrasound Changes in VAS pain Changes in physical functioning: WOMAC physical function subscale Secondary outcome Adverse events
Starting date	16 September 2022
Contact information	Moshiur Rahman Khasru, MBBS, FCPS Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh Email: drkhasrupmr@bsmmu.edu.bd
Notes	Trial registration: NCT05783154 registered on 3 February 2023 Funding: Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh Status: recruiting Estimated completion date: 30 September 2024

NCT05933434.

Study name	Allogenic Mesenchymal Stem Cell Intraarticular Injection for Knee Osteoarthritis Therapy (STEMJOINT)
Methods	Study design: double‐blinded, parallel, 2‐arm randomised controlled trial Setting: Aarhus University Hospital Trial time period: not reported Interventions: allogenic mesenchymal stem cell injection versus placebo (saline) injection Sample size calculations: 80
Participants	Inclusion criteria: Chronic knee pain (defined for at least 6 months with NRS 4 or above when pain worst) Patients with Grade II‐III osteoarthritis according to the Kellgren Lawrence Classification and a joint width space of 1‐3 mm Axial hip, knee, ankle x‐ray with no more than 5 degrees valgus/varus deformity Medial, lateral or dual compartment OA as determined above BMI < 35 Danish speaker Patients must be legally competent and must be able to sign the written consent Exclusion criteria: Severe osteoarthritis (Grade IV according to Kellgren Lawrence classification) Intra‐articular tumour, infection or fracture Pregnancy and breastfeeding Cognitive impairment Treatment with cytostatic drugs Previous intraarticular knee injection in the past 3 months Unable to perform MRI scan (non‐compatible implants, claustrophobia and severe obesity(> BMI 35) Previous ligament reconstruction Meniscal operation with resection with more than 50% or multiple meniscal operations (more than one resection) Diabetes mellitus type 1 and 2 Knee instability and anterior‐posterior laxity of 3 mm or above on physical examination History of allergy to antibiotics Concomitant severe infection, malignant tumour, coagulation diseases or uncontrolled or unmanaged systemic disease Presence of other types of inflammatory arthritis
Interventions	Stem cell injection: single intra‐articular knee injection with allogenic adipose‐derived mesenchymal stem cells Placebo injection: single intra‐articular knee injection with saline
Outcomes	Timepoints: 3 months, 12 months, 24 months, 3 years, 4 years and 5 years Primary outcomes KOOS score Adverse events Secondary outcomes Change in pain from baseline on NRS MRI assessment of cartilage changes Effusion test by clinical examination Range of motion
Starting date	October 2023
Contact information	Rasmus Aabling, MD Aarhus University Hospital Email Address: rasaab@clin.au.dk
Notes	Trial registration: NCT05933434 registered on 5 June 2023 Status: not yet recruiting Estimated completion date: not reported

NCT05936060.

Study name	Cartilage Recovery in Adults With Knee Osteoarthritis by Mesenchymal Cell Therapy: Randomized Trial of Radiologic and Clinical Outcomes (INMUNOCEM‐OA)
Methods	Study design: double‐blind, parallel, 2‐arm, placebo‐controlled randomised trial Setting: Instituto Distrital de Ciencia, Biotecnología e Innovación en Salud, Colombia Trial time period: not reported Interventions: stem cell injection versus placebo (plasmalyte) injection Sample size calculations: 32
Participants	Inclusion criteria Pain most days for the last month. Presence of osteophytes Synovial fluid with mechanical characteristics Morning stiffness for less than 30 minutes in the affected joint Patellar crepitus Patients aged 40 years or older and less than 60 years Radiological criteria for osteoarthritis of the knee Kellgren‐Lawrence 2 to 4 in comparative radiographs with knee support taken in the last 12 months prior to consultation Pain in one or both knees according to a visual analogue scale of 5 or more, out of 10 points in the last 3 months Exclusion criteria Consumption of non‐steroidal anti‐inflammatory drugs or anticoagulants in the last 14 days History of joint infiltration or arthroscopic surgery of the affected knee in the last 6 months Participants in another treatment or research study within the past year Pregnant or lactating patients Active tumour pathology or a history of oncological disease Metabolic disease or uncontrolled coagulopathy at the assessment time Patients who have received previous treatments such as microfractures, and osteochondral allografts Patients with present meniscal lesions. Patients with a history of thyroiditis or thyroid nodules with increased antithyroglobulin antibodies. Patients with a history of osteoarticular infection in the last 5 years or active at the time of assessment
Interventions	Stem cell injection Administration of umbilical cord‐derived mesenchymal stromal cell suspension Placebo injection Plasmalyte used as a vehicle for stem cell suspension
Outcomes	Timepoints: 1, 3, 6, 12 and 24 months Primary outcomes Change from baseline in VAS pain Change from baseline in KOOS total and subscale scores Radiological changes in magnetic resonance observation of cartilage repair tissue (MOCART 2.0)
Starting date	1 October 2023
Contact information	Gustavo Salguero, Instituto Distrital de Ciencia, Biotecnología e Innovación en Salud, Colombia
Notes	Trial registration: NCT05936060 registered on 16 June 2023 Funding: Gustavo Salguero, Instituto Distrital de Ciencia, Biotecnología e Innovación en Salud, Colombia Estimated completion date: July 2026 Status: not yet recruiting

NCT05996224.

Study name	Allogenic Adipose‐Derived Mesenchymal Progenitor Cells for the Treatment of Knee Osteoarthritis
Methods	Study design: multicentre, double‐blind, randomised controlled trial Setting: sports medicine clinic, Australia Trial time period: October 2023 to December 2027 Interventions: stem cell injection versus sodium hyaluronate injections Sample size calculations: 488
Participants	Inclusion criteria: Subjects who understand and voluntarily sign the consent form before this study According to the diagnostic criteria (American Rheumatology Association, clinical + radiology criteria), patients with knee osteoarthritis are definitely diagnosed Age: 40‐75, males and females The course of knee osteoarthritis was more than 6 months The subjects' WOMAC score was 24‐72, and the WOMAC pain score was 7‐17 (the WOMAC score at least 48 hours after discontinuation of all painkillers) The Kellgren Lawrence grade (X‐ray axial position of knee joint) of subjects was grade II/III Subjects are generally in good condition and can walk autonomously, except for those who use wheelchairs, walking aids or crutches Exclusion criteria: The subject may be allergic to the main cell preparation components (B vitamins, amino acids and so on) The subject received systemic and/or local treatment with autologous and/or allogeneic mesenchymal progenitor cells. The subject has a BMI of over 30 Laboratory test (any item meets): neutrophil absolute number < 1.0 × 10^9/L, platelet count < 50 × 10^9/L, serum albumin < 30g/L, serum creatinine > upper limit of 1.2 times normal value range, total bilirubin, alanine aminotransferase, aspartate aminotransferase > upper limit of 2 times of normal value range The subject has diseases or symptoms may affect VAS, WOMAC and so on The subject has serious and poorly controlled concomitant diseases, such as (but not limited to) nervous system, cardiovascular, liver, kidney, gastrointestinal and endocrine diseases, which may prevent the subjects from participating in the study according to the judgment of the researchers The subject has an history malignant tumour The subject has connective tissue disease or rheumatoid arthritis, chondropathy, Chondrocalcinosis articularis, Hemochromatosis, inflammatory arthropathy, avascular necrosis of femoral head, Paget's disease, haemophilic arthropathy, infectional arthritis, Charcot's disease, villonodular synovitis or synovial chondromatosis. The subject has severe generalised infectious diseases or local knee infection (including skin and intra‐articular infection) in the 3 months prior to this trial
Interventions	Stem cell injection: allogenic sdipose tissue‐derived mesenchymal progenitor cells administrated for intra‐articular use Sodium hyaluronate injection
Outcomes	Primary outcome WOMAC total score at 6 months Secondary outcomes Time Frame: 4, 12, 24, 36, 48, 60, 72, 84, 96 weeks WOMAC total score VAS pain Minimum joint space width (mJSW) of the knee MRI quantitative analysis of articular cartilage Adverse events
Starting date	October 2023
Contact information	Chunde Bao Department of Rheumatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Email: xck@renji.com
Notes	Trial registration: NCT05996224 registered on 18 August 2023 Estimated completion date: December 2027 Status: recruiting

NCT06084637.

Study name	Randomized Control Trial Comparison Between Intra‐articular Infiltrations of PRP, MFAT, and PRP‐MFAT in the Treatment of Symptomatic Knee Osteoarthritis.
Methods	Study design: single‐centre, 3‐arm parallel randomised controlled trial Setting: Assistance Publique Hopitaux De Marseille, France Trial time period: 2 February 2024 to 1 February 2027 Interventions: stem cell injection versus PRP injection versus stem cell injection plus PRP injection Sample size calculations: 180
Participants	Inclusion criteria Patients of both genders, between 20 and 75 years old Symptomatics degenerative or post‐traumatic chondropathy, on at least one of the 3 knee compartments ICRS grade 2, 3 or 4 with VAS > 4 and failure of well‐conducted medical treatment for at least 1 year Varus or valgus less than or equal to 5° BMI greater than 20 (in order to have sufficient fatty tissue) Informed consent signed by the patient HB > 10 g/dL Negative beta‐HCG at inclusion and effective contraception for patients of childbearing age, for 1 month Beneficiaries of or affiliated to a social security system Exclusion criteria Contraindications to MRI : ocular foreign bodies, pacemaker, neurostimulator, cochlear implant, vascular clips, metallic heart valve Body mass index (BMI) of less than 20 kg/m2 does not allow obtaining a sufficient quantity of adipose tissue Thrombocytopenia < 150 G/L Thrombocytosis > 450 G/L Known thrombopathy PT: PR < 70% APTT: PTR > 1.20s Anaemia HB < 10 g/dL Positive markers for the following active infectious diseases: HIV 1 and HIV 2 human immunodeficiency virus infection; HTLV I and II virus infection; hepatitis B virus infection; hepatitis C virus infection; syphilis causative agent infection Use of antiplatelet agents, aspirin, anti‐vitamin K drugs for less than 15 days Chronic treatment with oral corticosteroids or the use of such treatment less than 2 weeks prior to inclusion Intra‐articular corticosteroid injection less than 2 months prior to inclusion Intra‐articular injection of hyaluronic acid less than 2 months prior to inclusion Non‐steroidal anti‐inflammatory drugs less than 15 days prior to inclusion Recent fever or infection (bacterial or viral) less than one month old Autoimmune diseases Inflammatory arthritis Immune deficiency Ongoing or chronic infectious diseases (viral or bacterial) T Malignant tumours or history of malignant tumours less than 5 years prior to inclusion Pregnant or lactating women
Interventions	Intra‐articular injection of autologous microfat Intra‐articular injection of autologous platelet‐rich plasma Intra‐articular injection of autologous microfat and platelet‐rich plasma
Outcomes	VAS, KOOS, proportion of treatment failures at 1, 3, 6 and 12 months
Starting date	2 February 2024
Contact information	Alexandre ROCHWERGER, Pr richardalexandre.rochwerger@ap‐hm.fr
Notes	Trial registered on 10 October 2023 Status: not yet recruiting

RBR‐7qjcdd.

Study name	START Trial: Randomised, controlled, open and parallel trial to evaluate the efficiency and safety of intra‐articular infiltration of Autologous Bone Marrow Concentrate (BMC) or Mesenchymal Stem Cell (MSC) associated with Platelet Rich Plasma (PRP) in patients with primary knee osteoarthritis
Methods	Study design: randomised, controlled, open and parallel trial Setting: Brazil Trial time period: not reported Interventions: bone marrow stem cell injection plus PRP injection versus mesenchymal stem cell injection plus PRP injection versus PRP injection versus HA injection Sample size calculations: 256
Participants	Inclusion criteria Adults aged between 49 and 75 years old Clinical and radiological diagnosis of primary knee osteoarthritis with lesion of mild to moderate intensity (II and III) based on the classification criteria of the AmericanCollege of Rheumatology with radiological confirmation following a Kellgren and Laurence scale History of knee oedema, pain, stiffness, gait alteration and loss of movement due to the degenerative joint process Availability of follow‐up during the study period Have provided written voluntary consent to participate in the study, confirmed by the signature of Informed Consent Form Exclusion criteria BMI greater than or equal to 35 Being a carrier of other joint diseases or joint trauma, autoimmune diseases or have been subjected to the use of disease‐modifying drugs or intra‐articular medication in the last 6 months Evidence of secondary osteoarthrosis or with a history of other diseases in the articulation study, such as fractures, neoplasms, primary haematological disease, autoimmune, rheumatologic, neurological disease History of acute or chronic communicable diseases, including B hepatitis History of bone or cartilaginous disorders Diagnosis of type I or type II diabetes, poorly controlled Diagnosis of hip arthrosis through alteration in the physical examination or report with radiographic changes in the hip of the same side or contralateral Evidence of active infection or history of infection in the joint to be infiltrated in this study Any disease that affects the contralateral lower limb, such as consequence of OA of the knee Deviation of the axial axis varus of 10 degrees or 15 degrees in valgus or discrepancy greater than 2.5 cm diagnosed by panoramic radiographic examination of lower limbs Comorbidity that the physician considers as a contraindication for the infiltration of autologous stem cells Contraindication to aspiration of the bone marrow (severe coagulopathy, skin infection in the area of the posterior iliac crest) Chronic treatment with anticoagulant or immunosuppressive drugs, except AAS 100 mg Use of a systemic corticosteroid in the last 3 months Use of nonsteroidal anti‐inflammatory drugs in the last 15 days Change in the use of oral chondroprotection continued for less than 3 months Previous surgery (at any time) of the affected knee or orthopaedic surgery of lower limbs in the last 12 months Present renal and hepatic functions out of normality Hypersensitivity to any investigational product Other clinical conditions which may, according to medical criteria, discourage participation in the study Pregnant or otherwise pregnant women who do not use contraceptives Development of clinical conditions that compromise the response to questionnaire and that may influence the results of the study
Interventions	Group 1 (HA): 64 individuals who will receive a single intra‐articular infiltration of hyaluronic acid (Synvisc One ‐ 6 mL) and follow ‐ up periods of 12 months Group 2 (PRP): from 64 individuals will be collected 15 mL of blood and processed in the laboratory to form the substance called platelet‐rich plasma (PRP). This concentrate will be injected into the knee with pain, in three applications with intervals of one week between each, in addition to a follow‐up period of 12 months. Group 3 (bone marrow stem cell + PRP): approximately 100 mL of cells will be collected from within the basin bone under local anaesthesia and injected into the knee. In this group, 15 mL of blood will also be collected and processed in the laboratory to obtain platelet‐rich plasma. In the first application, cells and platelets will be injected, followed by two more applications of platelet‐rich plasma, with a one‐week interval between each application. Group 4 (mesenchymal stem cell + PRP): approximately 100 mL of cells will be collected from within the basin bone under local anaesthesia and injected into the knee. In this group, 15 mL of blood will also be collected and processed in the laboratory to obtain platelet‐rich plasma. In the first application, cells and platelets will be injected, followed by two more applications of platelet‐rich plasma, with a one‐week interval between each application.
Outcomes	Primary outcomes Pain, stiffness, level of physical activity, development of knee osteoarthritis and the efficacy of the investigational products at 12 months Secondary outcomes Serious and non‐serious adverse events
Starting date	18 January 2019
Contact information	Teresa Cristina Campos Mello Address: Rua Lourenço Marques, 158 10 andar 04547‐100, São Paulo, Brazil Email: teresa.mello@preventsenior.com.br
Notes	Trial registration: 07 June 2019 Trial status: recruiting Estimated study completion date: not reported

TCTR20230929002.

Study name	A comparative study between adipocyte‐derived mesenchymal stem cell versus intra‐articular hyaluronic acid interventions in early osteoarthritis: Prospective Randomized Open, Blinded End‐point
Methods	Study design: randomised, controlled, parallel trial Setting: Suranaree University of Technology, Thailand Trial time period: 12 October 2022 to 27 May 2023 Interventions: adipocyte‐derived mesenchymal stem cells (ADSCs) injection versus hyaluronic acid injection Sample size calculations: 44
Participants	Inclusion criteria: Patients with symptomatic knee osteoarthritis at Kellgren & Lawrence stage II who discontinued the use of nonsteroidal anti‐inflammatory drugs (NSAIDs) for at least 2 weeks Exclusion criteria: 1. Patients with secondary osteoarthritis 2. Patients with a history of significant trauma, such as fractures of the knee and malformation of the bones 3. Patients with cancer 4. Patients with swollen, red or hot knees 5. Patients experiencing worsening pain or side effects from the procedure 6. Patients with diabetes (DM), immunocompromised conditions 7. Patients who have previously received stem cell therapy 8. Patients with abnormal blood clotting or taking anticoagulant medications 9. Pregnant women and breastfeeding mothers
Interventions	Adipocyte‐derived mesenchymal stem cells (ADSCs) Hyaluronic acid
Outcomes	WOMAC, MRI ultrasound at 1, 3, 6 months
Starting date	12 October 2022
Contact information	Ponthep Tangkanjanavelukul pornthep@sut.ac.th
Notes	Trial registered: 28 September 2023 Status: recruitment completed Estimated completion: 27 May 2023

Abbreviations: AAS: acetylsalicylic acid; ACR: American College of Rheumatology; ADL: activities of daily living; AE: adverse events; ALT: alanine aminotransferase; APTT: activated partial thromboplastin time; AQOL: Assessment of Quality of Life; AST: aspartate aminotransferase; BMAC: bone marrow aspirate concentrate; BMC: bone marrow concentrate; BMI: body mass index; BML: bone marrow lesion; BMP: bone morphogenetic protein; CTCAE: Common Terminology Criteria for Adverse Events (CTCAE) classification of AE; CVA: cerebrovascular accident; ECG: electrocardiogram; G‐CSF: granulocyte colony stimulating factor; HA: hyaluronic acid; haMPC: human adipose‐derived mesenchymal progenitor cells; HB: haemoglobin; HBV: hepatitis C virus; HCV: hepatitis C virus; Hep: hepatitis; HTLV: human T‐cell leukaemia virus; IA: intra‐articular; ICOAP: Intermittent and Constant Osteoarthritis Pain; ICRS: International Cartilage Repair Society; IKDC: International Knee Documentation Committee; INR: international normalised ratio; IQR: interquartile range; K‐L: Kellgren‐Lawrence (grade); KOOS: Knee Injury and Osteoarthritis Outcome Score; KSFS: Knee Society Function Score; KSS: Knee Society Score; LCL: lateral collateral ligament; MCL: medial collateral ligament; MOAKS: MRI Osteoarthritis Knee Score; MOS: Medical Outcomes Study; MRI: magnetic resonance imaging; MSC: mesenchymal stem cells; NMR: nuclear magnetic resonance; NRS: numerical rating scale; NSAID: non‐steroidal anti‐inflammatory drug; OA: osteoarthritis; PR: prothrombin ratio; PRP: platelet‐rich plasma; PT: prothrombin time; PTR: prothrombin time ratio; QOL: quality of life; RAND‐36: RAND‐36 Measure of Health‐Related Quality of Life; ROM: range of motion; SAE: serious adverse events; SVF: stromal vascular fraction; UC‐MSC: umbilical cord mesenchymal stem cells; URTI: upper respiratory tract infection; VAS: visual analogue scale; VDRL: Venereal Disease Research Laboratory ; VSEL: very small embryonic‐like stem cells; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; WORMS: Whole‐Organ Magnetic Resonance Imaging Score

Differences between protocol and review

We have edited the Objectives to remove explicit mention of the outcomes of interest and to state that a secondary objective is to maintain this as a living systematic review.

No results from studies published as an abstract only, unpublished data or ongoing studies were included in the data syntheses. We have not contacted the authors of these publications for this version of the review, on the basis that they may become available in future updates of this living review.

We did not anticipate identifying trials with a no treatment or usual care control group, but we did identify two studies (Freitag 2019; Ren 2023); we therefore included the results for completeness and added a comparator: no treatment including control (described specifically as no intervention, or no other description provided by the trial authors); usual or normal care (participants could receive normal care, but this was not controlled by trial); wait list (no other description provided by the trial authors). We also clarified that we included trials that assessed stem cell injection as an adjunct to another intra‐articular therapy; thus, we included trials where participants in the stem cell and comparison groups were offered or received the same injectable intra‐articular co‐intervention, allowing the effect of the stem cell treatment to be isolated.

We updated the description of permitted co‐interventions to avoid confusion. We added an additional comparison (Comparison 8) ("Stem cell and comparison groups were offered, or received, the same additional injected intra‐articular therapy, allowing the effect of the stem cell treatment to be isolated") and we simplified the co‐interventions section to remove reference to "blood products or other bioactive carriers". Similarly, reference to co‐intervention with blood products or bioactive carriers was removed from the "Main planned comparisons" as this form of co‐intervention was now included in Comparison 8.

We updated the timing of outcome assessment to include participant‐reported global assessment of success (data extracted at the end of the trial period).

The frequency of running update searches has changed from monthly to quarterly. This reflects a more realistic timeframe for the accumulation of new studies to impact the review's findings.

Instead of applying a methodological filter for randomised trials for the MEDLINE and Embase search, we had planned to use the machine learning RCT classifier to remove ineligible records before screening. Since the RCT classifier was not implemented in Covidence until after the search was run, we thus opted to use a methodological filter.

We performed assessment of risk of bias in pairs drawn from three review authors (SC, JZ, TB) rather than the planned pair of authors (SW, RJ). Authors SW and RJ checked the risk of bias assessment against the trial report and resolved any disagreements.

We updated the methods used in Measures of treatment effect as follows:

• We removed: "In the 'Comments' column of the 'Summary of findings' table, we will report the absolute per cent difference, the relative per cent change from baseline, and for outcomes that show a clinically important difference between treatment groups, we will report the number needed to treat for an additional beneficial outcome (NNTB), or number needed to treat for an additional harmful outcome (NNTH). For dichotomous outcomes, we will calculate the NNTB or NNTH from the control group event rate and the relative risk using the Visual Rx NNT calculator (Cates 2008). The NNTB for continuous measures will be calculated using the Wells calculator (available at the Cochrane Musculoskeletal editorial office, musculoskeletal.cochrane.org/)."

• We removed additional detail regarding risk ratios, including "The relative per cent change will be calculated as the Risk Ratio‐1 and expressed as a percentage."

• We removed: "For continuous outcomes, we will calculate the absolute per cent change by dividing the mean difference by the scale of the measure and expressing this as a percentage. The relative difference will be calculated as the absolute benefit (mean difference) divided by the baseline mean of the control group, and expressed as a percentage." Instead, to improve the interpretability of the results, we estimated the control group risk using the mean value from a representative study (combination of the most representative study population and a large weighting in the overall result in RevMan). We calculated the corresponding intervention group risk by adding or subtracting the mean difference from the control group risk.

• We added detail regarding methods when different measures were used for the same outcome, as follows: "Where trials used different measures for the same outcome or concept, we used the reported outcome measure that was the highest in our hierarchy as an index measure (Guyatt 2013). We transformed means and standard deviations (SDs) of other outcome measures to the scale of the index instrument and pooled the data using MD as the summary estimate. For pain, we assumed the 0 to 10 visual analogue scale (zero represented no pain) as the index instrument. For function, we indexed the WOMAC disability subscale (normalised to a 0 to 100, where 0 represents best function)."

• We added detail regarding the reporting of outcomes in the summary of findings tables: "For each outcome, we reported the risks of events (for dichotomous data) or means (for continuous data) for all the intervention and comparison groups and the difference between groups in the summary of findings tables."

We restricted the sensitivity analyses to the primary comparison (stem cell injection versus placebo injection) for pain and function at the primary time point rather than including all major outcomes or including glucocorticoid injection as an additional comparator.

We did not calculate or report numbers needed to treat for benefit (NNTB) or harm (NNTH) in the 'Comments' section of the summary of findings tables as there was very low‐certainty evidence for all dichotomous outcomes.

Contributions of authors

SW: conception and design of the review; co‐ordination of the review; selection of studies for inclusion in the review; arbitration during data extraction and assessment of the risk of bias; data analysis; assessment of the certainty of the body of evidence; interpretation of the results; and writing of the review.

RJ: design of the review; co‐ordination of the review; selection of studies for inclusion in the review; arbitration during data extraction and assessment of the risk of bias; data analysis; assessment of the certainty of the body of evidence; interpretation of the results; and writing of the review.

SM: designed the database search strategies and conducted the search; reporting of the search results.

DW: design of the review; interpretation of the results; and editing of the review.

TC: design of the review; interpretation of the results; and editing of the review.

SC: data extraction; assessment of the risk of bias; data analysis; and reporting the results.

TB: data extraction; assessment of the risk of bias; and editing of the review.

JZ: data extraction; assessment of the risk of bias; and editing of the review.

RB: conception and design of the review; arbitration during study selection and assessment of the certainty of the evidence; interpretation of the results; writing of the review; and acting as guarantor for the review.

Sources of support

Internal sources

• School of Public Health and Preventive Medicine, Monash University, Australia

  In‐kind support (authors: S Whittle, R Johnston, S Cyril, T Bapna, J Zhang, R Buchbinder)

External sources

• Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trial Network NHMRC Centre of Research Excellence, Australia

  S Whittle is supported, in part, by an Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trial Network Practitioner Fellowship. The funder had no role in the design, conduct or publication of the review.

• The Hospital Research Foundation Group, South Australia, Australia

  S Whittle is supported, in part, by The Hospital Research Foundation Group, which provides part funding for his ANZMUSC Practitioner Fellowship. The funder had no role in the design, conduct or publication of the review.

• National Health and Medical Research Council (NHMRC), Other

  NHMRC Cochrane Collaboration Round 7 Funding Program Grant to R Johnston, R Buchbinder and S McDonald, to support the activities of Cochrane Musculoskeletal ‐ Australia and Cochrane Australia. The funders had no role in the design, conduct or publication of this review.

• National Health and Medical Research Council, Australia

  R Buchbinder is supported by an Australian National Health and Medical Research Council Investigator Lead 3 Fellowship. The funder had no role in the design, conduct or publication of the review.

Declarations of interest

Renea Johnston, Rachelle Buchbinder and Steve McDonald are recipients of a National Health and Medical Research Council Cochrane Collaboration Round 7 Funding Program Grant, which supports the activities of Cochrane Musculoskeletal ‐ Australia and Cochrane Australia, but the funders did not participate in the conduct of this review.

Tanay Bapna is a medical student at Monash University.

Rachelle Buchbinder is a Rheumatologist (adult) and the Co‐ordinating Editor of Cochrane Musculoskeletal. She was not involved in the editorial process for this review. RB declares royalties for a book chapter on plantar fasciitis.

Mark Campbell is a health professional and conducts clinical work at Bruyere Continuing Care, Ottawa, Canada. His clinical activities include treating patients with osteoarthritis; however, stem cell use for osteoarthritis has never been a part of his practice.

Sheila Cyril is the Assistant Managing Editor of Cochrane Musculoskeletal. She was not involved in the editorial process for this review.

Renea Johnston is the Managing Editor of Cochrane Musculoskeletal. She was not involved in the editorial process for this review.

Steve McDonald is Co‐Director of Cochrane Australia and an Information Specialist with the Cochrane Central Editorial Service. He was not involved in the editorial process for this review.

Samuel Whittle is a Senior Consultant Rheumatologist at The Queen Elizabeth Hospital, Vice President of the Australian Rheumatology Association and a Cochrane Musculoskeletal Editor. He was not involved in the editorial process for this review.

Daniel Worthley declares a patent for osteochondroreticular stem cells for bone and cartilage regeneration (US‐20170335283‐A1), which is held by his previous institution.

Jason Zhang declares that he has no conflicts of interest.

Edited (no change to conclusions)