. 2022 Feb 9;26:101804. doi: 10.1016/j.jcot.2022.101804

Table 2.

Summary of studies using Allogenic stem cell therapy in OA. Note that studies published in last five years have been included in the table. AQoL-4D - assessment of quality of life 4D questionnaire; Allo – allogeneic; BMAC – bone marrow aspirate concentrate; BMMSC- bone marrow derived Mesenchymal stromal cells; C2C - type II collagen C2C peptide; CTX – 1 - C-terminal telopeptide of type I collagen; CTX – II – C-terminal telopeptide of type II collagen; HA - hyaluronic acid; HKA, hip-knee-ankle; HTO – High Tibial Osteotomy; ICOAP - Intermittent and Constant Osteoarthritis Pain; ICRS - International Cartilage Repair Society Cartilage Injury Evaluation Package; IKDC - International Knee Documentation Committee subjective knee evaluation form; KL grade – Kellgren and Lawrence grade; KOOS - Knee Injury and Osteoarthritis Outcome Scores; KSS - Knee Society clinical rating system; MIF - macrophage migration inhibitory factor; MOAKS – MRI Osteoarthritis Knee Score; MOCART - Magnetic Resonance Observation of Cartilage Repair Tissue; MCS – Mesenchymal cell stimulation; MRI - magnetic resonance imaging; NA, not available OA – Osteoarthritis; RCT – randomized controlled trial; ROM – range of motion; SAE – Serious adverse event; SF-36- Short Form-36 quality of life questionnaire; SUSAR – suspected unexpected serious adverse reaction; TEAE – Treatment Emergent Adverse Event; UC-MSC – Umbilical cord derived MSC; VAS – visual analog pain score; WOMAC - Western Ontario and McMaster Universities Osteoarthritis Index; WORMS – Whole Organ Magnetic Resonance Imaging Score.

Author/Year	Sample size	Study design	Grade of OA	Treatment group- Cell type & dose	Control group	Outcome measures	Follow up period	Outcomes
Vega/2015⁵⁶	30	RCT. Multicentric, phase I/II study	KL grade 2 to 4	Allo-BMMSC 40 × 10⁶ cells	N = 15 intra-articular Hyaluronic Acid (HA) (60 mg, single dose)	Pain, disability, and quality of life. Articular cartilage quality was assessed by quantitative MRI T2 mapping	1 year	Significant improvement in algofunctional indices in treatment group versus the active controls treated with hyaluronic acid. MRI T2 mapping-significant decrease in poor cartilage areas, with cartilage quality improvements in MSC-treated patients.
Gupta PK/2016⁴⁶	60	Double-blind, phase II, RCT	KL grade 2 or 3	Allo-BMMSC + HA, four doses– 25, 50, 75, 150 × 10⁶ cells	N = 20 (placebo + HA)	Safety, VAS, ICOAP, WOMAC scores. MRI- WORMS score	24 months	Safety established. AE were predominant in the higher dose groups. VAS, ICOAP, WOMAC scores best in the lowest dose. MRI– no significant difference
Wang/2016⁵⁷	18	RCT	Moderate or severe degenerative knee OA	I/A injection of 2.5–3.0 mL HUC MSCs suspension containing (2–3) × 10⁷ cells -once a month for 2 times	Sodium hyaluronate IA injection- once a week for 5 times	SF-36 scale score, Lysholm score, and WOMAC score.	6 months	Significant improvement in joint function and quality of life with use of IA injection of HUC MSCs. It takes effect after 1 month and the treatment effect can be sustained for 6 months.
de Windt TS/2017⁴⁷	10	Phase I/II single centre study	Modified Outerbridge- Grade 3 or 4	Allo BMMSCs +10 or 20% autologous chondrons	Nil	Safety, KOOS, VAS, MRI, Second look arthroscopy, and histology	12 months	No SUSAR. KOOS & VAS scores improved significantly. MRI – complete filling of the defect. Arthroscopy - effective defect fill, and integration in the surrounding tissue. Histology - positive staining for both type I, type II collagen & proteoglycan
Park YB/2017⁵³	7	Open-label, single arm, Phase I/II	KL grade 3 and ICRS grade 4	Two doses; allo hUCB _MSCs and HA hydrogel	Nil	ICRS cartilage repair, VAS, IKDC, MRI, Histological findings	7 years	VAS & IKDC improved at 24 weeks & stable till 7 years, Histology at 1 year showed hyaline-like cartilage, MRI at 3 years showed the persistence of regenerated cartilage.
Kuah D/2018⁴⁹	20	RCT, double-blind, Placebo-controlled	KL grade 1 to 3	Randomized 4:1; Progenza (PRG) (Allo AD MSC + culture supernatant); 2 groups – 8 pts each – 3.9 or 6.7 million cells	4 patients, placebo administered	Safety, WOMAC, VAS, AQoL-4D, Biomarkers: urine– C2C & CTX – II, serum - MIF & CTX-I, MRI– MOAKS score	12 months	All patients experienced at least one TEAE, VAS & WOMAC - statistically significant within-group reduction from baseline in PRG group, no statistically significant differences at any time point between placebo and PRG groups, MRI - no decrease in lateral tibial cartilage volume while the placebo group showed a statistically significant cartilage loss
Matas J/2018⁵²	29	Phase I/II RCT, triple _blind trial	KL grade 1 to 3	Allo UC-MSC, single (20 × 10⁶) or repeat dose (20 × 10⁶- baseline & 6 months), 10 pts each.	9 patients, HA (baseline & 6 months)	VAS, WOMAC, MRI– WORMS score	12 months	No SAEs. Repeat dose group had a significant decrease in VAS & WOMAC scores as compared to HA group. No changes in function subscale, SF_36 & MRI
Khalifeh Soltani S/2019⁴⁸	20	RCT, double-blind, placebo-controlled	KL grade 2 to 4	Placental-derived MSC – 50–60 × 10⁶ cells (n = 10)	Normal saline (n = 10)	VAS, KOOS, knee flexion range of motion (ROM), MRI	24 weeks	No SAEs, Significant knee ROM improvement at 2 & 24 wks, VAS – no change, KOOS – improvement till 8 wks, MRI - Chondral thickness improved in about 10% of the total knee joint area AT 24 weeks
Ryu/2020⁵⁴	52	Retrospective cohort study	(K-L) grade ≤2 ICRS grade IV	hUCB-MSCs (Cartistem®, Medipost Inc.) composite of hUCB-MSCs 0.5 × 10⁷/ml and freeze-drying sodium hyaluronate (HA)	N = 25 BMAC + HA scaffold HA membrane (Hyalofast®, Anika Therapeutics Inc., Bedford, MA, USA)	VAS, IKDC, KOOS Scores. Cartilage repair was assessed with modified Magnetic Resonance Observation of Cartilage Repair Tissue (M-MOCART) score and the ICRS cartilage repair scoring system.	2 years	Both groups showed satisfactory clinical and MRI outcomes. Implantation of MSCs from BMAC or hUCB-MSCs is safe and effective for repairing cartilage lesion.
Song/2020⁵⁵	128	Retrospective case series	Full-thickness cartilage lesions ICRS grade 4 and K-L grade ≤3)	Therapeutic dosage of CARTISTEM® was 500 μL/cm² for a defect area with a cell concentration of 0.5 × 10⁷ cells/mL	No control group	VAS, WOMAC, IKDC Scores	2 years	Implantation of hUCB-MSCs is effective for treating knee osteoarthritis based on a follow-up lasting a minimum of 2 years
Lim/2021⁵¹	73	RCT, Phase 3 clinical trial	ICRS- grade 4 in a single compartment of the knee joint, as confirmed by arthroscopy	7.5 × 10⁶ cells per 1.5 mL	43 in the UCB-MSC-HA group and 46 in the microfracture group	Proportion of participants who improved by ≥ 1 ICRS grade. Macroscopic Cartilage Repair Assessment at 48-week arthroscopy. Histologic assessment; VAS score, WOMAC, & IKDC score from baseline	5 years	UCB-MSCs implantation resulted in improved cartilage grade at second-look arthroscopy and provided more improvement in pain and function up to 5 years compared with microfracture.
Lee/2021⁵⁰	74	Retrospective cohort study	Medial Uni-compartmental OA with kissing lesion, which was shown full-thickness cartilage defect (≥ICRS grade 3B) in medial femoral cartilage and medial tibial cartilage	Cartistem, hUCB-MSCs-HA hydrogel composites. Dose NA	N = 42 BMAC + HTO + Micro-fracture a fibrin sealant patch (TachoSil; Takeda Pharma A/S) soaked with the prepared BMAC was fixed with fibrin glue (Greenplast kit; Green Cross)	HSS score, KSS pain and function, and WOMAC score. Cartilage regeneration was graded by the ICRS grading system at second-look arthroscopy. Radiological measurement including HKA angle, posterior tibial slope angle, and correction angle were assessed.		hUCB-MSC procedure was more effective than the BMAC procedure for cartilage regeneration in medial uni-compartmental knee OA even though the clinical outcomes improved regardless of which treatment was administered