Table 1.

Clinical Trials Selected That Utilize Adult Human MSCs in the Treatment of KOA

Study	Patients Enrolled	Method	Intervention	Results	Conclusion	Limitation
Freitag J. et al, 20195	30 (Age 18+)	Randomized controlled trial (RCT)	Intra-articular injections of autologous ADMSCs: Placebo vs single (baseline) vs double dose (100 x106 ADMSCs) at baseline and 6 months.	Significant reduction in pain and functional improvement of the knee joint at 12 months. MRI and KOOS indicated disease modification. Double-dose treatment achieved more consistent OA stabilization.	Safe and effective therapy of KOA. No adverse AE observed.	First published RCT studying the effect of autologous expanded ADMSCs on KOA. Additional research with direct comparison required.
Frietag J. et al, 201510	40 (Age 18–50)	Pilot, single- center RCT	Placebo vs Arthroscopic M.F. vs Arthroscopic M.F. w/intra- articular injection of autologous ADMSCs.	The primary outcome of MRI and KOOS is being assessed with 12-month follow-up. Hypothesis: Treatment w/ADMSCs may result in increased type II collagen deposition and regeneration of hyaline-like cartilage. AEs will be noted.	The trial was in progress.	Lack of blinding in the trial, insufficient data for calculations due to small sample size and a larger phase-III RCT requiring greater funding.
Lamo- Espinosa J. et al, 201622	30 (Age 50–80)	Multicentre RCT	Intra-articular injections of autologous BM-MSCs: Placebo (H.A. only) vs Low dose (H.A. w/10 x106 BM-MSCs) vs High dose (H.A. w/100 x106 BM-MSCs).	Improvement in VAS & WOMAC scores at 12- months for both treatment groups. MRI demonstrates a decrease in joint damage high-dose treatment group. X-ray revealed decrease in joint space width only in control group.	Treatment of KOA w/H.A. and B.M.- MSCs is safe and feasible, especially in the high-dose treatment group.	Ethical issues prevented a double-blinded trial.
Lamo- Espinosa J. et al, 201823	Same Patients as Lamo-Espinosa J., et al (2016); 3 patients opted-out of long-term follow up	Multi- center RCT	Long-term follow up of 4 years with no additional intervention. Studying the clinical and radiographic evolution of KOA patients as a follow up to HA+ BM- MSCs treatment.	Positive results in both VAS and WOMAC scores for low and high dose groups. No clinical significance observed between the low and high dose treatment groups.	Clinical and functional improvement of the knee joint when compared to the control group.	Further research leading to phase-III required to better understand the efficacy of BM-MSCs in treating KOA.
Al Najar M. et al24	13 (Mean age 50 and under 65 years old)	Prospective Phase I open-label clinical trial	Two doses of Intra-articular injections of autologous BM-MSCs 1 month apart (totaling 61x106 ± 0.6x106).	Improvement in cartilage thickness and KOOS scores observed. No lasting AEs observed within 24-month from treatment.	Safe drug administration, clinical cartilage thickness and functional improvement of the knee joint.	No control group and a limited number of patients enrolled. Larger sample size required to better understand the efficacy of BM-MSCs therapy in KOA.
Shetty A. et al25	60 (Age 19–61)	Prospective phase I open-label clinical trial	MCIC- Arthroscopic procedure utilizing CO2 insufflation.	Postoperative clinical assessments demonstrated significant improvement of P < 0.05 in KOOS, LKSS and IKDC.	Regeneration of the cartilage observed. Effective and single-stage treatment. No serious AE recorded from operative procedures.	Not enough studies supporting long-term effects and insufficient health economic justification of the procedure. No placebo groups.
Wang Y. et al7	17 (Age 18–40)	Double- blind RCT	Intra-articular injections: Placebo (H.A. only) group vs allogenic MPC+HA (75x106) group.	Moderate arthralgia and swelling in 4 patients. MPC+HA patients demonstrated improvement in KOOS, ADL and SF-36 score (P < 0.05) compared to the placebo group.	Treatment was safe and well tolerated. Improvement in clinical and structural outcomes.	Further investigations required to modulate the understanding of the pathological processes responsible for regenerative restoration of articular cartilage.
Gupta P.K. et al15	60 (Age 40–70)	Multi- center, double- blind RCT	Intra-articular injections: Placebo (H.A. only) vs different doses of Stempeucel (25, 50, 75 or 150 x 106 cells) followed by 2mL H.A.	Stempeucel administration resulted in improvements in qualitative parameters (VAS, ICOAP & WOMAC) in all treatment groups compared to placebo at 12 months follow- up. Higher dose groups demonstrated mild-moderate AEs.	75x106 MSC treatment group demonstrated most effective improvement in clinical outcome.	Larger sample size required to demonstrate the therapeutic efficacy of Stempeucel in the treatment of KOA.
Pers Y.M. et al26	18 (Age 50–75)	Bicentric, uncontrolled, open phase I trial	Intra-articular injections of ASCs: low dose (2x106), medium dose (10x106), and high dose (50x106).	Clinical improvement and reduction in pain levels were recorded for all treatment groups. Statistically significant improvement was only seen in the low-dose treatment group.	Study demonstrated safety, drug tolerability and efficacy of the treatment.	Short-term study (6 months), uncontrolled experiment and small sample size.
Davatchi F. et al9	4 (Age 55–65)	Long-term follow up (5 years) of a 6-month preliminary study	Transplant of MSCs in the worse knee only (8/9x106 MSCs).	Improved VAS, functional outcome and reduced pain scores (PGA) for treated knee compared to untreated knee.	Early intervention utilizing MSCs would demonstrate promising long-term results.	Future studies are required with a larger population.
Song Y. et al1	18 (Age 40–70)	Prospective uncontrolled clinical trial	Three Intra- articular injections with ADMSCs: low-dose (1x107), mid-dose (2x107) and high-dose (5x107) for 96 weeks.	Improved pain, function and cartilage volume at the knee joint. The high-dose group exhibited the highest improvement.	ADMSCs treatment demonstrated safety and improvement of function at the knee joint.	Lack of placebo/control group and small sample size.
Hernigou P. et al27	30 (Age 18–41)	Prospective RCT	Bilateral KOA secondary to ON; One knee received TKA & the other received bone marrow graft (6500MSCs/mL) to subchondral bone.	Surgical complications were more frequent after TKA. Improvement observed in cartilage and bone marrow lesions at the injection site of BM-graft therapy on the other knee.	Treatment with BM-graft was effective, with fewer AEs and faster recovery compared to the TKA procedure.	Invasive surgical procedure and long-recovery time.
Vega A. et al14	30 (Age 18–75)	Multicenter RCT	Intra-articular injections: Placebo group (60mg HA only) vs treatment group (allogeneic BM-MSCs 40 x106 and HA) followed for 12 months.	Treatment with allogeneic MSCs demonstrated safety, feasibility and clinical efficacy. T2 measurements indicated an improvement in cartilage quality.	Allogeneic BM-MSC therapy is a valid alternative to autologous MSCs because it is more convenient and less invasive treatment alternative.	Future studies utilizing both allogenic and autologous MSCs are required to provide a better comparison between the efficacy of each type of MSC.
Bastos R. et al28	18 (Age 57.6 ± 9.6 years)	Randomized uncontrolled trial	Intra-articular injections: autologous MSCs only vs autologous MSCs+ PRP followed for 12 months	Both MSC & PRP+MSC indicated significant improvements in pain, function and activities of daily living (p < 0.05). Minimal AEs observed.	Adding PRP to the treatment did not indicate better clinical efficacy of MSC treatment. Both treatments were safe, minimally invasive and tolerable.	Lack of placebo/control group and small sample size.
Soler R. et al11	15 (Median age = 52 years)	Prospective Phase I–II, open-label, single-dose, single-arm clinical trial	Intra-articular infusion: (40.9x106 ± 0.4×106) autologous BM-MSCs.	Treatment decreased the intensity of pain. Physical improvement maintained for 12 months post-treatment. Mild AEs were recorded.	Treatment demonstrated safety, tolerability, cartilage repair and improvement of QoL (long- term benefit up to 4 years post-intervention).	Lack of placebo/control group and small sample size.
Koh Y.G. et al29	80 (Age 18–50)	Unblinded RCT	Arthroscopies: placebo (M.F. only) vs treatment group (ADSCs + M.F.) followed and assessed for 24 months.	Improvement in KOOS scores and cartilage coverage in the treatment group versus placebo group. ADL scores were not significantly different between both groups.	Treatment group demonstrated improvement in pain, function and radiologic imaging. Significant structural repair was observed in the cartilage of the knee in the treatment group.	Larger sample size and long-term follow up required to demonstrate therapeutic efficacy.
Emadedin M. et al12	43 (Median age = 53 years)	Single centre, Phase I/II, Triple blind RCT	Intra-articular implantation: Placebo (5mL Saline) vs treatment group (40x106 autologous BM-MSCs).	The treatment group demonstrated improvements in the total WOMAC score over six months follow- up. No major AEs recorded.	MSCs treatment provided patients with the significant clinical improvement compared to the placebo group.	Short-term study (6 months) and larger cohort required to better assess the efficacy of the treatment.
Shadmanfar S. et al13	30 (Age 18–65)	Single center, Phase I/II, Triple blind RCT- w/Rheumatoid Arthritis (R.A.) patients.	Intra-articular implantation: Placebo (Saline) vs treatment group (40x106 autologous BM-MSCs).	Patients receiving treatment demonstrated improved WOMAC and VAS scores during the 12-month follow-up compared to placebo. Reductions to methotrexate and prednisone use, was noticed in treatment group.	MSCs implantation demonstrated safety, tolerability, and a positive trend in clinical efficacy.	Improvement could not be significantly sustained after 12 months.
Mastas J. et al30	26 (Age 40–65)	Pilot Phase I/II, Double-blind, RCT	Intra-articular injections: Placebo (HA only at baseline and 6-month) vs Group-1(UC-MSCs at baseline and HA at 6-month) vs Group-2 (UC-MSCs at baseline and 6-month). Treatment injections contained: 20×106 UC‐MSCs, 3 cc of saline with 5% A.B. plasma.	At 12-month assessment, Group-2 patients reported significant improvements in knee function and reduction in pain levels when compared to the Placebo group. No differences in MRI between treatment and placebo group. No severe AE reported.	UC-MSC treatment demonstrated safety and clinical efficacy.	Effects of the treatment was studied on a small population. Repeated trials involving a larger population is required.
Khalifeh-Soltani S.et al31	20 (Age 35–75)	Double-blind, RCT	Intra-articular injections: Placebo (saline only) vs treatment group (0.5–0.6 × 108) allogenic placenta derived MSCs.	Clinical improvements, pain reduction, and 10% increase in chondral thickness observed in treatment group after 24-weeks. Mild AEs observed.	Allogenic-placenta derived MSC demonstrated safety and clinical efficacy after 24 weeks follow-up.	Small sample size and short-term study of 24-weeks.
Park YB. et al19	7 (Age 18–80)	Open-label, single-arm, single center, Phase I/II uncontrolled clinical trial	Arthroscopy procedure utilizing Cartistem (H.A. gel+ hUC-MSCs); Group A (low dose-1.15–1.25 ×107) vs Group B (high dose- 1.65–2.00x107) followed over 7 years.	Healed cartilage defect and hyaline-like cartilage seen after 1 year during arthroscopic exam. dGEMRIC showed regenerated cartilage w/high GAG content at 3 years. No significant deterioration of cartilage, and reduced pain after 7 years. Mild AEs observed in patients during treatment.	First-in human clinical trial utilizing Cartistem (composite of culture-expanded allogeneic hUCB-MSCs and HA hydrogel). The clinical outcomes showed improvement and stability in the knee joint for over seven years.	Further investigation with a larger number of patients is required to study the efficacy of Cartistem. This study only evaluated patients with grade-3 KOA, and only two patients consented to arthroscopic examination for a biopsy a year post-procedure.