What is the clinically significant ideal mesenchymal stromal cell count in the management of osteoarthritis of the knee? – Meta-analysis of randomized controlled trials

abstract
Study design: Meta-analysis. Objectives: We aim to identify the clinically significant ideal Mesenchymal Stem Cell (MSC) count in the management of osteoarthritis of knee from Randomized Controlled Trials (RCTs) available in the
literature. Materials and methods: We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library till August 2021 for RCTs conducted in the
management of knee osteoarthritis using MSC therapy specifying the quantity of MSCs delivered. We
categorized the studies based on the MSC count utilized in them into four groups namely <1 , 107 MSCs
(Group I), 1-5x107 MSCs (Group II), 5-10 - 107 MSCs (Group III), and >10 , 107 MSCs (Group IV). Visual Analog Score (VAS) for Pain, Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), Lysholm score, Knee Osteoarthritis Outcome Score (KOOS), and adverse events were the outcomes
analyzed. Analysis was performed in R-platform using OpenMeta [Analyst] software. Results: 14 studies involving 564 patients were included for analysis. We noted incremental decrease in the VAS with increasing dosage of MSCs at 12 months [Group I,WMD ¼ 2.641(p ¼ 0.854); Group II,
WMD ¼ 4.853(p ¼ 0.379); Group III, WMD ¼ 12.154 (p ¼ 0.316); Group IV, WMD ¼ 15.935(p ¼ 0.116)], and 24 months [Group I,WMD ¼ 6(p ¼ 0.001); Group II, WMD ¼ 15(p ¼ 0.001); Group IV, WMD ¼ 20(p ¼ 0.001)]. We also noted incremental improvement in the WOMAC, KOOS with increasing dosage of MSCs at 12 months [Group I, WMD ¼ 7(p ¼ 0.001); Group
II, WMD ¼ 28(p ¼ 0.001); Group IV, WMD ¼ 30(p ¼ 0.001)] and [Group II, WMD ¼ 2.562(p ¼ 0.676); Group III, WMD ¼ 7.670(p ¼ 0.099); Group IV, WMD ¼ 13.475(p ¼ 0.261)] respectively. However, we noted significant reduction in the Lysholm score in Group IV, compared to the others at 12 months
(WMD ¼ 12.5, 95%CI[-25.883,0.883]) and 24 months (WMD ¼ 6.6, 95%CI[-23.596,10.396]). We did not find any significant increase in the adverse events with incremental dosage of MSCs in any of the groups compared. Conclusion: Compared to the four dosage groups of MSCs analyzed, Group III showed consistent significant improvement in pain and functional outcomes analyzed compared to the other groups. Hence, we recommend a cell volume of 5-10 , 107 cells to be delivered to the target site to obtain superior
benefits out of the procedure. However, we urge future trials of sufficient quality to validate our findings to arrive at a consensus on the ideal count of MSCs to be delivered in the cellular therapy for knee osteoarthritis.