Intra-articular Injections of Mesenchymal Stem Cells Without Adjuvant Therapies for Knee Osteoarthritis: A Systematic Review and Meta-analysis

Abstract

Background: While many reviews have been performed to attempt to provide conclusive evidence regarding the outcomes of mesenchymal stem cells (MSCs) in osteoarthritis treatment, the evidence for MSC treatment in osteoarthritis remains contentious, as these reviews have been limited by the heterogeneous evidence available. Purpose: To pool the results of treatment using intra-articular injections of MSCs without any adjuvant therapies for osteoarthritis. Study Design: Systematic review and meta-analysis. Methods: The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. All clinical trials of level 1 or 2 evidence that reported clinical outcomes of patients with osteoarthritis of the knees treated using intra-articular injections of MSCs without any adjuvant therapies were included. Results: A total of 19 studies with 440 knees were included. All studies reported an improvement in the outcomes after intervention. The standardized mean differences (SMDs) for the visual analog scale (VAS) for pain at rest and upon exertion were –1.48 (95% CI, –1.85 to –1.11) and –2.25 (95% CI, –2.64 to –1.85), respectively. The SMDs for the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and total Knee injury and Osteoarthritis Outcome Score were –1.19 (95% CI, –1.53 to –0.84) and 0.88 (95% CI, 0.66-1.10), respectively. Only the source of MSCs and whether the MSCs were cultured or uncultured were clinically important and statistically significant moderators of the treatment outcome. The use of bone marrow MSCs reduced the VAS for pain by 1.50 (95% CI, 0.04-2.96; P = .04) and reduced the total WOMAC by 23.2 (95% CI, 10.0-36.4; P < .01) as compared with adipose MSCs. The use of cultured MSCs reduced the VAS for pain by 2.19 (95% CI, 0.57-3.81; P < .01) and reduced the total WOMAC by 14.4 (95% CI, 1.21-27.5; P = .03) as compared with uncultured MSCs. Conclusion: Intra-articular injections of MSCs without any adjuvant therapies improves pain and function for osteoarthritis. Significantly better outcomes were obtained with the use of bone marrow MSCs as compared with adipose MSCs and with the use of cultured MSCs as opposed to uncultured MSCs.

Methodological Quality and Risk of Bias of Systematic Reviews and Meta-Analyses on Stem Cells for Knee Osteoarthritis: A Cross-Sectional Survey

“…68.18% (n=15) of the SRs/MAs included both RCTs and/or non-RCTs with different RoB and investigated the impact of RoB on results [11, 13, 27-32, 34, 35, 39, 42-45] (rated as "Yes"). Among the 15 SRs/MAs, two discussed the RoB resulting from methodological quality [13,27]; two mentioned the RoB of different study designs [28,32]; one reported the RoB of outcome measurement, blinding and randomization [29]; one addressed the RoB of outcome measurement, blinding, randomization, allocation concealment and selective reporting [11]; one discussed the RoB of methodological quality and study design [30]; two addressed the risk of selection bias [31,34]; one discussed the RoB caused by randomization and small sample size [35]; one reported the RoB of outcome measurement and blinding [39]; one discussed the RoB of implementation [42]; one addressed the RoB of outcome measurement and implementation [43]; one discussed the RoB caused by small sample size [44]; and one addressed the RoB of confounding factors [45]. The remaining 31.82% (n=7) of the SRs/MAs did not investigate the impact of RoB on the total effect [12, 33, 36-38, 40, 41] (rated as "No").…”

“…In addition, 68.18% (n=15) of these SRs/MAs searched two or more databases, provided keywords and search strategy, and justi ed language or retrieval time restrictions, but supplementary retrieval contents (like published reviews, clinical trial registration platform, eld experts, gray literature) were not comprehensively searched. Among these SRs/MAs, one did not consult eld experts [11], while for the rest 14 SRs/MAs, one did not retrieve gray literature [43], three did not search the reference list of the included studies or gray literature [27,29,37], three did not search the clinical trial registration platform or gray literature [13,33,41], seven did not retrieve the reference list of the included studies, gray literature, or clinical trial registration platform [30,32,34,38,40,42,45], which met the minimal requirement (rated as "Partial Yes"). However, 31.82% (n=7) of the SRs/MAs failed to meet the minimal requirement (rated as "No"), among which, ve did not provide complete search strategies [28, 35,36,39,44], one did not explain the reason for restricting the English language [12], and one did not offer comprehensive search strategy or explain the reason for restricting the English language [31].…”

“…There were 50.00% (n=11) of the SRs/MAs rated as "High", among which, one did not describe the basic characteristics of the included studies in detail [45], seven did not use appropriate tools to evaluate the RoB [11, 27-29, 31, 36, 38], and three had both of the above two issues [32][33][34]. The remaining 50.00% (n=11) of the SRs/MAs were rated as "Unclear", since it was di cult to judge whether all the relevant research results were extracted for data synthesis, and ve of them did not describe the process of RoB assessment.…”

Post-Adipose-Derived Stem Cells (ADSC) Stimulated by Collagen Type V (Col V) Mitigate the Progression of Osteoarthritic Rabbit Articular Cartilage

“…Recent studies suggested that the irreparable injury of the cartilage is a major challenge in the treatment of human osteoarthritis and tissue engineering is considered to be an innovative and promising therapy for the patients (Wang et al, 2020;Kader et al, 2021;Tan et al, 2021;Xia et al, 2021). Among various cell therapies, adipose-derived stem cell (ADSC) therapy appears to hold promise (Bistolfi et al, 2021).…”

Mesenchymal Stem Cell Applications in Spine Disorders: A Comprehensive Review

“…Mesenchymal stem cells (MSCs) are increasingly being investigated in a number of different musculoskeletal conditions. MSCs have been investigated for osteoarthritis and chondral defects of the knee, ankle, and hip joints [1][2][3][4][5]. Similarly, MSCs have also been considered for the prevention and management of non-union or critical bone defects, but the data are not yet sufficient to determine their efficacy in these settings [6][7][8].…”