Meta-Analysis and Evidence Base for the Efficacy of Autologous Bone Marrow Mesenchymal Stem Cells in Knee Cartilage Repair: Methodological Guidelines and Quality Assessment

Abstract

The aim of this study is to review all the published clinical trials on autologous bone marrow mesenchymal stem cells (BM-MSCs) in the repair of cartilage lesions of the knee. We performed a comprehensive search in three electronic databases: PubMed, Medline via Ovid, and Web of Science. A systematic review was conducted according to the guidelines of PRISMA protocol and the Cochrane Handbook for Systematic Reviews of Interventions. The modified Coleman methodology score was used to assess the quality of the included studies. Meta-analysis was conducted to estimate the effect size for Pain and function change after receiving BM-MSCs. Thirty-three studies—including 724 patients of mean age 44.2 years—were eligible. 50.7% of the included patients received cultured BM-MSCs for knee cartilage repair. There was improvement in the MINORS quality score over time with a positive correlation with the publication year. Meta-analysis indicated better improvement and statistical significance in the Visual Analog Scale for Pain, IKDC Function, Tegner Activity Scale, and Lysholm Knee Score after administration of noncultured BM-MSCs when compared to evaluation before the treatment. Meanwhile, there was a clear methodological defect in most studies with an average modified Coleman methodology score (MCMS) of 55. BM-MSCs revealed a clinically relevant improvement in pain, function, and histological regeneration.

Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations

“…BM-MSC treatment in patients with OA results in an overall improvement in pain and symptoms and reduces synovial inflammation, but there is still an inconsistency in the literature related to the cartilage-regenerative ability of BM-MSCs [ 199 ]. These results were reinforced by a recent meta-analysis including 724 patients, which indicated improvement in pain level measured by Visual Analogue Scale (VAS), International Knee Documentation Committee (IKDC) function score, Tegner Activity Scale and Lysholm Knee score when compared to respective results before treatment with BM-MSCs [ 202 ]. There are also some therapeutic possibilities combining MSCs with biodegradable materials that seem promising but need to be investigated [ 203 ].…”

“…To date, there are no trials comparing the results of BM-MSC and AMFAT directly, but a comparative review of the literature found that both provide an excellent safety profile and favorable patient outcomes based on perceived pain, joint function and OA progression [ 216 ]. The key considerations that can be drawn from the reviewed literature are that there is a need for a more structured experimental method regarding the application of MSCs, as reported by Awad et al [ 202 ]. Another key point going forward is the standardization of applied doses and the determination of optimal MSC dose for various patient groups, possibly in regard to the phenotype of OA.…”

Mesenchymal Stem Cells in the Treatment of Cartilage Defects of the Knee: A Systematic Review of the Clinical Outcomes

“…13,55 PRP has the advantage of being biodegradable, and it contains chondrogenesis-inducing growth factors. 7 The ability of MSCs to adhere to and differentiate within the scaffold has been shown in a number of studies, 36,37,56 and the use of scaffolds has been shown to have favorable outcomes in the treatment of osteoarthritis. 59 We could not find any human study specifically investigating the efficacy of scaffolds.…”

Cell and Cell Free Therapies in Osteoarthritis

“…Doyle et al carried out a review to evaluate the efficacy of IA injections of these cells to treat knee OA, and concluded that low confidence in clinical efficacy is due to the heterogeneity of used methodologies, but most studies demonstrated a decrease in poor cartilage index, and improvements in pain, function, and quality of life, with moderate to high levels of evidence regarding safety for therapeutic administration [ 103 ]. Recently, a meta-analysis that included 724 patients reported improvements in pain level as measured by VAS, International Knee Documentation Committee (IKDC) function score, Tegner Activity Scale (TAS) and Lysholm Knee score, when the results were compared with the ones obtained before treatment with BMMSCs [ 104 ]. On the other hand, Zhi et al demonstrated that articular cartilage chondrocytes cocultured with BMMSCs could repair cartilage lesions and prevent the abnormal expression of KDM6A and SOX9 (key factors in the pathogenesis of OA), type II collagen, and aggrecan in rats with OA [ 105 ].…”

“…Some studies assessed different doses of BMMSCs. Clinical trials have demonstrated that high doses (25 × 10 6 cells and 40 × 10 6 cells) of autologous BMMSCs are safe [ 104 , 111 , 112 ] Lamo-Espinosa et al studied two BMMSCs doses in patients with knee OA, 1 × 10 7 and 1 × 10 8 , and demonstrated no clinical differences between groups after 4-year follow-up [ 113 ]. The same author tried different doses of autologous expanded BMMSCs, 10 × 10 6 and 100 × 10 6 , in association with HA (control group) in 30 patients with knee OA, and improvements in WOMAC were seen only in patients treated with the highest dose, while improvements in VAS scores were reported in both groups at 12-month follow-up [ 114 ].…”