Mesenchymal stem cells (MSCs) are the main cellular product currently driving regenerative approaches in orthopedics. They are multipotent stromal cells that can differentiate into bone, cartilage, and fat, but much of their therapeutic effect in joint disease comes from secreted anti-inflammatory and pro-regenerative factors rather than direct tissue replacement (Samsonraj et al., 2017; Zhuang et al., 2021). Clinically, most orthopedic MSC work uses cells expanded ex vivo from bone marrow or adipose tissue and delivered intra articularly for osteoarthritis or into defects for cartilage, bone, or osteonecrosis indications (Malige et al., 2024; Eder et al., 2020; McIntyre et al., 2018; Pal et al., 2024; Berebichez-Fridman et al., 2017).
Across 43 well defined MSC clinical studies in orthopedics, including osteoarthritis, cartilage defects, osteonecrosis, bone defects/nonunions, and spine, MSC use was consistently associated with improvements in radiographic, clinical, and patient reported outcomes, with a generally good safety profile (Malige et al., 2024). Systematic reviews focusing on intra articular MSCs in human joints (mostly knees) report that almost all studies show pain and function improvement over baseline, and no major MSC related adverse events, though methodological quality and heterogeneity limit firm efficacy conclusions (McIntyre et al., 2018). Meta-analyses of randomized trials in knee osteoarthritis show that intra articular MSCs significantly reduce pain (VAS, WOMAC) and improve function (WOMAC, IKDC, KOOS, Lysholm) at 6–24 months compared with controls, without an increase in adverse events (Yubo et al., 2017; Song et al., 2020; Tian et al., 2024; Cao et al., 2025). Recent analyses suggest higher doses and adipose-derived MSCs may yield somewhat greater effect, but follow-up remains relatively short and protocols differ widely (Song et al., 2020; Tian et al., 2024; Cao et al., 2025).
Because MSC products are heterogeneous, good practice starts with strict biological characterisation. Clinical studies that truly use MSCs typically verify expression of CD73, CD90, and CD105 with low expression of hematopoietic markers such as CD34, CD45, CD14, CD19, and HLA DR, in line with ISCT criteria (Malige et al., 2024; McIntyre et al., 2018; Wang et al., 2025). Reviews on MSC manufacturing stress the need for standardised preparation and characterisation protocols, including surface marker “surfactome,” differentiation potential, growth kinetics, senescence, and secretome profiling, to improve consistency and predict clinical behaviour (Samsonraj et al., 2017; Wang et al., 2025; Aabling et al., 2025; Pharoun et al., 2024). Yet, a systematic review of orthopaedic MSC trials found that, on average, only about half of the key variables in cell source, culture conditions, and product composition are reported; no study provided all critical details, making replication and comparison difficult (Robinson et al., 2019).
In osteoarthritis, particularly of the knee, the best current practice is converging on intra-articular injection of well-characterised, culture-expanded MSCs, often in early or moderate disease, with careful dosing, viability control, and transparent reporting of manufacturing steps (Eder et al., 2020; Song et al., 2020; Tian et al., 2024; Cao et al., 2025; Aabling et al., 2025). Emerging commentaries emphasise the need for harmonised efficacy criteria, better control of study heterogeneity, and longer term safety follow-up before MSCs can be fully integrated into formal treatment guidelines (Eder et al., 2020; Wang et al., 2025; Tian et al., 2024; Carneiro et al., 2023).
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