Abstract
BACKGROUND: Intra-articular injection of mesenchymal stem cells (MSCs) has emerged as a promising therapy for knee osteoarthritis (OA). However, uncertainty remains regarding the optimal cell dose for maximizing clinical benefit. This systematic review and meta-analysis aimed to evaluate the efficacy of MSC injections for knee OA and investigate the relationship between cell dose and treatment outcome. METHODS: A comprehensive literature search was conducted in PubMed and Scopus for randomized controlled trials (RCTs) published between 2015 and 2025. Eligible studies were RCTs that used intra-articular MSC injections for knee OA, and WOMAC scores were reported at baseline and 12-month follow-up. Standardized mean differences (SMDs) were pooled using a random-effects model. Subgroup analysis and meta-regression were performed to evaluate the effect of MSC dose on treatment outcomes. RESULTS: Eight treatment arms from six RCTs involving 300 patients were included. The pooled SMD in the WOMAC score at 12 months was -1.35 (95% CI: -1.97 to -0.74), indicating a moderate to large treatment effect. MSC doses of ≤ 25 million cells were associated with statistically significant improvement, while higher doses did not demonstrate additional benefit. Meta-regression confirmed no significant dose-response relationship. Heterogeneity was moderate (I2 = 49.8%). CONCLUSION: Intra-articular MSC therapy significantly improves clinical outcomes in knee OA at 12 months, with lower doses (≤ 25 million cells) appearing to be both effective and potentially more efficient. These findings support dose optimization as a critical consideration in advancing MSC therapy.