Regenerative therapies for knee osteoarthritis: a systematic review and meta-analysis of platelet-rich plasma and mesenchymal stromal cells with narrative synthesis of extracellular vesicles

Abstract

Osteoarthritis (OA) is a leading cause of pain and disability worldwide, with current treatments primarily focused on symptom relief rather than disease modification. In recent years, regenerative therapies such as platelet-rich plasma (PRP), mesenchymal stem cells (MSCs), and extracellular vesicles (EVs) have gained increasing attention for their potential to improve clinical outcomes and promote joint repair. A comprehensive literature search was conducted across multiple electronic databases, including PubMed, Scopus, Web of Science, Medline, and the Cochrane Central Register of Controlled Trials, up to March 10, 2026. Randomized controlled trials evaluating PRP and MSC-based therapies were included for quantitative synthesis. Because of the limited human evidence for EV-based therapies, human EV studies of any clinical design were also eligible and were synthesized narratively. No language restrictions were applied. The Cochrane Risk of Bias 2 (RoB 2) tool was used to assess the methodological quality of the included studies. Meta-analysis was conducted using a random-effects model. Continuous outcomes were expressed as standardized mean differences (SMD), and heterogeneity was assessed using the I ² statistic. Twenty-eight human studies involving 2,515 participants were included. Comparators included placebo/saline, hyaluronic acid, corticosteroids, other biologic treatments, and procedural controls. PRP and MSC evidence was synthesized quantitatively where suitable, whereas non-poolable PRP studies and the three EV studies were synthesized narratively. PRP was not associated with a statistically significant reduction in pain (SMD = −0.45; 95% CI: −0.98 to 0.08; p  = 0.09), whereas MSC therapy was associated with a statistically significant reduction in pain (SMD = −0.387; 95% CI: −0.634 to −0.140; p  = 0.002). Neither PRP (SMD = −0.16; 95% CI: −0.81 to 0.49; p  = 0.63) nor MSC therapy (SMD = −0.349; 95% CI: −0.726 to 0.029; p  = 0.070) demonstrated a statistically significant improvement in functional outcomes. For quality of life, MSC therapy showed a statistically significant improvement (SMD = 0.23; 95% CI: 0.02–0.44), whereas PRP did not show a statistically significant effect (SMD = 0.13; 95% CI: −0.06 to 0.32). EV therapy showed limited and heterogeneous findings, with some studies reporting dose-dependent pain reduction and variable functional and structural outcomes, while others showed no significant effect. MSC therapy was associated with a statistically significant reduction in pain, whereas PRP was not associated with a statistically significant reduction in pain. MSC therapy was also associated with a statistically significant improvement in quality of life, whereas the pooled PRP effect on quality of life was not statistically significant. EV-based therapies showed variable and heterogeneous findings, including possible dose-dependent effects, but the available clinical evidence remains limited. The available studies did not identify a statistically significant increase in reported short-term adverse events. Further large-scale, well-designed clinical trials of EV-based therapies are warranted.