Abstract / Summary
Knee osteoarthritis (OA) is a leading cause of global disability characterized by progressive cartilage loss and chronic inflammation. While platelet-rich plasma (PRP) and mesenchymal stem cells (MSC) have been proposed as regenerative therapies, a significant disconnect remains between clinical signals and objective data. This review examines the methodological and technical heterogeneity of PRP and MSC therapies for knee OA, and assesses the certainty with which symptomatic and structural conclusions can be drawn. Following PRISMA 2020 guidelines (PROSPERO CRD420251173033), a systematic search of PubMed/MEDLINE, Scopus, and Web of Science identified studies published between January 2010 and September 2025. Seventeen studies were selected using a PICO framework and assigned a priori to two evidence streams: a clinical stream ( n = 10), which formed the sole basis for efficacy and structural conclusions, and a supportive/contextual stream ( n = 7). Risk of bias was assessed using the Cochrane RoB 2.0 and ROBINS-I tools, the synthesis followed SWiM reporting guidance, and the certainty of evidence was appraised using GRADE. The synthesis reveals an “efficacy paradox” where patient-reported outcome measures, such as WOMAC and VAS, consistently show symptomatic improvement, while MRI data (T2 mapping and WORMS) do not consistently show evidence of structural cartilage regeneration. Certainty of evidence was low for symptomatic improvement (9 studies, n ≈ 1214) and very low for structural regeneration (4 studies, n = 99). Technical heterogeneity in PRP preparation and MSC sourcing remains a major obstacle, and reporting was incomplete: only 3 of 10 clinical studies (30%) classified their biologic product using a standardized system. The clinical impact of leukocyte content remains uncertain, as randomized trials report comparable outcomes for leukocyte-poor and leukocyte-rich PRP while laboratory findings remain conflicting. Patient factors, particularly age and KL grade, appear to influence treatment response, with available evidence suggesting more favorable outcomes in younger patients with early-stage OA (KL I–II); however, these observations derive from qualitative synthesis rather than pooled or subgroup analysis. PRP and MSC therapies appear to act primarily as symptom-modifying, immunomodulatory interventions rather than agents of structural cartilage restoration. However, the certainty of this evidence is low to very low, and the absence of demonstrated structural repair within follow-up windows rarely exceeding 12 months does not exclude late structural change. Standardizing preparation protocols, characterizing biologic products transparently, and aligning scientific conclusions with objective structural data are essential to move the field toward reliable clinical practice.