Extracellular vesicles outperform adipose derived-mesenchymal stromal cells in alleviating osteoarthritis chondrocyte inflammation in vitro when incorpo-rated into platelet-derived fibrin gel

Background: Orthobiologics are increasingly used in orthopedics, with platelet rich plasma (PRP) widely applied for its autologous origin and bioactive content. PRP fibrin gels allow local retention and sustained release but show limited ability to restore stable hyaline cartilage. Mesenchymal stromal cells (MSCs) and extracellular vesicles (EVs) contained in the secretome may stimulate hyaline cartilage formation and be combined with PRP gels, yet a direct comparison between cell- and EV-containing PRP gels is lacking. Methods: PRP fibrin gels embedding adipose-derived stromal cells (ASCs) or ASC-derived EVs (ASC-EVs) were compared in vitro on osteoarthritic chondrocytes. A vesicle-equivalent design was used: gels containing 5 ×106 ASCs/ml PRP, releasing ~10 ×109 EVs in 48 h, were compared with gels incorporating the same EV dose. Gel properties and effects of the gel released particles in 48 hours were assessed on pathologic chondrocyte viability, stress and inflammatory/catabolic gene expression. Results: ASC-EVs supplemented PRP gels allowed the generation of equivalent gel volumes from reduced plasma amounts. ASC-EVs release preserved chondrocyte viability and metabolic activity and induced a broader downregulation of OA-related inflammatory and catabolic genes. In contrast, ASC-supplemented gels induced cellular stress and showed weaker anti-inflammatory effects. Conclusions: ASC-EVs based PRP gels elicited a more favorable and controlled biological response than cell-based formulations, despite representing only part of the ASC secretome. These results support EV-based PRP gels as a promising, more standardized alternative for cartilage repair, deserving further in vivo validation.