Three-Dimensional Bioprinting of Growth Differentiation Factor 5-Preconditioned Mesenchymal Stem Cell-Derived Exosomes Facilitates Articular Cartilage Endogenous Regeneration

The repair of articular cartilage defects remains a major regenerative and clinical challenge. Exosomes (Exos) derived from mesenchymal stem cells (MSCs) have good application potential in cartilage tissue engineering. Numerous studies have indicated that appropriate preconditioning methods can promote the therapeutic effect of Exos. Growth differentiation factor 5 (GDF-5) plays a critical role in chondrogenesis and regeneration. In this study, GDF-5 was used to precondition synovial mesenchymal stem cells (SMSCs) to increase the chondrogenic-promoting effect of Exos (G-Exos). In addition, we demonstrated that G-Exos rich in miR-383-3p increased the chondrogenic potential of SMSCs by activating the Kdm2a/SOX2 signaling pathway. On this basis, G-Exos were loaded into a glycyrrhizic acid/methacrylate-acylated hyaluronic acid (GA/HA/G-Exos) scaffold via digital light processing (DLP) bioprinting to maintain bioactivity and sustained release. The GA/HA/G-Exos scaffolds not only presented significant biological properties in vitro but also significantly promoted the remodeling of the joint cavity regenerative microenvironment and the regeneration of articular cartilage in Sprague-Dawley rats. This study provides a promising cell-free regenerative strategy for cartilage defect repair via the use of engineered exofunctionalized biological scaffolds.