Exosome-Infused DTM-MPs Hydrogel Scaffold: A Smart Platform for Tendon Repair with Sustained Bioactivity and Anti-Inflammatory Benefits

The regeneration of tendons remains a major challenge in tissue engineering. In this study, we present an original scaffold-based approach for tendon repair that combines decellularized tendon matrix microparticles (DTM-MPs), exosomes derived from human adipose-derived stem/progenitor cells (sub-Exos), and collagen-binding domain (CBD) peptides. This hybrid scaffold (DTM-MPs/CBD@sub-Exos/Gel) was fabricated using a DTM-MPs-based hydrogel to provide sustained release of bioactive exosomes at the site of injury. Characterization of the scaffold revealed high bioactivity, biocompatibility, and enhanced mechanical properties compared to controls. <i>In vitro</i> studies demonstrated that sub-Exos significantly enhanced tendon-specific differentiation of rat tendon-derived mesenchymal stem cells (rTD-MSCs), while CBD modification facilitated controlled exosome release and promoted tendon healing. Macrophage polarization toward the anti-inflammatory M2 phenotype was also favored in the presence of the CBD@sub-Exos-loaded scaffold. <i>In vivo</i> evaluations in a rat Achilles tendon defect model confirmed that the DTM-MPs/CBD@sub-Exos/Gel scaffold accelerated tendon regeneration, restored mechanical properties, and exhibited sustained exosome release. Histological analysis revealed improved tendon matrix formation, with enhanced collagen synthesis and structural alignment in the CBD@sub-Exos-modified scaffold group. These findings suggest that the DTM-MPs/CBD@sub-Exos/Gel scaffold offers a promising therapeutic strategy for tendon injury repair by promoting tissue regeneration, modulating inflammation, and enhancing tissue repair outcomes.