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. In vitro 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. In vivo 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.