Immunomodulation effects of collagen hydrogel encapsulating extracellular vesicles derived from calcium silicate stimulated-adipose mesenchymal stem cells for diabetic healing

Abstract

Diabetic wounds are characterized by chronic inflammation, reduced angiogenesis, and insufficient collagen deposition, leading to impaired healing. Extracellular vesicles (EVs) derived from adipose-derived mesenchymal stem cells (ADSC) offer a promising cell-free therapeutic strategy, yet their efficacy and immunomodulation can be enhanced through bioactivation. In this study, we developed calcium silicate (CS)-stimulated ADSC-derived EVs (CSEV) incorporated into collagen hydrogels to create a sustained-release system for promoting diabetic wound healing. CSEV exhibited enhanced protein content, surface marker expression, and bioactive cargo enriched with pro-angiogenic and anti-inflammatory factors. In vitro, CSEV-loaded collagen significantly reduced reactive oxygen species production, promoted cell proliferation and migration compared to standard EV-loaded collagen. Cytokine profiling revealed the upregulation of anti-inflammatory cytokines and extracellular matrix components, highlighting their immunomodulatory and regenerative potential. In vivo, histological evaluation of diabetic rabbit models treated with CSEV-loaded collagen revealed superior reepithelialization and organized collagen deposition, indicating accelerated wound closure. These findings underscore the potential of CSEV-loaded collagen hydrogels as an innovative and effective therapeutic platform for enhancing diabetic wound healing by simultaneously addressing inflammation and tissue regeneration.