A 3D-bioprinted multifunctional ADM/CSMA/TA hydrogel scaffold for sustained delivery of mechanically stimulated fibroblast-derived exosomes accelerates diabetic wound healing

Mechanical stretching enhances the therapeutic potency of fibroblast-derived exosomes. • Mechanical conditioning reshapes the miRNA cargo and bioactivity of exosomes. • M-Exos promote fibroblast function, angiogenesis, and pro-reparative macrophage polarization. • A 3D-bioprinted ADM/CSMA/TA scaffold enables sustained local delivery of M-Exos. • The multifunctional scaffold accelerates tissue regeneration in diabetic wounds. Diabetic wound healing is hindered by impaired cellular function, insufficient angiogenesis, persistent inflammation, and bacterial infection. Here, we developed a 3D-bioprinted multifunctional M-Exos/ADM/CSMA/TA hydrogel scaffold for diabetic wound repair. Mechanical stimulation enhanced the therapeutic activity of fibroblast-derived exosomes (M-Exos), which promoted fibroblast and endothelial cell proliferation and migration, enhanced tube formation, and facilitated pro-reparative macrophage polarization. miRNA sequencing revealed distinct molecular profiles associated with tissue repair-related pathways. The incorporation of acellular dermal matrix, chitosan methacrylate, and tannic acid produced a porous, biocompatible, and antibacterial scaffold, and 3D bioprinting enabled sustained M-Exos release. In a diabetic full-thickness skin-defect model, the scaffold accelerated wound closure, re-epithelialization, collagen remodeling, and neovascularization while alleviating local inflammation and infection. This mechanically activated exosome-based scaffold integrates regenerative, angiogenic, immunomodulatory, and antibacterial functions, providing a promising strategy for diabetic wound treatment.