Chitosan hydrogel loaded with mesenchymal stem cell-derived exosomes significantly accelerated wound closure and enhanced tissue regeneration in a full thickness porcine skin defect model.

There is an urgent need for more effective wound healing therapies, particularly wound dressings that not only promote wound closure and reduce scar formation but also retain antibacterial properties. Chitosan, a natural copolymer with inherent hemostatic and antibacterial properties, and mesenchymal stem cell derived exosomes, which promote rapid re-epithelialization, collagen maturation, and scar reduction, were integrated into a single biofunctional dressing. This study evaluated the therapeutic efficacy and underlying mechanisms of this combined approach using a porcine full thickness skin excision model. In vitro, chitosan hydrogel effectively inhibited the growth of Escherichia coli and Staphylococcus aureus across various inoculation concentrations. Exosome treatment significantly suppressed the proliferation and migration of human dermal fibroblasts (HDFs), downregulated mRNA expression of collagen types I and III and α-smooth muscle actin, while upregulating basic fibroblast growth factor and elastin. Furthermore, exosomes markedly increased vascular endothelial growth factor and insulin like growth factor levels, while decreasing hepatocyte growth factor production compared to untreated HDF controls. Exosome treatment also attenuated lipopolysaccharide (LPS) induced inflammatory responses in HDFs, as evidenced by reduced interleukin-1β (IL-1β), IL-6, and IL-8 secretion. Similarly, chitosan hydrogel reduced IL-1β, IL-6, IL-8, and tumor necrosis factor-α expression while enhancing IL-10 levels in LPS-stimulated peripheral blood mononuclear cells. In vivo, the combination of chitosan hydrogel and high-concentration exosomes significantly accelerated wound closure, enhanced epithelialization, minimized wound contraction, and prevented infection. Histological analysis revealed more mature and well developed epidermal and dermal structures, increased epithelial thickness, reduced myofibroblast percentage and inflammatory cell infiltration, enhanced angiogenesis, and greater type I collagen deposition in treated wounds. Collectively, these findings demonstrate that the chitosan-exosome composite harnesses natural antibacterial activity, inflammation modulation ability and regenerative capacity, establishing it as a highly promising biomaterial dressing for promoting cutaneous wound healing.