Enhanced repair of type 2 diabetic wounds using combined hyperbaric oxygen and M2 macrophage-derived exosomes: An...

Diabetic wounds exhibit delayed healing due to impaired angiogenesis, excessive inflammation, oxidative stress, and insufficient extracellular matrix regeneration. Hyperbaric oxygen therapy (HBO) and M2 macrophage-derived exosomes (M2-Exosome) have each emerged as promising therapeutic strategies that enhance wound repair through complementary mechanisms. This study aimed to evaluate the individual and combined effects of HBO and M2-Exosome on wound closure dynamics, histological regeneration, oxidative status, biomechanical recovery, and gene expression in type 2 diabetic rats. Full-thickness excisional wounds were created in streptozotocin-induced diabetic rats and treated with HBO, exosomes, or a combination of both. Wound closure rate was assessed on days 7 and 14, followed by histological evaluation of angiogenesis and fibroblast proliferation, Masson's trichrome staining for collagen deposition, biomechanical tensile testing, oxidative stress biomarker analysis (CAT, SOD, GSH, MDA), and qRT-PCR quantification of TGF-β, VEGF, TNF-α, and IL-1β expression. Both HBO and exosome treatments significantly accelerated wound closure compared with untreated wounds, while the combined HBO + Exosome therapy produced the highest rate of wound contraction at both time points. Histological results demonstrated enhanced angiogenesis, increased fibroblast density, and markedly improved collagen organization in all treated groups, with the combined treatment consistently showing the greatest regenerative response. Biomechanical testing further confirmed superior tensile strength and structural recovery in the HBO + Exosome group. Antioxidant capacity (CAT, SOD, GSH) increased significantly in all treated wounds, accompanied by reduced MDA levels, indicating attenuation of oxidative damage, particularly under combined therapy. Gene expression analysis revealed upregulation of TGF-β and VEGF and downregulation of TNF-α and IL-1β, with the strongest modulation observed in the HBO + Exosome group. In conclusion, HBO and exosome therapies each exert beneficial effects on diabetic wound healing; however, their combined application generates a synergistic enhancement across cellular, molecular, and biomechanical parameters, representing a promising therapeutic approach for improving diabetic wound repair.