Modulation of angiogenic, inflammatory, and matrix remodeling responses in type 2 diabetic wounds by a decellularized dermal scaffold and adjunct biophysical stimulation.

Impaired wound healing in type 2 diabetes is largely attributed to dysregulated cellular responses, defective extracellular matrix (ECM) remodeling, insufficient angiogenesis, and a prolonged inflammatory microenvironment. Understanding how these processes can be modulated at the cellular and tissue levels remains essential for improving diabetic wound repair. In this study, we examined the effects of a decellularized dermal scaffold (DDS) combined with photobiomodulation therapy (PBM), applied as an adjunct biophysical stimulus, on angiogenic, inflammatory, and matrix remodeling responses in a type 2 diabetic rat wound model. Full-thickness excisional skin wounds were created and assigned to control, DDS-treated, PBM-treated, or combined DDS + PBM groups. Wound tissues were harvested on days 8 and 16 post-injury for macroscopic evaluation, biomechanical testing, histological and histochemical analyses, and cytokine quantification. Morphometric assessment revealed that wounds receiving the combined intervention exhibited significantly accelerated wound contraction compared with single-modality and untreated groups at both timepoints. Biomechanical analyses demonstrated improved tissue integrity in treated wounds, with the combined group showing the highest values of tensile strength, maximum force, energy absorption, and bending stiffness, indicative of enhanced structural organization. Histological evaluation showed that DDS combined with PBM markedly increased fibroblast density and neovascularization while reducing inflammatory cell infiltration. Histochemical staining further demonstrated more advanced and organized collagen deposition in the combined group, reflecting accelerated ECM maturation and remodeling. At the molecular level, treated wounds displayed elevated levels of pro-regenerative mediators, including transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF), with maximal expression observed in the combined group. Conversely, the expression of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was significantly attenuated. Collectively, these findings indicate that integrating a decellularized dermal scaffold with adjunct photobiomodulation effectively modulates cellular behavior, angiogenic signaling, inflammatory responses, and ECM remodeling in diabetic wounds. This study provides mechanistic insight into scaffold-based microenvironmental regulation of impaired wound healing under diabetic conditions.