Thermally denatured dermal matrix enhances diabetic wound vascularization by reactivating mitophagy

Delayed wound healing in diabetes mellitus (DM) is closely associated with endothelial mitochondrial dysfunction and impaired mitophagy. We therefore developed a liquid dermal matrix (LDM) and investigated its therapeutic efficacy and underlying mechanisms in diabetic wound repair.

The release behavior and biocompatibility of LDM were characterized. Its therapeutic effects were evaluated in a streptozotocin (STZ)-induced diabetic mouse full-thickness wound model, and mechanistic studies were conducted in high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs).

LDM exhibited sustained protein release over 96 h. In STZ-diabetic mice, topical application of Gel + LDM markedly accelerated wound closure; the wound closure rate at day 12 increased from 68.87 ± 3.98% in the Gel group to 94.80 ± 1.35% in the Gel + LDM group (P < 0.001). Laser speckle imaging confirmed enhanced wound perfusion at day 12, with perfusion units increasing from 489.96 ± 33.74 (Gel) to 707.21 ± 24.21 (Gel + LDM) (P < 0.001). Histological analyses revealed improved re-epithelialization and collagen remodeling, alongside increased angiogenesis as indicated by elevated CD31 and VEGFA staining. Mechanistically, in HG-treated HUVECs, LDM restored autophagic flux, evidenced by increased LC3-II and reduced P62 accumulation, and promoted PINK1/Parkin-dependent mitophagy. This was accompanied by attenuated mitochondrial fragmentation, reduced mtROS, and improved mitochondrial membrane potential (ΔΨm). Functionally, LDM improved endothelial proliferation, migration, and tube formation, while these protective effects were largely attenuated by 3-MA, MG-149, or PINK1 knockdown, supporting a mitophagy-dependent mechanism.

LDM accelerates diabetic wound healing and improves wound perfusion by restoring mitophagy and mitochondrial homeostasis in endothelial cells, highlighting LDM as a promising therapeutic strategy for DM-associated chronic wounds.