Copper-Epigallocatechin Gallate Enhances Therapeutic Effects of 3D-Printed Dermal Scaffolds in Mitigating Diabetic Wound Scarring

Morbid dermal templates, microangiopathy, and abnormalinflammationare the three most critical reasons for the scarred healing and thehigh recurrence rate of diabetic wounds. In this present study, acombination of a methacrylated decellularized extracellular matrix(ECMMA, aka EM)-based hydrogel system loaded with copper-epigallocatechingallate (Cu-EGCG) capsules is proposed to fabricate bio-printed dermalscaffolds for diabetic wound treatment. Copper ions act as a bioactiveelement for promoting angiogenesis, and EGCG can inhibit inflammationon the wound site. In addition to the above activities, EM/Cu-EGCG(E/C) dermal scaffolds can also provide optimized templates and nutrientexchange space for guiding the orderly deposition and remodeling ofECM. In vitro experiments have shown that the E/C hydrogel can promoteangiogenesis and inhibit the polarization of macrophages to the M1pro-inflammatory phenotype. In the full-thickness skin defect modelof diabetic rats, the E/C dermal scaffold combined with split-thicknessskin graft transplantation can alleviate pathological scarring viapromoting angiogenesis and driving macrophage polarization to theanti-inflammatory M2 phenotype. These may be attributed to the scaffold-actuatedexpression of angiogenesis-related genes in the HIF-1 & alpha;/vascularendothelial growth factor pathway and decreased expression of inflammation-relatedgenes in the TNF-& alpha;/NF-& kappa;B/MMP9 pathway. The results ofthis study show that the E/C dermal scaffold could serve as a promisingartificial dermal analogue for solving the problems of delayed woundhealing and reulceration of diabetic wounds.