Synergistic effects of berberine and adipose stem cells in a silk fibroin-PEG hydrogel for diabetic wound healing via macrophage polarization modulation

Abstract Diabetic wound repair remains a considerable clinical challenge, largely due to the limited efficacy of current therapies. Herein, we engineered a novel silk fibroin (SF)–polyethylene glycol (PEG) hydrogel (SPB) incorporated with berberine (BBR) and adipose-derived stem cells (ASCs) to synergistically promote diabetic wound healing. By optimizing the physicochemical properties of SPB, we found that a 7:3 SF:PEG ratio provided an ideal balance of pore size (25.83 ± 3.94 μm), mechanical strength (32.33 ± 4.07 kPa) and sustained BBR release. In vitro, SPB significantly enhanced ASC paracrine function, promoting the production of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF-2), stromal cell-derived factor 1 (SDF-1), platelet-derived growth factor-BB (PDGF-BB), and transforming growth factor beta (TGF-β). Accordingly, SF-based hydrogel system (SPBA) markedly stimulated fibroblast proliferation and migration and enhanced endothelial cell angiogenesis. Moreover, SPBA effectively modulated macrophage repolarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, thereby suppressing inflammation. In vivo, SPBA demonstrated remarkable therapeutic efficacy in diabetic rat full-thickness skin wounds, accelerating wound closure, promoting re-epithelialization, collagen deposition and neovascularization, while reducing local inflammation. These results highlight SPBA as a highly efficient and promising biomaterial strategy for diabetic wound treatment.