Synergistic Effects of Berberine and Adipose Stem Cells in a Silk Fibroin-PEG Hydrogel for Diabetic Wound Healing via Macrophage Polarization Modulation

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 VEGF, FGF-2, SDF-1, PDGF-BB, and TGF-β production. Accordingly, 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.