Silk Fibroin Composite Hydrogel: Modulating Immune Microenvironment to Enhance Diabetic Wound Healing

Abstract

To remodel the inflammatory microenvironment and accelerate chronic wound (such as diabetic wound) healing, this study proposes a novel multi-target immunomodulatory strategy based on an advanced silk fibroin composite hydrogel dressing that synchronously regulates macrophage polarization and regulatory T cell (Treg) proliferation. The rationally designed composite hydrogel is constructed from a three-component hydrogel (named GCS) consisting of gelatin methacryloyl (GelMA), quaternized chitosan (QCS), and thiolated silk fibroin (SF-TK). By further loading metformin (Met) and interleukin-2-incorporated poly(lactic-co-glycolic acid) microparticles (IL-2@PLGA), the final composite hydrogel denoted as Met/IL-2@PLGA/GCS was fabricated, which enabled sequential and controllable drug release. Scanning electron microscopy showed a well-defined three-dimensional microporous structure; rheological analysis and compressive stress-strain tests demonstrated favorable mechanical properties; in vitro drug release studies confirmed sequential release kinetics of the therapeutic agents. Live/dead cell staining confirmed that the composite hydrogel possessed excellent cytocompatibility. Immunofluorescence and flow cytometry results showed that the composite hydrogel significantly promoted M1-to-M2 macrophage polarization and enhanced Treg proliferation. In vitro angiogenesis assays with human umbilical vein endothelial cells (HUVECs) revealed an enhancement in tube formation capacity. In vivo experiments substantiated the hydrogel dressing’s superior wound healing performance. Collectively, these findings provide compelling evidence that the multifunctional Met/IL-2@PLGA/GCS composite hydrogel achieves synergistic therapy for diabetic wound healing through modulation of inflammation, promotion of angiogenesis, and acceleration of tissue regeneration.

Keywords

multifunctional hydrogel / modified silk fibroin / immune cell / diabetic wound healing / synergistic immunomodulation

Funding

National Key R&D Program of China(2022YFC2403000)