A Dual-Network Injectable Hydrogel Scaffold Integrating Glycyrrhizic Acid and Acellular Fat Extracts for Synergistic...

Chronic inflammation is a hallmark of diabetic wounds, severely disrupting the physiological healing cascade. Modulating this inflammatory microenvironment while ensuring biocompatibility remains a major challenge in regenerative medicine. Herein, we report the development of a multifunctional dual-network injectable hydrogel, incorporating glycyrrhizic acid (GA) and acellular fat extracts (FE), designed to enhance diabetic wound repair. The hydrogel comprises two interpenetrating networks: A reversible, dynamic network formed via Zn²⁺-coordinated GA confers excellent injectability and conformability, allowing tight adherence to irregular wound topographies. A secondary, physically cross-linked network is introduced by ultraviolet (UV)-induced polymerization of methacrylated hyaluronic acid (HAMA), which significantly reinforces mechanical strength and structural stability. GA exhibits inherent immunomodulatory activity, promoting macrophage polarization from the pro-inflammatory M1 phenotype to the reparative M2 phenotype, thereby attenuating local inflammation. Concurrently, FE provides a rich reservoir of pro-angiogenic and regenerative bioactive factors that synergistically promote neovascularization and tissue remodeling. In vitro and in vivo evaluations confirmed that this composite hydrogel accelerates wound closure, reduces inflammatory cytokine expression, enhances angiogenesis, and promotes granulation tissue formation. Collectively, this injectable, immunomodulatory, and pro-regenerative hydrogel platform offers a promising therapeutic strategy for the effective management of recalcitrant diabetic wounds.