Skin-mimetic bilayer hydrogel normalizes diabetic wound healing by orchestrating inflammatory cell dynamics: An early intervention strategy

Diabetic ulcers, characterized by persistent chronic inflammation and impaired healing, pose a significant clinical challenge. Inspired by the physiological healing process observed in healthy wounds, we develop an early intervention strategy by the spatiotemporal modulation of inflammatory cell dynamics to restore inflammation homeostasis in diabetic wounds. To achieve this, a skin-mimetic bilayer hydrogel that mimics the layered structure, composition, and pore size distribution of human skin is developed to allow for the sequential release of neuropeptide substance P and interleukin-10. Our findings demonstrate that this bilayer hydrogel achieves layer-specific pore size distributions and seamless interlayer integration through spontaneous dynamic crosslinking, along with clinically relevant multifunctionality. Notably, it enables rapid release of substance P from its loose bottom layer to enhance neutrophil recruitment within the first day and promote pro-inflammatory macrophage infiltration during the early inflammatory phase. Subsequently, the dense top layer enables delayed and sustained release of interleukin-10, which induces M2c macrophage polarization to facilitate inflammation resolution and support scarless wound closure. Overall, this study provides an effective early intervention strategy to reinstate the physiological healing process in diabetic wounds, thereby preventing chronic ulcer progression and non-healing outcomes. • Skin-mimetic bilayer hydrogel is designed to mimic the layered structure and composition of human skin. • Spatiotemporal modulation of inflammatory cell dynamics restores inflammation homeostasis in diabetic wounds. • Spontaneous dynamic crosslinking endows facile synthesis and clinically relevant multifunctionality. • An effective early intervention strategy is established for preventing chronic ulcer progression.