Novel asymmetrical double-layer structural adhesive hydrogels with synergetic neuroprotection and angiogenesis effect for diabetic wound healing

Hard-to-heal diabetic wound, often triggered by infections, neuropathy and peripheral vascular problems, present significant challenges to global health. Multifunctional hydrogels have emerged as promising candidates for diabetic wound healing due to their excellent antibacterial properties, ability to promote the functional recovery of injured nerves, vascular remodeling and enhanced vascularization. However, integrating all these properties into a single hydrogel remains a considerable challenge date. Herein, we propose a strategy for the targeted treatment of diabetic wounds using chemically modified chitosan (TA@CS) and jellyfish collagen (JDP), addressing the complexities associated with the neurogenesis-angiogenesis cycle in wounds, and a safe and effective multifunctional hydrogel based on chemically modified chitosan and jellyfish collagen was designed. The prepared hydrogels (W/PACT and W/PAHCT) consist of an outer hydrogel containing water chestnut starch (WCS) and an inner hydrogel composed of poly(acrylic acid), TA@CS and JDP. By mimicking the double-layer structure of the skin, we achieved superior mechanical strength and wet tissue adhesion through a combination of rigidity and softness strategies. The W/PACT or W/PAHCT hydrogel aims to reshape the diabetic wound microenvironment by providing long-lasting antimicrobial properties, antioxidant capacity, and macrophage polarization toward the M2 phenotype. Strikingly, the synergistic effect of JDP and TA@CS in the inner hydrogel enhances the efficiency of information exchange between nerve cells and endothelial cells, thereby promoting endothelial cell migration and blood vessel formation. A full-thickness skin wound model in diabetic mice demonstrated that the application of W/PACT or W/PAHCT hydrogel significantly accelerated wound healing by establishing a mutually supportive cycle of neurogenesis-angiogenesis at the wound site. In summary, these novel W/PACT and W/PAHCT hydrogels have potential application in skin wound healing due to their neurogenesis-angiogenesis effects.