Bioinspired Multifunctional Hydrogel Loaded with Netrin-1 for Diabetic Wound Healing

Fibroblast dysfunction is a key factor in the prolonged healing of diabetic wounds. Netrin-1 was found to be able to ameliorate high-glucose-induced fibroblast dysfunction. In this study, we developed a biomimetic dual-network hydrogel loaded with Netrin-1 to promote diabetic wound healing. The hydrogel was composed of natural ingredients, sodium alginate (SA) and glycyrrhizic acid (GA). In addition, with the octopus's suction cup structure on the surface, this hydrogel exhibited strong adhesion properties and provided protective and sustained release of Netrin-1. The released could promote autophagy by activating the AMPK-mTOR pathway under sustained hyperglycemic conditions, thereby reversing fibroblast dysfunction and restoring cell migration and collagen synthesis. The resultant SA/GA@Netrin-1 hydrogel not only possessed potent antioxidant and antimicrobial effects but also enhanced collagen deposition in diabetic rat wounds, attenuated the inflammatory response, promoted autophagy, and significantly accelerated wound closure. These findings suggest that the SA/GA@Netrin-1 hydrogel provided an innovative solution for chronic diabetic wound management and has the potential to be applied to other refractory wound therapies.