Drug conjugates crosslinked bioresponsive hydrogel for combination therapy of diabetic wound

Abstract

Basic fibroblast growth factor (bFGF) has proved to be effective for wound healing, yet its effectiveness is extremely retarded in diabetic wounds due to the severe oxidative stress in wound beds. To solve this issue, herein a novel combination therapy of bFGF and N-acetylcysteine (NAC, antioxidant) was devised for improved diabetic wound repair. To avoid rapid loss of both drugs in the wound beds, a bioresponsive hydrogel (bFGF-HSPP-NAC) was engineered by incorporating bFGF and NAC into polymer-drug conjugates (HSPP) via thiol-disulfide exchange reactions. In response to oxidative stress (e.g., reactive oxygen species), the disulfide bonds (SS) within the hydrogel are broken into thiol groups (-S-H), thereby promoting hydrogel degradation and enabling controlled drug release. Initially, NAC is released to scavenge free radicals and ameliorate oxidative damage. Subsequently, bFGF is released to expedite tissue regeneration. This combinatorial strategy is tailored to the specific characteristics of the wound microenvironment at various stages of diabetic wound healing, thereby achieving therapeutic efficacy. The results indicate that the bFGF-HSPP-NAC hydrogel markedly enhances re-epithelialization, collagen deposition, hair follicle regeneration, and neovascularization. In conclusion, the bioresponsive bFGF-HSPP-NAC hydrogel demonstrates significant potential for application in combinatorial therapeutic approaches for diabetic wound healing.