Glucose-responsive hydrogel with adaptive insulin release to modulate hyperglycemic microenvironment and promote wound healing.

Abstract

The hyperglycemic microenvironment contributes to the prolonged healing of diabetic wounds by impeding angiogenesis, cell proliferation, and migration. Insulin, a prevalent blood glucose-lowering pharmaceutical agent, has demonstrated the capacity to facilitate diabetic wound healing. Nevertheless, the optimal therapeutic concentration for its direct application at the wound site remains ambiguous. The direct external use of insulin solution is associated with the potential for adverse effects and reduced efficacy. In this article, a dual-network hydrogel (AP/SA gel) is developed for the intelligent delivery of insulin to the wound environment for therapeutic purposes. Phenylboronic acid-modified gelatin (AP) and sodium alginate (SA) were bonded via phenylboronic acid ester bond to enable the hydrogel to deliver insulin in a glucose-responsive manner. The calcium ions were then introduced to chelate with the sodium alginate, thereby rendering the hydrogel less susceptible to hydrolysis and extending the delivery time of the insulin. After determining the optimal concentration of insulin through preliminary experiments, the insulin-loaded hydrogel was administered to full-thickness skin defect model of diabetic mice. The results demonstrated that the hydrogel not only effectively reduced blood glucose levels in the mice but also significantly promoted cell proliferation and angiogenesis at the wound site. These findings suggest that the hydrogel may have the potential to facilitate healing in diabetic wounds. This experimental evidence provides a new solution for the direct use of insulin in diabetic wound treatment in the clinic.