In Vivo Wound-Healing Efficacy of Insulin-Loaded Strontium-Cross-Linked Alginate-Based Hydrogels in Diabetic Rats

The wound-healing effect of insulin is well studied and reported. However, prolonged topical application of insulin without compromising its biological activity is still a challenge. In this study, the effect of topically delivered insulin on promoting wound healing in diabetic animals was evaluated. Alginate diamine PEG-g-poly(PEGMA) (ADPM2S2) was the material used for the topical delivery of insulin. ADPM2S2 hydrogels release insulin and strontium ions, and they synergistically act to regulate different phases of wound healing. Insulin was released from the ADPM2S2 hydrogel for a period of 48 h, maintaining its structural stability and biological activity. In vitro studies were performed under high-glucose conditions to evaluate the wound-healing potential of insulin. Insulin-loaded ADPM2S2 hydrogels showed significant improvement in cell migration, proliferation, and collagen deposition, compared to control cells under high-glucose conditions. Immunostaining studies in L929 cells showed a reduction in phospho Akt expression under high-glucose conditions, and in the presence of insulin, the expression increased. The gene expression studies revealed that insulin plays an important role in regulating the inflammatory phase and macrophage polarization, which favors accelerated wound closure. In vivo experiments in diabetic rat excision wounds treated with insulin-loaded ADPM2S2 showed 95% wound closure within 14 days compared with 82% in control groups. Thus, both the in vitro and in vivo results signify the therapeutic potential of topically delivered insulin in wound management under high-glucose conditions.