Evaluation of an Antioxidative Thermoresponsive Polydiolcitrate Hydrogel in a Novel Diabetic Pig Impaired Wound Healing Model.

Purpose: Non-healing chronic wounds in diabetic patients pose a significant health and economic burden. We have previously shown that the citrate-based thermoresponsive macromolecule poly(polyethylene glycol citrate-co-N-isopropylacrylamide) displaying the laminin-derived peptide A5G81 (A5G81-PPCN) accelerates wound closure when used as a regenerative dressing in diabetic mice. Although results are promising, A5G81-PPCN should be evaluated in a relevant large animal model of impaired wound healing. While several large animal models of impaired wound healing have been reported, the Ossabaw miniature swine is unique because it exhibits the full spectrum of metabolic syndrome features and vascular complications that are most similar to those of humans. In this study we investigated whether alloxan-induced diabetic Ossabaw miniature swine would manifest impaired wound healing similar to that observed in humans and evaluated the efficacy and safety of A5G81-PPCN, PPCN, and the commercial dressing Promogran Prisma™. Methods: After at least 5 months of hyperglycemia (≥ 200 mg/dL) eight full-thickness wounds (3 cm × 3 cm × 5 mm) were created on the back of each animal. Weekly dressing changes, treatment reapplications, and monitoring of blood glucose and weight were performed for 8 weeks post-wounding. Results: Diabetic Ossabaw swine exhibited notable delayed healing compared to non-diabetic counterparts, validating the model's relevance. Moreover, PPCN and A5G81-PPCN exhibited accelerated wound closure rates relative to Promogran Prisma™. Conclusion: This research underscores the potential for this citrate-based thermoresponsive macromolecule to address an unmet clinical need for healing wounds in diabetic patients and highlights Ossabaw swine as a new model for studying impaired wound healing in diabetes. Lay Summary: Non-healing chronic wounds in diabetic patients pose a significant health and economic burden. We previously developed a unique regenerative dressing called A5G81-PPCN, made from a temperature-sensitive material with a peptide component that accelerates wound healing in diabetic mice. To test this dressing in a clinically relevant model, we used Ossabaw miniature pigs, which mimic human metabolic syndrome and blood vessel complications. After inducing diabetes in these pigs, we created skin wounds and monitored healing for eight weeks. Results show that A5G81-PPCN and PPCN dressings accelerate wound closure relative to a commercial dressing, Promogran Prisma™. This research suggests that A5G81-PPCN could be a valuable new approach to help heal diabetic wounds and positions the Ossabaw pig as an important model for studying diabetic wound healing. Supplementary Information: The online version contains supplementary material available at 10.1007/s40883-025-00425-w.