Calcium/Alginate Hydrogel with Hydroxytyrosol Improves Diabetic Wound Healing Through the Activation of Nuclear Factor Erythroid 2‐Related Factor 2 Signaling Pathway

Diabetes is a chronic disease that significantly impairs skin wound healing. There are not many efficient treatments to improve diabetic wound healing. Hydrogels are sustainable biomaterials used to release drugs on wound beds. In this study, a new hydrogel containing 3‐hydroxytyrosol (HT) which is a polyphenol with antioxidant and anti‐inflammatory properties was tested for its potential in diabetic wound healing. The hydrogel with HT presented a degradation rate of 99.8% at 24 h in vitro, a peak of HT release at 30 min, and higher scavenging activity at 24 h. In in vitro assays, the hydrogel with HT did not change the cell viability of fibroblasts and macrophages. The hydrogel with HT promoted cell migration and reduced lipid peroxidation in mouse fibroblasts under high glucose conditions. The hydrogel with HT also induced higher levels of interleukin‐10 and heme oxygenase‐1 under low and high glucose conditions in mouse macrophages. Topic application of hydrogel with HT augmented the collagen deposition and reduced the width of granulation tissue 7 days after wounding in diabetic mice. In conclusion, the hydrogel with HT is not cytotoxic, efficiently improves diabetic wound healing and it can be a promising therapeutic strategy for treatment of diabetic wounds.