Chronic non-healing diabetic wound therapy is an important clinical challenge. Manipulating the release of bioactive factors from an adhesive hydrogel is an effective approach to repair chronic wounds. As an endogenous antioxidant, bilirubin (BR) has been shown to promote wound healing. Nonetheless, its application is limited by its low water solubility and oxidative degradation.
Inclusion complexes of bilirubin using β-cyclodextrin (BR/β-CD) as the drug delivery system were formulated. Then BR/β-CD was further modified into a thiolated polyglutamic acid-based bioadhesive hydrogel (BR/β-CD/SGP) to achieve controlled release of BR and accelerate chronic wound healing. The formation of BR/β-CD inclusion complex and bioadhesive hydrogel were systemically characterized. The BR/β-CD inclusion complex appeared as an orange powder, soluble in aqueous solution, and stable in the presence of light, while retaining its antioxidative and anti-inflammatory properties. The BR/β-CD/SGP hydrogel promoted closure of chronic wounds in streptozotocin (STZ)-induced diabetic mice. These results demonstrated that BR/β-CD/SGP hydrogels can effectively promote diabetic wound healing.