Bioadhesive hydrogel comprising bilirubin/β-cyclodextrin inclusion complexes promote diabetic wound healing

Abstract

Context

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.

Objective

This study developed a bilirubin-based formulation for diabetic wound healing.

Materials and methods

Bilirubin was incorporated into β-CD-based inclusion complex (BR/β-CD) which was then loaded into a bioadhesive hydrogel matrix (BR/β-CD/SGP). Scratch wound assays were performed to examine the in vitro pro-healing activity of BR/β-CD/SGP (25 μg/mL of BR). Wounds of diabetic or non-diabetic rats were covered with BR or BR/β-CD/SGP hydrogels (1 mg/mL of BR) and changed every day for a period of 7 or 21 days. Histological assays were conducted to evaluate the in vivo effect of BR/β-CD/SGP.

Results

Compared to untreated (18.7%) and BR (55.2%) groups, wound closure was more pronounced (65.0%) in BR/β-CD/SGP group. In diabetic rats, the wound length in BR/β-CD/SGP group was smaller throughout the experimental period than untreated groups. Moreover, BR/β-CD/SGP decreased TNF-α levels to 7.7% on day 3, and elevated collagen deposition and VEGF expression to 11.9- and 8.2-fold on day 14. The therapeutic effects of BR/β-CD/SGP were much better than those of the BR group. Similar observations were made in the non-diabetic model.

Discussion and conclusion

BR/β-CD/SGP promotes wound healing and tissue remodelling in both diabetic and non-diabetic rats, indicating an ideal wound-dressing agent.

Keywords:

• Thiolated polyglutamic acid
• bilirubin inclusion complex
• rheological characterization
• anti-inflammation
• macrophage polarization
• tissue remodelling

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was supported by the National Natural Science Foundation of China [Grant 81903551 and 81803443], Zhejiang Province Natural Science Foundation [Grant No. LQ19H300001], Wenzhou Municipal Science and Technology Bureau [Grant No. Y20190177], and the Special Project for Significant New Drug Research and Development in the Major National Science and Technology Projects of China [2020ZX09201002].