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.

Fabrication of Cyclodextrin-Based Hydrogels for Wound Healing: Progress, Limitations, and Prospects

“…Yao et al first prepared the inclusion complex of bilirubin (BR) and β-CD by solvent evaporation, and then a bioadhesive hydrogel BR/β-CD/SGP was further synthesized with thiopoly­(glutamic acid) and poloxamer. This hydrogel could enhance the solubility of BR, and display effective anti-inflammatory and antioxidant effects, as well as promote the wound healing process in rats with chronic diabetes (Figure A) . Besides, Wang et al developed a hydrogel scaffold using a chemically modified HA, Dex, and resveratrol (Res)/β-CD inclusion complex, and then, plasmid DNA encoding vascular endothelial growth factor was loaded into the hydrogel scaffold to form a multifunctional hydrogel containing both Res and VEGF genes.…”

“…(A-I) Schematic graph of the BR/β-CD/SGP hydrogel for promoting diabetic wound healing; (A-II) bilirubin content of BR and BR/β-CD after standing for 7days; (A-III) in vitro release curves of BR, BR/β-CD, and BR/β-CD/SGP in the presence of H 2 O 2 . Reproduced with permission under a Creative Commons License CC-BY 4.0 from ref . Copyright 2021 MDPI.…”

“…This hydrogel could enhance the solubility of BR, and display effective anti-inflammatory and antioxidant effects, as well as promote the wound healing process in rats with chronic diabetes (Figure 8A). 135 Besides, Wang et al developed a hydrogel scaffold using a chemically modified HA, Dex, and resveratrol (Res)/β-CD inclusion complex, and then, plasmid DNA encoding vascular endothelial growth factor was loaded into the hydrogel scaffold to form a multifunctional hydrogel containing both Res and VEGF genes. It could accelerate the healing process of burn wounds in rats by inhibiting inflammation and promoting angiogenesis (Figure 8B).…”

Glutamine‐Based Metabolism Normalization and Oxidative Stress Alleviation by Self‐Assembled Bilirubin/V9302 Nanoparticles for Psoriasis Treatment

“…Our group also tested the potent of bilirubin in the application of islet preservation and transplantation, [11][12][13][14][15] acute pancreatitis treatment, [16] acute kidney injury, [17] and wound healing. [18,19] The brilliant properties of bilirubin based on ROS-scavenging make it potential for psoriatic treatment.…”

Current and future outlook of loaded components in hydrogel composites for the treatment of chronic diabetic ulcers

“…Around chronic diabetic wounds, inflammatory cells are activated and strongly induce the secretion of proinflammatory cytokines (IL-6 and TNF-α), which accumulate in large quantities at the wound site, ultimately leading to severe inflammatory damage ( Huang et al, 2019 ). In addition, glycosylation end products (dAGEs) in diabetic wounds also promote a persistent inflammatory cascade response, which affects the rate of diabetic wound healing ( Gao et al, 2021a ; Yao et al, 2021 ).…”