Cyclodextrin-based deep eutectic solvent-constructed chitosan eutectogel for therapeutic delivery of glabridin in diabetic wound management

Abstract

Diabetic wounds, characterized by delayed healing and susceptibility to infection, pose a significant clinical challenge. Glabridin (GLD), a natural product, has the potential to promote wound repair, but its application is hindered by poor solubility and low photostability. This study developed a novel adhesive deep eutectic gel (eutectogel) by combining a deep eutectic solvent (DES) formed from sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and levulinic acid (Lev) with chitosan (CS) for the efficient delivery of GLD. This system integrates DES with CS through supramolecular interactions, simultaneously addressing the solubility and photostability issues of GLD. The DES not only acts as a solubilizer but also serves as a dynamic crosslinker within the gel network, imparting favorable mechanical properties. The resulting GLD/CS/DES gel formed a flexible patch, enabling sustained GLD release for over 10 days and effectively protecting GLD from photodegradation. In vitro antibacterial assays demonstrated over 99% efficacy against S. aureus and E. coli, with the mechanism of action linked to disruption of bacterial cell membrane integrity. In an infected diabetic wound model, the GLD/CS/DES gel significantly accelerated wound healing, achieving a wound closure rate of 94.3% by day 21. Mechanistic studies revealed that the GLD/CS/DES gel ameliorated the immune microenvironment, promoted angiogenesis, and tissue regeneration by scavenging reactive oxygen species (ROS), inhibiting the nuclear factor kappa-B (NF-κB) signaling pathway, and facilitating macrophage polarization from the pro-inflammatory M1 phenotype to the reparative M2 phenotype. In summary, the GLD/CS/DES gel developed in this study integrates antibacterial, immunomodulatory, and pro-angiogenic functions, offering a promising therapeutic strategy for the management of infected diabetic wounds.