An antibacterial and antioxidant rosmarinic acid hydrogel normalizes macrophage polarization to expedite diabetic wound healing

The management of diabetic wounds (DW) is a significant challenge within the medical field. Effectively regulating the levels of reactive oxygen species (ROS) at the wound site and orchestrating the inflammatory response are effective strategies for DW treatment. In this study, a novel hydrogel was developed by cross-linking polyboronic acid-modified carboxymethyl chitosan with herbal active ingredient rosmarinic acid (RA), an active herbal ingredient, through dynamic boronic esters formation. In this RA hydrogel (RAgel), RA serves both as an active pharmaceutical ingredient and as a linker for the creation of a dynamic covalent hydrogel, which can decrease the potential toxicity of chemical crosslinking agents and improve the utilization of RA. RAgel demonstrated potential for controlling RA loading and responsiveness to ROS and glucose levels in a diabetic wound environment. Additionally, the intrinsic antioxidant and antibacterial properties of RA were effectively preserved and enhanced upon integration into RAgel. Furthermore, RAgel not only promoted the migration of L929 cells, a key aspect of tissue repair, but also induced M2 polarization in macrophages,while inhibiting the secretion of pro-inflammatory cytokines. In a murine model of diabetic wound healing, RAgel significantly enhanced the proliferation of both the epidermal and granulation tissues. It also exerts a marked anti-inflammatory effect and promotes collagen deposition, thereby expediting the overall wound healing process. The reported RAgel formulation has potential to address the complex challenges associated with diabetic wound management.