A multilayer hydrogel incorporating urolithin B promotes diabetic wound healing via ROS scavenging and angiogenesis

Impaired wound healing is one of the most prevalent complications associated with diabetes. Reactive oxygen species (ROS) and subsequent endothelial dysfunction are the primary causes of impaired wound healing in patients with diabetes. One of the metabolites of ellagitannins in gut microbiota, urolithin B (UB), has attracted increasing research interest due to its ability to scavenge ROS and exert anti-inflammatory effects. However, the role and molecular mechanisms of UB in diabetic wound healing have not yet been elucidated. We found that UB mitigated oxidative stress and cell senescence induced by tert-butyl hydroperoxide stimulation and restored angiogenesis in human umbilical vein endothelial cells (HUVECs) through the activation of the nuclear factor erythroid derived 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) pathway. Furthermore, a novel multilayer ROS-responsive hydrogel was designed and loaded with UB (MRRH@UB) to promote wound healing in diabetic wounds. This composite hydrogel exhibited excellent biocompatibility, robust mechanical properties and strong antioxidative activity. Additionally, by serving as a carrier, it facilitates the controlled and sustained release of UB, synergistically enhancing antioxidant stress. The in vivo and in vitro results demonstrate that MRRH@UB exhibits remarkable antioxidant and anti-senescence properties, promotes neovascularization, and enhances wound healing. Consequently, this composite hydrogel holds tremendous clinical potential for the treatment of chronic diabetic wounds.