Multi-Modal Therapy for Diabetic Ulcers: A Hydrogel Platform Combining Antibacterial, Oxygenating, ROS-Scavenging, and Pro-Healing Functions.

Abstract

Diabetic ulcers, characterized by excessive accumulation of reactive oxygen species (ROS), local hypoxia, persistent inflammation, and secondary bacterial infection, pose a serious threat to human health. To address these challenges, this study developed an injectable hydrogel based on covalent cross-linking between polyethylene glycol derivatives and ε-polylysine. This hydrogel is further loaded with recombinant Milk fat globule-epidermal growth factor-VIII (rMFG-E8) and ferulic acid (FA)-loaded mesoporous manganese dioxide (HM-FA), forming a "single application, multiple benefits" platform. The hydrogel effectively inhibited planktonic bacteria and controlled wound infection owing to the inherent antibacterial activity of ε-polylysine. Under the acidic microenvironment of diabetic ulcers, the hydrogel gradually degraded and released HM-FA, which scavenged excess ROS and continuously generated oxygen via, thereby alleviating local hypoxia and oxidative stress and reducing inflammatory responses. Subsequently, FA released from the further disintegration of HM-FA acted synergistically with rMFG-E8 to activate the PI3K/Akt signaling pathway, promoting angiogenesis and tissue regeneration. In vivo experiments demonstrated that the hydrogel exhibited good biocompatibility, significantly suppressed inflammatory responses, and accelerated wound closure in a diabetic ulcer mouse model. In summary, the integrated treatment strategy proposed in this study significantly simplifies clinical procedures and shows promising potential for translational application in diabetic ulcer therapy.