A Self-Healing Multifunctional Hydrogel System Accelerates Diabetic Wound Healing through Orchestrating Immunoinflammatory Microenvironment

Developing an effective treatment strategy of drug delivery to improve diabetic wound healing remains a major challenge in clinical practice nowadays, due to multidrug-resistant bacterial infections, angiopathy, and oxidative damage in the wound microenvironment. Herein, an effective and convenient strategy was designed through a self-healing multiple-dynamic-bond cross-linked hydrogel with interpenetrating networks, which was formed by multiple-dynamic-bond cross-linking of reversible catechol-Fe³⁺ coordinate bonds, hydrogen bonding, and Schiff base bonds. The excellent autonomous healing of the hydrogel was initiated and accelerated by Schiff bonds with reversible breakage between 3,4-dihydroxybenzaldehyde containing catechol and aldehyde groups and chitosan chains, and further consolidated by the co-optation of other noncovalent interactions contributed of hydrogen bonding and Fe³⁺ coordinate bonds. Intriguingly, cathelicidin LL-37 was introduced and uniformly dispersed in the dynamic interpenetrating networks of the hydrogel as a bioactive molecular to orchestrate the diabetic wound healing microenvironment. This multifunctional wound dressing can significantly promote diabetic wound healing by antibacterial activity, immunomodulation, anti-inflammation, neovascularization, and antioxidant activity. Therefore, this study provided an effective and safe strategy for guiding the diabetic wound treatment in clinical applications.