Bioinspired hierarchical fiber-hydrogel dressing with dual immunomodulatory and angiogenic functions for diabetic wound healing

Diabetic wound repair remains a huge clinical challenge due to the hostile pathological microenvironment, which is characterized by excessive inflammation, and impaired angiogenesis. The stimuli-responsive system with sequential therapeutic ability is required to improve the pathological microenvironment during the consecutive stages of inflammation and proliferation. Inspired by the dynamic nanofibrous network and hydrogel-like feature of native extracellular matrix, we developed a microenvironment responsive fiber-embedded hydrogel, which enabled sequential drug release to promote wound healing. The hierarchical hydrogel consisted of 4-carboxyphenylboronic acid-modified gelatin, oxidized dextran, gallic acid (GA), and deferoxamine (DFO)-loaded short fibers crosslinked via Schiff base and boronic ester bonds. Interestingly, the hydrogels possessed self-healing behavior and Reactive Oxygen Species and pH-responsive drug release owing to the existence of dynamic and responsive covalent bonds. The solid fiber-embedded hydrogel architecture guaranteed a sequential release of GA and DFO. The hydrogels showed antioxidant, anti-inflammatory, and macrophage polarization modulation, as well as proangiogenic behaviors to accelerate diabetic rat wound healing. This hydrogel provided a promising platform for controllable drug delivery and chronic wound management.