A multiple-crosslinked injectable hydrogel for modulating tissue microenvironment and accelerating infected diabetic wound repair

Elevated oxidative stress and inflammation, bacterial infections, and vascular impairment undoubtedly impede the normal diabetic wound healing process, which has encouraged the development of high-performance dressings for wound management. Herein, a new type of multiple-crosslinked injectable hydrogel, GCP, was developed via the radical polymerization of propenyl groups and the formation of copper‒polyphenol coordination bonds and Schiff base bonds. The copper‒polyphenol coordination and Schiff base bonds in the GCP hydrogel were disrupted in the acidic microenvironment of diabetic wound, resulting in the release of copper ions and protocatechualdehyde (PA) to scavenge reactive oxygen species (ROS), promote angiogenesis and cell migration, and exert antibacterial and anti-inflammatory activities via the CuPA complexes. Consequently, markedly accelerated infected diabetic wounds healing was achieved through this tissue microenvironment remodeling strategy. Moreover, the underlying mechanism of the antibacterial properties was investigated by 16S rRNA sequencing. The results indicated that the CuPA complexes can clearly inhibit the growth and reproduction of S. aureus by downregulating specific genes associated with ABC transporters, hindering bacterial protein synthesis, and enhancing oxidoreductase activity. This innovative hydrogel platform for wound management may inspire new methods for the preparation of high-performance biomedical materials and the treatment of other clinical diseases.