Inflammation-Responsive Drug-Loaded Hydrogels with Sequential Hemostasis, Antibacterial, and Anti-Inflammatory Behavior for Chronically Infected Diabetic Wound Treatment

Stimuli-responsive hydrogels possess unique advantages in drug delivery due to their variable performance and status based on the external environment. In the present study, a dual-responsive (pH and reactive oxygen species (ROS)) hydrogel was prepared to realize drug release properties under inflammatory stimulation. By grafting 3-carboxy-phenylboronic acid to the gelatin molecular backbone and cross-linking with poly(vinyl alcohol), we successfully synthesized the inflammation-responsive drug-loaded hydrogels after encapsulation with vancomycin-conjugated silver nanoclusters (VAN-AgNCs) and pH-sensitive micelles loaded with nimesulide (NIM). This novel design not only retained the dynamic functions of hydrogels, such as injectability, self-healing, and remodeling, but also realized sequential and on-demand drug delivery at diabetic-infected wound sites. In this work, we found that the hydrogel exhibited excellent biocompatibility and hemostasis properties owing to the enhanced cell-adhesive property of the gelatin component. The significant antibacterial and anti-inflammatory effect of the hydrogel was demonstrated in an in vitro experiment. Moreover, in the in vivo experiment, the hydrogel was found to play a role in promoting infected wound healing through sequential hemostasis and antibacterial and anti-inflammatory processes. Collectively, this inflammation-responsive hydrogel design containing VAN-AgNCs and NIM-loaded micelles has great potential in the application of chronically infected diabetic wound treatment, as well as in other inflammatory diseases.