Micro-environment Triple-Responsive Hyaluronic Acid Hydrogel Dressings to Promote Antibacterial, Collagen Deposition, and Angiogenesis for Diabetic Wound Healing

The clinical treatment of chronic diabetic wounds is a long-standing thorny issue. Strategies targeting the diabetic micro-environment have been developed to promote wound healing. However, it remains challenging to reverse the adverse conditions and re-activate tissue regeneration and angiogenesis. In this work, we develop injectable hydrogels that are responsive to the acid, reactive oxygen species (ROS), and high glucose levels in diabetic wound micro-environment to sustainably deliver tannic acid (TA) to augment antibacterial, anti-inflammation, and anti-oxidation potency. The triple-responsive mechanisms are designed by introducing dynamic acylhydrazone and phenylboronic ester bonds to crosslink modified hyaluronic acid (HA) chains. At the diabetic wound, the acylhydrazone bonds may be hydrolyzed at low pH. Meanwhile, glucose may compete with TA and ROS may oxidize the C-B bond to release TA. Thus, sustained release of TA is triggered by the diabetic micro-environment. The released TA effectively scavenges ROS and kills bacteria. In vivo experiments on diabetic mice demonstrate that the hydrogel dressing highly promotes angiogenesis and extracellular matrix (ECM) deposition, leading to eventual full healing of diabetic skin wound healing. This micro-environment-triggered triple-responsive drug release provides a promising method for diabetic chronic wound healing.