Cobalt-phenolic nanoparticles-driven self-assembly of hyaluronic acid hydrogels providing a multifactorial approach for chronic wound management

Chronic wounds are persistent non-healing lesions whose complex management is due to the interplay of multiple factors promoting chronicity, such as oxidative stress, overexpressed enzyme activities impeding the tissue repair and bacterial contamination. Currently marketed chronic wound dressings are designed mainly to absorb wound exudate, and at most to release antimicrobial agents, usually ionic silver. However, an effective wound repair requires addressing the multifactorial nature of the wound in a holistic approach. This study explores the potential of metal phenolic network (MPN) nanoparticles (NPs), comprised of epigallocatechin gallate (EGCG) and cobalt, as active agents and structural elements in wound dressings. The MPN NPs were able to generate reactive oxygen species (ROS), disturb bacterial membrane, and inhibit the biofilm of both gram-positive Staphylococcus aureus and gram-negative Pseudomonas aeruginosa. Owing to the high interfacial activity of their phenolic shells, the NPs drove the self-assembly of thiolated hyaluronic acid (THA) hydrogels featuring injectability, self-healing, stimuli-responsive NPs delivery in wound microenvironment, and control over deleterious enzyme activities, oxidative stress and bacterial colonisation. Specifically, the hydrogels inhibited matrix metalloproteinases (MMPs) and myeloperoxidase (MPO) by 60 and 80 %, respectively, and achieved 4-log reduction of S. aureus and 2-log reduction of P. aeruginosa concentrations. Finally, the hydrogels were in-vivo validated in a mouse animal model, showing lack of toxicity and similar wound healing efficiency as an antibiotic-containing commercial product.