ROS scavenging and immunoregulative EGCG@Cerium complex loaded in antibacterial polyethylene glycol-chitosan hydrogel dressing for skin wound healing

Abstract

The elevation of oxidative stress and inflammatory response after injury remains a substantial challenge that can deteriorate the wound microenvironment and compromise the success of wound healing. Herein, the assembly of naturally derived epigallocatechin-3-gallate (EGCG) and Cerium microscale complex (EGCG@Ce) was prepared as reactive oxygen species (ROS) scavenger, which was further loaded in antibacterial hydrogels as wound dressing. EGCG@Ce shows superior antioxidation capacity towards various ROS including free radical, O₂^- and H₂O₂ through superoxide dismutase-like or catalase-mimicking catalytic activity. Importantly, EGCG@Ce could provide mitochondrial protective effect against oxidative stress damages, reverse the polarization of M1 macrophages and reduce the secretion of pro-inflammatory cytokines. Furtherly, EGCG@Ce was loaded into the PEG-chitosan hydrogel with dynamic, porous, injectable and antibacterial properties as wound dressing, which accelerated the regeneration of both epidermal layer and dermis, resulting in improved healing process of full-thickness skin wounds in vivo. Mechanistically, EGCG@Ce re-shaped the detrimental tissue microenvironment and augmented the pro-reparative response through reducing ROS accumulation, alleviating inflammatory response, enhancing the M2 macrophage polarization and angiogenesis. Collectively, antioxidative and immunomodulatory metal-organic complex-loaded hydrogel is a promising multifunctional dressing for the repair and regeneration of cutaneous wounds without additional drugs, exogenous cytokines, or cells. STATEMENT OF SIGNIFICANCE: (1) We reported an effective antioxidant through self-assembly coordination of EGCG and Cerium for managing the inflammatory microenvironment at the wound site, which not only showed high catalytic capacity towards multiple ROS, but also could provide mitochondrial protective effect against oxidative stress damage, reverse the polarization of M1 macrophages and downregulate pro-inflammatory cytokines. EGCG@Ce was further loaded into porous and bactericidal PEG-chitosan (PEG-CS) hydrogel as a versatile wound dressing, which accelerated wound healing and angiogenesis. (2) The applicability of alleviating sustainable inflammation and regulating macrophage polarization through ROS scavenging is a promising strategy for tissue repair and regeneration without additional drugs, cytokines, or cells.

Keywords: Cerium; Hydrogel dressing; Immune regulation; ROS scavenging; Wound healing.