Controlled release of ionic carrier hydrogels for sequential immunomodulation to facilitate stage-specific treatment of infectious wound

Abstract

Infected wounds present a significant clinical challenge, exacerbated by antibiotic resistance, which complicates effective treatment. This study introduces a hydrogel (CC/AP@CM) embedded with core-shell bioactive glass nanoparticles designed for the controlled, sequential release of copper (Cu²⁺) and magnesium (Mg²⁺) ions. The hydrogel is crosslinked via a Schiff base reaction, endowing it with injectable, self-healing, and adhesive properties. Notably, the bilayer structure of the bioactive glass within the hydrogel allows an initial release of Cu²⁺ ions to trigger an early-stage pro-inflammatory and antimicrobial response, followed by Mg²⁺ ions that support tissue repair and an anti-inflammatory environment. This design aligns with natural wound healing stages, promoting a shift in macrophage polarization from the M1 to M2 phenotype, effectively balancing antibacterial defense with tissue regeneration. The hydrogel demonstrated robust antibacterial efficacy against MRSA, increased angiogenesis, and enhanced fibroblast proliferation and migration in vitro. In a murine wound model, it significantly accelerated wound closure and immune activation, including responses from dendritic cells and T cells. These findings suggest that this hydrogel, through its stage-specific immunomodulatory properties and temporally controlled ion release, offers a promising strategy for treating complex wound infections, supporting both immune defense and tissue healing.