Copper–Zinc‐Doped Bilayer Bioactive Glasses Loaded Hydrogel with Spatiotemporal Immunomodulation Supports MRSA‐Infected Wound Healing

Abstract Developing biomaterials with antimicrobial and wound‐healing activities for the treatment of wound infections remains challenging. Macrophages play non‐negligible roles in healing infection‐related wounds. In this study, a new sequential immunomodulatory approach is proposed to promote effective and rapid wound healing using a novel hybrid hydrogel dressing based on the immune characteristics of bacteria‐associated wounds. The hydrogel dressing substrate is derived from a porcine dermal extracellular matrix (PADM) and loaded with a new class of bioactive glass nanoparticles (BGns) doped with copper (Cu) and zinc (Zn) ions (Cu–Zn BGns). This hybrid hydrogel demonstrates a controlled release of Cu 2+ and Zn 2+ and sequentially regulates the phenotypic transition of macrophages from M1 to M2 by alternately activating nucleotide‐binding oligomerization domain (NOD) and inhibiting mitogen‐activated protein kinases (MAPK) signaling pathways. Additionally, its dual‐temporal bidirectional immunomodulatory function facilitates enhanced antibacterial activity and wound healing. Hence, this novel hydrogel is capable of safely and efficiently accelerating wound healing during infections. As such, the design strategy provides a new direction for exploring novel immunomodulatory biomaterials to address current clinical challenges related to the treatment of wound infections.