A Multifunctional Hydrogel with a Dual Network of Metal Ions/Sodium Alginate/Glycyrrhizic Acid for Wound Healing

Bacterial infection, excessive inflammation, and oxidative stress pose significant challenges to the wound healing process. Multifunctional hydrogels, as wound dressings, hold promising potential to overcome the current obstacles in wound treatment. In this study, three metal ions (copper, zinc, and calcium, CZC) were mixed with sodium alginate (SA) to form a slowly cross-linked network, followed by the incorporation of glycyrrhizic acid (GA) to establish a CZC-SA-GA dual-network hydrogel. Copper ions exhibit antibacterial and angiogenic properties. Zinc ions synergistically enhance antibacterial efficacy and provide antioxidant effects. Calcium ions promote structural cross-linking and facilitate cell migration. The introduction of GA significantly enhances the mechanical strength of the hydrogel (compressive modulus increased by approximately 67%) and endows it with anti-inflammatory activity. The CZC-SA-GA hydrogel demonstrates excellent cytocompatibility, promotes cell migration and angiogenesis (VEGF is significantly upregulated), and exhibits potent anti-inflammatory (reduces the expression levels of NO, IL-6, and iNOS) and antioxidant effects (reduces MDA activity and ROS accumulation and increases T-GSH level). Additionally, it shows broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria (bactericidal efficacy ≈100%). In a murine full-thickness skin wound model, the application of the CZC-SA-GA hydrogel accelerated wound healing (wound closure accelerated by ∼20%). The development of natural drug-based hydrogels with integrated antibacterial, anti-inflammatory, and antioxidant properties presents a promising strategy for treating severe skin wounds.