Injectable Cu2+-functionalized hyaluronic acid hydrogels via synergistic metal ion-carbodiimide crosslinking for durable antibacterial soft-tissue augmentation

Hyaluronic acid (HA) is widely used as a soft-tissue biomaterial due to its excellent biocompatibility and extracellular-matrix-like properties, yet its clinical utility is often limited by rapid biodegradation and bacteria-associated complication risk during subcutaneous procedures. Here, we developed an injectable copper-functionalized HA hydrogel (HACu-M) using a synergistic metal ion–carbodiimide crosslinking strategy that combines EDC/NHS-mediated covalent network formation with Cu 2+ coordination. HACu-M exhibited stable gelation, injectability, and self-healing behavior, together with improved mechanical robustness and physiological stability. In antibacterial assays, native HA promoted bacterial proliferation, whereas HACu-M reduced Staphylococcus aureus and Escherichia coli survival to <0.2% within 9 h and retained activity after long-term storage. HACu-M showed excellent hemocompatibility and cytocompatibility, supporting proliferation and migration of human skin fibroblasts and endothelial cells without inducing apoptosis. In a rat subcutaneous implantation model, HACu-M mitigated bacteria-associated tissue damage under S. aureus challenge, reduced inflammatory responses, and demonstrated prolonged in vivo retention compared with a commercial HA filler. Overall, HACu-M provides a multifunctional platform that integrates long-term stability with intrinsic antibacterial protection, highlighting its translational potential as a next-generation injectable filler for soft-tissue augmentation.