Zinc ion-releasing immunomodulatory hydrogels for enhanced wound healing

Effective wound healing requires a pro-regenerative immune microenvironment that supports tissue regeneration. Therefore, immunomodulatory biomaterials have gained increasing attention for wound healing. In this context, hydrogels have been widely investigated owing to their biocompatibility and structural similarity to the natural extracellular matrix. However, traditional hydrogels mainly provide physical protection and moisture retention while offering limited capacity for active immune modulation. To overcome this limitation, we fabricated zinc ion (Zn²⁺)-releasing immunomodulatory hydrogels using thiol-ene chemistry, zinc peroxide (ZnO₂)-mediated disulfide bond formation, and metal coordination. During gelation, ZnO₂ decomposed to release therapeutic Zn²⁺. These ions were retained within the network via thiol-Zn²⁺ coordination, allowing sustained release for up to 28 days. Sustained Zn²⁺ release corresponded with an increased M2 macrophage population and enhanced proliferative and angiogenic responses in vivo. In a mouse wound model, the Zn²⁺-releasing hydrogels enhanced wound closure by creating a pro-regenerative environment. Histological analysis showed complete re-epithelialization and collagen maturation in the Zn²⁺-releasing hydrogel-treated groups. The hydrogels also increased the expression of CCL2/MCP-1, A20/TNFAIP3, and IL-13, which are involved in macrophage recruitment and transition. Overall, these results indicate that Zn²⁺-releasing hydrogels offer a promising therapy for skin regeneration by actively modulating the wound immune environment.