Bioorthogonally Reinforced Injectable Granular Hydrogels Synergizing ECM Mimicry with Microporosity for Skin Tissue Engineering

Abstract

Designing injectable biomaterials that simultaneously recapitulate extracellular matrix (ECM) composition while maintaining interconnected microporosity remains a central challenge in regenerative scaffolds. Granular hydrogels offer unique opportunities to address this limitation because their jammed microgel architecture inherently supports injectability and cell-accessible porosity. Here, we report a bioorthogonally reinforced ECM-mimetic granular hydrogel platform assembled from complementary gelatin and hyaluronic acid–derived microparticles that anneal through dynamic hydrazone coupling. By integrating collagen-mimetic adhesive domains with glycosaminoglycan-mimetic hydrated phases within a jammed microgel network, the system recreates key biochemical and structural features of native ECM. The resulting hydrogels exhibit rapid self-assembly, pronounced shear-thinning injectability, and stable interparticle reinforcement while preserving interconnected microporosity. Consequently, the material functions both as an injectable scaffold and as a support-free bioink for extrusion-based 3D printing. The microporous architecture supports progressive cellular infiltration and spreading in vitro, while in vivo evaluation in a splinted full-thickness wound model demonstrates accelerated wound closure, enhanced granulation tissue formation, and increased neovascularization compared with bulk hydrogel controls. These findings establish ECM-mimetic granular hydrogels as a versatile platform for injectable and printable biomaterials in skin tissue regeneration.