Coagulative Granular Hydrogels with an Enzyme Catalyzed Fibrin Network for Endogenous Tissue Regeneration

Granular hydrogels, composed of densely packed microgels, are an emerging class of injectable microporous scaffolds that provide interstitial porosity for endogenous cell recruitment and tissue repair. However, weak bonding interactions between constituent microgels compromise the mechanical integrity of these biomaterials, limiting their scope and effectiveness for in vivo applications where structural support is required. To address this challenge, we introduce a new bioinspired stabilization method and a novel class of regenerative biomaterial: coagulative granular hydrogels, assembled from thrombin-functionalized gelatin methacryloyl microgels. The surface-bound thrombin is enzymatically active and catalyzes the conversion of fibrinogen into a fibrin hydrogel that extends throughout the interstitial voids of the granular hydrogel. This secondary network acts as a biological glue to stabilize the granular hydrogel, yielding shear and compressive properties comparable to bulk hydrogel controls. Furthermore, the interstitial fibrin network provides a favorable microenvironment for the adhesion, proliferation, and invasion of endothelial cells, highlighting the potential of the biomaterial to support endogenous tissue repair. Subcutaneous injection in mice showed that the coagulative granular hydrogels preserved structural integrity and supported fibrin deposition, cell infiltration, and collagen remodeling in vivo. Future work will adapt this technology to other biomaterials and validate its performance for different tissue repair applications.