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

Abstract

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 compromises the mechanical integrity of these biomaterials, limiting their scope and effectiveness for in vivo application 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. This innovative stabilization mechanism provides a responsive biomaterial system, and future studies will seek to explore how the biomaterial is annealed in vivo by the presence of blood plasma fibrinogen.