Engineering the Hierarchical Porosity of Granular Hydrogel Scaffolds Using Porous Microgels to Improve Cell Recruitment and Tissue Integration

Abstract Granular hydrogel scaffolds (GHS), composed of jammed hydrogel microparticles (microgels), have emerged to overcome the structural limitations of nonporous (bulk) hydrogels. Microscale void spaces among jammed microgels in GHS promote cell infiltration and host tissue integration; however, the prevalent use of spherical nonporous microgels limits the GHS void fraction to that of random close packing. To address this persistent challenge, a new class of gelatin methacryloyl (GelMA) GHS comprising porous microgels, fabricated via thermally induced polymer phase separation within composite microgels, is developed. These novel GHS not only attain hierarchical porosity across inter‐ and intramicrogel length scales, but also have up to ≈ 170% increase in void fraction compared with the nonporous microgel‐based GHS counterpart. Such increase in void fraction while maintaining structural stability, to the best of our knowledge, is among the highest increase reported in the literature. Compared with nonporous microgels in which cells cannot readily infiltrate, in vitro cell infiltration is significantly higher in the porous microgels. Furthermore, in vitro cell distribution in the GHS comprising porous microgels is more uniform compared with the GHS made up of nonporous microgels. In vivo subcutaneous implantation in mice shows that the GHS comprising porous microgels undergo higher and more uniform cell infiltration. Up to ≈ 78% increase in cell infiltration into GHS is yielded in vivo using the GHS fabricated from porous microgels. This work lays the foundation of engineering GelMA GHS with hierarchical porosity, superior cell infiltration, and enhanced tissue integration, which may open new opportunities for developing next‐generation granular biomaterials for accelerating tissue repair.