Engineering the microstructure and spatial bioactivity of granular biomaterials to guide vascular patterning

In tissues where the vasculature is either lacking or abnormal, biomaterial interventions can be designed to induce vessel formation and promote tissue repair. The porous architecture of biomaterials plays a key role in influencing cell infiltration and inducing vascularization by enabling the diffusion of nutrients and providing structural avenues for vessel ingrowth. Microporous annealed particle (MAP) scaffolds are a class of biomaterial that inherently possess a tunable, porous architecture. These materials are composed of small hydrogel particles, or microgels, that pack together to produce an interconnected, porous network. We first demonstrated that the particle fraction in MAP scaffolds serves as a bioactive cue for cell growth. To control this bioactive cue, we developed methods to form MAP scaffolds with user-defined particle fractions to reproducibly assess mechanical properties, macromolecular diffusion, as and cell responses. We then modulated the microstructure of the MAP scaffolds by changing microgel size as well as the spatial bioactivity using heterogeneous microgel populations to promote de novo assembly of endothelial progenitor-like cells into vessel-like structures. Through a combination of in silico and in vitro experimentation, we found that the microstructure (dimension of the void), integrin binding, and growth factor sequestration were all shown to guide vascular morphogenesis. We then demonstrated that the findings produced in a reductionist model of vasculogenesis translated to an in vivo effect on vessel formation in both dermal wounds and glioblastoma tumors.