Engineering the Microstructure and Spatial Bioactivity of MAP Scaffolds Instructs Vasculogenesis In Vitro and Modifies Vessel Formation In Vivo

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AbstractIn tissues where the vasculature is either lacking or abnormal, biomaterials can be designed to promote vessel formation and enhance tissue repair. In this work, the microstructure and bioactivity of microporous annealed particle (MAP) scaffolds are independently tuned to guide cell growth in 3D and promote de novo assembly of endothelial progenitor‐like cells into vessels. Both in silico characterization and in vitro experimentation are implemented to elucidate an optimal scaffold formulation for vasculogenesis. It is determined that MAP scaffolds with pore volumes on the same order of magnitude as cells facilitate cell growth and vacuole formation. Spatial control over cell spreading is achieved by incorporating adhesive microgels in well‐mixed, heterogeneous MAP scaffolds. While it is demonstrated that integrin engagement is the primary driver of network formation in these materials, introducing adhesive microgels loaded with heparin nanoparticles leads to the formation of vascular tubes after 3 days in culture. It is then shown in vivo that this unique scaffold formulation enhances vessel maturation in a wound‐healing model and instructs differential vascular development in the tumor microenvironment. Taken together, this work determines the optimal microstructure and ligand presentation within MAP scaffolds that leads to vascular constructs in vitro and facilitates vessel formation in vivo.