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Controllable and robust morphogenesis of functional vascular network assembly within synthetic environments

The generation of functional vascular networks by endothelial colony‐forming cells (ECFCs) has the potential to improve treatment for vascular diseases and to facilitate successful organ transplantation. Although this process has been elucidated using natural matrix, little is known about angiogenesis in synthetic matrix, a xeno‐free scaffold which can provide a more clinically relevant alternative for regenerative medicine. Here, we utilized chemically and mechanically tunable hyaluronic acid (HA) hydrogels as scaffolds to investigate angiogenesis by ECFCs. We are able to control vascular morphogenesis and form robust microvasculatures by adjusting matrix elasticity, RGD binding, and MMP‐sensitive crosslinkers. First we established the RGD concentration required to induce efficient vacuoles and lumen formation. Integration of MMP‐sensitive‐peptide enabled ECFCs to sprout, branch, and form complex vascular networks. Increased expression of Hyal‐1, ‐2, MMP‐1,‐2, and MT1‐MMP were followed by the decrease in matrix stiffness. Once the constructs were matured in vitro, indicated by an increased expression of TIMP‐2 and ‐3, the constructs were implanted in vivo. After two weeks, most of the microvessels found were positive for human CD31 and perfused with blood cells, indicating that the implanted human vascular networks were able to anastomose with the host vasculatures to form functional vessel.