Protease‐Sensitive PEG Hydrogels Regulate Vascularization In Vitro and In Vivo

Abstract

Forming functional blood vessel networks in engineered or ischemic tissues is a significant scientific and clinical hurdle. Poly(ethylene glycol) (PEG)‐based hydrogels are adapted to investigate the role of mechanical properties and proteolytic susceptibility on vascularization. Four arm PEG vinyl sulfone is polymerized by Michael‐type addition with cysteine groups on a slowly degraded matrix metalloprotease (MMP) susceptible peptide, GPQG↓IWGQ, or a more rapidly cleaved peptide, VPMS↓MRGG. Co‐encapsulation of endothelial cells and supportive fibroblasts within the gels lead to vascular morphogenesis in vitro that is robust to changes in crosslinking peptide identity, but is significantly attenuated by increased crosslinking and MMP inhibition. Perfused vasculature forms from transplanted cells in vivo in all gel types; however, in contrast to the in vitro results, vascularization in vivo is not decreased in the more crosslinked gels. Collectively, these findings demonstrate the utility of this platform to support vascularization both in vitro and in vivo. Co‐encapsulation of endothelial cells and supportive fibroblasts within proteolyzable poly(ethylene glycol) (PEG)‐based hydrogels leads to vascular morphogenesis in vitro that is robust to changes in crosslinking peptide identity but is significantly attenuated by gel crosslinking and MMP inhibition. In vivo, perfused vasculature forms from transplanted cells in all gel types, and vascularization is not attenuated in more crosslinked gels.