title: Two-tier hydrogel degradation to boost endothelial cell morphogenesis.
abstract: Cell-responsive degradation of biofunctional scaffold materials is required in many tissue engineering strategies and commonly achieved by the incorporation of protease-sensitive oligopeptide units. In extension of this approach, we combined protease-sensitive and -insensitive cleavage sites for the far-reaching control over degradation rates of starPEG-heparin hydrogel networks with orthogonally modulated elasticity, RGD presentation and VEGF delivery. Enzymatic cleavage was massively accelerated when the accessibility of the gels for proteases was increased through non-enzymatic cleavage of ester bonds. The impact of gel susceptibility to degradation was explored for the 3-dimensional ingrowth of human endothelial cells. Gels with accelerated degradation and VEGF release resulted in strongly enhanced endothelial cell invasion in vitro as well as blood vessel density in the chicken chorioallantoic membrane assay in vivo. Thus, combination of protease-sensitive and -insensitive cleavage sites can amplify the degradation of bioresponsive gel materials in ways that boost endothelial cell morphogenesis.
authors.affiliation: Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials Dresden & Technische Universität Dresden, Center for Regenerative Therapies Dresden, Hohe Str. 6, 01069 Dresden, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Chwalek
authors.forename: Kandice R
authors.initials: KR
authors.lastname: Levental
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Tsurkan
authors.forename: Andrea
authors.initials: A
authors.lastname: Zieris
authors.forename: Uwe
authors.initials: U
authors.lastname: Freudenberg
authors.forename: Carsten
authors.initials: C
authors.lastname: Werner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001673:Biodegradation, Environmental; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D002470:Cell Survival; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000378:metabolism; D006493:Heparin / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology*; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D011092:Polyethylene Glycols / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; D006493:Heparin