title: Differential regulation of angiogenesis using degradable VEGF-binding microspheres.
abstract: Vascular endothelial growth factor (VEGF) spatial and temporal activity must be tightly controlled during angiogenesis to form perfusable vasculature in a healing wound. The native extracellular matrix (ECM) regulates growth factor activity locally via sequestering, and researchers have used ECM-mimicking approaches to regulate the activity of VEGF in cell culture and in vivo. However, the impact of dynamic, affinity-mediated growth factor sequestering has not been explored in detail with biomaterials. Here, we sought to modulate VEGF activity dynamically over time using poly(ethylene glycol) microspheres containing VEGF-binding peptides (VBPs) and exhibiting varying degradation rates. The degradation rate of VBP microspheres conferred a differential ability to up- or down-regulate VEGF activity in culture with primary human endothelial cells. VBP microspheres with fast-degrading crosslinks reduced VEGF activity and signaling, while VBP microspheres with no inherent degradability sequestered and promoted VEGF activity in culture with endothelial cells. VBP microspheres with degradable crosslinks significantly reduced neovascularization in vivo, but neither non-degradable VBP microspheres nor bolus delivery of soluble VBP reduced neovascularization. The covalent incorporation of VBP to degradable microspheres was required to reduce neovascularization in a mouse model of choroidal neovascularization in vivo, which demonstrates a potential clinical application of degradable VBP microspheres to reduce pathological angiogenesis. The results herein highlight the ability to modulate the activity of a sequestered growth factor by changing the crosslinker identity within PEG hydrogel microspheres. The insights gained here may instruct the design and translation of affinity-based growth factor sequestering biomaterials for regenerative medicine applications.
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Belair
authors.affiliation: Department of Chemical and Biological Engineering, University of Wisconsin-Madison, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Miller
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, USA.
authors.forename: Shoujian
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, USA.
authors.forename: Soesiawati R
authors.initials: SR
authors.lastname: Darjatmoko
authors.affiliation: Department of Surgery, University of Wisconsin-Madison, USA.
authors.forename: Bernard Y K
authors.initials: BYK
authors.lastname: Binder
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, USA; Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, USA.
authors.forename: Nader
authors.initials: N
authors.lastname: Sheibani
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, USA; Material Science Program, University of Wisconsin-Madison, USA; Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, USA. Electronic address: wlmurphy@wisc.edu.
authors.forename: William L
authors.initials: WL
authors.lastname: Murphy
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000473:pathology; D003432:Cross-Linking Reagents / Q000737:chemistry; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008810:Mice, Inbred C57BL; D008863:Microspheres; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010455:Peptides / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols
keywords: Biomimetic microspheres; Choroidal neovascularization; Degradable biomaterials; Endothelial cells; Growth factor sequestering; Vascular endothelial growth factor