Engineered fibrin matrices for functional display of cell membrane-bound growth factor-like activities: study of angiogenic signaling by ephrin-B2.
With the rapid increase in approaches to pro- or anti-angiogenic therapy, new and effective methodologies for administration of cell-bound growth factors will be required. We sought to develop the natural hydrogel matrix fibrin as platform for extensive interactions and continuous signaling by the vascular morphogen ephrin-B2 that normally resides in the plasma membrane and requires multivalent presentation for ligation and activation of Eph receptors on apposing endothelial cell surfaces. Using fibrin and protein engineering technology to induce multivalent ligand presentation, a recombinant mutant ephrin-B2 receptor binding domain was covalently coupled to fibrin networks at variably high densities. The ability of fibrin-bound ephrin-B2 to act as ligand for endothelial cells was preserved, as demonstrated by a concomitant, dose-dependent increase of endothelial cell binding to engineered ephrin-B2-fibrin substrates in vitro. The therapeutic relevance of ephrin-B2-fibrin implant matrices was demonstrated by a local angiogenic response in the chick embryo chorioallontoic membrane evoked by the local and prolonged presentation of matrix-bound ephrin-B2 to tissue adjacing the implant. This new knowledge on biomimetic fibrin vehicles for precise local delivery of membrane-bound growth factor signals may help to elucidate specific biological growth factor function, and serve as starting point for development of new treatment strategies.
Department of Materials Science, Institute for Biomedical Engineering, ETH Zurich, University of Zurich, Moussonstr. 18, 8044 Zurich, Switzerland. andreas.zisch@mat.ethz.ch
Andreas H
AH
Zisch
Steffen M
SM
Zeisberger
Martin
M
Ehrbar
Valentin
V
Djonov
Cornelia C
CC
Weber
Andrew
A
Ziemiecki
Elena B
EB
Pasquale
Jeffrey A
JA
Hubbell
D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004343:Drug Implants / Q000008:administration & dosage / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D036388:Ephrin-B2 / Q000008:administration & dosage* / Q000737:chemistry* / Q000235:genetics; D005321:Extraembryonic Membranes / Q000098:blood supply* / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005337:Fibrin / Q000737:chemistry*; D006801:Humans; D008422:Materials Testing; D008567:Membranes, Artificial; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D043925:Angiogenesis Inducing Agents; D020099:Coated Materials, Biocompatible; D003692:Delayed-Action Preparations; D004343:Drug Implants; D036388:Ephrin-B2; D008567:Membranes, Artificial; D011994:Recombinant Proteins; D005337:Fibrin