title: Cell-Mediated Proteolytic Release of Growth Factors from Poly(Ethylene Glycol) Matrices.
abstract: Engineering in vitro tissue mimetics that resemble the corresponding living tissues requires the 3D arrangement of tissue progenitor cells and their differentiation by localized growth factor (GF) signaling cues. Recent technological advances open a large field of possibilities for the creation of complex GF arrangements. Additionally, cell-instructive biomaterials, which bind GFs by various mechanisms and release them with different kinetics depending on binding affinity, have become available. This paper describes the development of a matrix metalloproteinase (MMP)-degradable streptavidin-based linker module, which allows the release of immobilized GFs from synthetic biomimetic poly(ethylene glycol) hydrogels independently of the hydrogel degradation. The MMP-sensitive streptavidin linker is shown to efficiently bind biotinylated molecules, and as proof of concept, bone morphogenetic protein-2 (BMP-2) delivery via the MMP-degradable linker is used to induce osteogenic differentiation in C2C12 cells and mesenchymal stem cells. The results show a significantly increased net effect of proteolytically releasable BMP-2 in comparison to stably immobilized and soluble BMP-2. This study indicates that a GF delivery system directly responsive to cellular activity can have important implications for the synthesis of tissue mimetics and regenerative medicine, as it can influence the availability, the localization of effects, as well as efficacy of employed GFs.
authors.affiliation: Department of Obstetrics, University and University Hospital Zurich, Schmelzbergstrasse 12, 8091, Zurich, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Metzger
authors.affiliation: Department of Obstetrics, University and University Hospital Zurich, Schmelzbergstrasse 12, 8091, Zurich, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Blache
authors.affiliation: Department of Obstetrics, University and University Hospital Zurich, Schmelzbergstrasse 12, 8091, Zurich, Switzerland.|School of Engineering and Applied Sciences, Harvard University, 58 Oxford St., Cambridge, MA, 02138, USA.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Lienemann
authors.affiliation: Faculty of Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestrasse 18, 79104, Freiburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Karlsson
authors.affiliation: Department of Cranio Maxillofacial Surgery, Oral Biotechnology and Bioengineering, University and University Hospital Zurich, Schmelzbergstrasse 12, 8091, Zurich, Switzerland.
authors.forename: Franz E
authors.initials: FE
authors.lastname: Weber
authors.affiliation: Faculty of Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestrasse 18, 79104, Freiburg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Weber
authors.affiliation: Department of Obstetrics, University and University Hospital Zurich, Schmelzbergstrasse 12, 8091, Zurich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Ehrbar
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D018093:Gelatinases / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D059748:Proteolysis
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D011092:Polyethylene Glycols; D018093:Gelatinases; C000595209:polyethylene glycol 1000
keywords: PEG hydrogel; growth factor immobilization; osteogenic differentiation; proteolytic release; streptavidin linker