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MMP-2 sensitive, VEGF-bearing bioactive hydrogels for promotion of vascular healing

Authors

  • D. Seliktar,

    1. Institute for Biomedical Engineering, Swiss Federal Institute of Technology and University of Zurich, Moussonstrasse 18, CH-8044 Zurich, Switzerland
    2. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
    Current affiliation:
    1. Department of Biomedical Engineering, Technion, Technion City, Haifa 32000, Israel.
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  • A. H. Zisch,

    1. Institute for Biomedical Engineering, Swiss Federal Institute of Technology and University of Zurich, Moussonstrasse 18, CH-8044 Zurich, Switzerland
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  • M. P. Lutolf,

    1. Institute for Biomedical Engineering, Swiss Federal Institute of Technology and University of Zurich, Moussonstrasse 18, CH-8044 Zurich, Switzerland
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  • J. L. Wrana,

    1. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
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  • J. A. Hubbell

    Corresponding author
    1. Institute for Biomedical Engineering, Swiss Federal Institute of Technology and University of Zurich, Moussonstrasse 18, CH-8044 Zurich, Switzerland
    • Institute for Biomedical Engineering, Swiss Federal Institute of Technology and University of Zurich, Moussonstrasse 18, CH-8044 Zurich, Switzerland
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Abstract

We sought to develop bioactive hydrogels to facilitate arterial healing, e.g., after balloon angioplasty. Toward this end, we developed a new class of proteolytically sensitive, biologically active polyethylene glycol (PEG)-peptide hydrogels that can be formed in situ to temporarily protect the arterial injury from blood contact. Furthermore, we incorporated endothelial cell-specific biological signals with the goal of enhancing arterial reendothelialization. Here we demonstrate efficient endothelial cell anchorage and activation on PEG hydrogel matrices modified by conjugation with both the cell adhesive peptide motif RGD and an engineered variant of vascular endothelial growth factor (VEGF). By crosslinking peptide sequences for cleavage by MMP-2 into the polymer backbone, the hydrogels became sensitive to proteolytic degradation by cell-derived matrix metalloproteinases (MMPs). Analysis of molecular hallmarks associated with endothelial cell activation by VEGF-RGD hydrogel matrices revealed a 70% increase in production of the latent MMP-2 zymogen compared with PEG-peptide hydrogels lacking VEGF. By additional provision of transforming growth factor β1 (TGF-β1) within the PEG-peptide hydrogel, conversion of the latent MMP zymogen into its active form was demonstrated. As a result of MMP-2 activation, strongly enhanced hydrogel degradation by activated endothelial cells was observed. Our data illustrate the critical importance of growth factor activities for remodeling of synthetic biomaterials into native tissue, as it is desired in many applications of regenerative medicine. Functionalized PEG-peptide hydrogels could help restore the native vessel wall and improve the performance of angioplasty procedures. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 704–716, 2004

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