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Contrasting Biofunctionalization Strategies for the Enhanced Endothelialization of Biodegradable Vascular Grafts John P Fisher Biomacromolecules, Just Accepted Manuscript • Publication Date (Web): 29 Dec 2014 Downloaded from http://pubs.acs.org on January 5, 2015
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Contrasting Biofunctionalization Strategies for the Enhanced Endothelialization of Biodegradable Vascular Grafts
Journal: Manuscript ID: Manuscript Type: Date Submitted by the Author: Complete List of Authors:
Biomacromolecules bm-2014-01853s Article 20-Dec-2014 Melchiorri, Anthony; University of Maryland, Fischell Department of Bioengineering Hibino, Narutoshi; Nationwide Children's Hospital, Cardiothoracic Surgery Yi, Tai; Nationwide Children's Hospital, Tissue Engineering Program and Surgical Research Lee, Yong Ung; Children's Nationwide Hospital, Tissue Engineering Program and Surgical Research Sugiura, Tadahisa; Children's Nationwide Hospital, Tissue Engineering Program and Surgical Research Tara, Shuhei; Children's Nationwide Hospital, Shinoka, Toshiharu; Nationwide Children's Hospital, Cardiothoracic Surgery Breuer, Christopher; Nationwide Children's Hospital, Fisher, John; University of Maryland, Fischell Department of Bioengineering
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Biomacromolecules
Contrasting Biofunctionalization Strategies for the Enhanced Endothelialization of Biodegradable Vascular Grafts Melchiorri AJ1*, Hibino N2,3*, Yi T3, Lee YU3, Sugiura T3, Tara S3, Shinoka T2,3, Breuer C3, Fisher JP1# 1
Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742 Tissue Engineering Program and Surgical Research, Nationwide Children’s Hospital, Columbus, OH 43205 3 Department of Cardiothoracic Surgery, Nationwide Children’s Hospital, Columbus, OH 43205 2
*These authors contributed equally to this paper
Short Title:
Enhanced Endothelialization of Vascular Grafts
Submitted To:
Biomacromolecules
Keywords:
Vascular grafts, endothelialization, surface modification, growth factors, heparin
#
John P. Fisher Fischell Family Distinguished Professor and Associate Chair Fischell Department of Bioengineering University of Maryland 3238 Jeong H. Kim Engineering Building College Park, Maryland 20742 Work: 301 405 8782 Fax: 301 314 6868 Email:
[email protected] Corresponding Author:
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Page 2 of 42 Enhanced Endothelialization of Vascular Grafts December 11, 2014
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Abstract Surface modification of biodegradable vascular grafts is an important strategy to improve the
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in situ endothelialization of tissue engineered vascular grafts (TEVGs) and prevent major
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complications associated with current synthetic grafts. Important strategies for improving
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endothelialization include increasing endothelial cell mobilization and increased endothelial cell
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capture through biofunctionalization of TEVGs. The objective of this study was to assess two
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biofunctionalization strategies for improving endothelialization of biodegradable polyester
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vascular grafts. These techniques consisted of crosslinking heparin to graft surfaces to
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immobilize vascular endothelial growth factor (VEGF) or antibodies against CD34 (anti-
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CD34Ab). To this end, heparin, VEGF, and anti-CD34Ab attachment and quantification assays
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confirmed the efficacy of the modification strategy. Cell attachment and proliferation on these
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groups were compared to unmodified grafts in vitro and in vivo. To assess in vivo graft
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functionality, the grafts were implanted as inferior vena cava interpositional conduits in mice.
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Modified vascular grafts displayed increased endothelial cell attachment and activity in vivo,
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according to microscopy techniques, histological results, and eNOS expression. Inner lumen
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diameter of the modified grafts was also better maintained than controls. Overall, while both
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functionalized grafts outperform the unmodified control, grafts modified with anti-CD34Ab
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appeared to yield the most improved results compared to VEGF-loaded grafts.
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Biomacromolecules Enhanced Endothelialization of Vascular Grafts December 11, 2014
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Introduction
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Cardiovascular disease is the leading cause of mortality worldwide1. To treat many of the
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conditions associated with cardiovascular disease, autologous vessels or synthetic grafts are
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often used. However, autologous vessels may be limited by existing conditions or previous
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surgeries2,3. In synthetic grafts, complications include lack of growth potential, calcification from
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secondary graft failure, increased susceptibility to infection, and increased risk for
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thromboembolic events and stenosis4,5. Tissue engineered vascular grafts (TEVGs) offer a
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potential strategy for overcoming these complications by providing a biodegradable scaffold for
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the autologous cells to attach, proliferate, and provide physiologic functionality. A scaffold that
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enables and encourages healthy vascular tissue growth while degrading over time would
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eliminate many of the complications associated with permanent, synthetic grafts. However, a
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primary mode of failure of small-diameter (
