Date of Award

6-3-2009

Document Type

Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Christopher Breuer

Abstract

Biodegradable tubular scaffolds are currently being evaluated as vascular grafts in the surgical treatment of congenital heart disease. Seeding scaffolds with bone marrow-derived mononuclear cells (BMCs) prior to implantation has been shown to significantly improve outcomes, including the long-term patency and vascular development of these grafts. However, the role these cells play is poorly understood. An IVC interposition model in an immunodeficient mouse recipient was used to evaluate the developmental remodeling process of engineered blood vessels, constructed from polyester tubular scaffolds seeded with human or mouse BMCs. Seeding scaffolds with BMCs significantly improved patency rates and graft development. However, seeded BMCs did not directly contribute to the cellularity of the developing vessel, and were not detectable by three weeks. Rather, BMCs were found to produce significant amounts of MCP-1 in response to the scaffold biomaterials, resulting in early recruitment of recipient mouse monocytes to the scaffold and subsequent improvement in vascular neotissue formation. Seeding with mouse BMCs derived from MCP-1 knock out mice resulted in significant increases in late stenosis and graft wall thickening compared to wild type BMCs, demonstrating a direct role of MCP-1 in engineered blood vessel development and function. Furthermore, proper vessel development with increased early monocyte recruitment could be restored without the use of seeded BMCs by locally delivering MCP-1 directly from the scaffold. These results indicate that engineered blood vessels mature through an MCP-1 dependent pathway, and present an "off-the-shelf" approach to vascular tissue engineering using acellular, chemokine-delivery scaffold systems.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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