Date of Award

12-2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Advisor

Vyavahare, Narendra

Committee Member

LaBerge , Martine

Committee Member

Ramamurthi , Anand

Committee Member

Simionescu , Dan

Abstract

Cardiovascular diseases are the leading cause of death worldwide. Blood vessel replacement is a common treatment for vascular diseases such as atherosclerosis, restenosis and aneurysm, with over 300,000 bypass procedures performed each year. However, vein grafts are limited due to their availability. Although synthetic vascular replacements have been successful for large diameter arteries, they have shown minimal success in arteries with diameters <6mm. This is because most synthetic materials induce thrombus formation which, within a few months of implantation, causes failure of the vascular graft due to occlusion. Tissue engineering is a promising approach to the fabrication of non-thrombogenic vascular grafts, but a reliable and expandable cell source for tissue-engineered vascular graft (TEVG) has not been established.
The work presented here is motivated by the current unavailability of an ideal tissue engineered blood vessel replacement. Our overall goal is to create a living tissue engineered vascular graft that is biodegradable, non-thromobogenic, presents low antigenicity and has mechanical properties that match the native arterial tissue. For this purpose, we have created and characterized pure elastin (EL) tubes from porcine carotid arteries as the scaffolds. We have shown that these elastin scaffolds obtained by our technique are pure, have increased porosity (over decellularized arteries), are highly biocompatible and possess an architecture that is similar to the native artery which may help integration with the host tissue.
In order to repopulate the scaffold with vascular cells to make it a living, responsive blood vessel replacement, we developed a novel in vivo cell recruitment technique. The local release of growth factors through an agarose gel delivery system within the lumen of the scaffold attracted vascular cells into the scaffold when placed in adipose tissue in a rabbit model. To reduce thrombogenicity, heparin was immobilized onto the EL scaffolds. A significant improvement in in vitro blood compatibility was seen with heparin immobilization. Platelet adhesion was reduced, thrombin inactivation was elevated, and plasma clotting time was significantly prolonged. Endothelial cells seeded on these heparin immobilized EL scaffolds maintained a quiescent profile with high thrombomodulin and PECAM-1 expression and low ICAM-1 expression. A majority of the cells were even able to resist detachment on exposure to physiological levels of shear stress.
These studies provide a new strategy to engineer a small diameter blood vessel with excellent antithrombogenicity, tissue compatibility and mechanics to integrate with host tissue. The true test of function though, lies in future animal vascular implant studies.
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