Date of Award

12-2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Advisor

LaBerge, Martine

Committee Member

Langan, III , Eugene M

Committee Member

Miller , Richard S

Committee Member

Nagatomi , Jiro

Committee Member

Ramamurthi , Anand

Abstract

Restenosis remains a common problem affecting the patency of endovascular intervention such as balloon angioplasty and stent placement as treatments for atherosclerosis. Denudation of the endothelial layer and the increased injury from balloon deployment can cause phenotypic changes in surrounding vascular smooth muscle cells (SMCs) in vivo. The presented work modeled this mechanical environment in vitro to investigate the role of the altered mechanical environment on the phenotypic response of SMCs. Through the system design and CFD channel characterization, a six-independent-channel system providing low oscillating wall shear stress (WSS) was manufactured to apply concurrent shear and tensile forces with uniform strain and WSS profiles over the cell location. The project hypothesis that balloon angioplasty endovascular intervention exposing vascular smooth muscle cells to an altered mechanical environment would evoke a cell phenotype change. The exposure of SMCs to concurrent shear and tensile forces following balloon angioplasty resulted in a more synthetic phenotype behavior marked by such characteristics as increased synthetic morphology, increased proliferation, increased apoptosis and decreased expression of contractile markers.
Clinical implications for this work suggest that physiological dynamic regimens should be incorporated into in vitro studies. We simulated balloon angioplasty through increased strains and a clinical heparin bolus administration, both of which evoked different SMC responses compared to controls. SMC response triggered by exposure to the injury model resembled in vivo reactions following balloon angioplasty. Therefore, dynamic concurrent shear and tensile forces should be incorporated in vascular in vitro testing to possibly lead to better treatment and prevention of restenosis following endovascular intervention.

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