Date of Award

2018

Document Type

Open Access Dissertation

Department

Biomedical Engineering

Sub-Department

College of Engineering and Computing

First Advisor

John F. Eberth

Abstract

Coronary artery bypass grafting (CABG) restores myocardial perfusion in patients with severe coronary artery disease by utilizing autografts – usually at least one of the internal thoracic artery (ITA), radial artery (RA), and great saphenous vein (GSV) – to bypass stenosed regions of coronary arteries. While decades of research and clinical improvements have made CABG an indispensable procedure, tens of thousands of grafts fail each year, which is due, at least in part, to an inability of the source vessels to adapt to the altered stimuli of the coronary circulation. In this dissertation, we first quantify and compare the mechanical deviation experienced by ITAs, RAs, and GSVs when subjected to coronary loads to better understand the nature and magnitude of forces stimulating remodeling processes. Those mechanical deviations are correlated with known clinical failure rates taken from large-cohort meta-analysis in existing literature. To better understand the early signaling and gene expression activity of grafts subjected to these coronary loads, we then culture ITAs, RAs, and GSVs in an ex vivo perfusion bioreactor for up to one week, identifying differential responses across source vessels that are associated with adaptive and maladaptive remodeling. Maladaptive remodeling processes and eventual graft failure may be associated with the large mechanical mismatching that results from implantation in the coronary circulation and the sudden exposure to coronary loading. We therefore test a stepwise approach wherein gradual increases in pressure and flow of ex vivo culture conditions over three weeks stimulate adaptive GSV remodeling while avoiding maladaptive pathways. This adaptive culture technique could be applied to engineered grafts, such as xenografts to improve the material properties prior to decellularization. To demonstrate the range of scaffolds that may be available from animal donors, we evaluate the passive mechanical properties of carotid arteries from six species of mammal. Vascular graft remodeling may also be sensitive to the intricacies of applied pressure and flow waveforms, so we developed and validated a novel pulsatile perfusion bioreactor capable of replicating any in vivo hemodynamic waveform. The combination of these techniques and results furthers understanding of CABG failure and vascular remodeling, while also providing a framework for engineering improved vascular grafts.

Rights

© 2018, David Andrew Prim

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