Date of Award

1-1-2012

Document Type

Campus Access Dissertation

Department

Biomedical Engineering

First Advisor

Richard Goodwin

Abstract

One percent of the newborn population is born with a form of congenital heart disease (CHD), of which valve disease is most common. Many of these infants do not survive their first year of life and those that survive often require complex surgeries. An additional group of CHDs go undetected until adulthood, when clinical symptoms first appear. These adults undergo valve replacement, the second most common surgery, and receive valves with limited strength and biocompatibility. In an effort to address these problematic issues, researchers have attempted to create tissue engineered replacement valves, and carry out investigations on valve mechanics. These efforts depend on elucidating the mechanisms by which valves develop their fibrous phenotype. A longstanding hypothesis is that flow-induced forces directly regulate valve development, however, the mechanisms behind this mechanotransduction remain unclear. The purpose of this study was to i) quantify the flow-induced forces that act on valves during key stages in early development and to ii) test the cellular response to estimated physiological and pathological levels of flow using an in vitro system of valve development. These experiments tested the hypotheses that i) flow-mediated forces regulate the deposition and localization of fibrous extracellular matrix (ECM) proteins in developing valves through a series of interrelated pathways and ii) abnormal flow leads to altered pathway dynamics, resulting in pathological valve development.

To quantify the shear and normal forces exerted on developing valve tissue, two computational models were generated and compared. Initially, two-dimensional simulations were performed to represent a longitudinal section through the heart canal. A steady state flow representing either peak blood ejection and peak relaxation was applied at the inlet and forces on the heart wall were estimated. The second model incorporated fluid-structure interaction and idealized the heart as an axisymmetric channel undergoing peristaltic, elastic wall motion. Both models indicated that normal and shear forces are of comparable magnitudes and might equally contribute to valve developmental processes. A dynamic, 3D in vitro system was used to culture embryonic valve tissue inside tubular collagen scaffolds of varying dimensions. Tissue was cultured under different levels of flow as well as in the absence flow. Creeping or lack of flow stimulated valve precursor cells to take on a more primitive valve phenotype that is characteristic of an earlier developmental time point. Physiological flow initiated normal, fibrous valve development while supraphysiological levels of flow resulted in pathological tissue remodeling. These studies indicate that both the timing and the magnitude of flow alter cellular processes that determine if valve precursor tissue will undergo healthy or pathological development.

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