Composition, turnover, and mechanics of extracellular matrix in developing, aging, and pathological valves for application in the design of age-specific tissue engineered heart valves
Stephens, Elizabeth Humes
Grande-Allen, K. Jane
Doctor of Philosophy
Debilitating valve disease necessitating valve replacement affects patients of all ages, all of whom would benefit from a tissue engineered heart valve with immunocompatibility, the ability of the valve to remodel in response to altered hemodynamics or patient growth, and physiologic mechanics. However, there may be age-specific requirements for such a valve. The overarching goal of this thesis was to characterize the extracellular matrix in developing, aging, and pathological mitral and aortic valves (MV, AV) in order to provide design criteria for an age-specific tissue engineered heart valve. The extracellular matrix plays a vital role in valve function; not only does it comprise the bulk of the valve tissue, but it determines the material properties of the valve, is integrally involved in biological signaling processes, and is altered in a number of valve pathologies. To this end, the composition, structure, and material properties of normal MV and AV were characterized with particular attention paid to valve heterogeneity and aging-related changes. Valves from disease states such as functional mitral regurgitation, dilated cardiomyopathy, iatrogenic valve wounds, calcific aortic valve disease, and myxomatous mitral valve disease were also analyzed to provide negative design criteria for a tissue engineered heart valve. Lastly, preliminary work was performed in developing a tissue engineered heart valve using poly(ethylene) glycol (PEG) hydrogels and valve cells of different ages. In sum, this body of work provides necessary design criteria for an age-specific tissue engineered heart valve, but in the process of analyzing various aspects of normal and diseased MV and AV, this thesis additionally provides insight into a variety of aspects of normal valve physiology, such as the relationship between valve composition and material properties and the mechanical environment, as well as insight into various valve diseases, such as the role of MV remodeling in functional mitral regurgitation and disease progression, with potential clinical implications for patients with these diseases.
Biomedical engineering; Biophysics; Biomechanics