Date of Award
8-2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Bioengineering
Committee Chair/Advisor
Dr. Agneta Simionescu
Committee Member
Dr. Dan Simionescu
Committee Member
Dr. Leslie Sierad
Committee Member
Dr. Christopher Wright
Abstract
Heart valve disease affects an average of 2.5% of the population in the United States. The mitral valve (MV) is the most complex of the heart’s four valves and is most associated with the disease by exhibiting altered extracellular matrix (ECM) which translates into stenosis or regurgitation. These diseases are typically degenerative in nature and can be accelerated by risk factors such as diabetes and hypertension. With diabetes and hypertension affecting 425 million and 1.39 billion people worldwide, further investigation into these risk factors is warranted. This study aims to develop and test an in vitro model of MV disease. Utilizing tissue engineering methods and a custom bioreactor, the ability to simulate physiological and pathological conditions can be obtained. A dynamic in vitro method to study the 3D complexity of the MV and its associated pathologies is lacking. Here we propose a tissue engineered MV and a versatile MV bioreactor as a model for the identification of valvular component, cell, and matrix modifications that occur in diabetes and hypertension. First, a dynamic model was established as a resource to study MV pathologies' mechanisms. Decellularized porcine MV scaffolds showed comparable mechanical properties to native valves, while preserving crucial ECM components. A custom mounting apparatus was able to properly secure the tissue-engineered MV in the bioreactor while maintaining anatomical geometries. The bioreactor showed proper hemodynamic control of the MV through appropriate coaptation of the leaflets and opening during the cardiac cycle with tunable heart rate, pressures, and stroke volume. iiMV scaffolds were recellularized by seeding with valvular interstitial cells (VICs), and valvular endothelial cells (VECs) and conditioned under normal physiological parameters or hypertensive, diabetic (high glucose), and diabetic/hypertension combined conditions. We show here that under pathological conditions, VICs and VECs became activated and showed signs of ECM remodeling with increased MMP activity. To validate the in vitro model, we also studied MV pathology in a diabetic minipig model where similar cellular and ECM alterations were observed. Overall these results show that our dynamic in vitro model utilizing tissueengineered MVs can be used to study the effects of diabetes and hypertension, two major risk factors that could lead to MV disease, offering opportunities to strengthen knowledge in MV pathologies and develop targeted treatment options.
Recommended Citation
Owens, Collin, "Mitral Valve Tissue Engineering - A Dynamic Model for Investigating the Mechanism of Valvular Pathology" (2022). All Dissertations. 3107.
https://tigerprints.clemson.edu/all_dissertations/3107