Advisor(s)
Palaniappan Sethu
Committee Member(s)
Carlos Orihuela
Glenn Rowe
Mary Kathryn Sewell-Loftin
Min Xie
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Biomedical Engineering
Date of Award
1-7-2025
Abstract
Myocardial fibrosis often accompanies cardiovascular disease of varying etiologies. Initial reparative myocardial remodeling following insult, characterized by fibroblast-to-myofibroblast transdifferentiation and myofibroblast-mediated collagen deposition, can become a chronic, maladaptive process if injurious stimuli are not removed and inflammation persists, and the resultant fibrosis worsens cardiac function through myocardial stiffening and arrhythmogenic disruption of cardiomyocyte coupling. There are no FDA-approved therapies targeting myocardial fibrosis, in large part due to the complexity of the disease process. In vitro models can serve as useful complements to in vivo studies as they allow for significantly greater control over experimental variables. Cardiac tissue chips (CTCs) are in vitro platforms that replicate essential characteristics of myocardial structure and function through exposure of engineered cardiac tissues to cyclical pressure and/or stretch profiles experienced by myocardium in physiological and pathophysiological scenarios. This dissertation aims to develop CTCs that recapitulate critical molecular hallmarks of myocardial fibrosis in vitro through exposure of engineered cardiac tissues to clinically relevant mechanical stresses and/or profibrotic chemical mediators and to subsequently utilize these platforms to investigate the therapeutic potential of different anti-fibrotic treatments as well as the role of circulating macrophages in the propagation and resolution of fibrosis. Chapter 1 focuses on the establishment of a CTC model capable of recapitulating clinically-relevant hallmarks of left ventricular remodeling secondary to volume overload experienced by end-stage kidney disease patients in the window of time following placement of arteriovenous fistulae (AVFs) and preceding initiation of hemodialysis. Chapter 2 focuses on investigating the potential of SD-208, a TGF-β receptor I kinase inhibitor, and nintedanib, a multi-targeted small molecule tyrosine kinase inhibitor FDA-approved for treatment of idiopathic pulmonary fibrosis, to prevent and reverse cardiac fibroblast-to-myofibroblast transdifferentiation in 2D and 3D cell culture assays and their anti-fibrotic effects in a TGF-β-stimulated fibrotic CTC. Chapter 3 focuses on the development of a CTC model of senescent myocardium with incorporation of monocyte-derived macrophages and short-term hypoxic treatment as a platform for investigating the impact of circulating macrophages on aged myocardium.
ProQuest ID
Recommended Citation
Graham, Caleb, "Development Of Cardiac Tissue Chip Platforms For In Vitro Modeling Of Myocardial Fibrosis" (2025). All ETDs from UAB. 7310.
https://digitalcommons.library.uab.edu/etd-collection/7310
