Abstract

ABSTRACT OF THE DISSERTATION Effects of Mechanical Anisotropy on Physiology and Pathology of iPSC-Derived Engineered Heart Tissue Models of Healthy and Diseased Myocardium by Ghiska Ramahdita Doctor of Philosophy in Mechanical Engineering Washington University in St. Louis, 2025 Professor Nathaniel Huebsch, Chair Professor Guy Genin, Co-Chair Heart disease progression is characterized by changes in cardiomyocytes as well as significant cardiac fibrosis. This dissertation is motivated by the premise that mechanical forces on cardiomyocytes and fibroblasts may play a key role in the fibrotic response of the heart. Given that heart fibers are uniaxially aligned, the force is distributed anisotropically during the cycle of systolic contraction. However, there is a significant gap in our understanding of the impact that tensional anisotropy has on the physiology of cardiac cells and the processes of fibrosis. This dissertation addresses the gap by developing a medium throughput micro-engineered tissue platforms to study how tensional anisotropy affects fibroblasts and iPSC-derived cardiomyocytes. Using this platform, I found that tensional anisotropy has a significant effect on fibroblast morphology, alignment and transition toward a myofibroblast state. In addition, these processes were further accelerated by increased cell density. In cardiac micro-tissues, high tensional anisotropy promoted cellular alignment, uniaxial contractility, and electrophysiological maturation. Notably, improved action potential dynamics were linked to increased expression of the voltage-gated sodium channel Nav1.5 in tissues with tensional anisotropy. These results highlighted the critical role of mechanical anisotropy in affecting both physiological and pathological responses in engineered cardiac tissues. Incorporating anisotropic cues into in vitro heart models not only improves their physiological relevance but also opens a new way for designing regenerative therapies, such as cardiac patches for myocardial infarction. This work advances our understanding of cardiac mechanobiology and offers new directions for modeling and treating heart disease.

Committee Chair

Nathaniel Huebsch

Committee Members

Guy Genin; Elliot Elson; Farid Alisafaei; Jessica Wagenseil; Michael Greenberg

Degree

Doctor of Philosophy (PhD)

Author's Department

Mechanical Engineering & Materials Science

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

8-18-2025

Language

English (en)

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Available for download on Monday, August 14, 2028

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