Abstract

Valvular degenerative conditions are significant contributors to morbidity and mortality globally, presenting substantial medical challenges to public health. Despite this, obtaining comprehensive insights into the pathophysiology of valvular heart diseases remains complex. Valvular interstitial cells (VICs), the primary cell population in heart valves, are pivotal in the pathogenesis of these diseases. While VICs are typically quiescent in healthy adult heart valves, they undergo phenotypic activation in degenerative valves, transforming into myofibroblast-like cells, known as activated VICs. Mechanobiology plays a crucial role in valvular pathophysiology, with various mechanical forces triggering phenotypical transformations in VICs, leading to the onset of valvular degenerative diseases. Given the unique size, role, and location of heart valves within the body, there is a compelling need for in vitro systems capable of accurately recapitulating the initiation and progression of these diseases. This study introduces an in vitro model development and its utilization in mechanically stimulating valvular cells for transformation. Aortic valve interstitial cells from porcine source (PAVIC), grown on microfluidic devices constructed from polydimethylsiloxane (PDMS), experienced different levels of mechanical stimulation, with or without being exposed to tensile stretch. The mechanobiological responses of valvular interstitial cells were examined across a range of strains from 0 to 18%, encompassing relevant tensile strain ii values during peak diastole established for both normal and diseased valves. Morphological characterization of in vitro VIC activation was conducted, focusing on cell shape distribution at varying strain levels. At higher strains, there was an increase in myofibroblastic morphologies in the distribution, surpassing the known quiescent fibroblastic morphologies in cell cultures. Cells also exhibited elongation, and there was an up-regulation of PAVIC transformation, as evidenced by an increased expression of α-smooth muscle actin. This study establishes a link between the application of tensile stretch and phenotype transformations, an initial step towards the development of an elastic dome dedicated to exploring heart valve mechanobiology. This approach will facilitate investigations into the signaling pathways governing stretch-induced valvular degeneration, potentially paving the way for the discovery of therapeutic interventions for valvular degeneration.

Date of publication

Spring 5-16-2024

Document Type

Thesis (Local Only Access)

Language

english

Persistent identifier

http://hdl.handle.net/10950/4697

Committee members

Carla Lacerda, Shih-Feng Chou, Shawana Tabassum

Degree

Master of Science in Mechanical Engineering

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