Development of Human Valvular Calcification via Fluid-Induced Oscillatory Shear Stress-Based Cell and Tissue Culture

Authors

Chia-Pei Hsu, Florida International UniversityFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biomedical Engineering

First Advisor's Name

Sharan Ramaswamy

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Joshua Hutcheson

Second Advisor's Committee Title

Committee chair

Third Advisor's Name

Nikolaos Tsoukias

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Florence George

Fourth Advisor's Committee Title

Committee member

Fifth Advisor's Name

Elena Aikawa

Fifth Advisor's Committee Title

Committee member

Keywords

Oscillatory flow, OSI, cardiovascular, valvular, vascular, calcification, shear stress, bioreactor

Date of Defense

10-21-2022

Abstract

Cardiovascular diseases are the global leading causes of morbidity and mortality that includes conditions affecting the heart and blood vessels, with little or no treatment options in many severe cases. Calcific aortic valve disease (CAVD) is one of the most common chronic heart problems that involves build-up of calcified deposits on the aortic valve leaflet, resulting in hardening of valve leaflets and inefficient valve function, thereby severely compromising the systemic blood circulation. Currently, there are no treatment options or diagnostic tools for early and intermediate stages of CAVD, and the main factors associated with early formation of CAVD remain unclear. Severe treatment options for CAVD include transcatheter aortic valve replacements (TAVR) and surgical aortic valve replacements (SAVR) with mechanical or bioprosthetic valves, which involve various potential risks and are therefore limited to a selective patient subset.

A major obstacle in developing therapeutic targets for early CAVD intervention is an absence of human tissue model systems that can assess the responses to potential treatments. While forces generated by blood flow are known to affect cardiovascular development and remodeling, these hemodynamic forces induce molecular cues that are often communicated amongst various cell types, and the links between flow patterns and development of CAVD requires further investigation. Common animal models for cardiovascular diseases such as ovine and porcine models, do not mimic the human response following heart valve therapeutics. Therefore, understanding the specific effects of flow oscillations on human valve pathology can also help to establish the foundation for developing a human engineered tissue model system for early stages of CAVD, thereby forming a testbed for effective drug discovery. Using the oscillatory shear index (OSI) as a parameter to quantify the degree of flow oscillations, this PhD dissertation provides identification between a specific OSI-level and the clear induction of CAVD. In this regard, for 3D tissue culture assessment, an oscillatory flow bioreactor was built and used. This bioreactor facilitates a controlled oscillatory flow environment that allows mechanistic and longitudinal studies of evolving CAVD at the organ-level and may serve as a potential platform to facilitate drug discovery for effective pharmaceutical management of CAVD.

Identifier

FIDC010875

ORCID

https://orcid.org/0000-0001-8297-7162

Previously Published In

Gonzalez BA, Herrera A, Ponce C, Gonzalez Perez M, Hsu CPD, Mirza A, Perez M, Ramaswamy S. Stem Cell-Secreted Allogeneic Elastin-Rich Matrix with Subsequent Decellularization for the Treatment of Critical Valve Diseases in the Young. Bioengineering. 2022; 9(10):587. DOI: https://doi.org/10.3390/bioengineering9100587

Hsu CPD, Tchir A, Mirza A, Chaparro D, Herrera RE, Hutcheson JD, Ramaswamy S. Valve Endothelial Cell Exposure to High Levels of Flow Oscillations Exacerbates Valve Interstitial Cell Calcification. Bioengineering. 2022; 9(8):393. DOI: https://doi.org/10.3390/bioengineering9080393

Hsu CPD, Hutcheson JD, Ramaswamy S. (2020). Oscillatory Fluid-Induced Mechanobiology in Heart Valves with Parallels to the Vasculature. Vascular Biology, 2(1), R59-R71. DOI: https://doi.org/10.1530/VB-19-0031

Recommended Citation

Hsu, Chia-Pei, "Development of Human Valvular Calcification via Fluid-Induced Oscillatory Shear Stress-Based Cell and Tissue Culture" (2022). FIU Electronic Theses and Dissertations. 5203.
https://digitalcommons.fiu.edu/etd/5203