Engineering Next-Generation Cardiovascular Therapies

Date of Award

12-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioengineering

Committee Chair/Advisor

Ying Mei

Committee Member

Hai Yao

Committee Member

Michael Yost

Committee Member

Donald Menick

Abstract

Cardiovascular diseases are the leading cause of death worldwide. Heart disease, in particular, accounted for 1 in every 5 deaths in the United States in 2021, representing a substantial public health burden that will require more effective treatment options to alleviate. Heart transplant surgery is currently the only option to completely restore cardiac function, but many patients die while waiting for a transplant due to a longstanding organ donor shortage. Thus, there is a dire need for accessible treatment options that can repair damaged hearts. Recent advances in tissue engineering and regenerative medicine have accelerated the development of therapies for cardiac repair, enabling functional heart cells to be grown in the lab and transplanted directly into injured myocardium. However, cardiac tissue engineering faces several key hurdles, including vascularization of grafted tissue, long-term functional engraftment of transplanted cells, and an unclear understanding of their therapeutic mechanisms. In my doctoral research, I developed novel platforms to address these limitations and advance the translational potential of cardiac tissue engineering. My research focused on leveraging the native microenvironment of cells in vascularized, electrically conductive cardiac tissue to develop bioinspired therapies for cardiovascular disease. Engineering a chemically defined hydrogel matrix inspired by native angiogenesis mechanisms, I developed a bioink for bioprinting modular vascularized tissue engineering constructs that could be applied broadly to cardiovascular disease and wound healing. Next, inspired by the native cardiac conduction system, I developed human cardiac microtissues (organoids) embedded with electrically conductive silicon nanowires (e-SiNWs) to improve the efficiency and efficacy of cardiac cell therapy. Finally, I investigated therapeutic mechanisms of nanowired human cardiac organoids by analyzing the restorative capacity of the extracellular vesicles (EVs) they release. This investigation led to novel insight into the therapeutic nature of cardiac organoid derived EVs and how the nanowired bioelectric interface can be manipulated to augment EV production and function from cardiac tissue engineering constructs. The research established here provides a foundation for developing the next generation of clinically translational therapies for cardiovascular disease.

Author ORCID Identifier

0000-0001-7747-1941

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