Date of Award

8-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioengineering

Committee Member

Dr. Ying Mei, Committee Chair

Committee Member

Dr. Martine LaBerge

Committee Member

Dr. Donald Menick

Committee Member

Dr. Hai Yao

Abstract

The leading cause of death worldwide is cardiovascular disease (CVD). Myocardial infarction (MI) (i.e., heart attack) makes up ~8.5% of CVD and is a common cause of heart failure with a 40% five-year mortality after the first MI. This highlights a substantial patient population and an urgent need to develop new therapeutic strategies (e.g., regenerative cell therapies). Moreover, this also indicates that current models may not sufficiently recapitulate human cardiac tissue. To date, drug development strategies have largely depended on high throughput 2D cell models and pre-clinical testing in animal models of MI leading to minimal improvements in the heart failure treatment paradigm over the past 20 years. Relevant human cardiac models would provide insight into human cardiac tissue physiology and maturation while also providing an advanced in vitro screening tool to explore heart failure pathogenesis. Cardiac tissue engineering has allowed for advances in the development of cardiac constructs by combining developments in biomaterials, 3D microtissue culture, and human induced pluripotent stem cells (hiPSC) technology. Notably, approaches that mimic the natural processes in the body (i.e., biomimetic) have led to further insight into cardiac physiology. Here, I have pursued biomimetic strategies to create a biomimetic model of human cardiac tissue using hiPSC-derived cardiomyocytes (hiPSC-CMs). Throughout this development, I explored the role of the matrix microenvironment on cell behavior using functionalized alginate, the influence of pacemaker-like exogenous electrical stimulation on the maturation of hiPSC-CM spheroids with endogenous electrically conductive nanomaterials, and the development of vascularized, functional cardiac organoids by mimicking the coronary vasculogenesis stage of cardiac development. The research established here provided a biomimetic groundwork for future development into in vitro human cardiac tissue models for applications in basic research, drug discovery, and cell therapy.

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