Description
- Abstract:
- Cardiovascular disease (CVD) continues to be the leading cause of death globally, with myocardial infarctions (MI), or heart attacks, representing a major contributing event to ischemic cases of CVD. In MI, blood vessels supplying the heart with nutrients are blocked, starving downstream tissue of nutrients, and causing cell death that permanently decreases heart function. A new generation of cellularized therapeutics based on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) aims to remuscularize the heart through cellular tissue implants to augment contractile function post-MI. However, the creation of such implantable engineered human myocardium (EHM) necessitates a robust vascular supply to ensure the delivered cells survive and engraft on the heart. We hypothesized that patterning a defined arteriole-scale vascular network in our EHMs (vEHMs) would facilitate cell survival and engraftment, and thus improve maturation of delivered hiPSC-CMs. In this dissertation work, we adapted a vessel-patterning technique based on sacrificial biomaterial templates to create engineered tissues with patent vasculature. We then developed a novel in vitro platform inspired by the aortic ring assay to evaluate surrogate host-implant vascular outgrowth. Our experiments demonstrated improved vascular outgrowth between aortic rings and tissues with patterned vasculature. Next, we combined our vessel patterning methodology with hiPSC-CM tissue formation to create vascularized vEHMs and designed an Arduino-controlled perfusion bioreactor to enable dynamic perfusion culture. Implantation of these vEHMs in a rodent model of ischemia-reperfusion myocardial infarction demonstrated significantly improved cellular engraftment, vascularization, and muscle development compared to control non-vascularized and non-perfused tissues. Together, these aims demonstrate the innovative design process and improved therapeutic benefit of incorporating large, patterned vessels in EHMs vessels with in vitro perfusion for a dual remuscularization-revascularization treatment of myocardial infarction. This work serves as a foundation for developing sophisticated EHMs with translational applications for cardiac regeneration.
- Notes:
- Thesis (Ph. D.)--Brown University, 2022
Citation
Kant, Rajeev Josef,
"Patterned Arteriole-Scale Vessels Enhance Engraftment, Perfusion, and Maturation of Engineered Human Myocardium for Heart Regeneration"
(2022).
Biomedical Engineering Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:yv975v95/
Relations
Collection:
-
Biomedical Engineering Theses and Dissertations
Theses and Dissertations for the Biomedical Engineering department....