ABSTRACT

The developing human heart has a remarkable ability to transform itself under a variety of influences, including blood flow, tissue biomechanics, and tissue composition. Alterations in these parameters may result in abnormal growth of the heart, increasing the incidence of congenital (present at or before birth) heart disease. The overall goal of this CAREER project is to utilize advanced bioengineering tools, including 3D bioprinting and human induced pluripotent stem cell technologies, to create bioartificial tissue constructs that can serve as high-fidelity models of the human heart. The engineered models serve as a research enabling platform to examine cellular processes involved in normal development of the human heart as well as the formation of various heart defects. The research will be integrated with multiple educational programs geared towards building a dynamic scientific community in the joint biomedical engineering program at Emory University and Georgia Institute of Technology. The fundamental biomaterials design and bioprinting, stem cell culture and differentiation, and cardiac cellular biology principles will be integrated into various educational activities. Education plans include design and development of educational tools and outreach to local high school students through (A) a joint summer internship program; (B) bi-annual biomedical science and engineering exhibitions; and (C) outreach activities in the Children's Heart Research and Outcomes (HeRO) Center at Emory University. Further, the project includes plans to develop a new summer hybrid course that is specifically designed to introduce the basic principles of 3D bioprinting and its use in various biomedical applications.

The investigator?s research focus is on using a multidisciplinary approach to design and develop micro/nano-scale tissue engineering technologies with the ultimate goal of generating functional bioartificial tissues and organs. Toward this goal, this CAREER project focuses on: (1) Engineering 3D in vitro developing human heart models (3D-iDHHs)--embryonic, fetal, neonatal and adult--using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) and endothelial cells (ECs) that display functional maturity/stability for several weeks; and (2) Evaluating the ability of 3D-iDHHs to decipher clinically relevant mechanisms of congenital heart diseases (CHDs), e.g., hypoplastic left heart syndrome and dilated cardiomyopathy. A state-of-the-art 3D bioprinting systems will be used to build devices, allowing precise control of the tissue microenvironment to achieve functional and structural biomimicry. The project will build upon preliminary achievements to create various perfusable 3D cardiac tissue constructs utilizing hiPSC-derived cardiac cells to reconstruct the dynamic microenvironment of the developing human heart. Multi-material 3D bioprinting enables creating perfusable heart chamber-like constructs, allowing for exposure of cardiac cells to varying environmental factors such as flow hemodynamics, stiffness, and tissue composition (Aim 1). The project will then explore the utility of these 3D-iDHHs to decipher microenvironmental mechanisms underlying CHDs (Aim 2). This research could ultimately lead to the development of novel and more effective clinical interventions and/or therapeutics to treat various CHDs. More broadly, this device could be integrated with other tissue/organ models in a human-on-a-chip for a systems-level understanding of various developmental disorders.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

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