The Texas Heart Institute recently received a five-year, $2 million grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health to advance the technology supporting development of transplantable bioartificial hearts.
The project, funded by a Stephen I. Katz Early Stage Investigator Research Project Grant, will be led by Camila Hochman-Mendez, MSc, PhD, director of Regenerative Medicine Research and the Biorepository and Biospecimen Profiling Core Laboratory. The interdisciplinary research team includes Fernanda Mesquita, PhD, and Ernesto Curty da Costa, MD, PhD, in Regenerative Medicine Research and collaborating investigators Yaxin Wang, PhD, director of the Innovative Device & Engineering Applications (IDEA) Lab, and Mehdi Razavi, MD, director of the Electrophysiology Clinical Research & Innovations group.
Patients struggling with end-stage heart failure are reliant on a heart transplant for survival. Although the number of heart donations and transplantations has increased, demand still far exceeds supply; tragically, approximately 20% of heart transplant candidates either die before a suitable donor heart becomes available or are removed from the waitlist because they become too ill for transplantation. To address this need, scientists and bioengineers have been exploring the option of transplantable bioartificial hearts.
One approach pioneered at The Institute involves repopulating cell-free heart scaffolds with large quantities of new heart cells (cardiomyocytes) derived from human induced pluripotent stem cells (hiPSCs). These studies are performed in bioreactor device systems that support the specific biological needs of the organ while protecting it from contamination. Investigators have made tremendous progress in this area, especially in understanding the many biological cues necessary for heart cell maturation. However, the advanced bioreactor technologies needed to provide important mechanical and electrical stimulation, and nutritional support to a human-sized recellularized heart are not available.
Dr. Hochman-Mendez and her colleagues propose the development of a novel bioreactor system (called the coordinated heart stimulation testbed, or CHeST) to support bioartificial heart studies in her lab and others. The benchtop system would use a specially engineered perfusion-stimulation loop to provide mechanical and electrical stimulation to the heart while circulating fluid in a way that mimics blood flow through the organ. This would occur inside a new bioreactor that is rigorously designed to prevent contamination of the heart. The investigators will use a bioengineered heart ventricle (one of the lower, pumping chambers of the heart) to test the system.
To overcome current challenges in supplying oxygen and fuel to the maturing heart cells, the team also plans to develop improved nutritional solutions for the bioartificial heart. Successful repopulation of three-dimensional organs with cells is now limited by the depth that oxygen in the nutritional media can penetrate into the tissues. The investigators hope to biochemically improve this oxygen transport to replicate the levels of oxygenation that normally would be delivered by red blood cells in the human circulatory system. Similarly, fatty acids typically serve as a fuel source for cells in the heart and as metabolic signals for heart cell maturation. The team also intends to find better ways to deliver these important fatty acids to the bioartificial heart.
Importantly, the benchtop bioreactor system and nutrition solution improvements should be useful to other researchers in the field, regardless of how they create their bioengineered heart ventricles. The technology created by The Institute team will support additional breakthroughs in the tissue engineering of bioartificial hearts.
This significant grant accelerates our progress in creating bioartificial hearts to combat end-stage heart failure. It allows us to refine our bioreactor technologies and nutritional approaches that are critical for the maturation and functioning of bioartificial hearts. Our ultimate vision is to provide patients with a pathway to a better quality of life by contributing to the global effort to overcome the shortage of donated organs."
Dr. Camila Hochman-Mendez, MSc, PhD, Director of Regenerative Medicine Research and the Biorepository and Biospecimen Profiling Core Laboratory
Dr. Wang, whose lab will provide the engineering support for the bioreactor platform for the project, said, "We believe such a bioreactor will provide an accurate physiological bio-environment for the implanted heart cells, therefore enhancing the growth of the cells in the heart scaffold. The multidisciplinary collaboration between Regenerative Medicine Research and the IDEA Lab can accelerate the development of the platform and spark inspired interactions between engineering and bioscience."
Dr. Razavi, whose team of biomedical engineers will contribute their expertise to the study, said, "Designing a comprehensive bioreactor with the ability to provide predictable electrical stimuli to cells while optimizing the environmental and nutritional parameters necessary for cardiac tissue engineering is essential. Dr. Hochman-Mendez has assembled a talented multidisciplinary team with the right mix of skills to accomplish the study aims."
The research described above is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number R01HL169632. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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