Coordinated Heart Stimulation Testbed: A Platform for Contractile Ventricle Engineering

协调心脏刺激试验台：收缩心室工程平台

• 批准号: 10712502
• 负责人: Camila Hochman-Mendez
• 金额: $ 40.42万
• 依托单位: TEXAS HEART INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712502
• 关键词: 3-Dimensional; 3D Print; Address; Anatomy; Automobile Driving; Bioartificial Organs; Biochemical; Biological; Biomedical Engineering; Biophysics; Bioreactors; Cardiac Myocytes; Cardiovascular system; Cause of Death; Cell Maturation; Cell physiology; Cells; Cessation of life; Clinical; Coupled; Data; Development; Dilated Cardiomyopathy; Disease model; EFRAC; Electric Stimulation; Endothelial Cells; Engineering; Extracellular Matrix; Fatty Acids; Feedback; Fostering; Functional disorder; Generations; Glucose; Goals; Grant; Heart; Heart Rate; Heart Transplantation; Heart Ventricle; Heart failure; Human; Hypoxia; Impairment; Incubated; Left ventricular structure; Liquid substance; Measures; Mechanical Stimulation; Mechanics; Metabolic; Methods; Neonatal; Organ; Organ Donor; Oryctolagus cuniculus; Oxygen; Pathologic; Patients; Performance; Physiological; Protocols documentation; Public Health; Rattus; Regenerative Medicine; Regimen; Regulation; Reporting; Research; Research Personnel; Risk; Shapes; Signal Transduction; Stimulus; Stress; Structure; Supplementation; Surface; System; Technology; Thick; Tissue Engineering; Tissues; Training; Transplantation; Uterus; cardiac tissue engineering; deprivation; design; disability; experience; fatty acid metabolism; fatty acid supplementation; heart dimension/size; human stem cells; improved; in vivo; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; innovation; mechanical drive; metabolic profile; mimetics; novel; novel strategies; oxygen transport; prototype; response; restoration; scaffold; scale up; technological innovation

PROJECT SUMMARY Heart failure, the main clinical and public health problem, accounts for 13% of deaths in the US. Although transplantation is currently the only therapy for end-stage heart failure, the availability and compatibility of donor hearts cannot meet the clinical demand. Bioengineered whole hearts generated by using either 3D-printed or native scaffolds hold promise to alleviate the donor organ shortage. However, efforts to build a functional bioartificial heart chamber by using human-induced pluripotent stem cells (hiPSCs) are stymied by the immaturity of hiPSC-derived cardiomyocytes. Reliable incubation systems that deliver physiologically mimetic stimulation to train immature heart muscle cells and develop heart tissues are warranted. Without closing this technological gap, cardiovascular tissue engineering will not advance to organ-level engineering, foreclosing the clinical and discovery potential. The long-term goal of this research endeavor is to engineer a transplantable heart by using human cells. In this Katz R01 grant, we propose a new research direction to address the long-standing need for bioreactor cultivation and stimulation technologies completely reimagined for bioartificial organ engineering. Our central hypothesis is that integrating the different maturation approaches in one automated platform will achieve the physiologically relevant levels of function in bioengineered left ventricles. The objective is to engineer a recellularized left ventricle with a physiologically significant ejection fraction through the integration of mechanical, electrical, and metabolic stimuli: enable coordinated mechanical and electrical stimulation in a recellularized left ventricle through a novel multiparametric bioreactor design (Aim 1) and develop a whole organ media composition to support the increased metabolic demands of larger bioartificial left ventricles (Aim 2). Based on our unparalleled experience in regenerative medicine, we will develop the coordinated heart stimulation testbed (CHeST) combined with a novel artificial oxygen carrier and metabolic media supplementation tailor-fitted to the biophysical, biochemical, and metabolic requirements of developing contractile tissue. The expected deliverables of a contractile ventricle construct and multiparametric stimulation bioreactor will vertically advance the field, providing essential novel contributions to the issues impairing cardiac tissue engineering for generating bioengineered ventricles. Mechanistic discovery and bioengineering improvements will abound as other investigators create stimulation training protocols for the heart and other engineered organs. Thus the realization of this project will pave the way for a potential new wave of breakthroughs in cardiac tissue engineering toward building a bioartificial heart.

项目总结