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; 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.

项目摘要 心力衰竭是主要的临床和公共卫生问题，占美国死亡的13％。虽然 移植是目前终点心力衰竭的唯一疗法，供体的可用性和兼容性 心脏无法满足临床需求。通过使用3D打印或 本地脚手架有望减轻捐赠器官短缺。但是，努力建立功能 通过使用人工诱导的多能干细胞（HIPSC），生物人工心脏腔室受到不成熟 hipsc衍生的心肌细胞。可靠的孵化系统，可提供生理模拟刺激 必须训练未成熟的心肌细胞并发展心脏组织。不关闭这项技术 差距，心血管组织工程不会发展到器官水平的工程，取消临床和 发现潜力。这项研究努力的长期目标是通过使用 人类细胞。在这项Katz R01赠款中，我们提出了一个新的研究方向，以满足长期以来的需求 用于生物人工器官工程的生物反应器种植和刺激技术。 我们的核心假设是，将不同的成熟方法整合到一个自动化平台中 在生物工程的左心室中实现生理相关的功能水平。目的是 工程师通过整合具有生理上显着的射血分数的延迟左心室 机械，电和代谢刺激：在A中启用协调的机械和电刺激 通过新颖的多种物质生物反应器设计（AIM 1）进行重新细化的左心室，并发展整个器官 培养基组成，以支持较大的生物人工左心室的代谢需求增加（AIM 2）。 根据我们无与伦比的再生医学经验，我们将发展协调的心脏 刺激测试床（胸部）与新型的人造氧载体和代谢介质结合 适合生物物理，生化和代谢需求的补充量身定制 收缩组织。收缩心室结构和多参数刺激的预期可交付成果 生物反应器将垂直促进该领域，为损害心脏的问题提供必不可少的新颖贡献 组织工程，用于产生生物工程的心室。机械发现和生物工程 当其他研究人员为心脏和其他研究人员创建刺激训练方案时，改进将比比皆是 工程器官。因此，实现该项目将为潜在的新浪潮铺平道路 心脏组织工程的突破，以建立生物人工心脏。