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.

项目概要 心力衰竭是主要的临床和公共卫生问题，占美国死亡人数的 13%。虽然 移植是目前治疗终末期心力衰竭的唯一疗法，捐赠者的可用性和兼容性 心脏不能满足临床需求。通过使用 3D 打印或 原生支架有望缓解供体器​​官短缺问题。然而，努力建立一个功能 使用人类诱导多能干细胞（hiPSC）的生物人工心室因不成熟而受到阻碍 hiPSC 衍生的心肌细胞。可靠的孵化系统可提供生理模拟刺激 训练未成熟的心肌细胞和发育心脏组织是必要的。在不关闭这项技术的情况下 差距，心血管组织工程不会进步到器官级工程，排除了临床和应用 发现潜力。这项研究的长期目标是利用 人体细胞。在 Katz R01 资助中，我们提出了一个新的研究方向来解决长期存在的需求 针对生物人工器官工程完全重新设计的生物反应器培养和刺激技术。 我们的中心假设是，将不同的成熟方法集成到一个自动化平台中将 实现生物工程左心室的生理相关功能水平。目标是 通过整合设计具有生理意义射血分数的再细胞化左心室 机械、电和代谢刺激：实现协调的机械和电刺激 通过新颖的多参数生物反应器设计（目标 1）对左心室进行再细胞化并开发出完整的器官 培养基成分可支持较大的生物人工左心室增加的代谢需求（目标 2）。 基于我们在再生医学方面无与伦比的经验，我们将开发协调心脏 刺激试验台（CHeST）结合新型人工氧载体和代谢介质 适合发育中生物物理、生化和代谢需求的补充剂 收缩组织。收缩心室构造和多参数刺激的预期成果 生物反应器将垂直推进该领域，为损害心脏的问题提供重要的新颖贡献 用于生成生物工程心室的组织工程。机理发现和生物工程 随着其他研究人员为心脏和其他部位制定刺激训练方案，改进将会比比皆是。 工程器官。因此，该项目的实现将为潜在的新一波浪潮铺平道路。 心脏组织工程方面的突破，旨在构建生物人工心脏。