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 心力衰竭是主要的临床和公共健康问题，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方法，供体的可用性和相容 心脏不能满足临床需求。通过使用3D打印或 本土支架有望缓解捐赠器官短缺的问题。然而，努力建立一个功能强大的 利用人诱导多能干细胞(HiPSCs)构建的生物人工心腔受到不成熟的阻碍 HIPSC来源的心肌细胞。提供生理模拟刺激的可靠孵化系统 培养未成熟的心肌细胞和发育心脏组织是必要的。如果不关闭这项技术 心血管组织工程不会发展到器官水平的工程，排除了临床和 发现潜力。这项研究的长期目标是设计一种可移植的心脏，通过使用 人类细胞。在这项Katz R01拨款中，我们提出了一个新的研究方向，以解决长期存在的需求 用于生物反应器培养和刺激技术，完全重新设想为生物人造器官工程。 我们的中心假设是，在一个自动化平台中集成不同的成熟方法将 在生物工程左心室中实现生理相关水平的功能。我们的目标是 通过整合设计出具有生理上显著射血分数的再细胞化左心室 机械、电气和新陈代谢刺激：在 通过一种新的多参数生物反应器设计(目标1)使左心室重新细胞化并发育出一个完整的器官 支持较大生物人工左心室增加的代谢需求的介质组合物(目标2)。 基于我们在再生医学方面无与伦比的经验，我们将发展协调心脏 一种新型人工氧载体和代谢介质组合的刺激试验床(胸腔) 根据发育的生物物理、生化和代谢需求量身定制的补充剂 收缩组织。收缩脑室结构和多参数刺激的预期可利用性 生物反应器将垂直推进这一领域，为损害心脏的问题提供基本的新贡献 用于产生生物工程脑室的组织工程学。机械发现与生物工程 随着其他研究人员为心脏和其他方面创建刺激训练方案，改进将比比皆是 人造器官。因此，该项目的实现将为潜在的新一波 心脏组织工程在构建生物人工心脏方面的突破。