Bioprinted Human Ventricles for In Vitro Modeling of Cardiac Arrhythmias

用于心律失常体外建模的生物打印人心室

基本信息

批准号：
10325795
负责人：
Adam Walter Feinberg
金额：
$ 22.86万
依托单位：
FLUIDFORM, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10325795
关键词：
3-Dimensional 3D Print Action Potentials Adoption Adult Age Animal Model Architecture Arrhythmia Back Biological Biomechanics Biomedical Engineering Calcium Canis familiaris Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiotoxicity Cardiovascular Diseases Cell Line Cells Collaborations Collagen Complex Contractile Proteins Dangerousness Data Development Disease Disease model Dose Drug Prescriptions Drug Targeting Electrophysiology (science)Evaluation Extracellular Matrix Family suidae Fibrosis Foundations Genetic Predisposition to Disease Geometry Heart Heart Injuries Heart Ventricle Human Hydrogels In Vitro Industry Industry Standard Infarction Intellectual Property Ion Channel Ischemia Left Left ventricular structure Letters Link Modeling Mutation Myocardium Optics Organ Organoids Oryctolagus cuniculus Outcome Patients Pattern Performance Pharmaceutical Preparations Phase Pre-Clinical Model Process Productivity Property Research Risk Risk Factors Safety Science Small Business Innovation Research Grant Structure System Technology Testing Tissue Engineering Tissues Translating Universities Ventricular Work base bioprinting commercialization cost differential expression drug development drug sensitivity drug testing heart rhythm imaging platform improved in vitro Model induced pluripotent stem cell innovation manufacturing scale-up next generation phase 1 testing research and development response sex success sudden cardiac death three-dimensional modeling tool treatment duration voltage

项目摘要

Over the past 40 years nearly 45% of drugs withdrawn from the market have been due to cardiac safety concerns, contributing to the ever increasing cost and declining productivity of the biopharma R&D process. While the mechanisms of drug-induced cardiotoxicity vary widely by drug and target, the most common and dangerous manifestation is cardiac arrhythmia and sudden cardiac death. The biopharma industry has heavily invested in new tools that are sensitive to cardiotoxic effects, however, current preclinical models are a compromise in the structural, compositional, and functional complexity necessary to recapitulate and be predictive of human cardiac electrophysiology. Further, understanding how patient-specific risk factors including genetic predisposition, age, sex, and underlying cardiovascular disease (e.g. fibrosis, ischemia, infarction) contribute to a drug-induced proarrhythmogenic state requires the development of entirely new in vitro models of impulse conduction disorders. In this proposal our objective is to develop a new bioengineered human ventricle as a predictive in vitro model for identifying drug-induced proarrhythmogenic risks in the human heart. To overcome current limitations, FluidForm, Inc in collaboration with Carnegie Mellon University will develop a new freeform reversible embedding of suspended hydrogels (FRESH) 3D bioprinted left ventricle model that recreates the laminar architecture of ventricular myocardium and has tailored structure and composition to mimic proarrhythmogenic disease states. Our preliminary data establishes that we can build a functional ventricle with circumferential myofiber alignment, anisotropic action potential propagation, distinct arrhythmia features including rotors and multiple propagating waves, and complex biomechanical responses including wall thickening. Here we will improve ventricle performance for use in the biopharma R&D process via two research aims. First, we will establish baseline sensitivity of the FRESH 3D bioprinted human ventricle model to known proarrhythmogenic compounds and generate industry-standard does-response curves. Second, we will demonstrate tunable sensitivity by controlling cardiomyocyte and collagen architecture to mimic fibrotic disease and incorporate iPS-derived human cardiomyocytes with known conduction mutations. This will allow us to achieve patient-specific disease models that show dose-response curves that are left-shifted for proarrhythmogenic compounds. Phase I proof-of-concept success will provide a strong foundation for a Phase II SBIR project that will validate the complete FRESH 3D printed ventricle model in an in vitro high-content imaging platform to assess electrophysiology and biological response, and provide a critically needed, industry- leading capability to accurately predict human arrhythmias in drug development.

在过去的40年中担心，导致生物制药研发过程的成本不断提高和生产率下降。而药物诱导的心脏毒性的机制因药物和靶标而差异很大，但最常见的是危险的表现是心律不齐和心脏猝死。生物制药行业已经大大但是，投资于对心脏毒性影响敏感的新工具，但是，当前的临床前模型是在概括和BE所必需的结构，组成和功能复杂性中妥协预测人类心脏电生理学。此外，了解特定于患者的风险因素包括遗传易感性，年龄，性别和潜在的心血管疾病（例如纤维化，缺血，梗死）有助于药物诱导的促动脉鼻状状态需要发展全新的体外模型冲动传导障碍。在此提案中，我们的目标是开发一个新的生物工程性人心室作为一种预测性体外模型，用于鉴定人心脏中药物诱导的肾上腺心律运动风险。到克服当前限制，Fluidform，Inc与卡内基·梅隆大学合作将开发一个新的悬浮水凝胶（新鲜）3D生物打印的左心室模型的自由形式可逆嵌入重新创建心肌心肌的层状结构，并具有量身定制的结构和组成以模仿心律失常疾病状态。我们的初步数据确定我们可以与周向肌纤维对齐，各向异性动作电势传播，独特的心律失常特征包括转子和多个传播波，以及复杂的生物力学反应，包括墙增厚。在这里，我们将通过两项研究来改善在生物制药研发过程中使用的心室性能目标。首先，我们将建立新鲜3D生物打印的人心室模型对已知的基线灵敏度心律不足的化合物并产生行业标准的响应曲线。第二，我们会的通过控制心肌细胞和胶原蛋白结构对模拟纤维化疾病来证明可调敏感性并结合具有已知传导突变的IPS衍生的人类心肌细胞。这将使我们能够实现患者特异性疾病模型，这些模型显示出剂量反应曲线，这些曲线是左移的促动脉症化合物。第一阶段概念证明的成功将为一个阶段提供良好的基础 II SBIR项目将在体外高含量中验证完整的新鲜3D印刷心室模型成像平台评估电生理学和生物学反应，并提供迫切需要的行业领导能力可以准确预测药物发育中人类心律不齐。