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Over the past 40 years nearly 45% of drugs withdrawn from the market have been due to cardiac safety concerns, contributing to the ever increasing cost and declining productivity of the biopharma R&D process.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.

过去 40 年来，近 45% 的药物因心脏安全问题而退出市场的担忧，导致生物制药研发过程的成本不断增加和生产力下降。虽然药物引起的心脏毒性的机制因药物和靶标的不同而有很大差异，但最常见和最常见的是危险的表现是心律失常和心源性猝死。生物制药行业已成为重投资于对心脏毒性作用敏感的新工具，然而，目前的临床前模型是在结构、组成和功能复杂性上进行妥协，以概括和概括人类心脏电生理学的预测。此外，了解患者特定的风险因素如何包括遗传倾向、年龄、性别和潜在的心血管疾病（例如纤维化、缺血、梗塞）导致药物诱导的致心律失常状态需要开发全新的体外模型的冲动传导障碍。在本提案中，我们的目标是开发一种新的生物工程人类心室作为识别药物引起的人心脏致心律失常风险的预测体外模型。到为了克服当前的限制，FluidForm, Inc 与卡内基梅隆大学合作将开发一种新的自由形式可逆嵌入悬浮水凝胶 (FRESH) 3D 生物打印左心室模型重建心室心肌的层状结构，并定制结构和成分来模仿致心律失常疾病状态。我们的初步数据表明，我们可以构建一个功能性心室圆周肌纤维排列、各向异性动作电位传播、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响应，包括壁增稠。在这里，我们将通过两项研究来改善心室性能，用于生物制药研发过程目标。首先，我们将建立 FRESH 3D 生物打印人类心室模型对已知的基线敏感性致心律失常化合物并生成行业标准的剂量-反应曲线。其次，我们将通过控制心肌细胞和胶原蛋白结构来模拟纤维化疾病，展示可调节的敏感性并整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定的疾病模型，该模型显示左移的剂量反应曲线致心律失常化合物。第一阶段概念验证的成功将为第二阶段奠定坚实的基础 II SBIR 项目将在体外高内涵中验证完整的 FRESH 3D 打印心室模型成像平台，用于评估电生理学和生物反应，并提供急需的行业- 在药物开发中准确预测人类心律失常的领先能力。