NSF/FDA SIR: 3D Human Stem Cell Cardiac Model for Cardiac Electrophysiology Medical Device Safety Assessment

NSF/FDA SIR：用于心脏电生理学医疗器械安全评估的 3D 人体干细胞心脏模型

• 批准号: 2129369
• 负责人: John Fisher
• 金额: $ 10万
• 依托单位: University of Maryland, College Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2129369&HistoricalAwards=false
• 关键词: NSF; FDA; SIR; 3D; Human

Heart Failure (HF) is the leading cause of death worldwide. Recently, a new medical device therapy called Cardiac Contractility Modulation (CCM) has been approved by the Food and Drug Administration (FDA) to be used in eligible HF patients. CCM devices are implantable electrical pulse generators that deliver stimulations to the heart to increase the strength of the heart contraction during HF. The true benefit of these devices has not been reached due to a lack of predictive human-based preclinical test methods. The goal of this one-year NSF/FDA Scholar-in-Residence program is to develop a 3D Printed Human Heart Model to predict the effects of cardiac electrophysiology medical devices (e.g., CCM) at the bench. This model has a potential to reduce the burden on animal testing and clinical trials for cardiacmedical device development and may inform FDA regulatory review process and ultimately accelerate heart failure patients access to innovative, safe and effective devices. This study will partner faculty and students at the University of Maryland and regulatory scientists at the Center for Devices and Radiological Health (CDRH) at the FDA.The goals of this project are to develop a robust high-throughput 3D printed (3DP) engineered heart tissue (EHT) model composed of human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) and to apply this model to preclinical assessment of human cardiac electrophysiology medical devices in vitro. Specifically, we will leverage our previous experience and development of a cell adhesion centrifugation (CAC) assay to investigate its utility for generating EHTs in a quantity sufficient to support high-throughput regulatory studies. This model will be used to elucidate the acute effects of Cardiac Contractility Modulation (CCM) therapy medical devices on human cardiac function in vitro. As such we will investigate the functional consequences of clinical CCM stimulation parameters on 3DP EHTs and quantify the response for all three cardiac excitation-contraction coupling readouts (i.e., electrophysiology, calcium handling, and contraction) in a high-throughput manner. The work described in this project will address current regulatory knowledge gaps and demonstrate the utility of hiPSC-CM 3DP EHT constructs to assess safety and effectiveness of cardiac electrophysiology medical devices in vitro.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

心力衰竭（HF）是全世界死亡的主要原因。最近，一种名为心脏收缩调节（CCM）的新型医疗器械疗法已获得美国食品和药物管理局（FDA）批准用于符合条件的心力衰竭患者。 CCM 设备是植入式电脉冲发生器，可向心脏提供刺激，以增加心力衰竭期间心脏收缩的强度。由于缺乏基于人体的预测性临床前测试方法，这些设备的真正好处尚未实现。这项为期一年的 NSF/FDA 常驻学者计划的目标是开发 3D 打印人类心脏模型，以预测心脏电生理学医疗设备（例如 CCM）的效果。该模型有可能减轻心脏医疗设备开发的动物测试和临床试验的负担，并可能为 FDA 监管审查流程提供信息，并最终加速心力衰竭患者获得创新、安全和有效的设备。这项研究将与马里兰大学的教职员工和学生以及 FDA 设备和放射健康中心 (CDRH) 的监管科学家合作。该项目的目标是开发强大的高通量 3D 打印 (3DP) 工程心脏我们开发了由人诱导多能干细胞衍生的心肌细胞（hiPSC CM）组成的组织（EHT）模型，并将该模型应用于体外人体心脏电生理医疗器械的临床前评估。具体来说，我们将利用我们之前的经验和细胞粘附离心 (CAC) 测定的开发来研究其在生成足以支持高通量监管研究的数量的 EHT 方面的效用。该模型将用于阐明心脏收缩调节（CCM）治疗医疗设备对体外人体心脏功能的急性影响。因此，我们将研究临床 CCM 刺激参数对 3DP EHT 的功能影响，并以高通量方式量化所有三种心脏兴奋-收缩耦合读数（即电生理学、钙处理和收缩）的响应。该项目中描述的工作将解决当前的监管知识差距，并展示 hiPSC-CM 3DP EHT 结构在体外评估心脏电生理学医疗设备的安全性和有效性方面的实用性。该奖项反映了 NSF 的法定使命，并被认为值得通过以下方式获得支持：使用基金会的智力价值和更广泛的影响审查标准进行评估。