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

心力衰竭（HF）是世界范围内导致死亡的主要原因。最近，一种名为心脏收缩性调节（CCM）的新型医疗器械疗法已被美国食品和药物管理局（FDA）批准用于符合条件的心衰患者。CCM装置是一种植入式电脉冲发生器，在心衰期间向心脏传递刺激以增加心脏收缩的强度。由于缺乏预测性的基于人的临床前试验方法，这些装置的真正益处尚未达到。这项为期一年的NSF/FDA驻校学者计划的目标是开发3D打印人体心脏模型，以预测心脏电生理医疗设备（例如CCM）在工作台上的影响。这种模式有可能减轻心脏医疗设备开发的动物试验和临床试验的负担，并可能为FDA监管审查过程提供信息，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师和学生以及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一种强大的高通量3D打印（3DP）工程心脏组织（EHT）模型，该模型由人类诱导多能干细胞衍生的心肌细胞（hiPSC CMs）组成，并将该模型应用于体外人类心脏电生理医疗设备的临床前评估。具体来说，我们将利用我们之前的经验和开发的细胞粘附离心（CAC）测定来研究其在产生足够数量的eht以支持高通量监管研究方面的效用。该模型将用于阐明心脏收缩调节（CCM）治疗医疗器械对体外人心功能的急性影响。因此，我们将研究临床CCM刺激参数对3DP eht的功能影响，并以高通量的方式量化所有三种心脏兴奋-收缩耦合读数（即电生理、钙处理和收缩）的反应。本项目所描述的工作将解决当前的监管知识空白，并展示hiPSC-CM 3DP EHT结构的实用性，以评估体外心脏电生理医疗设备的安全性和有效性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.