In Vitro Cardiac Device for Assessing Proarrhythmic Risk

描述（由申请人提供）： 心脏中的电导对于协调心室和控制心率是重要的。主电信号起源于专门的组织，然后沿着心肌传播，心肌细胞在心肌中舒张和收缩。一些治疗剂会严重破坏这些电信号的产生和/或传播，导致心房和心室中不协调或不正确起搏的收缩，称为心律失常。这种严重的不良反应是终止新化合物临床开发、召回已批准产品和限制上市适应症的原因。临床前动物模型不足以评估心脏毒性的风险，并且经常提供不同物种之间相互矛盾的数据，这些数据混淆了将研究结果转化为man. Recent兴趣开发工程心脏组织用于许多医疗和研发应用，导致了用于体外培养心肌细胞和研究其机电特性的系统。虽然这些体外系统中的一些可用于评估药物产品的预防性风险，但没有一个理想地适合于同时评估药物引起的对电或机械心脏功能的不良影响。该STTR应用提出在专有的、柔性的电活性材料上开发心肌细胞微阵列，其中可以在存在测试化学品和与耦合机械功能相关的发现的情况下研究电脉冲的传播。所提出的设备结合了当前系统的最佳功能与新型材料技术，以提供对集成细胞功能的精确控制的询问，并且精确应用促进肌细胞长期存活的外部因素是设备的重复使用-最终是人类设备的重要问题。第一阶段研究的目的是实现使用大鼠心肌细胞的可行性和原理的证明，并将该系统扩展到犬心肌细胞。在第二阶段，将构建一个原型设备，并添加一个人类心肌细胞设备以完成面板。

DESCRIPTION (provided by applicant): Electrical conductance in the heart is important for coordinating the chambers and controlling heart rate. Master electrical signals originate in specialized tissues and then propagate along the myocardium, where cardiac myocytes depolarize and contract. Some therapeutic agents acutely disrupt the generation and/or propagation of these electrical signals, leading to uncoordinated or incorrectly paced contraction in the atria and ventricles called arrhythmia. This serious adverse effect is cause to terminate clinical development of new compounds, recall approved products, and restrict marketing indications. Preclinical animal models are inadequate for assessing cardiotoxic risk and too often provide conflicting data across different species that confuse translation of findings into man. Recent interest in developing engineered heart tissue for a number of medical and R&D applications has resulted in systems for in vitro cultivation of cardiac myocytes and study of their electromechanical properties. Although some of these in vitro systems can be used to assess proarrhythmic risk of pharmaceutical products, none are ideally suited for assessing drug-induced adverse effects on electrical or mechanical cardiac function simultaneously. This STTR application proposes to develop microarrays of cardiomyocytes on proprietary, flexible, electrically-active material, in which propagation of electrical impulses can be studied in the presence of test chemicals and findings related to coupled mechanical function. The proposed device combines the best features of current systems with novel material technology to offer precisely controlled interrogation of integrated cellular function and precisely applied external factors that promote long-term survival of myocytes are reuse of devices - ultimately an important issue for human devices. Phase I studies aim to achieve proofs of feasibility and principle using rat cardiomyocytes and extend the system to canine myocytes. In Phase II, a prototype device will be constructed and a human cardiomyocyte device added to complete the panel.