3D Bioprinting of a Bioelectric Cell Bridge for Re-engineering Cardiac Conduction

项目摘要/摘要 由于传导障碍，心脏出现多种心律失常情况，即 物理上相隔毫米(Mm)至厘米(Cm)的心肌细胞局部孤岛 指非传导性或传导性差的组织。而电子设备，如植入型心脏复律除颤器 长期为患者及其并发症和缺乏生物整合的患者提供救生支持 传导修复限制了他们的成功。一种新的治疗方法是提供基于细胞的物理 可使心脏电生理重新同步的电活动心肌细胞之间的联系 降低心律失常风险，促进有效的心脏泵血。我们的长期目标是重新设计 病变心脏的机电功能及其在临床心脏治疗中的特殊需要 具有生物响应性的持久解剖电连接的电生理学实践 在心脏中不同的心肌细胞岛之间。这项建议的目的是探索疗效。 我们正在开发的一种新型生物电线，它由天然生物材料和hPSC衍生而成 心肌细胞(HiPSC-CMS)。这项技术用于跨mm到cm的基于心肌细胞的偶联。 通过形成HiPSC-CMS的连续桥梁而产生的距离。我们的中心假设是 沿着微线的心肌细胞汇合层将通过细胞缝隙连接产生电桥 以已知的传导速度，这个生物细胞桥将在一周内建立起来，以 实现电生理同步并改善传导问题。我们的初步数据显示 HiPSC-CM沿微线传导传递动作电位信号和钙瞬变信号 以2.7 cm/S的传导速度在体外培养1天内，两个工程化心肌组织之间的传导速度至少为1.5 cm。 我们建议使用3D生物打印来推进生物电丝的生物制造，并开发一种 目标1中用于心脏精确植入的基于注射的设备。我们将在目标2中评估我们的假设 通过评估两种不同传导模式下的电耦合和心脏同步性的有效性 植入生物电丝后的异常。并行的目标开发了至关重要的技术 在组织工程方面，以促进心脏传导的再生。新的治疗方法的发展 持久的、生物响应的传导是重要的，因为目前患者的治疗方法失败 与心律失常和死亡风险增加相关，需要新的解决方案。该项目具有创新性。 在将3D生物打印用于生物电丝的生物制造中，开发了一种用于 精确的心脏局部植入，以及对不同传导障碍模型的疗效评估。这个 这项技术的成功开发需要在这个早期阶段进行投资，在这样做的过程中，很可能 这种生物电丝将把心脏传导修复领域带入一个新的时代，在那里再生 天然的解剖和功能成为心脏传导缺陷患者的一种有吸引力的策略。

Project Summary/Abstract Multiple arrhythmia conditions manifest in the heart due to conduction disorder, a failure of conduction between local islands of cardiomyocytes that are separated physically by millimeter (mm) to centimeter (cm) distances of non- or poorly conductive tissue. While electronic devices such as implantable cardioverter-defibrillators provide life-saving support for patients, their complications and lack of biological integration for long-term conduction restoration limit their success. A novel therapeutic approach is to provide cell-based physical connections between electrically active cardiomyocytes that could resynchronize cardiac electrophysiology to reduce arrhythmia risk and promote efficient cardiac pumping. Our long-term goal is to re-engineer electromechanical function of diseased hearts and specifically to address the critical need in clinical cardiac electrophysiology practice for long-lasting, anatomical electrical connections with biological responsiveness between disparate islands of cardiomyocytes in the heart. The objective of this proposal is to explore efficacy of a novel “bioelectric thread” we are developing that is made of natural biomaterials and hiPSC-derived cardiomyocytes (hiPSC-CMs). This technology is intended for cardiomyocyte-based coupling across mm to cm distances via formation of a continuous bridge of hiPSC-CMs. Our central hypotheses are that delivery of a confluent layer of cardiomyocytes along microthreads will create an electrical bridge via cellular gap junctions with known conduction velocity, and that this bioelectric cell bridge will be established within one week to enable electrophysiological synchronization and ameliorate conduction problems. Our preliminary data show that hiPSC-CM conduction along microthreads transmits action potential signals and calcium transients across at least 1.5 cm at 2.7 cm/s conduction velocity between two engineered cardiac tissues within 1 day in vitro. We propose to advance the biomanufacturing of bioelectric threads using 3D bioprinting and develop an injection-based device for precise implantation in the heart in Aim 1. We will assess our hypotheses in Aim 2 by evaluating electrical coupling and efficacy of cardiac synchrony in two different models of conduction anomalies after implantation of bioelectric threads. The parallel aims develop critically important technologies in tissue engineering to advance regeneration of cardiac conduction. The development of novel therapies for durable, biologically responsive conduction is significant because failure of current approaches in patients are associated with increased arrhythmia and mortality risk, necessitating novel solutions. This project is innovative in its use of 3D bioprinting for biomanufacturing of bioelectric threads, development of a delivery system for precise local implant in the heart, and evaluation of efficacy in diverse models of conduction disorder. The successful development of this technology requires investment in this early phase, and in doing so, it is likely that bioelectric threads will move the field of cardiac conduction repair into a new era, where regeneration of native-like anatomy and function becomes an attractive strategy for patients with cardiac conduction defects.