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

用于重新设计心脏传导的生物电细胞桥的 3D 生物打印

• 批准号: 10753836
• 负责人: Kareen LK Coulombe
• 金额: $ 25.43万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753836
• 关键词: 3-Dimensional; Action Potentials; Acute; Address; Anatomy; Arrhythmia; Atrial Fibrillation; Atrioventricular Block; Automation; Biocompatible Materials; Biological; Biomanufacturing; Bundle-Branch Block; Calcium; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Cardiac conduction system; Cells; Chronic; Cicatrix; Clinical; Connexin 43; Coupled; Coupling; Data; Defect; Development; Devices; Disease; Disparate; Electric Countershock; Electronics; Electrophysiology (science); Engineering; Etiology; Failure; Fibrin; Fibrosis; Gap Junctions; Genes; Goals; Heart; Heart Diseases; Human; Implant; Implantable Defibrillators; In Vitro; Incidence; Infarction; Injections; Investments; Island; Left ventricular structure; Life; Maps; Modeling; Myocardial Infarction; Myocardium; Natural regeneration; Needles; Optics; Patient-Focused Outcomes; Patients; Phase; Phenotype; Physiological; Positioning Attribute; Pump; Rattus; Risk; Sclerosis; Signal Transduction; Social Distance; Surgical sutures; System; Technology; Therapeutic; Tissue Engineering; Tissues; bioelectricity; bioprinting; calcium indicator; cardiac resynchronization therapy; cardiac tissue engineering; efficacy evaluation; high resolution imaging; implantation; improved; in vivo; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; innovation; millimeter; mortality risk; new technology; novel; novel therapeutic intervention; novel therapeutics; pressure; repaired; resilience; restoration; success; technology development; transmission process

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.

项目总结/摘要 由于传导障碍，在心脏中表现出多种心律失常状况， 心肌细胞的局部岛，物理上以毫米（mm）至厘米（cm）的距离分开 不导电或导电性差的组织。虽然诸如植入式心律转复器之类的电子设备 为患者及其并发症和长期缺乏生物整合提供救生支持 传导恢复限制了它们的成功。一种新的治疗方法是提供基于细胞的物理治疗。 电活性心肌细胞之间的联系，可以使心脏电生理学， 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 特别是为了解决临床心脏病的关键需求， 具有生物反应性的持久解剖电连接的电生理学实践 心脏中不同的心肌细胞岛之间。本提案的目的是探索有效性 我们正在开发一种新型的“生物电线”，它由天然生物材料和hiPSC衍生的 心肌细胞（hiPSC-CM）。该技术旨在用于跨mm到cm的基于心肌细胞的偶联 通过形成hiPSC-CM的连续桥来实现距离。我们的中心假设是， 心肌细胞沿着微丝的汇合层将通过细胞间隙连接产生电桥 以已知的传导速度，这个生物电细胞桥将在一周内建立， 使电生理同步并改善传导问题。我们的初步数据显示 hiPSC-CM传导沿着微线程传递动作电位信号和钙瞬变 在2.7cm/s的传导速度下，两个工程化心脏组织之间在体外1天内至少有1.5cm。 我们建议使用3D生物打印推进生物电线程的生物制造，并开发一种 目标1中用于精确植入心脏的注射式器械。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型中的电耦合和心脏同步性的功效， 植入生物电线后的异常。平行的目标是开发至关重要的技术 组织工程学来促进心脏传导的再生。新疗法的发展 持久的、生物响应的传导是重要的，因为当前方法在患者中的失败是 与增加的心律失常和死亡风险相关，需要新的解决方案。这个项目是创新的 在其用于生物电线的生物制造的3D生物打印的使用中， 心脏中的精确局部植入，以及在不同传导障碍模型中的疗效评估。的 要成功地开发这项技术，就需要在早期阶段进行投资，这样做， 生物电线将使心脏传导修复领域进入一个新时代， 类似天然的解剖结构和功能对于具有心脏传导缺陷的患者来说成为有吸引力的策略。