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.

项目摘要/摘要 多个心律不齐的病在心脏上表现出由于导致障碍而表现出来 通过毫米（mm）到厘米（cm）距离物理分离的心肌细胞的当地岛屿 非导电组织或不良组织。而电子设备，例如植入心脏逆变器除颤器 为患者提供挽救生命的支持，他们的并发症和长期缺乏生物融合 传导恢复限制了他们的成功。一种新型的热方法是提供基于细胞的物理 电活动的心肌细胞之间的连接可以使心脏电生理学重新同步为 降低心律不齐的风险并促进有效的心脏泵送。我们的长期目标是重新设计 患病心脏的机电功能，专门针对临床心脏的关键需求 具有生物学反应的持久，解剖电连接的电生理学实践 心脏中心肌细胞的不同岛之间。该建议的目的是探索效率 我们正在开发的新颖的“生物电线”，该线程由天然生物材料和HIPSC衍生 心肌细胞（HIPSC-CMS）。该技术旨在用于跨MM到CM的基于心肌细胞的耦合 通过形成HIPSC-CM的连续桥的距离。我们的中心假设是交付 沿微读的心肌细胞的汇合层将通过蜂窝间隙连接创建一个电桥 以已知的传导速度，该生物电细胞桥将在一周内建立 实现电生理同步和减轻传导问题。我们的初步数据显示 HIPSC-CM沿微读传导传输动作电位信号和钙瞬变 在1天的体外，在两个工程心脏组织之间至少在2.7 cm/s的传导速度下至少1.5 cm。 我们建议使用3D生物打印来推进生物电螺纹的生物制造，并开发 基于注射的装置，以在AIM 1中的心脏中精确植入。我们将评估AIM 2中的假设 通过评估两个不同模型的传导模型中心脏同步的电耦合和效率 植入生物电线后的异常。平行目的是开发至关重要的技术 在组织工程中，以推动心脏传导的再生。新疗法的发展 耐用的生物学反应性传导是显着的，因为患者当前方法的失败是 与心律不齐和死亡风险增加有关，这是必要的新解决方案。这个项目是创新的 在使用3D生物打印来进行生物电线生物制造时，开发了用于 精确的局部植入物，并评估传导障碍潜水模型的效率。 这项技术的成功开发需要在此早期阶段进行投资，而这样做，很可能 该生物电线将使心脏传导修复领域转移到一个新时代，再生 对于心脏传导缺陷患者而言，天然样的解剖结构和功能成为有吸引力的策略。