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.

项目概要/摘要 由于传导障碍（即心脏之间的传导失败），多种心律失常会出现在心脏中。 局部心肌细胞岛，物理距离为毫米 (mm) 到厘米 (cm) 而电子设备，例如植入式心律转复除颤器。 为患者及其并发症和缺乏长期生物整合提供挽救生命的支持 传导恢复限制了他们的成功，一种新颖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连接可以重新同步心脏电生理学 降低心律失常风险并促进有效的心脏泵血我们的长期目标是重新设计。 患病心脏的机电功能，特别是满足临床心脏的关键需求 电生理学实践，实现具有生物反应性的持久、解剖学电连接 该提案的目的是探索心脏中不同心肌细胞岛之间的效果。 我们正在开发一种新型“生物电线”，它由天然生物材料和 hiPSC 衍生制成 心肌细胞 (hiPSC-CM) 该技术旨在用于跨毫米至厘米的基于心肌细胞的耦合。 我们的中心假设是通过形成连续的 hiPSC-CM 桥来实现距离。 沿着微线的心肌细胞汇合层将通过细胞间隙连接形成电桥 已知传导速度，并且该生物电细胞桥将在一周内建立 我们的初步数据显示，可以实现电生理同步并改善传导问题。 hiPSC-CM 沿微线程传导，通过微线程传输动作电位信号和钙瞬变信号 体外 1 天内，两个工程心脏组织之间的传导速度为 2.7 厘米/秒，至少 1.5 厘米。 我们建议利用 3D 生物打印推进生物电线的生物制造，并开发一种 目标 1 中用于精确植入心脏的基于注射的装置。我们将评估目标 2 中的假设 通过评估两种不同传导模型中心脏同步的电耦合和功效 植入生物电线后的异常现象旨在开发至关重要的技术。 组织工程促进心脏传导再生。 持久的、生物反应性传导非常重要，因为目前的治疗方法对患者的失败是 与心律失常和死亡风险增加相关，因此需要新颖的解决方案。 使用 3D 生物打印进行生物电线的生物制造，开发了一种输送系统 精确的心脏局部植入，以及评估不同传导障碍模型的疗效。 这项技术的成功开发需要在早期阶段进行投资，这样做很可能 生物电线将把心脏传导修复领域带入一个新时代，其中 对于患有心脏传导缺陷的患者来说，类似天然的解剖结构和功能成为一种有吸引力的策略。