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.

Narrative Patients with electrical conduction problems in the heart have no current therapeutic options for regenerating the cardiac tissue to restore conduction and reduce arrhythmia risks. This project aims to address this gap by developing a new technology that will precisely deliver a cardiomyocyte-coated thread to the heart to create a conductive cell bridge for long-lasting improvement of coordination of cardiac excitation. Successful completion of this project will increase our capabilities to regenerate conduction in multiple etiologies of conduction disorder in the heart with the long-term goal of reducing arrhythmia and improving patient outcomes.