Heart rate control with bioengineered pacemakers

使用生物工程起搏器控制心率

基本信息

批准号：
10638779
负责人：
Hee Cheol Cho
金额：
$ 43.81万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-05 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638779
关键词：
Acute Animal Model Atrioventricular Block Biological Biological Pacemakers Biomedical Engineering Bradyarrhythmias Cardiac Myocytes Cardiomyopathies Chronic Clinical Congenital Heart Block Congenital Heart Defects Data Development Devices Disease Dose Embryo Excision Family suidae Fibrosis Foreign Bodies Gene Delivery Gene Transfer Genetic Goals Heart Block Heart Rate Heart failure Implant In Situ Infection Longevity Longitudinal Studies Mediating Messenger RNA Modality Modeling Molecular Myocardium Natural regeneration Operative Surgical Procedures Pacemakers Patients Procedures Rattus Research Rodent Model Route Signal Transduction Sinoatrial Node Site Symptoms Technology Testing Time Tissue Engineering Tissue constructs Tissues Transcend Transforming Growth Factor beta Transgenes Ventricular Work aortic valve replacement base cardiac pacing clinical outcome measures clinical practice clinically relevant comorbidity congenital heart disorder efficacy evaluation electronic pacemaker gene therapy heart rhythm implantable device miniaturize minimally invasive new technology nodal myocyte patient subsets pediatric patients porcine model regenerative tissue trait transcription factor transgene expression

项目摘要

Project Summary/Abstract For patients with symptomatic bradyarrhythmias, the current and only treatment is to implant an electronic pacemaker. Nearly all of the current research regarding rhythm management, including the leadless pacemakers, are invested in incremental progress in miniaturizing the indwelling devices. While the devices can provide stable and long-term pacing, the technology is far from ideal with problems inherent to the pacing technology and to foreign body issues due to the indwelling hardware. The problems can be severe for pediatric patients with congenital heart block as multiple and invasive surgeries are needed for replacement or revision of the implanted devices over the patients’ lifetime. Device-related acute problems are rising as well, include infections with the generator and/or leads wire, which require surgical removal of the entire implanted device. Bioengineered pacemakers, in contrast, transcend all current modalities by creating hardware-free cardiac pacing. We have previously demonstrated that minimally-invasive delivery of a natural transcription factor gene could pace the ventricles in both small and large animal models of complete heart block. The enabling technology is based on regenerative tissue engineering in which ordinary heart muscle is converted to specialized pacemaker tissue construct in situ with a focally delivered genetic construct. To advance this concept to clinical practice, two questions need to be answered: 1) how long can the bioengineered pacemaker retain its function, and 2) how well the bioengineered pacemaker be able to function in diseased myocardium since most patients with a pacemaker are also presented with underlying diseases in the myocardium. In this proposal, we will directly answer these questions by employing chronic heart block models that are known to elicit traits of heart failure, and examining the efficacy and durability of the gene therapy in a longitudinal study.

项目概要/摘要对于有症状的缓慢心律失常患者，目前唯一的治疗方法是植入电子装置几乎所有当前有关节律管理的研究，包括无引线起搏器，投资于留置装置小型化的渐进进展，同时这些装置可以提供稳定性。和长期起搏，由于起搏技术固有的问题，该技术远非理想。由于留置硬件而导致的异物问题对于患有以下疾病的儿科患者来说可能会很严重。先天性心脏传导阻滞，因为需要进行多次侵入性手术来更换或修复植入物患者一生中与设备相关的急性问题也在增加，包括感染。发电机和/或引线，需要手术切除整个植入装置。相比之下，生物工程起搏器通过创建无硬件的心脏起搏器超越了当前的所有模式我们之前已经证明了天然转录因子基因的微创递送。可以在完全心脏传导阻滞的小型和大型动物模型中调节心室。基于再生组织工程，将普通心肌转化为专门的心肌具有局部传递基因构建体的原位起搏器组织构建体将这一概念推向临床。实践中，需要回答两个问题：1）生物工程起搏器可以保留其功能多久， 2）生物工程起搏器在患病心肌中的功能如何，因为大多数患者带有心脏起搏器的人还患有心肌基础疾病。在这项建议中，我们将提出。通过采用已知可引发心脏特征的慢性心脏传导阻滞模型来直接回答这些问题失败，并在纵向研究中检查基因疗法的功效和持久性。