Cardiac Conduction through Engineered Tissue

通过工程组织的心脏传导

• 批准号: 7143425
• 负责人: DOUGLAS BURR COWAN
• 金额: $ 42.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-18 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143425
• 关键词: atrioventricular node; biomaterial compatibility; cell transplantation; collagen; congenital heart disorder; electrical conductance; electronic pacemaker; electrophysiology; gap junctions; heart block; heart function; heart pacemaker tissue; implant; laboratory rat; medical implant science; mesenchyme; muscle satellite cell; myoblasts; nonhuman therapy evaluation; sheep; stem cells; striated muscles; tissue /cell culture; tissue engineering

DESCRIPTION (provided by applicant): Disruption of cardiac atrioventricular (AV) impulse propagation is a serious clinical problem in infants and children as well as adults. Congenital complete heart block or AV block due to ischemic heart disease, endocarditis, maternal autoimmune disease during pregnancy, or surgery is currently treated by implanting an artificial pacemaker device. While the efficacy of pacemakers as a palliative therapy cannot be disputed, and the range of indications requiring intervention with these devices continues to expand; their long-term performance remains unsatisfactory, especially in pediatric patients. Children implanted with cardiac pacemakers have a substantially higher incidence of re-operation compared with adults due to limited battery life, lead fractures and failure, cardiac perforation, valve dysfunction, diminished ventricular function, and thrombus formation. In addition, the size of newborn and small children frequently requires the pacemaker leads to be positioned epicardially, rather than transvenously, which results in even greater failure rates and rising capture thresholds. Consequently, there is an pressing need for advancement of innovative, lasting pacing therapies designed specifically for pediatric patients. In view of that, we have been developing an engineered tissue construct that can function as an electrical conduit between the atria and ventricles for eventual use in children that lack normal AV node function. To be clinically applicable, we have focused our efforts on developing tissue that can be autologously-derived, is easy to fabricate and implant, and poses no risk of tumor development or arrhythmogenic potential. Ideally, the engineered tissue would account for patient growth, function for the lifespan of the individual, respond to autonomic stimuli, and allow for the orderly and sequential spread of electrical impulses from the upper to lower chambers of the heart through the insulating barrier formed by the fibrous annulus of the AV valves. A multi-disciplinary group has been assembled to address the following aims: 1) improve the conduction characteristics of a previously developed construct by optimizing it's cellularity and composition as well as identifying cells in muscle and bone marrow that approximate the electrical behavior of the AV node, 2) evaluate these improvements in Lewis rat hearts by implanting constructs that contain muscle- and marrow-derived cells, and 3) examine autologously-derived engineered tissue in an ovine model of pediatric complete AV conduction block.

描述(申请人提供)：心脏房室(AV)脉冲传播中断是婴幼儿和成人的一个严重的临床问题。由于缺血性心脏病、心内膜炎、妊娠期母体免疫性疾病或手术引起的先天性完全性心脏传导阻滞或房室传导阻滞，目前的治疗方法是植入人工起搏器。虽然起搏器作为一种姑息治疗的有效性是毋庸置疑的，需要使用这些设备进行干预的适应症范围也在继续扩大，但它们的长期表现仍然不令人满意，特别是在儿科患者中。与成人相比，植入心脏起搏器的儿童由于电池寿命有限、导线骨折和衰竭、心脏穿孔、瓣膜功能障碍、心功能减退和血栓形成，再次手术的发生率要高得多。此外，新生儿和幼儿的大小往往要求起搏器导线位于心外膜，而不是横置，这导致更高的失败率和更高的捕获阈值。因此，迫切需要发展专门为儿科患者设计的创新的、持久的起搏疗法。有鉴于此，我们一直在开发一种工程化的组织结构，它可以作为心房和脑室之间的电力管道，最终用于缺乏正常房室结功能的儿童。为了临床应用，我们致力于开发可自体衍生、易于制造和植入、不会导致肿瘤发展或心律失常的组织。理想情况下，工程化组织将考虑到患者的成长，在个人的生命周期内发挥作用，对自主神经刺激做出反应，并允许电脉冲通过由房室瓣膜纤维环形成的绝缘屏障，从心脏的上腔到下腔有序而有序地传播。一个多学科小组已经成立，以解决以下目标：1)通过优化先前开发的结构的细胞性和组成以及鉴定肌肉和骨髓中近似于房室结电行为的细胞来改善其传导特性，2)通过植入包含肌肉和骨髓来源的细胞的结构来评估Lewis大鼠心脏的这些改进，以及3)在儿童完全性房室传导阻滞的绵羊模型中检查自体衍生的工程组织。