Cardiac Conduction through Engineered Tissue

描述（由申请人提供）：心脏房室脉冲传播中断是婴儿和儿童以及成人的严重临床问题。由于缺血性心脏病、心内膜炎、妊娠期母体自身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通过植入人工起搏器装置来治疗。虽然起搏器作为一种姑息治疗的疗效无可争议，而且需要使用这些装置进行干预的适应症范围在不断扩大；它们的长期表现仍不令人满意，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、铅断裂和衰竭、心脏穿孔、瓣膜功能障碍、心室功能减弱和血栓形成，再次手术的发生率明显更高。此外，新生儿和幼儿的体型往往要求起搏器导联放置在心外膜上，而不是横过心外，这导致更高的失败率和更高的捕获阈值。因此，迫切需要为儿科患者设计创新的、持久的起搏疗法。鉴于此，我们一直在开发一种工程组织结构，它可以作为心房和心室之间的电通道，最终用于缺乏正常房室结功能的儿童。为了临床应用，我们将重点放在开发可自体衍生的组织上，这些组织易于制造和植入，并且没有肿瘤发展或心律失常的风险。理想的情况是，这种工程组织能够满足患者的生长、个体寿命的功能、对自主刺激的反应，并允许电脉冲通过由房室瓣膜纤维环形成的绝缘屏障从上心室有序有序地传播到下心室。成立了一个多学科小组，以实现以下目标：1)通过优化其细胞结构和组成以及识别肌肉和骨髓中近似房室结电行为的细胞来改善先前开发的构建物的传导特性；2)通过植入含有肌肉和骨髓来源细胞的构建物来评估Lewis大鼠心脏中的这些改善；3)在小儿完全房室传导阻滞的羊模型中检查自体来源的工程组织。

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.