Cardiac Conduction through Engineered Tissue

描述（由申请人提供）：心脏房室（AV）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进行治疗。虽然起搏器作为姑息治疗的有效性无可争议，并且需要使用这些器械进行干预的适应症范围不断扩大;但其长期性能仍然不令人满意，尤其是在儿科患者中。由于电池寿命有限、电极导线断裂和失效、心脏穿孔、瓣膜功能障碍、心室功能减弱和血栓形成，植入心脏起搏器的儿童再次手术的发生率显著高于成人。此外，新生儿和幼儿的体型通常需要将起搏器电极导线定位在心外膜，而不是经心外膜，这导致更大的失败率和更高的夺获阈值。因此，迫切需要推进专门为儿科患者设计的创新、持久的起搏治疗。有鉴于此，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导管，最终用于缺乏正常房室结功能的儿童。为了在临床上适用，我们集中精力开发可以自体来源的组织，易于制造和植入，并且不会造成肿瘤发展或肿瘤发生潜力的风险。理想情况下，工程组织将考虑患者的生长，在个体的寿命内发挥作用，对自主刺激做出反应，并允许电脉冲通过由AV瓣膜的纤维环形成的绝缘屏障从心脏的上腔室有序地和顺序地传播到下腔室。成立了一个多学科小组，以实现以下目标：1）通过优化先前开发的构建体的细胞结构和组成以及鉴定肌肉和骨髓中接近AV结的电行为的细胞来改善其传导特性，2）通过植入含有肌肉和骨髓来源的细胞的构建体来评估刘易斯大鼠心脏中的这些改善，和3）在小儿完全AV传导阻滞的绵羊模型中检查自体来源的工程化组织。

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.