Pre-clinical Testing of a VAD for Uni- and Bi-ventricular Support in Infants

描述（由申请人提供）：本研究的长期目标是提供一种专为婴儿设计的心室辅助装置（VAD），婴儿需要左心室、右心室或两个心室的机械循环支持。在成人中使用VAD已成为终末期心脏病的可行支持手段，作为移植的桥梁，最近作为目的地治疗。然而，目前可用于婴儿的唯一设备要么支持时间有限（通常为1个月），要么具有显著的血栓栓塞和出血风险。本项目的具体目标是对Pen State婴儿VAD进行临床前试验。Penn State Infant VAD是一种搏动性心脏起搏泵，每搏输出量为12-14 ml。该器械在初步动物研究中表现出低促凝性，部分原因是Thoratec成人VAD中使用的定制Bjork-Shiley单支柱瓣膜。单支柱瓣膜不存在聚合物三叶瓣膜中瓣叶后面的再循环区域。我们还开发了一种创新的插管设计方法，这是目前儿科VAD的一个缺点，对于降低血栓栓塞风险至关重要，特别是在婴儿和先天性解剖变异的患者中。本项目的主要目的是对enn State Infant VAD和新插管系统进行临床前试验（体内和体外），从而进行临床试验。次要目的是通过使用多种凝血、血小板功能、肾功能和取出物分析指标，在比监管批准通常要求的泵流量和抗凝状态范围更广的范围内测试婴儿VAD，研究VAD系统中血栓形成和血栓栓塞的机制。这一目标代表了一个机会，有助于更广泛的领域的循环支持设备的开发和动物试验方案的设计，特别是在抗凝方法。具体目标是：1）在动物中进行临床前试验，以在60天慢性研究中使用15-25 kg羔羊模型评估婴儿VAD系统的血栓形成，2）评估婴儿VAD系统在断奶模式下的血栓形成潜力，其中VAD流速降低，以及3）证明6个月系统设计的可靠性为0.80，置信度为80%，通过持续运行至少两倍于预期用途（即一年）的时间来证明器械可靠性的测试。 公共卫生相关性：正在开发一种心室辅助装置（VAD），为等待心脏移植或需要时间恢复心脏功能的婴儿提供循环支持。VAD将利用创新的插管设计， 和最小血栓栓塞风险的右心支持。在该项目下，婴儿VAD将进行临床前动物试验和耐久性试验。

DESCRIPTION (provided by applicant): The long term objective of this research is to provide a Ventricular Assist Device (VAD) designed specifically for infants, who require mechanical circulatory support of left, right, or both ventricles. The use of VADs in adults has become a viable means of support in end stage heart disease, as a bridge-to-transplant, and more recently as destination therapy. However, the only devices currently available for infants are either limited in support duration (typically 1 month) or carry significant thromboembolic and bleeding risks. The specific objective of this project is to perform pre-clinical testing of the Pen State Infant VAD. The Penn State Infant VAD is a pulsatile pneumatically-actuated pump with a 12-14 ml stroke volume. The device has demonstrated low thrombogenicity in pilot animal studies, in part due to the custom Bjork-Shiley monostrut valves, as used in the Thoratec adult VAD. The monostrut valve does not exhibit the recirculation regions found behind the leaflets in polymer trileaflet valves. We have also developed an innovative approach to cannulae design, which has been a shortcoming in current pediatric VADs, and which is critical to reducing thromboembolic risk, especially in infants and in those with congenital anatomic variability. The primary objective of this project is to perform pre-clinical testing (in vivo and in vitro) of the enn State Infant VAD and new cannulae system, leading to a clinical trial. A secondary objective is to investigate the mechanisms of thrombus formation, thromboembolism in a VAD system, by testing of the Infant VAD over a wider range of pump flow and anticoagulation states than would normally be required for regulatory approval, using multiple measures of coagulation, platelet function, renal function, and explant analyses. This objective represents an opportunity to contribute to the broader field of circulatory support device development and the design of animal testing protocols, especially in regards to anticoagulation approaches. The specific aims are: 1) to perform pre-clinical testing in animals to assess thrombogenicity of the Infant VAD system utilizing the 15-25 kg lamb model in 60 day chronic studies, 2) to assess the thrombogenic potential of the Infant VAD system in weaning mode, in which the VAD flowrate is reduced, and 3) to demonstrate reliability of 0.80 with 80% confidence for a six-month system design, with testing to demonstrate device reliability by sustained operation for periods at least twice as long as the intended use (i.e. one year). PUBLIC HEALTH RELEVANCE: A Ventricular Assist Device (VAD) is being developed to provide circulatory support in infants who are awaiting heart transplantation or who need time to recover their heart function. The VAD will utilize innovative cannulae designs to provide both left and right heart support with minimal thromboembolic risk. Under this project, the Infant VAD will undergo pre-clinical animal testing and durability testing.