TGA-ethanol Pretreated Bovine Pericardium for the Norwood Procedure

描述（由申请人提供）： 诺伍德分期修复左心发育不全综合征（HLHS）挽救了数千名儿童的生命。该手术的第一阶段涉及增强发育不全的主动脉，目前这是使用冷冻保存的人同种异体移植材料（肺动脉或主动脉）或戊二醛预处理的牛心包完成的。本研究以牛心包为材料，采用本课题组合成的新型交联剂三甘醇二胺（TGA）进行预处理。TGA用于交联异种移植生物材料时，其稳定性、生物相容性、抗钙化性和机械性能上级戊二醛（用于制备临床使用的异种移植生物材料的交联剂）。此外，我们将使用TGA结合乙醇预处理，这赋予额外的抗钙化性。假设TGA-乙醇预处理的牛心包是比戊二醛固定的牛心包更好的候选材料，用于I期诺伍德主动脉扩张术，因为TGA交联相比戊二醛具有许多优势，包括更高的材料稳定性、与天然组织更相似的机械性能和抗钙化性。这些研究的目的是根据GLP在绵羊模型中进行临床前研究，以提交给FDA申请TGA-乙醇预处理牛心包植入物的IDE。这将是我们在拟议的最初两年NHLBI C-TRIP计划结束后提交的竞争性第2阶段申请的基础。具体目标1。制备并表征TGA-乙醇预处理的牛心包。将该材料与当前生产的戊二醛预处理牛心包（对照植入物）进行比较。终点将包括交联稳定性指数、微观形态和单轴测试的机械性能。具体目标2。在存活至150天的幼龄绵羊中，使用TGA-乙醇预处理的牛心包与戊二醛预处理的牛心包（对照）进行诺伍德I主动脉根部增强术的动物模型研究。安乐死前，动物将接受心导管插入术和血管造影术，以获得生理终点和主动脉增强部位的成像研究，比较两种类型的异种移植物植入物。具体目标3。在150天取出后，将对主动脉加固样本进行多个终点分析，包括材料完整性、钙化、血栓形成和炎症的肉眼和显微镜评估。将对外植体进行钙化分析，还将研究样品与未植入材料参数相比的机械性能变化。 相关性（参见说明）：先天性心脏病影响着美国成千上万的儿童，并占数十亿美元的医疗费用。该提案将研究一种新的儿科心脏手术器械，即TGA-乙醇预处理的牛心包异种移植物，该器械可能改善最严重形式的先天性心脏病（左心发育不良综合征）的结局。

DESCRIPTION (provided by applicant): The Norwood staged repair for hypoplastic left heart syndrome (HLHS) has saved the lives of thousands of children. Stage I of this procedure involves augmenting the underdeveloped aorta, and at present this is done using either cryopreserved human allograft material (pulmonary artery or aorta) or glutaraldehyde pretreated bovine pericardium. The proposed research will investigate using bovine pericardium, pretreated with a novel cross-linker, triglycidylamine (TGA), synthesized by our group. TGA, when used to crosslink heterograft biomaterials, confers stability, biocompatibility, calcification resistance and mechanical properties that are superior to glutaraldehyde, the cross-linker used to prepare clinically used heterograft biomaterials. In addition we will use TGA in combination with ethanol pretreatment, which confers additional calcification resistance. TGA-ethanol pretreated bovine pericardium is hypothesized to be a better candidate material than glutaraldehyde fixed bovine pericardium for Stage I Norwood aortic augmentation because of a number of advantages of TGA cross-linking compared to glutaraldehyde including greater material stability, mechanical properties more comparable to native tissue and calcification resistance. The goal of these investigations is to carry out preclinical studies in a sheep model under GLPs for submission to the FDA for an IDE for a TGA-ethanol pretreated bovine pericardium implant. This will be the basis of our competitive Phase 2 submission following the conclusion of the proposed initial two year NHLBI C-TRIP program. Specific Aim 1. Prepare and characterize TGA-ethanol pretreated bovine pericardium. This material will be compared with the currently manufactured glutaraldehyde pretreated bovine pericardium (control implants). Endpoints will include indices of crosslink stability, microscopic morphology and mechanical properties per unaxial testing. Specific Aim 2. Carry out animal model studies of the Norwood I aortic root augmentation procedure using TGA-ethanol pretreated bovine pericardium versus glutaraldehyde pretreated bovine pericardium (controls) in juvenile sheep with survival to 150 days. Prior to euthanasia animals will undergo a cardiac catheterization and angiography procedure in order to obtain physiologic endpoints and imaging studies of the aortic augmentation site comparing two types of xenograft implants. Specific Aim 3. Explantation at 150 days will be followed by analyses of aortic augmentation specimens for a number of endpoints including macroscopic and microscopic assessment of material integrity, calcification, thrombosis, and inflammation. Calcification analyses will be carried out on explants and samples will also be studied for changes in mechanical properties compared to unimplanted material parameters. RELEVANCE (See instructions): Congenital heart disease affects thousands of children in the United States, and accounts for billions of dollars in medical care costs. This proposal will investigate a new pediatric cardiac surgery device, a TGA-ethanol pretreated bovine pericardial xenograft, that may improve outcomes for the most severe form of congenital heart disease, the hypoplastic left heart syndrome.