TGA-ethanol Pretreated Bovine Pericardium for the Norwood Procedure

描述(由申请人提供)： 诺伍德对左心发育不良综合征(HLHS)的分期修复拯救了数千名儿童的生命。该手术的第一阶段包括扩大发育不全的主动脉，目前这项工作是使用冷冻保存的同种异体人体材料(肺动脉或主动脉)或戊二醛处理的牛心包来完成的。这项拟议的研究将使用牛心包进行研究，用我们小组合成的新型交联剂甘油三酯(TGA)进行预处理。TGA用于异种生物材料的交联化，具有优于戊二醛的稳定性、生物相容性、抗钙化性和力学性能，而戊二醛是用于制备临床使用的异种生物材料的交联剂。此外，我们将使用TGA与乙醇预处理相结合，这可以提供更多的钙化抗性。TGA-乙醇处理的牛心包被认为是一种比戊二醛固定的牛心包更好的候选材料，因为与戊二醛相比，TGA交联具有许多优点，包括更好的材料稳定性、更接近天然组织的机械性能和抗钙化。这些研究的目标是在GLP下的绵羊模型上进行临床前研究，以提交给FDA用于TGA-乙醇预处理的牛心包植入物的IDE。这将是我们在拟议的两年期NHLBI C-Trip计划结束后提交竞争第二阶段的基础。具体目的1.热重-乙醇处理的牛心包的制备及表征。该材料将与目前生产的经戊二醛处理的牛心包(对照植入物)进行比较。终点将包括交联剂稳定性指数、微观形态和单轴试验的力学性能。具体目的2.对存活至150天的幼年绵羊，分别用TGA-乙醇处理的牛心包和戊二醛处理的牛心包进行NorwoodⅠ型主动脉根部扩大术的动物模型研究。在安乐死之前，动物将接受心脏插管和血管造影术，以获得生理终点和比较两种类型的异种植入物的主动脉增强部位的成像研究。具体目的3.移植150天后，将对一些终点的主动脉增强标本进行分析，包括对材料完整性、钙化、血栓形成和炎症的宏观和微观评估。将对外植体进行钙化分析，并将研究样品的机械性能与未植入材料参数相比的变化。相关性(见说明)：在美国，先天性心脏病影响着数以千计的儿童，并造成数十亿美元的医疗费用。这项提案将研究一种新的儿科心脏手术装置，经TGA-乙醇处理的牛心包异种移植，可能会改善最严重的先天性心脏病-左心发育不良综合征的预后。

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.