Compliant Thoracic Artificial Lungs

描述（由申请人提供）：每年有13万美国人死于慢性呼吸道疾病。目前，正在研究几种呼吸支持手段作为肺移植的桥梁，但支持的持续时间有限，无法提供目的地治疗。因此，我们的团队一直在为此目的开发顺应性的胸部人工肺（cTALs）。cTALs直接附着于肺循环，因此不需要辅助泵或大型体外循环。cTALs提供全面的呼吸支持，必要时可以消除肺动脉高压，并引起最小的血液学改变。我们目前的cTAL可以动脉输送超过7l /min的静脉血，血流阻力小于正常健康肺的一半。此外，一个单一的，未涂覆的cTAL可以使用14天，几乎没有血栓形成。因此，血流阻力也没有改变，也没有因血栓栓塞而引起的器官功能障碍。本提案的目标是在这些积极结果的基础上，将cals的安全使用范围扩大到两个月以上不更换，以及几年的定期选择性设备更换。这将使cTAL被用作更多慢性肺病患者的目标治疗。为了实现这一目标，我们将首先优化纤维束表面积与血容量比（SA:V），以最大限度地减少血栓的形成。其次，我们将通过结合两种有前途的方法：超低蛋白吸附聚羧基甜菜碱（pCB）表面涂层和表面一氧化氮（NO）通量，创建具有内皮样表面聚焦抗凝（SFA）的cTAL。初步的体外实验数据表明，这种组合可以完全消除血小板与生物材料表面的结合至少8小时，因此在长期使用中应该可以显著降低凝血。计划进行下列研究以进一步发展这一方法。首先，我们将优化用于人造肺表面的pCB涂层。其次，用小尺度人工肺进行4小时的家兔实验，以确定纤维束SA:V对血小板活化和血栓形成的影响。第三，将使用全尺寸的pcb涂层cals进行24小时的绵羊实验，以确定理想的NO扫描气体浓度，该浓度可以最大限度地减少血小板粘附和凝块形成，同时保持metHb <总血红蛋白的5%。最后，将进行为期两个月的绵羊实验，以优化后的SA:V、pCB涂层和NO通量率来检测cTAL功能。在这项研究的结论中，cTAL应该能够在不进行置换的情况下提供超过两个月的临床支持，并将为能够在选择性置换的情况下提供数年支持的人工肺铺平道路。

DESCRIPTION (provided by applicant): 130,000 Americans die from chronic respiratory disease every year. Currently, several means of respiratory support are being examined as a bridge to lung transplantation, but the duration of support is limited and incapable to provide destination therapy. Thus, our group has been developing compliant, thoracic artificial lungs (cTALs) for this purpose. cTALs are attached directly to the pulmonary circulation and thus require no auxiliary pump or large extracorporeal circuit. cTALs provide full respiratory support, can eliminate pulmonary hypertension if necessary, and cause minimal hematological changes. Our current cTAL can arterialize over 7 L/min of venous blood and has a blood flow resistance less than half of a normal healthy lung. Moreover, a single, uncoated cTAL can be used for 14 days with little to no clot formation. Thus, there is also no change in blood flow resistance and no organ dysfunction due to thromboemboli. The goal for this proposal is to build upon these positive results and expand the safe use of cTALs to beyond two months without replacement and several years with regular, elective device replacement. This would allow the cTAL to be used as destination therapy for a larger group of chronic lung disease patients. To achieve this, we will first optimize the fiber bundle surface area to blood volume ratio (SA:V) to minimize clot formation. Second, we will create a cTAL with endothelial-like, surface-focused anticoagulation (SFA) by combining two promising approaches: ultra-low protein-adsorption poly(carboxybetaine) (pCB) surface coatings and surface nitric oxide (NO) flux. Preliminary in vitro data indicates this combination can completely eliminate platelet binding to the biomaterial surface for at least 8 hours and should, therefore, markedly reduce coagulation during long-term use. The following studies are planned to further develop this approach. First, we will optimize the pCB coatings for artificial lung surfaces. Second, 4 hour rabbit studies with small scale artificial lungs will be performed to determine the effect of fiber bundle SA:V on platelet activation and clot formation. Third, 24 hour sheep experiments will be performed with full-sized, pCB-coated cTALs to determine an ideal NO sweep gas concentration that minimizes platelet adhesion and clot formation while keeping metHb < 5% of total hemoglobin. Lastly, two month sheep experiments will be performed to examine cTAL function with the optimized SA:V, pCB coating, and NO flux rate. At the conclusion of this research, the cTAL should be capable of greater than two months of clinical support without replacement and will pave the way toward artificial lungs capable of several years of support with elective replacement.