Compliant Thoracic Artificial Lungs

描述（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胸人工肺（cTAL）。cTAL直接连接到肺循环，因此不需要辅助泵或大型体外回路。cTAL提供完全的呼吸支持，必要时可以消除肺动脉高压，并引起最小的血液学变化。我们目前的cTAL可以使超过7 L/min的静脉血动脉化，并且具有小于正常健康肺的一半的血流阻力。此外，单个未包衣的cTAL可使用14天，几乎没有凝块形成。因此，血流阻力也没有变化，也没有由于血栓栓塞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cTAL的安全使用范围扩大到两个月以上，无需更换，以及定期择期更换器械的数年。这将允许cTAL用作更大组慢性肺病患者的目的地治疗。为了实现这一点，我们将首先优化纤维束表面积与血液体积比（SA：V），以最大限度地减少凝块形成。其次，我们将通过结合两种有前途的方法来创建具有内皮样表面聚焦抗凝（SFA）的cTAL：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。初步的体外数据表明，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，在长期使用过程中应显着减少凝血。计划开展以下研究，以进一步发展这一方法。首先，我们将优化用于人工肺表面的pCB涂层。其次，将使用小规模人工肺进行4小时家兔研究，以确定纤维束SA：V对血小板活化和凝块形成的影响。第三，将使用全尺寸的pCB涂层cTAL进行24小时绵羊实验，以确定理想的NO吹扫气体浓度，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，将进行两个月的绵羊实验以检查具有优化的SA：V、pCB涂层和NO通量率的cTAL功能。在这项研究结束时，cTAL应该能够在不更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更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.