Compliant Thoracic Artificial Lungs

摘要 每年有13万美国人死于慢性呼吸道疾病。目前，有几种呼吸途径 目前正在研究支持作为肺移植的桥梁，但支持的持续时间是有限的，而且 不能提供目的地治疗。因此，我们的团队一直在开发顺应性的胸腔假体 肺(CTAL)用于此目的。CTAL直接附着在肺循环上，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，可以消除肺脏 必要时可引起高血压，并引起轻微的血液学改变。我们目前的CTAL可以动脉化超过7 L的静脉血和每分钟的血流阻力都不到正常健康肺的一半。此外，一个 单一的，无涂层的cTAL可以使用14天，几乎没有凝块形成。因此，也没有改变 血流阻力，无血栓栓子引起的器官功能障碍。 这项提议的目标是在这些积极成果的基础上，将cTALs的安全使用扩大到更远的地方 两个月不更换，几年定期、可选设备更换。这将允许 CTAL将被用作更大范围的慢性肺部疾病患者的目的地治疗。为了实现这一目标， 我们将首先优化纤维束表面积与血液体积的比率(SA：V)，以最大限度地减少凝块的形成。 其次，我们将通过将两种方法相结合，创建具有内皮样、表面聚焦抗凝(SFA)的cTAL 前景看好的方法：超低蛋白质吸附的聚羧基甜菜碱(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。 与生物材料表面结合至少8小时，因此应显著减少凝血 在长期使用过程中。 为了进一步发展这一方法，计划进行以下研究。首先，我们将优化印刷电路板涂层以 人工肺表面。其次，将进行4小时的小型人工肺兔实验，以 测定纤维束SA：V对血小板活化和凝块形成的影响。第三，24小时绵羊 将使用全尺寸的、涂有印刷电路板的cTALs进行实验，以确定理想的无扫描气体 最大限度地减少血小板黏附和凝块形成，同时保持MetHb&lt；5%的浓度 血红蛋白。最后，将进行两个月的绵羊实验，以检验cTAL功能与 优化的SA：V，印刷电路板涂层，无熔剂速率。在这项研究的结论中，cTAL应该能够 超过两个月的临床支持而无需替换，将为人工肺铺平道路 能够提供数年的支持，并可选择更换。

Abstract 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.