Compliant Thoracic Artificial Lungs

描述(由申请人提供)：这项提案的长期目标是开发符合要求的胸腔人工肺(CTAL)，可用作终末期呼吸系统疾病患者移植的桥梁。作为通向肺移植的桥梁，cTAL将允许更多的患者进行移植，并改善预后。流向cTAL的血液来自右心室驱动的肺动脉(PA)。血流回到PA远端或PA分支(PA-PA附着部)或左心房(PA-LA附着部)。与体外膜氧合(ECMO)相比，这些设备旨在满足患者的全部气体传输需求，并显著减少凝血和炎症。我们团队之前的工作导致了在大型动物身上实现这些目标的设备。然而，这项工作也表明，当连接到PA-PA配置中时，这些装置的流体机械阻抗可以导致心输出量(CO)显著降低。如果不是因为CO的减少，PA-PA附着物将是附着cTALs的理想方法，因为它允许自然肺保持其正常的过滤和代谢功能。CO降低的原因在很大程度上是由于cTAL阻抗过大。本方案中的研究旨在设计一种具有非常低阻抗的cTAL，使得它可以在几乎不减少CO的情况下用于任何连接结构。这种设计还应该允许随着运动而增加一氧化碳。为了达到这一目标，提出了五项研究。(1)采用完整的心脏大动物模型，确定肺系统阻抗与CO的关系。开发的关系将用于设置阻抗基准，用于设计改进的cTAL，使PA-PA连接过程中的CO几乎不会减少。(2)采用流体结构相互作用(FSI)模型来设计符合阻抗基准的cTAL。初步的FSI和体外数据表明，cTAL阻抗至少可以降低到目前胸腔人工肺的33-50%。这应该会在cTAL使用期间导致CO的大幅改善。(3)选定的设计将在体外脉动流条件下进行测试，以确认血流动力学性能。(4)cTAL将在体内进行测试，以确定在CO正常和升高情况下PA-PA和PA-LA配置的短期(&lt；8小时)气体交换和血流动力学性能。最后，(5)cTAL将在体内进行为期14天的测试，以评估设备性能和动物生理学。所有动物研究都将利用慢性肺部疾病期间的肺动脉高压模型。由此产生的设备将准备好进行临床前测试。公共卫生相关性：该项目的目标是设计和测试符合要求的人工肺。这些设备将让慢性肺病患者有更多的时间寻找供体肺，并在移植前后改善自己的健康。

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to develop compliant, thoracic artificial lungs (cTALs) that can be used as a bridge to transplant for patients with end-stage respiratory disease. As a bridge to lung transplantation, a cTAL would allow for more patients to be transplanted and improve outcomes. Blood flow to the cTAL comes from the pulmonary artery (PA), driven by the right ventricle. Blood flow returns to the distal PA or branch of the PA (PA-PA attachment) or the left atrium (PA-LA attachment). These devices are designed to supply a patient's full gas transfer requirements with significantly less coagulation and inflammation than with extracorporeal membrane oxygenation (ECMO). Our group's previous work has led to devices that met these goals in large animals. However, this work also indicates that the fluid mechanical impedance of these devices can cause a significant reduction in cardiac output (CO) when attached in the PA- PA configuration. If not for this reduction in CO, PA-PA attachment would be the ideal means of attaching cTALs, as it allows the natural lung to maintain its normal filtration and metabolic functions. The cause of the reduction in CO is due, in large part, to excessive cTAL impedance. The studies in this proposal are aimed at designing a cTAL with very low impedance such that it can be used in any attachment configuration with little to no reduction in CO. This design should also allow for increases in CO with exercise. Five studies are proposed to meet this goal. (1) The relationship between pulmonary system impedance and CO will be determined using an intact heart, large animal model. The developed relationship will be used to set impedance benchmarks for the design of an improved cTAL that causes little to no reduction in CO during PA-PA attachment. (2) Fluid structure interaction (FSI) modeling will be used to design a cTAL that meets the impedance benchmarks. Preliminary FSI and in-vitro data indicates that cTAL impedance can be reduced to at least 33-50% of current thoracic artificial lungs. This should result in large improvements in CO during cTAL use. (3) The selected design will be tested in-vitro under pulsatile flow to confirm hemodynamic performance. (4) The cTAL will be tested in-vivo to determine short term (< 8 hrs) gas exchange and hemodynamic performance in the PA-PA and PA-LA configurations at normal and elevated CO. Lastly, (5) the cTAL will be tested in-vivo over 14 days to assess device performance and animal physiology. All animal studies will utilize a model of pulmonary hypertension during chronic lung disease. The resulting device will be ready for pre- clinical testing. PUBLIC HEALTH RELEVANCE: The goal of this project is to design and test compliant artificial lungs. These devices will give chronic lung disease patients more time to find a donor lung and improve their health before and after transplantation.