Compliant Thoracic Artificial Lungs

描述（由申请方提供）：本提案的长期目标是开发顺应性胸人工肺（cTAL），可用作终末期呼吸系统疾病患者移植的桥梁。作为肺移植的桥梁，cTAL将允许更多的患者接受移植并改善预后。流向cTAL的血液来自肺动脉（PA），由右心室驱动。血流返回远端PA或PA的分支（PA-PA附着）或左心房（PA-LA附着）。这些器械旨在满足患者的全部气体输送需求，与体外膜氧合（ECMO）相比，凝血和炎症明显减少。我们小组以前的工作已经导致了在大型动物中达到这些目标的设备。然而，这项工作还表明，当连接在PA-PA配置中时，这些器械的流体机械阻抗可能导致心输出量（CO）显著降低。如果不是因为CO的这种减少，PA-PA附着将是附着cTAL的理想手段，因为它允许天然肺维持其正常的过滤和代谢功能。CO减少的原因在很大程度上是由于cTAL阻抗过大。本提案中的研究旨在设计具有极低阻抗的cTAL，以便其可用于任何附件配置，CO几乎没有减少。该设计还应允许运动时CO增加。为实现这一目标，提出了五项研究。(1)将使用完整心脏、大型动物模型确定肺系统阻抗与CO之间的关系。所开发的关系将用于为改进的cTAL的设计设定阻抗基准，该改进的cTAL在PA-PA连接期间几乎不导致CO减少。(2)将使用流体结构相互作用（FSI）建模来设计符合阻抗基准的cTAL。初步FSI和体外数据表明，cTAL阻抗可降低至当前胸人工肺的至少33-50%。这应导致cTAL使用期间CO的大幅改善。(3)所选设计将在脉动流下进行体外试验，以确认血流动力学性能。(4)cTAL将在体内进行测试，以确定在正常和升高的CO下PA-PA和PA-LA配置中的短期（< 8小时）气体交换和血液动力学性能。最后，（5）cTAL将在体内进行14天的测试，以评估器械性能和动物生理学。所有动物研究都将利用慢性肺病期间的肺动脉高压模型。所得器械将准备进行临床前试验。公共卫生相关性：该项目的目标是设计和测试兼容的人工肺。这些设备将为慢性肺病患者提供更多时间来寻找供体肺，并改善他们在移植前后的健康状况。

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.