Compliant Thoracic Artificial Lungs

顺应性胸腔人工肺

• 批准号: 9013492
• 负责人: Keith E Cook
• 金额: $ 63.92万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9013492
• 关键词: Adhesions; Adsorption; Air; American; Anticoagulation; Area; Binding; Biocompatible Materials; Blood; Blood Platelets; Blood Volume; Blood coagulation; Blood flow; Characteristics; Chest; Chronic; Chronic lung disease; Clinical; Coagulation Process; Control Groups; Data; Destinations; Development; Devices; Extracorporeal Membrane Oxygenation; Extravasation; Failure; Fiber; Fibrinogen; Functional disorder; Gases; Goals; Health; Hematology; Hemoglobin; Hemorrhage; Hour; In Vitro; Life; Lung; Lung Transplantation; Lung diseases; Methods; Nitric Oxide; Organ; Oryctolagus cuniculus; Outcome Measure; Patients; Phenylalanine; Plasma; Platelet Activation; Polymers; Proteins; Pulmonary Circulation; Pulmonary Hypertension; Pump; Research; Resistance; Respiratory physiology; Right ventricular structure; Sheep; Solvents; Surface; Techniques; Testing; Time; Transplantation; Venous; artificial lung; base; biomaterial compatibility; covalent bond; design; driving force; hemodynamics; improved; in vivo; miniaturize; new technology; primary outcome; research study; respiratory; secondary outcome; surface coating

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.

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，作为进行肺移植的桥梁，但支撑持续时间是有限的，无法提供目的地治疗。因此，为此，我们的小组一直在开发合规性的胸部人造肺（CTAL）。 CTAL直接连接到肺循环，因此不需要辅助泵或大型体外电路。 CTAL提供全部呼吸支持，如有必要，可以消除肺动脉高压，并导致最小的血液学变化。我们目前的CTAL可以在7 l/min的静脉血液中进行动脉序列化，并且血流阻力小于正常健康肺部的一半。此外，单个未涂层的ctal可以使用14天，几乎没有凝块形成。因此，血流抗性也没有变化，并且由于血栓栓塞造成的器官功能障碍。该提案的目标是建立这些积极的结果，并将CTAL的安全使用扩大到两个月以上，而无需更换，并且通过常规的选择性设备更换了几年。这将使CTAL被用作较大的慢性肺部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量比（SA：V），以最大程度地减少凝块的形成。其次，我们将通过结合两种有希望的方法来创建一个具有内皮样的，以表面为中心的抗凝作用（SFA）的CTAL：超低蛋白质吸附poly（羧酸酯）（PCB）（PCB）表面涂层和表面氮（NO）助剂。初步的体外数据表明，这种组合可以完全消除与生物材料表面的血小板结合至少8小时，因此应显着减少长期使用期间的凝血。计划进一步开发这种方法。首先，我们将优化人造肺表面的PCB涂料。第二，4小时的兔子研究将进行小型人造肺，以确定纤维束SA：V对血小板激活和凝块形成的影响。第三，24小时的绵羊实验将使用全尺寸的PCB涂层CTAL进行，以确定理想的无扫气浓度，可最大程度地减少血小板粘附和凝块的形成，同时保持甲虫<5％的总血红蛋白。最后，将进行两个月的绵羊实验，以使用优化的SA：V，PCB涂层和无通量速率检查CTAL功能。在这项研究结束时，CTAL应能够在不替代的情况下能够超过两个月的临床支持，并将为人工肺部铺平道路，并通过选择性替换来获得数年的支持。