Copper Nanoparticle Impregnated, Nitric Oxide Generating Hollow Fibers for Artifi

描述(申请人提供)：美国每年有19万多人患有急性呼吸窘迫综合征(ARDS)，采用最好的治疗方法，死亡率为25%-40%。此外，还有1200多万慢性肺部疾病患者。 这些患者通常每年有1-3次疾病状态的急性加重，导致额外的短期呼吸功能障碍，其中每年将有超过17万人死亡。机械通风不足以支持其中许多患者。因此，各种类型的人工肺被用来支持几个星期的呼吸功能。目前所有用于这些应用的人工肺都使用中空纤维填充床来实现气体交换。这些设备极易形成凝块，导致这些设备在1-2周内失效。因此，全身抗凝被用来减少血栓的形成，但这会导致出血并发症。因此，所有这些应用仍然容易出现设备故障和出血并发症。这项提议的目标是开发一种新型的人造肺纤维，它只在纤维表面主动提供抗凝作用。铜纳米粒子被嵌入到这种中空纤维的聚二甲基硅氧烷(PDMS)壁中。当与血液接触时，纳米颗粒催化血液中一氧化氮供体在纤维表面生成一氧化氮(NO)。一氧化氮直接抑制血小板，血小板是催化血栓形成的主要细胞，但不会引起系统抗凝。其结果是更长的人工肺寿命，并有可能改善结果，因为较低的出血和 血栓栓塞症并发症。在初步研究中，我们已经：1)确定了表面铜暴露、NO生成和抗凝之间的关系；2)用浸渍铜纳米颗粒的PDMS(铜-PDMS)纤维构建了人工肺；3)证明了在侵略性、高度促凝血剂的环境中，所产生的装置在短期体内测试中显著减少了血栓的形成。这项工作产生的纤维浸渍了10重量百分比(wt%)的50 nm铜颗粒。这些纤维产生12？4x10-10mol/cm2/min的NO通量，导致PDMS表面的凝结速度减慢8倍。在第一阶段，我们建议在绵羊身上进行72小时的静脉-静脉(VV)体外膜氧合(ECMO)(5次成功实验，n=7)，以比较浸铜PDMS和商用聚甲基戊烯(PMP)中空纤维的血栓形成和气体交换能力。这项研究的第一阶段成功标准是，与使用PMP的人工肺相比，使用铜-PDMS纤维的人工肺的凝块形成更少，阻力增加明显更小 纤维。一旦满足这一标准，纤维将能够在第二阶段进行更长期的， 临床前研究既检查设备功能，又评估对动物的潜在生理影响。

DESCRIPTION (provided by applicant): More than 190,000 people suffer from acute respiratory distress syndrome (ARDS) in the US each year, with mortality rates from 25-40% with the best treatment. In addition, there are over 12 million patients with chronic lung disease. These patients typically have 1-3 acute exacerbations of their disease state per year that cause additional short term respiratory dysfunction, and over 170,000 of these patients will die every year. Mechanical ventilation is insufficient to support many of these patients. As a result, variou types of artificial lungs are being used to support respiratory function for several weeks. All of the current artificial lungs for these applications use a packed bed of hollow fibers to achieve their gas exchange. These devices are highly prone to clot formation, causing these devices to fail within 1-2 weeks. Systemic anticoagulation is thus used to reduce clot formation, but this leads to bleeding complications. Thus, all of these applications remain prone to both device failure and bleeding complications. The goal of this proposal is to develop a new type of artificia lung fiber that actively provides anticoagulation only at the fiber surface. Copper (Cu) nanoparticles are embedded in the polydimethylsiloxane (PDMS) wall of this hollow fiber. When in contact with blood, the nanoparticles catalyze nitric oxide (NO) formation at the fiber surface from NO donors in blood. Nitric oxide directly inhibits platelets, the cell primarily responsible fr catalyzing clot formation, but does not cause system anticoagulation. The result is longer artificial lung lifespan and the potential for improved outcomes due to lesser risk of bleeding and thromboembolic complications. In preliminary studies, we have i) determined the relationship between surface Cu exposure, NO generation, and anticoagulation, ii) built artificial lungs with Cu nanoparticle impregnated PDMS (Cu-PDMS) fibers, and iii) proven that the resulting device leads to a marked reduction in clot formation during short-term, in vivo testing in an aggressive, highly pro-coagulant setting. The fibers resulting from this work are impregnated with 10 weight percent (wt%) of 50 nm Cu particles. These fibers generate a flux of 12 ¿ 4 x 10-10 mol/cm2/min of NO, resulting in 8 times slower coagulation at the PDMS surface. In phase I, we propose to perform 72-hour veno-venous (VV) extracorporeal membrane oxygenation (ECMO) in sheep (n=7 for 5 successful experiments) to compare the thrombogenicity and gas exchange of Cu- impregnated PDMS with commercially available polymethylpentene (PMP) hollow fibers. The Phase I success criterion from this study is that artificial lungs with Cu-PDMS fibers will have less clot formation and a significant smaller increase in resistance than artificial lungs with PMP fibers. Upon meeting this criterion, the fibers will be able to proceed in Phase II to longer-term, preclinical studies that examine both device function and assess potential physiologic effects upon the animal.