Copper Nanoparticle Impregnated, Nitric Oxide Generating Hollow Fibers for Artifi

用于 Artifi 的铜纳米颗粒浸渍、产生一氧化氮的中空纤维

• 批准号: 8645873
• 负责人: Jean Montoya
• 金额: $ 17.76万
• 依托单位: MEDARRAY, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2015-07-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645873
• 关键词: Acute; Adult Respiratory Distress Syndrome; Animals; Anticoagulation; Area; Beds; Blood; Blood Cells; Blood Platelets; Blood coagulation; Blood flow; Carbon Dioxide; Cells; Chest; Chronic lung disease; Clinical; Coagulants; Coagulation Process; Copper; Critical Illness; Devices; Dialysis procedure; Disease; Equilibrium; Equipment Malfunction; Excision; Extracorporeal Membrane Oxygenation; Fiber; Force of Gravity; Functional disorder; Gases; Generations; Goals; Half-Life; Hemorrhage; Hour; Legal patent; Longevity; Lung; Measures; Mechanical ventilation; Membrane; Nitric Oxide; Nitric Oxide Donors; Outcome; Oxygen; Patients; Phase; Physiological; Problem Solving; Process; Production; Resistance; Respiratory physiology; Risk; S-Nitroso-N-Acetylpenicillamine; Saline; Sheep; Surface; System; Technology; Testing; Thromboembolism; Time; Venous; Ventilator; Weight; Work; artificial lung; biomaterial compatibility; improved; in vivo; meetings; mortality; nanoparticle; particle; polydimethylsiloxane; preclinical study; public health relevance; research study; respiratory; success; Acute; Adult Respiratory Distress Syndrome; Animals; Anticoagulation; Area; Beds; Blood; Blood Cells; Blood Platelets; Blood coagulation; Blood flow; Carbon Dioxide; Cells; Chest; Chronic lung disease; Clinical; Coagulants; Coagulation Process; Copper; Critical Illness; Devices; Dialysis procedure; Disease; Equilibrium; Equipment Malfunction; Excision; Extracorporeal Membrane Oxygenation; Fiber; Force of Gravity; Functional disorder; Gases; Generations; Goals; Half-Life; Hemorrhage; Hour; Legal patent; Longevity; Lung; Measures; Mechanical ventilation; Membrane; Nitric Oxide; Nitric Oxide Donors; Outcome; Oxygen; Patients; Phase; Physiological; Problem Solving; Process; Production; Resistance; Respiratory physiology; Risk; S-Nitroso-N-Acetylpenicillamine; Saline; Sheep; Surface; System; Technology; Testing; Thromboembolism; Time; Venous; Ventilator; Weight; Work; artificial lung; biomaterial compatibility; improved; in vivo; meetings; mortality; nanoparticle; particle; polydimethylsiloxane; preclinical study; public health relevance; research study; respiratory; success

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.

描述（由适用提供）：每年美国有超过19万人患有急性呼吸窘迫综合征（ARDS），死亡率为25-40％，并获得最佳治疗。此外，还有超过1200万慢性肺部疾病的患者。 这些患者通常每年患有1-3个急性加重，导致额外的短期呼吸功能障碍，其中170,000多名患者每年都会死亡。机械通气不足以支持许多此类患者。结果，人造肺的变量类型用于支持呼吸功能数周。这些应用的所有当前人造肺都使用堆满的空心纤维床来实现其气体交换。这些设备很容易凝块形成，导致这些设备在1-2周内失败。因此，全身性抗凝治疗用于减少凝块的形成，但这导致出血并发症。这是所有这些应用都容易出现设备故障和出血并发症。该提案的目的是开发一种新型的人造肺纤维，该肺纤维仅在纤维表面积极提供抗凝性。将铜（Cu）纳米颗粒嵌入该空心纤维的聚二甲基硅氧烷（PDMS）壁中。当与血液接触时，纳米颗粒会催化血液中无供体的纤维表面的一氧化氮（NO）形成。一氧化氮直接抑制血小板，该血小板是细胞的原发性FR催化凝块形成，但不会引起系统抗凝作用。结果是人造肺寿命更长，并且由于出血的风险较小，因此可能改善结果的潜力 血栓并发症。在初步研究中，我们有i）确定表面Cu暴露，没有产生和抗凝作用之间的关系，ii）用Cu纳米颗粒浸入PDM（CU-PDMS）纤维的人工肺和III）证明，所得的设备在短期内进行了积分测试，从而导致了在Clot形成中显着降低，并在攻击性测试过程中进行了积极的攻击。这项工作产生的纤维被50 nm Cu颗粒中的10％（wt％）浸渍。这些纤维产生的通量为12»4 x 10-10 mol/cm2/min的NO，导致PDMS表面的凝结速度慢8倍。在第一阶段，我们建议在绵羊中执行72小时的静脉内膜（VV）体外膜氧合（ECMO）（5个成功实验的n = 7），以比较Cu-Imprementated PDM的血栓形成和气体交换与市售的可用聚合物甲基甲基甲基甲基（PMP）holtow fibers hollow fibers hollow fibers hollow fibers的血栓形成和气体交换。这项研究的I阶段成功标准是，与具有PMP的人造肺相比，具有Cu-PDMS纤维的人造肺的凝块形成较少，耐药性的增加显着较小 纤维。符合此标准后，纤维将能够在第二阶段进行长期进行， 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。