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

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（由申请人提供）：在美国，每年有超过190，000人患有急性呼吸窘迫综合征（ARDS），最佳治疗的死亡率为25-40%。此外，还有超过1200万慢性肺病患者。 这些患者通常每年有1-3次疾病急性加重，导致额外的短期呼吸功能障碍，每年有超过170，000名患者死亡。机械通气不足以支持许多这样的患者。因此，各种类型的人工肺被用来支持呼吸功能几个星期。目前用于这些应用的所有人工肺都使用中空纤维的填充床来实现其气体交换。这些器械非常容易形成凝块，导致这些器械在1-2周内失效。因此，全身抗凝用于减少凝块形成，但这会导致出血并发症。因此，所有这些应用仍然容易发生器械失效和出血并发症。该提案的目标是开发一种新型的人工肺纤维，其仅在纤维表面主动提供抗凝作用。铜（Cu）纳米颗粒嵌入该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NO供体在纤维表面形成一氧化氮（NO）。一氧化氮直接抑制血小板，细胞主要负责催化凝块形成，但不引起系统抗凝。其结果是人工肺寿命更长，由于出血风险更低， 血栓栓塞并发症在初步研究中，我们已经i）确定了表面Cu暴露、NO生成和抗凝之间的关系，ii）用Cu纳米颗粒浸渍的PDMS（Cu-PDMS）纤维构建人工肺，以及iii）证明了所得装置在侵袭性的高度促凝血环境中的短期体内测试期间导致凝块形成的显著减少。由该工作产生的纤维用10重量%（wt%）的50 nm Cu颗粒浸渍。这些纤维产生12 - 4 x 10-10 mol/cm 2/min的NO流量，导致PDMS表面的凝固速度慢8倍。在第一阶段，我们建议在绵羊中进行72小时的静脉-静脉（VV）体外膜氧合（ECMO）（n=7，5次成功实验），以比较Cu浸渍的PDMS与市售聚甲基戊烯（PMP）中空纤维的血栓形成和气体交换。本研究的I期成功标准是，与PMP人工肺相比，Cu-PDMS纤维人工肺的凝块形成较少，阻力增加显著较小 纤维在满足这一标准后，纤维将能够在第二阶段进行更长期的， 检查器械功能并评估对动物潜在生理影响的临床前研究。