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.
