Reducing Artificial Lung Fouling: Nitric Oxide Release and Microscale Clot Evaluation

The prevalence of obstructive chronic lung disease in the United States is close to 15% and affects 35 million Americans today. Artificial lungs are employed to support patients that are affected most severely, but need to be replaced every one to four weeks primarily due to clot formation on circuit and oxygenator surfaces. A secondary issue that leads to device replacement is biofouling of the oxygenator surface from adhesion of bacteria from infection. Device surface fouling from clot and bacteria can be reduced through use of anticoagulant drugs, antibiotic drugs, and surface coatings. However, none of these current treatments have produced long-term effectiveness without significant side effects and risks. To address this clinical need, two approaches were used. First, surface generated nitric oxide (NO) from a novel material, Cu-PDMS, was tested for its antithrombotic and antimicrobial properties in the context of hollow fiber membrane artificial lungs. Second, the formation of clot inside hollow fiber membrane lungs was studied at the macro- and micro-scale to determine design recommendations to reduce coagulation.In this thesis work, miniature artificial lungs were tested in parallel, one with 10% wt Cu-PDMS hollow fibers and one with polymethylpentene hollow fibers, the clinical standard. To study the longer-term effects of surface generated NO from Cu-PDMS hollow fibers, this study was conducted in a 72-hour veno-venous extracorporeal membrane oxygenation attachment in a sheep model. The Cu-PDMS fibers markedly reduced blood flow resistance, an indicator of clot formation, when compared to PMP fibers and produced the most effect in the 12-36-hour range. This material was then studied for its antimicrobial effect in an environment that simulated artificial lung conditions in vitro. This study leveraged known antimicrobial agents, NO and copper, to prevent bacterial adhesion in a bioreactor system that simulated a blood stream infection in an ECMO circuit. Short-term and long-term effects of these agents were observed on the growth of Gram-negative bacteria, P. aeruginosa, and Gram-positive bacteria, S. aureus. Reduced adhesion of both strains of bacteria was observed after independent 4-hour exposure of surface generated NO, gaseous NO, and copper. However, the antimicrobial effects were short-term, and the combination of NO delivery with copper did not provide an enhanced antimicrobial effect. Lastly, the effect of different fiber bundle parameters on the initiation and progression of clot formation was studied. Current commercial oxygenators vary widely and are difficult to compare. There is no consensus on how artificial lung parameters such as packing density, path length, and frontal area affect clot formation. This study used a standardized platform in which human blood was pumped through a one-directional flow circuit that included 3D printed urethane acrylate flow chambers of various parameters that simulated the flows and conditions in an adult Quadrox oxygenator with 2 L/min flow. Micro computed tomography captured clot formation at the macro-scale, and fluorescence imaging captured clot formation at the micro-scale. These high throughput, easily repeatable studies concluded that a longer path length and small frontal area with a loosely packed fiber bundle can reduce coagulation. Furthermore, these results enable validation of computational clot models for predicting clot in an artificial lung and inform future artificial lung design.