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The hollow fiber membrane bundle is the functional component of artificial lungs, transferring oxygen to and carbon dioxide from the blood. It is also the primary location of blood clot formation and propagation in these devices. The geometric design of fiber bundles is defined by a narrow set of parameters that determine gas exchange efficiency and blood flow resistance, principally: fiber packing density, path length, and frontal area. These same parameters also affect thrombosis. This study investigated the effect of these parameters on clot formation using 3D printed flow chambers that mimic the geometry and blood flow patterns of fiber bundles. Hollow fibers were represented by an array of vertical micro‐rods (380 μm diameter) arranged with three packing densities (40%, 50%, and 60%) and two path lengths (2 and 4 cm). Blood was pumped through these devices corresponding to three mean blood flow velocities (16, 20, and 25 cm/min). Results showed that (1) clot formation decreases dramatically with decreasing packing density and increasing blood flow velocity, (2) clot formation at the outlet of the fiber bundle enhances deposition upstream, and consequently (3) greater path length provides greater clot‐free fiber surface area for gas exchange than a shorter path length. These results can help guide the design of less thrombogenic, more efficient artificial lung designs. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) increases right ventricular (RV) workload and decreases myocardial oxygen reserve, eventually leading to poor cardiac output. This study created and assessed a novel model of RV work output based on RV hemodynamics and oxygen supply, allowing new insight into causal mechanisms of RV dysfunction. Methods: The RV function model was built upon an earlier, left ventricular model and further adjusted for more accurate clinical use. The model assumes that RV total power output (1) is the sum of isovolumic and stroke power and (2) is linearly related to its right coronary artery oxygen supply. Thus, when right coronary artery flow is limited or isovolumic power is elevated, less energy is available for producing cardiac output. The original and adjusted models were validated via data from patients with idiopathic PAH (n = 14) and large animals (n = 6) that underwent acute pulmonary banding with or without hypoxia. Results: Both models demonstrated strong, significant correlations between RV oxygen consumption rate and RV total power output for PAH patients (original model, R2 = 0.66; adjusted model, R2 = 0.78) and sheep (original, R2 = 0.85; adjusted, R2 = 0.86). Furthermore, the models demonstrate a significant inverse relationship between required oxygen consumption and RV efficiency (stroke power/total power) (p < 0.001). Lastly, higher NYHA class was indicative of lower RV efficiency and higher oxygen consumption (p = 0.013). Conclusion: Right ventricular total power output can be accurately estimated directly from pulmonary hemodynamics and right coronary perfusion during PAH. This model highlights the increased vulnerability of PAH patients with compromised right coronary flow coupled with high afterload. [ABSTRACT FROM AUTHOR]

Background: Extracorporeal membrane oxygenation (ECMO) research using large animals requires a significant amount of resources, slowing down the development of new means of ECMO anticoagulation. Therefore, this study developed and evaluated a new rat ECMO model using a 3D-printed mock-oxygenator.Methods: The circuit consisted of tubing, a 3D-printed mock-oxygenator, and a roller pump. The mock-oxygenator was designed to simulate the geometry and blood flow patterns of the fiber bundle in full-scale oxygenators but with a low (2.5 mL) priming volume. Rats were placed on arteriovenous ECMO at a 1.9 mL/min flow rate at two different heparin doses (n = 3 each): low (15 IU/kg/h for eight hours) versus high (50 IU/kg/h for one hour followed by 25 IU/kg/h for seven hours). The experiment continued for eight hours or until the mock-oxygenator failed. The mock-oxygenator was considered to have failed when its blood flow resistance reached three times its baseline resistance.Results: During ECMO, rats maintained near-normal mean arterial pressure and arterial blood gases with minimal hemodilution. The mock-oxygenator thrombus weight was significantly different (p < 0.05) between the low (0.02 ± 0.006 g) and high (0.003 ± 0.001 g) heparin delivery groups, and blood flow resistance was also larger in the low anticoagulation group.Conclusions: This model is a simple, inexpensive system for investigating new anticoagulation agents for ECMO and provides low and high levels of anticoagulation that can serve as control groups for future studies. [ABSTRACT FROM AUTHOR]

Inhibiting thrombosis without generating bleeding risks is a major challenge in medicine. A promising solution may be the inhibition of coagulation factor XII (FXII), because its knock-out or inhibition in animals reduced thrombosis without causing abnormal bleeding. Herein, we have engineered a macrocyclic peptide inhibitor of activated FXII (FXIIa) with sub-nanomolar activity (Ki = 370 ± 40 pM) and a high stability (t1/2 > 5 days in plasma), allowing for the preclinical evaluation of a first synthetic FXIIa inhibitor. This 1899 Da molecule, termed FXII900, efficiently blocks FXIIa in mice, rabbits, and pigs. We found that it reduces ferric-chloride-induced experimental thrombosis in mice and suppresses blood coagulation in an extracorporeal membrane oxygenation (ECMO) setting in rabbits, all without increasing the bleeding risk. This shows that FXIIa activity is controllable in vivo with a synthetic inhibitor, and that the inhibitor FXII900 is a promising candidate for safe thromboprotection in acute medical conditions. Inhibiting thrombosis without inducing bleeding is a major challenge for anticoagulant agents. Here the authors describe a synthetic FXIIa inhibitor able to efficiently prevent thrombosis in mice and suppress coagulation in artificial lungs in rabbits without increasing the risk of bleeding. [ABSTRACT FROM AUTHOR]

The functions of anti-fouling, zwitterionic polycarboxybetaine (pCB) coating, and anti-platelet nitric oxide (NO) release replicate key anticoagulant properties of the endothelium. The two approaches, only tested separately thus far, are paired on gas permeable polydimethylsiloxane (PDMS) membranes and evaluated for fibrinogen (Fg) and platelet adsorption. Uncoated (control) and pCB-coated PDMS separate sheep plasma (108 platelets per milliliter) and gas flow chambers within bioreactors used in this study, and either 100 or 0 ppm of NO/N2 flows through the gas chamber so PDMS transfers NO into flowing plasma. Surface-adsorbed platelets are quantified using a lactate dehydrogenase assay after 8h plasma recirculation. Fg and platelet adsorption on pCB-coated PDMS are 10.40% ± 3.0% of control ( p < 0.01) and 23.3% ± 7.4% ( p < 0.01) of control, respectively. NO flux alone limits platelet adsorption to 79.0% ± 5.0% ( p < 0.05) of control. Together, NO and pCB reduce platelet adsorption to 6.90% ± 1.30% of control ( p < 0.001). The data suggest that pCB coating and NO act in concert to reduce platelet fouling at significantly higher levels than either pCB coating or NO release alone. [ABSTRACT FROM AUTHOR]

Hollow fiber artificial lungs are increasingly being used for long-term applications. However, clot formation limits their use to 1-2 weeks. This study investigated the effect of nitric oxide generating (NOgen) hollow fibers on artificial lung thrombogenicity. Silicone hollow fibers were fabricated to incorporate 50 nm copper particles as a catalyst for NO generation from the blood. Fibers with and without (control) these particles were incorporated into artificial lungs with a 0.1 m2 surface area and inserted in circuits coated tip-to-tip with the NOgen material. Circuits ( N = 5/each) were attached to rabbits in a pumpless, arterio-venous configuration and run for 4 h at an activated clotting time of 350-400 s. Three control circuits clotted completely, while none of the NOgen circuits failed. Accordingly, blood flows were significantly higher in the NOgen group (95.9 ± 11.7, p < 0.01) compared to the controls (35.2 ± 19.7; mL/min), and resistance was significantly higher in the control group after 4 h (15.38 ± 9.65, p < 0.001) than in NOgen (0.09 ± 0.03; mmHg/mL/min). On the other hand, platelet counts and plasma fibrinogen concentration expressed as percent of baseline in control group (63.7 ± 5.7%, 77.2 ± 5.6%; p < 0.05) were greater than those in the NOgen group (60.4 ± 5.1%, 63.2 ± 3.7%). Plasma copper levels in the NOgen group were 2.8 times baseline at 4 h (132.8 ± 4.5 μg/dL) and unchanged in the controls. This study demonstrates that NO generating gas exchange fibers could be a potentially effective way to control coagulation inside artificial lungs. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 3511-3519, 2013. [ABSTRACT FROM AUTHOR]