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A laptop-driven, benchtop control system that automatically adjusts carbon dioxide (CO(2)) removal in artificial lungs is described. The proportional-integral-derivative (PID) feedback controller modulates pump-driven air sweep gas flow through an artificial lung to achieve a desired exhaust gas CO(2) partial pressure (EGCO(2)). When EGCO(2) increases, the servoregulator automatically and rapidly increases sweep flow to remove more CO(2). If EGCO(2) decreases, the sweep flow decreases to reduce CO(2) removal. System operation was tested for 6 hr in-vitro using bovine blood and in-vivo in three proof-of-concept sheep experiments. In all studies, the controller automatically adjusted the sweep gas flow to rapidly (

Background A wearable artificial lung could improve lung transplantation outcomes by easing implementation of physical rehabilitation during long-term pretransplant respiratory support. The Modular Extracorporeal Lung Assist System (ModELAS) is a compact pumping artificial lung currently under development. This study evaluated the long-term in vivo performance of the ModELAS during venovenous support in awake sheep. Feedback from early trials and computational fluid dynamic analysis guided device design optimization along the way. Methods The ModELAS was connected to healthy sheep via a dual-lumen cannula in the jugular vein. Sheep were housed in a fixed-tether pen while wearing the device in a holster during support. Targeted blood flow rate and support duration were 2-2.5 L/min and 28-30 days, respectively. Anticoagulation was maintained via systemic heparin. Device pumping and gas exchange performance and hematologic indicators of sheep physiology were measured throughout support. Results Computational fluid dynamic-guided design modifications successfully decreased pump thrombogenicity from initial designs. For the optimized design, 4 of 5 trials advancing past early perioperative and cannula-related complications lasted the full month of support. Blood flow rate and CO2 removal in these trials were 2.1 ± 0.3 L/min and 139 ± 15 mL/min, respectively, and were stable during support. One trial ended after 22 days of support due to intradevice thrombosis. Support was well tolerated by the sheep with no signs of hemolysis or device-related organ impairment. Conclusions These results demonstrate the ability of the ModELAS to provide safe month-long support without consistent deterioration of pumping or gas exchange capabilities.

Objectives: To assess the in vivo hemodynamic effects on the pressure overloaded right ventricle of RAS-Q® technology, the world’s first gas exchanger with a fully integrated compliance. Methods: In six acute in vivo trials RAS-Q was implanted in sheep between the pulmonary artery and left atrium. Right ventricular pressure overload was induced by pulmonary artery banding. Pressures and flows were recorded in baseline, moderate and severe pulmonary hypertension conditions. In one trial, RAS-Q was benchmarked against the pediatric Quadrox-i®. Results: With 1.00 and 1.17 L/min, RAS-Q delivered 31% and 39% of the total cardiac output in moderate and severe pulmonary hypertension, respectively. Pulmonary artery pressures and mean pulmonary artery pressure/mean arterial blood pressure ratio successfully decreased, implying a successful right ventricular unloading. Cardiac output was restored to normal levels in both pulmonary hypertension conditions. With both devices in parallel, RAS-Q provided three times higher flow rates and a 10 times higher pressure relief, compared to the pediatric Quadrox-i. Conclusion: A gas exchanger with a fully integrated compliance better unloads the right ventricle compared to a non-compliant gas exchanger and it can restore cardiac output to normal levels in cases of severe pulmonary hypertension.

Only a very small portion of end-stage organ failures can be treated by transplantation because of the shortage of donor organs. Although artificial long-term organ support such as ventricular assist devices provide therapeutic options serving as a bridge-to-transplantation or destination therapy for end-stage heart failure, suitable long-term artificial lung systems are still at an early stage of development. Although a short-term use of an extracorporeal lung support is feasible today, the currently available technical solutions do not permit the long-term use of lung replacement systems in terms of an implantable artificial lung. This is currently limited by a variety of factors: biocompatibility problems lead to clot formation within the system, especially in areas with unphysiological flow conditions. In addition, proteins, cells, and fibrin are deposited on the membranes, decreasing gas exchange performance and thus, limiting long-term use. Coordinated basic and translational scientific research to solve these problems is therefore necessary to enable the long-term use and implantation of an artificial lung. Strategies for improving the biocompatibility of foreign surfaces, for new anticoagulation regimes, for optimization of gas and blood flow, and for miniaturization of these systems must be found. These strategies must be validated by in vitro and in vivo tests, which remain to be developed. In addition, the influence of long-term support on the pathophysiology must be considered. These challenges require well-connected interdisciplinary teams from the natural and material sciences, engineering, and medicine, which take the necessary steps toward the development of an artificial implantable lung.

Microfluidic artificial lungs (µALs) have the potential to improve the treatment and quality of life for patients with acute or chronic lung injury. In order to realize the full potential of this technology (including as a destination therapy), the biocompatibility of these devices needs to be improved to produce long-lasting devices that are safe for patient use with minimal or no systemic anticoagulation. Many studies exist which probe coagulation and thrombosis on polydimethyl siloxane (PDMS) surfaces, and many strategies have been explored to improve surface biocompatibility. As the field of µALs is young, there are few studies which investigate biocompatibility of functioning µALs; and even fewer which were performed in vivo. Here, we use both in vitro and in vivo models to investigate two strategies to improve µAL biocompatibility: 1) a hydrophilic surface coating (polyethylene glycol, PEG) to prevent surface fouling, and 2) the addition of nitric oxide (NO) to the sweep gas to inhibit platelet activation locally within the µAL. In this study, we challenge µALs with clottable blood or platelet-rich plasma (PRP) and monitor the resistance to blood flow over time. Device lifetime (the amount of time the µAL remains patent and unobstructed by clot) is used as the primary indicator of biocompatibility. This study is the first study to: 1) investigate the effect of NO release on biocompatibility in a microfluidic network; 2) combine a hydrophilic PEG coating with NO release to improve blood compatibility; and 3) perform extended in vivo biocompatibility testing of a µAL. We found that µALs challenged in vitro with PRP remained patent significantly longer when the sweep gas contained NO than without NO. In the in vivo rabbit model, neither approach alone (PEG coating nor NO sweep gas) significantly improved biocompatibility compared to controls (though with larger sample size significance may become apparent); while the combination of a PEG coating with NO sweep gas resulted in significant improvement of device lifetime. STATEMENT OF SIGNIFICANCE: The development of microfluidic artificial lungs (µALs) can potentially have a massive impact on the treatment of patients with acute and chronic lung impairments. Before these devices can be deployed clinically, the biocompatibility of µALs must be improved and more comprehensively understood. This work explores two strategies for improving biocompatibility, a hydrophilic surface coating (polyethylene glycol) for general surface passivation and the addition of nitric oxide (NO) to the sweep gas to quell platelet and leukocyte activation. These two strategies are investigated separately and as a combined device treatment. Devices are challenged with clottable blood using in vitro testing and in vivo testing in rabbits. This is the first study to our knowledge that allows statistical comparisons of biocompatible µALs in animals, a key step towards eventual clinical use.

Extracorporeal CO(2) removal (ECCO(2)R) can permit lung protective or noninvasive ventilation strategies in patients with chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). With evidence supporting ECCO(2)R growing, investigating factors which affect CO(2) removal is necessary. Multiple factors are known to affect the CO(2) removal rate (vCO(2)) which can complicate the interpretation of changes in vCO(2); however, the effect of hematocrit on the vCO(2) of artificial lungs has not been investigated. This in vitro study evaluates the relationship between hematocrit level and vCO(2) within an ECCO(2)R device. In vitro gas transfer was measured in bovine blood in accordance with the ISO 7199 standard. Plasma and saline were used to hemodilute the blood to hematocrits between 33% and 8%. The vCO(2) significantly decreased as the blood was hemodiluted with saline and plasma by 42% and 32%, respectively, between a hematocrit of 33% and 8%. The hemodilution method did not significantly affect the vCO(2). In conclusion, the hematocrit level significantly affects vCO(2) and should be taken into account when interpreting changes in the vCO(2) of an ECCO(2)R device.

Background Artificial lungs have the potential to serve as a bridge to transplantation or recovery for children with end-stage lung disease dependent on extracorporeal life support, but such devices currently require systemic anticoagulation. We describe our experience using the novel Nitric Oxide (NO) Surface Anticoagulation (NOSA) system—an NO-releasing circuit with NO in the sweep gas—with the Pediatric MLung—a low-resistance, pumpless artificial lung. Methods NO flux testing: MLungs (n = 4) were tested using veno-venous extracorporeal life support in a sheep under anesthesia with blood flow set to 0.5 and 1 L/min and sweep gas blended with 100 ppm NO at 1, 2, and 4 L/min. NO and NO2 were measured in the sweep and exhaust gas to calculate NO flux across the MLung membrane. Pumpless implants: Sheep (20–100 kg, n = 3) underwent thoracotomy and cannulation via the pulmonary artery (device inflow) and left atrium (device outflow) using cannulae and circuit components coated with an NO donor (diazeniumdiolated dibutylhexanediamine; DBHD-N2O2) and argatroban. Animals were connected to the MLung with 100 ppm NO in the sweep gas under anesthesia for 24 h with no systemic anticoagulation after cannulation. Results NO flux testing: NO flux averaged 3.4 ± 1.0 flux units (x10−10 mol/cm2/min) (human vascular endothelium: 0.5–4 flux units). Pumpless implants: 3 sheep survived 24 h with patent circuits. MLung blood flow was 716 ± 227 mL/min. Outlet oxygen saturation was 98.3 ± 2.6%. Activated clotting time was 151±24 s. Platelet count declined from 334,333 ± 112,225 to 123,667 ± 7,637 over 24 h. Plasma free hemoglobin and leukocyte and platelet activation did not significantly change. Conclusions The NOSA system provides NO flux across a gas-exchange membrane of a pumpless artificial lung at a similar rate as native vascular endothelium and achieves effective local anticoagulation of an artificial lung circuit for 24 h.

Extracorporeal membrane oxygenation (ECMO) has become a mainstay of therapy for patients suffering from severe respiratory failure. Ambulatory ECMO systems aim to provide long-term out-of-hospital respiratory support. As a patient’s activity level changes, the required level of ECMO support varies with oxygen consumption and metabolic fluctuations. To compensate for such changes, an Auto-Regulatory ECMO system (AR-ECMO) has been developed and its performance was evaluated as a proof-of-concept in an acute ovine model. The AR-ECMO system consists of a regular ECMO circuit and an electromechanical control system. A custom fuzzy-logic control algorithm was implemented to adjust the blood flow and sweep gas flow of the ECMO circuit to meet the varying respiratory demand by utilizing two noninvasive sensors for venous oxyhemoglobin saturation and the oxygenator exhaust gas CO2 concentration. Disturbance responses of the AR-ECMO to induced acute respiratory distress were assessed for six hours in four juvenile sheep cannulated with a veno-pulmonary artery ECMO configuration, including acute ventilator shutoff, ventilator step-change (off-on-off), and forced desaturation. All sheep survived for the study duration. The AR-ECMO system was able to respond and maintain stable hemodynamics and physiological blood gas contents (SpO(2) = 96.3 % ± 4.29, pH = 7.44 ± 0.09, pCO(2) = 38.9 ± 9.9 mmHg, and pO(2) =237.9 ± 123.6 mmHg) during simulated respiratory distress. Acceptable correlation between oxygenator exhaust gas CO(2) and oxygenator outlet pCO(2) were observed (R(2)= 0.84). In summary, the AR-ECMO system successfully maintained physiologic control of peripheral oxygenation and carbon dioxide over the study period, utilizing only measurements taken directly from the ECMO circuit. The range of system response necessitates an adaptable system in the setting of variable metabolic demands. The ability of this system to respond to significant disturbances in ventilator support is encouraging. Future work to evaluate our AR-ECMO system in long-term, awake animal studies is necessary for further refinement.

Wearable extracorporeal membrane oxygenation (ECMO) circuits may soon become a viable alternative to conventional ECMO treatment. Common device-induced complications, however, such as blood trauma and oxygenator thrombosis, must first be addressed to improve long-term reliability, since ambulatory patients cannot be monitored as closely as intensive care patients. Additionally, an efficient use of the membrane surface can reduce the size of the devices, priming volume, and weight to achieve portability. Both challenges are linked to the hemodynamics in the fiber bundle. While experimental test methods can often only provide global and time-averaged information, computational fluid dynamics (CFD) can give insight into local flow dynamics and gas transfer before building the first laboratory prototype. In this study, we applied our previously introduced micro-scale CFD model to the full fiber bundle of a small oxygenator for gas transfer prediction. Three randomized geometries as well as a staggered and in-line configuration were modeled and simulated with Ansys CFX. Three small laboratory oxygenator prototypes were built by stacking fiber segments unidirectionally with spacers between consecutive segments. The devices were tested in vitro for gas transfer with porcine blood in accordance with ISO 7199. The error of the predicted averaged CFD oxygen saturations of the random 1, 2, and 3 configurations relative to the averaged in-vitro data (over all samples and devices) was 2.4%, 4.6%, 3.1%, and 3.0% for blood flow rates of 100, 200, 300, and 400 ml/min, respectively. While our micro-scale CFD model was successfully applied to a small oxygenator with unidirectional fibers, the application to clinically relevant oxygenators will remain challenging due to the complex flow distribution in the fiber bundle and high computational costs. However, we will outline our future research priorities and discuss how an extended mass transfer correlation model implemented into CFD might enable an a priori prediction of gas transfer in full size oxygenators.

Artificial lung (AL) membranes are used for blood oxygenation for patients undergoing open-heart surgery or acute lung failures. Current AL technology employs polypropylene and polymethylpentene membranes. Although effective, these membranes suffer from low biocompatibility, leading to undesired blood coagulation and hemolysis over a long term. In this work, we propose a new generation of AL membranes based on amphiphobic fluoropolymers. We employed poly(vinylidene-co-hexafluoropropylene), or PVDF-co-HFP, to fabricate macrovoid-free membranes with an optimal pore size range of 30-50 nm. The phase inversion behavior of PVDF-co-HFP was investigated in detail for structural optimization. To improve the wetting stability of the membranes, the fabricated membranes were coated using Hyflon AD60X, a type of fluoropolymer with an extremely low surface energy. Hyflon-coated materials displayed very low protein adsorption and a high contact angle for both water and blood. In the hydrophobic spectrum, the data showed an inverse relationship between the surface free energy and protein adsorption, suggesting an appropriate direction with respect to biocompatibility for AL research. The blood oxygenation performance was assessed using animal sheep blood, and the fabricated fluoropolymer membranes showed competitive performance to that of commercial polyolefin membranes without any detectable hemolysis. The data also confirmed that the bottleneck in the blood oxygenation performance was not the membrane permeance but rather the rate of mass transfer in the blood phase, highlighting the importance of efficient module design.

Cardiovascular engineering and technology : CVET 13(2), 318-330 (2022). doi:10.1007/s13239-021-00579-y, Published by Springer, New York, NY

Once pulmonary disease progresses to end-stage pulmonary disease, treatment options are very limited. An important advance in the field is the development of a bioartificial lung derived from a generic matrix scaffold populated with patients' own cells. Significant progress has already been made in the engineering of bioartificial lungs.This review explains how previous and current research contributes to the goal of creating a successful bioartificial lung, and the barriers faced in doing so. We will also highlight some of the design considerations being explored to optimize bioartificial lungs and considerations for clinical translation.While current bioartificial lungs are able to provide short-term gas exchange in large-animal studies, much work is still required to combine the disciplines of cell biology, materials science, and tissue engineering to create such clinically useful and functioning artificial lungs.

Circulating venous blood outside the body, through an artificial lung (membrane oxygenator), and returning oxygenated blood to the patient is extracorporeal gas exchange. Oxygen and carbon dioxide exchange in a membrane lung is controlled by regulating blood flow, blood composition, and device design. With this control, lung function can be replaced for weeks by artificial organs. © 2020 American Physiological Society. Compr Physiol 10:879-891, 2020.

Blood contact with high surface area medical devices, such as dialysis and extracorporeal life support (ECLS), induces rapid surface coagulation. Systemic anticoagulation, such as heparin, is thus necessary to slow clot formation, but some patients suffer from bleeding complications. Both problems might be reduced by 1) replacing heparin anticoagulation with artificial surface inhibition of the protein adsorption that initiates coagulation and 2) selective inhibition of the intrinsic branch of the coagulation cascade. This approach was evaluated by comparing clot formation and bleeding times during short-term ECLS using zwitterionic polycarboxybetaine (PCB) surface coatings combined with either a potent, selective, bicyclic peptide inhibitor of activated Factor XII (FXII900) or standard heparin anticoagulation. Rabbits underwent venovenous ECLS with small sham oxygenators for 60 min using three means of anticoagulation (n = 4 ea): (1) PCB coating + FXII900 infusion, (2) PCB coating + heparin infusion with an activated clotting time of 220-300s, and (3) heparin infusion alone. Sham oxygenator blood clot weights in the PCB + FXII900 and PCB + heparin groups were 4% and 25% of that in the heparin group (p < 10-6 and p < 10-5), respectively. At the same time, the bleeding time remained normal in the PCB + FXII900 group (2.4 ± 0.2 min) but increased to 4.8 ± 0.5 and 5.1 ± 0.7 min in the PCB + heparin and heparin alone groups (p < 10-4 and 0.01). Sham oxygenator blood flow resistance was significantly lower in the PCB + FXII900 and PCB + heparin groups than in the heparin only group (p < 10-6 and 10-5). These results were confirmed by gross and scanning electron microscopy (SEM) images and fibrinopeptide A (FPA) concentrations. Thus, the combined use of PCB coating and FXII900 markedly reduced sham oxygenator coagulation and tissue bleeding times versus the clinical standard of heparin anticoagulation and is a promising anticoagulation method for clinical ECLS.

A pediatric artificial lung (PAL) is under development as a bridge to transplantation or lung remodeling for children with end-stage lung failure (ESLF). In order to evaluate the efficiency of a PAL, a disease model mimicking the physiologic derangements of pediatric ESLF is needed. Our previous right pulmonary artery ligation (rPA-LM) ovine model achieved that goal, but caused immediate mortality in nearly half of the animals. In this study, we evaluated a new technique of gradual postoperative right pulmonary artery (rPA) occlusion using a Rummel tourniquet (rPA-RT) in seven (25–40 Kg) sheep. This technique created a stable model of ESLF pathophysiology, characterized by high alveolar dead space (58.0±3.8 %), pulmonary hypertension (38.4±2.2 mmHg), tachypnea (79±20 breaths per minute), and intermittent supplemental oxygen requirement. This improvement to our technique provides the necessary physiologic derangements for testing a PAL, while avoiding the problem of high immediate perioperative mortality.

Objectives Minimally invasive extracorporeal CO2 removal is an accepted supportive treatment in chronic obstructive pulmonary disease patients. Conversely, the potential of such technique in treating acute respiratory distress syndrome patients remains to be investigated. The aim of this study was: 1) to quantify membrane lung CO2 removal (VCO2ML) under different conditions and 2) to quantify the natural lung CO2 removal (VCO2NL) and to what extent mechanical ventilation can be reduced while maintaining total expired CO2 (VCO2tot = VCO2ML + VCO2NL) and arterial PCO2 constant. Design Experimental animal study. Setting Department of Experimental Animal Medicine, University of Gottingen, Germany. Subjects Eight healthy pigs (57.7 ± 5 kg). Interventions The animals were sedated, ventilated, and connected to the artificial lung system (surface 1.8 m, polymethylpentene membrane, filling volume 125 mL) through a 13F catheter. VCO2ML was measured under different combinations of inflow PCO2 (38.9 ± 3.3, 65 ± 5.7, and 89.9 ± 12.9 mm Hg), extracorporeal blood flow (100, 200, 300, and 400 mL/min), and gas flow (4, 6, and 12 L/min). At each setting, we measured VCO2ML, VCO2NL, lung mechanics, and blood gases. Measurements and main results VCO2ML increased linearly with extracorporeal blood flow and inflow PCO2 but was not affected by gas flow. The outflow PCO2 was similar regardless of inflow PCO2 and extracorporeal blood flow, suggesting that VCO2ML was maximally exploited in each experimental condition. Mechanical ventilation could be reduced by up to 80-90% while maintaining a constant PaCO2. Conclusions Minimally invasive extracorporeal CO2 removal removes a relevant amount of CO2 thus allowing mechanical ventilation to be significantly reduced depending on extracorporeal blood flow and inflow PCO2. Extracorporeal CO2 removal may provide the physiologic prerequisites for controlling ventilator-induced lung injury.

In-line free propagation phase-contrast synchrotron tomography of the lungs has been shown to provide superior image quality compared with attenuation-based computed tomography (CT) in small-animal studies. The present study was performed to prove the applicability on a human-patient scale using a chest phantom with ventilated fresh porcine lungs. Local areas of interest were imaged with a pixel size of 100 µm, yielding a high-resolution depiction of anatomical hallmarks of healthy lungs and artificial lung nodules. Details like fine spiculations into surrounding alveolar spaces were shown on a micrometre scale. Minor differences in artificial lung nodule density were detected by phase retrieval. Since we only applied a fraction of the X-ray dose used for clinical high-resolution CT scans, it is believed that this approach may become applicable to the detailed assessment of focal lung lesions in patients in the future.

Gas transfer through hollow fiber membranes (HFM) can be increased via fiber oscillation. Prior work, however, does not directly translate to present-day, full-scale artificial lungs. This in vitro study characterized the effects of HFM oscillations on oxygenation and hemolysis for a pediatric-sized HFM bundle. Effects of oscillation stroke length (2–10 mm) and frequency (1–25 Hz) on oxygen transfer were measured according to established standards. The normalized index of hemolysis was measured for select conditions. All measurements were performed at a 2.5 L min(−1) blood flow rate. A lumped parameter model was used to predict oscillation-induced blood flow and elucidate the effects of system parameters on oxygenation. Oxygen transfer increased during oscillations, reaching a maximum oxygenation efficiency of 510 mL min(−1) m(−2) (97% enhancement relative to no oscillation). Enhancement magnitudes matched well with model-predicted trends and were dependent on stroke length, frequency, and physical system parameters. A 40% oxygenation enhancement was achieved without significant hemolysis increase. At a constant enhancement magnitude, a larger oscillation frequency resulted in increased hemolysis. In conclusion, HFM oscillation is a feasible approach to increasing artificial lung gas transfer efficiency. The optimal design for maximizing efficiency at small fiber displacements should minimize bundle resistance and housing compliance.

In situ restoration of severely damaged lung remains difficult due to its limited regeneration capacity after injury. Artificial lung scaffolds are emerging as potential substitutes, but it is still a challenge to reconstruct lung regeneration microenvironment in scaffold after lung resection injury. Here, a 3D biomimetic porous collagen scaffold with similar structure characteristics as lung is fabricated, and a novel collagen binding hepatocyte growth factor (CBD-HGF) is tethered on the collagen scaffold for maintaining the biomimetic function of HGF to improve the lung regeneration microenvironment. The biomimetic scaffold was implanted into the operative region of a rat partial lung resection model. The results revealed that vascular endothelial cells and endogenous alveolar stem cells entered the scaffold at the early stage of regeneration. At the later stage, inflammation and fibrosis were attenuated, the microvascular and functional alveolar-like structures were formed, and the general morphology of the injured lung was restored. Taken together, the functional 3D biomimetic collagen scaffold facilitates recovery of the injured lung, alveolar regeneration, and angiogenesis after acute lung injury. Particularly, this is the first study of lung regeneration in vivo guided by biomimetic collagen scaffold materials, which supports the concept that tissue engineering is an effective strategy for alveolar regeneration.

Ambulating patients on extracorporeal membrane oxygenation (ECMO) or extracorporeal CO2 removal (ECCO2R) improves outcomes. These systems would further simplify ambulation if made more compact. This study investigates blood recirculation to decrease device size by increasing efficiency. The required hollow fiber membrane (HFM) area was determined by numerically modeling gas transfer. An oxygenation device with recirculating blood flow was designed using computational fluid dynamics (CFD). Hydrodynamic performance and shear stresses of the device were analyzed using CFD at 2,000, 2,250 and 2,500 RPM. A prototype (0.38 m) was manufactured for in-vitro oxygenation testing. Oxygenation was measured at a constant 3.5 L/min blood flow while recirculation flow rate varied up to 6.5 L/min. Hemolysis was measured at 3.5 L/min blood flow and 6.5 L/min recirculation flow. A 0.3 m prototype device was used to test in-vitro ECCO2R recirculation at a constant 500 ml/min blood flow rate and recirculation flow rates up to 5.5 L/min. Computational fluid dynamics analysis showed that the oxygenation device could produce over 250 mm Hg while maintaining 3.5 L/min blood flow and 6.5 L/min recirculation flow. The model predicted oxygenation within 8% and overestimated ECCO2R by up to 32%. Measured gas transfer was 180 ml O2/min and 62 ml CO2/min. Normalized index of hemolysis contribution of the HFM was 0.012 gm/100 L.

One in five children with end-stage lung failure (ESLF) die while awaiting lung transplant. No suitable animal model of ESLF exists for the development of artificial lung devices for bridging to transplant. Small lambs weighing 15.7 ± 3.1 kg (n = 5) underwent ligation of the left anterior pulmonary artery (PA) branch, and gradual occlusion of the right main PA over 48 hours. All animals remained hemodynamically stable. Over seven days of disease model conditions, they developed pulmonary hypertension (mean PA pressure 20 ± 5 vs. 33 ± 4 mm Hg), decreased perfusion (SvO2 66 ± 3 vs. 55 ± 8%) with supplemental oxygen requirement, and severe tachypneic response (45 ± 9 vs. 82 ± 23 breaths/min) (all p < 0.05). Severe right heart dysfunction developed (tricuspid annular plane systolic excursion 13 ± 3 vs. 7 ± 2 mm, fractional area change 36 ± 6 vs. 22 ± 10 mm, ejection fraction 51 ± 9 vs. 27 ± 17%, all p < 0.05) with severe tricuspid regurgitation and balloon-shaped dilation of the right ventricle. This model of pediatric ESLF reliably produces pulmonary hypertension, right heart strain, and impaired gas exchange, and will be used to develop a pediatric artificial lung.

Previous studies have shown that Automatic Positive Airway Pressure devices display different behaviors when connected to a bench using theoretical respiratory cycle scripts. However, these scripts are limited and do not simulate physiological behavior during the night. Our aim was to develop a physiological bench that is able to simulate patient breathing airflow by integrating polygraph data. We developed an algorithm analyzing polygraph data and transformed this information into digital inputs required by the bench hardware to reproduce a patient breathing profile on bench. The inputs are respectively the simulated respiratory muscular effort pressure input for an artificial lung and the sealed chamber pressure to regulate the Starling resistor. We did simulations on our bench for a total of 8 hours and 59 minutes for a breathing profile from the demonstration recording of a Nox T3 Sleep Monitor. The simulation performance results showed that in terms of relative peak-valley amplitude of each breathing cycle, simulated bench airflow was biased by only 1.48% ± 6.80% compared to estimated polygraph nasal airflow for a total of 6,479 breathing cycles. For total respiratory cycle time, the average bias ± one standard deviation was 0.000 ± 0.288 seconds. For patient apnea events, our bench simulation had a sensitivity of 84.7% and a positive predictive value equal to 90.3%, considering 149 apneas detected both in polygraph nasal simulated bench airflows. Our new physiological bench would allow personalizing APAP device selection to each patient by taking into account individual characteristics of a sleep breathing profile.

Blood oxygenators act as an extracorporeal artificial lung during certain types of cardiac surgery and intensive care therapies. Inside these devices, blood is forced to flow across an oxygenating bundle, encountering interstitial gaps comparable to those typical of the microvasculature. Despite the well-known effects of such length scales on haemorheology and red blood cell (RBC) behavior, these are generally overlooked in oxygenator modeling and design; it is persistently assumed that RBCs are homogeneously distributed throughout the oxygenating bundle, independently of their microstructure arrangement or main flow directions. The goal of this study is to provide preliminary experimental evidence of heterogeneous RBC distributions inside oxygenating fibre bundles. To this end, a number of microchannels were manufactured inspired by actual oxygenating devices, considering simplified versions of their microstructure. These comprise staggered arrays of micro pillars, which were perfused with RBC suspensions, with feed haematocrit (Ht) and velocities relevant for clinical use. The microchannels were imaged using a microscope and high-speed camera to accurately capture cell distribution. The imaged blood flows revealed the non-uniform nature of RBC distributions in the arrays, characterized by local Ht gradients particularly around the O2 sources inside the bundle. These heterogeneous distributions should be accounted for during oxygenator design, as RBC concentration plays a key role in O2 transport and, ultimately, overall device performance.

Current artificial lungs fail in 1-4 weeks due to surface-induced thrombosis. Biomaterial coatings may be applied to anticoagulate artificial surfaces, but none have shown marked long-term effectiveness. Poly-carboxybetaine (pCB) coatings have shown promising results in reducing protein and platelet-fouling in vitro. However, in vivo hemocompatibility remains to be investigated. Thus, three different pCB-grafting approaches to artificial lung surfaces were first investigated: 1) graft-to approach using 3,4-dihydroxyphenylalanine (DOPA) conjugated with pCB (DOPA-pCB); 2) graft-from approach using the Activators ReGenerated by Electron Transfer method of atom transfer radical polymerization (ARGET-ATRP); and 3) graft-to approach using pCB randomly copolymerized with hydrophobic moieties. One device coated with each of these methods and one uncoated device were attached in parallel within a veno-venous sheep extracorporeal circuit with no continuous anticoagulation (N = 5 circuits). The DOPA-pCB approach showed the least increase in blood flow resistance and the lowest incidence of device failure over 36-hours. Next, we further investigated the impact of tip-to-tip DOPA-pCB coating in a 4-hour rabbit study with veno-venous micro-artificial lung circuit at a higher activated clotting time of 220-300 s (N ≥ 5). Here, DOPA-pCB reduced fibrin formation (p = 0.06) and gross thrombus formation by 59% (p 0.05). Therefore, DOPA-pCB is a promising material for improving the anticoagulation of artificial lungs. STATEMENT OF SIGNIFICANCE: Chronic lung diseases lead to 168,000 deaths each year in America, but only 2300 lung transplantations happen each year. Hollow fiber membrane oxygenators are clinically used as artificial lungs to provide respiratory support for patients, but their long-term viability is hindered by surface-induced clot formation that leads to premature device failure. Among different coatings investigated for blood-contacting applications, poly-carboxybetaine (pCB) coatings have shown remarkable reduction in protein adsorption in vitro. However, their efficacy in vivo remains unclear. This is the first work that investigates various pCB-coating methods on artificial lung surfaces and their biocompatibility in sheep and rabbit studies. This work highlights the promise of applying pCB coatings on artificial lungs to extend its durability and enable long-term respiratory support for lung disease patients.

Objective: Microfluidic artificial lungs (μALs) are being researched for future clinical use due to the potential for increased gas exchange efficiency, small blood contacting surface area, small priming volume, and biomimetic blood flow paths. However, a current roadblock to clinical use is the need to stack hundreds to thousands of these small-scale μALs in parallel to reach clinically relevant blood flows. The need for so many layers not only increases the complexity and projected cost to manufacture a μAL, but also could result in devices which are cumbersome, and, therefore, not suitable for portable artificial lung systems. Methods: Here, we describe the design analysis and optimization of a single-layer μAL that simultaneously calculates rated blood flow, blood contacting surface area, blood volume, pressure drop, and shear stress as a function of blood channel height using previously developed closed-form mathematical equations. A μAL designed using this procedure is then implemented and tested. Results: The resulting device exhibits a rated flow of 17 mL/min and reduces the number of layers required for clinically relevant μAL devices by a factor of up to 32X compared to previous work. Conclusion: This procedure could significantly reduce manufacturing complexity as well as eliminate a barrier to the clinical application of these promising devices. Significance: The described method results in the highest rated flow for any single-layer μAL to date.

Despite the promising potential of microfluidic artificial lungs, current designs suffer from short functional lifetimes due to surface chemistry and blood flow patterns that act to reduce hemocompatibility. Here, we present the first microfluidic artificial lung featuring a hemocompatible surface coating and a biomimetic blood path. The polyethylene-glycol (PEG) coated microfluidic lung exhibited a significantly improved in vitro lifetime compared to uncoated controls as well as consistent and significantly improved gas exchange over the entire testing period. Enabled by our hemocompatible PEG coating, we additionally describe the first extended (3 h) in vivo demonstration of a microfluidic artificial lung.

Recent studies show improved outcomes in ambulated lung failure patients. Ambulation still remains a challenge in these patients. This necessitates development of more compact and less cumbersome respiratory support specifically designed to be wearable. The Paracorporeal Ambulatory Assist Lung (PAAL) is being designed for providing ambulatory support in lung failure patients during bridge to transplant or recovery. We previously published in vitro and acute in vivo results of the PAAL. This study further evaluates the PAAL for 5 days. Five-day in vivo studies with the PAAL were conducted in 50-60 kg sheep after heparinization (activated clotting time range: 190-250 s) and cannulation with a 27 Fr. Avalon Elite dual-lumen cannula. The animals were able to move freely in a stanchion while device flow, resistance, and hemodynamics were recorded hourly. Oxygenation and hemolysis were measured daily. Platelet activation, blood chemistry, and comprehensive blood counts are reported for preoperatively, on POD 0, and POD 5. Three animals survived for 5 days. No study termination resulted from device failure. One animal was terminated on POD 0 and one animal was terminated at POD 3. The device was operated between 1.93 and 2.15 L/min. Blood left the device 100% oxygenated. Plasma-free hemoglobin ranged 10.8-14.5 mg/dl. CD62-P expression was under 10%. Minimal thrombus was seen in devices at explant. Chronic use of the PAAL in awake sheep is promising based on our study. There were no device-related complications over the study course. This study represents the next step in our pathway to eventual clinical translation.

Inspired by the increasing burden of lung associated diseases in society and an growing demand to accommodate patients, great efforts by the scientific community produce an increasing stream of data that are focused on delineating the basic principles of lung development and growth, as well as understanding the biomechanical properties to build artificial lung devices. In addition, the continuing efforts to better define the disease origin, progression and pathology by basic scientists and clinicians contributes to insights in the basic principles of lung biology. However, the use of different model systems, experimental approaches and readout systems may generate somewhat conflicting or contradictory results. In an effort to summarize the latest developments in the lung epithelial stem cell biology, we provide an overview of the current status of the field. We first describe the different stem cells, or progenitor cells, residing in the homeostatic lung. Next, we focus on the plasticity of the different cell types upon several injury-induced activation or repair models, and highlight the regenerative capacity of lung cells. Lastly, we summarize the generation of lung mimics, such as air-liquid interface cultures, organoids and lung on a chip, that are required to test emerging hypotheses. Moreover, the increasing collaboration between distinct specializations will contribute to the eventual development of an artificial lung device capable of assisting reduced lung function and capacity in human patients.

The critically ill subjects are represented by a heterogeneous group of patients suffering from a life-threatening event of different origin, e.g. trauma, cardiopulmonary failure, surgery or sepsis. The majority of these patients are dependent on the artificial lung ventilation, which means a life-saving chance for them. However, the artificial lung ventilation may trigger ventilation-associated lung injury (VALI). The mechanical ventilation at higher volumes (volutrauma) and pressure (barotrauma) can cause histological changes in the lungs including impairments in the gap and adherens junctions and desmosomes. The injured lung epithelium may lead to an impairment of the surfactant production and function, and this may not only contribute to the pathophysiology of VALI but also to acute respiratory distress syndrome. Other components of VALI are atelectrauma and toxic effects of the oxygen. Collectively, all these effects may result in a lung inflammation associated with a subsequent profibrotic changes, endothelial dysfunction, and activation of the local and systemic endocrine responses such as the renin-angiotensin system (RAS). The present review is aimed to describe some of the pathophysiologic aspects of VALI providing a basis for novel therapeutic strategies in the critically ill patients.

There exists a growing demand for new technology that can take over the function of the human lung, from assisting an injured or recently transplanted lung to completely replacing the native organ. Many obstacles must be overcome to achieve the lofty goals and expectations of such a device. An artificial lung must be able to sustain the gas exchange requirements of a normal functioning lung. Pursuant to this purpose, the device must maintain appropriate blood pressure, decrease injury to blood cells and minimize clotting and immunologic response. Attachment methods vary, and, ideally, researchers want to find a way that minimizes bodily trauma, maximizes gas exchange and utilizes the inherent properties of the native lung. The currently proposed methods include the parallel, in-series and venous double-lumen cannula configurations. For the time being, current research focuses on the extracorporeal (i.e., outside the body) placement, but ultimate long-term goals look toward total implantation.

We report on the experimental application of nafamostat mesilate (NM, 6-amidino-2-naphthyl p-guanidinobenzoate dimethanesulfonate, FUT), a new anticoagulant, to extracorporeal lung assist (ECLA) with an artificial membrane lung. Venovenous ECLA, from the jugular vein to the femoral vein, was performed with a hollow-fiber membrane lung at a blood flow rate of approximate 82 ml kg-1 min-1 for 24 h in 7 dogs under anesthesia and hypoventilation. Heparin (10 U ml-1 in a priming lactated Ringer solution of 140 ml, and 200 U kg-1) was administered before blood access cannulation. After start of ECLA, however, no heparin was used, and nafamostat mesilate was continuously infused into the drainage line of the bypass circuit to control activated coagulation time (ACT) at about 150 to 200 s. To maintain the prolonged ACT, 8.0 +/- 1.7 mg kg-1 h-1 of NM was required. Arterial blood pressure and pulse rate decreased significantly. Though fibrin monomer test revealed hypercoagulability after 6 h of ECLA, platelet counts did not significantly decrease. Total blood loss remained less than 40 g. The artificial membrane lung sustained a good gas exchange and low flow resistance throughout ECLA. Macroscopic examination revealed small spotty thrombi in the artificial lung but no major pathologic changes of the visceral organs in the all dogs at autopsy. High-dose NM administration could control blood coagulation and decrease blood loss during ECLA for 24 h without deterioration of the artificial lung and systemic complication other than mild hypotension and bradycardia.

We are developing a high performance double lumen cannula (DLC) for a minimally invasive, ambulatory and percutaneous paracorporeal artificial lung (PAL). The Wang-Zwische (W-Z) DLC was designed for percutaneous insertion into the Internal Jugular (IJ) vein with a drainage lumen open to both the superior vena cava (SVC) and the inferior vena cava (IVC) maximizing venous drainage. A separate collapsible but nondistensible membrane infusion lumen open to the right atrium (RA) achieves minimal recirculation allowing for total gas exchange. The W-Z DLC prototypes are made by a proprietary dip molding process with the "molded in" flat wire spiral stainless steel spring resulting in a flexible yet kink resistant thin wall (0.1 mm) outer cannula with one piece construction. With the ultra thin membrane infusion lumen collapsed, an introducer shaft fits tightly within the drainage lumen to facilitate insertion with placement at the SVC-RA-IVC junction. The W-Z DLC prototypes were tested while connected to a compact pump-gas exchanger circuit in three sheep (2 acute and one 15 day performance study). Insertion was simple, using standard percutaneous insertion techniques. Recirculation was as low as 2%. The 15 day performance study demonstrated our prototype 26 Fr W-Z DLC can achieve 2 L/min blood flow with minimal recirculation. The W-Z DLC design minimizes recirculation rate, maximizes flow lumen cross-sectional area, and maximizes achievable blood flow to enhance gas exchange performance allowing for one site percutaneous venovenous support.

Supplemental oxygenation is important in reversible pulmonary failure. To determine whether the peritoneal cavity can be used as a source of "extrapulmonary respiration," we perfused the peritoneal cavity with oxygenated red blood cells (RBCs) and saline, and measured the amount of oxygenation delivered through the peritoneum of dogs under controlled ventilation. Inflow and outflow catheters were placed in the peritoneal cavity and connected to a perfusion circuit. We investigated the safety of this procedure by examining the relationship between intraperitoneal infusion volume and hemodynamic changes in dogs that underwent peritoneal perfusion with oxygenated RBC (n = 6) and with oxygenated saline (n = 6). The controls comprised dogs that underwent a sham operation (n = 6). We found that an intraperitoneal infusion of less than 1,250 mL was hemodynamically safe. Oxygenation levels (PaO2) increased most obviously with an intraperitoneal infusion of oxygenated RBC. The peritoneum can potentially serve as an "artificial lung" in critically ill patients.

A large animal model is needed to study artificial lung attachment in a setting simulating chronic lung disease with significant pulmonary hypertension (PH). This study sought to create a sheep model that develops significant PH within 60 days with a low rate of mortality. Sephadex beads were injected in the pulmonary circulation of sheep every other day for 60 days at doses of 0.5, 0.75, and 1 g (n = 10, 10, 7). Mean pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output were obtained every 2 weeks. In the 0.5, 0.75, and 1-g groups, 90, 70, and 14.3% of sheep completed the study, respectively, with the remainder experiencing heart failure. By the 60th day, pulmonary vascular resistance had increased (p < 0.01) from 0.89 +/- 0.3 to 3.2 +/- 0.9 mm Hg/(L/min) and from 0.9 +/- 0.3 to 4.3 +/- 3.2 mm Hg/(L/min) in the 0.5 and 0.75-g groups, respectively. Significant right ventricular hypertrophy was observed in the 0.75-g group but not in the 0.5-g group. Data from the 1-g group were insufficient for analysis due to high mortality. Thus, the 0.5 and 0.75-g groups generate significant PH, but the 0.75-g group is a better model of chronic PH in lung disease due to the development of right ventricular hypertrophy.

Lithographic techniques were used to develop patterned silicone rubber membranes that provide 15 microm high microchannels for artificial lungs. Two types of devices were fabricated as a proof-of-concept: one has a series of parallel, straight, open rectangular channels that are each 300 microm wide, separated by 200-microm walls, and 3-mm long and the other is a wide rectangular channel with support posts, also 3- mm long. Experiments with 30% hematocrit, venous, bovine blood showed average oxygen fluxes ranging from 11 x 10(-7) moles/(min x cm(2)) at a residence time of 0.04 sec to 6.5 x 10(-7) moles/(min x cm(2)) at a residence time of 0.20 sec. The average oxygen flux vs. residence time, which is due to transverse molecular diffusion, follows the same relation for all membranes tested. The corresponding increase in hemoglobin saturation ranged from 9% at the residence time of 0.04 sec to 24% at the residence time of 0.20 sec. The support-post channel membranes are attractive for designers because they can be arbitrarily wide and would be less prone to blockage.

Background A thoracic artificial lung, the MC3 Biolung, is being developed as a bridge to lung transplantation or as a treatment for acute respiratory insufficiency. Methods The thoracic artificial lung was tested in 10 sheep with the goal of 7 days of respiratory support. The sheep were recovered from surgery and monitored awake for 7 days. Hemodynamics, blood gases, blood cell counts, and organ function were recorded, and after 7 days, all sheep were euthanized and necropsied. Results Seven sheep survived the full duration. Cardiac output and mean arterial blood pressure were unchanged, averaging 4.7 ± 0.8 L/min and 98 ± 10 mm Hg, respectively. Arterial oxygen tension and device oxygen transfer rate were also unchanged, averaging 110 ± 26 mm Hg and 97.7 ± 35 mL/min, respectively. Arterial carbon dioxide tension was within normal ranges during the entire experiment, averaging 37.4 ± 3.8 mm Hg. Artificial lung blood flow decreased from 51% ± 14% of cardiac output on day 1 to 30% ± 16% by day 7 because of changes in natural and artificial lung resistance. White blood cell counts were significantly elevated on days 5 and 7, and lastly, kidney and liver function remained normal, although signs of kidney infarction or hemorrhage were noted. Conclusions The thoracic artificial lung is suitable for 7-day attachment, but improvements in blood biocompatibility are warranted.

Introduction: Our group has developed a paracorporeal artificial lung (PAL) attached in a pulmonary artery (PA) to PA in series configuration to address profound respiratory failure and serve as a bridge to transplant and/or recovery. We recently designed, developed and converted our passive pre-PAL compliance chamber to an active, synchronized, counterpulsating assist device to relieve right heart strain and offset increased work placed on the right ventricle when the PAL is attached. In this study, we evaluated the safety and performance of both a valved and non-valved optional active compliance chamber (OACC) in a PA-PA PAL for right heart assistance in normal adult sheep. Methods : Eleven sheep (30—50 kg) were divided into non-valved OACC (n = 6) and valved (n = 5) OACC groups. To mimic pulmonary hypertension, a C-clamp was placed distal to the OACC-PAL and occluded until a 20% decrease in cardiac output (CO) was achieved. The OACC was activated, and right ventricular pressure (RVP), pulmonary artery pressure (PAP), mean arterial pressure (MAP) and CO were recorded. Results: All eleven animals tolerated the implantation of the OACC PAL. Activation of the OACC resulted in a significant increase in CO. Systolic and diastolic right ventricular pressure decreased in both groups. Lastly, counterpulsation increased the mean PAP in all animals and peak PAP reached 89 mmHg. Despite providing right heart assistance, synchronizing the counterpulsation was technically difficult, and the high peak PA pressures resulted in anastomotic bleeding in all animals and anastomotic breakdown in 4/11 animals. Conclusions: An OACC PAL perfused by the right ventricle applied in series with the pulmonary circulation reduces ventricular load and improves cardiac efficiency. These preliminary data suggest the potential of an artificial lung in unloading the strained right ventricle and acting as a bridge to transplantation. The augmented peak PA pressures, resulting in bleeding and anastomotic breakdown, and complexity in synchronizing the cardiac cycle with the pulsations of the augmented OACC, compromise this configuration. Perfusion (2007) 22, 81—86.

Native lung extracellular matrix can be isolated from cadaveric organs via perfusion decellularization and provides a novel scaffold material for lung engineering. Based on this platform, several proof-of-principle studies have demonstrated the feasibility of whole organ recellularization and culture in rodent models and have helped us better understand the numerous challenges in up-scaling to clinically relevant tissues. Standardized protocols to generate whole lung scaffolds of porcine and human scale have been reported, but our understanding of the remaining extracellular matrix components and their properties is incomplete. Effective recellularization will require the isolation and in vitro expansion of clinically relevant cell sources, either from primary or stem cell-derived populations, and techniques to effectively deliver these populations throughout the lung scaffold. Ultimately, only tightly controlled recapitulation of tissue development and repair in vitro will enable us to mature lung grafts to function before implantation. Although substantial progress has been made, we are only beginning to grasp the complexity of this exciting new technology.

Lung disease is the fourth leading cause of death (one in seven deaths) in the USA. Acute respiratory distress syndrome (ARDS) affects approximately 150,000 patients a year in the USA, and an estimated 16 million Americans are afflicted with chronic lung disease, accounting for 100,000 deaths per year. Medical management is the standard of care for initial therapy, but is limited by the progression of disease. Chronic mechanical ventilation is readily available, but is cumbersome, expensive and often requires tracheotomy with loss of upper airway defense mechanisms and normal speech. Lung transplantation is an option for less than 1100 patients per year since demand has steadily outgrown supply. For the last 15 years, the authors' group has studied ARDS in order to develop viable alternative treatments. Both extracorporeal gas exchange techniques, including extracorporeal membrane oxygenation, extracorporeal and arteriovenous CO(2) removal, and intravenous oxygenation, aim to allow for a less injurious ventilatory strategy during lung recovery while maintaining near-normal arterial blood gases, but precludes ambulation. The paracorporeal artificial lung (PAL), however, redefines the treatment of both acute and chronic respiratory failure with the goal of ambulatory total respiratory support. PAL prototypes tested on both normal sheep and the absolute lethal dose smoke/burn-induced ARDS sheep model have demonstrated initial success in achieving total gas exchange. Still, clinical trials cannot begin until bio- and hemodynamic compatibility challenges are reconciled. The PAL initial design goals are for a short-term (weeks) bridge to recovery or transplant, but eventually, for long-term support (months).

This study examined the effect of artificial lung compliance (C) on pulmonary system (PS) impedance and right ventricular function during in-series attachment of the MC3 Biolung in adult sheep. Compliances, C, of 0-20 ml/mm Hg were tested at the Biolung inlet. Results indicate the PS 0 harmonic input impedance modulus was not affected by C. The PS first harmonic input impedance modulus (Z1) was 10.9 +/- 3.2 mm Hg/(l/min) at C = 0 ml/mm Hg and minimized to 2.41 +/- 0.79 mm Hg/(l/min) at Cor = 0.5 ml/mm Hg. Cardiac output was 58% +/- 10% of its pre-Biolung attachment, baseline value at C = 0 ml/mm Hg and was maximized to an average of 75% +/- 11% at Cor = 0.5 ml/mm Hg. The left ventricular lateral-to-anteroposterior axis length ratio, which decreases with leftward septal shift, increased with C from 0.52 +/- 0.12 at C = 0 ml/mm Hg to 0.76 +/- 0.06 at C = 5 ml/mm Hg (p0.05), but decreased slightly with C at C5 ml/mm Hg. Therefore, the ideal C for right ventricular function is at least 0.5 ml/mm Hg and may be as high as 5 ml/mm Hg to minimize septal shift.

We have extended our model of the ovine pulmonary circulation to include a model of a paracorporeal artificial lung (AL) and its attachments to the natural pulmonary circulation in two configurations: in series and in parallel. Our model of the natural lung (NL) circulation is first shown to be in agreement with hemodynamic and input impedance data from the open literature. We then study design efficacy of the AL in terms of its housing and attachments. A sensitivity analysis of the modified pulmonary circulation model reveals that there are three key parameters: inlet graft length (IGL) and the compliances of the inlet compliance chamber (CC) and housing of the artificial lung. Based on literature reports, we assume the right ventricle is well-matched to the impedance of the natural pulmonary circulation and adjust the parameters of the modeled AL circuit to achieve the best least-squares fit to natural pulmonary input impedance data. Best-fit parameters produce impedance curves that fit natural impedance well, particularly below 3 Hz, where both compliance and graft length have their largest effects. Of these parameters, the impedance profile is most sensitive to IGL. However, the compliances are important, as well, particularly at low frequencies.

Artificial lungs may serve as transplant alternatives to patients with respiratory failure. To provide a pulmonary replacement, the device cannot significantly alter right ventricular afterload. We sought to characterize cardiac load using a prototype artificial lung as a pulmonary replacement. An artificial lung was implanted into 13 adult sheep, 7 using a noncompliant original prototype and 6 using a modified device with a compliance chamber. Inflow was from the pulmonary artery and outflow into the left atrium. Pulmonary impedance was determined and pulse wave reflections analyzed. Resistance was similar in the original prototype artificial lung and in the native pulmonary circulation (3.0 vs 3.2 Woods units, p = 0.5). First harmonic impedance was significantly increased in the original prototype artificial lung (0.4 vs 5.9 Woods units, p < 0.01). High-amplitude pulse wave reflections were identified and right ventricular function was altered. The addition of compliance to the artificial lung reduced impedance at the first harmonic (5.9 vs 1.9 Woods units, p < 0.01), decreased the amplitude of pulse wave reflections, and normalized right ventricular function. A low-resistance but noncompliant artificial lung increases pulmonary impedance and alters right ventricular function. Addition of a compliance chamber reduces pulse wave reflections and normalizes ventricular function.

A thoracic artificial lung (TAL) was attached to the pulmonary circulation in a porcine model. Proximal main pulmonary artery (PA) blood flow, in part or whole, was diverted to the TAL, and TAL outlet blood flow was split between the distal main PA and left atrium (LA). The right ventricle (RV) drove blood flow through the combined TAL/natural lung (NL) pulmonary system. Selective banding placed the TAL in parallel with the NLs, in series with the NLs, or in an intermediary hybrid configuration. Parallel TAL attachment lowered pulmonary system impedance, raised cardiac output (CO), and provided the greatest TAL blood flow rate, but reduced the NL blood flow rate which is important for pulmonary embolic clearance and metabolic blood processing. Hybrid or series TAL attachment raised pulmonary system impedance, lowered CO, increased RV oxygen consumption, and reduced RV oxygen supply. Redesign of the PA anastomoses, TAL inlet graft, and TAL entrance and exit would significantly improve hemodynamics and RV function with TAL attachment. Mean LA pressure increased throughout the experiment, which may indicate damage caused by graft attachment to the LA. Pulmonary resistance-flow rate curves may enable clinical prediction of tolerable TAL attachment configurations.

A compliant thoracic artificial lung (TAL) has been developed for acute respiratory failure or as a bridge to transplantation. The development goal was to increase TAL compliance, lower TAL impedance, and improve right ventricular function during use. Prototypes were tested in vitro and in vivo in eight pigs between 67 and 79 kg to determine hemodynamic and gas transfer properties. The in vitro compliance was 16.2 +/- 4.4 ml/mm Hg at pressures7.8 mm Hg and 4.3 +/- 1.1 ml/mm Hg above 7.8 mm Hg. In vivo, this compliance significantly reduced blood flow pulsatility from 1.7 at the inlet to 0.36 at the outlet. Device resistance was 1.9 and 1.8 mm Hg/(L/min) at a flow rate of 4 L/min in vitro and in vivo, respectively. Approximately 75% of the resistance was at the inlet and outlet. In vivo TAL O2 and CO2 transfer rates were 188 and 186 ml/min, respectively, at 4 L/min of blood and gas flow, and average outlet O2 saturations exceeded 98% for average flow rates up to and including the maximum tested, 5.3 L/min. The new design has a markedly improved compliance and excellent gas transfer but also possesses inlet and outlet resistances that must be reduced in future designs.

Thrombosis and bleeding are major complications in cases of prolonged extracorporeal lung assist (ECLA) with an artificial-membrane lung. Antithrombogenic treatment of the artificial-membrane oxygenator and circuits is indispensable for safe ECLA. The efficacy of a new heparin-coated membrane lung with minimal systemic heparinization was evaluated for 7 days and compared with a nonheparin-coated membrane lung in goats. The animals were randomly assigned to either the heparin-coated membrane group (HM group, n = 5) or nonheparin-coated membrane group (NHM group, n = 5). Activated coagulation time (ACT) during ECLA was controlled to below 150 s in the HM group, and to near 200 s in the NHM group. All goats in the HM group were sustained on ECLA for 7 days, but two goats in the NHM group died on the 4th and 6th days, respectively. The mean systemic administration rate of heparin during ECLA was 22.4 +/- 4.4 U/kg/h in the HM group and 39.0 +/- 10.0 U/kg/h in the NHM group. There was a significant difference between the two groups (P < 0.05). The oxygen transfer rate, the Pco(2) difference, the perfusion resistance, and platelet counts showed no significant changes. There was no plasma leakage from the artificial lung. Although several clots were observed in the stagnant areas of the artificial lung, they did not lead to deterioration of the function of the artificial lung. The excellent antithrombogenicity, gas exchange ability, and durability of this new artificial lung with circuits might contribute to successful prolonged ECLA with minimal systemic heparinization.

Objective: To analyze the correlations of the blood flow/pump rotation ratio and the transmembrane pressure, CO2 and O2 transfer during the extracorporeal respiratory support. Methods: Five animals were instrumented and submitted to extracorporeal membrane oxygenation in a five-step protocol, including abdominal sepsis and lung injury. Results: This study showed that blood flow/pump rotations ratio variations are dependent on extracorporeal membrane oxygenation blood flow in a positive logarithmic fashion. Blood flow/pump rotation ratio variations are negatively associated with transmembrane pressure (R2 = 0.5 for blood flow = 1500mL/minute and R2 = 0.4 for blood flow = 3500mL/minute, both with p 6L/minute, p = 0.006), and the blood flow/pump rotation ratio is not associated with O2 transfer variations (R2 = 0.01 for blood flow = 1500mL/minute, p = 0.19, and R2 = - 0.01 for blood flow = 3500 mL/minute, p = 0.46). Conclusion: Blood flow/pump rotation ratio variation is negatively associated with transmembrane pressure and positively associated with CO2 transfer in this animal model. According to the clinical situation, a decrease in the blood flow/pump rotation ratio can indicate artificial lung dysfunction without the occurrence of hypoxemia. Objetivo: Analisar as correlacoes da taxa de fluxo sanguineo e rotacao da bomba com a pressao transmembrana e a transferencia de CO2 e O2 durante o suporte respiratorio extracorporeo.

An implantable pediatric artificial lung (PAL) may serve as a bridge to lung transplantation for children with end-stage lung failure (ESLF); however, an animal model of pediatric lung failure is needed to evaluate the efficacy of PAL before it can enter clinical trials. The objective of this study was to assess ligation of the right pulmonary artery (rPA) as a model for pediatric ESLF. Seven lambs weighing 20-30 kg underwent rPA ligation and were recovered and monitored for up to 4 days. Intraoperatively, rPA ligation significantly increased physiologic dead space fraction (Vd/Vt; baseline = 48.6 ± 5.7%, rPA ligation = 60.1 ± 5.2%, p = 0.012), mean pulmonary arterial pressure (mPPA; baseline = 17.4 ± 2.2 mm Hg, rPA ligation = 28.5 ± 5.2 mm Hg, p < 0.001), and arterial partial pressure of carbon dioxide (baseline = 40.4 ± 9.3 mm Hg, rPA ligation = 57.3 ± 12.7 mm Hg, p = 0.026). Of the seven lambs, three were unable to be weaned from mechanical ventilation postoperatively, three were successfully weaned but suffered cardiorespiratory failure within 4 days, and one survived all 4 days. All four animals that were successfully weaned from mechanical ventilation had persistent pulmonary hypertension (mPPA = 28.6 ± 2.2 mm Hg) and remained tachypneic (respiratory rate = 63 ± 21 min). Three of the four recovered lambs required supplemental oxygen. We conclude that rPA ligation creates the physiologic derangements commonly seen in pediatric ESLF and may be suitable for testing and implanting a PAL.

Blood contact with the prosthetic surfaces of artificial lungs causes extensive activation of molecular and cellular mediators of coagulation and inflammation that can lead to patient morbidity and mortality. To determine the effects of artificial lung fiber bundle shear stress and surface area on blood activation, porcine blood was recirculated for 4 hours through circuits containing mock artificial lungs with bundle shear stresses of 11.6, 7.3, and 3.9 dynes/cm2 and surface areas of 5.2, 3.5, and 1.7 cm2/ml of circuit volume. Blood from these circuits was assayed for platelet and leukocyte counts, soluble P-selectin concentrations, and lactoferrin concentrations to determine the level of platelet and leukocyte adherence to the circuit, platelet activation, and leukocyte activation, respectively. Neither platelet nor leukocyte counts were significantly affected by shear stress or surface area. P-selectin and lactoferrin concentrations were significantly greater at a fiber bundle shear stress of 11.6 dynes/ cm2. P-selectin and lactoferrin concentrations were significantly greater at a fiber bundle surface area of 5.2 cm2/ml of circuit volume. Artificial lungs, therefore, should be designed with average bundle shear stresses < 11.6 dynes/cm2 and with surface areas < 5.2 cm2/ml of circuit volume. Current thoracic artificial lungs meet both these requirements.