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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 (

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.

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.

Microchannel artificial lungs may provide highly efficient, long-term respiratory support, but a robust predictive oxygen transfer (VO2) model is needed to better design them. To meet this need, we first investigated the predictive accuracy of Mikic, Benn, and Drinker's advancing front (AF) oxygen transfer theory by applying it to previous microchannel lung studies. Here, the model that included membrane resistance showed no bias toward overprediction or underprediction of VO2 (median error: -1.13%, interquartile range: [-26.9%, 19.2%]) and matched closely with existing theory. Next, this theory was expanded into a general model for investigating a family of designs. The overall model suggests that, for VO2 = 100 ml/min, fraction of delivered oxygen (FDO2) = 40%, wall shear stress ((Equation is included in full-text article.)) = 30 dyn/cm, and blood channel height = 20-50 μm, a compact design can be achieved with priming volume ((Equation is included in full-text article.)) = 5.8-32 ml; however, manifolding may be challenging to satisfy the rigorous total width ((Equation is included in full-text article.)) requirement ((Equation is included in full-text article.)= 76-475 m). In comparison, 100-200 μm heights would yield larger dimensions ((Equation is included in full-text article.)122-478 ml) but simpler manifolding ((Equation is included in full-text article.)4.75-19.0 m). The device size can be further adjusted by varying FDO2, (Equation is included in full-text article.), or VO2. This model may thus serve as a simple yet useful tool to better design microchannel artificial lungs.

Artificial organs 46(3), 412-426 (2022). doi:10.1111/aor.14081, Published by Wiley-Blackwell, Oxford [u.a.]

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.

The use of extracorporeal oxygenation and CO2 removal has gained clinical validity and popularity in recent years. These systems are composed of a pump to drive blood flow through the circuit and a hollow fiber membrane bundle through which gas exchange is achieved. Mathematical modeling of device design is utilized by researchers to improve device hemocompatibility and efficiency. A previously published mathematical model to predict CO2 removal in hollow fiber membrane bundles was modified to include an empirical representation of the Haldane effect. The predictive capabilities of both models were compared to experimental data gathered from a fiber bundle of 7.9 cm in length and 4.4 cm in diameter. The CO2 removal rate predictions of the model including the Haldane effect reduced the percent error between experimental data and mathematical predictions by up to 16%. Improving the predictive capabilities of computational fluid dynamics for the design of hollow fiber membrane bundles reduces the monetary and manpower expenses involved in designing and testing such devices.

Artificial lung technology is advancing at a startling rate raising hopes that it would better serve the needs of those requiring respiratory support. Whether to assist the healing of an injured lung, support patients to lung transplantation, or to entirely replace native lung function, safe and effective artificial lungs are sought. After 200 years of bioengineering progress, artificial lungs are closer than ever before to meet this demand which has risen exponentially due to the COVID-19 crisis. In this review, the critical advances in the historical development of artificial lungs are detailed. The current state of affairs regarding extracorporeal membrane oxygenation, intravascular lung assists, pump-less extracorporeal lung assists, total artificial lungs, and microfluidic oxygenators are outlined.

Measurements of transcutaneous carbon dioxide (tcCO2) have been used in multiple venues, such as during procedures utilizing jet ventilation, hyperbaric oxygen therapy, as well as both the adult and neo-natal ICUs. However, tcCO2 measurements have not been validated under conditions which utilize an artificial lung, such cardiopulmonary bypass (CPB). The purpose of this study was to (1) validate the use of tcCO2 using an artificial lung during CPB and (2) identify a location for the sensor that would optimize estimation of PaCO2 when compared to the gold standard of blood gas analysis. tcCO2 measurements ( N = 185) were collected every 30 min during 54 pulsatile CPB procedures. The agreement/differences between the tcCO2 and the PaCO2 were compared by three sensor locations. Compared to the earlobe or the forehead, the submandibular PtcCO2 values agreed best with the PaCO2 and with a median difference of –.03 mmHg (IQR = 5.4, p 2 measurement. The multiple linear regression model for predicting the agreement between the submandibular tcCO2 and PaCO2 included the SvO2, the oxygenator gas to blood flow ratio, and the native perfusion index ( R2 = 0.699, df = 1, 60; F = 19.1, p Our experience in utilizing tcCO2 during CPB has demonstrated accuracy in estimating PaCO2 when compared to the gold standard arterial blood gas analysis, even during CO2 flooding of the surgical field.

Lung transplantation may be a final destination therapy in lung failure, but limited donor organ availability creates a need for alternative management, including artificial lung technology. This invited review discusses ongoing developments and future research pathways for respiratory assist devices and tissue engineering to treat advanced and refractory lung disease. An overview is also given on the aftermath of the coronavirus disease 2019 pandemic and lessons learned as the world comes out of this situation. The first order of business in the future of lung support is solving the problems with existing mechanical devices. Interestingly, challenges identified during the early days of development persist today. These challenges include device-related infection, bleeding, thrombosis, cost, and patient quality of life. The main approaches of the future directions are to repair, restore, replace, or regenerate the lungs. Engineering improvements to hollow fiber membrane gas exchangers are enabling longer term wearable systems and can be used to bridge lung failure patients to transplantation. Progress in the development of microchannel-based devices has provided the concept of biomimetic devices that may even enable intracorporeal implantation. Tissue engineering and cell-based technologies have provided the concept of bioartificial lungs with properties similar to the native organ. Recent progress in artificial lung technologies includes continued advances in both engineering and biology. The final goal is to achieve a truly implantable and durable artificial lung that is applicable to destination therapy.

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.

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.

Children with end-stage lung failure awaiting lung transplant would benefit from improvements in artificial lung technology allowing for wearable pulmonary support as a bridge-to-transplant therapy. In this work, we designed, fabricated, and tested the Pediatric MLung-a dual-inlet hollow fiber artificial lung based on concentric gating, which has a rated flow of 1 L/min, and a pressure drop of 25 mm Hg at rated flow. This device and future iterations of the current design are designed to relieve pulmonary arterial hypertension, provide pulmonary support, reduce ventilator-associated injury, and allow for more effective therapy of patients with end-stage lung disease, including bridge-to-transplant treatment.

Under physiological conditions, up to 97% of the oxygen in blood that is transported from lungs to tissue is bound to hemoglobin. To predict oxygen transfer in artificial lungs on a membrane fiber level with computational fluid dynamics (CFD), previous investigators have incorporated the hemoglobin-oxygen interaction into an effective diffusivity coefficient to modify the convection-diffusion equation. Based on our own simulations and experiments, these approaches tend to significantly overestimate the oxygen transfer. The present study introduces a novel approach to model the oxygen transfer in blood on a fiber level with CFD. Plasma and red blood cells were implemented as two phases and the reaction of hemoglobin and oxygen to oxyhemoglobin was included in the convection-diffusion equation in form of a source term. The model was implemented with the commercial software Ansys CFX 18.1. CFD simulations were compared with in vitro experiments on three micro oxygenators with a staggered fiber configuration under multiple blood flow conditions. To calibrate the model, a reaction rate R0 was introduced and experimental data was fitted to a blood flow of 50 mL/h. Our model approximated the oxygen transfer rates with a difference, relative to in vitro results, of -23.7 and +6.3% for blood flows of 20 and 90 mL/h, respectively. The effective diffusivity model, used by previous authors, was implemented for comparison and approximated oxygen transfer rates with a difference, relative to in vitro data, of +13.7, +68.8, and +121.0% for blood flows of 20, 50, and 90 mL/h, respectively. A well-established numerical mass transfer correlation approximated the gas transfer with a difference, referenced on the average in vitro data, of 31.8, 13.1, and 5.0% for blood flows of 20, 50, and 90 mL/h, respectively. Even though results are promising, a thorough validation of the model will require extensive CFD and in vitro studies of multiple fiber arrangements, fiber diameters, and therefore fiber bundle porosities in the future. This article should be understood as a first feasibility study to evaluate the potential of the novel oxygen transfer model.

The compliant thoracic artificial lung (cTAL) has been studied in acute in vivo and in vitro experiments. The cTAL's long-term function and potential use as a bridge to lung transplantation are assessed presently. The cTAL without anticoagulant coatings was attached to sheep (n = 5) via the pulmonary artery and left atrium for 14 days. Systemic heparin anticoagulation was used. Compliant thoracic artificial lung resistance, cTAL gas exchange, hematologic parameters, and organ function were recorded. Two sheep were euthanized for nondevice-related issues. The cTAL's resistance averaged 1.04 ± 0.05 mmHg/(L/min) with no statistically significant increases. The cTAL transferred 180 ± 8 ml/min of oxygen with 3.18 ± 0.05 L/min of blood flow. Except for transient surgical effects, organ function markers were largely unchanged. Necropsies revealed pulmonary edema and atelectasis but no other derangements. Hemoglobin levels dropped with device attachment but remained steady at 9.0 ± 0.1 g/dl thereafter. In a 14 day experiment, the cTAL without anticoagulant coatings exhibited minimal clot formation. Sheep physiology was largely unchanged except for device attachment-related hemodilution. This suggests that patients treated with the cTAL should not require multiple blood transfusions. Once tested with anticoagulant coatings and plasma resistant gas exchange fiber, the cTAL could serve as a bridge to transplantation.

Current hollow fiber membrane lungs feature a predominantly straight blood path length across the fiber bundle, resulting in limited oxygen transfer efficiency due to the diffusion boundary layer effect. Using computational fluid dynamics and optical flow visualization methods, a hollow fiber membrane lung was designed comprising unique concentric circular blood flow paths connected by gates. The prototype lung, comprising a fiber surface area of 0.28 m2, has a rated flow of 2 L/min and the oxygenation efficiency is 357 mL/min/m2. The CO2 clearance of the lung is 200 mL/min at the rated blood flow. Given its high gas transfer efficiency, as well as its compact size, low priming volume, and propensity for minimal thrombogenicity, this lung design has the potential to be used in a range of acute and chronic respiratory support applications, including providing total respiratory support for infants and small children and CO2 clearance in adults.

Extracorporeal membrane oxygenation (ECMO) is a life support system that circulates the blood through an oxygenating system to temporarily (days to months) support heart or lung function during cardiopulmonary failure until organ recovery or replacement. Currently, the need for high levels of systemic anticoagulation and the risk for bleeding are main drawbacks of ECMO that can be addressed with a redesigned ECMO system. Our lab has developed an approach using microelectromechanical systems (MEMS) fabrication techniques to create novel gas exchange membranes consisting of a rigid silicon micropore membrane (SμM) support structure bonded to a thin film of gas-permeable polydimethylsiloxane (PDMS). This study details the fabrication process to create silicon membranes with highly uniform micropores that have a high level of pattern fidelity. The oxygen transport across these membranes was tested in a simple water-based bench-top set-up as well in a porcine in vivo model. It was determined that the mass transfer coefficient for the system using SµM-PDMS membranes was 3.03 ± 0.42 mL O2 min−1 m−2 cm Hg−1 with pure water and 1.71 ± 1.03 mL O2 min−1 m−2 cm Hg−1 with blood. An analytic model to predict gas transport was developed using data from the bench-top experiments and validated with in vivo testing. This was a proof of concept study showing adequate oxygen transport across a parallel plate SµM-PDMS membrane when used as a membrane oxygenator. This work establishes the tools and the equipoise to develop future generations of silicon micropore membrane oxygenators.

Introduction: To offer respiratory support for patients with lung disease, a novel technological solution for blood pumping and oxygenation is being developed. The pump–lung system was designed to integrate fiber membranes into six packages radially embedded in a rotating hollow shaft placed along the longitudinal axis of the device. Fiber packages are inclined with respect to the rotation axis so that the rotational motion of the rotating shaft allows a self-pumping system to be obtained. Method: Both hemodynamic and gas transfer performances were investigated using both in vitro experiments and in silico flow analyses. Results: The predicted flow velocity in the pump chamber was smooth and characterized by high peripheral velocities near the housing wall. As the blood flow enters the inlet, the static pressure increased with the angular momentum imparted to the fiber packages. Experiments confirmed that the proposed pump–lung system can provide adequate blood flow and oxygen transfer over the range of intended operating conditions (0.5–5 L/min and 500–1500 r/min). Conclusion: Although the study did not include animal testing, the novel pump-oxygenator solution is feasible for respiratory support in patients with lung diseases.

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.

Flow distribution is key in artificial lungs, as it directly influences gas exchange performance as well as clot forming and blood damaging potential. The current state of computational fluid dynamics (CFD) in artificial lungs can only give insight on a macroscopic level due to model simplification applied to the fiber bundle. Based on our recent work on wound fiber bundles, we applied particle image velocimetry (PIV) to the model of an artificial lung prototype intended for neonatal use to visualize flow distribution in a stacked fiber bundle configuration to (i) evaluate the feasibility of PIV for artificial lungs, (ii) validate CFD in the fiber bundle of artificial lungs, and (iii) give a suggestion how to incorporate microscopic aspects into mainly macroscopic CFD studies. To this end, we built a fully transparent model of an artificial lung prototype. To increase spatial resolution, we scaled up the model by a factor of 5.8 compared with the original size. Similitude theory was applied to ensure comparability of the flow distribution between the device of original size and the scaled-up model. We focused our flow investigation on an area (20 × 70 × 43 mm) in a corner of the model with a Stereo-PIV setup. PIV data was compared to CFD data of the original sized artificial lung. From experimental PIV data, we were able to show local flow acceleration and declaration in the fiber bundle and meandering flow around individual fibers, which is not possible using state-of-the-art macroscopic CFD simulations. Our findings are applicable to clinically used artificial lungs with a similar stacked fiber arrangement (e.g., Novalung iLa and Maquet QUADROX-I). With respect to some limitations, we found PIV to be a feasible experimental flow visualization technique to investigate blood-sided flow in the stacked fiber arrangement of artificial lungs.

Stability and antithrombotic functionality of endothelial cells on silicone hollow fibers (SiHFs) are critical in the development of biohybrid artificial lungs. Here we aimed to enhance endothelial cell retention and anti-thrombotic function by low (12 dyn/cm2 , 24 h) fluid shear stress ("flow") preconditioning of endothelial cells seeded on collagen-immobilized SiHFs. The response of endothelial cells without preconditioning (48 h static culture) and with preconditioning (24 h static culture followed by 24 h flow preconditioning) on hollow fibers to high fluid shear stress (30 dyn/cm2 , 1 h) was assessed in a parallel-plate flow chamber. Finite element (FE) modeling was used to simulate shear stress within the flow chamber. We found that collagen immobilization on hollow fibers using carbodiimide bonds provided sufficient stability to high shear stress. Flow preconditioning for 24 h before treatment with high shear stress for 1 h on collagen-immobilized hollow fibers increased cell retention (1.3-fold). The FE model showed that cell flattening due to flow preconditioning reduced maximum shear stress on cells by 32%. Flow preconditioning prior to exposure to high fluid shear stress enhanced the production of nitric oxide (1.3-fold) and prostaglandin I2 (1.2-fold). In conclusion, flow preconditioning of endothelial cells on collagen-immobilized SiHFs enhanced cell retention and antithrombotic function, which could significantly improve current biohybrid artificial lungs.

Respiratory failure is one of the major causes of mortality and morbidity all over the world. Therapeutic options to treat respiratory failure remain limited. The objective of this study was to evaluate the gas transfer performance of a newly developed miniature portable integrated pediatric pump-lung device (PediPL) with small membrane surface for respiratory support in an acute ovine respiratory failure model. The respiratory failure was created in six adult sheep using intravenous anesthesia and reduced mechanical ventilation at 2 breaths/min. The PediPL device was surgically implanted and evaluated for respiratory support in a venovenous configuration between the right atrium and pulmonary artery. The hemodynamics and respiratory status of the animals during support with the device gas transfer performance of the PediPL were studied for 4 h. The animals exhibited respiratory failure 30 min after mechanical ventilation was reduced to 2 breaths/min, indicated by low oxygen partial pressure, low oxygen saturation, and elevated carbon dioxide in arterial blood. The failure was reversed by establishing respiratory support with the PediPL after 30 min. The rates of O2 transfer and CO2 removal of the PediPL were 86.8 and 139.1 mL/min, respectively. The results demonstrated that the PediPL (miniature integrated pump-oxygenator) has the potential to provide respiratory support as a novel treatment for both hypoxia and hypercarbia. The compact size of the PediPL could allow portability and potentially be used in many emergency settings to rescue patients suffering acute lung injury.

This response explores and discusses the critiques of Wagneret al.in their “Comment on ‘The promise of microfluidic artificial lungs’ by Joseph A. Potkay,Lab Chip, 2014,14, 4122–4138”.

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.

Extracorporeal membrane oxygenation (ECMO) is increasingly being used to support adults with severe forms of respiratory failure. Fueling the explosive growth is a combination of technological improvements and accumulating, although controversial, evidence. Current use of ECMO extends beyond its most familiar role in the support of patients with severe acute respiratory distress syndrome (ARDS) to treat patients with various forms of severe hypoxemic or hypercapnic respiratory failure, ranging from bridging patients to lung transplantation to managing pulmonary hypertensive crises. The role of ECMO used primarily for extracorporeal carbon dioxide removal (ECCO2R) in the support of patients with hypercapnic respiratory failure and less severe forms of ARDS is also evolving. Select patients with respiratory failure may be liberated from invasive mechanical ventilation altogether and some may undergo extensive physical therapy while receiving extracorporeal support. Current research may yield a true artificial lung with the potential to change the paradigm of treatment for adults with chronic respiratory failure.

Providing partial respiratory assistance by removing carbon dioxide (CO2 ) can improve clinical outcomes in patients suffering from acute exacerbations of chronic obstructive pulmonary disease and acute respiratory distress syndrome. An intravenous respiratory assist device with a small (25 Fr) insertion diameter eliminates the complexity and potential complications associated with external blood circuitry and can be inserted by nonspecialized surgeons. The impeller percutaneous respiratory assist catheter (IPRAC) is a highly efficient CO2 removal device for percutaneous insertion to the vena cava via the right jugular or right femoral vein that utilizes an array of impellers rotating within a hollow-fiber membrane bundle to enhance gas exchange. The objective of this study was to evaluate the effects of new impeller designs and impeller spacing on gas exchange in the IPRAC using computational fluid dynamics (CFD) and in vitro deionized water gas exchange testing. A CFD gas exchange and flow model was developed to guide a progressive impeller design process. Six impeller blade geometries were designed and tested in vitro in an IPRAC device with 2- or 10-mm axial spacing and varying numbers of blades (2-5). The maximum CO2 removal efficiency (exchange per unit surface area) achieved was 573 ± 8 mL/min/m(2) (40.1 mL/min absolute). The gas exchange rate was found to be largely independent of blade design and number of blades for the impellers tested but increased significantly (5-10%) with reduced axial spacing allowing for additional shaft impellers (23 vs. 14). CFD gas exchange predictions were within 2-13% of experimental values and accurately predicted the relative improvement with impellers at 2- versus 10-mm axial spacing. The ability of CFD simulation to accurately forecast the effects of influential design parameters suggests it can be used to identify impeller traits that profoundly affect facilitated gas exchange.

The purpose of this study was to assess the biocompatibility of a newly developed long-term wearable artificial pump-lung (APL) in a clinically relevant ovine animal model. The wearable APL device was implanted in five sheep through left thoracotomy. The device was connected between the right atrium and pulmonary artery and evaluated for 30 days. Three sheep were used as the sham control. Platelet activation was assessed by measuring platelet surface P-selectin (CD62P) expression with flow cytometry and plasma soluble P-selectin with an enzyme-linked immunosorbent assay. Thrombotic deposition on the device components and hollow fiber membranes were analyzed with digital imaging and scanning electron microscopy. Surface P-selectin of the APL and sham groups changed significantly over the study period, but without significant differences between the two groups. Soluble P-selectin for the two groups peaked in the first 24 h after the surgery. Soluble P-selectin of the APL group remained slightly elevated over the study period compared to the presurgical baseline value and was slightly higher compared to that of the sham group. Plasma free hemoglobin remained in the normal ranges in all the animals. In spite of the surgery-related alteration in laboratory tests and elevation of platelet activation status, the APL devices in all the animals functioned normally (oxygen transfer and blood pumping) during the 30-day study period. The device flow path and membrane surface were free of gross thrombus. Electron microscopy images showed only scattered thrombi on the fibers (membrane surface and weft). In summary, the APL exhibited excellent biocompatibility. Two forms of platelet activation, surgery-related and device-induced, in the animals implanted with the wearable APL were observed. The limited device-induced platelet activation did not cause gross thrombosis and impair the long-term device performance.

Mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) are the only viable treatment options for lung failure patients at the end-stage, including acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). These treatments, however, are associated with high morbidity and mortality because of long wait times for lung transplant. Contemporary clinical literature has shown ambulation improves post-transplant outcomes in lung failure patients. Given this, we are developing the Pittsburgh Ambulatory Assist Lung (PAAL), a truly wearable artificial lung that allows for ambulation. In this study, we targeted 180 ml/min oxygenation and determined the form factor for a hollow fiber membrane (HFM) bundle for the PAAL. Based on a previously published mass transfer correlation, we modeled oxygenation efficiency as a function of fiber bundle diameter. Three benchmark fiber bundles were fabricated to validate the model through in vitro blood gas exchange at blood flow rates from 1 to 4 L/min according to ASTM standards. We used the model to determine a final design, which was characterized in vitro through a gas exchange as well as a hemolysis study at 3.5 L/min. The percent difference between model predictions and experiment for the benchmark bundles ranged from 3% to 17.5% at the flow rates tested. Using the model, we predicted a 1.75 in diameter bundle with 0.65 m surface area would produce 180 ml/min at 3.5 L/min blood flow rate. The oxygenation efficiency was 278 ml/min/m and the Normalized Index of Hemolysis (NIH) was less than 0.05 g/100 L. Future work involves integrating this bundle into the PAAL for which an experimental prototype is under development in our laboratory.

Mechanical ventilation and extracorporeal membrane oxygenation are the only immediate options available for patients with respiratory failure. However, these options present significant shortcomings. To address this unmet need for respiratory support, innovative respiratory assist devices are being developed. In this study, we present the computational model-based design, and analysis of functional characteristics and hemocompatibility performance, of an innovative wearable artificial pump-lung (APL) for ambulatory respiratory support. Computer-aided design and computational fluid dynamics (CFD)-based modeling were utilized to generate the geometrical model and to acquire the fluid flow field, gas transfer, and blood damage potential. With the knowledge of flow field, gas transfer, and blood damage potential through the whole device, design parameters were adjusted to achieve the desired specifications based on the concept of virtual prototyping using the computational modeling in conjunction with consideration of the constraints on fabrication processes and materials. Based on the results of the CFD design and analysis, the physical model of the wearable APL was fabricated. Computationally predicted hydrodynamic pumping function, gas transfer, and blood damage potential were compared with experimental data from in vitro evaluation of the wearable APL. The hydrodynamic performance, oxygen transfer, and blood damage potential predicted with computational modeling, along with the in vitro experimental data, indicated that this APL meets the design specifications for respiratory support with excellent biocompatibility at the targeted operating condition.

Extracorporeal membrane oxygenation (ECMO) is a well-established therapy for several lung and heart diseases in the field of neonatal and pediatric medicine (e.g., acute respiratory distress syndrome, congenital heart failure, cardiomyopathy). Current ECMO systems are typically composed of an oxygenator and a separate nonpulsatile blood pump. An oxygenator with an integrated pulsatile blood pump for small infant ECMO was developed, and this novel concept was tested regarding functionality and gas exchange rate. Pulsating silicone tubes (STs) were driven by air pressure and placed inside the cylindrical fiber bundle of an oxygenator to be used as a pump module. The findings of this study confirm that pumping blood with STs is a viable option for the future. The maximum gas exchange rate for oxygen is 48mL/min/L(blood) at a medium blood flow rate of about 300mL/min. Future design steps were identified to optimize the flow field through the fiber bundle to achieve a higher gas exchange rate. First, the packing density of the hollow-fiber bundle was lower than commercial oxygenators due to the manual manufacturing. By increasing this packing density, the gas exchange rate would increase accordingly. Second, distribution plates for a more uniform blood flow can be placed at the inlet and outlet of the oxygenator. Third, the hollow-fiber membranes can be individually placed to ensure equal distances between the surrounding hollow fibers.

In this work an automatic control strategy is presented for the simultaneous control of oxygen and carbon dioxide blood gas partial pressures to be used during cardiopulmonary bypass surgery with heart-lung machine support. As the exchange of blood gases in the artificial extracorporeal lung is a highly nonlinear process comprising varying time delays, uncertainties, and time-varying parameters, it is currently being controlled manually by specially trained perfusionist staff. The new control strategy includes a feedback linearization routine with augmented time-delay compensation and two external linear gain-scheduled controllers, for partial oxygen and carbon dioxide pressures. The controllers were robustly tuned and tested in simulations with a detailed artificial lung (oxygenator) model in cardiopulmonary bypass conditions. Furthermore, the controllers were implemented in an ex vivo experiment using fresh porcine blood as a substitute fluid and a special deoxygenation technique to simulate a patient undergoing cardiopulmonary bypass. Both controllers showed robust stability during the experiments and a good disturbance rejection to extracorporeal blood flow changes. This automatic control strategy is proposed to improve patient's safety by fast control reference tracking and good disturbance rejection under varying conditions.

Artificial lungs composed of bundles of micro-porous hollow fiber membranes (HFMs), which are made from polymeric materials such as poly (methylpentene) and poly(propylene), are routinely employed to both oxygenate blood and remove carbon dioxide (CO2) in an extraluminal blood flow format. The efficiency of CO2 and oxygen (O2) gas exchange in the current artificial lung model, which is based on passive diffusion, is limited by the fiber surface area to blood volume ratio with devices requiring approximately 1–2 m2 of HFM surface to provide adequate gas exchange (1,2). Such large blood-contacting surfaces present significant challenges to hemocompatibility, necessitating aggressive anticoagulation and stimulating research into devices with improved efficiency (i.e., smaller) and hemocompatibility. A wide variety of surface modification techniques have been evaluated to reduce the thrombogenicity of blood-contacting biomaterials, although there have been relatively few reports specifically focused on the HFMs utilized in artificial lung applications. Siloxane-grafted HFMs prepared by a plasma polymerization process with 1,3,3,7-tetramethyhydrocyclosiloxane (TMCTS)-coated fibers have shown reduced thrombogenesis relative to unmodified fibers (3). Plasma polymerization techniques have a number of advantages with regard to surface modification including: facile preparation of a thin, conformal, and pinhole-free coating; amenability to a wide variety of substrates; achievement of good adhesion between coating and substrate; and the ability to generate coatings that present excellent thermal and chemical resistance (4,5). Another approach to improving artificial lung biocompatibility is to effectively reduce the required HFM surface area by increasing the gas exchange rate of HFM-based devices. Increasing the efficiency of CO2 removal is especially important because the natural concentration gradient for CO2 diffusion is much smaller than that for O2 addition. Furthermore, in many patients with respiratory failure, the need for CO2 removal is more important clinically, as oxygenation can be provided by nasal cannula or lung-protective ventilation (1,6–8). In a previous study, we reported the development of a bioactive HFM that could improve CO2 removal rates in lung failure patients (9). Carbonic anhydrase (CA) was covalently immobilized to the surface of a conventional HFM, and by catalyzing the dehydration of bicarbonate in blood was shown to facilitate diffusion of CO2 toward the fiber membranes, essentially mimicking the function of the enzyme on lung capillary surfaces. Results indicated that CO2 exchange rates from buffer were increased by as much as 75% in the model device. In this brief report, we addressed whether the attachment of CA onto a HFM surface increased fiber thrombogenicity, which would negate the biocompatibility benefits associated with a smaller device. A commercial poly(propylene) HFM (Celgard, Charlotte, NC,USA) was used as the base material and for control purposes. Fibers representing the intermediate modification steps of siloxane coating and amine grafting on siloxane (Alung Technologies, Pittsburgh, PA, USA) as well as the final CA-modified fiber were evaluated. A second control of a commercial poly (methyl pentene) HFM (Oxyplus, Membrana, Wuppertal, Germany) was also included.

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.

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.

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.

Thrombogenicity, a problem with long-term artificial lungs, is caused by blood-biomaterial interactions and is made worse by nonuniform flow, which also causes decreased gas exchange. To overcome these obstacles, we changed the inlet and added a uniform flow pump to our previous oxygenator design. Conventional membrane oxygenators have a ½-inch port for the inlet of blood. These port structures make it difficult for the blood to flow uniformly in the oxygenator. In addition, the complex blood flow patterns that occur in the oxygenator, including turbulence and stagnation, lead to thrombogenicity. A cross-flow pump (CFP) can result in uniform blood flow to the inlet side of an oxygenator. In this study, we evaluated the usefulness of an integrated oxygenator with a fiber bundle porosity of 0.6 and a membrane surface area of 1.3 m 2 . The inlet part of the oxygenator is improved and better fits the outlet of the CFP. Each of the three models of the improved oxygenator has a different inlet taper angle. The computational fluid dynamics analysis showed that, compared with the original design, uniform flow of the integrated oxygenator improved by 88.8% at the hollow fiber membrane. With the integrated oxygenator, O 2 transfer increased by an average of 20.8%, and CO 2 transfer increased by an average of 35.5%. The results of our experiments suggest that the CFP, which produces a wide, uniform flow to the oxygenator, is effective in attaining high gas exchange performance.

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.

This in vitro study sought to determine what compliance minimizes thoracic artificial lung impedance and pump power output. A pulsatile pump drove 3.0 cP glycerol through a circuit consisting of an MC3 Biolung preceded by a piston-cylinder (PC, n = 5) chamber with a variable compliance or a polyurethane (n = 4) chamber with a fixed, yet pressure-dependent, compliance. Each chamber was tested at flow rates of 1.8, 3.0, and 5.0 l/min and heart rates of 60, 75, and 100 bpm. Compliances, C, from 0-20 ml/mm Hg were tested in the PC chamber. Instantaneous pump outlet flow and pressure were acquired for determination of device zeroth and first harmonic input impedance, Z(0) and Z(1), and pump steady and pulsatile output powers, P(s) and P(p). PC chamber results indicate that Z(0), Z(1), P(s), and Pp were minimized at C > 1, 5, 0.5, and 4 ml/mm Hg, respectively. This suggests that C should be 1 ml/mm Hg at minimum and ideally 5 ml/mm Hg. The polyurethane chamber was statistically similar to the PC chamber at C = 1 ml/mm Hg when comparing Z(0) and P(s), but was statistically inferior when comparing Z(1) and P(p). The polyurethane compliance chamber, therefore, should be redesigned with greater compliance.

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.