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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 (

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.

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 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 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.

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.

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.

Patients experiencing acute respiratory failure or acute exacerbations of chronic respiratory failure (e.g., chronic obstructive pulmonary disease [COPD]) can potentially be supported through intravenous respiratory assist devices.1–4 This next generation of artificial lung support, under development but not in clinical use, provides supplemental oxygenation or removal of carbon dioxide through bundles of microporous hollow fiber membranes (HFMs). This technique involves placing the HFM bundle into the vena cava through a peripheral vein (e.g., femoral vein) and connecting the fibers to an external oxygen source.5 Diffusion gradients are created when pure oxygen flows through the fibers, causing O2 diffusion into the blood stream and CO2 diffusion out of the blood (through the gas permeable fiber wall) and into the exhaust gas (mixture of O2 and CO2) exiting the device. Placement within the vena cava provides time for the natural lungs to heal because the oxygenation and CO2 removal is independent of the lungs, which is a benefit over mechanical ventilation,6,7 the most commonly used therapy. Intravenous respiratory assistance is less complicated than extracorporeal respiratory support because an external blood circuit and pump are not required. Our group is developing an intravenous respiratory assist catheter to support patients with acute lung failure by improving oxygen delivery and CO2 removal.8–12 In its application in patients with COPD, the catheter focuses upon CO2 removal because oxygenation can be adequately addressed through nasal O2.13 Our catheter, seen in Figure 1, uses microporous hollow fiber membranes wrapped into a bundle around a pulsating balloon. Pulsation of this centrally located balloon at increasing frequencies creates higher blood velocities past the fiber surfaces than would exist with a passive device. This generates an active mixing environment, in turn facilitating greater gas transfer, subsequently increasing the CO2 removal capacity of the device.14 Our previous bench, ex vivo, and acute animal testing of our pulsating device5,10,12 have confirmed that enhanced gas exchange is possible with balloon pulsation10 when compared with a nonpulsating device, the IVOX.3,4,15–17 Figure 1 Catheter schematic including cross‐sections of pathway tubing and balloon/hollow fiber section. The balloon within our respiratory assist catheter does not collapse and inflate axisymmetrically. Rather, the balloon collapses asymmetrically into a crescent shape, and the fibers around the balloon move similarly with balloon pulsation in an asymmetric manner. The fibers adjacent to the convex region of the crescent shaped balloon collapse are more stationary during balloon pulsation than the other fiber regions. We hypothesized that asymmetric balloon collapse and inflation within the fiber bundle might cause nonuniform flow patterns and nonuniform gas exchange in different regions of the fiber bundle. We also hypothesized that gas exchange may differ from fibers on the outside of the fiber bundle compared with fibers on the inside of the bundle near the pulsating balloon. To test these hypotheses, we evaluated the local carbon dioxide gas exchange for individual fiber bundle quarters around the central balloon and for inner and outer fiber rings around the balloon (i.e., the inner layer of the fiber bundle closest to the balloon and the outer most layers away from the balloon).

Matching the impedance of an artificial lung for pulmonary replacement to native pulmonary impedance is important in preventing right ventricular dysfunction. A lumped-parameter theoretical model and bench-top experiments were used to investigate the effect of a prototype compliance chamber on input impedance. The bench-top simulation consisted of a pulsatile flow generator, a prototype compliance chamber, and a low resistance artificial lung connected in series. Effective compliance was varied using pneumatic compression. The theoretical model considered a similar circuit with resistors before and after a compliance element. The bundle flow pulsatility (flow amplitude divided by average flow) and input impedance were calculated in the theoretical and experimental models. More compliance and lower upstream resistance result in lower bundle flow pulsatility and reduced first harmonic impedance. Matching the time scale of the circuit to the period of pulsatile flow also reduces impedance. The bench-top circuit demonstrated an optimal chamber pressure at which first harmonic impedance is reduced by 80%. The prototype compliance chamber in series with the artificial lung more closely matches native pulmonary impedance. The lumped-parameter model and the bench-top simulation will aid in the design and testing of compliance chamber modifications to improve its efficiency.

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.

An artificial lung is used during cardiopulmonary bypass to oxygenate blood and control blood temperature. The oxygen transfer rate-flow rate characteristics of three hollow fiber membrane artificial lungs (Sarns Turbo 440, Cobe Optima, Dideco Compactflo) were determined in vitro to characterize design features. Results are presented as a unique dimensionless relationship between Sherwood number, NSh (ratio of convective to diffusive mass transfer), Schmidt number, NSc (ratio of momentum to diffusive transport), and Reynolds number, NRe (ratio of inertial to viscous forces). This relationship is a function of device porosity, epsilon, and characteristic device length, xi, defined as the ratio of the mean blood path and manifold length: Nsh/NSc(1/3) x xi(1/2) = phi x (epsilon(1/m) x NRe)(m) where phi = 0.26 and m = 1.00 for NPe3,200 and phi = 0.47 and m = 0.64 for NPe3,200 where NPe is the dimensionless Péclet number defined as NRe x NSc. We found good correspondence between the model predictions and in vitro blood oxygen transfer rates. We conclude that this dimensionless approach allows us (1) to compare artificial lungs independently, (2) to relate water tests to blood, and (3) to predict the oxygen transfer rate of a new artificial lung design.

Oxygen transfer across a single cotyledon of the human placenta was assessed by using three different perfusates in the maternal circuit: 1) M-199 culture medium, 2) human adult red blood cells (RBCs), and 3) perflubron. These maternal circuit perfusates were oxygenated with a membrane oxygenator. RBCs were perfused on the fetal side of the circuit and samples were taken preplacenta and postplacenta for each maternal perfusate. PO2 and PCO2 were measured and O2 transfer was calculated for each maternal perfusate. O2 transfer per single cotyledon (mean +/- SE) was 0.18 +/- 0.04, 0.20 +/- 0.03, and 0.15 +/- 0.05 ccO2/min when using: 1) M-199, 2) RBCs, and 3) perflubron, respectively. O2 transfer per kilogram of placental tissue was 13.08 +/- 2.78, 14.57 +/- 2.05, and 10.43 +/- 3.79 ccO2/kg per minute when using: 1) M-199, 2) RBCs, and 3) perflubron, respectively. When extrapolated to the individual weights of the entire placenta, the O2 transfer was 9.15 +/- 1.95, 10.20 +/- 1.43, and 7.30 +/- 2.65 when using: 1) M-199, 2) RBCs, and 3) perflubron, respectively. We conclude from these data that O2 transfer can be accomplished during placental perfusion. Larger studies are required to differentiate efficacy among the three maternal circuit perfusates.

A thoracic artificial lung (TAL) was designed to treat respiratory insufficiency, acting as a temporary assist device in acute cases or as a bridge to transplant in chronic cases. We developed a computational model of the pulmonary circulatory system with the TAL inserted. The model was employed to investigate the effects of parameter values and flow distributions on power generated by the right ventricle, pulsatility in the pulmonary system, inlet flow to the left atrium, and input impedance. The ratio of right ventricle (RV) power to cardiac output ranges between 0.05 and 0.10 W/(L/min) from implantation configurations of low impedance to those of high impedance, with a control value of 0.04 W/(L/min). Addition of an inlet compliance to the TAL reduces right heart power (RHP) and impedance. A compliant TAL housing reduces flow pulsatility in the fiber bundle, thus affecting oxygen transfer rates. An elevated bundle resistance reduces flow pulsatility in the bundle, but at the expense of increased right heart power. The hybrid implantation mode, with inflow to the TAL from the proximal pulmonary artery (PA), outflow branches to the distal PA and the left atrium (LA), a band around the PA between the two anastomoses, and a band around the outlet graft to the LA, is the best compromise between hemodynamic performance and preservation of some portion of the nonpulmonary functions of the natural lungs.

Lung transplantation is the only treatment option for patients suffering form end-stage respiratory failure. To date, no mechanical device is available to support patients on the waiting list up to months. Here, we summarize our experience with our first two patients, who were supported with a paracorporeal artificial lung (PAL) placed in parallel to the pulmonary circulation with connection to the pulmonary artery and to the left atrium. A low resistance membrane oxygenator (iLA, Novalung, Hirrlingen, Germany) was attached in both patients. Our first patient suffering from a pulmonary veno-occlusive disease was supported for 18 days until he died due to severe sepsis. Our second patient with a primary pulmonary hypertension of unknown origin was supported 62 days followed by successful lung transplantation. In conclusion, the experience obtained with these first two patients under PAL encourages further studies and introduction of this promising concept into clinical practice.

A low input impedance, intrathoracic artificial lung is being developed for use in acute respiratory failure or as a bridge to transplantation. The device uses microporous, hollow fibers in a 0.74 void fraction, 1.83 m2 surface area bundle. The bundle is placed within a thermoformed polyethylene terephthalate glucose modified housing with a gross volume of 800 cm3. The blood inlet and outlet are 18 mm inner diameter vascular grafts. Between the inlet graft and the device is a 1 inch inner diameter, thin-walled, latex tubing compliance chamber. These devices were implanted in Yorkshire pigs via median sternotomy with an end to side anastomosis to the pulmonary artery and left atrium. The distal pulmonary artery was occluded to divert the right ventricular output to the device. Pigs 1 and 2 were supported fully for 24 hrs and then killed. Pig 3 was supported partially for 20 hrs and died from bleeding complications. The first implant, in a 55 kg male pig, transferred an average of 176 ml/min +/- 42.4 of O2 and 190 ml/min +/- 39.7 of CO2 with an average blood flow rate of 2.71/min +/- 0.46. The normalized average right ventricular output power, Pn, was 0.062 W/(L/min) +/- 0.0082, and the average device resistance, R, was 3.5 mmHg/(L/min) +/- 0.62. The second implant, in a 60 kg male pig, transferred an average of 204 ml/min +/- 22.5 of O2 and 242 ml/min +/- 17.2 of CO2 with an average blood flow rate of 3.7 L/min +/- 0.45, Pn of 0.064 W/(L/min) +/- 0.0067, and R of 4.3 mmHg/(L/min) +/- 0.89. The third implant, in an 89 kg male pig, transferred an average of 156 ml/min +/- 39.6 of O2 and 187 ml/min +/- 21.4 of CO2 with an average blood flow rate of 2.5 L/min +/- 0.49, Pn of 0.052 W/(l/min) +/- 0.0067, and R of 3.4 mmHg/(L/min) +/- 0.74. These experiments suggest that such an artificial lung can temporarily support the gas transfer requirements of adult humans without over-loading the right ventricle.

A new prototype of a pumping artificial lung (PAL) has been designed and tested. The device performs the functions of both the pump and oxygenator components of an extracorporeal perfusion circuit. Previous prototypes that the authors developed (Type A) had gas exchanging microporous fibers formed into propeller-like vanes that, upon rotation, pump the blood. The design of the new PAL prototypes (Type B) uses the rotation of an annular bank of fibers to drive flow. The fiber bank, including sealed gas manifolds, lies within the housing of a modified Bio-Medicus BMP-50 pump head (Bio-Medicus, Eden Prairie, MN). Rotation of the fiber bank is driven through a magnetic coupling. Inlet and outlet gas lines enter the pump head through a sealed bearing. The Type A PAL suffered from insufficient pumping rates and gas exchange, necessitating redesign. The authors have constructed two PAL-B prototypes with a priming volume of only 140 ml and gas exchange surface areas of 0.16 and 0.60 m2. During in vitro saline testing, these prototypes showed significant pump performance, pumping 7.0 L/min against zero head at 3,500 rpm. The larger prototype had exchange rates in saline of up to 71 ml O2/min and 75 ml CO2/min. Gas exchange fluxes (O2 = 119 ml/[min $$ m2] and CO2 = 125 ml/[min $$ m2]) for the PAL-B are significantly higher than that of commercially available oxygenators in saline. Future prototypes will have increased surface area and fibers smaller than the 0.038 cm outside diameter fibers used in the present prototypes. A primary concern in using microporous fibers to push the blood was the durability of the fibers at high pump speeds, High speeds exhibited no negative effects on gas exchange abilities or fiber duarbility

A novel cardiopulmonary support (CPS) system as a long-term total substitute for the natural heart and lung was designed and evaluated. The CPS system is composed of a ventricular assist device (VAD) and a newly developed compact artificial lung (AL). The pneumatic VAD was originally developed in the authors' institute and has proven durable and antithrombogenic in over 120 clinical uses. The AL, with 1.2 m2 membrane surface area and 140 ml priming volume, consists of a special gas exchange membrane where not only are micropores blind-ended to prevent serum leakage, but the blood contacting surface is treated with heparin binding to ease systemic anticoagulation. Chronic animal experiments of total CPS were carried out in three goats weighing from 28 to 36 kg. Venoarterial bypass was instituted with the CPS system in which all venous blood was drawn from both the right atrium and ventricle and returned to the aorta. No systemic anticoagulation was conducted except for heparin added fluid infusion from pressure lines. One animal survived for 2 weeks without any device related problems until electively euthanized. Blood flow rate ranged between 3.2 to 4.5 L/min, O2 transfer between 120 to 220 ml/min, and CO2 removal between 60 to 210 ml/min. No substantial changes were found in platelet count or other coagulation factors. These results indicate that the system has the ability to be used for long-term CPS, such as a bridge to lung or heart-lung transplantation.

This report describes the development of an implantable gas exchange device. The device is composed of hollow fiber elements wound around a central open core enclosed in a compliant outer casing, offering very low resistance to blood while providing adequate gas exchange. The purpose of this study was to determine if this device design can completely support the gas exchange requirements of a large animal when the device is placed in series with the main pulmonary artery (PA). Six 40-80 kg adult sheep were used. The device was placed with vascular grafts anastomosed end to side on the proximal and distal main PA. The study began with the entire right ventricular blood flow being diverted through the device by occlusion of a snare around the PA between the vascular grafts. Total gas exchange then was provided by the device and the endotracheal tube was clamped. Results showed that this pumpless potentially implantable device is capable of completely supporting the gas exchange requirements of the experimental animals for up to 8 hours in the acute setting without significant change in cardiac index (CI) and oxygen consumption (VO2) compared with baseline. CI = 55.0 +/- 17.0 cc/min/kg versus 45.0 +/- 17.3 cc/min/kg. VO2 = 1.90 +/- 0.96 cc O2/min/kg versus 2.08 +/- 0.54 cc O2/min/kg.

Intravascular lung assist devices (ILADs) must transfer sufficient amounts of oxygen and carbon dioxide to and from limited surface areas. It has become apparent that passive devices, i.e., those without an active means for enhancing transfer, cannot achieve sufficient transfer within the space available. High speed rotation or oscillation of fiber sheets can increase transfer rates up to 800% over the rates achieved by a stationary device, judiciously configured fiber sheets cause an additional benefit when rotated: reduced resistance to blood flow across the device. The authors have developed a series of device prototypes based on these principles of transfer augmentation and minimization of flow resistance. The prototypes are small enough to fit inside the vena cava, with transfer surface areas ranging from 0.1 m2 to 0.5 m2. Transfer rates of O2 up to 53 ml/min and CO2 up to 51 ml/min and fluxes of 208 ml (min/m2) for O2 and 310 ml (min/m2) for CO2 have been achieved.

Extracorporeal membrane oxygenation (ECMO) has developed over the past 4 decades of research to enjoy limited clinical success today as the state-of-the-art artificial lung for long-term use. The sustained efforts of clinicians, corporations, and research scientists may achieve the promise of membrane technology in the future: an implantable artificial lung. The clinical trials considered necessary for the validation of ECMO have introduced ethical and economic dilemmas for research and corporate interests, which are typical of the development of life supporting and life sustaining technologies. The evolution of patient selection criteria and techniques for clinical trials has relied on previously recorded data. This history shows that although ECMO has been applied in the past, controlled clinical trials remain controversial, and yet in both recent and retrospective studies, survival statistics have become encouraging for certain patients.