Novel Size-Variable Dedicated Rodent Oxygenator for ECLS Animal Models-Introduction of the "RatOx" Oxygenator and Preliminary In Vitro Results.

The overall survival rate of extracorporeal life support (ECLS) remains at 60%. Research and development has been slow, in part due to the lack of sophisticated experimental models. This publication introduces a dedicated rodent oxygenator ("RatOx") and presents preliminary in vitro classification tests. The RatOx has an adaptable fiber module size for various rodent models. Gas transfer performances over the fiber module for different blood flows and fiber module sizes were tested according to DIN EN ISO 7199. At the maximum possible amount of effective fiber surface area and a blood flow of 100 mL/min, the oxygenator performance was tested to a maximum of 6.27 mL O2/min and 8.2 mL CO2/min, respectively. The priming volume for the largest fiber module is 5.4 mL, while the smallest possible configuration with a single fiber mat layer has a priming volume of 1.1 mL. The novel RatOx ECLS system has been evaluated in vitro and has demonstrated a high degree of compliance with all pre-defined functional criteria for rodent-sized animal models. We intend for the RatOx to become a standard testing platform for scientific studies on ECLS therapy and technology.

Development and evaluation of a variable, miniaturized oxygenator for various test methods.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) became an accepted therapy for the treatment of severe acute respiratory distress syndrome and chronic obstructive pulmonary disease. However, ECMO systems are still prone to thrombus formation and decrease of gas exchange over time. Therefore, it is necessary to conduct qualified studies to identify parameters for optimization of ECMO systems, and especially the oxygenator. However, commercially marketed oxygenators are not always appropriate and available for certain research use cases. Therefore, we aimed to design an oxygenator, which is suitable for various test conditions such as blood tests, numerical simulation, and membrane studies, and can be modified in membrane area size and manufactured in laboratory. METHODS: Main design criteria are a homogeneous blood flow without stagnation zones, low pressure drop, manufacturability in the lab, size variability with one set of housing parts and cost-efficiency. Our newly designed oxygenator was tested comparatively regarding blood cell damage, gas transfer performance and pressure drop to prove the validity of the design in accordance with a commercial device. RESULTS: No statistically significant difference between the tested oxygenators was detected and our new oxygenator demonstrated sufficient hemocompatibility. Furthermore, our variable oxygenator has proven that it can be easily manufactured in the laboratory, allows to use various membrane fiber configurations and can be reopened easily and non-destructively for analysis after use, and the original geometry is available for numerical simulations. CONCLUSION: Therefore, we consider this newly developed device as a valuable tool for basic experimental and numerical research on the optimization of oxygenators.

In-Vitro Visualization of Thrombus Growth in Artificial Lungs Using Real-Time X-Ray Imaging: A Feasibility Study.

PURPOSE: Extracorporeal membrane oxygenation has gained increasing attention in the treatment of patients with acute and chronic cardiopulmonary and respiratory failure. However, clotting within the oxygenators or other components of the extracorporeal circuit remains a major complication that necessitates at least a device exchange and bears risks of adverse events for the patients. In order to better predict thrombus growth within oxygenators, we present an approach for in-vitro visualization of thrombus growth using real-time X-ray imaging. METHODS: An in-vitro test setup was developed using low-dose anticoagulated ovine blood and allowing for thrombus growth within 4 h. The setup was installed in a custom-made X-ray setup that uses phase-contrast for imaging, thus providing enhanced soft-tissue contrast, which improves the differentiation between blood and potential thrombus growth. During experimentation, blood samples were drawn for the analysis of blood count, activated partial thromboplastin time and activated clotting time. Additionally, pressure and flow data was monitored and a full 360° X-ray scan was performed every 15 min. RESULTS: Thrombus formation indicated by a pressure drop and changing blood parameters was monitored in all three test devices. Red and white thrombi (higher/lower attenuation, respectively) were successfully segmented in one set of X-ray images. CONCLUSION: We showed the feasibility of a new in-vitro method for real-time thrombus growth visualization by means of phase contrast X-ray imaging. In addition, with more blood parameters that are clinically relevant, this approach might contribute to improved oxygenator exchange protocols in the clinical routine.

Low-Resistance, Concentric-Gated Pediatric Artificial Lung for End-Stage Lung Failure.

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.

How Computational Modeling can Help to Predict Gas Transfer in Artificial Lungs Early in the Design Process.

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.

Technical Indicators to Evaluate the Degree of Large Clot Formation Inside the Membrane Fiber Bundle of an Oxygenator in an In Vitro Setup.

The most common technical complication during ECMO is clot formation. A large clot inside a membrane oxygenator reduces effective membrane surface area and therefore gas transfer capabilities, and restricts blood flow through the device, resulting in an increased membrane oxygenator pressure drop (dpMO). The reasons for thrombotic events are manifold and highly patient specific. Thrombus formation inside the oxygenator during ECMO is usually unpredictable and remains an unsolved problem. Clot sizes and positions are well documented in literature for the Maquet Quadrox-i Adult oxygenator based on CT data extracted from devices after patient treatment. Based on this data, the present study was designed to investigate the effects of large clots on purely technical parameters, for example, dpMO and gas transfer. Therefore, medical grade silicone was injected into the fiber bundle of the devices to replicate large clot positions and sizes. A total of six devices were tested in vitro with silicone clot volumes of 0, 30, 40, 50, 65, and 85 mL in accordance with ISO 7199. Gas transfer was measured by sampling blood pre and post device, as well as by sampling the exhaust gas at the devices' outlet at blood flow rates of 0.5, 2.5, and 5.0 L/min. Pre and post device pressure was monitored to calculate the dpMO at the different blood flow rates. The dpMO was found to be a reliable parameter to indicate a large clot only in already advanced "clotting stages." The CO2 concentration in the exhaust gas, however, was found to be sensitive to even small clot sizes and at low blood flows. Exhaust gas CO2 concentration can be monitored continuously and without any risks for the patient during ECMO therapy to provide additional information on the endurance of the oxygenator. This may help detect a clot formation and growth inside a membrane oxygenator during ECMO even if the increase in dpMO remains moderate.

Computational Modeling of Oxygen Transfer in Artificial Lungs.

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.

Effects of Pulsatile Blood Flow on Oxygenator Performance.

Extracorporeal membrane oxygenation (ECMO) is mainly used for the therapy of acute respiratory distress syndrome and chronic obstructive lung disease. In the last years, the development of these systems underwent huge steps in optimization, but there are still problems with thrombus formation, clogging, and thus insufficient gas exchange. One idea of ECMO optimization is a pulsatile blood flow through the oxygenator, but this is still a controversy discussion. Analyzing available publications, it was not possible to identify a general statement about the effect of pulsatile blood flow on the gas exchange performance. The variety of parameters and circuit components have such a high influence on the outcome that a direct comparison of the studies is difficult. For this reason, we performed a structured study to evaluate the effects of pulsatile blood flow on the gas exchange performance of oxygenator. In in vitro tests according to DIN EN ISO 7199, we tested a small oxygenator (0.25 m2 exchange surface, polymethylpentene fibers, 33 mL priming volume) with constant and pulsatile blood flow in comparison. Therefore, we varied the mean blood flow from 250 to 1200 mL/min, the amplitude of 0, 20, and 50%, and the frequency of 30, 60, and 90 bpm. The results demonstrate that the gas transfer for pulsatile and constant blood flow was similar (oxygen: 36-64 mLO2 /LBlood ; carbon dioxide 35-80 mLCO2 /LBlood ) for the same mean blood flow ranges. Over all, the results and analyses showed a statistically nonsignificant difference between pulsatile and nonpulsatile flow. Consequently, we conclude that the implementation of pulsatile blood flow has only a small to no effect on the gas exchange performance in an oxygenator. As the results were obtained using an oxygenator with a coiled fiber bundle, the test must be verified for a stacked fiber oxygenator.

CO2 clearance by membrane lungs.

INTRODUCTION: Commercial membrane lungs are designed to transfer a specific amount of oxygen per unit of venous blood flow. Membrane lungs are much more efficient at removing CO2 than adding oxygen, but the range of CO2 transfer is rarely reported. METHODS: Commercial membrane lungs were studied with the goal of evaluating CO2 removal capacity. CO2 removal was measured in 4 commercial membrane lungs under standardized conditions. CONCLUSION: CO2 clearance can be greater than 4 times that of oxygen at a given blood flow when the gas to blood flow ratio is elevated to 4:1 or 8:1. The CO2 clearance was less dependent on surface area and configuration than oxygen transfer. Any ECMO system can be used for selective CO2 removal.

A Membrane Lung Design Based on Circular Blood Flow Paths.

Current hollow fiber membrane lungs feature a predominantly straight blood path length across the fiber bundle, resulting in limited O2 transfer efficiency because of 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 m, has a rated flow of 2 L/min, and the oxygenation efficiency is 357 ml/min/m. 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.

Experimental Approach to Visualize Flow in a Stacked Hollow Fiber Bundle of an Artificial Lung With Particle Image Velocimetry.

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.

Comment on "The promise of microfluidic artificial lungs" by J. A. Potkay, Lab Chip, 2014, 14, 4122-4138.

This comment on an article that appeared in this journal (Potkay, Lab Chip, 2014, 14, 4122-4138) presents an alternative view on the feasibility and clinical application of current microfluidic artificial lungs.