Search

Resource-scarce regions with serious COVID-19 outbreaks do not have enough ventilators to support critically ill patients, and these shortages are especially devastating in developing countries. To help alleviate this strain, we have designed and tested the accessible low-barrier in vivo-validated economical ventilator (ALIVE Vent), a COVID-19-inspired, cost-effective, open-source, in vivo-validated solution made from commercially available components. The ALIVE Vent operates using compressed oxygen and air to drive inspiration, while two solenoid valves ensure one-way flow and precise cycle timing. The device was functionally tested and profiled using a variable resistance and compliance artificial lung and validated in anesthetized large animals. Our functional test results revealed its effective operation under a wide variety of ventilation conditions defined by the American Association of Respiratory Care guidelines for ventilator stockpiling. The large animal test showed that our ventilator performed similarly if not better than a standard ventilator in maintaining optimal ventilation status. The FiO2, respiratory rate, inspiratory to expiratory time ratio, positive-end expiratory pressure, and peak inspiratory pressure were successfully maintained within normal, clinically validated ranges, and the animals were recovered without any complications. In regions with limited access to ventilators, the ALIVE Vent can help alleviate shortages, and we have ensured that all used materials are publicly available. While this pandemic has elucidated enormous global inequalities in healthcare, innovative, cost-effective solutions aimed at reducing socio-economic barriers, such as the ALIVE Vent, can help enable access to prompt healthcare and life saving technology on a global scale and beyond COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s42242-021-00164-1.

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 (

Bio-design and manufacturing 5(1), 141-152 (2022). doi:10.1007/s42242-021-00139-2 special issue: "Smart bioelectronics and biomedical devices", Published by Springer Singapore, Singapore

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.

We investigate the suitability of statistical and model-based iterative reconstruction (IR) algorithm strengths and their influence on image quality and diagnostic performance in low-dose computer tomography (CT) protocols for lung-cancer screening procedures. We evaluate the inter- and intra-observer performance for the assessment of iterative CT reconstruction. Artificial lung foci shaped as spheres and spicules made from material with calibrated Hounsfield units were pressed within layered granules in lung lobes of an anthropomorphic phantom. Adaptively, a soft-tissue- and fat- extension ring were attached. The phantom with foci was scanned using standard high contrast, low-dose and ultra lowdose protocols. For reconstruction the IR algorithm ADMIRE at four different strength levels were used. Two ranking tests and Friedman statistics were performed. Fleiss k and modified Cohen’s kneywere used to quantify inter- and intra-observer performance. In conjunction with the standard lung kernel BL75 radiologists evaluated medium to high IR strength, with preference to S4, as suitable for lung foci detection. When varying reconstruction kernels the ranking became more random than with varying phantom diameter. The inter-observer reliability shows poor to slight agreement expressed by kney=0-0.20and moderate agreement with kney=0.60-0.79 for the first ranking test, and almost perfect agreement with kney>0.90 for the second ranking test was observed. In conclusion, our validation suggests radiological preference of medium to high iteration strengths, especially S4, for lung foci detection. An investigation of the correlation between diagnostic experience and the subjective perception of IR reconstructed CT images still needs to be investigated.

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

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

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

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.

Annals of biomedical engineering 48(2), 747-756 (2020). doi:10.1007/s10439-019-02401-2, Published by Springer Science + Business Media B.V, Dordrecht [u.a.]

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.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can spread through virus-containing aerosols ( ≤ 5 μm) and larger airborne droplets. Quantifying filtration efficiency of different kinds of masks and linings for aerosols that fall within the most penetrating particle size (80-400 nm) is critical to limiting viral transmission. The objective of our experiment was to compare the “real-world” filtering efficiency of different face masks for fine aerosols (350 nm) in laboratory simulations.Methods: We performed a simulated bench test that measured the filtering efficiency of N95 vs. N99 masks with elastomeric lining in relation to baseline (“background”) aerosol generation. A mannequin head was placed within a chamber and was attached to an artificial lung simulator. Particles of known size (350 ± 6 nm aerodynamic diameter) were aerosolized into the chamber while simulating breathing at physiological settings of tidal volume, respiratory rate, and airflow. Particle counts were measured between the mannequin head and the lung simulator at the tracheal airway location.Results: Baseline particle counts without a filter (background) were 2,935 ± 555 (SD) cm−3, while the N95 (1348 ± 92 cm−3) and N99 mask with elastomeric lining (279 ± 164 cm−3; p Conclusion: The filtration efficiency of the N95 (54.1%) and N99 (90.5%) masks were lower than the filtration efficiency rating. N99 masks with elastomeric lining exhibit greater filtration efficiency than N95 masks without elastomeric lining and may be preferred to contain the spread of SARS-CoV-2 infection.

BackgroundNebulizers are medical devices that deliver aerosolized medication directly to lungs to treat a variety of respiratory diseases. However, breathing patterns, respiration rates, airway diameters, and amounts of drugs delivered by nebulizers may be respiratory disease dependent.MethodIn this study, we developed a respiratory simulator consisting of an airway model, an artificial lung, a flow sensor, and an aerosol collecting filter. Various breathing patterns were generated using a linear actuator and an air cylinder. We tested six home nebulizers (jet (2), static (2), and vibrating mesh nebulizers (2)). Nebulizers were evaluated under two conditions, that is, for the duration of nebulization and at a constant output 1.3 mL using four breathing patterns, namely, the breathing pattern specified in ISO 27427:2013, normal adult, asthmatic, and COPD.ResultsOne of the vibrating mesh nebulizers had the highest dose delivery efficiency. The drug delivery efficiencies of nebulizers were found to depend on breathing patterns.ConclusionWe suggest a quantitative drug delivery efficiency evaluation method and calculation parameters that include considerations of constant outputs and residual volumes. The study shows output rates and breathing patterns should be considered when the drug delivery efficiencies of nebulizers are evaluated.

Ventilator shortages occurred due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This in vitro study evaluated the effectiveness of 3-dimensional (3D)-printed splitters and 3D-printed air flow limiters (AFL) in delivering appropriate tidal volumes (TV) to lungs with different compliances. Groups were divided according to the size of the AFL: AFL-4 was a 4-mm device, AFL-5 a 5-mm device, AFL-6 a 6-mm device, and no limiter (control). A ventilator was split to supply TV to 2 artificial lungs with different compliances. The AFL improved TV distribution.

We demonstrate Endoscopic Optical Coherence Elastography (Endo-OCE) imaging of bronchus in an artificial breathing lung model that can breathe at 10 times per minute with a tidal volume of 500 ml. A 1.2 mm motorized catheter was delivered to the distal bronchus via the working channel of a clinical bronchoscope. Endo-OCE images was acquired at 3000 frames/s during the exhalation of the "breath". The results show that the passive breathing of the lung model can induce sufficient tissue deformation (strain) for Endo-OCE imaging. The lung model can be a useful tool to validate the Endo-OCE technology.

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

Left ventricular assist devices (LVADs) are increasingly used as destination therapy or as a bridge to future cardiac transplant in patients with end-stage heart failure. Extracorporeal membrane oxygenation (ECMO) can be used to bridge patients in cardiogenic shock or with decompensated heart failure to durable mechanical circulatory support. We assessed outcomes in patients in critical cardiogenic shock (Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] profile 1) who underwent implantation of a continuous-flow (CF)-LVAD, with or without preoperative ECMO bridging. For this retrospective study, we selected INTERMACS profile 1 patients who underwent CF-LVAD implantation at our institution between Sep 1, 2004 and Nov 30, 2018. Of 768 patients identified, 133 (17.3%) were INTERMACS profile 1; 26 (19.5%) received preoperative ECMO support, and 107 (80.5%) did not. Postimplantation outcomes were compared between the ECMO and no-ECMO groups. No significant differences were found in 30-day mortality (15.4 vs. 15.9%, P = 0.95) or survival at 1 year (53.8 vs. 60.9%, P = 0.51). Three patients who received ECMO before CF-LVAD implantation subsequently underwent cardiac transplant. In the ECMO group, the lactate level 1 day after ECMO initiation was lower in survivors than nonsurvivors (2.7 ± 2.2 vs. 7.4 ± 4.2 mmol/L, P = 0.02; area under the curve = 0.85, P = 0.01) after CF-LVAD implantation. Bridging with ECMO to CF-LVAD implantation in carefully selected INTERMACS profile 1 patients (those who are at the highest risk for critical cardiogenic shock and for whom palliation may be the only other option) produced acceptable postoperative outcomes. Field of research: Artificial lung/ECMO.

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.

In this article, we introduce a portable and low-cost ventilator that could be rapidly manufactured, to meet the increasing demand of ventilators worldwide produced by COVID-19 pandemic. These ventilators should be rapidly deployable and with functional capabilities to manage COVID-19 patients with severe acute respiratory distress syndrome (ARDS). Our implementation offers robustness, safety and functionality absent in existing solutions to the ventilator shortage (i.e., telemonitoring, easy-to-disinfect, modularity) by maintaining simplicity. The design makes use of a manual resuscitator as the core respiration component activated by a compression mechanism which consist of two electronically controlled paddles. The quality measurements obtained after testing on a calibrated artificial lung demonstrate repeatability and accuracy exceeding human capabilities of manual ventilation. The complete design files are provided in the supplementary materials to facilitate ventilator production even in resource-limited settings. The implementation of this mechanical ventilator could eliminate device rationing or splitting to serve multiple patients on ICUs. (C) 2021 Pontificia Universidad Catolica del Peru. Published by Elsevier Ltd. This work has been funded by the 055-2020-FONDECYT GRANT from the Peruvian government and the donations of the enterprises mentioned in our webpage: https://www.proyectomasi.pe/.In addition,the authors would like to thank to all the members of the Masi team, especially to all of the collaborators working at the five institutions involved in this project (BREIN, DIACSA, EAT, PUCP and Zolid). Without all of their effort, professionalism and sacrifice while working steadily during the pandemic; this device would have not existed.

Graphical abstract, This study describes the development of a simple and easy-to-build portable automated bag valve mask (BVM) compression system, which, during acute shortages and supply chain disruptions can serve as a temporary emergency ventilator. The resuscitation system is based on the Arduino controller with a real-time operating system installed on a largely RepRap 3-D printable parametric component-based structure. The cost of the materials for the system is under $170, which makes it affordable for replication by makers around the world. The device provides a controlled breathing mode with tidal volumes from 100 to 800 mL, breathing rates from 5 to 40 breaths/minute, and inspiratory-to-expiratory ratio from 1:1 to 1:4. The system is designed for reliability and scalability of measurement circuits through the use of the serial peripheral interface and has the ability to connect additional hardware due to the object-oriented algorithmic approach. Experimental results after testing on an artificial lung for peak inspiratory pressure (PIP), respiratory rate (RR), positive end-expiratory pressure (PEEP), tidal volume, proximal pressure, and lung pressure demonstrate repeatability and accuracy exceeding human capabilities in BVM-based manual ventilation. Future work is necessary to further develop and test the system to make it acceptable for deployment outside of emergencies such as with COVID-19 pandemic in clinical environments, however, the nature of the design is such that desired features are relatively easy to add using protocols and parametric design files provided.

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

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.

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.

Purpose Admixture of nitric oxide (NO) to the gas inspired with mechanical ventilation can be achieved through continuous, timed, or pulsed injection of NO into the inspiratory limb. The dose and timing of NO injection govern the inspired and intrapulmonary effect site concentrations achieved with different administration modes. Here we test the effectiveness and target reliability of a new mode injecting pulsed NO boluses exclusively during early inspiration. Methods An in vitro lung model was operated under various ventilator settings. Admixture of NO through injection into the inspiratory limb was timed either (i) selectively during early inspiration (“pulsed delivery”), or as customary, (ii) during inspiratory time or (iii) the entire respiratory cycle. Set NO target concentrations of 5–40 parts per million (ppm) were tested for agreement with the yield NO concentrations measured at various sites in the inspiratory limb, to assess the effectiveness of these NO administration modes. Results Pulsed delivery produced inspiratory NO concentrations comparable with those of customary modes of NO administration. At low (450 ml) and ultra-low (230 ml) tidal volumes, pulsed delivery yielded better agreement of the set target (up to 40 ppm) and inspiratory NO concentrations as compared to customary modes. Pulsed delivery with NO injection close to the artificial lung yielded higher intrapulmonary NO concentrations than with NO injection close to the ventilator. The maximum inspiratory NO concentration observed in the trachea (68 ± 30 ppm) occurred with pulsed delivery at a set target of 40 ppm. Conclusion Pulsed early inspiratory phase NO injection is as effective as continuous or non-selective admixture of NO to inspired gas and may confer improved target reliability, especially at low, lung protective tidal volumes.

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.

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

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.

Extracorporeal membrane oxygenation (ECMO) has been used clinically for more than 40 years as a bridge to transplantation, with hollow-fiber membrane (HFM) oxygenators gaining in popularity due to their high gas transfer and low flow resistance. In spite of the technological advances in ECMO devices, the inevitable contact of the perfused blood with the polymer hollow-fiber gas-exchange membrane, and the subsequent thrombus formation, limits their clinical usage to only 2–4 weeks. In addition, the inhomogeneous flow in the device can further enhance thrombus formation and limit gas-transport efficiency. Endothelialization of the blood contacting surfaces of ECMO devices offers a potential solution to their inherent thrombogenicity. However, abnormal shear stresses and inhomogeneous blood flow might affect the function and activation status of the seeded endothelial cells (ECs). In this study, the blood flow through two HFM oxygenators, including the commercially available iLA® MiniLung Petite Novalung (Xenios AG, Germany) and an experimental one for the rat animal model, was modeled using computational fluid dynamics (CFD), with a view to assessing the magnitude and distribution of the wall shear stress (WSS) on the hollow fibers and flow fields in the oxygenators. This work demonstrated significant inhomogeneity in the flow dynamics of both oxygenators, with regions of high hollow-fiber WSS and regions of stagnant flow, implying a variable flow-induced stimulation on seeded ECs and possible EC activation and damage in a biohybrid oxygenator setting.

Cardiovascular engineering and technology : CVET (2020). doi:10.1007/s13239-020-00466-y, Published by Springer, New York, NY

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.

Blood oxygenators, also known as artificial lungs, are widely used in cardiopulmonary bypass surgery to maintain physiologic oxygen (O2) and carbon dioxide (CO2) levels in blood, and also serve as respiratory assist devices to support patients with lung failure. The time- and cost-consuming method of trial and error is initially used to optimize the oxygenator design, and this method is followed by the introduction of the computational fluid dynamics (CFD) that is employed to reduce the number of prototypes that must be built as the design is optimized. The CFD modeling method, while having progress in recent years, still requires complex three-dimensional (3D) modeling and experimental data to identify the model parameters and validate the model. In this study, we sought to develop an easily implemented mathematical models to predict and optimize the performance (oxygen partial pressure/saturation, oxygen/carbon dioxide transfer rates, and pressure loss) of hollow fiber membrane-based oxygenators and this model can be then used in conjunction with CFD to reduce the number of 3D CFD iteration for further oxygenator design and optimization. The model parameters are first identified by fitting the model predictions to the experimental data obtained from a mock flow loop experimental test on a mini fiber bundle. The models are then validated through comparing the theoretical results with the experimental data of seven full-size oxygenators. The comparative analysis show that the model predictions and experimental results are in good agreement. Based on the verified models, the design curves showing the effects of parameters on the performance of oxygenators and the guidelines detailing the optimization process are established to determine the optimal design parameters (fiber bundle dimensions and its porosity) under specific system design requirements (blood pressure drop, oxygen pressure/saturation, oxygen/carbon dioxide transfer rates, and priming volume). The results show that the model-based optimization method is promising to derive the optimal parameters in an efficient way and to serve as an intermediate modeling approach prior to complex CFD modeling.

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.

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

Chronic lung disease is the 4th leading cause of death in the United States. Due to a shortage of donor lungs, alternative approaches to support failing, native lungs have been attempted, including mechanical ventilation and various forms of artificial lungs. However, each of these support methods causes significant complications when used for longer than a few days and are thus not capable of long-term support. For artificial lungs, complications arise due to interactions between the artificial materials of the device and the blood of the recipient. A potential new approach is the fabrication of lungs from biological materials, such that the gas exchange membranes provide a more biomimetic blood-contacting interface. Recent advancements with three-dimensional, soft-tissue biofabrication methods and the engineering of thin, basement membranes demonstrate the potential of fabricating a lung scaffold from extracellular matrix materials. This scaffold could then be seeded with endothelial and epithelial cells, matured within a bioreactor, and transplanted. In theory, this fully biological lung could provide improved, long-term biocompatibility relative to artificial lungs, but significant work is needed to perfect the organ design and construction methods. Like artificial lungs, biofabricated lungs do not need to follow the shape and structure of a native lung, allowing for simpler manufacture. However, various functional requirements must still be met, including stable, efficient gas exchange for a period of years. Design decisions depend on the disease state, how the organ is implanted, and the latest biofabrication methods available in a rapidly evolving field.

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.

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

Background: Many oscillatory positive expiratory pressure (OPEP) devices exist and some of them use unique mechanism to produce air-flow oscillations. However their operational parameters and elicited therapeutic effects may vary. Objectives: To assess the mechanical performance of 6 OPEP devices at different resistance levels. Methods: Four gravity-dependent (Flutter, Gelomuc, Shaker, PARI-OPEP) and 2 gravity-independent OPEP devices (Acapella Choice and Aerobika) were tested at 3 resistance levels (low, medium, high). Each device was independently attached to an artificial lung driven by a ventilator in order to simulate an active exhalation. Ventilator settings were adjusted to produce peak expiratory flow rate between 40-45 L.min-1 at 10 breaths.min-1. The middle-third of the exhalation phase was used to compare positive expiratory pressure (PEP), oscillatory frequency (OF) and pressure amplitude (PA). Optimal operational parameters were defined as OFs of 12 Hz or above and PEP ranging between 10-20 cmH2O. Corresponding PAs at these settings were analysed. Results: Only gravity-dependent devices at medium and high resistance levels produced the desired OFs and PEP settings, ranging from 16 to 22 Hz and 12 to 18 cmH2O, respectively. Corresponding PAs ranged from 0.6 to 1.8 cmH2O. Compared to these devices, Acapella and Aerobika elicited higher PAs (from 1.7 to 4.2 cmH2O) although they did not achieve optimal PEP or OF parameters. Conclusions: The gravity-dependent devices displayed close mechanical performances and produced optimal operational parameters at the simulated exhalation settings. Acapella and Aerobika probably require higher expiratory pressure to reach theoretical therapeutic effectiveness.

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

The treatment with a mechanical ventilator is required whenever a patient’s respiratory system becomes unable to keep the concentrations of O2 and CO2 in blood at tolerable levels. However, in particular cases, the thoracic artificial lung (TAL) can be regarded as a viable alternative to mechanical ventilation (MV). We aim at studying the effects of mechanical ventilators and thoracic artificial lungs devices will have on the cardiovascular system. We will give careful consideration to cardiovascular energetic parameters, such as left and right ventricular external work, pressure-volume area, and cardiac mechanical efficiency. We simulated both, mechanically ventilated patients who are not subject to the application of an artificial lung and patients who are provided with a thoracic artificial lung (TAL). In the case of a thoracic artificial lung, we involved in our simulation studies all the usual operating modes of a TAL, viz. series mode, parallel mode, and hybrid mode of the TAL with regard to the native lung. In particular, the presented simulation results will contribute to elucidate the specific characteristics of each of the aforementioned operating modes. Generally, the energetic variables are influenced by different values of input TAL resistance in both modes: parallel and in series. In this paper, we concentrated on simulation studies of the effects evoked by TAL assistance on cardiac energetic and some other important circulatory parameters. The simulation results presented show that at all modes of TAL assistance exists a strong dependency on the TAL input variables and on the value of the mean intrathoracic pressure which has been assumed for a given situation.

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”.