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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 (

There are many studies of single lung ventilation (SLV), which are mostly limited to reducing lung damage by changing ventilation strategies or comparing differences in lung damage caused by different lung isolation devices. There is no study comparing the morphological changes of ventilated lungs using different strategies of artificial lung ventilation. The aim of the study was to examine pathomorphological changes in the ventilated lung during thoracic surgery using SLV. A randomized study was performed on 40 patients who underwent thoracic surgery using SLV. After signing the informed consent, the patients were divided into two groups. In the control group (40 patients) with ventilation “by volume” (VCV), in the study group – ventilation “by pressure” (PCV) with the addition of PEEP 5 mm. During surgery in the thoracic cavity with the help of SLV performed transbronchial biopsy of the parenchyma of the ventilated lung to study the pathomorphological changes after ventilation with different modes. The biopsy was performed using a bronchoscope, which was inserted through the endotracheal tube into the lung, opposite the side of the operation (after the end of SLV and “inclusion” of the collapsed lung). The morphological changes caused by the ventilator were investigated. Pathomorphological examination of the non-collapsed lung (which participated in gas exchange during SLV) was as follows: the control group found significant changes in the alveolar wall with its edema, thickening of the interstitial lung, vascular occlusion, severe inflammatory cell infiltration and damage to alveolar structures. The alveoli collapsed and disappeared. The alveolar structures of the study group were better than the control group: pulmonary interstitial and alveolar exudates, as well as inflammatory cell infiltration were significantly reduced compared to those in the control group. The results of the study suggest that the use of PCV with “moderate” PEEP can significantly improve oxygenation and reduce acute ventilatory injury of the lungs compared to VCV during SLV.

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

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

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

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

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

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.]

EDAC is defined by an abnormal expiratory reduction of the tracheal lumen leading to an elevation of airflow resistance. No data supports the clinical threshold of 50% closure. The aim of our study was to develop an experimental model of EDAC in order to assess the consequences of airway collapse on the work of breathing (WOB) and evaluate the impact of CPAP. We have modelled and manufactured a realistic 3D silicon trachea and a static compression system to simulate tracheal collapse. The trachea was linked to a dummy head with realistic upper airways and to an artificial lung (ASL 5000, IngMar Medical) which simulated tidal breathing (TB) from three lung models (normal, COPD and restrictive). We simulated tracheal compressions (length 4 or 8 centimeters, closure of 0,31,49,63 and 87%) at rest and on exercise, without and with CPAP (PEP 5, 10, 15 and 20cmH2O). We measured pressure on both sides of collapse and computed expiratory resistance Rexp, flow Qexp and pressure time product (PTPexp which reflects WOB). There was a significant impact of the degree of collapse on Rexp, Qexp and PTPexp for a closure ≥49%. During TB, median Rexp was 8,05 [6,60;9,90]cmH2O.s/L at 87% collapse versus 0,12 [0,11;0,14]cmH2O.s/L without collapse (p Our experimental model supports the 49% closure threshold associated with significant consequences on WOB.

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

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

Optimizing patient care based on precision oncology will inevitably become the standard of care. If we accept the principle that every persons’ cancer is different then the most effective therapies will have to be designed for the individual patient and for their tumors genetic profile. Access to tumor mutational profiling is now widely available but continues to be limited by cost and actionable information. For example, novel combinations of approved drugs are rarely considered. These considerations lead us to hypothesize that artificially induced Lung Adenocarcinoma (LUAD) derived lung organoids could provide a novel, alternate approach for LUAD disease modeling and large-scale targeted drug screening.In this project, we used data from a commercially available tumor mutation profile to generate and then validate the artificially induced LUAD-derived lung organoid simulations (aiLUNG-LUAD) to model LUAD and identify several drug combinations that effectively reverse the tumors’ genotypic and phenotypic features when compared with placebo. These results complement previous LUAD-derived lung organoids research and provide a novel and widely applicable cancer drug-screening approach for precision/individualized oncology.

Introduction: An important phase in surgical training is gaining experience in real human anatomical situations. When a cadaver is available it may complement the various artificial practice models. However, it is often necessary to supplement the characteristics of the cadavers with a simulation of a tumor. Our objective was to develop an easy-to-create, realistic artificial tumor-mimic model for peripheral lung tumor resection practice.Methods: In our work we injected barium sulphate enriched silicone suspension into 10 isolated, non-fixed lungs of human cadavers, through the puncture of the visceral pleura. Four lesions–apical, hilar and two peripheral–were created in each of ten specimens. After fixation CT scans were obtained and analyzed. The implanted tumor-mimics were examined after anatomical preparation and slicing. Also performed CT-guided percutaneous puncture was also performed to create the lesions in situ in two lungs of human cadavers.Results: Analyzing the CT data of 10 isolated lungs, out of 40 lesions, 34 were nodular (85.0%) and in the nodular group five were spiculated (12.5%). Satellite lesions were formed in two cases (5.0%). Relevant outflow into vessels or airway occurred in five lesions (12.5%). Reaching the surface of the lung occured in 11 lesions (27.5%). The tumor-mimics were elastic and adhered well to the surrounding tissue. The two lesions, implanted via percutaneous puncture, both were nodular and one also showed lobulated features.Conclusion: Our artificial tumor-mimics were easy to create, varied in shape and size, and with percutaneous implantation the lesions provide a model for teaching every step of a surgical procedure.

While previous in vitro studies showed divergent results concerning the influence of pulsatile blood flow on oxygen advection in oxygenators, no study was done to investigate the uncertainty affected by blood flow dynamics. The aim of this study is to utilize a computational fluid dynamics model to clarify the debate concerning the influence of pulsatile blood flow on the oxygen transport. The computer model is based on a validated 2D finite volume approach that predicts oxygen transfer in pulsatile blood flow passing through a 300-micron hollow-fiber membrane bundle with a length of 254 mm, a building block for an artificial lung device. In this study, the flow parameters include the steady Reynolds number (Re = 2, 5, 10 and 20), Womersley parameter (Wo = 0.29, 0.38 and 0.53) and sinusoidal amplitude (A = 0.25, 0.5 and 0.75). Specifically, the computer model is extended to verify, for the first time, the previously measured O2 transport that was observed to be hindered by pulsating flow in the Biolung, developed by Michigan Critical Care Consultants. A comprehensive analysis is carried out on computed profiles and fields of oxygen partial pressure (PO2) and oxygen saturation (SO2) as a function of Re, Wo and A. Based on the present results, we observe the positive and negative effects of pulsatile flow on PO2 at different blood flow rates. Besides, the SO2 variation is not much influenced by the pulsatile flow conditions investigated. While being consistent with a recent experimental study, the computed O2 volume flow rate is found to be increased at high blood flow rates operated with low frequency and high amplitude. Furthermore, the present study qualitatively explains that divergent outcomes reported in previous in vitro experimental studies could be owing to the different blood flow rates adopted. Finally, the contour analysis reveals how the spatial distributions of PO2 and SO2 vary over time.

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.

Whole-body plethysmography (WBP) is an established method to determine physiological parameters and pathophysiological alteration of breathing in animals and animal models of a variety of diseases, reaching from pulmonary diseases to complex neurological syndromes. Although frequently used, there is ongoing debate about what exactly is measured by whole-body-plethysmography and how reliable the data derived from this method are? Here, we designed a simple device that can serve as an artificial lung model that enables a thorough evaluation of different predictions about and around whole-body plethysmography. Using our lung model, we confirmed that during WBP two components contribute to the pressure changes detected in the chamber: 1) the increase of the pressure due to heating and moistening of the air, termed as conditioning, during inspiration; 2) changes of chamber pressure that depend on airway resistance. Both components overlap and contribute to the temporal pressure-profile measured in the chamber or across the wall of the chamber. Our data showed that a precise measurement of the breathing volume appears to be hindered by at least two factors: 1) the unknown relative contribution of each of these components; 2) not only the air in the inspired volume is conditioned during inspiration, but also air within the residual volume and death space that is recruited during inspiration. Moreover, our data suggest that the expiratory negative pressure peak that is used to determine the so called “enhanced pause” (Penh) parameter is not a measure for airway resistance as such but rather a consequence of the animal’s response to the airway resistance, using active expiration to overcome the resistance by a higher thoracic pressure.

Background: For children with severe lung disease that cannot wean from ECMO, an implantable artificial lung would permit extubation and support gradual lung recovery from acute disease or provide a bridge to transplantation. We evaluate the function of the novel Pediatric MLung—an efficient, implantable, pumpless artificial lung developed specifically for children—in healthy animal subjects. Methods: Adolescent “mini sheep” weighing 12-20 …

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.

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.

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.

Mechanical ventilators are the instruments that assist breathing of the patients having respiratory diseases e.g., pneumonia and coronavirus disease 2019 (COVID-19). This paper presents a modified lung model under volume-controlled ventilation to describe the lung volume and air flow in terms of air pressure signal from the ventilator. A negative feedback is incorporated in the model to balance the lung volume that is influenced by a lung parameter called positive end expiration pressure. We partially solved the lung model equation which takes the form of a first-order differential equation and then unknown parameters associated with the model were computed using a nonlinear least-squares method. Experimental data required for parameter identification and validation of the lung model were obtained by running a volume-controlled ventilator connected to a reference device and an artificial lung. The proposed model considering negative feedback achieves a better accuracy than that without feedback as demonstrated by test results. The developed model can be used in intensive care units (ICU) to evaluate mechanical ventilation performance and lung functionality in real-time.

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

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.

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

A potential shortage of intensive care ventilators has led to the idea to ventilate more than one patient with a single ventilator. Besides other problems, this is associated with the lack of knowledge concerning distribution of tidal volume and the patients’ individual respiratory system mechanics.In this study we used two simple hand-manufactured adaptors to connect physical models of two adult respiratory systems to one ventilator. The artificial lungs were ventilated in the pressure-controlled mode and we investigated if disconnecting one lung from the ventilation circuit for several breaths would allow to determine reliably the other lung’s tidal volume and compliance.Compliances and volumes were measured both with the ventilator and external sensors corresponded well. However, tidal volumes measured via the ventilator were smaller compared to the tidal volumes measured via the external sensors with an absolute error of 5.3 ± 2.5%. The tidal volumes of the individual artificial lungs were distributed in proportion to the compliances and did not differ relevantly when both artificial lungs were connected to when one was disconnected.We conclude that in case of emergency, ventilation of two patients with one ventilator requires two simple hand-crafted tubes as adaptors and available standard breathing circuit components. In such a setting, respiratory system mechanics and tidal volume of each individual patient can be reliably measured during short term clamping of the tracheal tube of the respective other patient.

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.

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

Although lung transplantation is an effective treatment for end-stage lung failure, its limitations have led to renewed interest in artificial lung support for patients with lung failure. The use of ventricular assist devices has significantly improved the quality of life and survival of patients with end-stage heart failure. In contrast, there are no devices that can be used long term as destination therapy for end-stage lung failure, and there is a strong need for them. Extracorporeal membrane oxygenation is widely used as a temporary treatment for acute lung failure and as a bridge to lung transplant. Many patients with advanced lung failure cannot return home with good quality of life once they are hospitalized. In this review, the authors discuss the history, status, and future of artificial lungs, focusing on long-term artificial respiratory support as a destination therapy. Respiratory assist devices, such as artificial lungs, could eventually become analogous to ventricular assist devices.

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.

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.

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

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

Identifying patients who are ready for weaning and liberation from veno-venous extracorporeal membrane oxygenation (ECMO) is challenging in clinical practice. Compared to the several trials addressing the safety and efficacy of ECMO in severe ARDS [1–4], the body of literature regarding ECMO weaning is remarkably scarce. Therefore, this essential component of the management of patients on ECMO is highly variable and often lacks of a systematic approach [5], analogously to the weaning protocols and spontaneous breathing trials used for liberation from mechanical ventilation [6]. The trajectory from ECMO cannulation to lung recovery and ECMO decannulation consists in the transition from a phase in which ECMO is essential to meet the patient’s metabolic needs (i.e. metabolic oxygen consumption and CO2 production) to a phase in which the native lung function has recovered to satisfy completely the metabolic demands, even if with a degree of ventilatory support considered “safe”. In between these two phases is a continuum of lung healing, during which lung function becomes sufficient to maintain a gas exchange compatible with life, but at the expenses of a high respiratory drive and large swings in transpulmonary pressures. In these conditions, ECMO has the role of maintaining lung protection partially contributing to the patient’s gas exchange [5]. In the effort to track the progress of an individual patient along this imaginary line, it is necessary to measure the relative contribution of the membrane and native lungs in terms of gas exchange, as well as the response of the patient’s respiratory drive and mechanics to the variation in ECMO settings. We propose a physiology-based assessment protocol, which combines an objective assessment of the native and artificial lung function and quantifies the patient’s response to a standardised weaning trial.

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.

In the last decade, primarily following the H1N1 pandemics [1], the extracorporeal respiratory assist is increasingly used [2, 3]. The acronym “ECMO”, i.e., ExtraCorporeal Membrane Oxygenation, is, however, somehow misleading as the artificial extracorporeal assist may affect both oxygenation and CO2 removal, as well as the hemodynamics, depending on how it is applied. In this commentary, we will limit our discussion to the respiratory extracorporeal support in veno-venous mode, primarily discussing the aspects, which are usually under-evaluated. Various options for extracorporeal support Table 1 was first published more than 40 years ago [4] and summarizes the main characteristics and options through which the extracorporeal support may be applied. As shown, all the possible application were foreseen and most of them actually tested in the following years. As shown, two main features characterize the extracorporeal support: cannulation (veno-venous vs veno-arterial) and extracorporeal blood flow. In the veno-venous configuration, the artificial and the natural lung are connected in series, as the blood flow entering the membrane lung is re-directed into the natural lung, after the artificial gas exchange. The hemodynamics are not affected by this configuration, which works solely as a respiratory support. In contrast, in the veno-arterial configuration, the artificial and the natural lung are arranged in parallel: the flow leaving the artificial lung is diverted in the arterial section and the natural lung is proportionally under-perfused. The greatest difference between veno-venous and veno-arterial approach is not related to the gas exchange, as the amount of oxygen transferred and CO2 removed are exactly the same (if the operating conditions of the membrane lung are the same), but to the hemodynamic impact, as the veno-arterial configuration provides both respiratory and cardiac support. The second feature is the amount of blood flow and gas flow used to ventilate the artificial lung: to oxygenate venous blood entering the membrane lung, the gas flow required equals the oxygen sufficient to fully saturate the hemoglobin passing through the artificial lung. As an example, if 1 l of venous blood with10 g/dL of hemoglobin and saturation 70% enters the membrane lung every minute, a transfer of 42 ml of 100% oxygen per minute from the gas compartment of the membrane lung would be sufficient to fully saturate the blood leaving the membrane lung. Therefore, being the possibility to “charge” oxygen limited by the hemoglobin concentration and its saturation in the venous blood, the oxygen transfer to the membrane lung is primarily function of the extracorporeal blood flow. In the previous example, 4 l of extracorporeal blood flow, in the absence of re-circulation, would provide fully saturated blood with a gas flow into the membrane lung of only 168 ml/min. All the gas is absorbed, and no gas leaves the membrane lung Table 1 Comparative technical difficulty of hemodialysis, extracorporeal removal of carbon dioxide, and extracorporeal oxygenation