Aortic Valve Stenosis Causes Accumulation of Extracellular Hemoglobin and Systemic Endothelial Dysfunction.

BACKGROUND: Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown. METHODS: We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and NO consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system. RESULTS: In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb and plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress. CONCLUSIONS: AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05603520. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01805739.

Detection of physiological control inputs preload and afterload from intrinsic pump parameters in total artificial heart.

BACKGROUND: In the total artificial heart (TAH), the inputs to the physiological control unit, preload, and afterload, are detected from intrinsic pump parameters (e.g., motor current). Within this study, their detection techniques are developed, and their reliability in pre- and afterload prediction is mapped for a broad range of cardiovascular system states. METHODS: We used ReinHeart TAH which is a fully implantable TAH with a plunger coil drive that is alternately emptying the left and right chambers. From the coil currents we first derived a force generated by the piston with respect to its position and then analyzed its pattern to detect (1) preload-chamber filling, found as piston position at begin ejection and (2) afterload-mean outflow pressures, determined as linearly calibrated average piston force during ejection. TAH is then integrated into a mock loop circulation (MLC) which is set to 135 different steady operating points varying in chamber filling (0%-100%, five steps), mean outflow pressures (system circulation: 60-90-120 mm Hg, pulmonary circulation: 15-30-45 mm Hg), and heart cycle duration (171-600 ms in seven non-equidistant steps). The detected preload and afterload are compared to MLC set values, and the errors are mapped. RESULTS: Respectively for the left and right chambers, the preload was detectable in 134 and 118 operating points and the mean error was ±3% and ±2%. The afterload was detectable in 135 and 87 operating points and the mean error was 37% and 30% respectively for left and right circulation. The operational points that are further away from homeostatic equilibrium values generally yielded larger errors. The largest errors were observed for right circulation at long cycle duration, low afterload, and low filling. CONCLUSIONS: The study yields reliable preload estimation in a broad range of physiological states, particularly for left circulation. Detection of afterload needs further improvements. The study revealed a need for piston movement optimization within the ReinHeart TAH during the early phase of systole.

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

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

Controlling the flow balance: In vitro characterization of a pulsatile total artificial heart in preload and afterload sensitivity.

The objective of this study is to identify the preload and afterload sensitivity of the ReinHeart TAH 2.0. For adequate left-right flow balance, the concept of a reduced right stroke volume (by about 10%) and active adaption of the right diastole duration are evaluated concerning the controllability of the flow balance. This study used an active mock circulation loop to test a wide range of preload and afterload conditions. Preload sensitivity was tested at atrial pressures (APs) between 4 and 20 mm Hg. Left afterload was varied in a range of 60-140 mm Hg mean aortic pressure (MAP), right afterload was simulated between 15 and 40 mm Hg. Four scenarios were developed to verify that the flow difference fully covers the defined target range of 0-1.5 L/min. Although a positive correlation between inlet pressure and flow is identified for the right pump chamber, the left pump chamber already fills completely at an inlet pressure of 8-10 mm Hg. With increasing afterload, both the left and right flow decrease. A positive flow balance (left flow exceeds right flow) is achieved over the full range of tested afterloads. At high APs, the flow difference is limited to a maximum of 0.7 L/min. The controllability of flow balance was successfully evaluated in four scenarios, revealing that a positive flow difference can be achieved over the full range of MAPs. Under physiological test conditions, the linear relationship between flow and heart rate was confirmed, ensuring good controllability of the TAH.

Three-dimensional membranes for artificial lungs: Comparison of flow-induced hemolysis.

BACKGROUND: Membranes based on triply periodic minimal surfaces (TPMS) have proven a superior gas transfer compared to the contemporary hollow fiber membrane (HFM) design in artificial lungs. The improved oxygen transfer is attributed to disrupting the laminar boundary layer adjacent to the membrane surface known as main limiting factor to mass transport. However, it requires experimental proof that this improvement is not at the expense of greater damage to the blood. Hence, the aim of this work is a valid statement regarding the structure-dependent hemolytic behavior of TPMS structures compared to the current HFM design. METHODS: Hemolysis tests were performed on structure samples of three different kind of TPMS-based designs (Schwarz-P, Schwarz-D and Schoen's Gyroid) in direct comparison to a hollow fiber structure as reference. RESULTS: The results of this study suggest that the difference in hemolysis between TPMS membranes compared to HFMs is small although slightly increased for the TPMS membranes. There is no significant difference between the TPMS structures and the hollow fiber design. Nevertheless, the ratio between the achieved additional oxygen transfer and the additional hemolysis favors the TPMS-based membrane shapes. CONCLUSION: TPMS-shaped membranes offer a safe way to improve gas transfer in artificial lungs.

In-vitro performance of a single-chambered total artificial heart in a Fontan circulation.

An in-vitro study was conducted to investigate the general feasibility of using only one pumping chamber of the SynCardia total artificial heart (TAH) as a replacement of the single ventricle palliated by Fontan circulation. A mock circulation loop was used to mimic a Fontan circulation. The combination of both ventricle sizes (50 and 70 cc) and driver (Freedom Driver and Companion C2 Driver) was investigated. Two clinical relevant scenarios (early Fontan; late Fontan) as derived from literature data were set up in the mock loop. The impact of increased transpulmonary pressure gradient, low atrial pressure, and raised central venous pressure on cardiac output was studied. From a hemodynamic point, the single-chambered TAH performed sufficiently in the setting of the Fontan circulation. Increased transpulmonary pressure gradient, from ideal to pulmonary hypertension, decreased the blood flow in combinations by almost 2 L/min. In the early Fontan scenario, a cardiac output of 3-3.5 L/min was achieved using the 50 cc ventricle, driven by the Companion C2 Driver. Even under pulmonary hypertension, cardiac outputs greater than 4 L/min could be obtained with the 70 cc pump chamber in the late Fontan scenario. In the clinically relevant Fontan scenarios, implementation of the single chambered TAH performed successfully from a hemodynamic point of view. The replacement of the failing univentricular heart by a single chamber of the SynCardia TAH may provide an alternative to a complex biventricular repair procedure or ventricular support in Fontan patients.

Hemolysis at low blood flow rates: in-vitro and in-silico evaluation of a centrifugal blood pump.

BACKGROUND: Treating severe forms of the acute respiratory distress syndrome and cardiac failure, extracorporeal membrane oxygenation (ECMO) has become an established therapeutic option. Neonatal or pediatric patients receiving ECMO, and patients undergoing extracorporeal CO2 removal (ECCO2R) represent low-flow applications of the technology, requiring lower blood flow than conventional ECMO. Centrifugal blood pumps as a core element of modern ECMO therapy present favorable operating characteristics in the high blood flow range (4 L/min-8 L/min). However, during low-flow applications in the range of 0.5 L/min-2 L/min, adverse events such as increased hemolysis, platelet activation and bleeding complications are reported frequently. METHODS: In this study, the hemolysis of the centrifugal pump DP3 is evaluated both in vitro and in silico, comparing the low-flow operation at 1 L/min to the high-flow operation at 4 L/min. RESULTS: Increased hemolysis occurs at low-flow, both in vitro and in silico. The in-vitro experiments present a sixfold higher relative increased hemolysis at low-flow. Compared to high-flow operation, a more than 3.5-fold increase in blood recirculation within the pump head can be observed in the low-flow range in silico. CONCLUSIONS: This study highlights the underappreciated hemolysis in centrifugal pumps within the low-flow range, i.e. during pediatric ECMO or ECCO2R treatment. The in-vitro results of hemolysis and the in-silico computational fluid dynamic simulations of flow paths within the pumps raise awareness about blood damage that occurs when using centrifugal pumps at low-flow operating points. These findings underline the urgent need for a specific pump optimized for low-flow treatment. Due to the inherent problems of available centrifugal pumps in the low-flow range, clinicians should use the current centrifugal pumps with caution, alternatively other pumping principles such as positive displacement pumps may be discussed in the future.

Understanding the influence of left ventricular assist device inflow cannula alignment and the risk of intraventricular thrombosis.

BACKGROUND: Adverse neurological events associated with left ventricular assist devices (LVADs) have been suspected to be related to thrombosis. This study aimed to understand the risks of thrombosis with variations in the implanted device orientation. A severely dilated pulsatile patient-specific left ventricle, modelled with computational fluid dynamics, was utilised to identify the risk of thrombosis for five cannulation angles. With respect to the inflow cannula axis directed towards the mitral valve, the other angles were 25° and 20° towards the septum and 20° and 30° towards the free wall. RESULTS: Inflow cannula angulation towards the free wall resulted in longer blood residence time within the ventricle, slower ventricular washout and reduced pulsatility indices along the septal wall. Based on the model, the ideal inflow cannula alignment to reduce the risk of thrombosis was angulation towards the mitral valve and up to parallel to the septum, avoiding the premature clearance of incoming blood. CONCLUSIONS: This study indicates the potential effects of inflow cannulation angles and may guide optimised implantation configurations; however, the ideal approach will be influenced by other patient factors and is suspected to change over the course of support.

Tipless transseptal cannula concept combines improved hemodynamic properties and risk-reduced placement: An in silico proof-of-concept.

As a leading cause of death worldwide, heart failure is a serious medical condition in which many critically ill patients require temporary mechanical circulatory support (MCS) as a bridge-to-recovery or bridge-to-decision. In many cases, the TandemHeart system is used to unload the left heart by draining blood from the left atrium (LA) to the femoral artery via a transseptal multistage cannula. However, even though the correct positioning of the cannula is crucial for a safe treatment, the long cannula tip currently used in transseptal cannulas complicates positioning, making the cannula vulnerable to displacement during MCS. To overcome these limitations, we propose the development of a new tipless transseptal cannula with improved hemodynamic properties. We discuss the tipless cannula concept by comparing it to the common multistage cannula concept using computational fluid dynamics simulations and assess the flow field in the LA, the wall shear stresses (WSS), and the pressure loss. Across the two distinct time points of end-systole and end-diastole and two drainage flow rates of 3.5 and 5.0 L/min, we find a more homogeneous inlet flow pattern for the tipless cannula concept, accompanied by a remarkably reduced area of platelet-activating WSS (up to 10-times smaller area compared to the multistage cannula). Moreover, pressure loss is up to 14.5% lower in the tipless cannula concept, confirming overall improved hemodynamic properties of the tipless cannula concept. Finally, a diameter-dependent study reveals that lower WSS and pressure losses can be further reduced by large-lumen designs for any simulation setting. Overall, our results suggest that a tipless cannula concept remedies the crucial disadvantages of a long-tip multistage cannula by reducing the risk of misplacement, and it furthermore promotes optimized hemodynamics. With this successful proof-of-concept, we underscore the potential for and encourage the realization of further experimental investigations regarding the development of a tipless transseptal cannula for MCS.

Hemodynamics inside the neo- and native sinus after TAVR: Effects of implant depth and cardiac output on flow field and coronary flow.

Transcatheter aortic valve replacement (TAVR) has emerged as a widely used therapy for aortic valve diseases. With TAVR, flow hemodynamics may change leading to areas of flow stagnation prone to thrombosis risk. The neo-sinus, created by introducing a prosthesis inside the diseased native valve, may prompt leaflet thrombosis due to areas of flow stasis. This study attempted to understand the effect of different prosthesis implant depths on the flow field within the neo- and native sinus and on the coronary perfusion. Experiments were performed inside an in vitro pulse duplicator producing physiological conditions according to ISO 5840-1:2015 standard. Flow fields were obtained for two cardiac outputs (CO) using particle image velocimetry (PIV). Washout was calculated as a measure of flow stasis. The two main results are: a lower implant position and a lower CO/frequency led to better native sinus washout, but worsened neo-sinus washout. In contrast, a higher implant position led to higher coronary flow (for higher CO/frequency). No significant effect of implant depth on coronary flow was observed for lower CO/frequency. In summary, a higher implant position using this self-expanding prosthesis is associated with reduced neo-sinus flow stasis. Hereby, washout of the native sinus, as well as coronary flow, are dependent on cardiac output.

In vitro thrombogenicity testing of pulsatile mechanical circulatory support systems: Design and proof-of-concept.

Thrombogenic complications are a main issue in mechanical circulatory support (MCS). There is no validated in vitro method available to quantitatively assess the thrombogenic performance of pulsatile MCS devices under realistic hemodynamic conditions. The aim of this study is to propose a method to evaluate the thrombogenic potential of new designs without the use of complex in-vivo trials. This study presents a novel in vitro method for reproducible thrombogenicity testing of pulsatile MCS systems using low molecular weight heparinized porcine blood. Blood parameters are continuously measured with full blood thromboelastometry (ROTEM; EXTEM, FIBTEM and a custom-made analysis HEPNATEM). Thrombus formation is optically observed after four hours of testing. The results of three experiments are presented each with two parallel loops. The area of thrombus formation inside the MCS device was reproducible. The implantation of a filter inside the loop catches embolizing thrombi without a measurable increase of platelet activation, allowing conclusions of the place of origin of thrombi inside the device. EXTEM and FIBTEM parameters such as clotting velocity (α) and maximum clot firmness (MCF) show a total decrease by around 6% with a characteristic kink after 180 minutes. HEPNATEM α and MCF rise within the first 180 minutes indicate a continuously increasing activation level of coagulation. After 180 minutes, the consumption of clotting factors prevails, resulting in a decrease of α and MCF. With the designed mock loop and the presented protocol we are able to identify thrombogenic hot spots inside a pulsatile pump and characterize their thrombogenic potential.

Experimental investigation of right-left flow balance concepts for a total artificial heart.

A total artificial heart (TAH) must be designed to autonomously balance the flows of the systemic and pulmonary circulation to prevent potentially lethal lung damage. The flow difference between the systemic and pulmonary circulation is mainly caused by the bronchial (arteries) shunt flow and can change dynamically. The ReinHeart TAH consists of only one actuator that ejects blood alternately from the right and left pump chamber. This design entails a coupling of the right and left stroke and thus, complicates the independent adaptation of the right and left flow. In this experimental study on the ReinHeart TAH, four concepts to keep the flows well balanced were investigated using an active mock circulation loop for data acquisition. Three concepts are based on mechanical design changes (variation of pusher plate shape, flexible right pump chamber housing, and reduced right stroke volume) to achieve a static flow difference. In combination with these static concepts, a concept influencing the ratio of systole and diastole duration to respond to dynamic changes was studied. In total, four measurement series, each with 270 operating points, to investigate the influence of circulatory filling volume, heart rate, bronchial shunt flow, and lung resistance were recorded. In the course of this study, we introduce a concept deviation indicator, providing information about the efficiency of the concepts to balance the flows based on changes in lung's blood pressures. Furthermore, the distribution of the measured data was evaluated based on bubble plot visualizations. The investigated variation of the right pusher plate shape results in high lung pressures which will cause lethal lung damage. In comparison, a flexible right pump chamber housing shows lower lung pressures, but it still has the potential to damage the lungs. Reducing the stroke volume of the right pump chamber results in proper lung pressures. The flow balance can dynamically be influenced with a positive effect on the lung pressures by choosing a suitable systole-diastole-ratio. The results of this study suggest that an adequate right-left flow balance can be achieved by combining the mechanical concept of a reduced right stroke volume with an active control of the systole-diastole-ratio.

Artificial lungs--Where are we going with the lung replacement therapy?

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.

An advanced mock circulation loop for in vitro cardiovascular device evaluation.

Controlled and repeatable in vitro evaluation of cardiovascular devices using a mock circulation loop (MCL) is essential prior to in vivo or clinical trials. MCLs often consist of only a systemic circulation with no autoregulatory responses and limited validation. This study aimed to develop, and validate against human data, an advanced MCL with systemic, pulmonary, cerebral, and coronary circulations with autoregulatory responses. The biventricular MCL was constructed with pneumatically controlled hydraulic circulations with Starling responsive ventricles and autoregulatory cerebral and coronary circulations. Hemodynamic repeatability was assessed and complemented by validation using impedance cardiography data from 50 healthy humans. The MCL successfully simulated patient scenarios including rest, exercise, and left heart failure with and without cardiovascular device support. End-systolic pressure-volume relationships for respective healthy and heart failure conditions had slopes of 1.27 and 0.54 mm Hg mL-1 (left ventricle), and 0.18 and 0.10 mm Hg mL-1 (right ventricle), aligning with the literature. Coronary and cerebral autoregulation showed a strong correlation (R2 : .99) between theoretical and experimentally derived circuit flow. MCL repeatability was demonstrated with correlation coefficients being statistically significant (P < .05) for all simulated conditions while MCL hemodynamics aligned well with human data. This advanced MCL is a valuable tool for inexpensive and controlled evaluation of cardiovascular devices.

In vitro study on the hemocompatibility of plasma electrolytic oxidation coatings on titanium substrates.

Passively levitated ventricular assist devices (VADs) are vulnerable to impeller-housing contact and could benefit from surface coatings that improve wear resistance. Such coatings can be manufactured by plasma electrolytic oxidation (PEO), but their suitability for blood-contact applications needs further investigation. We therefore compared blood-surface interactions of polished titanium grade 5 (Ti Gr 5), as a general VAD reference material, uncoated ground titanium grade 4 (Ti Gr 4) and two commercially available PEO coatings on Ti Gr 4. In n = 4 static platelet adhesion tests, material samples were incubated with platelet-rich plasma (PRP) and consecutively analyzed for adhesive platelets by immunofluorescence microscopy. Additionally, PRP supernatant of incubated material samples was analyzed for changes in antithrombin III and fibrinogen concentrations by turbodimetry and enzyme-linked immunosorbent assay, respectively. We could not find any significant differences between the materials in the analyzed hemocompatibility markers (P > .05). Thus, we conclude that PEO coatings might offer a similar hemocompatibility to that of polished Ti Gr 5 and uncoated Ti Gr 4. Nevertheless, future studies should investigate blood-surface interactions of PEO coatings under realistic VAD-related flow conditions to better evaluate their potential for VAD applications.

Low-flow assessment of current ECMO/ECCO2R rotary blood pumps and the potential effect on hemocompatibility.

BACKGROUND: Extracorporeal carbon dioxide removal (ECCO2R) uses an extracorporeal circuit to directly remove carbon dioxide from the blood either in lieu of mechanical ventilation or in combination with it. While the potential benefits of the technology are leading to increasing use, there are very real risks associated with it. Several studies demonstrated major bleeding and clotting complications, often associated with hemolysis and poorer outcomes in patients receiving ECCO2R. A better understanding of the risks originating specifically from the rotary blood pump component of the circuit is urgently needed. METHODS: High-resolution computational fluid dynamics was used to calculate the hemodynamics and hemocompatibility of three current rotary blood pumps for various pump flow rates. RESULTS: The hydraulic efficiency dramatically decreases to 5-10% if operating at blood flow rates below 1 L/min, the pump internal flow recirculation rate increases 6-12-fold in these flow ranges, and adverse effects are increased due to multiple exposures to high shear stress. The deleterious consequences include a steep increase in hemolysis and destruction of platelets. CONCLUSIONS: The role of blood pumps in contributing to adverse effects at the lower blood flow rates used during ECCO2R is shown here to be significant. Current rotary blood pumps should be used with caution if operated at blood flow rates below 2 L/min, because of significant and high recirculation, shear stress, and hemolysis. There is a clear and urgent need to design dedicated blood pumps which are optimized for blood flow rates in the range of 0.5-1.5 L/min.

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

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

Mechanical properties of currently available left atrial appendage occlusion devices: A bench-testing analysis.

Endoluminal left atrial appendage occlusion is an emerging therapy to treat patients suffering from atrial fibrillation with contraindications against oral anticoagulation. Different occlusion devices have been introduced into the clinical setting while comparative studies between the devices are sparse. This in vitro study compares several endoluminal left atrial appendage occlusion systems regarding 2 mechanical properties: radial (RF) and tug force (TF). Seven different occluder systems of various sizes (24 in total) underwent testing throughout their recommended sizing range. RF was measured in a commercial RF tester. TF was assessed according to a recently published bench test. RF increased with compression of the devices: The LAmbre 2228 device exerted the highest RF (8.6 N) at maximum compression of 16 mm. The lowest RF of 0.1 N was exhibited by the 27 mm Occlutech occluder at minimal compression. The highest TFs were exerted by the WaveCrest devices at maximum compression with 4.6 and 3.6 N for the 22 mm and the 27 mm device, respectively. The lowest TFs were measured for the first-generation Occlutech devices, particularly for the 24 mm device with 1.1 N at maximum compression and 0.4 N at minimum compression. A strong positive correlation was found between the number of hooks per millimeter circumference of an occluder and its tug force (r = 0.87, P < 0.01). The analysis revealed device stability to be more dependent on anchoring structures than on RF. The wide range of mechanical properties makes comparison of current LAA occluders difficult and emphasizes the need for standardized preclinical testing to prompt clinical compatibility.

Mesh Sensitivity Analysis for Quantitative Shear Stress Assessment in Blood Pumps Using Computational Fluid Dynamics.

The reduction of excessive, nonphysiologic shear stresses leading to blood trauma can be the key to overcome many of the associated complications in blood recirculating devices. In that regard, computational fluid dynamics (CFD) are gaining in importance for the hydraulic and hemocompatibility assessment. Still, direct hemolysis assessments with CFD remain inaccurate and limited to qualitative comparisons rather than quantitative predictions. An underestimated quantity for improved blood damage prediction accuracy is the influence of near-wall mesh resolution on shear stress quantification in regions of complex flows. This study investigated the necessary mesh refinement to quantify shear stress for two selected, meshing sensitive hotspots within a rotary centrifugal blood pump (the blade leading edge and tip clearance gap). The shear stress in these regions is elevated due to presence of stagnation points and the flow around a sharp edge. The nondimensional mesh characteristic number y+, which is known in the context of turbulence modeling, underestimated the maximum wall shear stress by 60% on average with the recommended value of 1, but was found to be exact below 0.1. To evaluate the meshing related error on the numerical hemolysis prediction, three-dimensional simulations of a generic centrifugal pump were performed with mesh sizes from 3 × 106 to 30 × 106 elements. The respective hemolysis was calculated using an Eulerian scalar transport model. Mesh insensitivity was found below a maximum y+ of 0.2 necessitating 18 × 106 mesh elements. A meshing related error of up to 25% was found for the coarser meshes. Further investigations need to address: (1) the transferability to other geometries and (2) potential adaptions on blood damage estimation models to allow better quantitative predictions.

Computational Modeling of Oxygen Transfer in Artificial Lungs.

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