Critical evaluation of kinetic schemes for coagulation.

Two well-established numerical representations of the coagulation cascade either initiated by the intrinsic system (Chatterjee et al., PLOS Computational Biology 2010) or the extrinsic system (Butenas et al., Journal of Biological Chemistry, 2004) were compared with thrombin generation assays under realistic pathological conditions. Biochemical modifications such as the omission of reactions not relevant to the case studied, the modification of reactions related to factor XI activation and auto-activation, the adaptation of initial conditions to the thrombin assay system, and the adjustment of some of the model parameters were necessary to align in vitro and in silico data. The modified models are able to reproduce thrombin generation for a range of factor XII, XI, and VIII deficiencies, with the coagulation cascade initiated either extrinsically or intrinsically. The results emphasize that when existing models are extrapolated to experimental parameters for which they have not been calibrated, careful adjustments are required.

Assessing a heterogeneous model for accounting for endovascular devices in hemodynamic simulations of cerebral aneurysms.

The heterogeneous model developed by Berod et al [Int J Numer Method Biomed Eng 38, 2021] for representing the hemodynamic effects of endovascular prostheses is applied to a series of 10 patient specific cerebral aneurysms, 6 being treated by flow diverters, 4 being equipped with WEBs. Two markers correlated with the medical outcome of the treatment are used to assess the potential of the model, namely the saccular mean velocity and the inflow rate at the neck of the aneurysm. The comparison with the corresponding wire-resolved simulations is very favorable in both cases, and the model-based simulations also retrieve the jetting-type flows generated downstream of the struts. Noteworthy, the very same model was used for representing the flow diverters and the WEBs, showing the versatility and robustness of the heterogeneous modeling of the devices.

From Microscopic Droplets to Macroscopic Crowds: Crossing the Scales in Models of Short-Range Respiratory Disease Transmission, with Application to COVID-19.

Short-range exposure to airborne virus-laden respiratory droplets is an effective transmission route of respiratory diseases, as exemplified by Coronavirus Disease 2019 (COVID-19). In order to assess the risks associated with this pathway in daily-life settings involving tens to hundreds of individuals, the chasm needs to be bridged between fluid dynamical simulations and population-scale epidemiological models. This is achieved by simulating droplet trajectories at the microscale in numerous ambient flows, coarse-graining their results into spatio-temporal maps of viral concentration around the emitter, and coupling these maps to field-data about pedestrian crowds in different scenarios (streets, train stations, markets, queues, and street cafés). At the individual scale, the results highlight the paramount importance of the velocity of the ambient air flow relative to the emitter's motion. This aerodynamic effect, which disperses infectious aerosols, prevails over all other environmental variables. At the crowd's scale, the method yields a ranking of the scenarios by the risks of new infections, dominated by the street cafés and then the outdoor market. While the effect of light winds on the qualitative ranking is fairly marginal, even the most modest air flows dramatically lower the quantitative rates of new infections.

Red blood cell rheology during a complete blood count: A proof of concept.

Counting and sizing blood cells in hematological analyzers is achieved using the Coulter principle. The cells flow in a micro-aperture in which a strong electrical field is imposed, so that an electrical perturbation, called pulse, is measured each time a cell crosses the orifice. The pulses are expected to contain information on the shape and deformability of Red Blood Cells (RBCs), since recent studies state that RBCs rotate and deform in the micro-orifice. By implementing a dedicated numerical model, the present study sheds light on a variety of cells dynamics, which leads to different associated pulse signatures. Furthermore, simulations provide new insights on how RBCs shapes and mechanical properties affect the measured signals. Those numerical observations are confirmed by experimental assays. Finally, specific features are introduced for assessing the most relevant characteristics from the various pulse signatures and shown to highlight RBCs alterations induced by drugs. In summary, this study paves the way to a characterization of RBC rheology by routine hematological instruments.

Accelerated sequences of 4D flow MRI using GRAPPA and compressed sensing: A comparison against conventional MRI and computational fluid dynamics.

PURPOSE: To evaluate hemodynamic markers obtained by accelerated GRAPPA (R = 2, 3, 4) and compressed sensing (R = 7.6) 4D flow MRI sequences under complex flow conditions. METHODS: The accelerated 4D flow MRI scans were performed on a pulsatile flow phantom, along with a nonaccelerated fully sampled k-space acquisition. Computational fluid dynamics simulations based on the experimentally measured flow fields were conducted for additional comparison. Voxel-wise comparisons (Bland-Altman analysis, L 2 $$ {L}_2 $$ -norm metric), as well as nonderived quantities (velocity profiles, flow rates, and peak velocities), were used to compare the velocity fields obtained from the different modalities. RESULTS: 4D flow acquisitions and computational fluid dynamics depicted similar hemodynamic patterns. Voxel-wise comparisons between the MRI scans highlighted larger discrepancies at the voxels located near the phantom's boundary walls. A trend for all MR scans to overestimate velocity profiles and peak velocities as compared to computational fluid dynamics was noticed in regions associated with high velocity or acceleration. However, good agreement for the flow rates was observed, and eddy-current correction appeared essential for consistency of the flow rates measurements with respect to the principle of mass conservation. CONCLUSION: GRAPPA (R = 2, 3) and highly accelerated compressed sensing showed good agreement with the fully sampled acquisition. Yet, all 4D flow MRI scans were hampered by artifacts inherent to the phase-contrast acquisition procedure. Computational fluid dynamics simulations are an interesting tool to assess these differences but are sensitive to modeling parameters.

Full-volume three-component intraventricular vector flow mapping by triplane color Doppler.

Objective. Intraventricular vector flow mapping (iVFM) is a velocimetric technique for retrieving two-dimensional velocity vector fields of blood flow in the left ventricular cavity. This method is based on conventional color Doppler imaging, which makesiVFM compatible with the clinical setting. We have generalized theiVFM for a three-dimensional reconstruction (3D-iVFM).Approach.3D-iVFM is able to recover three-component velocity vector fields in a full intraventricular volume by using a clinical echocardiographic triplane mode. The 3D-iVFM problem was written in the spherical (radial, polar, azimuthal) coordinate system associated to the six half-planes produced by the triplane mode. As with the 2D version, the method is based on the mass conservation, and free-slip boundary conditions on the endocardial wall. These mechanical constraints were imposed in a least-squares minimization problem that was solved through the method of Lagrange multipliers. We validated 3D-iVFMin silicoin a patient-specific CFD (computational fluid dynamics) model of cardiac flow and tested its clinical feasibilityin vivoin patients and in one volunteer.Main results.The radial and polar components of the velocity were recovered satisfactorily in the CFD setup (correlation coefficients,r = 0.99 and 0.78). The azimuthal components were estimated with larger errors (r = 0.57) as only six samples were available in this direction. In bothin silicoandin vivoinvestigations, the dynamics of the intraventricular vortex that forms during diastole was deciphered by 3D-iVFM. In particular, the CFD results showed that the mean vorticity can be estimated accurately by 3D-iVFM.Significance. Our results tend to indicate that 3D-iVFM could provide full-volume echocardiographic information on left intraventricular hemodynamics from the clinical modality of triplane color Doppler.

A Pipeline for the Generation of Synthetic Cardiac Color Doppler.

Color Doppler imaging (CDI) is the modality of choice for simultaneous visualization of myocardium and intracavitary flow over a wide scan area. This visualization modality is subject to several sources of error, the main ones being aliasing and clutter. Mitigation of these artifacts is a major concern for better analysis of intracardiac flow. One option to address these issues is through simulations. In this article, we present a numerical framework for generating clinical-like CDI. Synthetic blood vector fields were obtained from a patient-specific computational fluid dynamics CFD model. Realistic texture and clutter artifacts were simulated from real clinical ultrasound cineloops. We simulated several scenarios highlighting the effects of 1) flow acceleration; 2) wall clutter; and 3) transmit wavefronts, on Doppler velocities. As a comparison, an "ideal" color Doppler was also simulated, without these harmful effects. This synthetic dataset is made publicly available and can be used to evaluate the quality of Doppler estimation techniques. Besides, this approach can be seen as a first step toward the generation of comprehensive datasets for training neural networks to improve the quality of Doppler imaging.

A heterogeneous model of endovascular devices for the treatment of intracranial aneurysms.

Numerical computations of hemodynamics inside intracranial aneurysms treated by endovascular braided devices such as flow-diverters contribute to understanding and improving such treatment procedures. Nevertheless, these simulations yield high computational and meshing costs due to the heterogeneity of length scales between the dense weave of the fine struts of the device and the arterial volume. Homogeneous strategies developed over the last decade to circumvent this issue substitute local dissipations due to the wires with a global effect in the form of a pressure-drop across the device surface. However, these methods cannot accurately reproduce the flow-patterns encountered near the struts, the latter strongly dictating the intra-saccular flow environment. In this work, a versatile theoretical framework which aims at correctly reproducing the local flow heterogeneities due to the wires while keeping memory consumption, meshing and computational times as low as possible is introduced. This model reproduces the drag forces exerted by the device struts onto the fluid, thus producing local and heterogeneous effects on the flow. Extensive validation for various flow and geometric configurations using an idealized device is performed. To further illustrate the method capabilities, a real patient-specific aneurysm endovascularly treated with a flow-diverter is used, enabling quantitative comparisons with classical approaches for both intra-saccular velocities and computational costs reduction. The proposed heterogeneous model endeavors to bridge the gap between computational fluid dynamics and clinical applications and ushers in a new era of numerical treatment planning with minimally costing computational tools.

Physics-constrained intraventricular vector flow mapping by color Doppler.

Color Doppler by transthoracic echocardiography creates two-dimensional fan-shaped maps of blood velocities in the cardiac cavities. It is a one-component velocimetric technique since it only returns the velocity components parallel to the ultrasound beams. Intraventricular vector flow mapping (iVFM) is a method to recover the blood velocity vectors from the Doppler scalar fields in an echocardiographic three-chamber view. We improved ouriVFM numerical scheme by imposing physical constraints. TheiVFM consisted in minimizing regularized Doppler residuals subject to the condition that two fluid-dynamics constraints were satisfied, namely planar mass conservation, and free-slip boundary conditions. The optimization problem was solved by using the Lagrange multiplier method. A finite-difference discretization of the optimization problem, written in the polar coordinate system centered on the cardiac ultrasound probe, led to a sparse linear system. The single regularization parameter was determined automatically for non-supervision considerations. The physics-constrained method was validated using realistic intracardiac flow data from a patient-specific computational fluid dynamics (CFD) model. The numerical evaluations showed that theiVFM-derived velocity vectors were in very good agreement with the CFD-based original velocities, with relative errors ranged between 0.3% and 12%. We calculated two macroscopic measures of flow in the cardiac region of interest, the mean vorticity and mean stream function, and observed an excellent concordance between physics-constrainediVFM and CFD. The capability of physics-constrainediVFM was finally tested within vivocolor Doppler data acquired in patients routinely examined in the echocardiographic laboratory. The vortex that forms during the rapid filling was deciphered. The physics-constrainediVFM algorithm is ready for pilot clinical studies and is expected to have a significant clinical impact on the assessment of diastolic function.

Model-based assessment of the risks of viral transmission in non-confined crowds.

This work assesses the risks of Covid-19 spread in diverse daily-life situations involving crowds of maskless pedestrians, mostly outdoors. More concretely, we develop a method to infer the global number of new infections from patchy observations, by coupling ad hoc spatial models for disease transmission via respiratory droplets to detailed field-data about pedestrian trajectories and head orientations. This allows us to rank the investigated situations by the infection risks that they present; importantly, the obtained hierarchy of risks is very largely conserved across transmission models: Street cafés present the largest average rate of new infections caused by an attendant, followed by busy outdoor markets, and then metro and train stations, whereas the risks incurred while walking on fairly busy streets are comparatively quite low. While our models only approximate the actual transmission risks, their converging predictions lend credence to these findings. In situations with a moving crowd, density is the main factor influencing the estimated infection rate. Finally, our study explores the efficiency of street and venue redesigns in mitigating the viral spread: While the benefits of enforcing one-way foot traffic in (wide) walkways are unclear, changing the geometry of queues substantially affects disease transmission risks.

Detecting cells rotations for increasing the robustness of cell sizing by impedance measurements, with or without machine learning.

The Coulter principle is a widespread technique for sizing red blood cells (RBCs) in hematological analyzers. It is based on the monitoring of the electrical perturbations generated by cells passing through a micro-orifice, in which a concentrated electrical field is imposed by two electrodes. However, artifacts associated with near-wall passages in the sensing region are known to skew the statistics for RBCs sizing. This study presents numerical results that emphasize the link between the cell flow-induced rotation in the detection area and the error in its measured volume. Based on these observations, two methods are developed to identify and reject pulses impaired by cell rotation. In the first strategy, the filtering is allowed by a metric computed directly from the waveform. In the second, a numerical database is employed to train a neural network capable of detecting if the cell has experienced a rotation, given its electrical pulse. Detecting and rejecting rotation-associated pulses are shown to provide results comparable to hydrodynamical focusing, which enforces cells to flow in the center of the orifice, the gold standard implementation of the Coulter principle.

Numerical simulation of time-resolved 3D phase-contrast magnetic resonance imaging.

A numerical approach is presented to efficiently simulate time-resolved 3D phase-contrast Magnetic resonance Imaging (or 4D Flow MRI) acquisitions under realistic flow conditions. The Navier-Stokes and Bloch equations are simultaneously solved with an Eulerian-Lagrangian formalism. A semi-analytic solution for the Bloch equations as well as a periodic particle seeding strategy are developed to reduce the computational cost. The velocity reconstruction pipeline is first validated by considering a Poiseuille flow configuration. The 4D Flow MRI simulation procedure is then applied to the flow within an in vitro flow phantom typical of the cardiovascular system. The simulated MR velocity images compare favorably to both the flow computed by solving the Navier-Stokes equations and experimental 4D Flow MRI measurements. A practical application is finally presented in which the MRI simulation framework is used to identify the origins of the MRI measurement errors.

Speech can produce jet-like transport relevant to asymptomatic spreading of virus.

Many scientific reports document that asymptomatic and presymptomatic individuals contribute to the spread of COVID-19, probably during conversations in social interactions. Droplet emission occurs during speech, yet few studies document the flow to provide the transport mechanism. This lack of understanding prevents informed public health guidance for risk reduction and mitigation strategies, e.g., the "6-foot rule." Here we analyze flows during breathing and speaking, including phonetic features, using orders-of-magnitude estimates, numerical simulations, and laboratory experiments. We document the spatiotemporal structure of the expelled airflow. Phonetic characteristics of plosive sounds like "P" lead to enhanced directed transport, including jet-like flows that entrain the surrounding air. We highlight three distinct temporal scaling laws for the transport distance of exhaled material including 1) transport over a short distance (<0.5 m) in a fraction of a second, with large angular variations due to the complexity of speech; 2) a longer distance, ∼1 m, where directed transport is driven by individual vortical puffs corresponding to plosive sounds; and 3) a distance out to about 2 m, or even farther, where sequential plosives in a sentence, corresponding effectively to a train of puffs, create conical, jet-like flows. The latter dictates the long-time transport in a conversation. We believe that this work will inform thinking about the role of ventilation, aerosol transport in disease transmission for humans and other animals, and yield a better understanding of linguistic aerodynamics, i.e., aerophonetics.

Numerical simulation of deformable particles in a Coulter counter.

In Coulter counters, cells counting and volumetry are achieved by monitoring their electrical print when they flow through a sensing zone. However, the volume measurement may be impaired by the cell dynamics, which may be difficult to control. In this paper, numerical simulations of the dynamics and electrical signature of red blood cells in a Coulter counter are presented, accounting for the deformability of the cells. In particular, a specific numerical pipeline is developed to overcome the challenge of the multi-scale nature of the problem. It consists in segmenting the whole computation of the cell dynamics and electrical response in a series of dedicated computations, with a saving of one order of magnitude in computational time. This numerical pipeline is used with rigid spheres and deformable red blood cells in an industrial Coulter counter geometry, and compared with experimental measurements. The simulations not only reproduce electrical signatures typical of those measured experimentally, but also allow an analysis of the electrical signature in terms of the heterogeneity of the electrical field and dynamics of the particles in the measurement zone. This study provides a methodology for computing the sizing of rigid or deformable particles by Coulter counters, opening the way to a better understanding of cells signatures in such devices.

Kinetics of the coagulation cascade including the contact activation system: sensitivity analysis and model reduction.

Thrombus formation is one of the main issues in the development of blood-contacting medical devices. This article focuses on the modeling of one aspect of thrombosis, the coagulation cascade, which is initiated by the contact activation at the device surface and forms thrombin. Models exist representing the coagulation cascade by a series of reactions, usually solved in quiescent plasma. However, large parameter uncertainty involved in the kinetic models can affect the predictive capabilities of this approach. In addition, the large number of reactions of the kinetic models prevents their use in the simulation of complex flow configurations encountered in medical devices. In the current work, both issues are addressed to improve the applicability and fidelity of kinetic models. A sensitivity analysis is performed by two different techniques to identify the most sensitive parameters of an existing detailed kinetic model of the coagulation cascade. The results are used to select the form of a novel reduced model of the coagulation cascade which relies on eight chemical reactors only. Then, once its parameters have been calibrated thanks to the Bayesian inference, this model shows good predictive capabilities for different initial conditions.

Self-organization of red blood cell suspensions under confined 2D flows.

Dynamic self-organized structures with long-range order have been observed in emulsions and suspensions of particles under confined flows. Here, experiments on red blood cell suspensions under quasi-2D confined flows and numerical simulations were combined to explore long-distance self-organization as a function of the channel width, red blood cell concentration and flow rate. They reveal and quantitatively describe the existence of red blood cell long-range alignments and heterogeneous cross-stream concentration profiles characterized by red blood cell-enriched bands parallel to the flow. Numerical simulations show that, in addition to the degree of lateral confinement, the key factor for the structural self-organization of a suspension of particles under a confined flow is the deformability of the constituent particles.

Reconciling PC-MRI and CFD: An in-vitro study.

Several well-resolved 4D Flow MRI acquisitions of an idealized rigid flow phantom featuring an aneurysm, a curved channel as well as a bifurcation were performed under pulsatile regime. The resulting hemodynamics were processed to remove MRI artifacts. Subsequently, they were compared with CFD predictions computed on the same flow domain, using an in-house high-order low dissipative flow solver. Results show that reaching a good agreement is not straightforward but requires proper treatments of both techniques. Several sources of discrepancies are highlighted and their impact on the final correlation evaluated. While a very poor correlation (r2 = 0.63) is found in the entire domain between raw MRI and CFD data, correlation as high as r2 = 0.97 is found when artifacts are removed by post-processing the MR data and down sampling the CFD results to match the MRI spatial and temporal resolutions. This work demonstrates that, in a well-controlled environment, both PC-MRI and CFD might bring reliable and correlated flow quantities when a proper methodology to reduce the errors is followed.

Flow-Induced Transitions of Red Blood Cell Shapes under Shear.

A recent study of red blood cells (RBCs) in shear flow [Lanotte et al., Proc. Natl. Acad. Sci. U.S.A. 113, 13289 (2016)PNASA60027-842410.1073/pnas.1608074113] has demonstrated that RBCs first tumble, then roll, transit to a rolling and tumbling stomatocyte, and finally attain polylobed shapes with increasing shear rate, when the viscosity contrast between cytosol and blood plasma is large enough. Using two different simulation techniques, we construct a state diagram of RBC shapes and dynamics in shear flow as a function of shear rate and viscosity contrast, which is also supported by microfluidic experiments. Furthermore, we illustrate the importance of RBC shear elasticity for its dynamics in flow and show that two different kinds of membrane buckling trigger the transition between subsequent RBC states.

Introducing the pro-coagulant contact system in the numerical assessment of device-related thrombosis.

Thrombosis is a major concern in blood-coated medical devices. Contact activation, which is the initial part of the coagulation cascade in device-related thrombosis, is not considered in current thrombus formation models. In the present study, pro-coagulant reactions including the contact activation system are coupled with a fluid solver in order to evaluate the potential of the contact system to initiate thrombin production. The biochemical/fluid model is applied to a backward-facing step configuration, a flow configuration that frequently appears in medical devices. In contrast to the in vivo thrombosis models in which a specific thrombotic zone (injury region) is set a priori by the user to initiate the coagulation reaction, a reactive surface boundary condition is applied to the whole device wall. Simulation results show large thrombin concentration in regions related to recirculation zones without the need of an a priori knowledge of the thrombus location. The numerical results align well with the regions prone to thrombosis observed in experimental results reported in the literature. This approach could complement thrombus formation models that take into account platelet activity and thrombus growth to optimize a wide range of medical devices.

Fluid-structure interaction of a pulsatile flow with an aortic valve model: A combined experimental and numerical study.

The complex fluid-structure interaction problem associated with the flow of blood through a heart valve with flexible leaflets is investigated both experimentally and numerically. In the experimental test rig, a pulse duplicator generates a pulsatile flow through a biomimetic rigid aortic root where a model of aortic valve with polymer flexible leaflets is implanted. High-speed recordings of the leaflets motion and particle image velocimetry measurements were performed together to investigate the valve kinematics and the dynamics of the flow. Large eddy simulations of the same configuration, based on a variant of the immersed boundary method, are also presented. A massively parallel unstructured finite-volume flow solver is coupled with a finite-element solid mechanics solver to predict the fluid-structure interaction between the unsteady flow and the valve. Detailed analysis of the dynamics of opening and closure of the valve are conducted, showing a good quantitative agreement between the experiment and the simulation regarding the global behavior, in spite of some differences regarding the individual dynamics of the valve leaflets. A multicycle analysis (over more than 20 cycles) enables to characterize the generation of turbulence downstream of the valve, showing similar flow features between the experiment and the simulation. The flow transitions to turbulence after peak systole, when the flow starts to decelerate. Fluctuations are observed in the wake of the valve, with maximum amplitude observed at the commissure side of the aorta. Overall, a very promising experiment-vs-simulation comparison is shown, demonstrating the potential of the numerical method.