Cell-free Layer Research Articles

The influence of red blood cell deformability on hematocrit profiles and platelet margination.

The influence of red blood cell (RBC) deformability in whole blood on platelet margination is investigated using confocal microscopy measurements of flowing human blood and cell resolved blood flow simulations. Fluorescent platelet concentrations at the wall of a glass chamber are measured using confocal microscopy with flowing human blood containing varying healthy-to-stiff RBC fractions. A decrease is observed in the fluorescent platelet signal at the wall due to the increase of stiffened RBCs in flow, suggesting a decrease of platelet margination due to an increased fraction of stiffened RBCs present in the flow. In order to resolve the influence of stiffened RBCs on platelet concentration at the channel wall, cell-pair and bulk flow simulations are performed. For homogeneous collisions between RBC pairs, a decrease in final displacement after a collision with increasing membrane stiffness is observed. In heterogeneous collisions between healthy and stiff RBC pairs, it is found that the stiffened RBC is displaced most. The influence of RBC deformability on collisions between RBCs and platelets was found to be negligible due to their size and mass difference. For a straight vessel geometry with varying healthy-to-stiff RBC ratios, a decrease was observed in the red blood cell-free layer and platelet margination due to an increase in stiffened RBCs present in flow.

The effect of hemicylindrical disruptors on the cell free layer thickness in animal blood flows inside microchannels

AbstractBlood-side resistance to oxygen transport in extracorporeal membrane blood oxygenators (MBO) depends on fluid mechanics governing the laminar flow in very narrow channels, particularly the hemodynamics controlling the cell free layer (CFL) built-up at solid/blood interfaces. The CFL thickness constitutes a barrier to oxygen transport from the membrane towards the erythrocytes. Interposing hemicylindrical CFL disruptors in animal blood flows inside rectangular microchannels, surrogate systems of MBO mimicking their hemodynamics, proved to be effective in reducing (ca. 20%) such thickness (desirable for MBO to increase oxygen transport rates to the erythrocytes). The blockage ratio (non-dimensional measure of the disruptor penetration into the flow) increase is also effective in reducing CFL thickness (ca. 10–20%), but at the cost of risking clot formation (undesirable for MBO) for disruptors with penetration lengths larger than their radius, due to large residence times of erythrocytes inside a low-velocity CFL formed at the disruptor/wall edge.

A Two-Zone Shear-Induced Red Blood Cell Migration Model for Blood Flow in Microvessels

The Fahraeus and Fahraeus-Lindqvist effects are both associated with the concentration of red blood cells (RBCs) in the core region of microvessels. The annular region is a cell-free layer. Blood flow dynamics and both effects are related to the hematocrit level profile. The aim is to propose a model for blood flow in microvessels that is not compute intensive like many other models such as those using finite element methods. Modeling blood flow requires solving for both the hematocrit level and velocity profiles as blood viscosity depends on the hematocrit level. The two-zone shear-induced model for blood flow is adopted while including an annular cell-free layer, as in the marginal zone theory and in consistency with experimental observations. In the core region, the hematocrit level is not considered to be uniform, and the concentration and viscous fluxes are equal in magnitude and opposite in directions in the fully developed velocity and concentration profiles case. The momentum and hematocrit balance equations are solved. Both analytical and numerical solutions for the velocity and hematocrit level profiles are determined. The numerical results are found to exactly match the analytical solutions, and to be in very good agreement with published experimental data for the cell-free layer thickness, the velocity profile, and the hematocrit ratio.

3D Bioprinted GelMA Based Models for the Study of Trophoblast Cell Invasion

Bioprinting is an emerging and promising technique for fabricating 3D cell-laden constructs for various biomedical applications. In this paper, we employed 3D bioprinted GelMA-based models to investigate the trophoblast cell invasion phenomenon, enabling studies of key placental functions. Initially, a set of optimized material and process parameters including GelMA concentration, UV crosslinking time and printing configuration were identified by systematic, parametric study. Following this, a multiple-ring model (2D multi-ring model) was tested with the HTR-8/SVneo trophoblast cell line to measure cell movement under the influence of EGF (chemoattractant) gradients. In the multi-ring model, the cell front used as a cell invasion indicator moves at a rate of 85 ± 33 µm/day with an EGF gradient of 16 µM. However, the rate was dramatically reduced to 13 ± 5 µm/day, when the multi-ring model was covered with a GelMA layer to constrain cells within the 3D environment (3D multi-ring model). Due to the geometric and the functional limitations of multi-ring model, a multi-strip model (2D multi-strip model) was developed to investigate cell movement in the presence and absence of the EGF chemoattractant. The results show that in the absence of an overlying cell-free layer of GelMA, movement of the cell front shows no significant differences between control and EGF-stimulated rates, due to the combination of migration and proliferation at high cell density (6 × 106 cells/ml) near the GelMA surface. When the model was covered by a layer of GelMA (3D multi-strip model) and migration was excluded, EGF-stimulated cells showed an invasion rate of 21 ± 3 µm/day compared to the rate for unstimulated cells, of 5 ± 4 µm/day. The novel features described in this report advance the use of the 3D bioprinted placental model as a practical tool for not only measurement of trophoblast invasion but also the interaction of invading cells with other tissue elements.

Influence of Heat and Mass Transfer on Two-Phase Blood Flow with Joule Heating and Variable Viscosity in the Presence of Variable Magnetic Field

In this paper, simultaneous effects of viscous dissipation and Joule heating on unsteady two-phase blood flow through a stenosed artery in the presence of variable applied magnetic field have been investigated. The present two-layered model of blood flow consists of a central core of suspended erythrocytes and a cell-depleted plasma layer surrounding the core. It is assumed that the viscosity of the cell-free plasma layer is constant while the viscosity of the core is a function of the hematocrit level. A consistent system of nonlinear partial differential equations is solved numerically using shooting methods to estimate the flow rate, flow resistance and wall shear stress. The quantitative profile analysis of velocity, temperature and concentration as well as the Nusselt number and Sherwood number is carried out over the entire arterial segment. To validate the model, a comparative study has been done between the present results and the experimental results for the cell velocity distribution of 40% RBC containing blood which exhibits that the present results are in fairly good agreement with the experimental results. The velocity contours have been plotted to understand the flow pattern in the diseased narrowed artery, which alters significantly in the downstream of the stenosis under the influence of magnetic field.

Stiff Erythrocyte Subpopulations Biomechanically Induce Endothelial Inflammation in Sickle Cell Disease

Background: Originally described as a monogenic hemoglobin disorder resulting in increased red blood cell (RBC) stiffness leading to vaso-occlusion, sickle cell disease (SCD) is now known to be a vasculopathic disease with some semblance to cardiovascular disease in which the endothelium is inflamed. While adhesive RBC-endothelial interactions, inflammatory cytokines, and hemolysis all contribute to SCD vasculopathy, whether the increased stiffness of sickle RBCs directly contributes to endothelial inflammation is unknown. Endothelial cells are now known to mechanotransduce shear forces into biological signals. Pathological alteration of such forces leads to proinflammatory endothelial cell signaling including upregulation of VCAM-1 and E-selectin, which contribute to atherosclerotic plaques leading to myocardial infarction and stroke (Abe, ATVB, 2014). In addition, under normal homeostatic conditions, RBCs do not come into contact with the endothelium due to a cell-free layer created by the Fåhræus-Lindqvist effect. Studies including our own have shown in silico that increasing RBC stiffness diminishes or eliminates the cell-free layer, allowing stiff RBCs to contact the vessel wall (Kumar, Phys Rev E, 2011). This is particularly pertinent in SCD, as all patients have a small population (1-10%) of sickle RBCs that are permanently stiff and misshapen. We therefore hypothesize that purely physical interactions - akin to "scratches" or collisions - between endothelial cells and stiff SCD RBCs breaking through the cell-free layer are sufficient to cause endothelial inflammation in the absence of adhesion or vaso-occlusion (Fig. 1A). Methods: We performed computational direct numerical simulations using the boundary integral method for a binary suspension of flexible biconcave discs and stiff curved prolate spheres modeling healthy RBCs and ISCs, respectively. Experimentally, we leveraged our microfluidic microvasculature models of human umbilical vein endothelial cells cultured throughout each microchannel (Fig. 2). RBCs from SCD patients were "spiked" into normal RBC suspensions to comprise 5 and 10% of the overall population (a representation of ISCs in vivo), suspended in media to 25% hematocrit mimicking conditions seen in SCD patients, and perfused into the microfluidics for 4 hours. Samples of 100% normal RBCs or SCD RBCs were run in parallel. To isolate the stiffness effects of sickle RBCs without confounding hemolytic and adhesive effects, parallel experiments were conducted using nystatin-treated normal RBCs to create artificially stiffened RBC subpopulations, defined by elevated mean corpuscular hemoglobin concentrations (MCHCs), at the same proportion of the overall RBC population (0, 5, 10 and 100%). The endothelialized models were then fixed, permeabilized, and immunostained with antibodies against VCAM-1 and E-selectin. Mean fluorescence intensity was measured to quantify endothelial inflammation. Results: In silico, we observed that ISCs strongly marginate towards the vessel walls due to their stiffness and "pointy" shape, and heterogeneous suspensions with small fractions of stiff, pointy cells (5 and 10%) caused the highest degree of margination (Fig. 1B). Experimentally, endothelium exposed to 5, 10, and 100% SCD RBCs exhibited increased VCAM-1 and E-selectin expression over normal RBCs, and the degree of expression increased with higher percentages of SCD RBCs. While endothelial cells exposed to nystatin-stiffened RBCs also showed increased VCAM-1 and E-selectin expression, those exposed to a lower percentage of stiff cells (5 and 10%) exhibited higher expression than the homogenously stiff (100%) condition (Fig. 3), which is consistent with our computer simulations. Conclusions: Here we demonstrate that purely non-adhesive, physical interactions between endothelial cells and SCD RBCs are sufficient to cause endothelial inflammation. Furthermore, heterogeneous RBC populations, comprised of a small minority of stiff cells, cause more inflammation than uniformly stiff RBCs. Studies elucidating the underlying mechanisms, using different endothelial cell types, and analyzing the effect of vessel curvature are ongoing. Our results introduce a new paradigm for understanding SCD pathophysiology and may help explain how chronic diffuse vasculopathy develops, which could lead to more biophysically-based therapeutic strategies. Disclosures Carden: GBT: Honoraria; NIH: Research Funding. Mannino:Sanguina, LLC: Employment, Equity Ownership. Lam:Sanguina, LLC: Equity Ownership.

Shear-induced non-monotonic viscosity dependence for model red blood cell suspensions in microvessels.

The cell-free layer thickness of an aggregating red blood cell (RBC) suspension in a rectangular microchannel is investigated by hybrid fluid-particle numerical modeling. Several factors affect the suspension viscosity, cell-free layer thickness, and the cell aggregate distribution. These include the hematocrit, vessel size, red cell stiffness, aggregation interaction, and shear rate. In particular, the effect of the shear rate on the cell-free layer thickness is controversial. We found that the suspension viscosity increases along with a decrease in the cell-free layer thickness as the shear rate increases for aggregating model RBCs at low shear rates. At moderate to high shear rates, the cell-free layer thickness increases with the increasing shear rate from medium to strong shear flow for both 10% and 20% red blood cell suspensions.

Lessons Learned from 50 Years of Hemoglobin Research: Unstirred and Cell-Free Layers, Electrostatics, Baseball Gloves, and Molten Globules.

Significance: Over the past 50 years, the mechanisms for O2 storage and transport have been determined quantitatively on distance scales from millimeters to tenths of nanometers and timescales from seconds to picoseconds. Recent Advances: In this review, I have described four key conclusions from work done by my group and our close colleagues. (i) O2 uptake by mammalian red cells is limited by diffusion through unstirred water layers adjacent to the cell surface and across cell-free layers adjacent to vessel walls. (ii) In most vertebrates, hemoglobins (Hbs) and myoglobins (Mbs), the distal histidine at the E7 helical position donates a strong hydrogen bond to bound O2, which selectively enhances O2 affinity, prevents carbon monoxide poisoning, and markedly slows autoxidation. (iii) O2 binding to mammalian Hbs and Mbs occurs by migration of the ligand through a channel created by upward rotation of the His(E7) side chain, capture in the empty space of the distal pocket, and then coordination with the ferroprotoporphyrin IX (heme) iron atom. (iv) The assembly of Mbs and Hbs occurs by formation of molten globule intermediates, in which the N- and C-terminal helices have almost fully formed secondary structures, but the heme pockets are disordered and followed by high-affinity binding of heme. Critical Issues: These conclusions indicate that there are often compromises between O2 transport function, holoprotein stability, and the efficiency of assembly. Future Directions: However, the biochemical mechanisms underlying these conclusions provide the framework for understanding globin evolution in greater detail and for engineering more efficient and stable globins.

Study of the Partitioning of Red Blood Cells Through Asymmetric Bifurcating Microchannels

The heterogeneous distribution of red blood cells (RBCs) in the microcirculatory system is a complicated phenomenon because many factors influence how they are partitioned at microvascular bifurcations. In this study, we investigated the RBC partitioning mechanism by fabricating an in vitro experimental apparatus. The apparatus comprised a bifurcating, microfluidic channel, and the flow rate through the channels can be controlled readily over a wide range. The division turning point at which an RBC trajectory changes from one bifurcation to the other was identified via particle-tracking velocimetry on individual RBCs. The experimental results were close to the theoretical predictions and numerical simulations. The hematocrit variation before and after bifurcation was quantitatively estimated by image analysis and compared to the prediction based on Pries’ empirical model. The Zweifach–Fung effect was enhanced in the smaller fractional flow, increasing the RBC flux bias. Moreover, a cell-free layer with axial symmetry was formed in the parent channel, and an asymmetric cell-free layer was formed immediately after bifurcation. These obtained results will help clarify the RBC partitioning mechanism at microvascular bifurcations.

Flexible PDMS microparticles to mimic RBCs in blood particulate analogue fluids

Polydimethylsiloxane (PDMS) has a wide variety of commercial and industrial applications due to its mechanical and rheological properties in a range similar to the living tissues. In this study, we demonstrate that PDMS can be used to produce deformable microparticles to be integrated in the development of particulate blood analogue fluids. The difficulties associated with the use of in vitro blood make it necessary to perform in vitro experiments of blood flow with blood analogue fluids. However, an ideal analogue must match the rheology of blood at several points, and for that, blood analogue fluids should be a suspension of microparticles with similar properties (size, shape and flexibility) to blood cells, in particular to the red blood cells (RBCs). The microparticles used in this study were produced from a transparent PDMS with crosslinking ratios of 10:1, 8:2 and 6:4; from a black PDMS with a ratio of 1:1 and from a red-pigmented PDMS. Each PDMS microparticles sample was suspended in Dextran 40 to perform deformability assays and cell-free layer analysis in a hyperbolic-shaped microchannel and steady shear viscosity measurements in a rheometer. The proposed microparticles suspensions show a great potential to mimic the structural and rheological properties of RBC suspensions and consequently to develop blood analogue fluids with rheological properties similar to real blood.

Experimental and Numerical Study of Blood Flow in μ-vessels: Influence of the Fahraeus–Lindqvist Effect

The study of hemodynamics is particularly important in medicine and biomedical engineering as it is crucial for the design of new implantable devices and for understanding the mechanism of various diseases related to blood flow. In this study, we experimentally identify the cell free layer (CFL) width, which is the result of the Fahraeus–Lindqvist effect, as well as the axial velocity distribution of blood flow in microvessels. The CFL extent was determined using microscopic photography, while the blood velocity was measured by micro-particle image velocimetry (μ-PIV). Based on the experimental results, we formulated a correlation for the prediction of the CFL width in small caliber (D < 300 μm) vessels as a function of a modified Reynolds number (Re∞) and the hematocrit (Hct). This correlation along with the lateral distribution of blood viscosity were used as input to a “two-regions” computational model. The reliability of the code was checked by comparing the experimentally obtained axial velocity profiles with those calculated by the computational fluid dynamics (CFD) simulations. We propose a methodology for calculating the friction loses during blood flow in μ-vessels, where the Fahraeus–Lindqvist effect plays a prominent role, and show that the pressure drop may be overestimated by 80% to 150% if the CFL is neglected.

A unified analysis of nano-to-microscale particle dispersion in tubular blood flow

Transport of solid particles in blood flow exhibits qualitative differences in the transport mechanism when the particle varies from nanoscale to microscale size comparable to the red blood cell (RBC). The effect of microscale particle margination has been investigated by several groups. Also, the transport of nanoscale particles (NPs) in blood has received considerable attention in the past. This study attempts to bridge the gap by quantitatively showing how the transport mechanism varies with particle size from nano-to-microscale. Using a three-dimensional (3D) multiscale method, the dispersion of particles in microscale tubular flows is investigated for various hematocrits, vessel diameters, and particle sizes. NPs exhibit a nonuniform, smoothly dispersed distribution across the tube radius due to severe Brownian motion. The near-wall concentration of NPs can be moderately enhanced by increasing hematocrit and confinement. Moreover, there exists a critical particle size (∼1 μm) that leads to excessive retention of particles in the cell-free region near the wall, i.e., margination. Above this threshold, the margination propensity increases with the particle size. The dominance of RBC-enhanced shear-induced diffusivity (RESID) over Brownian diffusivity (BD) results in 10 times higher radial diffusion rates in the RBC-laden region compared to that in the cell-free layer, correlated with the high margination propensity of microscale particles. This work captures the particle size-dependent transition from Brownian-motion dominant dispersion to margination using a unified 3D multiscale computational approach and highlights the linkage between the radial distribution of RESID and the margination of particles in confined blood flows.

Effects of red blood cell aggregation on the blood flow in a symmetrical stenosed microvessel.

In order to figure out whether red blood cell (RBC) aggregation is beneficial or deleterious for the blood flow through a stenosis, fluid mechanics of a microvascular stenosis was examined through simulating the dynamics of deformable red blood cells suspended in plasma using dissipative particle dynamics. The spatial variation in time-averaged cell-free layer (CFL) thickness and velocity profiles indicated that the blood flow exhibits asymmetry along the flow direction. The RBC accumulation occurs upstream the stenosis, leading to a thinner CFL and reduced flow velocity. Therefore, the emergence of stenosis produces an increased blood flow resistance. In addition, an enhanced Fahraeus-Lindqvist effect was observed in the presence of the stenosis. Finally, the effect of RBC aggregation combined with decreased stenosis on the blood flow was investigated. The findings showed that when the RBC clusters pass through the stenosis with a throat comparable to the RBC core in diameter, the blood flow resistance decreases with increasing intercellular interaction strength. But if the RBC core is larger and even several times than the throat, the blood flow resistance increases largely under strong RBC aggregation, which may contribute to the mechanism of the microthrombus formation.

가상경계기법을 통한 협착된 미세혈관에서 적혈구 분포의 수치 해석

In order to investigate the distribution of red blood cells in a stenosed microvessel, three-dimensional blood flow simulations are conducted using immersed boundary methods. To treat deformable structures like blood cells, a continuous-forcing immersed boundary method is employed. Also, a ghost-cell immersed boundary method is employed to treat rigid and complex structures like a stenosed vessel. In the present study, two immersed boundary methods are integrated into a single computational framework by treating each structure separately. The present framework is validated through the simulation of blood flow in a straight microvessel compared with related previous studies. Present simulations of blood flow in a stenosed microvessel reveal that distribution of RBCs passing the stenosis is changed uniformly and the cell-free layer has significant spatial variation across the stenosis, which might induce the change of wall shear stress and flow resistance.

In vitro blood flow visualizations and cell-free layer (CFL) measurements in a microchannel network

Microvascular networks are not simple straight microchannels but rather complex geometries composed by successive asymmetric divergent and convergent bifurcations. Despite the extensive research work in this field, still lack of knowledge about the blood flow behavior in microvascular networks. The current study applies the most current advanced visualization and microfabrication techniques to provide further insights into to the blood flow in network geometries. Hence, by using a high-speed video microscopy system, blood flow measurements and visualizations of the cell-free layer (CFL) were performed along a microchannel network composed by several divergent and convergent bifurcations. The inlet flow rate was kept constant whereas the hematocrit (Hct) and the depth of the geometry was changed in order to evaluate their effects into the CFL thickness. The results, show clearly that the Hct has a significant impact on the CFL thickness whereas the effect of reducing the depth did not contribute to a noticeable change on the CFL. In addition, the in vitro blood flow results reported here provide for the first time that in microfluidic devices having several asymmetric confluences it is likely to have the formation of several CFLs not only around the walls but also in middle of the main channels just downstream of the last confluence apex. Although, to best of our knowledge there is no evidence that this kind of flow phenomenon also happens in vivo, we believe that for microvascular networks with similar geometries and under similar flow conditions tested in this work, this kind of phenomenon may also happen in vivo. Furthermore, the results from this study could be extremely helpful to validate current numerical microvascular network models and to develop more realistic multiphase numerical models of blood flow in microcirculation.

Computational analysis of nitric oxide biotransport in a microvessel influenced by red blood cells

It is pivotal that endothelium-dependent Nitric Oxide (NO) consumed by hemoglobin (Hb) inside red blood cells (RBCs) membrane, regulates the vascular tone. The whole processes of NO transport in vessel containing flowing RBCs is still not clear, such as NO production in endothelium, diffusion in plasma and consumption inside RBCs. In this work, the motion of RBCs in a microvessel is investigated by using immersed boundary lattice Boltzmann method (IB-LBM) first and the deformability of RBCs is expressed by using spring network model which is based on the minimum energy principle. Furthermore, the interaction between RBCs is considered. Based on the wall shear stress (WSS), NO production rate originated from endothelium was obtained by using a hyperbolic model. NO distribution inside the microvessel with multiple RBCs was computed by using immersed boundary finite difference method (IB-FDM). The result shows that a large (small) WSS exists at locations with a relatively wide(narrow) gap between the wall and cell. In terms of mass transfer, an increase of RBC membrane permeability leads to a decrease of NO concentration in the vessel and the surrounding endothelium significantly. In addition, with the increasing of hematocrit (Hct) value, NO concentration distribution in the whole vessel decreases both in the lumen and vascular wall. Finally, the thickness of RBCs-depleted layer gradually decreases with the weakened deformability of RBCs membrane, and the change degree of cell free layer (CFL) thickness decreases as the bending stiffness is relatively higher. Thus, when bending stiffness is higher, the NO concentration in vascular wall is reduced resulting from the thinner CFL.

Reduced weld strength due to secondary cell formation in vibration weld region of microcellular glass fiber reinforced nylon-6 shells

Microcellular plastic parts reduce weight and increase dimensional stability, but a significant decrease in weld strength is observed when the weld region reaches the cell area. In this study, 30 wt.% glass fiber reinforced nylon-6 shells with weight reductions of 0%, 7%, and 10% were fabricated by microcellular injection molding with nitrogen gas followed by vibration welding. Although the weld depth of the vibration weld was much less than the thickness of the cell-free surface layer, microstructural analysis of fracture surfaces by scanning electron microscopy and optical microscopy confirmed the presence of cells at the weld region that lowered burst pressures by 17% and 22% for shells with weight reductions of 7% and 10%, respectively, when compared with the burst pressure of 1.16 MPa for solid shells. The irregular sizes and elongated shapes of these cells suggest that they were generated in the molten polymer by secondary nucleation of residual nitrogen gas during the vibration welding process. This assumption is corroborated by the fact that no cells are formed in the weld area of solid shells with 0% weight reduction and is consistent with recently reported similar findings for glass fiber reinforced polypropylene.

High‐fidelity Modeling of Blood Flow in Physiologically Realistic Microvascular Networks

High-fidelity in silico modeling of blood flow in microvascular networks continues to be a challenge. Blood in small vessels behaves as a concentrated suspension of red blood cells (RBC), which are extremely deformable. Computational modeling must resolve the dynamics and deformation of individual RBC while simultaneously extending to a dense suspension. Most cellular-scale in silico models to date have considered blood flow in simple geometries, such as straight tubes or channels, which do not represent physiological conditions, since the architecture of vascular networks in vivo is characterized by bifurcating, merging, and winding vessels. Such geometrical differences result in significant deviations in hemodynamics between that achieved in a straight conduit versus a vascular network. We have recently developed a high-fidelity, multiscale, 3D computational model of flow of deformable RBCs in complex microvascular networks resembling in vivo-like architectures. The vascular networks are designed following in vivo images and data, and are comprised of bifurcating, merging, and tortuous vessels. Our model accurately resolves the large deformation and dynamics of each individual RBC, while simultaneously retaining complex geometric details of the vascular architecture. The model is versatile, and can consider networks irrespective of topological/geometrical complexities. Flow can be driven by either pressure or flow boundary conditions of physiological values. Cell distributions naturally develop in the networks from an initial random distribution, eventually resulting in a heterogeneous cell distribution as observed in vivo. Extreme deformation and a wide range of RBC shapes are observed that are in agreement with in vivo observations. Quantitative comparisons were made with in vivo data using hemodynamic quantities such as flow resistance, wall shear stress, cell-free layer, etc., and good agreement was observed. The model can also consider white blood cells and platelets, and receptor-mediated adhesion between vascular wall and cells. The model provides a full 3D quantification of hemodynamic quantities with unprecedented details that are not available in experimental measurements. For example, the model allows full 3D characterizations of the near-wall cell-free layer (CFL) and wall shear stress (WSS) and gradients (WSSG). It predicts that CFL becomes more asymmetric along vessel lengths with increasing vessel tortuosity. While WSS itself decreases from arterial to venous sides, the model predicts that WSS in presence of RBCs increases more than that without RBCs on the venous sides and at capillary bifurcations. This implies that the effect of RBCs on WSS is more enhanced at specific locations in a microvascular network. WSSG is also predicted to be much higher in presence of the RBCs, and increase at capillary bifurcations. The model is used further to study transport and deposition of nanoparticle drug carriers in the microvasculature. Results show that nanoparticle accumulation is highly nonuniform across the vasculature with the highest accumulation occurring in bifurcations and the lowest in venules. Support or Funding Information Supported by the National Science Foundation In silico model of flow of blood cells in a microvascular network. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Migration velocity of red blood cells in microchannels

The lateral migration of red blood cells (RBCs) in confined channel flows is an important ingredient of microcirculatory hydrodynamics and is involved in the development of a cell free layer near vessel walls and influences the distribution of RBCs in networks. It is also relevant to a number of lab-on-chip applications. This migration is a consequence of their deformability and is due to the combined effects of hydrodynamic wall repulsion and the curvature of the fluid velocity profile. We performed microfluidic experiments with dilute suspensions of RBCs in which the trajectories and migration away from the channel wall are analyzed to extract the mean behavior, from which we propose a generic scaling law for the transverse migration velocity valid in a whole range of parameters relevant to microcirculatory and practical situations. Experiments with RBCs of different mechanical properties (separated by density gradient sedimentation or fixed with glutaraldehyde) show the influence of this parameter which can induce significant dispersion of the trajectories.

Red blood cell and platelet diffusivity and margination in the presence of cross-stream gradients in blood flows

The radial distribution of cells in blood flow inside vessels is highly non-homogeneous. This leads to numerous important properties of blood, yet the mechanisms shaping these distributions are not fully understood. The motion of cells is governed by a variety of hydrodynamic interactions and cell-deformation mechanics. Properties, such as the effective cell diffusivity, are therefore difficult to investigate in flows other than pure shear flows. In this work, several single-cell, cell-pair, and large-scale many-cell simulations are performed using a validated numerical model. Apart from the single-cell mechanical validations, the arising flow profile, cell free layer widths, and cell drift velocities are compared to previous experimental findings. The motion of the cells at various radial positions and under different flow conditions is extracted, and evaluated through a statistical approach. An extended diffusive flux-type model is introduced which describes the cell diffusivities under a wide range of flow conditions and incorporates the effects of cell deformability through a shear dependent description of the cell collision cross sections. This model is applicable for both red blood cells and platelets. Further evaluation of particle trajectories shows that the margination of platelets cannot be the net result of gradients in diffusivity. However, the margination mechanism is strongly linked to the gradient of the hematocrit level. Finally, it shows that platelets marginate only until the edge of the red blood cell distribution and they do not fill the cell free layer.