Why and how does collective red blood cells motion occur in the blood

microcirculation?
Giovanni Ghigliotti, Hassib Selmi, Lassaad El Asmi, and Chaouqi Misbah
Citation: Phys. Fluids 24, 101901 (2012); doi: 10.1063/1.4757394
View online: http://dx.doi.org/10.1063/1.4757394
View Table of Contents: http://pof.aip.org/resource/1/PHFLE6/v24/i10
Published by the American Institute of Physics.

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PHYSICS OF FLUIDS 24, 101901 (2012)

Why and how does collective red blood cells motion occur
in the blood microcirculation?
Giovanni Ghigliotti,1,a) Hassib Selmi,2 Lassaad El Asmi,2
and Chaouqi Misbah3
1

Department of Mathematics, University of British Columbia, 1984 Mathematics Road,

Vancouver, B.C. V6T 1Z2, Canada
2
Laboratoire dIngenierie Mathematique, Ecole Polytechnique de Tunisie, Universite de
Carthage, B.P. 743 - 2078 La Marsa, Tunisia
3
Universite Joseph Fourier and CNRS (UMR5588), Laboratoire Interdisciplinaire de
Physique, 140 Avenue de la Physique, 38402 Saint Martin dH`eres, France
(Received 4 May 2012; accepted 17 September 2012; published online 8 October 2012)

The behaviour of red blood cells (RBCs), modelled as vesicles, in Poiseuille flow,
mimicking the microvasculature, is studied with numerical simulations in two dimensions. RBCs moving in the centre of the Poiseuille flow (as in blood capillaries)
are shown to attract each other and form clusters only due to hydrodynamic interactions, provided that their distance at a given time is below a certain critical value.
This distance depends on physical parameters, such as the flow strength. Our simulations reveal that clusters are unstable above a threshold value in the number of
forming RBCs, beyond which one or few cells escape the pack by a self-regulating
mechanism that select the marginally stable size. This size selection depends on the
flow strength as well as on the RBC swelling ratio. The results are interpreted via
the analysis of the perturbation of the flow field induced by the vesicles and the
interplay with bending and tension forces. This sheds a novel light on the process of
C 2012 American Institute of Physics.
collective motion of RBCs observed in vivo. 
[http://dx.doi.org/10.1063/1.4757394]

I. INTRODUCTION

Red blood cells (RBCs) are deformable cells in charge of gas exchange in the human body.
Gas exchange takes place in the arterioles and capillaries, where RBCs are submitted to a Poiseuille
(parabolic) flow profile.1 How do RBCs organize themselves in the microvasculature may impact
flow efficiency and oxygen transport.
RBC spatial organization is thus of great relevance to biology and medicine, and several attempts
have been made in the past to model the dynamics of an ensemble of RBCs in a capillary. Early
attempts have been focusing on a sequence of rigid spheres.2, 3 It turns out that RBC deformability
plays a fundamental role in the collective behaviour: contrary to sets of rigid spheres,3 RBCs in
capillaries have the tendency to aggregate to form clusters.4 Clusters, in which RBCs are close one
to another in a single-file configuration shall not be confused with rouleaux, a term indicating a stack
of RBCs adhering one to the other. Rouleaux occur in presence of fibrinogen, the most accepted
mechanism being the depletion forces generated in presence of high molecular weight proteins (as
fibrinogen).5, 6 Clusters are due to hydrodynamical interactions between RBCs, since the distances
between neighbouring cells are too large to be explained by depletion forces (or even by chemical
bonds between membranes).
In order to take into account their deformability, RBCs have been in recent years extensively
modelled as vesicles711 (liquid drops delimited by a lipid bilayer, that is the main constituent of the
membrane of living cells) or elastic capsules.1215 In the following, we will adopt the former model.
a) Author to whom correspondence should be addressed. Electronic mail: gghiglio@math.ubc.ca. Tel.: +1 604 827 3296.

Fax: +1 604 822 6074.

1070-6631/2012/24(10)/101901/11/$30.00

24, 101901-1


C 2012 American Institute of Physics

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Under parabolic flow, a single vesicle assumes a stationary centered shape,16 which may enjoy
the mirror symmetry with respect to the centre line, in which case it is called a parachute. If the
mirror symmetry is absent, the shape is non-symmetric and is called slipper. Whether the vesicle
assumes one shape or another depends on its swelling (i.e., the volume to surface ratio) and on the
flow intensity.
The collective motion of one-dimensional files of RBCs in capillaries has been first studied
numerically under the hypotheses of axisymmetric cell shape and periodic spatial distribution.17
This approach, based on the simulation of a single cell in a periodic domain, allowed to estimate the
influence of the RBC volume concentration (haematocrit) on the cell shape and flow rate.
Even in the simple case in which RBCs assume a symmetric position centred in the flow, a set
of RBCs shows a non-homogeneous spatial organization,4 i.e., RBCs form clusters (clearly, nonuniform spatial organization is out of reach of the one-cell approach17 ). While this non-homogeneity
was previously considered to be due to the polydispersity in size of the RBCs (larger ones are
advected more slowly by the flow, and thus are caught up by the following ones),4 very recently
cluster formation has been numerically observed in the case of vesicles monodisperse in size18, 19
and also experimentally observed for RBCs in vitro.20 Since the only forces implemented in the
simulations were hydrodynamical forces, these must be responsible for clustering. Those authors
studied three systems, consisting of one, three, and six vesicles. They could observe the formation
of clusters, and identified the cause in the coupling between cell deformability and hydrodynamical
interactions.
Nevertheless, a precise link between hydrodynamical interactions and cluster formation/destruction has not been established yet. Furthermore, previous simulations used periodic
boundary conditions along the flow direction. So the finite size effect may interfere with the intrinsic mechanism of the cluster formation, as hydrodynamics is of long range and it is not clear
how the appropriate cut-off has to be chosen.
In this work, we use the boundary integral method (BIM), which, besides its high precision,
allows one to study infinite systems, avoiding any possible artifact related to non-physical boundaries.
The nonlocal character of the BIM method sets, however, a severe limitation on the computational
time as well as on the storage memory, both behave as O(N2 )where N is the total number of
discretization points of the full boundaries. To circumvent this problem, we make use of a fast
multipole method (FMM) that lowers the complexity down to O(N). Thus, our method is a coupled
BIM-FMM one that will allow us investigating large clusters.
Several basic and natural yet unanswered questions arise: when does a cluster form, i.e., what
is the initial interdistance that leads to a cluster? Does each cluster maintain its size, or do some
clusters loose their integrity in the course of time? If so, what are the physical mechanisms that
govern this evolution? How does a maximum stable size (if any) depend on flow conditions and
other parameters? The use of extensive numerical BIM-FMM simulations allows one to gain an
important step toward answering this set of questions.
In order to gain progressive insight into this complex question, we shall first study the case
where the set of vesicles are not confined at all. This will serve as basic problem, which is already
complex by itself. In addition, we shall show that the cluster formation is an intrinsic property, not
triggered by any confinement. We shall then briefly discuss how some of the reported phenomena
are affected by lateral boundaries (i.e., confinement), mimicking blood vessel walls.
II. THE MODEL

We consider the simplified problem of clusters of RBCs in an unbounded Poiseuille flow in two
dimensions. A two-dimensional model has been favoured over a three-dimensional axisymmetric
one, which would have a comparable numerical cost, due to the possible axial-symmetry breaking
by the cells in a parabolic flow.16, 21 In this way axial symmetry is not imposed, so that whenever
axisymmetric solutions are observed, they are stable solutions. The Reynolds number Re is, in the
physiological conditions and in the available experiments (except in arterioles or in some site of
sudden aneurysm where it can become of order unity,22 strongly impacting dynamics), of the order
of 103 Re 102 , so that inertia is negligible compared to viscous forces. This allows us to

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use the Stokes equation to describe the hydrodynamics. For simplicity, we consider the situation in
which the viscosity of the fluid inside the RBCs is equal to that of the outer fluid (this point is
further addressed at the end of this section). The velocity field obeys the Stokes equations:
p + u = 0,

(1)

u = 0.

(2)

In two dimensions there is, from the mechanical point of view, no distinction between RBCs and
vesicles, due to the fact that membrane plane shear elasticity (present
in RBCs) looses it meaning.
We take the radius R of the equivalent circle as a length unit: R = A/ , where A is the surface of
the vesicle. The vesicle membrane is subject to the constraint of local inextensibility and is endowed
with bending energy. The membrane free energy can be expressed as



(s) + [c(s)]2 ds,
(3)
E =

where is the membrane position, is a local Lagrange multiplier associated with the constraint
of inextensibility, is the bending modulus, c is the membrane curvature, and ds is the perimeter
element. The variation of the free energy of Eq. (3) gives the force f by which the membrane acts on
the surrounding fluids:

 2
d
d c 1 3
t,
(4)
+ c n + cn +
f =
2
ds
2
ds
where n and t are the outward normal and clockwise tangent vector, respectively.
We consider vesicles in an unbounded Poiseuille (parabolic) flow, defined as
b 2
y ex .
(5)
2
The local shear rate is (y) = du x /dy = by, where b is the curvature of the flow profile. In the
following, we will use the value of (y = R) = b R for the scale of flow strength.
As seen below in the mathematical integral formulation, one can handle exactly a completely
unbounded geometry. It must be, however, kept in mind that in practice the unbounded flow is taken
to mean weakly confined flow (the channel width is large enough in comparison to the cell size).
We shall come back to this point in the section devoted to discussion.
The problem is described in terms of three dimensionless parameters:
r The number N of vesicles composing a cluster.
r The reduced area of the vesicles, defined as the ratio between the surface A of the vesicle
u=

and the surface of a circle having the same perimeter p (i.e., = A/[ (p/2 )2 ]); , chosen to
be the same for all the vesicles in a given simulation, assumes the values [0.65, 0.70, 0.75];
it represents the swelling of the vesicles.
r The capillary number Ca that defines the relative strength of the imposed flow and the bending
forces, Ca = R 3 /. The values explored are Ca [5.0, 10.0].

It is known that by decreasing either or Ca a single vesicle in a Poiseuille flow shows a transition
from a symmetric shape (parachute-like, with the centre of mass on the Poiseuille centreline) to a
non-symmetric one (slipper-like, with the centre of mass out of the centreline).16 In order to avoid
mixing several effects at once, for ease of a sound understanding of phenomena, the values of
and Ca are chosen so that a single vesicle is stable on the Poiseuille centreline with a parachute-like
shape.
We consider sets of vesicles aligned along the Poiseuille centreline, with varying numbers of
cells. These quasi one-dimensional configurations are found to be stable, i.e., all the vesicles stay on
the centreline, in the explored range of and Ca .
Vesicles are initialized as ellipses elongated in the direction of the velocity gradient and with the
centre of mass on the centreline. One might ask why the vesicles are initialized in such an artificial
shape instead of the more natural choice of the equilibrium shape of a single vesicle in a parabolic

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Phys. Fluids 24, 101901 (2012)

flow (parachute shape). Indeed it turns out that the elliptical initial shapes allow for a faster drainage
of the fluid between two vesicles, thus reducing the relaxation time toward the equilibrium parachute
shapes (note that these shapes differ from the single vesicle one due to hydrodynamical interactions).
In this sense, this initial condition facilitates the cluster formation and minimizes the possibility that
a cluster does not form due to the choice of the initial configuration.
In most of simulations the initial distance between the centers of consecutive vesicles is chosen
to be equal to 1.6R, corresponding to a membrane-to-membrane distance of approximately 0.4R.
This distance is on one side small enough to allow a strong interaction between vesicles, and on the
other is big enough to avoid transverse elastic instabilities on the cluster (i.e., the lateral expulsion of
one or several vesicles from the cluster) during the initial transient. Reasonable variations of the value
of the initial distance do not affect the final configurations. We have determined the maximal value of
the interdistance below which a cluster form, and have found that it can significantly exceeds 1.6R,
as discussed in Sec. IV. By virtue of the initial condition (vesicles centered on the flow centreline),
the vesicles are not subject to any major shearing, in particular there is no tank-treading movement of
the membrane at any moment during the whole time evolution of the system. As a consequence, the
viscosity of the inner fluid plays only a very minor role in the first part of the dynamics (relaxation
from ellipse to parachute), and no role at all in the stationary states, in which the inner fluid is
quiescent.

III. THE NUMERICAL METHODS

The simulations are carried out in two dimensions by using the boundary integral method23, 24
with the implementation detailed elsewhere.25 Moreover, we make use of a parallel implementation
of the fast multipole method that sensibly decreases the computing time.26 In this section, we give a
short description of the two methods.
BIM allows to solve Eqs. (1) and (2) by computing integrals on the surfaces delimiting different
fluid domains, so that the evolution of a two-dimensional system can be performed through onedimensional integrals. In the case treated here these surfaces are the membranes of the vesicles. If
the viscosity is uniform throughout the system, the equation for the velocity of a point x0 lying on
the vesicle membrane is


u(x0 ) = u (x0 ) +
G(x x0 )f(x)d S(x),
(6)
N
i=1
i

where u represents the imposed velocity field (in our case, an unbounded parabolic profile) and
the integral represents the perturbation created by the vesicles. Each i is the position of one of the
N vesicles, f is the force exerted by the membrane on the fluids and dS is the membrane arc-length.
G is the free-space Green tensor, given by the expression
G i j (r) = i j ln r +

ri r j
.
r2

(7)

The direct solution of the integral Eq. (6) requires O(N2 ) computations, where N is the number
of discretization points. We make use of FMM to compute an approximate solution with O(N)
computations. FMM is based on a double multipolar expansion with respect to the source points x
and the target points x0 of Eq. (6).26, 27
In fact, the FMM method replaces the classical matrix-vector product by a multipole product,
that allows to obtain, by a fast algorithm, a good approximation of the solution. The basic idea of
the fast mutipole method is the separation of variables in the Green function. This Green function
is rewritten differently in an expression that determines the form of the moments and the transfer
functions, multipolar and local moments are then calculated. The adaptation of the FMM method
to this problem is explained elsewhere.26 Truncation errors of the resulting scheme and comparison
with the classical BIM method are presented in Ref. 27. The implementation of the resulting method
achieves a high accuracy in a reasonable time, and thus allows us to study complex phenomena.

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Phys. Fluids 24, 101901 (2012)

IV. RESULTS

In this section, we present the results obtained through the numerical simulations. We first
describe the behaviour for fixed and Ca , and we vary N. This first case will allow to present the
overall features of the observed dynamics.
A. General behaviour

We first consider the case of sets of vesicles with a reduced area = 0.70 at a capillary number
Ca = 10 (Fig. 1); other values have been explored (see below). This value of Ca is bigger than
the critical capillary number Ca at which the slipper-to-parachute transition occurs (Ca  4 for
= 0.70), so all the vesicles assume a parachute shape. We run simulations by increasing the number
N. For 1 N 10, we observe that the vesicles always attract each other and form a cluster, provided
that the initial interdistance is below a certain value (to be anaylzed below). A cluster is defined
as a set of cells whose interdistances approach finite and constant values after an initial transient.
The clusters are entirely due to hydrodynamical interactions, since hydrodynamics is the only force
implemented in the simulations (in particular no attraction/repulsion potentials are present). During
the dynamical evolution the membranes of neighbouring cells keep at a certain finite distance and
never touch each other. The dynamics of these clusters is nontrivial. First of all, the vesicles distribute
in a non homogeneous way in the clusters, with the distance between consecutive vesicles being
bigger at the front than at the back. Second, although all the vesicles show a parachute shape, the
width in the direction of the velocity gradient of every parachute differs from the others, with the
vesicles in the front being more squeezed in the vertical direction.
For N 11, we observe that the clusters are not stable, and that vesicles detach from the front,
one by one, until the number of vesicles in the cluster goes down to 10. This has been verified for 11
N 15; for example, starting from N = 13 a cluster of 13 vesicles forms, and after some time the
cluster looses its integrity by successively loosing 3 vesicles (one by one) at the front. This happens
via a self-regulating mechanism, and highlights the existence of an intrinsic maximal cluster size
N*, with N* = 10 for Ca = 10.
B. Dependence on and Ca cluster velocity

We have investigated the behavior of the cluster upon variation of two main parameters, and
Ca . The results are qualitatively similar to those presented above, with a critical cluster size above
which clusters are unstable and vesicles detach from the front.
The velocity of clusters as a function of these two parameters is shown in Fig. 2. The cluster
velocity Vcluster is defined as the lag velocity, i.e., the difference between the velocity of the centreline
of the unperturbed parabolic flow and the cluster velocity. The cluster velocity is a decreasing function
of the number of vesicles in the cluster. This is not surprising, since they are passively transported by
the flow: when their number increases, they shield each other and the drag on each vesicle decreases,
thus decreasing the cluster velocity. Moreover, the magnitude of the velocity also increases with
both and Ca . Similarly, an increase in leads to more curved parachutes (more squeezed in the
direction of the velocity gradient), i.e., mass distribution of the vesicleor more precisely the inertia
moment with respect to the center lineis smaller, and hence the vesicle moves faster.
An interesting feature is the behavior of the maximal cluster length (in number of vesicles) as
a function of and Ca (Figure 3). Higher flow strength increases very significantly the maximum
number of vesicles in a cluster. The same holds when decreasing the reduced area (Fig. 2).
C. Cluster (in)stability via self-regulation

A cluster of a given size is found to be stable or not, depending on the flow strength (for a given
reduced area ). Why should a cluster form at all, and what are the physical mechanisms that dictate
their stability or instability? Let us first analyze the flow field perturbation caused by a single vesicle
(Fig. 4). It is clearly seen that the vesicle creates two counter-rotating vortices converging at the

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101901-6

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Phys. Fluids 24, 101901 (2012)

FIG. 1. Cluster steady states for Ca = 10, = 0.70 for different number of vesicles N in an unbounded parabolic flow.

front and diverging at the back. If a second vesicle is introduced at the front, it will be captured
by the converging vortices. This second vesicle (becoming now the leading one) will in turn create
a similar flow pattern at the front which is capable of capturing a new vesicle ahead, and so on.
The combination between the converging and diverging vortices leads to an equilibrium distance
between two successive vesicles. The capture zone ahead of the vesicle is wide enough so that even
if the initial distance is as large as 3.1 radii, the vesicles attract each other (for = 0.70, N = 8, Ca

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Ghigliotti et al.

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-0.7
=0.65 Ca = 5
=0.65 Ca = 7.5
=0.65 Ca = 10
=0.70 Ca=5
=0.70 Ca=7.5
=0.70 Ca=10
=0.75 Ca=5
=0.75 Ca=7.5
=0.75Ca=10

Vcluster / R0

-0.8

-0.9

-1

-1.1

6
N

12

10

FIG. 2. Cluster velocities as a function of N for different and Ca .

= 10). Figure 5 shows the distance between the first and second vesicle in the cluster as a function
of time for different initial distances.
Two natural questions arise: how many vesicles can adhere to a given cluster? If the allowed
maximum number is finite, how and by which mechanism are extra vesicles expelled from the
cluster? A detailed analysis of the velocity field around the vesicles can help answering these
questions. As seen in Fig. 4, the flow pattern is convergent at the front and divergent at the back. This
means that for a cluster of two vesicles, the leading one will be compressed (in the vertical direction
of the figure) by the perturbation created by the trailing one, and the trailing one will be stretched
by the leading one: vesicles act here as hydrodynamic tweezers. A first consequence is that the

12

N*

10

8
= 0.65
= 0.70
= 0.75

10

Ca
FIG. 3. Cluster size as a function of Ca for different .

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Ghigliotti et al.

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Phys. Fluids 24, 101901 (2012)

FIG. 4. Perturbation to the velocity field created by a single vesicle in an unbounded Poiseuille flow ( = 0.70, N = 1, Ca
= 10, stationary state). The presence of attraction and repulsion zones (in front of the vesicle and on its back, respectively)
is evident.

10
d0 = 1.6
d0 = 2.7
d0 = 3.1
d0 = 3.2
d0 = 3.3

9
8

d / R0

7
6
5
4
3
2
1

10

20

30
Time (a.u.)

40

50

60

FIG. 5. Distance between the first and the second vesicles as a function of time ( = 0.70, N = 8, Ca = 10).

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101901-9

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Phys. Fluids 24, 101901 (2012)

(a)

ves 1
ves 2
ves 3

FIG. 6. (a) Perturbations to the velocity field created by every of the three vesicles composing a cluster (N = 3). The vesicle
contours and perturbations are translated in such a way to superimpose the centers of mass of the vesicles. Vesicles are
numbered starting from the front (left) of the cluster. (b) Schematic view showing that the leading (resp. trailing) vesicle is
compressed (resp. stretched) by the trailing (resp. leading) one.

two vesicles do not form a twin due to their shape difference. In Fig. 6, we have superimposed
the perturbations produced by each vesicle in a cluster made up of N = 3 vesicles; in other words,
we represent the perturbation by one vesicle as if the two others were absent (this can easily be
accomplished in a BIM formulation simply by considering in Eq. (6) only the integration over a
single vesicle). The perturbation streamlines are more elongated in the direction of the imposed flow
while moving toward the front of the cluster. The equilibrium distance of two vesicles (named here
a and b) is achieved when the force (linked to the velocity field perturbation) of a on b is equal to
that of b on a. This equality is fulfilled for a bigger inter-distance if the streamlines of either a or b
are more elongated in the flow direction. This explains, qualitatively, why the vesicles on the front
of the cluster are more spaced than the vesicles at the back.

FIG. 7. Velocity field in the frame moving with the vesicles ( = 0.70, N = 10, Ca = 10), zoom on the first two. The two
vortices merge on the centreline for N = N*.

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Ghigliotti et al.

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3.4
3.2

d / R0

3
2.8
=0.65 Ca=5
=0.65 Ca=7.5
=0.65 Ca=10
=0.70 Ca=5
=0.70 Ca=7.5
=0.70 Ca=10
=0.75 Ca=5
=0.75 Ca=7.5
=0.75 Ca=10

2.6
2.4
2.2
2

10

12

N*
FIG. 8. Distance d/R0 between the first and the second vesicles as a function of the number N* of vesicles in a cluster for
different and Ca . The two horizontal lines emphasize that d/R0 is relatively constant for different N*.

This observation also allows us to unveil the detachment mechanism. Since the velocity of
the fluid between two consecutive vesicles is smaller than that of the surrounding fluid (due to the
nonzero shear rate of the imposed flow), vortices due to viscous drag will take place between a
vesicle and its neighbors (Figure 7). The size of the vortices is given, typically, by the interdistance
between two vesicles. Since the leading vesicle is squeezed (in the vertical direction), its natural
tendency is to move further ahead in order to relax the stresses imposed by the following ones, but
still, it remains within the cluster as long as it stays within the capture zone. The larger vortices are
those lying between the first and the second vesicle, owing to the larger distance. As the number
of the vesicle increases, the additive effects of the trailing vesicles makes the leading one slightly
escaping ahead, to release further squeezing.
There is a critical distance at which the two vortices merge (Fig. 7), causing a net flow between
the first vesicle and the rest of the cluster. This net flow triggers the detachment of the leading vesicle
from the cluster. The merging of the vortices happens for a critical size N = N*. The detachment
of the first vesicle is then completely determined by the space separating it from the second. This
is why the distance d/R0 between the first and second vesicle for N = N* is more or less constant
(2.85 d/R0 3.2) when varying N* (upon variation of the control parameters Ca and ), as can be
appreciated in Figure 8. Small fluctuations of d/R0 for N = N* are understandable due to the discrete
character of N.
We have investigated the role played by bounding walls. If w denotes the channel width, Cn
= R/w measures the degree of confinement. We have found that for Cn 0.05 (weak confinement)
the same qualitative and quantitative results are recovered. Preliminary results show that as the
confinement increases the same type of flow pattern is observed, but the presence of the walls makes
the range of interaction smaller (due to the cut-off length D that reduces the range of the vortices
ahead of the leading vesicle). As a first consequence the interdistances within the cluster become
larger, and thus the extent of the cluster is wider, as compared to the unconfined one. A quantitative
study, including convergence tests, is time consuming. We hope to investigate this matter further in
the future.
V. CONCLUSION

The main result of this paper is to show the mechanism of formationand destructionof
clusters of red blood cells, modelled as vesicles. The effect is purely hydrodynamical, and has been

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101901-11

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Phys. Fluids 24, 101901 (2012)

explained by the analysis of the perturbation of the velocity field done by the deformable RBCs. In
particular, the ample effect due to deformability has been put forward. A criterion for cluster breakup
based on the size of the recirculations between the first and the following RBCs has been suggested.
1 S.

Guido and G. Tomaiuolo, Microconfined flow behavior of red blood cells in vitro, C. R. Phys. 10, 751763 (2009).
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