Cell manipulation with magnetic particles toward microfluidic cytometry

Chengxun Liu, Tim Stakenborg, Sara Peeters, and Liesbet Lagae

Citation: Journal of Applied Physics 105, 102014 (2009); doi: 10.1063/1.3116091

View online: http://dx.doi.org/10.1063/1.3116091
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 JOURNAL OF APPLIED PHYSICS 105, 102014 共2009兲

Cell manipulation with magnetic particles toward microfluidic cytometry

Chengxun Liu,1,2,a兲 Tim Stakenborg,1 Sara Peeters,1 and Liesbet Lagae1
1
Interuniversity Microelectronics Center (IMEC), Kapeldreef 75, Leuven 3001, Belgium
2
Department of Electrical Engineering (ESAT), Katholieke Universiteit Leuven, Kasteelpark Arenberg 10,
Leuven 3000, Belgium
共Received 5 April 2008; accepted 15 October 2008; published online 19 May 2009兲
Magnetic particles have become a promising tool for nearly all major lab-on-a-chip 共LOC兲
applications, from sample capturing, purification, enrichment, transport to detection. For biological
applications, the use of magnetic particles is especially well established for immunomagnetic
separation. There is a great amount of interest in the automation of cell sorting and counting with
magnetic particles in LOC platforms. So far, despite great efforts, only few fully functional LOC
devices have been described and further integration is necessary. In this review, we will describe the
physics of magnetic cell sorting and counting in LOC formats with a special focus on recent
progress in the field. © 2009 American Institute of Physics. 关DOI: 10.1063/1.3116091兴

I. INTRODUCTION crometer sized MPs generally have a uniform size, shape,

and magnetic content. However, they suffer from a relatively
Ever since the invention of flow cytometry in the mid-
low magnetic content 共⬍60%兲 and a small surface area for
20th century,1 the demand for efficient techniques to divide,
cell capture compared to smaller MPs 共Table I兲. For nano-
count, or even sort different cell subpopulations has been
meter sized MPs, the magnetic content is much higher 共
steadily increasing. This growing need, together with the re-
⬎70%兲 and the surface/volume ratio is larger, but the disper-
cent advances in micro- and nanotechnology, has resulted in
sity is normally worse than micro-MPs.
a certain transfer of these technologies toward small-scaled,
The magnetic properties of MPs are clearly the enabling
portable biochips, also known as lab-on-a-chip 共LOC兲 or mi-
features which make MPs suitable for cell manipulations.
crototal analysis systems. Some of such cell sorting ap-
Among these properties, superparamagnetism and the mag-
proaches described are based on different intrinsic physical
netic susceptibility are of the utmost importance for mag-
properties between cells. These include cell isolations by mi-
netic cell separations.
crofluidic sieving,2,3 size-dependent hydrodynamic
filtration, paramagnetic5 and dielectrophoretic6,7 separa-
4

tions. Most methodologies, however, are affinity based. Typi- 1. Superparamagnetism

cally, specific antibodies that are fluorescently labeled 共i.e.,
immunofluorescent兲 or linked to magnetic beads 共immuno-
magnetic兲 are used. The use of magnetic beads has some
important advantages. Immunomagnetic separation is gener-
ally fast and easy to perform. It enables the isolation of an
even lower number of cells and can be attained to almost any
sample matrix. As the motivation of this review, immuno-
magnetic separation is suitable for LOC platforms with a
high degree of automation and integration.8
II. MAGNETIC PARTICLES
In this section the underlying physics and biofunctional-
ization of magnetic particles 共MPs兲 relating to immunomag-
netic cell manipulations are briefly summarized.
A. The physical properties of MPs
For different applications, MPs vary in size ranging from
ferromagnetic, nanometer sized crystallites to MPs of a few
micrometer consisting of a large number of small nanopar-
ticles embedded in a polymer matrix. Most water soluble
commercial particles adopt iron oxide as the material for the
magnetic content because of the ease of manufacture. Mi-
a兲
Electronic mail: chengxun.liu@imec.be.
Superparamagnetism refers to the random magnetization
of magnetic crystallites in the absence of an external field.
Because the magnetic crystallites in MPs are already smaller
than the superparamagnetic size limit 共i.e., ⬃20 nm for iron
oxide兲, the magnetic crystalline anisotropy energy is ex-
ceeded by the thermal energy at room temperature.9 As a
result, these tiny magnetic crystallites exhibit a random mag-
netization unless they are subjected to an external magnetic
field because their magnetizations are thermally fluctuated.
Thus, the net ensemble magnetization of the MP is zero.
Superparamagnetism is a very important characteristic as the
magnetization of MPs can be virtually turned on or off by
external magnetic fields without hysteresis. A zero rema-
nence is desirable for cell capturing because otherwise MPs
will strongly interact with each other to form aggregations
and the cell capture capability is impaired during the cell-MP
mixing. Such nonideal superparamagnetism was found in
some commercial MPs and considered to significantly influ-
ence MP manipulations at weak magnetic fields.10
2. Magnetic susceptibility ␹
The magnetic susceptibility indicates the extent to which
an object can be magnetized. For micro- and nano-MPs, the
magnetic susceptibility can be described by the Langevin
function by taking into account both the external-field in-

0021-8979/2009/105共10兲/102014/11/$25.00 105, 102014-1 © 2009 American Institute of Physics

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 102014-2 Liu et al. J. Appl. Phys. 105, 102014 共2009兲

TABLE I. Comparison of seven types of commercial MPs. All MPs were coated with streptavidin molecules, often used for indirect bindings 共Sec. II B兲. The
magnetization is saturated at 0.8 T. The diameters were obtained from official datasheets. The mass contents and magnetic content percentages were measured
by thermal gravimetric analysis 共Q5000 IR™, TA Instruments, New Castle, DE兲. The mass magnetizations at different fields were measured by alternating
gradient force magnetometry 共Micromag™ 2900, Princeton Measurements Corp., Princeton, NJ兲.

Diameter Mass content Magnetic Mass magnetization at 0.001 T Mass magnetization at 0.8 T
Manufacturer and product name 共␮m兲 共mg/ml兲 content percentage 共A m2 / kg兲 共A m2 / kg兲

Ademtech Bio-Adembeads™ 0.51 15.26 72.5% 1.12 22.9

Seradyn Sera-Mag™ 0.783 17 43.3% 2.64 28.5
Bangs Laboratories ProActive® 0.86 12 57.5% 1.68 33.3
Indicia 1.05 8.5 62% 3.88 52.9
Invitrogen Dynabeads® MyOne™ C1 1.05 18 N/A 1.51 17.9
Invitrogen Dynabeads® MyOne™ T1 1 9.89 37.9% 1.79 22.2
Micromod
Micromer®-M 2 53.68 8.9% 1.08 12.1

duced magnetization and the thermal fluctuation.9,11,12 The
magnetic susceptibility is the intrinsic parameter which de-
termines the magnetic moment, and hence the magnetic
force, exerted to a MP by an external field. MPs have lower
magnetic susceptibilities than bulk materials. The low mag-
netic susceptibility can be attributed to the fact that the mag-
netic crystallites take only a portion of the MP content and
that the superparamagnetic crystallites are more difficult to
align to external fields.
The magnetic susceptibilities of some common commer-
cial MPs are summarized in the literature.13,14 Two additional
points with regard to the magnetic susceptibility must be
kept in mind for the manipulation or detection of MPs or
cell-MP complexes with microdevices. First, the magnetic
susceptibility of individual MPs may vary by an order of
magnitude.15 Second, the magnetic susceptibility of MPs is
never a constant according to the definition. The susceptibil-
ity is maximal at a very weak field and is much smaller for
saturated magnetization. Therefore, different magnetic sus-
ceptibility values have to be adopted for magnetic fields of
different strength. This is an important consideration particu-
larly for the simulation of MP behaviors in a micromagnetic
field where a constant susceptibility value may lead to a sig-
nificant error.10
The binding of the antibodies to antigens is by means of
weak, noncovalent Liftshitz–van der Waals, electrostatic and
polar interactions.21 As this interaction is often weak and
never fully specific, the selection of a perfect antigen or
biomarker is hard to attain. Moreover, cell populations are
heterogeneous in nature and the number of biomarkers or
competing binding sites may depend on the sample itself, the
storage conditions, or the expression level of the
biomarker.22 Therefore, instead of only one marker, a set of
biomarkers is often used. The use of multiple antibodies dur-
ing immunomagnetic separation may increase the sensitivity
or recovery rate23 but will at the same time lower the speci-
ficity.
C. Particle selection for cell manipulations
For specific cell manipulations, a suitable type of MPs
needs to be selected. Such selection is seldom straightfor-

B. The binding of MPs to cells

Nonmagnetic cells can only acquire magnetic activity
when they are attached by magnetic labels 共Fig. 1兲 to form
cell-MP complexes. Although different ligands 共lectins,16,17
aptamers,18 receptors,19 etc.兲 have been described, specific
antibodies are typically used for magnetic cell capture ex-
periments. Specific antibodies of interest can be coupled di-
rectly to the MPs for their use in direct assays, but other
Non-specific cell receptor
strategies have been described as well. In indirect assays,
Specific cell receptor
specific antibodies are first added to the sample. Only in a
Biotinylated antibody
second step, these antibodies are captured by secondary an-
tibodies immobilized on the beads. Indirect assays are gen- Streptavidin coated magnetic nanoparticle
erally more time consuming. They also need higher levels of
antibodies and may have limited recovery rates if unbound FIG. 1. 共Color online兲 Overview of a typical cell-MP interaction. As sche-
antibodies cannot be washed away. Nevertheless, they may matically shown, antibodies can be immobilized on the MP surface by
streptavidin-biotin interactions. 共For the clarity reason only one biotin mol-
be preferred over direct assays because of less steric hin-
ecule is conjugated to the antibody in the illustration.兲 As the antibodies
drance, when targeting multiple antigens or when less biom- specifically recognize a marker on the cell membrane, the MP is able to bind
arkers are present.20 the cell.
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 102014-3 Liu et al.
ward because different parameters of both the MP and cell
need to be taken into account 共e.g., cell type, concentration,
matrix characteristics, and characteristics of the magnetic
field兲.
In the physical aspect, the particle size is the parameter
to be determined in the first place. Large MPs may generate
stronger magnetic forces, allowing for a faster manipulation
共see Sec. III C兲. The large stray fields of big MPs also result
in a higher detection signal for magnetic sensors 共see Sec.
IV A兲. On the other hand, the sedimentation rate is also high.
Moreover, the large size permits only a few particles bound
to every cell, which may degrade the cell capture efficiency.
In other words, the determination of particle size is a trade-
off between the cell capture efficiency and the manipulation
efficiency.
The particle surface chemistry should also be carefully
considered.20,24,25 The surface of the particles not only deter-
mines the possible strategies to couple antibodies26 but also
greatly influences the grade of nonspecific binding. As a re-
sult, hydrophobic particles, whether or not in combination
with a blocking reagent,27–29 are generally preferred over
more hydrophilic particles during cell separation experi-
ments. The surface functionalization and charging also
strongly affects the force interactions among cells, MPs, and
the device surface.30
To give an example, seven commercial MPs with
streptavidin coatings were compared in Table I.
III. CELL MANIPULATION USING MPS
Once the target cells are specifically bound with MPs,
cell manipulations virtually become the handling of MPs by
the magnetic force in a carefully designed micromagnetic
field. On the scale of a cell size, the behavior of the cell-MP
complexes is still governed by the theory of classical me-
chanics, i.e., Newton’s second law. In this chapter the phys-
ics relating to the manipulations of cell-MP complexes in
microfluidics is discussed, followed by some state-of-the-art
examples.
A. A force study for MP actuation in microfluidics
Although the magnetic force is the dominant force for
magnetic cell manipulations, other force effects also take im-
portant roles for a successful manipulation in microfluidic
environments. The movement of the cell-MP complex is de-
termined by all the forces, both in and perpendicular to the
device plane.
Magnetic force. The physical origin of the magnetic
force is the Lorenz force describing the force exerted to an
electrical current in a magnetic field. The magnetic force for
a superparamagnetic MP in a magnetic field can be simpli-
fied to Eq. 共1兲, where m is the magnetic moment and B the
applied magnetic induction. Here a MP is simply regarded as
a magnetic dipole when it is magnetized by the applied mag-
netic field. If the MP is small in comparison with the mag-
netic field, in other words, if the magnetic field is only mildly
nonuniform, Eq. 共1兲 can be further simplified to Eq. 共2兲,
where ⌬␹ is the difference of volume magnetic susceptibility
between the MP and the medium, Vm is the volume of the
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J. Appl. Phys. 105, 102014 共2009兲
MP, and ␮0 is the magnetic permeability of vacuum.
Fmag = ⵜ共m · B兲, 共1兲
⌬␹Vm
Fmag = 共B · ⵜB兲. 共2兲
␮0
According to Eq. 共2兲, the force is dependent on the mag-
netic susceptibility of the MP. As the magnetic susceptibility
of MPs is always positive, the MP is magnetized in the di-
rection of the applied field B and hence moves toward the
field maximum. Meanwhile, the magnetic field does not have
any force effect on the objects nearby, e.g., biomolecules or
cells not conjugated by MPs, because these objects are usu-
ally diamagnetic. In this sense, the magnetic actuation is a
very specific technique compared with other manipulation
principles such as dielectrophoresis, electro-osmosis, cen-
trifugation, or optical tweezers.
Also according Eq. 共2兲, the magnetic force is determined
by both the magnetic field 共induction兲 strength and the field
gradient. Therefore, the magnetic force can be generally in-
creased either by a stronger magnetic field or a higher field
gradient. It should be noted that this statement is only valid
when the particle magnetization is unsaturated. In saturation
the magnetic moment m remains a constant independent of
the increase of field B. To obtain a strong magnetic force, a
strong magnetic field is usually not the best option for mi-
crofluidic applications. A strong magnetic field can easily
cause MP aggregations and lead to a series of problems such
as reduced surface-volume ratio and mobility, channel clog-
ging, and surface adhesion. Furthermore, if a strong mag-
netic field is globally applied over the complete device, the
field may hamper the integration or functionality of other
magnetic components 共e.g., magnetic pumps, valves, or sen-
sors兲 in the same device. Therefore, the magnetic field is
often kept at a mild strength, mostly from a few to a few
hundreds of millitesla. Based on this fact, efforts were made
to increase the gradient to obtain a strong magnetic force, as
termed high gradient magnetic separation 共HGMS兲.20,31,32
For microfluidic systems, a high magnetic field gradient
关e.g., 103 ⬃ 104 T / m 共Refs. 33 and 34兲兴 can be easily
achieved as the device size is very small. In comparison, the
gradient in most desktop HGMS instruments normally falls
in the range of 关10, 100兴 T/m. However, a major drawback of
microfluidic HGMS is that the magnetic field dampens
quickly away from the magnetic elements because of the
high gradient. Therefore, the high gradient is effective only
in the vicinity of the magnetic elements.
The magnetic field is generated either by a permanent
magnet or an electrical current. Permanent magnets are ca-
pable of giving very strong magnetic induction up to 1 T
without any energy consumption. In contrast, electromag-
netic fields require electrical currents, but the magnetic fields
can be applied in various wave forms over a wide frequency
band. In a microsystem, the magnetic field gradient is often
generated by external magnets, on-chip magnetic elements or
current-carrying conductors 共see Sec. III D兲.
Hydrodynamic drag force. When a MP is driven by the
magnetic force and moves in the medium, the resistance
from the medium molecules is named the hydrodynamic
 102014-4 Liu et al.
drag force. The force is caused by the viscosity of the me-
dium and can be calculated for a sphere in a low Reynolds
number flow, as shown in Eq. 共3兲, where D is the hydrody-
namic size of the sphere, ␩ is the viscosity of the medium,
and v is the velocity. The hydrodynamic size D is a hypo-
thetical dimension to characterize the diffusivity of a par-
ticle. It differs from the physical size of the particle by taking
into account the particle shape and the electrical double lay-
ers around the particle, the latter represented by the Debye
length. The hydrodynamic size is often measured with dy-
namic light scattering instruments. When the MP is very
close to the device surface, which is often the case when
on-chip microelectromagnets are involved, the increase in
viscosity in both in-plane and out-of-plane directions should
be taken into account for a precise calculation 共the “wall
effect”兲.35–37 In addition, the viscosity is temperature depen-
dent and decreases significantly when the medium is heated
up, e.g., the value reduces by half from 20 to 60 ° C.
Fd = − 3␲D␩vជ .
Derjaguin–Landau–Verwey–Overbeek (DLVO) force.
The surfaces of MPs, cells, and devices are normally charged
in an electrolytic solution. The interaction between charged
surfaces is described by the DLVO theory.38 The DLVO
force is simply the sum of the van der Waals force FvdW 关Eq.
共4兲兴 and the electrostatic force Fel 关Eq. 共5兲兴, both of which
become significantly large when the MPs are close to each
other or to the device surface.30,36,37 For MP manipulations in
the vicinity of the device surface, the DLVO force often de-
termines the out-of-plane movement of the MP. The van der
Waals force and the electrostatic force can be calculated ac-
cording to Eqs. 共4兲 and 共5兲, with H132 the Hamak constant, R
the radius of the MP, z the distance between MPs or between
the MP and the surface, ␧0 the permittivity of free space, ␧r
the relative permittivity, ␺s and ␺ p the surface potentials for
the device surface and the particle, respectively, ␬ the
Debye–Hückel inverse double-layer thickness, k the Boltz-
mann constant, T the temperature, NA the Avogadro constant,
e the elementary charge, and i the ionic strength of the me-
dium. The van der Waals force is always attractive and the
electrostatic force can be either attractive or repulsive de-
pending on the surface charges. Generally a repulsive DLVO
force is desirable between MPs and the device surface to
ensure the stability of the colloid. A poor DLVO configura-
tion may result in MP aggregations and the adhesion between
MPs and device surfaces. The surface charging, as a function
of pH and the ionic strength i, is the only tunable parameter
to configure FDLVO. In a cell amicable buffer, however, there
is only a very limited pH and ionic strength flexibility. This
makes the coating of both MP and devices as one of the
major, often only, controllable setting.
H132R
FvdW = − , 共4兲
6z2
2 ␲ ␧ 0␧ r
Fel = 关2␺s␺ pe−␬z + 共␺s2 + ␺2p兲e−2␬z兴
1 − e−2␬z
with
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J. Appl. Phys. 105, 102014 共2009兲
␬= 冉冑 ␧0␧rkT
2000NAe2i
冊 −1
.
Brownian motion. MPs are constantly collided by the
water molecules, which causes a random movement of the
MPs, i.e., the Brownian motion. The Brownian motion am-
plitude is the average displacement of every random walk.
As described by the Stokes–Einstein equation, the displace-
ment amplitude of a sphere is inversely proportional to the
diameter.39 The thermodynamics of the Brownian motion is
described by the Langevin equation and the Fokker–Planck
equation. Aside from the motion equation 共see Sec. III C兲,
the MP hydrodynamics can also be calculated with the
Brownian motion equations by regarding all other forces
共e.g., magnetic force and DLVO force兲 as additionally ap-
plied energy fields. An averaged hitting force from medium
molecules colliding with MP, termed Langevin force, can be
estimated by Eq. 共6兲,40 which is derived from the Langevin
equation in equilibrium. The equation indicates that Brown-
共3兲 ian motion has a stronger force impact on large particles,
although they have less pronounced displacements. As the
Brownian motion is closely related to the medium viscosity,
it is also a function of the distance between the particle and
the solid device surface 共see the explanation for the hydro-
dynamic drag force兲.
具Flang
2
共f兲典 = 6␲kT␩D. 共6兲
Gravity. MPs normally have a higher density than the
aqueous medium. With MPs completely immersed in the me-
dium, the gravity is largely canceled by the buoyancy. The
relationship is expressed in Eq. 共7兲, where ␳MP and ␳0 are the
densities of the MP and medium, respectively, g is the accel-
eration of the gravity, and V is the volume of the MP. There-
fore, it is usually not considered in the calculation of MP
movement. Nevertheless, the gravity is the essential force
responsible for particle sedimentation, before the MP reaches
the device surface.
FG = 共␳MP − ␳0兲gV. 共7兲
B. The force scaling
The forces scale monotonously as a function of the MP
size, schematically plotted in Fig. 2. The scaling has more
impact on the magnetic force because of the proportionality
with MP volume, if the embedded magnetic crystallites are
assumed to be uniformly dispersed in the particle. To illus-
trate the scaling trend, a brief calculation was performed for
all the forces using the device and parameter settings adopted
from literature.41 With a 50 mT magnetic induction and a 500
T/m gradient, the magnetic force starts to lose the dominance
over other forces when MPs are smaller than ⬃200 nm. Us-
ing these conditions, magnetic manipulations on micro-MPs
are more effective than nano-MPs in microfluidic environ-
共5兲
ments. Usually nano-MP manipulation demands a very
strong magnetic field or field gradient, e.g., the MACS®
separation column.
 102014-5 Liu et al. J. Appl. Phys. 105, 102014 共2009兲

-8
10 Due to the fact that all the forces are somehow position
dependent, either in plane or out of plane if not both, it is
-10
10 difficult to obtain an explicit solution. However, the equation
-12
can often by simplified with some assumptions. For example,
10 Eq. 共8兲 retards to Eq. 共9兲 when only magnetic forces are
considered.
Forces (N)

-14
10
d 2r dr ⌬␹Vm共B · ⵜB兲
2 + 3␲D␩ 共9兲
-16
10 w· − = 0.
dt dt ␮0
Magnetic force
-18
10 Hydrodynamic force Since the Reynolds number in a microfluidic scenario is
DLVO force
-20 Langevin force
always very low, normally smaller than 10−3, the viscosity
10 effect often dominates over the inertia. With the ignorance of
Gravity
-22 the inertia, the second derivative in Eq. 共8兲 becomes zero,
10
10
-8
10
-7
10
-6
10
-5 leading to
Particle diameter (m) B · ⵜB
vs = P , 共10兲
FIG. 2. 共Color online兲 Illustration of the strength of magnetic force, hydro- ␮0
dynamic drag force, DLVO force, Langevin force, and gravity, as a function
of the particle size. To simplify the calculation, all parameters were set to be with vs the saturation velocity and the magnetophoretic mo-
constant, as follows: ␹ = 0.1, B = 50 mT, ⵜB = 1000 T / m, ␩ = 1, v
bility P = ⌬␹Vm / 3␲D␩.
= 10 ␮m / s, T = 298 K, H132 = 3.4⫻ 10−21, z = 50 nm, ␧0 = 8.854⫻ 10−12, ␧r
= 80, ␺s = −2.9 mV, ␺ p = −28 mV, k = 1.38⫻ 10−23 J/K, NA = 6.02⫻ 1023, e As seen in Eq. 共10兲, the hydrodynamic drag force equals
= 1.602⫻ 10−19 C, I = 0.03 mol/ l, ␳MP = 1.6⫻ 103 kg/ m3, and ␳0 = 1 the magnetic force. Consequently, the MP velocity becomes
⫻ 103 kg/ m3. independent of time, i.e., it is quickly saturated. Clearly P is
independent of magnetic field but is only determined by the
C. The motion equation and magnetophoretic
properties of the MP and the cell. When necessary and ap-
mobility plicable, the determination of P can be further refined by
taking into account the antibody binding capacity of cells.42
The movement of an object actuated by magnetic forces Equation 共10兲 predicts a linear dependency of the saturation
in a medium is termed magnetophoresis. According to New- velocity on the volume of the magnetic content, i.e., the
ton’s second law, the translational magnetophoresis of a MP number of MPs bound to the cell. However, the dependency
or cell-MP complex is described by Eq. 共8兲, where r is the in reality can deviate from linearity, as shown in Fig. 3. In
position coordinate of the particle, w is the mass of the MP this particular study, the on-chip micromagnetic field damp-
of cell-MP complex, t is the time, and ⌺F共r兲 is the sum of all ens quickly in the out-of-plane direction, resulting in less
the forces 关except the hydrodynamic drag force, i.e., the first contribution of the MPs further away from the device sur-
order derivative in Eq. 共8兲兴. The physical nature of Eq. 共8兲 is face.
the competition between the inertia and the viscosity effect, Aside from the in-plane movement, the distance of the
with additional continuous work of other actuation forces. MPs to the surface is determined by the magnetic force,
DLVO force, gravity, and the Brownian motion.36 Though
there is virtually no useful magnetophoresis in this out-of-
d 2r dr plane direction, a poor force configuration may lead to the
w· + 3␲D␩ − ⌺F共r兲 = 0. 共8兲
dt2 dt adhesion between the MPs or cell-MP complexes to the de-

TABLE II. Summary of a few magnetic cell sorting approaches.

Source of magnetic field External permanent magneta,b Buried micromagnetic stripsc,d Static currente Traveling magnetic fieldf,g

Particle Type N/A Miltenyi MACS® Bangs Laboratories 4962 Dynabead® CD45
Size 8.4 nm 50 nm 0.96 ␮m 4.5 ␮m
Cell Mouse macrophages 共13.1 ␮m兲
Type and size and Hela cells 共9 ␮m兲 Human leukocytes N/A Molt-4 cells 共15 ␮m兲
Physical settings B 共T兲 0.4 0.08 0.016 0.006
ⵜB 共T/m兲 20 共average兲 5000 共max.兲d 102 – 103 250
Linear flow
velocity 共mm/s兲 1.2 0.24 1 0.2
a
Reference 65.
b
Reference 67.
c
Reference 70.
d
Reference 71.
e
Reference 72.
f
Reference 37.
g
Reference 43.
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 102014-6 Liu et al.
μm/sec) 50
40
Velocity (μ
30
20
Single cells bound by particles
10 Unbound single particle
0
0 1 2 3 4 5 6 7
Number of particles bound to a single cell
FIG. 3. 共Color online兲 The mobility of MPs and cell-MP complex measured
by an on-chip traveling magnetic field 共Ref. 43兲. The cell is Molt-4 cell, with
an average diameter of 15 ␮m. The MP is Dynabeads® CD45, with a
diameter of 4.5 ␮m and a volume susceptibility of 0.1 at 关10, 50兴 Oe. Please
refer to Fig. 8共a兲 for a detailed description of the device.
vice surface. The problem can be minimized by
precoatings,44–46 detergents,47 or the inclusion of additional
repulsive forces.41
D. Microfluidic magnetic cell sorting devices
Several types of magnetic cell sorting techniques have
been proposed and implemented on a microscale. Depending
on the specific application, magnetically labeled cells can be
captured to a specified location by magnetic forces 共Sec.
III D 1兲, or be continuously separated from each other in a
flow-based system 共Secs. III D 2–III D 4兲. For the latter cat-
egory, sorting of MPs with different magnetophoretic mobili-
ties is commonly used as a proof of principle.
1. Magnetic traps
The most straightforward cell separation approach is to
capture the magnetically labeled cells by a magnetic field.
Such devices on microscale level are often called magnetic
traps. The magnetically labeled cells are attracted to the mag-
netic elements when they flow through the microfluidic
channel. After capturing, the local field maxima, given by the
elements, can be turned off by shutting down the external
field. The passive magnetic elements can consist either of a
single “soft” magnetic material with a very low coercivity
such as permalloy5,48–51 or of a heterogeneous structure such
as spin valves.52 Aside from the passive micromagnetic ele-
ments, the local field maxima can also be produced by
current-carrying conductors.53–57 Furthermore, a magnetic
pillar fabricated at the center of microcoils combines the
benefits of both elements,58–60 in a very high gradient to 3
⫻ 104 T / m, for instance. Both passive and current-carrying
magnetic elements can be easily fabricated into arrays with
scalable trapping capability, making it very suitable for cell
capturing. The trajectory dynamics of magnetic trappings are
also studied to optimize the capturing and sorting.61–64 How-
ever, the traps mostly deal with the isolation of magnetic
moieties from nonmagnetic ones, with difficulty to discrimi-
nate magnetic moieties of different mobilities. The traps are
also not likely to capture a large amount of cells, because
once a trap is occupied by a cell it becomes difficult or un-
able to capture the second.
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J. Appl. Phys. 105, 102014 共2009兲
magnetic field
M(b)
M(a) buffer
sample
non-M y mixture
x
FIG. 4. A magnetic cell sorter based on a permanent magnet 共Refs. 65–69兲.
The sample mixture, including cells labeled with MPs, cells without MPs
and excessive MPs, is injected from the bottom inlet channel. Magnetically
labeled cells are collected from top to down, corresponding to the magne-
tophoretic mobilities from high to low 共Ref. 67兲. 共Reprint with permission
from Elsevier.兲
2. Flow cell sorting with external permanent magnets
A typical magnetic flow sorting device separates mag-
netic moieties in a continuous flow by magnetophoresis. The
following reports for magnetic flow cell sorting are summa-
rized in Table II.
For continuous magnetic sorting, a straightforward ap-
proach is to place a permanent magnet beside a microfluidic
channel. If the flow is sufficiently laminar, MPs will be de-
flected from the straight flow by the magnetic field. There-
fore, different MPs can form their characteristic trajectories
due to their different magnetophoretic mobility, and are col-
lected at different places at the outlet. An example of such a
device has multiple inlet and outlet channels and a free space
in between for free-flow magnetophoresis65 共Fig. 4兲. A Nd-
FeB magnet was used. The major magnetic field gradient
was perpendicular to the flow. In comparison with a typical
quadrupole separator, the setup can be conceptually viewed
as a unipolar separator in a two dimensional format. The
separation capability was first demonstrated by differentiat-
ing different MPs. The device has been used for bioassays
and separations of MP-coated cells.66–68
The strong magnetic field created by permanent magnets
ensures a high efficiency of magnetophoresis and thus allows
for a high flow rate. The strong field also allows the use of
nano-MPs. Finally, the integration of a magnet does not com-
plicate the microfluidic construction, as the magnet can be
simply placed outside of the system. However, as the size of
the permanent magnet was much larger than the particles, the
resultant field gradient in the microfluidic channel was low
compared with other approaches.
3. Flow cell sorting with magnetic field guides
Instead of a single external permanent magnet 共Sec.
III D 2兲, micromagnetic structures were also employed to in-
crease the local magnetic field and gradient. The microstruc-
tures can be either elements made of ferromagnetic materials
or current-carrying conductors.
Microfabricated ferromagnetic structures can produce a
very high local field gradient when they are magnetized by
an applied field. In this way, the field gradient is a monoto-
nous function of the applied field. Inglis et al.70,71 placed
 102014-7 Liu et al.
FIG. 5. Cell separation using parallel magnetic stripes 共Ref. 70兲. The mag-
netic stripes are deliberately aligned with an angle 共⌰兲 to the flow direction.
The total force moves the cell downstream along the stripes. 共Reprint with
permission from American Institute of Physics.兲
parallel nickel stripes at the bottom of a microfluidic channel
共Fig. 5兲. The nickel strips were magnetized by an externally
applied field to produce a periodic magnetic field gradient.
Coated by 50 nm MPs, leukocytes were attracted to the strips
in a flow. As the parallel stripes were carefully aligned with
an angle to the flow direction, the vector summation of the
in-plane magnetic force and the flow-induced hydrodynamic
drag force led to a total force in parallel with the stripes. The
leukocyte-MP complexes were moved downstream along the
stripes by the total force. Represented by this example, mi-
cromagnetic structures are capable of delivering a very high
field gradient and thus a strong magnetic force without any
energy cost or heat dissipation. The microstructures can also
be easily integrated into LOC systems due to the simple
fabrication. However, the magnetic field gradient is less con-
trollable unless adjusted by the external field. The choice of
geometry may also be limited because of the magnetic shape
anisotropy.
An even more versatile gradient generator is an electrical
current running in a dedicated structure. The microstructures
are often made of metals and are designed in accordance
with specific cell, particle, and microfluidics characteristics.
Pekas et al.72 integrated an aluminum current under the junc-
tion of a Y-shape fluidic channel in order to create an elec-
trically controllable local gradient 共Fig. 6兲. In addition to the
current wire, a mild permanent magnetic field was applied to
magnetize the particles. Carried by a flow, MPs were di-
verted at the junction to one of the downstream channels.
Similar to the design in Fig. 6, Martins et al.73 placed a series
of sloped current lines with an angle to the flow. Magneti-
cally labeled cells were diverted by the current-induced mag-
netic fields and flowed toward spin valve sensors for count-
ing. Similar to passive micromagnetic elements, in both
reports microcurrent-carrying conductors produced very high
local field gradients because of the microsize of the conduc-
tors. Furthermore, the field gradient is more controllable than
passive magnetic elements. The polarity, amplitude, and fre-
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J. Appl. Phys. 105, 102014 共2009兲
FIG. 6. A Y-shape microfluidic sorting gate 共Ref. 72兲. The fluid flows from
left to right. A high magnetic field gradient is produced by the current wires
under the junction, by which the MPs can be diverted to either one of the
downstream branches, depending on the current direction. 共Reprint with
permission from Elsevier.兲
quency can be easily adjusted by varying the current. In ad-
dition, the combination of current-carrying conductors and
permanent magnets may allow for an independent control of
the magnetic field and field gradient.37,72 Despite the number
of advantages, electrical currents consume a considerable
amount of energy. The Joule heating in the microfluidic
channel should be considered in the device design. The mag-
netic field and field gradient are only proportional to current
I but the heating power to I2, although a considerable amount
of heat can be carried away for microfluidic cell sorting.
4. Flow sorting with traveling magnetic fields
A high magnetic field gradient can also be produced by a
traveling magnetic field.37,41,47,74–79 In the context of MP 共or
cell-MP complex兲 manipulation, a traveling magnetic field is
defined as an on-chip magnetic field which moves in the
device plane as a function of time. Such a traveling magnetic
field is most often generated by multiphase currents, but
other mechanisms such as domain wall movements80 or dedi-
cated external-field-driven micromagnetic elements were
also proposed.78 For multiphase currents, when the current is
switched from one conductor to the next, the magnetic field
profile shifts by one step in space, too 关Figs. 7共a兲兴. The
shape, aspect ratio, spacing, and connection of the conduc-
tors are carefully designed in order to adapt the magnetic
field to the specific magnetic manipulation scenario.81
In a recent report, four-phase conductors were used to
separate 4.5 ␮m from 2 ␮m MPs.37 The two types of MPs
exhibited different velocities due to their individual charac-
teristic magnetophoretic mobilities 关Eq. 共10兲兴. When the
switching frequency for the four-phase current is increased
above a certain value 共i.e., cutting frequency兲, the slower MP
共2 ␮m兲 cannot follow the traveling field any more but the
fast MPs 共4.5 ␮m兲 will keep up. Therefore, they were sepa-
rated in a microfluidic channel. The original design was fur-
 102014-8 Liu et al. J. Appl. Phys. 105, 102014 共2009兲

B0
lattice.94,95 When a MP is magnetized, the stray field dictates
A B A B A
1
the magnetization of one or more layers in the GMR sensor
Cell-MP
and hence changes the resistance of the sensor. In addition to
B0
A B A B A MP
the resistance, the impedance of GMR sensors, i.e., GMI, is
1
2 also employed as one of the magnetic sensing principles.96
Spin valve sensor is a special type of GMR sensor with only
B0
A B A B A
2 two magnetic layers separated by a nonmagnetic layer. Spin
3
valve sensors have already been widely used in the hard disk
Z B0 readhead technology. Both multilayer GMR and spin valve
A B A B A 40 µm
4 3 sensors are only sensitive to in-plane magnetic fields.
X Current (IDC) (a) (b) TMR biosensors consist of multiple magnetic thin films
sandwiched by a thin metal oxide layer.97,98 TMR effect
FIG. 7. 共Color online兲 MPs transported by a traveling magnetic field 共Ref. makes use of the spin-dependent tunneling over a potential
41兲. 共a兲 A device composed of two meandering conductors 共A and B兲. A
current was periodically switched between the two conductors with an al- barrier, where the density of states is determined by the ap-
ternate current direction 共steps 1–4兲. A 共bidirectional兲 traveling magnetic plied external magnetic field. The tunnel barrier is given by
field was thus generated. 共b兲 Using the device a cell-MP complex was sepa- the metal oxide layer between adjacent magnetic layers.
rated from single particles because of the higher magnetophoretic mobility. TMR sensors provide a much higher magnetoresistive signal
Besides the traveling magnetic field, a negative dielectrophoresis was super-
imposed onto the cell-MP complex in order to control the distance between for particle detections.
the cell and the device plane. 关Reprint with permission from American In- Hall sensor, on the other hand, is not an effect of elec-
stitute of Physics.兴 tron spins, but of charges. When charges pass a magnetic
field, they are deflected by the Lorenz force, and thus accu-
ther optimized to separate cell-MP complexes from single mulate in the conductor perpendicular to both the current
MPs using a combined magnetophoresis and dielectrophore- flow and the magnetic field direction, giving rise to the Hall
sis 关Fig. 7共b兲兴.41 voltage. For engineering considerations, Hall sensors, both
Traveling magnetic fields are capable of maintaining a metallic and semiconductive, are almost exclusively de-
high gradient over a long distance, whereas the gradient of a signed to sense perpendicular-to-plane magnetic fields.
nontraveling magnetic field quickly dampens from the high All solid state magnetic sensors mentioned above are
gradient spot. Thus, traveling magnetic fields are more suit- designed to detect the stray field of magnetized MPs. To a
able to separate moieties with very close magnetophoretic good approximation the magnetized MPs are simply re-
mobilities which demands a long separation distance. The garded as magnetic dipoles, when they are magnetized either
separation efficiency is higher, too, due to the always-strong in the device plane or perpendicular to the plane. In either
magnetic force. Furthermore, the switching frequency of the manner, the stray field generated by a magnetic dipole is
multiphase magnetic field becomes a new degree of freedom expressed in Eq. 共11兲, where m is the dipole moment and r is
for separations. the vector pointing to the dipole.

ជ 共rជ兲 = ␮0 3r̂共r̂ · mជ兲−m

ជ
IV. MAGNETIC SENSING TOWARD CELL COUNTING B . 共11兲
4␲ r 3

MPs are not only magnetic carriers for cell sorting but
According to Eq. 共11兲, the stray field increases propor-
can be used for detection, and thus cell counting, as well.
tional to the magnetic moment but decreases quickly as a
The counting of cell-MP complexes is equivalently the sens-
function of r3. Therefore, large MPs are favorable for a
ing of MPs conjugated to the cells. Various magnetic sensing
higher signal because of their strong magnetic moments and
devices have been described to detect MPs. These include
large range of stray fields. Meanwhile, MPs need to be suf-
induction coils, superconducting quantum interference de-
ficiently close to the sensor, either by magnetic forces or by
vices 共SQUIDs兲, and solid state magnetic sensors.82–84 Solid
matching the height of the flow channel to the size of the
state sensors are particularly interesting as they can be rather
cell. Aside from the strength, the signal signature is also
easily integrated in microfluidic channels. The microfluidic
dependent on how the MPs are coated on the cell.
magnetic cell counter may be an interesting alternative to
With the solid state magnetic sensors, single particle de-
flow cytometries based on the detection of fluorescent
tection has been achieved using a 2.8 ␮m MP for a GMR
labels85–91 or electrical impedance.92,93
sensor99 and a TMR sensor,97 2 ␮m MP for a spin valve
sensor,100 and 1.2 ␮m MP for a semiconductor Hall
A. Principle of magnetic sensing using solid state sensor.101
magnetic sensors
Solid state magnetic sensors typically include giant mag-
B. Micromagnetic cell counting systems „␮MACSs…
netoresistive 共GMR兲 sensors, tunneling magnetoresistive
共TMR兲 sensors, and Hall sensors. As MPs can be detected individually and cells are nor-
A typical GMR sensor has repeating magnetic and non- mally coated with multiple MPs, counting of cell-MP com-
magnetic alternating thin films. The GMR effect is based on plexes is primarily not a technical hurdle using magnetic
the different scatter rates of conducting electrons with spin sensors. In fact, the major challenges are the system integra-
orientations relative to different local magnetizations of the tion toward a high throughput cytometry and the discrimina-
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 102014-9 Liu et al.
FIG. 8. 共Color online兲 A microfluidic magnetic cell sorting and counting system. 共a兲 The cell-MP complexes with a high magnetophoretic mobility are
transported by the separation device from channel 1 to channel 2, while the single MPs with lower mobilities are delivered to outlet 1. The cell-MP complexes
are detected by spin valve sensors in channel 2. 共b兲 The signal given by a spin valve sensor for a Molt-4 cell coated by around five Dynabeads® CD45
particles.
tion of cell-MP complexes from excessive MPs. The latter is
important when cell-MP complexes and excessive MPs give
similar signals to magnetic sensors.
Sandin et al.102,103 directly connected a magnetic sorter
to a magnetic flow cytometer. A permanent magnet was used
for the magnetophoretic sorting in a microfluidic capillary
tube. The sorted sample was then carried by the flow to the
magnetic cytometer. Although the system was tested only for
micro-MPs, two magnetic techniques, high temperature su-
perconductor SQUID 共HTS SQUID兲 and GMR, were evalu-
ated toward an optimal magnetic detector. Despite the superb
intrinsic signal-to-noise ratio of HTS SQUID, GMR was
considered more suitable for a high-throughput flow cytom-
etry because of the higher signal, better integration capabil-
ity, and much lower cost.
Different reports describe the use of solid state magnetic
sensors integrated in a microfluidic channel.43,73,104,105 In one
of these examples, a spin valve sensor was combined with a
cell sorting device37,43 关Fig. 8共a兲兴. In an H-shape microfluidic
channel, cell-MP complexes were diverted from excessive
single MPs by a traveling magnetic field. The cell-MP com-
plexes were then carried by the separation device to the de-
tection channel where the complexes were counted by the
spin valve sensor. The magnetic signature of the cell-MP
complex is shown in Fig. 8共b兲. Another microfluidic platform
has been able to detect single MPs with AMR sensor and
pseudo-spin-valve sensors, in which work the integrated mi-
crofluidic cell 共IMC兲 is directly ready for bioassays.
V. CONCLUSION AND OUTLOOK
Among numerous formats of microscaled cytometries,106
microfluidic cytometry using MPs offers some unprec-
edented benefits. First, magnetic forces are insensitive to the
complexity of the sample, such as the charges, ionic strength,
conductivity, viscosity, etc., and can thus be used in order to
overcome other forces. Therefore, it is reliable for a variety
of samples such as blood or bone marrow. Second, a high
magnetic field and field gradient are achievable with low
energy consumption. This is of great importance for portable
applications. Third, the integration efforts and costs are
lower when one batch of MPs has multiple functions, such as
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J. Appl. Phys. 105, 102014 共2009兲
both cell carriers and signal labels. Finally, magnetic devices
and the microfluidic components are all scalable in accor-
dance to target cells to be analyzed.
Despite these numerous benefits, microfluidic magnetic
cell sortings are still in research phase or have only gone as
far as a proof of concept with rare use of actual clinical
samples. The reasons lie in both the microfluidic and mag-
netic aspects.
The LOC technology is relatively new and, although
costs generally scale with size, the fabrication and launching
costs are still far higher than those of conventional
techniques.107 Established lithographic and packaging tech-
niques have solely been optimized for materials typically
used in semiconductors. To further reduce costs, new tech-
nologies and polymeric construction materials are needed for
versatile and rapid prototyping. Besides costs, there are also
a number of technical challenges regarding to system inte-
grations. Although different methodologies were proven to
work fine individually, combining them in a fully operational
LOC platform appears more challenging than originally ex-
pected. Conditions that are optimal for a certain step may
have adverse effects on subsequent handlings. As such, de-
signing a total system may become a cumbersome task. In
the case of cell separation, special considerations may be
needed toward a high throughput in order to compete with
conventional fluorescence based cytometers.108,109
Besides the challenges for microfluidics, there are spe-
cial considerations for the microfluidic magnetic cytometry.
A high MP dose may lead MPs to stick to or even block
microfluidic channels. MP aggregations can change the char-
acteristic magnetophoretic mobility of cells or excessive
MPs, leading to inefficient cell sorting and false cell count-
ing. At the system level, when MPs are used as both cell
carriers and signal labels, an adequate separation of cell-MP
complexes from excessive 共single兲 MPs is crucial as the lat-
ter may result in false positive signals. Therefore, continuous
efforts are needed in the aspects of particle and device engi-
neering, the innovation of separation techniques as well as
the adaptation of the magnetic separations to specific appli-
cations.
In conclusion, micro- and nano-MPs hold unique and
advantageous physical properties in the LOC context. In
 102014-10 Liu et al. J. Appl. Phys. 105, 102014 共2009兲

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