Personal Account DOI: 10.1002/tcr.

201800018

1
2
3
THE
4
5 CHEMICAL
Microfluidics Based Magnetophoresis: A
6
7
RECORD Review
8
9
10
11 Fadi Alnaimat,*[a] Sawsan Dagher,[a] Bobby Mathew,[a] Ali Hilal-Alnqbi,[a, b] and
12 Saud Khashan[c]
13
14
15
16 Abstract: Magnetophoresis, the manipulation of trajectory of micro-scale entities using magnetic
17 forces, as employed in microfluidic devices is reviewed at length in this article. Magnetophoresis
18 has recently garnered significant interest due to its simplicity, in terms of implementation, as well
19 as cost-effectiveness while being efficient and biocompatible. Theory associated with magneto-
phoresis is illustrated in this review along with different sources for creating magnetic field
20
gradient commonly employed in microfluidic devices. Additionally, this article reviews the state-
21
of-the-art of magnetophoresis based microfluidic devices, where positive- and negative-magneto-
22 phoresis are utilized for manipulation of micro-scale entities (cells and microparticles), employed
23 for operations such as trapping, focusing, separation, and switching of microparticles and cells.
24 The article concludes with a brief outlook of the field of magnetophoresis.
25
Keywords: Applications, magnetophoresis, microfluidics, nanotechnology, nanoparticles
26
27
28
1. Introduction
29 expensive reagents. In addition, hazardous materials (if
30 Miniaturization has progressed significantly in the last decade any) will be minimized to manageably small amount.
31 which in turn enabled the development of several micro- (ii) Their enhanced mass and heat transfer coefficients
32 fluidic devices.[1] Microfluidic devices with their networks of significantly decrease the time required for reaction and
33 microchannels, fabricated in solid substrates, carryout analysis analysis.
34 or processing of fluids and suspensions with volumes in the (iii) Microfluidics with its fully-developed laminar flow
35 sub-microliter range. Microfluidic devices have been exten- nature, enable precise control and optimization of the
36 sively used for mechanical, electrical, biological, and medical processes.
37 applications.[1] The appeal for microfluidic devices can be (iv) Microfluidic devices are compact, which allows analyses
38 attributed to the following features: and process parallelization and, therefore, yields high
39 (i) They are capable of handling small quantities of sample throughput. As well, the small scale of these devices
40 which speeds synthesis and analysis and reduces the improves their implementation as point-of-care devices.
41 consumption of reagent whilst generating minimal Manipulating microparticles and cells in microfluidic
42 waste. This can be very cost-effective when dealing with devices is required for several applications in the fields of
43 engineering, science, and medicine.[1] Microparticles have
44 seen increased interest in recent years, owing to their surface
[a] F. Alnaimat, S. Dagher, B. Mathew, A. Hilal-Alnqbi
45
Mechanical Engineering Department, College of Engineering, UAE
that can be functionalized, high surface-to-volume ratio, small
46 University, Al Ain, Abu Dhabi, UAE sizes, and suitability of manipulation via external fields
47 Ph: + 9713-713-5117 including magnetic fields.[2] Manipulation of microparticles
48 E-mail: falnaimat@uaeu.ac.ae and cells can be attained by using active methods.[3,4] Active
49 [b] A. Hilal-Alnqbi methods depend on external fields, associated with acoustic,
Abu Dhabi Polytechnic, Abu Dhabi, UAE
50 [c] S. Khashan electrical, optical, thermal, and magnetic phenomena, to
51 Mechanical Engineering Department, Jordan University of Science manipulate the trajectory of microparticles and cells.[3,4]
52 and Technology, Irbid, Jordan

Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley Online Library 1
 Pe r s o n a l A c c o u n t
1 Acoustophoresis is the phenomenon of manipulating
2 microparticles or cells using acoustic forces. It is a label-free
3 and non-contact type manipulation technique operated under
4 continuous flow mode.[5] In addition to the particle’s size and
5 density, it depends on the particle’s compressibility and has
6 the amplitude and frequency of acoustic waves as the
7 controlling parameters. To generate acoustic waves, it is
8 necessary to employ piezoelectric wafers which becomes part
9 of the device. Acoustophoresis is generally inefficient when
10 handling sub-micrometer particles for purposes of focusing
11 and separation.[6] Additionally, heating problems can be
12 encountered during long-term operation which affect the
13 applicability of acoustophoresis for biomedical application.[7]
14 Electrophoresis refers to the movement of charged micro-
15 particles relative to the suspension fluid when subjected to a
16 uniform electric field generated by macroscale electrodes
17 located at the ends of the microchannel.[8] The phenomenon
18 works when electrophoretic forces push the charged micro-
19 particles towards oppositely charged electrode. Key parame-
20 ters of this phenomenon include the viscosity of fluid, particle
21 size, permittivity of microparticles, and applied voltage.
22 Electrophoresis has certain limitations; the microparticles’
23 migration time is slow, it is purely limited to separation
24 applications, and the particles needs to be charged, i.e. it
25 cannot handle electrically neutral particles. Multiple applica-
26 tions of electrophoresis based on manipulation have been
27 reported in the field of biotechnology, such as the preparation
28 of proteins, DNA and RNA samples.[8] Researchers also have
29 reported the use of electrophoresis based liquid purification
30 processes in non-biological applications.[8]
31 Dielectrophoresis (DEP), another active method, is based
32 on the migration of dielectric microscale entities, such as
33 microparticles and cells, by polarization effects attained with
34 respect to the suspension medium when subjected to a non-
35 uniform electric field.[9] Similar to the electrophoresis, key
36 parameters include size of microparticle/cell, applied electric
37 potential, and the permittivity and conductivity of the
38 microparticles/cells and the suspension medium. DEP has
39 been successfully implemented in microfluidic devices for
40 manipulation of micro and nano-particles as well as cells. As
41 non-uniform electric field is required for realizing DEP, the
42 efficiency of DEP based microfluidic devices is strongly
43 influenced by the geometry of the electrode configuration.
44 DEP has limited applicability to applications handling cells as
45 it exposes the same to high electric field.
46 Thermophoresis utilizes the thermal properties of media
47 and particles’ and temperature gradients as key control
48 parameters for active manipulation.[10] However, it has some
49 difficulties in controlling the particles’ heat convection rate
50 which limits its applicability.[10] Optical manipulation is
51 controlled by optical wavelength and intensity.[11] Where
52 volume and permittivity of particles, as well permittivity of
Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
THE CHEMICAL RECORD
suspension play a big role in the active manipulation. The
main limitation of the optical manipulation is the generated
heat during the process, therefore it is not suitable for
biological applications. Nevertheless, it has been used
extensively in particle separation and characterization.[12]
Magnetophoresis utilize non-uniform magnetic field for
manipulation of microparticles and cells. It is a technique
with little heat generation. Moreover, there is little limitation
on the choice of device construction material as magnetic
fields can penetrate most materials of choice for fabricating
microfluidic devices such as glass and polymers.[13] Magneto-
phoresis is usually gentle and nondestructive for biological
analyses of proteins or peptides, and even suitable for large
protein complexes which tend to be broken up in traditional
column chromatography. Besides, it is one approach for the
separation of cells with slight or no aggression to the
biophysical integrity of living cells, and can be used directly
for raw biological samples with several simple steps.
Furthermore, magnetic forces can be much stronger than
other forces which makes it a long range force relative to
other active manipulation techniques. Crucial factors that
affect the efficiency of this method comprise of the
magnitude and the non-uniformity of the magnetic field,
particle/cell size, particle/cell magnetic susceptibilities, and
suspension media. In this article, we will review the
fundamental principles of magnetophoresis and its recent
applications in microfluidics based manipulation of micro-
particles and cells, in which they are either trapped within
microchannels or manipulated whilst in continuous flow.
2. Fundamentals of Microfluidic and Magnetism
The types of forces on a particle in the microchannel of a
magnetophoretic devices are magnetic force, hydrodynamic
drag, gravitational, buoyant, and lift forces as shown in
Figure 1. The balance of many forces on a moving particle/
cell according to Newton’s second law determines its motion
in microfluidic devices.[14,15]
dup
m ¼ Fm þ Fd þ Fg þ Fb þ FL ð1Þ
dt
Where m (kg) is the mass of a single particle/cell, up (m/s)
is the particle/cell velocity, Fm (N) is the magnetic force, Fd
(N) is the hydrodynamic drag force, Fg (N) is gravitational
force, Fb (N) is buoyancy force, and FL (N) is the lift force.
The term on the left hand side of Eq. (1) represent inertial
force. The most relevant among these are the hydrodynamic
drag force and the magnetic force. Gravitational, buoyancy,
and lift forces act in the vertical direction; however, the
movement of microparticles/cells in magnetophoretic devices
is predominantly in the lateral, i. e. horizontal, direction due
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 Pe r s o n a l A c c o u n t THE CHEMICAL RECORD

1 near to a wall the coefficient is greater than unity and it can

2 be determined using Eq. (5).[19]
3
4 Cw ¼
    3  4  5 1
5 9 Dp 1 Dp 45 Dp 1 Dp
1 þ  
6 16 Dp þ 2L 8 Dp þ 2L 256 Dp þ 2L 16 Dp þ 2L
7 ð5Þ
8
9 Herein, Dp is the diameter of the particle and the L is the
10 shortest distance between the surface of the microparticle or
11 cells and the wall. Magnetoviscous effect is pronounced in
12 highly concentrated (> 10 %) ferrofluids, where magnetic
13 nanoparticles tend to form a chain structure due to inter-
14 particle interaction, leading to an increase of the overall liquid
15 Figure 1. Schematic of the dominant forces on a particle in magnetophoresis. viscosity.[20] However, for cases where microparticles and cells
16 are suspended in ferrofluids, the concentration of ferrofluids
17 is less than 1 % which allows for neglecting magnetoviscous
18 to which these are relatively less relevant compared with drag effect.[20]
19 and magnetic forces.
20
2.2. Magnetic Force
21
2.1. Hydrodynamic Drag Force
22 Magnetism in materials is caused by the intrinsic spin of
23 The flow in microfluidic devices is always in the laminar electrons and their orbital motion around the nucleus.
24 regime as the flowrate is very small.[14] In addition, the Materials can be classified into three, based on their response
25 flowrate in microfluidic devices that particularly handle to a magnetic field, such as diamagnetic, paramagnetic, and
26 microparticles is very low with Reynolds number as defined ferromagnetic materials. Diamagnetic materials are non-
27 in Eq. (2) being less than unity.[16,17] magnetic and examples include water, wood, and most
28 biological cells. As the atoms of a diamagnetic material is
29 Re ¼ 1Dh uf =h ð2Þ exposed to an external magnetic field, the orbiting electrons
30 are slightly unbalanced and small magnetic dipoles are created
Here, 1 (kg m3) is the density, h (kg m1 s1) is the
31 within the atoms that oppose the applied field. Paramagnetic
dynamic viscosity, Dh (m)is the hydraulic diameter of the
32 materials show weak attraction in the presence of magnetic
microchannel, and uf (m s1) is the average fluid velocity. For
33 field. In the absence of magnetic field, the magnetic dipoles
noncircular channels, Dh can be calculated using the cross-
34 of paramagnetic materials have random orientation leading
sectional area, A (m2), and the wetted perimeter, P (m), of the
35 them to behave like diamagnetic materials. On the other
microchannel as shown in Eq. (3).[17]
36 hand, in the presence of magnetic field the individual
37 4A magnetic dipole moments of their atoms or molecules align
Dh ¼ ð3Þ
38 P themselves in the direction of the magnetic field thereby
39 leading them to be attracted to magnetic field. The para-
40 For microparticles in microchannels operating under low magnetic effect disappears when the magnetic field is
41 Re the dominant force is hydrodynamic drag force (Fd). This removed. Paramagnetic materials have small susceptibility
42 force is estimated from the Stokes’ law and the relative (106 to 109). Examples include materials such as Chromi-
43 velocity as in Eq. (4).[14,18,19] um (Cr), manganese (Mn), O2, NO2, rare earth metals and
44 oxides. Ferromagnetic materials are strongly attracted to
F d ¼ 6ph r ðuf  up Þ C w ð4Þ
45 magnets and retain magnetization even in the absence of
46 magnetic field. Examples include materials such as Iron (Fe),
Where r (m) is the radius of the particle, and uf (m/s) and
47 Cobalt (Co), and Nickel (Ni). In an applied magnetic field,
up (m/s) are the velocities of the fluid and the microparticles/
48 spontaneous magnetization is produced by the alignment of
cells, respectively; Cw is a constant that accounts for the
49 the 3d electrons’ spins, of the adjacent atoms in a parallel
influence of wall on the drag force of the microparticle. For
50 direction.[21] The force on a magnetic dipole in a non-
microparticles and cells far away from the wall, this
51 homogeneous magnetic field is given in Eq. (6).[19]
coefficient is unity; on the other hand, when the particle is
52

Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley Online Library 3
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1 ðm: rÞB the microparticles or cells. It can be noticed from Eq. (8) that
Fm ¼ ð6Þ
2 m0 when the magnetic field and magnetic susceptibilities of the
3 microparticles/cells and medium are kept constant, umag
4 Where m is the magnetic moment, B is magnetic flux depends only on the sizes.
5 density and m0 = 4p 3 107 Tesla.meter/Ampere is the perme-
6 ability of free space. In the case of magnetophoresis, which is
the motion of the particle under a magnetic force, the generic 2.3. Positive and Negative Magnetophoresis
7
8 equation of the magnetic force experienced by a particle is The mobility of microparticles or cells relative to the ambient
9 expressed in Eq. (7).[19,22] fluid depends, as shown in Eq. 8, on two factors – the
10
susceptibility mismatch, between the particle and the
Vp Xp  Xf
11 Fm ¼ ðB: rÞB ð7Þ surrounding fluid, and the gradient of the magnetic field.
m0
12 Thus, two approaches are used to manipulate microparticles
13 Where V p is the volume of the particle, X p and X f are the or cells for the purpose of trapping, focusing, and separation.
14 dimensionless volume magnetic susceptibilities of the particle First is positive magnetophoresis which involves magnetic
15 and fluid, respectively. B and rB are the magnetic flux microparticles suspended in diamagnetic (i. e., nonmagnetic)
16 density and its gradient. Difference in susceptibility is surrounding medium as shown in Figure 2a and 2b. Second
17 required to induce a magnetic force on a particle. The approach is the negative magnetophoresis, where the diamag-
18 magnetophoretic force can be positive or negative depending netic microparticles are suspended within a magnetic
19 the magnitude of the susceptibilities. Positive magnetopho- medium, such as paramagnetic medium or ferrofluid, as
20 resis will happen when X p is larger than X f in which case the shown in Figure 2c.[22]
21 microparticle/cell will be drawn towards the maxima of the
22 non-uniform magnetic field.. Examples include magnetic
23 microparticles suspended in water. On the other hand, when
24 diamagnetic particles ðX p < 0) are dispersed in a magnetic
25 medium (paramagnetic solutions or ferrofluids), then the
26 microparticle will be drawn towards the minima of the non-
27 uniform magnetic field and this is specifically referred to as
28 negative magnetophoresis. For example, polystyrene micro-
29 particles suspended in ferrofluids or paramagnetic solutions
30 will be drawn towards the minima of the gradient of the non-
31 uniform magnetic field and thus experience negative magne-
32 tophoresis.
33
34 In microfluidic devices, the magnetic field is applied
35 perpendicular to the direction of flow due to which the
36 hydrodynamic drag force ðF vis Þ experienced by a micro- Figure 2. Schematic of positive magnetophoresis and negative magneto-
37 particle or cell as it moves towards or away from the maxima phoresis as exhibited by different types of entities.
38 of the magnetic

field is equal but opposite to the magnetic
39 force F mag .[22]
40 In positive magnetophoresis the magnetization of micro-
41 V p ðX p  X f ÞðB: rÞB particles is greater than the surrounding medium due to
F mag ¼ F vis ) umag ¼ ð8Þ
6phrCw m0
42 which they move towards the field maxima when magnetized
43 by an external magnetic field, Figure 2a and 2b. Positive
The magnetic field gradient applied perpendicular to the
44 magnetophoresis is used to manipulate magnetic micro-
direction of fluid flow causes the microparticles/cells to be
45 particles or biological entities with intrinsic magnetic proper-
repelled or attracted with a velocity of umag . The
resultant
46 ties, such as red blood cells or magnetotactic bacteria.[21,23]
deflection velocity of the microparticles/cells udef across the
47 However, in order to magnetically manipulate diamagnetic
chamber is thus given by the vector
sum of umag and the
48 cells, positive magnetophoresis technique requires the mod-
hydrodynamic flow velocity uhyd which is proportional to
49 ification of their magnetic properties by attaching magnetic
the volumetric flowrate, i. e. udef ¼ uhyd þ umag .[22] Hence, if
50 nanoparticles to cells. For labeling them with magnetic
uhyd is kept constant, the extent of deflection depends only on
51 nanoparticles as shown in Figure 2c, the cells and magnetic
umag , which in turn depends on F mag and F vis forces acting on
52 nanoparticles must be incubated together for several hours;

Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley Online Library 4
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1 incubation is typically followed by multiple washing steps.[23]
2 The effectiveness of employing positive magnetophoresis
3 depends on loading of magnetic nanoparticles on cells, which
4 is greatly affected by their endocytotic capacities or ligand-
5 receptor interactions, which can vary among the same type of
6 cells.[23]
7 Negative magnetophoresis is a label-free technique, where
8 diamagnetic microparticles or cells suspended in a magnetic
9 medium (ferrofluid or paramagnetic salt solution) move
10 towards the field minima of a non-uniform magnetic field,
11 Figure 2c.[22,24–26] The approach of employing negative mag-
12 netophoresis for size-based separation of diamagnetic particles
13 is specifically termed as Diamagnetophoresis.[24] The repul-
14 sion experienced by diamagnetic microparticles/cells can be
15 enhanced by using high magnetic fields and gradients such as
16 those generated by superconducting magnets.[22,24] Negative
17 magnetophoresis is suitable for live cell manipulation, of
18 certain cell types, since magnetic fluids can potentially be
19 biocompatible.[27] Ferrofluids have less interferences with
20 biological samples compared to paramagnetic salt solutions.
21 Thus, with recent developments of biocompatible ferrofluids,
22 negative magnetophoresis can be applied to the manipulation
23 of trajectory of cells.[28] Furthermore, diamagnetic micro-
24 particles, such as polystyrene microparticles, have been
25 successfully manipulated by negative magnetophoresis.[26,29]
26
27
2.4. Sources of Magnetic Field
28
29 Several magnetic sources are employed in microfluidic devices
30 for realizing the magnetic fields and gradients.[30] The first
31 option is Neodymium-Iron-Boron (NdFeB) permanent mag-
32 nets.[30] Permanent magnets of several shapes and arrange-
33 ments can be positioned in proximity of the microchannel to
34 generate the desired magnetic fields (~ 0.5–1 Tesla) and field
35 gradient (hundreds of Tesla/meter) for manipulating cells and
36 microparticles.[31,32] Herein, the required Fm is achieved
37 without any external power and their setup is easy compared
38 to other sources of magnetic field. Furthermore, high gradient
39 microscale permanent magnets can be integrated on-chip very
40 close to the microchannel.
41 Electromagnets, including microscale electromagnets,
42 represent the second option for realizing the magnetic field
43 and associated gradient. Electromagnets consist of coils
44 wound around a metal strip and the passage of high density
45 electric current through these coils create the magnetic field
46 and associated magnetic field gradient (~ 104 Tesla/meter).[33]
47 Electromagnets have the advantage that they easily switched
48 on and off; additionally, the strength of the magnetic field
49 can be easily altered by controlling the electric current flow.
50 Additionally, the electromagnet can be integrated on-chip
51 very close to the microchannel using microfabrication
52 techniques. The disadvantage with electromagnets is that they
need external power for generating the magnetic field and
this in turn can lead to Joule heating which is unsuitable for
most biological applications.[34] Although electromagnets
produce a high magnetic gradient, they yield a low magnetic
induction – 100 times smaller than that reported by the
permanent magnets.[32,35,36] In addition, the design and
fabrication processes of the circuitry is complex.[41]
The third option for realizing magnetic field gradient in
microchannels is by employing soft ferromagnetic micro-
structures (e. g. nickel, permalloys) and subjecting them to an
external magnetic field.[30] The ferromagnetic microstructures
alter the external magnetic field in its vicinity to generate the
desired non-uniform magnetic field for exerting force on
microparticles/cells in the microchannel. This approach has
the advantage that it can easily be controlled by controlling
the external magnetic field. Additionally, the small size of the
microstructures allows for generating large magnetic field
gradients which subsequently result in large magnetic force.
Several approaches of integrating microstructures in micro-
fluidic devices for realizing the local magnetic gradients have
been reported.[37]
3. Magnetophoresis Based Manipulation of
Microparticles and Cells
There are many methods to handle and manipulate micro-
particles and cells inside microfluidic devices. Specifically,
microfluidics based magnetophoresis procedures can largely
be classified, based on the method by which the micro-
particles are collected, into two main categories: Trapping-
based (i. e. batch-based) and continuous flow-based (i. e.
focusing, concentration, and separation).
3.1. Trapping and Concentration
Trapping cells or microparticles in microfluidic devices
implies their collection at a particular location inside the
microchannel using actuation forces including magnetic
force.[4–6] Cells or microparticles can be trapped across the
width of the wall of a microfluidic channel or on trapping
elements using a magnetic field. Following this, reagents and
washing solutions can be flowed over the trapped species as
desired for treating the same. Finally, the trapped cells or
microparticles are recovered by removing the magnetic field.
By trapping a cell or particle in a microchannel, and utilizing
the multilaminar flow streams, it is possible to achieve the
simultaneous exposure of cells/microparticles to various
stimuli and multiple reagent streams. This allows for studying
the influence of different reagents on the cell concurrently, or
to observe the migration of different species within the cell

Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley Online Library 5
 Pe r s o n a l A c c o u n t THE CHEMICAL RECORD

1 once they have been acted upon by simultaneous reagent towards a single permanent magnet. The magnetic micro-
2 streams. particles are attracted to the magnet while the diamagnetic
3 Magnetic microparticles are trapped in microfluidic microparticles are repelled away from the magnet and trapped
4 devices for immunoassay experiments, where the microfluidic within the microchannel as a result of the negative magneto-
5 devices act as miniaturized labs that enable the reduction of phoresis.[41] Figure 3c and 3d show a simple concentration
6 measurement times and quantity of sample and reagents.[19,38] method that can achieve simultaneous trapping of diamag-
7 However, when using microfluidic devices, magnetic micro- netic and magnetic microparticles in a capillary using a pair
8 particles accumulate at the capturing sites leading to of permanent magnets positioned symmetrically on either
9 reduction in flow area which subsequently leads to reduction side of a microchannel (i. e., opposite poles facing each other).
10 in flow rate and stagnation of capture efficiency.[39] Therefore, The device was used to trap magnetic microparticles (Fig-
11 magnetic field has to be removed after a certain duration of ure 3c) and streptavidin coated diamagnetic microparticles in
12 usage to dissociate the microparticles’ agglomeration and a capillary (Figure 3d).[40] Khashan et al.[43] developed a device
13 extract them from the microfluidic device. Its working for separating magnetic and diamagnetic microparticles, by
14 mechanisms and performance are summarized in Table 1 and employing a permalloy wire oriented vertically passing
15 Figure 3.[40–54] invasively through the fluid at the center of the microchannel,
16 Figure 3e. The magnetic microparticles are captured on the
17 surface of the wire while the diamagnetic microparticles move
18 unaffected. The wire is magnetized along its height due to
19 which this device allows for handling high throughput.
20 In general, trapping mode operation require long oper-
21 ation times and complex fluidic connections and the
22 disruption of the operation is required for sample elution
23 which makes it suitable only for certain analytical applica-
24 tions. However, trapping mode allows for treating the
25 microparticles or cells with different reagents, in a sequential
26 manner, while being retained inside the microfluidic device.
27 This is important in reducing loss of microparticles or cells
28 that occurs while transferring them between devices for
29 purposes of treatment with different reagents.[55] The
30 limitations on trapping in microfluidic devices can be
31 mitigated by the use of continuous flow microfluidic devices
32 in which the selective separation of microparticles and cells is
33 possible.
34 Figure 3. Schematic representation of trapping based manipulation (a)
35 magnetic microparticles in diamagnetic fluid, (b) simultaneous trapping of
diamagnetic particles across the width of the T-shaped microchannel, and the 3.2. Focusing
36
magnetic microparticles trapped on the wall next to the magnet in a
37 ferrofluid, (c) magnetic microparticles in paramagnetic fluid with an Focusing microparticles and cells, in continuous flow, into a
38 asymmetric magnet configuration, (d) diamagnetic microparticles in para- narrow confined and tight stream within a microchannel is
39 magnetic fluid with an asymmetric magnet configuration, (e) microchannel essential for many microfluidic applications such as cell
with hydrodynamic focused flow, and the wire embedded in the center of the
40 microchannel, demonstrates the trapping of magnetic particles and the cytometry, processing, counting, and separation.[56] As well,
41 elution of diamagnetic particles in the presence of an asymmetric magnet focusing helps to avoid microparticles’ adhesion to micro-
42 configuration. channel walls for an enhanced recovery rate which is
43 particularly important when dealing with precious samples.[57]
44 In general, positive magnetophoresis is unsuitable for
45 Figure 3a shows a device to trap 10 mm magnetic micro- focusing magnetic microparticles as they will always be
46 particles in a paramagnetic salt solution (0.79 M MnCl2). attracted towards the region of highest gradient which is
47 Herein, several permanent magnets positioned external to the almost always located at the microchannel wall. However,
48 microchannel wall, resulted in the complete trapping within magnetic attraction can be used as a pre-focusing step, to
49 the microchannel, while the remaining diamagnetic (non- draw magnetic microparticles close to the chip surface, at
50 magnetic) fluid eluted outside the channel.[40] Figure 3b which point another phenomenon can be employed for lateral
51 shows both magnetic and diamagnetic microparticles carried focusing.[58]
52 by a diamagnetic fluid through a T-shaped microchannel

Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley Online Library 6
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51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
35
34
33
32
31
30
29
28
27
26
25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
Table 1. Studies on trapping of microparticles and cells in microfluidic devices.
Channel W 3 D Fluid (flow rate in mL h1) Magnetic source Particle type and Capture Efficiency (%) and com- Ref.
(mm) Size (mm) ments
Capillary tube, MnCl2 Permanent magnet Polystyrene microparticles 100 [40]
100 mm (10 – streptavidin coated (10 – streptavidin coated polystyrene) 100
polystyrene) (10 – plain polystyrene)
(7 – plain polystyrene)

Chem. Rec. 2018, 18, 1 – 18

T-shaped rectangle Ferrofluid (NA) Permanent magnet Diamagnetic and magnetic particles Simultaneous trapping [41]
Pe r s o n a l A c c o u n t

of diamagnetic and
magnetic particles, 105 particles
h1
Straight rectangle Water (1800-36000) Permanent magnet/ Fe3O4 magnetic particles (4.3) 100 for flow rate [43]
200 3 500 Permalloy wire less than 7200 mL h1
Straight rectangle Culture medium (2000) Permanent magnet Circulating tumor cells tagged 90.3 % [44]
2000 3 120 with nanoparticles
Straight rectangle Blood (2000) Permanent magnet Circulating tumor cells tagged 82 % [44]
2000 3 120 with nanoparticles
Capillary square MnCl2 (NA) Two permanent mag- Diamagnetic polystyrene particles NA [45]
100 3 100 nets (1.53, 2.77, 5.87, 9.14)
Square fused silica MnCl2 (NA) Permanent magnet Diamagnetic particles and cell 100 [46]
capillary and iron pieces
Straight, Water (60) Micro-electromagnet Magnetic particles (1.05) 89 [47]
150 3 1500
Straight, Water (120) Ni posts and Magnetic particles (4.5) 95 [48]
50 3 150 permanent magnet
Straight, PBS (0.01–10) Micro-electromagnets Magnetic particles (0.2–4.5) 100 at flow velocity [49]
20 3 100 with Ni microposts of 0.12–72 cm h1
Straight, PBS with PEG (NA) Permanent magnets Magnetic particles (2) 44–70 based on the width [50]
120 3 600 of the co-flowing streams
Straight, Water (360) Switchable perma- Magnetic particles (0.25, 0.5, 1) 15 for 0.25 mm, 95 for 0.5 mm, [51]
150 3 D nent magnets and 100 for 1 mm
Straight, PBS (1 % SDS) (600- Permalloy soft mate- Magnetic particles (1.05) 49–96 without mixers, [52]
200 3 80, 3600) rial 89–100 with mixers
400 3 80 and permanent mag-
nets
Straight PBS (1200) Micro Electromag- Magnetic particles (1) 50–80 for current intensities of 5– [53]

© 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5000 3 100 nets 250 mA
with ferromagnetic
pillars
3D manipulation Gd.DTPA (NA) Permanent magnet Polystyrene particles (NA), NIH-3T3 cells (NA), Saccha- NA [54]
model romyces cerevisiae (NA),
Chlamydomonas reinhardtii (NA)

Wiley Online Library

THE CHEMICAL RECORD

7
 Pe r s o n a l A c c o u n t THE CHEMICAL RECORD

1 Table 2. Studies on magnetophoretic focusing in a continuous flow microfluidic channels.

2
Channel Fluid (flow rate in mL h1) Magnetic source Particle type (Size in mm) Ref.
3 W 3 D (mm) or
4 OD 3 ID (mm)
5
Capillary round tube MnCl2 (average flow speed of 650 Two permanent Diamagnetic polystyrene microparticles (10) [40]
6
NA 3 150 mm.s-1) magnets
7 Straight rectangle Ferrofluid (60 to 480) Two permanent Diamagnetic microparticles (4.8, 5.8, 7.3) [57]
8 1600 3 28 magnets
9 Capillary round tube MnCl2, GdCl3 (30, 40, 50) Two permanent Polystyrene microparticles (10, 20) and Ha- [59]
10 363 3 150 magnets CaT cells (10)
Straight rectangle MnCl2 (NA: 200, 400, 600 mm Permanent magnet Polystyrene microparticles (5, 10, 15) [60]
11
200 3 25 s1)
12 Straight rectangle Ferrofluid (480) Permanent magnet Polystyrene microparticles (2.2, 5, 10) [61]
13 200 3 70
14 Straight rectangle Ferrofluid (NA: 0.4, 0.8, 1.2 mm Permanent magnet Polystyrene microparticle (1, 5) [62]
15 600 3 60 s1) Yeast cells (5)
T-shaped rectangle Ferrofluid-water (NA: 0.5, 1.0, Single permanent Polystyrene particles (5, 10) [63]
16 400 3 40 (main channel) 2 mm s1) magnet
17 200 3 40 (side channel)
18 Straight rectangle Ferrofluid-water (180) Permanent magnet Diamagnetic microparticles (2, 7) [64]
19 100 3 35
150 3 35
20
21
22
23 Negative magnetophoresis is often utilized to focus
24 diamagnetic microparticles and cells in microfluidic devices.
25 Focusing involves employing negative magnetophoresis that is
26 experienced by diamagnetic microparticles and cells, when
27 suspended in magnetic medium, and subjected to non-
28 uniform magnetic field. Negative magnetophoresis will push
29 the diamagnetic microparticles and cells towards the minima
30 of the magnetic field gradient, inside the microchannel, due
31 to which it can be used for focusing the diamagnetic
32 microparticles and the cells at the center of the microchannel.
33 Working mechanisms and performances of focusing schemes
34 developed by researchers are summarized in Table 2 and
35 Figure 4.
36 Negative magnetophoresis can be used for focusing of
37 diamagnetic microparticles and cells using the three different
38 approaches listed below.
39 (i) The first approach involves using magnetic medium and Figure 4. Schematic representations of particles focusing; (a) focusing
40 two opposing magnetic fields as shown in Figure 4a. diamagnetic microparticles suspended in a magnetic medium using a pair of
symmetric magnetic fields, (b) focusing of diamagnetic microparticles near
41 Diamagnetic microparticles and cells, suspended in a the wall using a single magnet field, and (c) focusing particles of diamagnetic
42 magnetic medium, are focused by means of two microparticles at the interface between the magnetic and diamagnetic
43 repulsive magnets positioned symmetrically on either medium using a single magnet field.

44 side of a microfluidic channel, Fig. 4a. The results

45 showed that with this arrangement of magnets, a pair of
46 symmetric counter-rotation circulations of concentrated magnetic field pushes the microparticles or cells leading
47 microparticles formed in the microchannel, which them to focus at the farthest location from the magnet
48 increased in size and progressed downstream over time. which in most cases is the bottom corner of the sidewall
49 Furthermore, the degree of focusing improved with farthest from the magnet, Figure 4b.
50 reducing flow rate or increasing magnetic particle size. (iii) The last approach is based on using co-flowing magnetic
51 (ii) The second approach involves using a single magnetic medium and diamagnetic medium and a single magnetic
52 field and magnetic medium. In this approach, the field as shown in Figure 4c. The microparticles are

Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley Online Library 8
 Pe r s o n a l A c c o u n t
1 initially suspended in the ferrofluid and they are repelled
2 away from the magnet towards the fluids’ interface due
3 to negative magnetophoresis. Once the microparticles
4 reach the interface, they are surrounded by diamagnetic
5 fluid due to which magnetophoretic force disappears
6 leading to the focusing of the microparticles at this
7 location.
8 Researchers have used all three approaches for focusing
9 microparticles and cells in microfluidic devices. Using the
10 approach shown in Figure 4a, Payman et al.[40] developed a
11 device consisting of fused silica capillary and a pair of
12 magnets to continuously focus 10 mm diamagnetic micro-
13 particles at a flow rate of 40 mL h1. Zhu et al.[57] employed a
14 pair of permanent magnets integrated into the microfluidic
15 device for focusing diamagnetic microparticles suspended in
16 ferrrofluid; they achieved focusing of microparticles of differ-
17 ent sizes for varying flowrates. Rodriguez-Villarreal et al.[59]
18 achieved focusing of diamagnetic microparticles (10 mm and
19 20 mm) and HaCaT cells (spontaneously immortalized
20 human skin keratinocyte) in a continuous flow mode. They
21 considered the magnetic susceptibility of the medium, flow
22 rate, particle size, and exposure time of microparticles to the
23 magnetic field as optimization parameters for the opera-
24 tion.[59] Zhu et al.[60] employed the second approach men-
25 tioned above to focus diamagnetic microparticles, with
26 different sizes, suspended in a MnCl2 solution (paramagnetic
27 solution). They studied the effects of several parameters on
28 particle deflection, specifically microparticle position, size,
29 flow rate, and concentration of salt solution. They reported
30 slower focusing speeds and lower throughputs when using
31 paramagnetic salt solutions instead of ferrofluids. That is
32 attributed to the low susceptibility of paramagnetic salt
33 solutions compared with ferrofluids. Liang et al.[61] employed
34 the same approach as Zhu et al.[60] for focusing diamagnetic
35 microparticles suspended in ferrofluid. The third approach
36 has been employed by researchers for focusing microparticles
37 at the interface between a magnetic medium and diamagnetic
38 medium.[62–64] In these devices the diamagnetic microparticles
39 are pushed towards the interface, formed by a magnetic and
40 diamagnetic fluid, by a non-uniform magnetic field.
41
42
3.3. Separation
43
44 In continuous flow systems, microparticles are deflected by
45 the magnetic force into different trajectories thereby enabling
46 them to leave the microfluidic device through several outlets.
47 Target microparticles are separated or sorted from a heteroge-
48 neous mixture based on their size, shape, density, and
49 magnetic properties. The use of continuous flow based
50 separation increases the throughput. Furthermore, it allows
51 for real-time process monitoring and optimization by adjust-
52 ing the operation conditions. In comparison with the
Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
THE CHEMICAL RECORD
trapping mode of separation, the continuous flow mode of
separation enables a higher level of integration with other
stream processes such as labeling cells with magnetic nano-
particles.[65,66] Among the several designs reported in liter-
ature, the most common, due to the simplicity and ease of
processing, is the straight microchannel. Other configurations
like serpentine, H-, Y-, U-, L- and T-shaped channels have
also been investigated and documented in Table 3.[22,40,61,63–92]
Figure 5a shows a microdevice in which magnetic micro-
particles or magnetically tagged-cells can be selectively
separated from flowing biological fluids (diamagnetic fluid)
without any wash steps. Herein, microfabricated ferromag-
netic structures, made from NiFe with micro-comb sharp
tips, were integrated on one side of the microchannel to
generate, upon magnetization, the required local magnetic
field gradient. This microdevice was used to separate living E.
coli, bound to magnetic nanoparticles, from a mixture of the
same and Red Blood Cells (RBCs) under continuous mode
operation.[67]
Figure 5b shows a microfluidic device that use ferrofluid
as the carrier medium to continuously separate binary
mixtures of diamagnetic microparticles under non-uniform
magnetic fields generated by permanent magnets. The device
is reported to achieve size-based separation with efficiency
close to 100 % for throughput of 105 microparticles per
hour.[26] Later on, Zhu et al.[68] separated E. Coli from
Saccharomyces cerevisiae cells in a continuous-flow manner,
using ferrofluid resulting in the same efficiency at higher
throughput (  107 cells h1). Recently, Zhao et al.[69] demon-
strated the separation of HeLa cells (cervical carcinoma) and
blood cells in a custom-made biocompatible ferrofluid at
high throughput (  106 cells h1) and separation efficiency
(~ 99 %). Liang et al.[70] separated binary mixture of micro-
particles (5 and 15 mm) dispersed in ferrofluids. Zeng et al.[71]
achieved the separation of microparticles and live yeast cells
suspended in ferrofluids using the approach represented in
Figure 5c.
Figure 5d shows a separation scheme for separation of
diamagnetic microparticles or cells suspended in a solution
composed of viscoelastic medium and ferrofluid. Small and
large diamagnetic microparticles are focused and then the
small microparticles are separated from the larger ones in a
medium composed of a viscoelastic fluid, specifically a
mixture of Poly(ethylene oxide) and glycerol, and ferrofluid
using negative magnetophoresis, Figure 5d.[72] The viscoelastic
force induced on the microparticles concentrates them into a
single stream along the centerline of the microchannel.
Afterwards, the negative magnetophoretic force deflects the
microparticles away from the magnet in a wider microchannel
as shown in Figure 5d. By employing PEO/ferrofluid
solution, sheathless and continuous separation of diamagnetic
particles based on particle size has been demonstrated.[72] The
Wiley Online Library 9
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51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
35
34
33
32
31
30
29
28
27
26
25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
Table 3. Studies on magnetophoretic separation in a continuous flow microfluidic channels.
Microchannel Fluid and Magnetic source Particles and Size (mm) Efficiency (%) and Comments Ref.
Width (mm) 3 Flow rate (mL h1)
Depth (mm)
Straight and MnCl2 solution (400 - par- Superconducting Polystyrene particles (5, 10) NA and 16 inlets feed 6 mm 3 6 mm separation [22]
100 3 D with 16 ticle suspension) magnet chamber
co-flowing

Chem. Rec. 2018, 18, 1 – 18

streams
Pe r s o n a l A c c o u n t

Straight, L, T- Water NiFe soft mag- Fe3O4 (0.5) 43.7 for straight microchannel 63.4 for L-shaped [40]
shaped nets and perma- microchannel and 100 for T-shaped microchannel
200 3 D nent magnet
Rectangular Ferrofluid (240-960) Permeant magnet Polystyrene particles (2.2, 5, 10) NA, separated based on flow rate, size and concen- [61]
200 3 70 tration of particles in 2 cm long channel
T-shaped Ferrofluid with water and Permeant magnet Polystyrene particles (5, 10) Particle stream width varied from 20 to 170 mm based [63]
400 3 40 glycerol solution (20–100) on the flow rate and particles size
Straight Ferrofluid-ferrofluid particle Permanent mag- Polystyrene particles (2, 7) NA and separation increased with increase in ferrofluid [64]
100 3 35 suspension- water (240- fer- net to ferrofluid suspension flowrate
rofluid total; 210-water)
(15)
Varying width DI water buffer – DI water Permanent mag- Polystyrene microparticles (0.4; func- > 95 [65]
and shape suspensions of microparticles net tionalized and non-functionalized),
NA 3 30 (30 – suspensions; 240 - magnetic microparticles (2.8; function-
buffer) alized)
Varying width Cord blood (NA) Permanent mag- Supermagnetic particles (4.5) and 88 and single chip for cell isolation, counting, and [66]
and shape net tagged Hematopoietic stem cell sorting
NA 3 200

Straight, H- PBS and saline (25-40) Permanent mag- Magnetic particles (1.6), non-magnetic 86-92 (1.6 and 2 in PBS) [67]
shaped net microparticles (2), RBCs, and E.coil 79-83 (1.6 and RBCs in saline)
200 3 50 and magnetic microparticle (0.13) com- 83-89
bination (E.coil + 0.13 in PBS)
44-78 (E.coil + 0.13 and RBCs in saline)

H-shaped micro- Ferrofluid (60-600 suspen- Permanent mag- Polystyrene microparticles (1, 7.3), 100 (E.Coil and 7.3) & [68]
channel 1500 sion sample) net E.Coil, and Yeast Cell) 100 (Yeast cells and 1) &

© 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
(central channel) 100 (Yeast cells and E.Coil)
3 38

Converging mi- Ferrofluid (480) Permanent mag- Polystyrene microparticles (5.8 and 100 (5.8 and 15.8) & [69]
crochannel net 15.8) > 87 (5.8 and HeLa cells)
NA 3 50 HeLa cells (NA) and Red Blood Cells 100 % (cells)
(NA)
U-shaped Ferrofluid (average flow Permeant magnet Polystyrene particles (5, 15) NA, Size based separation [70]
200 3 40 speed is 0.7 mm.s1)

Wiley Online Library

Rectangular Ferrofluid (average flow Permanent mag- Polystyrene particles (3, 10) NA, size based separation [71]
speed of 0.6, 0.8, net
1.2 mm.s1)

10
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 52
51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
35
34
33
32
31
30
29
28
27
26
25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
Table 3. continued
Microchannel Fluid and Magnetic source Particles and Size (mm) Efficiency (%) and Comments Ref.
Width (mm) 3 Flow rate (mL h1)
Depth (mm)
Rectangular Ferrofluid (average flow Permanent mag- Live yeast cells (5) and polystyrene NA, size based separation [71]
speed of 0.6 mm.s1) net particles (10)
Rectangular PEO- ferrofluid mixture (5- Permanent mag- Polystyrene microparticles (5 and 20) ~ 100 (5 and 20) at 5 ml/hr & [72]

Chem. Rec. 2018, 18, 1 – 18

250 3 50 200) net Chlorella vulgaris (5.26) and Synecho- NA (cells),
Pe r s o n a l A c c o u n t

coccus sp cells (2.51) size based separation

H-shaped 0.5 wt.% polyacrylamide Permanent mag- Magnetic (10) and Polystyrene particles > 96%, separating magnetic from diamagnetic par- [74]
200 3 50 (PAM) solution (viscoelastic) net (6, 20) ticles at the outlet bifurcation
(30-240)
Straight with Sample mixture/buffer Planar Nickel Magnetic/diamagnetic particles (1.4, > 90 % [75]
side outlets (47000) strips and perma- 2.25, 2.5)
500 3 50 (main nent magnet
microchannel)
300 3 50 (side
outlet micro-
channel)
Straight with Sample mixture/buffer Planar Nickel Cells tagged to 2.8 and 4.5 magnetic > 90 % [75]
side outlets (427000) strips and perma- particles, non-tagged bacteria (NA)
500 3 50 (main nent magnet
microchannel)
300 3 50 (side
outlet micro-
channel)
Straight Blood (2.5 to 20) Three dimension- Deoxyhemoglobin Red blood cells 94.8 % (for 2.5 ml h1) [78]
360 3 50 al Nickel wire (NA) and Breast cancer cells (NA)
and permanent
magnet
Straight Sample/Buffer solution (50 Permanent mag- Paramagnetic microparticles (2.0, 4.5) NA, separation based on size, sample introduced [80]
6000 3 20 to 200) net through one inlet and buffer introduced through
multiple inlets
Straight Sample/Buffer solution (200 Permanent mag- Paramagnetic microparticles (2.8, 4.5) NA, separation based on size, sample introduced [81]
6000 3 25 to 600) net through single inlet and buffer introduced through
multiple inlets

© 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Y-shaped and Water (0.036) Micro-Electro- Magnetic particles (0.96) 85 [83]
18 3 6 magnets
Y-shaped Water (50) Permanent mag- FeO4 (0.04 – 0.28) NA, obtained two samples after operation (sample 1 [84]
200 3 50-70 net size range: 0.06 – 0.15 and sample 2 size range: 0.12 –
0.2)
T-shaped Diluted Ferrofluid (150- Permeant magnet Magnetic (2.85) and Polystyrene par- ~ 100 at flow rate less than 240 mL h1 [85]
400 3 40 350) ticles (10)

Wiley Online Library

T-shaped micro- Water o (150) Permeant magnet Magnetic (2.85) and Polystyrene par- Separation of particles at higher throughput possible in [85]
channel ticles (10) (NA) ferrofluid than in water
400 3 40

11
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 Pe r s o n a l A c c o u n t THE CHEMICAL RECORD

[88]
[86]

[87]

[89]

[90]
Ref.

2
3

NA, 736-fold enrichment of CTC via negative enrich-

NA, 20000-fold enrichment for sample with 0.001%

50, but with purity ~ 98% for throughput as 109 cell

4
Sorting rate of microparticle (1) ~ 5500 particles per

microparticles at 175 ml min-1, 70-95% purity over

magnetic microparticle in 109 ml-1 of polystyrene
5
6 100, for concentration from10-10000 cell/ml
7
8
9
10
Efficiency (%) and Comments

11
12
13
14
ment of WBCs
flow rate range

15
16
per hour

17
minute

18
19
20
Magnetic (1) and diamagnetic micro-

21
Magnetic particles (0.525) tagged to

Circulating tumor cells (CTCs) and

22
Supermagnetic particles (0.05)

23
Magnetic particles (1, 2.8, 5)

cancer cell line MCF-7 (7.5)

tagged Acinetobacter, E. coli

White Blood Cells (WBCs)

24
Particles and Size (mm)

25
26
27
28
particle (1)

29
30
31
32
Permanent mag-

Permanent mag-
Magnetic source

Nanostructured

Integrating per-

33
manent micro-
Electromagnet
soft magnetic

magnet array

34
net array

35
layer

36
nets

37
38
Aqueous solution (25-250)

39
Figure 5. Schematic of magnetophoretic microfluidic device for particle
40 separation: (a) a micro-comb with sharp tips to generate a non-uniform
Aqueous solution (-)

41 magnetic field using magnetic field from permanent magnet, (b) separation
Flow rate (mL h1)

42 of diamagnetic microparticles suspended in ferrofluid (initial focusing using

sheath flow) using permanent magnet, (c) separation of diamagnetic micro-
Blood (400)
Water (720)

43 particles suspended in ferrofluid (initial focusing using negative magneto-

Water (60)
Fluid and

44 phoresis) using permanent magnet, (d) separation of diamagnetic micro-

particles suspended in viscoelastic/ferrofluid using permanent magnet, (e)
45
separation of magnetic and diamagnetic microparticles suspended in
46 viscoelastic medium (diamagnetic fluid) using permanent magnet, (f )
Table 3. continued

47 separation of tagged and non-tagged cells suspended in diamagnetic fluid

using soft magnetic material integrated in the microchannel, (g) separation of
Straight micro-

Straight micro-
Width (mm) 3

PDMS micro-

48
Microchannel

RBC and WBC suspended in diamagnetic fluid using planar soft magnetic
Depth (mm)

49
1000 3 50
Serpentine

material integrated in the microchannel, (h and i) angled ferromagnetic wire

W 3 930
250 3 D
100 3 D

W3D
Straight

Straight

array used for separation of WBC and Deoxyhemoglobin RBC, (j) a spinning
channel

channel

channel

50
array of permanent magnets used in a magnetic trap device, and (k) on-chip
51 free-flow magnetophoretic device for separation of mixtures of magnetic and
52 non-magnetic particles.

Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley Online Library 12
 Pe r s o n a l A c c o u n t
1 bigger particles are displaced farther from the magnet due to
2 negative magnetophoretic force. The device is also inves-
3 tigated for the separation of two different-sized biological
4 entities, specifically Chlorella vulgaris and Synechococcus
5 sp.[72] Later Zhang et al.[73] developed a two-stage microfluidic
6 sorter that employed PEO/ferrofluid solution for size-based
7 separation of diamagnetic microparticles; experiments were
8 done to separate 5 mm and 13 mm diameter diamagnetic.
9 Furthermore, they compare the results with that in a
10 conventional aqueous ferrofluid.[73]
11 Figure 5e shows a H-shaped channel that was developed
12 for separating a heterogeneous mixture of magnetic and
13 diamagnetic microparticles into two homogeneous samples.[74]
14 The microparticles are suspended in a viscoelastic medium
15 and introduced into the microdevice through one of the
16 inlets. A buffer solution (diamagnetic medium) is introduced
17 into the microdevice through another inlet and it co-flows
18 with the viscoelastic solution. The microparticles undergo
19 focusing while inside the viscoelastic medium. Afterwards the
20 focused stream of microparticles were subjected to a non-
21 uniform magnetic field wherein the magnetic microparticles
22 moved into the co-flowing buffer solution. The diamagnetic
23 microparticles remained unaffected in the magnetic field and
24 was transported out of the microfluidic device by viscoelastic
25 stream. This device has reported separation efficiency as high
26 as 96 % while separating a heterogeneous mixture of 10 mm
27 diameter magnetic microparticles and 6 mm or 20 mm
28 diameter diamagnetic microparticles into homogeneous
29 samples based on magnetic property.
30 Figure 5f is a microdevice for continuously separating two
31 types of magnetically labelled cells.[75] Micromachined ferro-
32 magnetic strips were used to create high magnetic field
33 gradient in the microchannel. The device represented in
34 Figure 5f is an example of the type of devices which have soft
35 magnetic material integrated inside the microchannel for
36 realizing high magnetic field gradient.[75] Here, the combina-
37 tion of hydrodynamic force and magnetophoretic force is
38 utilized to achieve separation at purity higher than 90 % and
39 a throughput of 109 cells per hour.[75] Jung and Han[76]
40 demonstrated continuous magnetophoretic separation of
41 RBCs and WBCs, in blood samples, based on their intrinsic
42 magnetic properties. Herein, an array of ferromagnetic wires
43 integrated on the bottom surface of the microchannel at an
44 angle to the direction of the continuous flow was used to
45 create the required non-uniform magnetic field. For an
46 applied external magnetic field of 0.3 Tesla, separation
47 efficiencies of 93.9 % for RBCs and 89.2 % for WBCs were
48 reported.[76] Figure 5h and 5i shows a microfluidic device,
49 where a rectangular nickel (ferromagnetic material) wire
50 integrated on the bottom surface of the microchannel, for
51 separating WBCs and Deoxyhemoglobin RBCs in blood
52 samples.[77] The presence of the nickel wire makes the
Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
THE CHEMICAL RECORD
otherwise uniform magnetic field non-uniform in its vicinity.
As WBCs are diamagnetic while the Deoxyhemoglobin RBCs
are paramagnetic due to which the WBCs experience negative
magnetophoresis and the RBCs experience positive magneto-
phoresis. When the external magnetic field is applied along
the height of the microchannel as shown in Figure 5h, the
RBCs are pushed towards the side walls while the WBCs are
attracted closer to the nickel wire; the WBCs exit through the
central outlet while the RBCs exit through the side outlets.
On the other hand, when the external magnetic field is
applied along the width of the microchannel as shown in
Figure 5i, the RBCs are attracted closer to the nickel wire
while the WBCs are pushed towards the sidewalls; the RBCs
exit through the central outlet while the WBCs exit through
the side outlets. Separation of the breast cancer cells from
peripheral blood based on their electrophysiological character-
istics without any tagging has been reported.[78]
Figure 5j shows a magnetic trap (MagTrap) device.[79] The
device is capable of performing automated target capture,
mixing with reagents, and release the targeted cells in a single
microfluidic channel, by rotating the magnet wheel. The
external magnetic field can be further optimized by arranging
the permanent magnet so the position of the maximum field
gradient in the microchannel can be adjusted. MagTrap
device consists of six pairs of magnets in a rotating wheel,
situated immediately beneath the microchannel. The working
mechanism of the MagTrap device is as follow: Firstly, the
wheel rotates in the direction opposite to the continuous flow
to entrap and concentrate the magnetically tagged-cells and
separates them from the original sample matrix. Secondly,
during the rotation of the wheel, the active pair of magnets
moves away from the microchannel. Consequently, magneti-
cally tagged-cells are released and the surface of each cell is
exposed to reagents which prevents their aggregation. Finally,
to release of the magnetic tagged-cells for further analysis the
rotational direction of the wheel is reversed. Thus, the cells
swept downstream. The next pair of magnets repeat this
dynamic step and ensure the continuous movement of the
cells.
Figure 5k shows a continuous flow microdevice utilizing
magnetophoresis for the separation of magnetic particles
based on their size and magnetic susceptibility. The device
consists of a chamber with multiple inlets and outlets; flow
exchange between the microfluidic device and the external
occurs through all the inlets and outlets. Magnetic field,
generated by a permanent magnet, is applied perpendicular to
the flow direction as shown in the Figure 6.[80,81] Since the
deflection of particles depends on the particle size and
susceptibility, the diamagnetic particle leaves the chamber,
without any deflection, through outlet aligned with the inlet
through which the sample was introduced. On the other
hand, big magnetic particles were deflected more than the
Wiley Online Library 13
 Pe r s o n a l A c c o u n t THE CHEMICAL RECORD

1 device similar to that of Peyman et al.[91] for creating cyborg

2 cells–cells coated with polymers; in this device magnetically
3 labelled yeast cells were drawn through a layer of polyelec-
4 trolytes and then a buffer solution to create cyborg cells.
5
6
Figure 6. Continuous deflection of particles across multilaminar co-flowing 4. Summary and Outlook
7 streams.
8 Magnetophoresis in microfluidic devices have been reviewed
9 in this article. Laminar flow is an intrinsic component of
10 smaller ones when subjected to non-uniform magnetic field microfluidic devices and can be exploited along with
11 and this allowed for separating magnetic particles based on magnetophoresis in a variety of ways to manipulate micro-
12 size using the same device. The separation of biological cells, particles and cells for reactions and immunoassays. Magneto-
13 such as tumor cells and macrophages, labeled with magnetic phoresis, is proportional to the gradient of the magnetic field,
14 nanoparticles has been reported.[82] as well as the magnetic susceptibility difference between the
15 Zhou et al.[65] developed a continuous-flow microdevice, fluid and the microparticles or cells in the microchannel.
16 for separation and immunoassay, consisting of an incubator Positive magnetophoresis can be achieved by microparticles
17 and a separator that are serially connected and placed next to or cells having intrinsic magnetic properties as well as by
18 a permanent magnet. Firstly, the target molecules and microparticles and cells that are magnetically labelled. Cells
19 magnetic particles are introduced into the incubator, shaped separated by this method can be used for subsequent bio-
20 as a serpentine channel, to assist in the deflection of the molecular analyses with little or no alteration of their
21 particles back-and-forth into a sample stream and, therefore, genetics. In the same way as a magnetic material is attracted
22 to ensure binding of target molecules to the magnetic towards a magnetic field, a diamagnetic material experiences a
23 particles. Secondly, the tagged molecules pass into the repulsive force leading to negative magnetophoresis effects.
24 separation chamber that uses magnetic fractionation, to be Diamagnetic forces are much weaker than magnetic forces.
25 separated from the sample stream. However, by applying very high magnetic fields and gradients
26 such as those generated by super-conducting magnets or soft
27 magnetic microstructures diamagnetic repulsion forces have
3.4. Switching
28 been used to manipulate large label-free microparticles and
29 Switching refers to altering the path of microparticles or cells diamagnetic materials, such as cells for a range of bioanalyt-
30 so as to move the same to different locations inside the ical and separation techniques. However, a significant
31 microchannel. Switching has applications in washing as well challenge facing this technique is the biocompatibility of
32 as sorting. Researchers have employed positive magneto- magnetic fluids in which cells are manipulated. Because, it is
33 phoresis for purposes of switching. Peyman et al.[91] extended critical to preserving cell integrity during the cell manipu-
34 the concept developed by Pamme et al.[80,81] to include lation process, a specific magnetic fluid can be determined
35 multiple reaction and washing processes; the device is shown only after a rigorous investigation for each cell type, to ensure
36 in Figure 6. In Pamme et al.[80,81] all inlets were used for it is truly biocompatible.
37 introducing buffer solutions; however, in Peyman et al.[91] There are two techniques available for separation of
38 certain inlets introduced reagent solutions while the remain- microparticles and cells, specifically the trapping and con-
39 ing inlets introduced buffer solutions. As a microparticle or tinuous mode. By employing trapping mode, it is possible
40 cell with magnetic characteristics was drawn through a that fluid flow be restricted which in turn affects the
41 particular reagent solution, surface reactions occurred which efficiency and capacity. In addition, strong particle-particle
42 was later terminated by drawing the microparticle or cell interactions at the capture sites often create stable aggregates
43 through the adjacent co-flowing buffer solution. In Peyman which hinders their further utilization. Another constraint for
44 et al.[91] demonstrated the working of microfluidic device by the use of trapping microdevices is the entrapment of non-
45 pulling streptavidin coated magnetic microparticles through specific impurities of sample in the capturing regions.
46 reaction solution, having fluorescent labeled biotin, and Furthermore, it requires long operation times and complex
47 buffer solution. Vojtı́šek et al.[92] developed a microfluidic fluid connections and is suitable only for certain analytical
48 device based on the concept of Peyman et al.[91] for DNA applications. On the other hand, by using continuous flow
49 hybridization. In this device, magnetic microparticles that mode the selective separation of microparticles and cells is
50 were introduced through one of the inlets is pulled through a possible due to their continuous deflection through multiple
51 co-flowing streams of DNA sample, buffer solutions, and reagent and washing streams resulting in a large reduction in
52 intercalator solution. Tarn et al.[93] developed a microfluidic processing times. As well, the multi-step procedures carried

Chem. Rec. 2018, 18, 1 – 18 © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley Online Library 14
 Pe r s o n a l A c c o u n t THE CHEMICAL RECORD

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 1 PERSONAL ACCOUNT
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Magnetophoresis have gained significant F. Alnaimat*, S. Dagher, B. Mathew, A.
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renewed interest in recent years due to Hilal-Alnqbi, S. Khashan
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the possibility of integrating it with mi-
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crofluidics. Theory and applications
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related to microfluidics based magneto- Microfluidics Based Magnetophoresis:
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phoresis are discussed in this article. The A Review
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different forces relevant to magnetopho-
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resis based on microfluidic devices are
12 detailed in this review along with
13 different sources for creating magnetic
14 forces employed in microfluidic devices.
15 This article reviews different magneto-
16 phoretic microfluidic devices employed
17 for applications such as trapping,
18 focusing, separation, and switching.
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