Magnetism and microfluidics

Nicole Pamme

Received 13th September 2005, Accepted 3rd November 2005

First published as an Advance Article on the web 28th November 2005

DOI: 10.1039/b513005k

Magnetic forces are now being utilised in an amazing variety of microfluidic applications.

Magnetohydrodynamic flow has been applied to the pumping of fluids through microchannels.

Magnetic materials such as ferrofluids or magnetically doped PDMS have been used as valves.

Magnetic microparticles have been employed for mixing of fluid streams. Magnetic particles have

also been used as solid supports for bioreactions in microchannels. Trapping and transport of

single cells are being investigated and recently, advances have been made towards the detection of

magnetic material on-chip. The aim of this review is to introduce and discuss the various

developments within the field of magnetism and microfluidics.

Introduction

Magnetism and microfluidics; neither of these two concepts

are new, yet it has only been in recent years that they have been

combined. Electric fields have long been utilised in micro-

fluidic applications, such as capillary electrophoretic separa-

tions, electroosmotic pumping and dielectrophoretic

trapping.1–3 Magnetic fields however were initially employed

relatively rarely, despite the great advantages they could offer.

For example, objects inside a microfluidic channel can be

manipulated by an external magnet that is not in direct contact

with the fluid. Biomolecules can be isolated from a sample by

attaching them to small magnetic particles and then recovered

using an external magnetic field. In contrast to electric

manipulation, magnetic interactions are generally not affected

by surface charges, pH, ionic concentrations or temperature.

What has prevented researchers from utilising magnetic

forces? There are a number of reasons for this. MEMS

techniques for fabrication of miniaturised magnets have only

recently been combined with microfluidic fabrication.

Microfluidic researchers have been somewhat reluctant to

place objects such as magnetic particles into microchannels.4

Furthermore, magnetic microparticles functionalised with

antibodies or other biomolecules have only become off the

shelf products in the last few years.

Today we can see magnetic forces being combined with

microfluidics in an amazing variety of ways. Magnetic forces

can not only be utilised to manipulate magnetic objects such as

magnetic particles, magnetically labelled cells or plugs of

ferrofluids inside a microchannel; they can also be used to

manipulate non-magnetic, i.e. diamagnetic objects. Magnetic

fields are usually applied from outside the microchannel,

sometimes by means of sophisticated microfabricated electro-

magnets and sometimes by an approach as low tech as a

conventional benchtop stirrer plate. Applications include

pumping and mixing of fluids, as well as the incorporation

of switches and valves into lab-on-a-chip devices. Magnetic

forces are used for transport, positioning, separation and

sorting of magnetic as well as non-magnetic objects. Bio-assays

have been performed on the surface of magnetic particles

trapped inside a microchannel. More recently, on-chip detec-

tion techniques based on magnetic forces have been investi-

gated and basic research of magnetic behaviour, not possible

on the large scale, has been undertaken in the confined space

of microchannels. The objective of this review paper is to give

the reader a summary of the developments of magnetism in

microfluidics.

Magnetic theory

Magnetic field lines can reach a certain density within a

material, quantified by the material’s magnetic permeability, m.

The magnetic flux density, B (in Tesla or T) describes the

number of field lines per unit area. The flux density decreases

quickly with increasing distance from the magnet surface

(Fig. 1(a)). If a magnetic material, such as soft iron, is placed in

a magnetic field, the magnetic field lines are redirected through

National Institute for Materials Science (NIMS), International Centrefor Young Scientists (ICYS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044,Japan. E-mail: pamme.nicole@nims.go.jp; Fax: +81-29-860-4706

Nicole Pamme obtained aDiploma in Chemistry fromthe University of Marburg,Germany, in 1999. For herPhD she went to ImperialCollege London, where sheworked on single particleanalysis in microfluidic chipsuntil 2004. Since then she hasbeen living and working inTsukuba, Japan as an indepen-dent research fellow in theInternational Centre forYoung Scientists (ICYS) atthe National Institute forMaterials Science (NIMS).

Her current research interests include analysis of biomagneticparticles/cells in microfluidic devices. From December 2005,she will be joining the University of Hull, UK, as a lecturer inAnalytical Chemistry.

Nicole Pamme

CRITICAL REVIEW www.rsc.org/loc | Lab on a Chip

24 | Lab Chip, 2006, 6, 24–38 This journal is � The Royal Society of Chemistry 2006

that material to take advantage of its greater permeability

(Fig. 1(b)).

By combining magnets into arrays, complex magnetic field

patterns can be achieved even on the micron-size scale. In this

context it is important to differentiate between homogeneous

and inhomogeneous magnetic fields. In a homogeneous magne-

tic field, the density of flux lines is constant over a distance x,

there is no gradient in the flux density. In an inhomogeneous

magnetic field however, there is a gradient in the density of

flux lines over a distance x. Homogeneous fields are required

for NMR spectroscopy and magnetohydro-dynamic pumping.

To achieve this, magnets of rather large size with respect to the

fluidic volume are often employed (Fig. 2(a)). Inhomogeneous

fields with high magnetic field gradients are desired, when

the aim is to trap particles or transport materials within a

fluid volume (see eqn (1) below). To this end, tapered mag-

nets (Fig. 2(b)) or even layered structures (Fig. 2(c)) can be

used.

Magnetic field design is often accompanied by computer

simulations. As a basic option, the freely available software

FEMM (http://www.femm.foster-miller.net) can be employed.

More dedicated packages include MagNet (http://www.

infolytica.com) or FEMLAB (http://www.comsol.com).

Permanent magnets retain their magnetic properties once

any external magnetising field has been removed. Materials

that exhibit this behaviour include iron, nickel and cobalt.

Some of the strongest magnetic fields can be achieved with

alloys such as samarium cobalt (SmCo) or neodymium iron

boron (NdFeB). Electromagnetic fields are generated around

any current carrying wire. Such fields can be switched on and

off and tuned depending on the applied current. Furthermore,

time-varying fields can be obtained with alternating currents

(ac). Care has to be taken to insulate the wires and to avoid

Fig. 1 (a) The magnetic flux decreases rapidly with distance

from the magnet surface, as plotted here for a NdFeB magnet. (b)

Influence of a magnetically permeable material on the magnetic

field lines.

Fig. 2 Magnetic fields from permanent NdFeB magnets modelled with FEMM-freeware (http://www.femm.foster-miller.net): (a) A homogeneous

field at a distance of 1 mm along the surface of a large magnet. (b) An inhomogeneous field 100 mm above the surface of a tapered magnet. (c) A

magnetic field with local minima and maxima at 100 mm distance above a stack of alternating iron and aluminium blocks.

This journal is � The Royal Society of Chemistry 2006 Lab Chip, 2006, 6, 24–38 | 25

excessive heating at high currents. Strong magnetic fields can

be achieved by using an electromagnet with a highly permeable

core material such as soft iron or mMetal.

According to their magnetic susceptibility, x, materials are

classified as diamagnetic, paramagnetic and ferromagnetic.

Diamagnetic materials (x , 0) are repelled from magnetic

fields, i.e. they are forced towards minima of magnetic field

strength. Most materials are weakly diamagnetic, including

water, proteins, DNA, cells, polymers, wood and glass. Often

such materials are simply called non-magnetic. Paramagnetic

materials (x . 0) align in a magnetic field and experience a

small force towards magnetic field maxima, i.e. they are

attracted to magnetic fields. Examples of paramagnetic mater-

ials include oxygen, platinum and manganese(II) salts.

Ferromagnetic materials such as iron, cobalt and nickel have

x & 0 and are strongly attracted to magnetic fields. Another

special case of paramagnetism is superparamagnetism. Super-

paramagnetic particles have a core of small iron oxide crystals

encased by a polymer shell. The particles are magnetised in a

magnetic field. However, they have no magnetic memory.

Once the external field is removed, the particles redisperse and

behave like a non-magnetic material.

Force on a magnetic particle

The force on a magnetic particle inside a magnetic field

depends on the volume of the particle (V), the difference in

magnetic susceptibilities, Dx , between the particle (xp) and

surrounding buffer medium (xm), as well as the strength and

gradient of the applied magnetic field:

F~V :Dx

m0

B :+ð ÞB (1)

Note that for a homogeneous field, i.e. for a field with +B =

0, the force on the particle is zero. In this case, a particle would

merely be magnetised in the field but not be pulled into any

direction. Typically, forces on magnetic particles range from a

few pN to a few tens of pN.

The term Dx = xp 2 xm is the difference in magnetic

susceptibility between the magnetic particle, xp, and its

surrounding buffer or medium, xm. For diamagnetic objects

(xp , 0) in a diamagnetic medium (xm , 0), the term Dx can be

positive or negative, i.e. the particle can be repelled from or

attracted to the magnetic field. Since the magnetic suscepti-

bilities of a particle or cell and the surrounding material are

generally very close to each other, the term Dx is rather small,

i.e. the force on the particle is almost negligible. The buffer

medium however, can also be made paramagnetic, for example

by adding Mn2+ ions5,6 or Gd3+ ions.7 When a diamagnetic

object (xp , 0) is placed into a paramagnetic medium (xm . 0),

then the term Dx is always negative and thus the diamagnetic

object is repelled from the magnetic field and pushed towards

field minima. The larger xm, the stronger the repelling force. At

the same time, a paramagnetic particle (xp . 0) can be made to

act like a diamagnetic material by placing it into a strongly

paramagnetic medium, (xm . xp . 0). In this case, Dx is also

negative and hence the paramagnetic particle is repelled from

the magnetic field.

Magnet selection and fabrication

It can be rather challenging to achieve the desired magnetic

field pattern, strength and gradient over the confined space

of a microfluidic channel, especially when keeping in mind

how quickly the flux density decreases with distance from

the magnet surface (Fig. 1(a)). For manipulation in micro-

fluidic channels, two approaches can be taken: (i) con-

ventional permanent magnets or electromagnets are placed

outside the microchip, or (ii) microfabricated permanent

or electromagnets are incorporated into the microchip.

Approach (i) has the obvious advantage of ease of

fabrication, and low cost. Approach (ii) allows for a much

more confined spatial control of field strength and pattern

and also often allows for closer proximity of the magnet to

the microchannel.

(i) Conventional magnets

Permanent magnets used in microfluidic applications are

usually small neodymium iron boron (NdFeB) magnets featur-

ing magnetic flux densities of up to 500 mT at the pole surface.

This allows for manipulation of magnetic particles or cells

inside a microchannel even when the magnet is placed at

several mm distance from the channel. Depending on the

application, large or small magnets are required. For magneto-

hydrodynamic pumping, the entire channel area must be

subjected to a homogeneous magnetic field, i.e. large magnets

are required that are several cm long.8 For trapping magnetic

particles into a small plug, local magnetic field maxima are

necessary and magnets with diameters of only a few mm are

used.9 Rotation of magnetic material inside a microchannel

can be achieved by a rotating external magnet for example

with a conventional stirrer plate.10–12

Electromagnets frequently feature tapered cores in order to

achieve high field gradients13–15 (see Fig. 2(b)). Electro-

magnets have not been as popular as permanent magnets,

although they can be switched on and off and their field

strength can be tuned. Even when using a large number of

windings and high currents, it is difficult to build a small

electromagnet with a field strength comparable to that of a

small NdFeB magnet. Bulkiness and Joule heating quickly

become problematic.

(ii) Microfabricated magnets

Integrating microfabricated magnets into microfluidic devices

involves a considerable number of fabrication steps, not to

mention cost. On the other hand, small integrated magnets

permit very precise control of the magnetic field. When posi-

tioned in close proximity to the microchannel, the require-

ments for field strength are also reduced (Fig. 1(a)).

The techniques for micromagnet fabrication resemble those

employed for microfluidic chip fabrication (Fig. 3). Metal

layers are obtained either by sputtering,16 electroplating,17

evaporation18 or vapour deposition.19 Lithography and photo-

resists are used for patterning in combination with etching

and lift-off techniques. Substrates are either silicon20–22 or

glass.23–26 In many cases a seed layer is required to obtain

good adhesion between the desired metal and the substrate.

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Electrical insulation is realised by spin-coating with poly-

imide18 or by putting down a layer of silicon oxide.18,21,22

Ferromagnetic materials such as permalloy17,26,27 or nickel16

are used for permanent magnets or as cores for electro-

magnets. Planar electromagnets consisting simply of a current

carrying wire, can be fabricated easily by depositing a

conducting material, such as copper,20,23 gold18,25,28,29 or

aluminium.19,24 Joule heating, wire insulation and connection

to an external power supply must all be considered when

designing an electromagnet. More complex magnets with a

core and a wire wound around it, require further fabrication

steps, often with sacrificial layers.25,31–33 Choi and Ahn have

been pioneering in this field. In order to trap magnetic particles

in flow they developed several integrated electromagnets

including a meandering permalloy-core, copper-wire design,31

as well as serpentine27 and spiral26 copper-wires with a semi-

encapsulated permalloy. Integrated electromagnets were also

fabricated as coils for NMR on chip.22–25,34

Another approach to obtain precise control and strong

gradients in a microchannel is to micropattern magnetically

susceptible features in close proximity to the microchannel and

to magnetise these with an external magnet.28,35 For example,

Deng et al. fabricated Ni posts at the bottom of a PDMS

channel36 and Inglis et al. patterned narrow nickel strips on the

bottom of a microchamber.16 These features were then

magnetised with external NdFeB magnets.

Manipulated material

Magnetic materials

In some applications, small bars of steel37 or permalloy11,17

have been used inside microfluidic chambers. Most commonly,

however, magnetic particles are employed, as reviewed

recently.38,39 These range in size from a few nm to many mm.

The majority of these particles are superparamagnetic, i.e. they

have no magnetic memory. Although much is now commer-

cially available, the development of new types of magnetic

particles and their surface modification are still an area of

ongoing research.40–43

Superparamagnetic particles are available with carboxyl

groups or amino groups on their surface. Biomolecules such as

DNA strands or antibodies can then easily be attached to the

particle surface. Many companies offer particles with the

desired biomolecule already immobilised (Fig. 4). Popular

suppliers of such particles include Dynal (www.dynalbiotech.

com), Micromod (www.micromod.de), Bangs Laboratories

(www.bangslabs.com), Polysciences (www.polysciences.com),

Seradyn (www.seradyn.com) and Estapor (www.estapor.com).

Dynal’s Dynabeads are by far the most commonly used

superparamagnetic particles, due to their spherical shape and

highly uniform size distribution. Two sizes of Dynabeads are

available, 2.8 mm and 4.5 mm diameter. The magnetic core

comprises only a small fraction of the particle volume.44

Particles with a higher magnetite content have a stronger

Fig. 3 Fabrication steps for a micro-electromagnet with wires and

core, redrawn with permission from ref. 30.

Fig. 4 Surface functionalised particles can be used for a wide variety

of biochemical reactions.

This journal is � The Royal Society of Chemistry 2006 Lab Chip, 2006, 6, 24–38 | 27

interaction with applied magnetic fields.13 Best are Ni30Fe7045

or NdFeBLa46 particles, however, these uncoated metal

particles are not biocompatible.

Two types of cells are naturally magnetic:47 red blood cells

because of their paramagnetic haemoglobin and magnetotactic

bacteria which synthesise intracellular chains of magnetic

nanoparticles and use these to orient themselves along the

geomagnetic field. All other types of cells must be labelled to

render them magnetic. External magnetisation with micro-

particles is most common, although internal magnetisation

with nanoparticles48 is also possible. Cells have also been

labelled with paramagnetic lanthanide ions,49 such as Er3+.

Magnetic fluids or ferrofluids are another class of material

that can be used in microfluidic devices. A ferrofluid is a stable

suspension of magnetic nanoparticles in a carrier liquid such as

water, or an organic solvent. The particles are coated with a

surfactant in order to prevent aggregation. A ferrofluid can be

moved through channels and adopt any geometry. Even in

intense magnetic fields it retains fluidity. Since the suspension

is composed of nanometer sized particles, ferrofluids are

superparamagnetic. Ferrofluidic foams, i.e. ferrofluids with air

bubbles, have also been investigated.50

Diamagnetic objects

As mentioned above (eqn (1)), it is possible to manipulate

diamagnetic objects with magnetic fields. Such objects

experience a force towards magnetic field minima, allowing

for levitation and trapping. This was impressively shown by

Simon and Geim when they levitated a frog.51 Examples on the

microfluidic scale include the trapping of polystyrene parti-

cles,6 the patterning of cells7 and the levitation of droplets.52

Pumps

Magnetohydrodynamic (MHD) pumps

MHD pumps are an alternative to pressure driven or

electroosmotic flows. MHD flow is generated when an electric

field and a magnetic field are applied perpendicular to each

other across the height and width of a microchannel filled with

a conducting buffer solution. A Lorentz force acts in the

direction of the channel length and induces fluid movement.

MHD pumping is suitable for any conducting liquid and does

not require any moving parts. Pumping can be achieved in

straight channels as well as in circular channels. The flow

velocity can be adjusted by changing the applied current and

magnetic field or the ionic concentration of the buffer.

MHD micropumps operating with dc and homogeneous

magnetic fields are relatively easy to realise. For example,

seawater was pumped at velocities up to 2.5 mm s21 in a

straight silicon channel53 using aluminium electrodes, depos-

ited above and below the channel in combination with a

NdFeB magnet (440 mT). Bau’s group pumped mercury slugs,

saline solutions and deionised water through toroidal channels

at flow rates of up to 200, 12 and 0.5 mm s21, respectively.54

However, electrolysis can be problematic for dc-MHD pumps.

A high current density dc-MHD micropump8 transported

buffer solutions at up to 1 mm s21. To avoid bubble forma-

tion in the pumping channel, electrodes were located in a

neighbouring channel which was connected to the main

pumping channel via small channels.

Electrolysis can be avoided altogether with ac-MHD pumps.

With simultaneous switching of the electric and magnetic

fields, the Lorentz force always points into the same direction.

However, well-designed switching circuits are required. Lemoff

and Lee deposited platinum electrodes on the side of a looped

silicon channel and generated a magnetic field with small

commercial electromagnets.55 Flow velocities between 0.3 mm

s21 and 1.5 mm s21 were obtained for NaCl solutions with

concentrations between 0.01 M and 1 M. PBS buffer was

pumped at 0.16 mm s21. West et al. combined circular MHD

pumping with on-chip polymerase chain reactions (PCR) using

concentrated buffer solutions.56 Pt electrodes were deposited

on the vertical channel walls and a custom made electromagnet

generated a flux density of 11 mT across the channel. Eijkel

et al. designed a pump for circular chromatography57,58 with

gold electrodes on the channel side walls. The magnetic field

was generated by five custom made electromagnets, each

100 mT, that covered about 40% of the channel circumference.

Maximum flow rates obtained were 40 mm s21 for a 1 M

solution of KNO3, unfortunately too slow for the anticipated

chromatography application.

Ferrofluidic pumps

Plugs of ferrofluid, transported by external magnetic fields,

can be used for pumping liquids through channels. Such

pumps can be easy and cheap to realise. Ferrofluid and

pumped liquid must be immiscible, hence hydrophobic

ferrofluids are used for the pumping of aqueous solutions.

Hatch et al. fabricated a circular ferrofluidic micropump

(Fig. 5) based on two Nd magnets and two plugs of

ferrofluid.59 One plug was held in place between the inlet

and outlet channel, acting as a closed valve. A second plug

was moved around a circle by a rotating external magnet.

This plug pulled and pushed liquid into and out of the circular

channel. Water was pumped at 4 to 8 rpm, corresponding to

Fig. 5 The principle of a circular ferrofluid pump, redrawn with

permission from ref. 59. Two magnets (M) were employed to

manipulate ferrofluid plugs in a circular microchannel.

28 | Lab Chip, 2006, 6, 24–38 This journal is � The Royal Society of Chemistry 2006

2.1 to 4.2 mm s21. Choi and Ahn investigated pumping of

small volumes (7 to 60 nL) by rotating an external magnet

(340 mT) with steps of 18u above a plug of ferrofluid.60

Hartshorne et al. could pump both air and water, in a

T-shaped microfluidic network containing three plugs of

ferrofluid.61 Two plugs were used as valves. To close the

valve, ferrofluid was pulled with an external magnet from a

side pocket into the main channel. Another plug was used as

a piston. By switching the valves in the main channel and

moving the piston in the vertical channel, air could be pumped

from the atmosphere to an off-chip pressure sensor. Due to

the high viscosity of the ferrofluid, the piston could only be

moved at slow speeds of 30 to 50 mm s21. Thus, each cycle took

about 30 min and allowed for pumping of 300 nL of air. For

pumping of water, the channel surface was coated with hydro-

phobic silane in order to prevent leakage around the ferrofluid

plugs. Numerical simulations on how an array of micro-

electromagnets could be used to induce flow of ferrofluids in

microchannels62,63 were also reported.

Thermal and magnetic fields were combined for a magneto-

caloric pump.64 Materials lose their magnetic properties when

heated to their Curie temperature (TC). Conventional ferro-

fluids have a TC so high that any liquid would boil before

demagnetisation occurred. Here, ferrofluids containing Mn

and Zn were investigated with a TC below 80 uC. A uniform

magnetic field and a temperature gradient were applied over a

plug of such a ferrofluid. As the ferrofluid reached its TC, the

attraction towards the magnetic field was lost and the hot fluid

was displaced by cooler fluid. With the resulting pressure

gradient, a flow of 2 mm s21 was achieved.

Other pumps

Fluid movement in a microchannel can also be induced by

rotating small bar magnets in a reservoir adjacent to the

channel. A micro stirrer bar integrated into a polymer

(parylene) microchannel was rotated using a conventional

benchtop stirrer plate.17 The 400 mm long and 15 mm thick

permalloy bar was positioned in the centre of a 420 mm

diameter and 25 mm depth microchamber adjacent to a

microchannel of 200 mm width. Flow velocities of up to

200 mm s21 were achieved. However, a back pressure as small

as 10 Pa was enough to reverse the flow. With the rather

complex fabrication of the integrated stirrer bar, the usefulness

of such a pump in its present form is questionable.

A biomimetic pump based on vortices was reported by

Atencia and Beebe.65 In the same way as animals utilise

vortices to swim or fly with a minimum amount of energy,

local vortices can be employed to propel fluid through shallow

fluidic networks. A magnetic bar integrated into a microfluidic

structure was restricted by posts or channel walls, so that the

bar oscillated when a rotating magnetic field was applied. The

oscillation induced local vortices which created fluid flow of

between 3 to 600 mL min21 inside the channel.

Valves and switches

Valves based on ferrofluid plugs have already been mentioned

with ferrofluid-based pumps. In Hatch et al.’s design,59 a plug

held in a fixed position with an external magnet blocked fluid

flow and forced liquid to take an alternative route (Fig. 5).

Hartshorne et al. used ferrofluid valves for water as well as

air.61 With a 280 mT magnet the valve could operate against a

pressure of 0.5 bar, with a 580 mT magnet operation was

possible up to 1.2 bar.

Magnetically modified PDMS can also be used for valves.

Mixing iron powder with the PDMS precursor solution results

in a flexible magnetic material. A PDMS microchannel

network was fabricated with 5 mm long sections of magnetic

PDMS66 and attached to a circuit board containing electro-

magnets. When a magnet was switched on, the elastic magnetic

PDMS was deformed and blocked the channel. With 87 mT

flux from the magnet, the valve could resist water at a pressure

of 0.15 bar. A cycle time of 1 s was reported.

Magnetohydrodynamic flow can act as a switch to guide

flow along a channel network. MHD pumps were integrated

into the two branches of a Y-shaped channel network.67 Flow

could be switched between the branches by activating one

MHD pump and setting the other to counter-acting pressure.

No physical barriers or moving parts were required. However,

the pump could not withstand large back pressures and careful

adjustment of voltages and currents were necessary. Bau et al.

also controlled flow through a microfluidic network using

MHD pumps.68 Individual pairs of gold electrodes were

located on opposing channel walls of each of the branches

and a uniform magnetic field was applied over the entire

network with a Nd magnet (400 mT). By addressing the

appropriate electrodes, a plug of fluorescent dye was shown to

flow along the desired branches of the fluidic network. Flow

velocities of up to cm s21 could be attained.

Mixing

Mixing with magnetic stirrers

A very simple and effective combination of macroscopic stirrer

bars and microfluidic mixing was demonstrated by placing two

5 mm long stirrer bars into the inlet reservoirs at opposing

sides of a microchamber.10 The bars were rotated with a

conventional stirrer plate which initiated flow through the

chamber. The reaction efficiency of a DNA array could be

increased 5-fold.

Stirrer bars could also be integrated directly into a channel.

Magnetic permalloy rotors were fabricated on a glass substrate

and enclosed by a PDMS channel network.11 Rotation was

initiated with a conventional stirrer plate at 1.5 mT in the rotor

plane. When a 400 mm wide rotor was used in a 750 mm wide

channel, little mixing was achieved at the edges, where the

rotor did not reach. After some design improvements,17 a

permalloy bar of 400 mm width could be fitted into a

microchamber of 420 mm diameter (Fig. 6). With this design,

continuous flow mixing of two dyes was feasible over the entire

channel width.

Using a less elaborate fabrication regime, a steel blade (3 mm

long, 800 mm wide) was positioned at the junction of a

Y-shaped fluid network and rotated by a benchtop stirrer plate

at 2200 rpm.37 Two dyes were pumped through the device and

mixed at velocities between 1 and 240 mm s21. The authors

identify applications for mixing in channels where diffusion

based mixing alone is too slow.

This journal is � The Royal Society of Chemistry 2006 Lab Chip, 2006, 6, 24–38 | 29

Small magnetic nickel bars of 40 mm length and 1 mm

diameter controlled by three external electromagnets were also

suggested for mixing in microchannels.69 The mixing efficiency

of these bars has not yet been tested.

Mixing with magnetic particles

An easier way to integrate a miniaturised stirrer bar into a

microchannel is to assemble a chain of magnetic micro-

particles.70 To increase the stability of the chain, the particles

were bonded together with linker molecules. The channel

network contained three inlet channels merging into one outlet

channel. A rotating magnetic field (60 to 600 rpm, 1.5 mT) was

generated by two pairs of electromagnets that were supplied

with sinusoidal ac currents. A dye and two buffer streams all

containing particle chains were merged and mixed quickly

upon rotation of the chains. Also, an acid and a base were

mixed in the presence of a fluorescent pH indicator. Flow rates

were between 0.3 and 1.4 mm s21.

In another approach, two principles of efficient mixing, i.e.

fast magnetic rotation and utilising an array of rotors, were

combined. A PDMS device was fabricated with an array mag-

netic flux concentrators at the bottom of a mixing chamber.71

These concentrators were 25 to 100 mm diameter sections of

magnetically doped PDMS integrated into regular PDMS. A

suspension of iron filings (5 mm) was filled into the chamber.

When a permanent magnet (50 mT) was rotated below the

device, the magnetic field was concentrated to the regions with

the magnetic PDMS. The iron filings aggregated above the

concentrators into needle-like structures and rotated around

their bases. The mixing efficiency of these rotating spikes was

tested by pumping dye solutions through the chamber. Best

results were achieved in a pear-shaped chamber with semi-

circular wall indentations.

Magnetic particles moving at random were also suggested

for mixing of two fluid streams.13,72 A plug of magnetic

particles (1 mm) was formed in a microchannel by means of an

electromagnet. The magnet poles were tapered to increase the

force on the particles (see Fig. 2(b), eqn (1)). The particles

however did not form a static plug. Instead they were moved

over short distances due to the ever changing magnetic field

which was modified by an arbitrary wave form generator. A

mixing efficiency of 95% was reported for a fluorescent dye

and water, measured at a point 400 mm downstream of the

particle plug with flow rates of 5 mm s21.

Chaotic mixing was reported in a serpentine microchannel

with copper wire electromagnets, embedded transverse to the

direction of flow.73 The magnetic field generated from these

wires was used to attract nearby magnetic particles. Time

varying magnetic fields in combination with the serpentine

geometry lead to efficient mixing.

Magnetohydrodynamic (MHD) mixing

Magnetohydrodynamic flow was described above as a pump-

ing method. The same principle can also be utilised for mixing

fluids by integrating several MHD pumps into a microfluidic

device and by utilising time varying flow patterns in order to

achieve mixing. For example, a microchamber with several

electrodes along the walls and additional electrodes at the

bottom was subjected to uniform magnetic field from a large

Nd-magnet.68,74 Circulatory fluid motion was induced in the

chamber by applying potential differences between the

electrodes. Time and space variations in the electric field led

to chaotic motion and thus mixing, as visualised with a dye. In

another example, the parabolic flow profile of MHD-flow was

exploited for mixing in circular channels.75,76 Two solutions

were injected into the channel and MHD flow was initiated.

The parabolic flow profile led to a large increase in interfacial

surface area and thus to mixing. For example, fluorescein and

1 M KCl solution were mixed within 30 s at flow rates of

8 mm s21.

Trapping and transporting

Transport with electromagnets

Magnetic particles can be transported by pulling them from

one field maximum to the next. In an early example, a plug of

2.8 mm particles was moved along a capillary by consecutive

switching of several external tapered electromagnets.15 The

same principle was used on a smaller scale to transport parti-

cles along meandering gold wires (Fig. 7(a)).28 Here, local field

maxima were obtained by combining the field from the wires

with a uniform background field. A plug of 4.5 mm particles

was trapped from the suspension within the 200 mm 6 200 mm

area of a meander and moved along by switching between the

wires. On a larger scale, transport of magnetic beads (1 mm)

over a distance of 40 mm was reported using overlapping

electromagnets, each 3.5 mm in diameter.20

Very refined magnetic field maxima were obtained with saw-

tooth shaped current carriers fabricated from gold (Fig. 7(b)).18

A single bead (2 mm) was trapped at the location of highest

field gradient, i.e. at the edge of a ratchet element. By alter-

nating the current between the wires at 0.1 Hz, the bead was

pulled from one ratchet element to the next at 20 mm s21.

Loops and meshes of gold wires were effective for trapping

of magnetic particles,21 magnetically labelled yeast cells77 and

magnetotactic bacteria.29 A loop of 120 mm diameter could

Fig. 6 Magnetic mixing with a permalloy rotor (400 mm length)

controlled with a conventional benchtop stirrer plate.17

30 | Lab Chip, 2006, 6, 24–38 This journal is � The Royal Society of Chemistry 2006

trap magnetic particles (1–2 mm) from a drop of suspension.21

A smaller ring trap of 5 mm diameter, at the bottom of a

PDMS microchannel was employed to capture magnetotactic

bacteria.29 Meshes of 7 6 7 and 10 6 10 straight gold wires

(Fig. 7(c)), each individually addressable, generated localised

maxima of up to 100 mT.29 Cooling was necessary to prevent

boiling. Magnetic particles as well as magnetically labelled

yeast cells were trapped in these localised field maxima, i.e.

with a precision of less than 10 mm. Particles could be

transported in all directions across the mesh. Two groups of

particles could be merged into a single group. Similarly, a

group of cells was separated into two groups. Even single cell

manipulation was feasible. Magnetotactic bacteria were

trapped, lysed and the magnetic nanocrystals were retained.

Magnetic tweezers have been investigated for trapping of

particles in microfluidic channels. Exact positioning was

reported of magnetic particles (2.8 mm) in a capillary with a

tapered electromagnet that was mounted onto a mechanical

positioning stage.78 Magnetic nickel bars (250 nm wide and

9 mm long) were also suggested as a clamping system.14

Manipulation of diamagnetic objects

As mentioned earlier (eqn (1)), diamagnetic objects can be

trapped in magnetic field minima and the trapping force can be

increased by using a paramagnetic buffer. Polymer particles in

a paramagnetic 0.6 M MnCl2 solution and human blood cells

in a 0.1 M Mn2+ solution were trapped inside a capillary.79 A

magnetic field minimum over the channel was realised by using

two tapered NdFeB magnets with their north poles facing each

other. Blood cells could be trapped from flows travelling up

to 30 mm s21. Trapping and manipulation of cells suspended in

a paramagnetic buffer with 40 mM Gd3+ was also demon-

strated.7 Again, two magnets were arranged with their north

poles facing each other and tapered pole shapes were used to

localise the field minimum. Polystyrene particles and a variety

of cells were trapped from drops of suspension. The smallest

item to be trapped was 2.5 mm in diameter. Transport over

50 mm was possible by moving the magnets and shifting the

field minimum.

Diamagnetic objects could also be levitated and transported

along a 10 mm long channel.52 Droplets (30 mm) of glycerine/

water in air were levitated and transported with 300 nm

accuracy. To achieve levitation, two NdFeB magnets (500 mT)

were arranged with their north poles facing each other such

that a magnetic field minimum was present in the centre of the

gap. The droplets overcame gravity and were levitated into this

minimum. At the bottom of the gap, 25 mm wide electrodes

were positioned in order to generate localised field minima.

Sequential switching of these electromagnets enabled transport

of the levitated droplets. Even rotation and merging of two

droplets was possible. Other objects were levitated including

microparticles, nanotube powders and blood cells. The trapp-

ing of diamagnetic objects has been proposed as an alternative

to optical tweezers.7,52 This technique has a number of advan-

tages: the capturing volume is large, objects larger than 10 mm

can be trapped, trapping of a wider range of materials is feasible

and heat problems due to high optical flux density do not occur.

Sorting and separation

High gradient magnetic separations are commonly performed

in tubes or capillaries for separation of magnetic particles or

cells.49,80,81 Field-flow fractionation (FFF)82,83 and split-flow

thin (SPLITT) fractionation84,85 are continuous flow particle

separation methods in which several forces, such as gravity,

thermal gradients, electric or magnetic fields are combined.

On the microfluidic scale, H-shaped channel networks can

be used for magnetic separation. In one example (Fig. 8(a)),

electromagnets A and B, 220 mT each, were positioned at each

end of the connecting channel.86 Magnetic particles (2.8 mm)

Fig. 7 Magnetic particles can be transported with time-varying

electromagnetic fields. This can be achieved (a) along a track of

meandering gold wires,28 (b) along a saw tooth gold wire18 and (c)

along a gold wire mesh.29 All figures were redrawn with permission.

Fig. 8 Principle of H-shaped separators: (a) for particle isolation into

separate streams86 and (b) for continuous flow separation.87 Redrawn

with permission.

This journal is � The Royal Society of Chemistry 2006 Lab Chip, 2006, 6, 24–38 | 31

were pumped through one of the parallel channels with the

magnet adjacent to this channel, i.e. magnet A, switched on.

However, when magnet A was switched off and the magnet

adjacent to the opposite parallel channel, i.e. magnet B, was

switched on, particles at the channel junction were dragged

through the connecting channel into the neighbouring channel.

About 30 particles were isolated into the opposite parallel

stream during each cycle. Another H-shaped device with two

inlet channels merging into a wider channel and splitting into

two outlet channels was also suggested for the separation of

magnetic particles87 (Fig. 8(b)). A sample stream with particles

could be introduced into one of the inlets, buffer solution

through the other inlet. Without magnetic forces, the two

streams left unmixed through the corresponding outlet chan-

nels. Application of a magnetic field gradient over the middle

channel would drag magnetic particles out of their original

stream into the buffer stream. The device has not yet been

quantitatively evaluated.

A continuous flow method capable of separating magnetic

from non-magnetic particles as well as separating different

magnetic particles from each other was termed on-chip free-

flow magnetophoresis.88 Laminar flow was generated over a

flat separation chamber by a number of inlet and outlet

channels (Fig. 9(a)). Perpendicular to the direction of flow, a

magnetic field was applied by an assembly of NdFeB magnets,

resulting in a field gradient over the separation chamber. Non-

magnetic particles left the chamber opposite the sample inlet.

Magnetic particles however were dragged into the magnetic

field and left the chamber via one of the other outlet channels

(Fig. 9(b)). This deflection depended on the particle’s magnetic

susceptibility and the particle size (eqn (1)). The complete

separation of 2.8 mm and 4.5 mm magnetic particles was

demonstrated.89 Biological cells such as tumour cells and

macrophages, internally labelled with magnetic nanoparticles,

were separated according to their magnetic loading.90 In

another example, ferromagnetic strips at the bottom a

separation chamber assisted the separation of magnetic cells

in continuous flow.16 The 10 mm wide nickel strips ran at an

angle of 11u to the fluid flow. The flux lines from an external

magnet (100 mT) were concentrated by the nickel strips,

leading to local field gradients. Magnetically labelled leuco-

cytes were attracted to the strips and found to flow along

the strips rather than to follow the direction of fluid flow.

Similar to free-flow magnetophoresis,88 flow rates had to be

,1 mm s21 in order for the magnetic force to be sufficient to

induce deflection.

Zabow et al.91 used magnetic forces in combination with

capillary forces and surface tension to focus magnetic particles

into the centre of a microchannel. An aqueous suspension of

magnetic particles and air were pumped through a PDMS

channel with a hydrophilic bottom and a hydrophobic top.

The aqueous phase at the bottom bulged upwards. With a

magnetic field applied at the top, the particles were pulled

upwards to the air/water interface and subsequently they were

focussed at the point of highest magnetic force along the

interface, i.e. at the centre of the bulge.

Magnetic particles as solid supports for bioassays

Magnetic microparticles coated with biomolecules (Fig. 4) are

often used as solid supports for biochemical reactions. Particle

plugs can be formed in microchannels, featuring high surface

to volume ratios and low diffusion distances for the reagents to

the particle surface.4 Magnetic particles can be trapped

without physical barriers by simply stopping them in flow

with an external magnet. They can be released on demand by

removing the magnetic field (Fig. 10).

Plug formation in microchannels

Choi, Ahn and co-workers reported several microfluidic

devices with integrated electromagnets for trapping magnetic

particles in flow. They fabricated 3D electromagnets with poles

adjacent to a microchannel31 and planar magnets with

serpentine27 and spiral shapes.26 Depending on the magnet

design, currents of 500 mA31 to 30 mA27 were required to

capture magnetic particles (1 mm) and hold them at the magnet

poles. Particles could be retained at flow rates ,1 mm s21. A

change in inductance was observed, when the particles were

immobilised on the magnet, which could be exploited for

particle quantification. Smistrup et al. also fabricated spiral

electromagnets beneath a microchannel (Fig. 3)30 and applied

Fig. 9 (a) The principle of free-flow magnetophoresis. (b) Separation

of different types of magnetic particles from each other as well as from

non-magnetic particles88 (redrawn with permission).

Fig. 10 (a) Loading of magnetic particles into a microchannel. (b)

Flushing with sample and reagents for bioanalysis. (c) Release of

particles for downstream applications or disposal.

32 | Lab Chip, 2006, 6, 24–38 This journal is � The Royal Society of Chemistry 2006

360 mA to the coil. Magnetic particles (1 mm) were captured in

the region of strongest magnetic field on the magnet surface at

a flow rate of 74 mm s21. The capture efficiency was simulated

to be about 90% but has not yet been verified experimentally.

Nickel posts integrated at the bottom of a channel were also

demonstrated for the capture of magnetic particles in flow.36

PDMS was bonded to a wafer which was patterned with nickel

posts of 7 mm in height and 15 mm in diameter. Using an exter-

nal NdFeB magnet (500 mT), the nickel posts were magne-

tised. With the strong field gradients over the posts, 4.5 mm

diameter magnetic particles flowing through the channel could

be captured, even though the posts were much smaller than the

channel height. At a flow rate of 4.4 mm s21 a capture

efficiency of 95% was reported. Magnetic particles were also

isolated from a mixture containing non-magnetic particles.

Immunoassays

Commercial capillary electrophoresis instrumentation in com-

bination with external magnets was utilised for assays on

magnetic particles.92 Dynabeads (2.8 mm) were coated with

antibodies and stopped in flow with a cobalt magnet. Several

enzymatic assays and antibody isolation were performed on

the 2–3 mm long plug. Hayes et al. conducted immunoassays

inside capillaries and glass chips.93 Magnetic particles coated

with an appropriate antibody were trapped with a NdFeB

magnet (240 mT). Antigen containing sample was slowly

flushed through the channel, at about 1 mm s21, to allow for

antibody–antigen binding. The fast reaction times (few min)

and the small reaction volume (mL) enabling high sensitivity

detection were highlighted. Assays for fluorescein isothiocya-

nate (FITC), parathyroid hormone (PTH) and interleukin-5

(IL-5) were also demonstrated.

Choi, Ahn and co-workers demonstrated an enzyme

immunoassay94 by immobilising particles with a spiral electro-

magnet26 and detecting the assay reaction product with an

integrated electrochemical sensor positioned at the top of the

channel above the magnet. The sandwich assay was based on

2.8 mm Dynabeads coated with an antibody. These were

trapped, reacted with antigen solution and subsequently with a

secondary antibody, which was labelled with an enzyme. The

authors emphasise the fast reaction time of 20 min for the

entire assay procedure and low sample volumes of a few mL.

DNA and RNA hybridisation

Fast DNA hybridisation was reported on plugs of magnetic

particles within a microfluidic device.95 Magnetic particles

(2.8 mm) were coated with target DNA, pumped through a

microfluidic network with eight parallel channels and trapped

with external permanent magnets (600 mT) to form a plug of

less than 1 mm in length. Complementary probe DNA was

then pumped through the channel network for reaction with

the particle surface. Captured probe DNA could also be

released from the plug by heating to 87 uC. Thus, the beads

could be re-used up to 12 times.

mRNA was isolated from total RNA with capture efficien-

cies of 50% using a plug of magnetic particles in a microfluidic

channel.96 Magnetic particles (2.8 mm) coated with oligo-dT

were immobilised at a flow rate of 4.8 mm s21. Specific

capturing of RNA from Dengue fever virus in a polymer

microchip was also reported.97 Magnetic particles (2.8 mm)

were coated with an appropriate DNA probe and immobilised

using a small permanent magnet (250 mT) positioned near the

microchannel. The flow rate was 3 mm s21. The authors stress

the high sensitivity of their sensor in comparison to conven-

tional sensors for the same pathogen.

Tryptic digestion

Tryptic digestion of proteins was demonstrated on-chip with a

plug of magnetic particles that were coated with trypsin.98 A

protein solution was passed through the 6 mm long particle

plug at 3.5 mm s21. Digestion of glycoproteins was possible

within 15 min, in a very small reaction volume.

Cells

Magnetically labelled cells have been investigated only recently.

Jurkat cells were isolated from blood with anti-CD3 coated

magnetic particles (1–2 mm diameter).99 Blood and particles

were mixed off-chip and then trapped in the microchannel at

flow rates between 0.14 and 1.4 mm s21. The capture rate was

about 50% from a 2 mL sample. In another device, low

abundance T-cells were isolated from whole blood.9 A small

NdFeB magnet was employed to capture anti-CD3 coated

Dynabeads. Subsequently, whole blood was pumped through

the particle bed at 190 mm s21. Best capture rates were

achieved in a device with 8 parallel channels, but efficiencies

did not exceed 37%. Optimisation was a trade-off between a

sufficiently dense particle bed and the high shear stresses that

would ultimately push the magnetic particles out of the trap. A

more complex microdevice for cell capture on chip and PCR

combined with DNA detection was employed for E. coli

analysis.100 The bacteria cells contained in a blood sample

were attached to 2.8 mm Dynabeads during a 20 min incuba-

tion step. Subsequently the mixture was pumped into the

microdevice and the magnetic E. coli cells were captured and

isolated from the blood sample with an external magnet. This

was followed by on-chip PCR and DNA detection.

Self-assembly and patterning

The term self-assembly has often been used to describe the

formation of particle plugs or chains in microchannels.

Dynamic self-assembly has been used to describe the behaviour

of magnetic particles in time-varying or rotating magnetic

fields. Here, the emphasis is on the study of basic phenomena

of magnetic particle assembly and on controlling the assembly

into specific features and patterns.

Studies on micron-scale magnetic behaviour

Microfluidic devices offer the possibility to study fundamental

aspects of magnetism that are impossible to access in the bulk.

Researchers have calculated and verified experimentally the

formation of chains or columns of magnetic particles within

microfluidic chambers and how these columns interact with

each other to form characteristic patterns.101,102 Physical

laws were found to explain the spacing of particle columns

in droplets of ferrofluids.103

This journal is � The Royal Society of Chemistry 2006 Lab Chip, 2006, 6, 24–38 | 33

The behaviour of magnetic particle columns was examined

under the influence of electroosmotic and pressure driven

flows.104 In a uniform magnetic field (500 mT) the particles

formed columns in the direction of the field lines. Upon

application of a pressure driven flow of 20 mm s21, the particle

columns were pushed through the channel, but no deformation

was observed as might have been expected from the parabolic

flow profile. Aggregation of magnetic particles in the presence

of pressure driven flow was also studied.105 A suspension of

particles (0.83 mm) was introduced into a microchannel and a

uniform magnetic field (17 mT or 40 mT) was applied parallel

to the flow direction with SmCo magnets. The particles did not

form any aggregates, because there was no field gradient and

thus no force on the particles (see eqn (1)). When flow was

applied with rates between 21 and 333 mm s21, the particles

started to move past each other in close proximity and formed

particle chains along the field lines of the applied magnetic

field, before they were dragged away by the fluid. The authors

investigated this behaviour theoretically and experimentally.

Magnetic microparticles can be forced to assemble into

pyramids106 and small rings107 (Fig. 11). In a homogeneous

magnetic field particles generally form chains. Self-assembly

into pyramids is favourable, if the particles forming the base of

the pyramid are fixed, for example at the liquid/air interface of

a droplet. The authors verified this theory with a particle

suspension (2.8 mm) and a magnetic field of about 1 mT, which

is less than the magnetic saturation of the beads. In another

example, a domain wall of a magnetic film, i.e. a bismuth line

in a ferrite film was used for patterning. Particles were

attracted towards the domain wall. At flux densities between

0.5 mT and 1.25 mT, pyramids of 3, 6, 10, 15 or even 21

particles formed, the domain wall being at the base of the

pyramid. At fields larger than 1.25 mT, colloidal chains were

formed. The concept of domain walls was investigated further

by arranging these domain walls into stripes and mazes.108

Magnetic particles accumulated at the domain boundaries and

were observed to self-assemble into patterns depending on the

complexity of the domain pattern. Patterns changed when the

applied magnetic field strength was changed. Rings of magne-

tic particles were obtained from an emulsion of decane

droplets (10 to 100 mm diameter) in water.107

DNA separation on self-assembled magnet columns

Magnetic particle columns have been used as a sieving matrix

for DNA separation as an alternative to gels or tediously

fabricated nanocolumns. Viovy’s group investigated this

approach109,110 by assembling magnetic particles (0.5 or

1 mm) into columns inside a microchannel using a homo-

geneous magnetic field (10 mT). A fairly regular inter-column

distance was observed which could also be fine tuned by

changing the particle concentration or the magnetic flux

density. A mixture of DNA molecules was pumped through

the channel by electroosmotic flow and the DNA molecules

became entangled with the columns. The longer the DNA

molecule, the longer it was retarded by the column, thus DNA

strands of different lengths could be separated from each

other. This was demonstrated with the rapid separation of

l-phage DNA, 2 l-DNA and bacteriophage T4 DNA.110 The

particle bed could be flushed out of the microchannel easily

and a new plug of particles could be introduced and assembled.

Patterning of surfaces

A modulated magnetic field (see Fig. 2(c)) was employed to

pattern diamagnetic particles and cells onto a surface.5,6 The

modulated field was obtained by a stack of alternating iron

and aluminium sheets, each layer 300 mm thick, which was

placed into a homogeneous magnetic field of 1 T. Due to the

different magnetic susceptibilities, the field lines were denser in

the iron layers. Hence, the flux density was lower above the

iron, and higher above the aluminium layers. When a

suspension containing diamagnetic polymer particles was

placed above this modulator, the particles accumulated above

the iron layers, in the form of lines with 300 mm width.6 The

process took about 15 min. When manganese chloride was

added to the buffer, the magnetic susceptibility of the buffer

was increased and hence the force on the polystyrene particles

was increased (see eqn (1)). The particles were then observed to

move almost immediately to the area above the iron layers.

The same principle was also applied to biological cells.5

Detection

In most of the examples above, magnetic particles were observed

using optical microscopy. In some cases, bioassays were carried

out using fluorescence signals. However, the magnetic properties

of the particles could also be used for detection. The technical

challenge is to develop detectors that are sensitive enough to

count a single magnetic particle, ideally in continuous flow.

Giant magnetoresistive (GMR) sensors

GMR sensors consist of a film made from alternating magnetic

and non-magnetic layers. The electrical resistance of this film

Fig. 11 Magnetic microparticles (2.8 mm Dynabeds) assembled into rings107 and pyramids106 (with permission of the ACS).

34 | Lab Chip, 2006, 6, 24–38 This journal is � The Royal Society of Chemistry 2006

undergoes a large change as a function of the applied magnetic

field strength. When a magnetic particle is in the vicinity of the

sensor, the magnetic field on the sensor will be slightly altered

and this can be detected.

Miniaturised GMR sensors have so far been mostly

employed for the detection of DNA hybridisation. Typically,

DNA probes have been immobilised on the insulating layer

above such a sensor. Then, sample DNA was flushed over the

sensors and allowed to hybridise with complementary DNA.

The hybridised double strands were then labelled with

magnetic particles which could be detected by the GMR

sensor. In one example, a flow cell was positioned over an

array of 64 GMR sensors, divided into eight groups for the

detection of up to eight DNA sequences.44 Dynabeads of

2.8 mm diameter were used for magnetic labelling. The beads

could be detected with the GMR sensor and the signal

intensity indicated the amount of particles. However, detection

was not possible at the single bead level. Sensitivity could be

improved by using a thinner insulating layer above the sensor,

or by using particles with a greater magnetic susceptibility. In a

more recent paper, the detection of as little as ten Dynabeads

per sensor was achieved.45 Single bead detection was possible

with a highly magnetic uncoated nickel–iron particle (3.3 mm),

which unfortunately, was not biocompatible. In another

example, an array of 206 sensor elements was fabricated.

Each element had a diameter of 70 mm.111 Three types of

commercially available magnetic particles with 0.35, 0.86 and

0.90 mm diameters were compared. Detection was feasible with

a surface coverage of at least 5%, corresponding to about 2000

magnetic particles.

Pekas et al. demonstrated the use of GMR sensors for

magnetic detection in continuous flow within a microfluidic

channel.112 In this case, plugs of ferrofluid in a non-magnetic

oil were passed through a PDMS channel. Four GMR sensors

(20 mm 6 4 mm) were located at the bottom of this channel.

The ferrofluid plugs were 86 mm long, each containing about

5 6 108 magnetic nanoparticles. 5 plugs could be measured in

50 ms. Measurement of plug velocities and size and counting

of the number of plugs were possible.

Spin-valve sensors

Spin-valve sensors also consist of multiple layers of magnetic

and non-magnetic metals. Their magnetoresistance (MR)

changes depending on the magnetic field. Magnetic particles

in the vicinity of the sensor can be directly detected as an

electrical signal. Traditionally, such sensors have been used as

read-heads of hard-disk drives.

The velocity detection of 250 nm paramagnetic particles

within microfluidic channels was investigated.113 A PDMS

channel was fitted on a substrate with two integrated spin-

valve sensors, 1.65 mm apart, each sensor with an area of 2 mm

by 6 mm. The particles were pumped through the channel and

magnetised in flow by two aluminium wire electromagnets

positioned next to the sensors. A field gradient pulled the

particles close to the sensor, so that the passing particles could

be detected. The velocity was measured from the time it took

the particles to pass between two sensors. In this case flow

rates between 50 and 300 mm s21 were used. Detection of single

particles was not possible. Instead the authors reported

detection of particle plugs that were pumped through the

channel alternately with water plugs. DNA hybridisation has

also been detected using spin-valve sensors.114 Probe DNA was

immobilised on the sensor surface and the target DNA was

labelled with magnetic beads (250 nm). Aluminium wire

electromagnets were again used to attract the magnetic

particles into close proximity to the sensor and to allow for

the hybridisation reaction to take place. After washing away of

any unbound molecules, the remaining magnetic-DNA mole-

cules could be detected by the sensor. About 50 to 100

magnetic particles were sufficient for detection. These reac-

tions were performed in 10 to 20 mL droplets.

Superconducting quantum interference devices (SQUID)

SQUID microscopes can scan surfaces and provide magnetic

mapping with very high sensitivity (nT) at modest spatial

resolution (10 mm). Instrumental demands include magneti-

cally shielded rooms and cooling for the superconductors to

work. Katsura et al. worked on applications that are close to

microfluidics.115 An 8 mm long plug of ferrofluid (11 nm

diameter particles) was pumped through a plastic tube at flow

rates of 0.3 to 1.1 mm s21 and this could be detected by the

microscope. The minimum number of particles for detection

was 108. They also performed a DNA hybridisation assay on a

glass slide with magnetic particles used as labels. After washing

off any unbound label, they scanned the surface and were able

to detect hybridisation.

Miniaturised hall sensors

The Hall effect occurs when a current and a magnetic field

are applied perpendicular to each other over a conducting

material. Perpendicular to both fields, a change in voltage can

be detected that is proportional to the magnetic field strength.

Microfabrication of Hall sensors is somewhat easier than

SQUID or GMR sensors. Hall sensors with a footprint area of

several tens to 100 mm2 were fabricated from nickel or perm-

alloy connected to aluminium wires. With a micromanipulator,

a single 2.8 mm Dynabead was placed on the sensor and could

be detected.116 Clusters of nanoparticles (250 nm) and single

2 mm particles could also be detected from droplets.117,118 The

authors stressed that Hall sensors should exhibit a lower

noise level than GMR or SQUID sensors. They envisage an

array of such sensors to be used for mapping, for example in

combination with DNA hybridisation arrays.

In conclusion, there have been promising developments in

magnetic particle detection in recent years. Single particle

detection is now feasible, if a particle is in close vicinity to a

sensor. Continuous flow detection was possible for plugs of

ferrofluids. However, the counting of single particles in

continuous flow has not yet been achieved.

NMR on microchips

NMR spectroscopy is one of the most powerful methods for

the structural elucidation of molecules. Microfluidics in

combination with NMR would allow for measuring small

sample volumes. Kakuta et al. used a microfluidic mixing chip

This journal is � The Royal Society of Chemistry 2006 Lab Chip, 2006, 6, 24–38 | 35

that was directly connected to a microcoil NMR probe in

order to study the kinetics of protein conformation changes.119

Several groups, however, have attempted to miniaturise the

coil for excitation and detection of NMR signals and fabricate

it in close proximity to a microfluidic channel.120 A particular

challenge is the fact, that the magnetic field must be strong as

well as uniform in order get sufficient sensitivity and spectral

resolution. This imposes certain requirements for the coil

design and also for the flow cell.

Trumbull et al. reported the first example of on-chip

NMR.34 They integrated a planar NMR coil onto the back

surface of a glass microfluidic chip. The fluidic network

contained a reservoir of 1.4 mm diameter and 20 mm depth. A

single turn coil copper electromagnet was located below the

reservoir and connected to a PCB board for electrical control.

The chip was inserted into the bore of a 5.9 T superconducting

magnet. The miniaturised integrated coil was used for pulse

transmission and for receiving the free induction decay (FID)

signals. Proton spectra of a 30 nL sample of water/ethanol

were measured with a linewidth of 1.39 Hz. Massin et al.

reported NMR spectroscopy with a three-turn copper micro-

coil integrated into glass microfluidic chips with chambers of

30 nL, 120 nL or 470 nL volume.23,121 The coils had a diameter

of 2 mm or less and the distance between the channel and

the coil was 65 mm. Again the microchip was connected to a

PCB board and the assembly was inserted into a modified

conventional NMR machine. Spectra were taken of 160 mg of

sucrose in D2O for proof of concept with a line width of much

larger than 1 Hz.

Sorli et al. fabricated a copper microcoil of 500 mm 6500 mm at 200 mm distance to a microchannel of a silicon/glass

device.22 The device was inserted into a 2 T magnetic field.

Spectra of water and ethanol were reported with a linewidth of

12 Hz. Wensink et al. fabricated a coil at 80 mm distance from

a microchannel.24 The detection volume above the coil was

56 nL and residence times were between 9 s and 30 min,

depending on the applied flow rates. The chip was placed into

a superconducting magnetic field of 1.4 T. Two chemicals were

introduced into the microfluidic chip (benzaldehyde and

aniline) and merged just upstream of the coil section. The

formation of the reaction products (imine and water) was

studied at different flow rates.

Walton, Goleshevsky and others fabricated a dual coil

microfluidic NMR cell.25,120 Three-turn coils with diameters of

about 4 mm were located above and below a microchannel.

The authors took 13C spectra of labelled methanol with a

linewidth of 15 Hz, as well as 31P spectra of phosphoric acid

with a linewidth of 12 Hz. Even a 13C COSY pulse sequence of

acetic acid was achieved with a sampling time of one hour.

Outlook

Magnetism is now a widely applicable item in the micro-

fluidicist’s tool box. Many applications have been investigated,

but not all of them are competitive with the more convention-

ally used methods. For example, some of the magnetic mixers

are complex to fabricate in comparison to other microfluidic

mixers. Some of the magnetic pumps are too slow or generate

poor pressure heads. As always, the question lies in the

requirements for a particular application. The unique advan-

tages of magnetic manipulation lie in the possibility of

externally controlling matters inside a microchannel. This

can be a magnetic rotor for mixing or a single magnetic

particle or cell for trapping and transport.

Further developments are likely in several areas. One trend

within the microfluidics community is the design of integrated

devices in which sample pre-treatment, isolation, separation

and/or detection are combined. Labelling with magnetic

particles for isolation is an elegant option in such devices.100

Another trend is cell analysis on microfluidic platforms.

Magnetic forces can be employed to trap and position cells7,9

and more work is likely to emerge in this field. Reactions on

plugs of magnetic particles have so far been limited to one

plug. In the future, a sample could be flushed through several

particle beds with different surface chemistries, in order to test

for several analytes simultaneously.122 Several fundamental

studies on magnetic particle behaviour have been published.

With increasing insight into the fabrication of stronger and/or

smaller magnetic particles, more studies are likely to be

undertaken, possibly even in nanochannels to study single

domains. The effect of magnetic fields on bioreactions123 and

cells, as well as on the growth of crystals and films124 is of great

interest and could be studied in microfluidic devices. Self-

assembly of magnetic objects into complex three-dimensional

structures125 or into small machines126 is only starting to be

investigated and may soon be transferred to the micro- or

nanoscale. New materials, such as magnetically doped

PDMS,61 magnetic microgels,127 magnetic wires, magnetic

nanotubes are or will soon be finding their way into

microfluidic applications.

The potential of magnetic forces for microfluidic applica-

tions has been realised and many proof of principle devices

have been reported. With advances in this field on so many

fronts, more sophisticated devices will emerge and be part of

integrated and hopefully widely applicable micro-total analysis

systems.

Acknowledgements

The author would like to thank Alexander Iles for comments

on the manuscript and the Japanese Ministry for Education,

Culture, Sports, Science and Technology (MEXT) for funding.

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