Trends in Analytical Chemistry 62 (2014) 2836

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Trends in Analytical Chemistry

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a c

Sensors and biosensors based on magnetic nanoparticles

Teresa A.P. Rocha-Santos *
Department of Chemistry & CESAM, University of Aveiro, Campus de Santiago, Aveiro 3810-193, Portugal
ISEIT/Viseu, Instituto Piaget, Estrada do Alto do Gaio, Galifonge, Lordosa Viseu 3515-776, Portugal

A R T I C L E

I N F O

Keywords:
Analytical gure of merit
Biosensor
Electrochemical
Label
Magnetic eld
Magnetic nanoparticle
Optical
Piezoelectric
Sensor
Transducer

A B S T R A C T

Magnetic nanoparticles (MNPs) have attracted a growing interest in the development and fabrication of
sensors and biosensors for several applications. MNPs can be integrated into the transducer materials
and/or be dispersed in the sample followed by their attraction by an external magnetic eld onto the
active detection surface of the (bio)sensor. This review describes and discusses the recent applications
of MNPs in sensors and biosensors, taking into consideration their analytical gures of merit. This work
also addresses the future trends and perspectives of sensors and biosensors based on MNPs.
2014 Elsevier B.V. All rights reserved.

Contents
1.
2.
3.

4.

Introduction ...........................................................................................................................................................................................................................................................
Synthesis, properties and characterization of magnetic nanoparticles ............................................................................................................................................
Sensors and biosensors based on magnetic nanoparticles ...................................................................................................................................................................
3.1.
Electrochemical ......................................................................................................................................................................................................................................
3.2.
Optical .......................................................................................................................................................................................................................................................
3.3.
Piezoelectric ............................................................................................................................................................................................................................................
3.4.
Magnetic eld .........................................................................................................................................................................................................................................
Conclusions and future trends ........................................................................................................................................................................................................................
Acknowledgements .............................................................................................................................................................................................................................................
References ..............................................................................................................................................................................................................................................................

1. Introduction
Nanotechnology has been one of the most important research
trends in material sciences. Nanomaterials (nanoparticle (NP) size
range 1100 nm) compared with non-NP materials show remarkable differences in physical and chemical properties, such as unique
optical, electrical, catalytic, thermal and magnetic characteristics,
due to their small size [1]. In recent years, considerable efforts were
therefore made to develop magnetic NPs (MNPs), due to their own
advantages, such as their size, physicochemical properties and low
cost of production [2,3]. MNPs exhibit their best performance at sizes
of 1020 nm due to supermagnetism, which makes them especially suitable when looking for a fast response due to applied magnetic

* Tel.: +351 232 910 100; Fax: +351 232 910 183.
E-mail address: ter.alex@ua.pt; teralexs@gmail.com (T.A.P. Rocha-Santos).
http://dx.doi.org/10.1016/j.trac.2014.06.016
0165-9936/ 2014 Elsevier B.V. All rights reserved.

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elds [4]. MNPs also have large surface area and high mass transference. Since the properties of MNPs depend strongly on their
dimensions, their synthesis and their preparation have to be designed in order to obtain particles with adequate size-dependent
physicochemical properties. MNPs possessing adequate
physicochemistry and tailored surface properties have been synthesized under precise conditions for a plethora of applications, such
as sample preparation [57], wastewater treatment [8], water purication [9], disease therapy [3,10], disease diagnosis (magnetic
resonance imaging) [3,11,12], cell labelling and imaging [3,11], tissue
engineering [3], and sensors, biosensors and other detection systems
[1317]. Furthermore, MNPs have been used to enhance the sensitivity and the stability of sensors and biosensors for the detection
of several analytes in clinical, food and environmental applications. Taking into consideration the broad application of MNPs in
sensing and biosensing systems, this review describes and discusses the current state of recent applications of MNPs in sensors
and biosensors.

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29

2. Synthesis, properties and characterization of

magnetic nanoparticles

[5,7,21,22], so detailed discussion on such methods is beyond the

scope of this review.

In the past few years, many types of MNP were synthesized, including: iron oxides (Fe2O3 and Fe3O4); ferrites of manganese, cobalt,
nickel, and magnesium; FePt, cobalt, iron, nickel, CoPt and FeCo particles; and, multifunctional composite MNPs, such as Fe3O4-Ag, Fe3O4Au, FePt-Ag, and CdS-FePt heterodimers of NPs. MNPs can be synthetized
by physical methods (e.g., gas-phase deposition and electron-beam lithography), wet chemical methods (e.g., coprecipitation, hightemperature thermal decomposition and/or reduction, sol-gel synthesis,
ow-injection synthesis, oxidation method, electrochemical method,
aerosol/vapor-phase method, supercritical uid method, and synthesis using nanoreactors) and microbial methods [2,3,14].
According to Reddy et al. [3], the physical methods are limited
by their inability to control particle size down to the nanometer scale
while the microbial approach ensures high yield, good reproducibility and stability associated with low cost. A detailed discussion
of MNP synthesis, beyond the scope of this review, can be found
elsewhere [3,11,18,19].
MNPs need to be stabilized in order to prevent irreversible agglomeration and to enable dissociation. Such stabilization can be
performed by surface coating using appropriate polymers/surfactants
[e.g., dextran, and poly(ethylene glycol)], generating polymeric shells
that avoid cluster growth after nucleation and hold the particle
domains against attractive forces (e.g., nanosphere and nanocapsule),
and formation of lipid-like coatings around the magnetic core (e.g.,
liposomes) [3].
Materials are classied by their response to a magnetic eld
applied externally and there are the ve basic types of magnetism
(i.e., diamagnetism, paramagnetism, ferromagnetism, antiferromagnetism and ferrimagnetism) [2]. Materials whose atomic
magnetic moments are uncoupled display paramagnetism [2]. Due
to their small volume, MNPs are generally superparamagnetic, which
means that they have no net magnetic dipole. Thus, thermal uctuations cause random orientation of the spins (i.e., thermal energy
may be enough to cause the spontaneous change in the magnetization of each MNP). Therefore, in the absence of an electromagnetic
eld, the net magnetic moment of an MNP will be zero at high
enough temperatures, but, when a magnetic eld is applied to the
NP, a magnetic dipole is induced and there will be a net alignment
of magnetic moments. After the external magnetic eld is removed,
the MNPs randomly orient and return to their native non-magnetic
state. The shape and the size of NPs will also contribute to determine their magnetic behavior. The superparamagnetism in NPs is
determined by the crystallinity of the structures, the type of material, and the number of spins, and there is no general rule that
predicts the magnetic properties of an MNP. Magnetism is usually
evaluated using a magnetometer that monitors magnetization as
a function of applied magnetic eld [5].
The common analytical techniques used to measure the concentration and the composition of metallic NPs were recently
described by Silva et al. [20], including:

3. Sensors and biosensors based on magnetic nanoparticles

scanning electron microscopy (SEM), near eld scanning optical

microscopy (NSOM), transmission electron microscopy (TEM),
scanning transmission electron microscopy (STEM), atomic force
microscopy (AFM) and environmental scanning electron microscopy (ESEM) to assess the size and the shape of NPs; and,
energy-dispersive X-ray transmission - electron microscopy (EDXEM), electron-energy-loss spectrometry (EELS), X-ray
diffractometry (XRD) and X-ray uorescence (XRF) to measure
the elemental compositions of single NPs.

Those methods were also the most commonly used for characterization of MNPs applied in sensing and biosensing systems

Sensing strategies based on MNPs offer advantages in terms of

analytical gures of merit, such as enhanced sensitivity, low limit
of detection (LOD), high signal-to-noise ratio, and shorter time of
analysis than non-MNP-based strategies [23,24]. In sensing applications, MNPs are used through direct application of tagged supports
to the sensor, being integrated into the transducer materials, and/
or dispersion of the MNPs in the sample followed by their attraction
by an external magnetic eld onto the active detection surface of
the (bio)sensor.
Table 1 shows examples of MNP-based sensors and biosensors
for the detection of several analytes in different samples [22,2559],
taking into consideration their analytical gures of merit, such as
LOD and linear range. Table 1 shows that these sensors and
biosensors are based on different transduction principles (electrochemical, optical, piezoelectric and magnetic eld), which we present
and discuss in the following sub-sections according to their classication.
3.1. Electrochemical
Electrochemical (EC) devices measure EC signals (current, voltage,
and impedance) induced by the interaction of analytes and electrodes that can be coated with chemicals, biochemical materials or
biological elements to improve their surface activity [60,61]. EC
devices possess advantages of rapidity, high sensitivity, low cost and
easy miniaturization and operation, so being attractive in applications, such as clinical, environmental, biological and pharmaceutical
[13,60]. EC devices can be classied as amperometric, potentiometric, voltammetric, chemiresistive, and capacitive, according to
their working principles [60]. The EC immunosensors, and enzyme,
tissue and DNA biosensors are designed through immobilizing
biological-recognition elements of antibodies, enzyme, tissue and
DNA, respectively, on the working electrode surface. To improve the
sensitivity of EC devices, signal amplication has been attempted
using MNPs. MNPs can be used in EC devices through their contact
with the electrode surface, transport of a redox-active species to
the electrode surface, and formation of a thin lm on the electrode surface. For MNP-based EC biosensors [22,2527,3239],
Table 1 shows different detection modes, such as voltammetry
[2531], amperometry [32,33], potentiometry [34,35],
electrochemiluminescence (ECL) [36,37] and EC impedance [38,39],
which were used for analyte detection and quantication. Among
the sensors, the detection mode most used was voltammetry
[2831].
Due to its superparamagnetic property, biocompatibility with antibodies and enzymes and ease of preparation, Fe 3 O 4 is most
commonly used in developing biosensors. However, Fe3O4 magnetic dipolar attraction and its large ratio of surface area to volume may
lead to aggregation in clusters when exposed to biological solutions. Functionalization can overcome this problem and also enhance
biocompatibility.
A broad variety of functionalized MNPs have been used, such as
core-shell Au-Fe3O4 [25], core-shell Au-Fe3O4@SiO2 [32], core-shell
Fe3O4@SiO2 [28], Au-Fe3O4 composite NPs [22], Fe3O4@SiO2/MWCNTs
[33], Fe3O4 anchored on reduced graphene oxide [29] and Fe3O4@
Au-MWCNT-chitosan [30].
Core-shell Fe3O4@SiO2 is one of the most used in biosensors, since
it contributes to stabilization of MNPs in solution and enhances the
binding of ligands at the surface of MNPs. Core-shell Fe3O4@SiO2 is
also much used in modifying electrode surfaces, since its characteristics, such as good electrical conductivity, large surface area and

30

Table 1
Selected examples of sensors and biosensors based on magnetic nanoparticles
Transduction
principle
Electrochemical

Sensor type

0.01 ng mL1
0.22 ng mL1
5.6 104 ng mL1
2.0 105 M
1.8 108 M
ND
1.5 109 mol L1
0.13 M
0.01 mM
800 nM
0.007 g mL1

0.00550 ng mL1
0.5200.0 ng mL1
1.0 10310 ng mL1
2.0 1052.5 103 M
5.0 1081.0 106 M
0.20.6 nM
1.0 106-1.0 103 mol L1
0.60100.0 M
0.051.0 mM/ 1.0 mM8.0 mM
1 M30 mM
ND

Potentiometric enzyme based biosensor

Electrochemoluminescent immunosensor
Electrochemoluminescent immunosensor
Electrochemical impedance immunosensor

Core-shell Fe3O4
Core-shell Fe3O4 Au nanoparticles
Core-shell Fe3O4@Au
Iron oxide carboxyl-modied magnetic
nanoparticles
Fe@Au nanoparticles-2-aminoethanethiol
functionalized graphene nanoparticles
Magnetic nanoparticles (uidMAG-ARA)
with iron oxide core
Fe3O4@Au magnetic nanoparticles
Fe3O4 magnetic nanoparticles
Fe3O4/Ag/Au magnetic nanocomposites
Fe3O4-Au nanorod
Core/shell Fe3O4/SiO2
Core/shell Fe3O4/Ag/SiO2
Iron oxide carboxyl-modied magnetic
nanoparticles
Fe3O4
Iron oxide magnetic nanobeads

0.5 M
0.2 pg mL1
0.25 ng mL1
0.01 ng mL1

SPR immunosensor

Fluorescence immunosensor
QCM immunosensor
QCM biosensor
QCM immunosensor
Electrochemical QCM immunosensor
QCM immunosensor
Giant magnetoresistive immunosensor
Giant magnetoresistive immunosensor
Giant magnetoresistive sensor
Magneto-optical ber sensor
Magneto-optical ber sensor
Superconducting quantum
interference device sensor
Hall sensor
Hall sensor

Analyte

Ref.

[25]
[26]
[22]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]

0.5 M34 mM
0.00055.0 ng mL1
06 ng mL1
0.015 ng mL1

Carcinoembryonic antigen (N/A)

Clenbuterol (pork)
Organochloride pesticides (cabbage)
H2O2 (contact lens care solution)
Metronidazole (milk, honey)
Cr(III) (N/A)
Streptomycin (N/A)
Uric acid (blood serum, urine)
Glucose (human serum)
Glucose (glucose solution)
Zearalenone (maize certied
reference material, baby food cereal,
wheat, rice, maize, barley, oats, sorghum,
rye, soya our)
Glucose (human serum)
-fetoprotein (human serum)
Cry1Ac (N/A)
Ochratoxin A (wine)

2.0 1015 M

1.0 1041.0 108 M

DNA (N/A)

[39]

0.45 pM

ND

-human chronic gonadotropin (N/A)

[40]

mL1

mL1

[35]
[36]
[37]
[38]

0.65 ng
0.017 nM
ND
ND
ND
ND
0.94 ng mL1

1.0200.0 ng
0.2727 nM
0.1540.00 g mL1
0.1540.00 g mL1
1.2520.00 g mL1
0.3020.00 g mL1
150 ng mL1

-fetoprotein (N/A)
Thrombin (N/A)
Dog IgG (N/A)
Goat IgM (N/A)
Rabbit IgG (N/A)
Rabbit IgG (N/A)
Ochratoxin A (wine)

[41]
[42]
[43]
[44]
[45]
[45]
[38]

ND
0.0128 HA unit

103108 cfu mL1

0.12812.8 HA unit

[46]
[47]

Iron oxide magnetic nanoparticles

Fe3O4@SiO2
Core-shell Fe3O4@Au-MWCNTcomposites
Iron oxide magnetic nanoparticles
Cubic FeCo nanoparticles
Cubic FeCo nanoparticles
Iron oxide with polyethylene glycol coating
Fe3O4 nanoparticles
Fe3O4 in magnetic uid
Carboxyl functionalized iron oxide nanoparticles

ND
0.3 pg mL1
0.3 pg mL1
53 cfu mL1
83 fM
ND
8 Oe shift*
592.8 pm Oe1 **
162.06 pm mT1 **
1.3 106 cells

1.8 1041.8 107 cfu mL1

0.001100 ng mL1
0.0015 ng mL1
ND
ND
125 fM41.5 pM
ND
ND
ND
ND

Escherichia coli (N/A)

Avian inuenza virus H5N1 (chicken
tracheal swab)
D. desulfotomaculum (N/A)
C-reactive protein (human serum)
Myoglobin (human serum)
Escherichia coli O157:H7 (Milk)
Endoglin (human urine)
Interleukin-6 (human serum)
N/A
N/A
N/A
MCF7/Her2-18 breast cancer cells (mice cells)

Manganese-doped ferrite (MnFe2O4)

Manganese-doped ferrite (MnFe2O4)

ND
ND

101105 cells
101106 counts

Rare cells: MDA-MB-468 cancer cells (whole blood)

Staphylococcus aureus, Enterococcus faecalis and
Micrococcus luteus (spiking cultured bacteria
in liquid media)

[58]
[59]

* Shift due to deposition of 7 MNPs.

** Sensitivity.
MWCNT, Multiwalled carbon nanotube; N/A, not applied; ND, not determined; QCM, Quartz-crystal microbalance; SPR, Surface-plasmon resonance.

[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]

T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014) 2836

Magnetic eld

Detection range

Core-shell Au-Fe3O4
Fe3O4 Au nanoparticles
Au-Fe3O4 composite nanoparticles
Fe3O4 Au nanoparticles
Core-shell Fe3O4@SiO2
Fe3O4 anchored on reduced graphene oxide
Fe3O4@Au-MWCNT-chitosan
Core-shell Fe3O4@SiO2/MWCNT
Core-shell Au-Fe3O4@SiO2
Fe3O4@SiO2/MWCNT
Magnetic beads Dynabeads Protein G

SPR immunosensor
SPR immunosensor
SPR immunosensor
SPR immunosensor
SPR immunosensor
SPR immunosensor
SPR immunosensor

Piezoelectric

Detection limit

Voltammetric immunosensor
Voltammetric immunosensor
Voltammetric enzyme based biosensor
Voltammetric enzyme based biosensor
Voltammetric sensor
Voltammetric sensor
Voltammetric sensor
Voltammetric sensor
Amperometric enzyme based biosensor
Amperometric enzyme based biosensor
Potentiometric immunosensor

Electrochemical impedance biosensor

Optical

Modes of magnetic nanoparticles

T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014) 2836

31

Fig. 1. Example of an electrochemical (voltammetric enzyme-type) biosensor: view of the apparatus from (a) plane and (b) vertical directions; (c) detection principle for
the detection of organophosphorous pesticides (OPs); CV, Cyclic voltammetry; DPV, differential pulse voltammetry; SPCEs, screen printed carbon electrodes; TCh, thiocholine;
AChE, Acetylcholinesterase; ATCh, Acetylthiocholine; GMP, Fe3O4/Au (GMP) magnetic nanoparticles; GMP-AChE, Acetylcholinesterase-coated Fe3O4/Au magnetic nanoparticles;
PB, Prussian blue; CHI 660B, Electrochemical workstation. {Reprinted from Open Access [22] 2010, MDPI}.

more electroactive interaction sites, can provide enhanced mass

transport and easier accessibility to the active sites, thus increasing the analytical signal and the sensitivity.
Carbon materials, such as carbon nanotubes (CNTs) are also
widely used to functionalize MNPs due to their physical properties, such as large surface area, chemical and thermal stability,
controlled nanoscale structure, and electronic and optical properties [30]. Recently, a nanocomposite of multi-walled CNTs (MWCNTs)
decorated with magnetic core-shell Fe3O4@SiO2 was synthetized and
used to fabricate a modied carbon-paste electrode (CPE) for the
determination of uric acid (Fe3O4@SiO2/MWCNT-CPE) [31]. The ECsensing characteristics were studied by cyclic voltammetry for an
MNP-modied CPE (Fe3O4@SiO2/MWCNT-CPE), an unmodied CPE
and an MWCNT-CPE. The anodic peak current of MNP-modied CPE
was found to be 2.7 times higher than that of the MWCNT-CPE and
4.6 times higher than that of the unmodied CPE. The increased sensitivity can be attributed to the core-shell Fe3O4@SiO2/MWCNT that
has fast electron-transfer kinetics and a larger electroactive surface
area compared to the other two electrodes (MWCNT-CPE and unmodied CPE).
Au-Fe3O4-composite NPs [22] are also used due to their ease
of preparation, large specic surface area, good biocompatibility,
strong adsorption ability and good conductivity, enhanced by using
AuNPs. As an example, Gan et al. [22] modied a screen-printed
carbon electrode using a composite of MNPs. Fig. 1 shows the biosensor apparatus and the biosensor-detection principle of
organophosphorous pesticides. In this device, acetylcholinesterase (AChE)-coated Fe3O4/Au MNPs were synthetized and then
absorbed on the surface of a CNT/nano-ZrO2/Prussian blue/Naonmodied screen-printed carbon electrode. The biosensor was applied
to determine dimethoate in cabbage and showed performance comparable to gas chromatography coupled to ame photometric
detector (GC-FPD). The biosensor showed advantages, such as a fast
response, adequate linear range (Table 1) and adequate sensitivity
for the detection of organophosphorous pesticides due to the conductive Fe3O4/Au MNPs that were used to provide a large electrode
surface area to amplify the current response signal of thiocholine
(TCh) and to enhance sensitivity. Furthermore, the biosensor surface
can easily be renewed on removing Fe3O4/Au/AChE from the biosensor by applying an external magnetic eld due to its
superparamagnetism. Nevertheless, the easy immobilization of
enzyme/MNPs (Fe3O4/Au/AChE) on the screen-printed carbon electrode reduces the manufacturing costs, since it has the advantages

of integration of the electrodes, simple manipulation, low consumption of sample, reduced use of expensive reagents, and simple
experimental design.
As another example, Zamr et al. [38] developed an ECimpedance immunosensor for the detection of ochratoxin-A based
on anti-ochratoxin-A monoclonal-antibody-iron-oxide carboxylmodied MNPs at the surface of an Au working electrode. The use
of iron-oxide carboxyl-modied MNPs for anti-ochratoxin-A
monoclonal-antibody immobilization allows easy regeneration of
the electrode and also reduces the impedance of the system, thus
increasing its sensitivity.
In both these examples, the MNPs were concentrated on
electrode-surface materials and have advantages, such as increased sensitivity and stability, besides ease of renewing the
electrode by releasing the MNPs and replacing them with new MNPs.
ECL immunosensors currently use MNPs as labeling agent or immobilization support. The ECL signal is based on a sequence of stages,
such as EC (single electron redox processes of substance), chemical (biradical combinations) and optical (emission of the ECL quanta)
[62]. The ECL assays can have three main formats (i.e., direct interaction, competition assay and sandwich-type assay) [62]. Quantum
dots, such as CdS, CdSe or core/shell type ZnS/CdSe, have been of
greatest interest in ECL applications due to the quantum connement effect having optical and electronic properties that make them
excellent labels for improving the sensitivity of transducer surfaces coated with MNPs and magnetic capture probes.
An ECL immunosensor was developed for detecting -fetoprotein
(AFP) based on a sandwich immunoreaction strategy using magnetic particles as capture probes and quantum dots as signal tags
[36]. Fig. 2 shows the process used for preparing magnetic capture
probes Fe3O4-Au/primary AFP antibody (Ab1) and signal tag of CdSAu/ secondary AFP antibody (Ab2). The Ab1 was rst anchored in
the surface of Fe3O4-Au nanospheres by the Au-S bond. The products with an Ab1 immobilized on the surface of Fe3O4-Au captured
AFP (antigen) from a solution. Finally, the protein-labeled CdSAuNPs were introduced to the immunoreaction with the exposed
part of AFP. The Fe3O4-Au/Ab1/AFP/Ab2/CdS-Au was used to construct the ECL immunosensor. It was observed that the Fe3O4 MNPmodied electrode, in the solution, had almost no ECL signal, while
the Fe3O4-Au MNP-modied electrode had a slightly enhanced ECL
signal. The signal of the immunosensor was therefore further enhanced by adding CdS-Au as a label compared to the non-labeled
system (Fe3O4-Au/Ab1/AFP). It was also observed that, when the

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T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014) 2836

Fig. 2. Example of the preparation procedure of an electrochemiluminescent (ECL) immunosensor. BSA, Bovine serum albumin; AFP, -fetoprotein; Ab1, Primary antibody
of AFP; Ab2, CdS-Au labeled secondary antibody. {Reprinted [36] 2012, with permission from Elsevier}.

CdS-Au composite lm was used instead of CdS NPs, the ECL signal
increased 2.5 times. This increase can be attributed to the catalytic activity of AuNPs that enhanced electrical conductivity and
sensitivity. The immunosensor showed performance comparable to
ELISA in detecting AFP in human serum and therefore potential for
clinical application.
3.2. Optical
Optical devices have been applied to the detection of several
analytes in clinical samples [24,63], environmental samples [6466]
and food samples [67] due to their main characteristics, such as low
signal-to-noise ratio, reduced interferences, and reduced costs of
manufacture. Optical devices can be classied by their principles
of detection (i.e., uorescence spectroscopy, interferometry, reectance, chemiluminescence (CL), light scattering and refractive index).
CL-detection systems have to be enhanced in emission intensity and
improved in selectivity for use in quantitative analysis of complex
matrices, such as biological and environmental samples. In order
to overcome such limitations, MNPs can play a useful part in the
CL reactions as catalyst, biomolecule carrier and separation tool [16].
Iranifam [16] recently reviewed and discussed the analytical applications of CL-detection systems assisted by MNPs, so a detailed
presentation and discussion on such methods is beyond the scope
of this review.
Table 1 shows that, among the MNP-based optical devices, the
detection modes used were surface plasmon resonance (SPR)
[38,4045], and uorescence spectroscopy [46]. Fig. 3 shows an
immunosensor that combines SPR technology with MNP assays for
detection and manipulation of human chorionic gonadotropin (hCG) [40]. The approach is based on a grating-coupled SPR sensor
chip that is functionalized by antibodies recognizing the target
analyte (-hCG). The MNPs were conjugated with antibodies and
were used both as labels for enhancing refractive-index changes due

to the capture of analyte and also as carriers for fast delivery of the
analyte at the sensor surface, thus enhancing the SPR-sensor response. A magnetic eld was used to capture the MNPs-antibodyanalyte on the sensor surface. The use of MNPs together with its
collection on the sensor surface by applying a magnetic eld improved the sensitivity by four orders of magnitude with respect to
regular SPR using direct detection. This enhancement was attributed to the larger mass and higher refractive index of MNPs. An LOD
of 0.45 pM was achieved for the detection of -hCG. This working
principle should be further investigated for the analysis of analytes,
such as viruses or bacterial pathogens, since it can overcome the
problems of the low sensitivity of SPR-biosensor technology due to
mass transfer to the sensor surface being strongly hindered by diffusion for these analytes.
The analytical signal associated with uorescence intensity can
also be enhanced using MNPs, such as Fe 3 O 4 . A microuidic
immunosensor chip was developed having circular microchannels
[46] for detection of Escherichia coli. The methodology used involves, in a rst step, the conjugation of Fe3O4 MNPs with antibody
and, in a second step, the in-ow capture of antigens in the
microchannels. The captured MNPs create a heap-like structure at
the detection site under the inuence of a reversed magnetic ow
that increases the retention time of antigens at the site of capture
and the capture eciency of antigens, so enhancing the intensity
of the uorescence signal.
3.3. Piezoelectric
Piezoelectric devices can be quartz-crystal microbalance
(QCM) and surface acoustic wave (SAW). Table 1 shows that the
MNP-based piezoelectric sensors and biosensors are based on
QCM transduction [4751]. The QCM is a quartz-crystal disk
with metal electrodes in each side of the disk [6870] that vibrates under the inuence of an electric eld. The frequency of

T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014) 2836

33

this oscillation depends on the cut and the thickness of the disk.
This resonant frequency changes as compound(s) adsorb or desorb
from the surface of the crystal. A reduction in frequency is proportional to the mass of adsorbed compound. QCMs are small and
robust, inexpensive, and capable of giving a rapid response down
to a mass change of 1 ng. The major drawback of these devices is
the increase in noise with the decrease in dimensions due to instability as the surface area-to-volume ratio increases. More
disadvantages of QCM are the interference from atmospheric humidity and the diculty in using them for the determination of
analytes in solution [71].
MNPs with piezoelectric properties can easily eliminate these
problems, since they offer an attractive transduction mechanism and
recognition event with advantages, such as solid-state construction and cost effectiveness. The frequency enhancement in the
presence of MNPs can be due to:
(1) the MNPs possessing some inherent piezoelectricity;
(2) the MNPs binding and helping to concentrate the analyte molecules at the QCM surface; and,
(3) the MNPs acting as matrix carriers to load labels.

Fig. 3. Example of a surface-plasmon resonance (SPR) immunosensor: (A) Optical

sensor set-up and (B) a sensor chip of the magnetic nanoparticle (NP)-enhanced
grating coupled SPR sensor. (C) The analytical signal before and after immobilization of the capture antibody. {Reprinted with permission from [40], 2011, American
Chemical Society}.

A QCM immunosensor for detection of C-reactive protein (CRP)

in serum was developed. In a rst step, a sandwich-type
immunoreaction was made between the capture probe (silicon
dioxide-coated magnetic Fe3O4 NPs) labeled with primary CRP antibody (MNs-CRPAb1), CRP and signal tag [horseradish peroxidase
(HRP) coupled with HRP-linked secondary CRP antibody coimmobilized on AuNPs (AuNPs-HRP/HRP-CRP Ab2)] [49]. In a second
step, the immunocomplex was exposed to 3-amino-9-ethylcarbazole
(AEC) and hydrogen peroxide. Fig. 4 shows the preparation procedures and the detection principle. The capture probe containing the
MNPs (MNs-CRPAb1) enhanced the analytical signal due to both
magnetic separation and immobilization at the electrode surface.
Further, the advantages of the magnetic beads (Fe3O4@SiO2) for labeling CRPAb1 include the mono-disperse size distribution and easy
preparation of the labeled conjugates. The performance of the QCM
methodology was comparable with the ELISA methodology when
detecting CRP in human serum. Moreover, the QCM-sensor surface
can be regenerated easily and used repeatedly due to the use of the
MNPs.
More research is needed on the development of magnetic
nanostructures, characterization of their piezoelectric behavior and
their application in piezoelectric sensors and biosensors, since they
promise to overcome the sensitivity and stability issues characteristic of these kind of devices.

Fig. 4. Example of a quartz-crystal-microbalance (QCM) immunosensor. (Left) Procedures of the preparation of Fe3O4@SiO2-Ab1 and AuNPs-HRP/HRP-Ab2 conjugations.
(Right) Detection principle. TEOS, Tetraethyl orthosilicate; EDC, 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide; NHS, Amine-reactive N-hydroxysuccinimide; CRP, C-reactive
protein; Ab1, Primary CRP antibody; Ab2, Secondary CRP antibody; AuNP, Gold nanoparticle; HRP, Horseradish peroxidase; AEC, 3-amino-9-ethylcarbazole; MNP, Fe3O4@
SiO2 nanoparticle. {Reprinted from [49], 2013, with the permission from Elsevier}.

34

T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014) 2836

Fig. 5. Example of the use of magnetic nanoparticles (MNPs) and giant magneto-resistive (GMR) sensors in two different methodologies. (A) Sandwich-type approach, where
the GMR sensor is functionalized with capture antibodies, for subsequent analyte binding. The detection antibodies labeled with MNPs are then applied and bind to the
captured analyte. (B) Two-layer approach, where the GMR sensor is functionalized with capture antibodies for the direct application and capture of the MNP-modied analyte.
(C) GMR biosensor working principle. {Reprinted with permission from [53], 2010, American Chemical Society}.

3.4. Magnetic eld

Table 1 shows that the magnetic eld devices using MNPs [5259]
include giant magnetoresistive (GMR), Hall Effect, magnetooptical and superconducting quantum interference sensors.
Magnetoresistive sensors are based on the intrinsic magnetoresistance of a ferromagnetic material or on ferromagnetic/nonmagnetic heterostructures [72]. Depending on the nanostructure
of the nanomaterial layer, these devices can show the GMR effect
or the tunneling magnetoresistance effect. In these devices, the analytical signal (change in electrical resistance) is measured following
the analyte binding in the presence of a magnetic eld. The analytical signal can therefore be obtained by small changes in the
magnetic eld and depends on the magnetic eld along the sensor
area [73]. When using a GMR device and MNPs for interleukin-6
(analyte) detection, two methodologies have been attempted (Fig. 5)
[53]. In the rst possible methodology, the GMR sensor is
functionalized with capture antibodies and the analyte binds to
the capture antibody. The detection antibodies labeled with MNPs
bind to the analyte captured. The second detection methodology
involves functionalization of the GMR sensor with capture antibodies, and then the direct capture of the MNP-labeled analyte on
the GMR biosensor. In both cases, the GMR biosensor detects the
dipole eld generated by the MNPs captured on the sensor surface,
which is sensitive to distance. The quality of the MNPs is very important for successful magnetoresistive detection, so ideal probes
should be superparamagnetic, having high magnetic moment and

large susceptibility, in order to enable their magnetization in a small

magnetic eld. The MNPs also need to have uniform size and shape,
since the magnetic signal depends on it, and to be stable in physiological solutions, so that their coupling with biomolecules can
be controlled [73]. Moreover, the choice of MNPs with high
magnetic moment leads to increased signal and therefore high sensitivity. Taking this into consideration, for sensitive magnetoresistive
detection, the ideal candidates have been metallic Fe, Co, or their
alloy MNPs [73]. According to Li et al. [53], considering the
same NP volume and an applied eld of 10 Oe, the net magnetic
moment of one FeCo NP is 711 times higher than that of one
Fe3O4 NP.
MNPs can also be used in microuidic devices, which, due to their
permanent magnetic moment, can be controlled via external inhomogeneous magnetic elds and also detected by magnetoresistive
sensors. There are also two types of microfabricated magnetic eld
devices, which are the magnetoresistive and the Hall Effect. A microHall sensor was developed for the enumeration of rare cells ex vivo
[58]. The microuidic chip-based micro-Hall sensor measures the
magnetic moments of cells in ow that have been labeled with
MNPs. The micro-Hall sensor integrates several technological advances for accurate measurements of biomarkers on individual cells
such as:
(1) linear response, which enables operation at such high magnetic elds (>0.1 T) that MNPs can be completely magnetized
to generate maximal signal strength;

T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014) 2836

(2) the Hall element is similar size to the cells that pass over it,
thus increasing the sensitivity of the device;
(3) an array of eight sensors constituting the micro-Hall sensor
allows less-stringent uidic control than if the cells had to
be focused over a single sensor; and,
(4) an array that integrates the overall magnetic ux from each
cell enables measurement of the total magnetic moment of
a single cell. The micro-Hall sensor is capable of highthroughput screening and has demonstrated clinical utility
by detecting circulating tumor cells in whole blood of 20
ovarian cancer patients at higher sensitivity than currently
possible with clinical standards.
A magnetic eld sensor was developed combining a magnetic
uid (Fe3O4 NPs) and an optical ber Loyt-Sagnac interferometer
[55]. The sensor takes advantage of the magnication of the birefringence effect of the magnetic uid by the properly designed optical
ber Loyt-Sagnac interferometer structure. The sensor demonstrated a sensitivity enhanced by 13 orders of magnitude, compared
to existing magnetic uid sensors.
Magnetic eld sensors are not easily extended to the detection
of multi-analytes since the analytical signal arises from the magnetic moment, m, which is a single physical parameter. By using
superparamagnetic NPs with different sizes or different materials,
the analytical signals can be distinguished by their unique nonmagnetization curves, thus enabling multi-analyte detection by
magnetic eld devices [58].
4. Conclusions and future trends
In the past decade, MNPs have gained much attention and were
used in several analytical applications, such as sensors and
biosensors. In (bio)sensing devices, MNPs can be applied in the
sensor surface or as labels. Magnetic labeling of biomolecules is an
attractive proposition, due to the absence of magnetic background in almost every biological sample. However, implementation
of magnetic labels requires biocompatibility, monodispersion and
adequate functionalization to reduce non-specic binding. The
functionalized MNPs with proper functional groups and the surface
immobilization technique can therefore play a vital role in significant improvement in the sensitivity of (bio)sensing devices. In this
context, research focused on synthesis and characterization of MNP
composites and their behavior in (bio)sensing devices is still needed.
We therefore recommend further work investigating more suitable functionalized magnetic nanomaterials that will be t for multianalyte detection systems in the future.
The majority of the developed devices using MNPs as labels or
introduced into the transducer material are based on EC transduction. EC devices were successfully applied to sensitively quantifying
different multi-analytes in environmental, clinical and food samples.
These devices can be disposable, labeled or label-free, integrated
into microuidic structures, and inexpensive.
Optical devices have been developed almost always based on CL
detection, and a few used detection by SPR and uorescence spectroscopy, so more research is needed on the development of new
optical sensors and biosensors using MNPs.
Concerning piezoelectric devices, more research is needed on the
development of new sensors and biosensors, since the magnetic
nanostructures have the potential to overcome sensitivity and stability problems.
Magnetic eld sensors have been used as detectors of MNP labels.
In MNP-based magnetic eld sensors, the next step is to take the
technology to the micrometer and nanometer scale and extend their
application to a broad range of environmental, food and clinical
samples, since MNPs can enhance the analytical signal. Sensing multiple analytes into a single magnetic eld device also needs to be

35

further developed by the use of superparamagnetic NPs with different characteristics, such as size and type of material.
We recommend integration of MNP-based devices and
microuidic structures onto single chips, since it will enable the combination of several steps, such as sample preparation, molecular
labeling, detection and analysis into a single device for multianalyte detection.
Acknowledgements
This work was supported by European Funds through COMPETE
and by National Funds through the Portuguese Science Foundation (FCT) within project PEst-C/MAR/LA0017/2013. This work was
also funded by FEDER under the Programa de Cooperao Territorial Europeia INTERREG IV B SUDOE within the framework of the
research project ORQUE SUDOE, SOE3/P2/F591.
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