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Sensors and biosensors based on magnetic nanoparticlesTeresa
A.P. Rocha-Santos *Department of Chemistry & CESAM, University
of Aveiro, Campus de Santiago, Aveiro 3810-193,
PortugalISEIT/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
meritBiosensorElectrochemicalLabelMagnetic eldMagnetic
nanoparticleOpticalPiezoelectricSensorTransducer
A B S T R A C T
Magnetic nanoparticles (MNPs) have attracted a growing interest
in the development and fabrication ofsensors and biosensors for
several applications. MNPs can be integrated into the transducer
materialsand/or be dispersed in the sample followed by their
attraction by an external magnetic eld onto theactive detection
surface of the (bio)sensor. This review describes and discusses the
recent applicationsof MNPs in sensors and biosensors, taking into
consideration their analytical gures of merit. This workalso
addresses the future trends and perspectives of sensors and
biosensors based on MNPs.
2014 Elsevier B.V. All rights reserved.
Contents
1. Introduction
...........................................................................................................................................................................................................................................................
282. Synthesis, properties and characterization of magnetic
nanoparticles
............................................................................................................................................
293. Sensors and biosensors based on magnetic nanoparticles
...................................................................................................................................................................
29
3.1. Electrochemical
......................................................................................................................................................................................................................................
293.2. Optical
.......................................................................................................................................................................................................................................................
323.3. Piezoelectric
............................................................................................................................................................................................................................................
323.4. Magnetic eld
.........................................................................................................................................................................................................................................
34
4. Conclusions and future trends
........................................................................................................................................................................................................................
35Acknowledgements
.............................................................................................................................................................................................................................................
35References
..............................................................................................................................................................................................................................................................
35
1. Introduction
Nanotechnology has been one of the most important researchtrends
in material sciences. Nanomaterials (nanoparticle (NP) sizerange
1100 nm) compared with non-NP materials show remark-able
differences in physical and chemical properties, such as
uniqueoptical, electrical, catalytic, thermal and magnetic
characteristics,due to their small size [1]. In recent years,
considerable efforts weretherefore made to develop magnetic NPs
(MNPs), due to their ownadvantages, such as their size,
physicochemical properties and lowcost of production [2,3]. MNPs
exhibit their best performance at sizesof 1020 nm due to
supermagnetism, which makes them especial-ly suitable when looking
for a fast response due to applied magnetic
elds [4]. MNPs also have large surface area and high mass
trans-ference. Since the properties of MNPs depend strongly on
theirdimensions, their synthesis and their preparation have to be
de-signed in order to obtain particles with adequate
size-dependentphysicochemical properties. MNPs possessing
adequatephysicochemistry and tailored surface properties have been
syn-thesized under precise conditions for a plethora of
applications, suchas sample preparation [57], wastewater treatment
[8], water pu-rication [9], disease therapy [3,10], disease
diagnosis (magneticresonance imaging) [3,11,12], cell labelling and
imaging [3,11], tissueengineering [3], and sensors, biosensors and
other detection systems[1317]. Furthermore, MNPs have been used to
enhance the sen-sitivity and the stability of sensors and
biosensors for the detectionof several analytes in clinical, food
and environmental applica-tions. Taking into consideration the
broad application of MNPs insensing and biosensing systems, this
review describes and dis-cusses the current state of recent
applications of MNPs in sensorsand biosensors.
* Tel.: +351 232 910 100; Fax: +351 232 910 183.E-mail address:
[email protected]; [email protected] (T.A.P. Rocha-Santos).
http://dx.doi.org/10.1016/j.trac.2014.06.0160165-9936/ 2014
Elsevier B.V. All rights reserved.
Trends in Analytical Chemistry 62 (2014) 2836
Contents lists available at ScienceDirect
Trends in Analytical Chemistry
journal homepage: www.elsevier.com/ locate / t rac
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2. Synthesis, properties and characterization ofmagnetic
nanoparticles
In the past few years, many types of MNP were synthesized,
in-cluding: iron oxides (Fe2O3 and Fe3O4); ferrites of manganese,
cobalt,nickel, and magnesium; FePt, cobalt, iron, nickel, CoPt and
FeCo par-ticles; and, multifunctional compositeMNPs, such as
Fe3O4-Ag, Fe3O4-Au, FePt-Ag, andCdS-FePtheterodimers of NPs.MNPs
canbe synthetizedby physical methods (e.g., gas-phase deposition
and electron-beam li-thography), wet chemical methods (e.g.,
coprecipitation, high-temperature thermal decomposition and/or
reduction, sol-gel synthesis,ow-injection synthesis, oxidation
method, electrochemical method,aerosol/vapor-phase method,
supercritical uid method, and synthe-sis using nanoreactors) and
microbial methods [2,3,14].
According to Reddy et al. [3], the physical methods are
limitedby their inability to control particle size down to the
nanometer scalewhile the microbial approach ensures high yield,
good reproduc-ibility and stability associated with low cost. A
detailed discussionof MNP synthesis, beyond the scope of this
review, can be foundelsewhere [3,11,18,19].
MNPs need to be stabilized in order to prevent irreversible
ag-glomeration and to enable dissociation. Such stabilization can
beperformed by surface coating using appropriate
polymers/surfactants[e.g., dextran, and poly(ethylene glycol)],
generating polymeric shellsthat avoid cluster growth after
nucleation and hold the particledomains 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
eldapplied externally and there are the ve basic types of
magnetism(i.e., diamagnetism, paramagnetism, ferromagnetism,
antiferro-magnetism and ferrimagnetism) [2]. Materials whose
atomicmagnetic moments are uncoupled display paramagnetism [2].
Dueto their small volume, MNPs are generally superparamagnetic,
whichmeans that they have no net magnetic dipole. Thus, thermal
uc-tuations cause random orientation of the spins (i.e., thermal
energymay be enough to cause the spontaneous change in the
magneti-zation of eachMNP). Therefore, in the absence of an
electromagneticeld, the net magnetic moment of an MNP will be zero
at highenough temperatures, but, when a magnetic eld is applied to
theNP, a magnetic dipole is induced and there will be a net
alignmentof magnetic moments. After the external magnetic eld is
removed,the MNPs randomly orient and return to their native
non-magneticstate. The shape and the size of NPs will also
contribute to deter-mine their magnetic behavior. The
superparamagnetism in NPs isdetermined by the crystallinity of the
structures, the type of ma-terial, and the number of spins, and
there is no general rule thatpredicts the magnetic properties of an
MNP. Magnetism is usuallyevaluated using a magnetometer that
monitors magnetization asa function of applied magnetic eld
[5].
The common analytical techniques used to measure the
con-centration and the composition of metallic NPs were
recentlydescribed by Silva et al. [20], including:
scanning electron microscopy (SEM), near eld scanning
opticalmicroscopy (NSOM), transmission electron microscopy
(TEM),scanning transmission electron microscopy (STEM), atomic
forcemicroscopy (AFM) and environmental scanning electron
mi-croscopy (ESEM) to assess the size and the shape of NPs;
and,
energy-dispersive X-ray transmission - electronmicroscopy
(EDX-EM), electron-energy-loss spectrometry (EELS),
X-raydiffractometry (XRD) and X-ray uorescence (XRF) to measurethe
elemental compositions of single NPs.
Those methods were also the most commonly used for
charac-terization of MNPs applied in sensing and biosensing
systems
[5,7,21,22], so detailed discussion on such methods is beyond
thescope of this review.
3. Sensors and biosensors based on magnetic nanoparticles
Sensing strategies based on MNPs offer advantages in terms
ofanalytical gures of merit, such as enhanced sensitivity, low
limitof detection (LOD), high signal-to-noise ratio, and shorter
time ofanalysis than non-MNP-based strategies [23,24]. In sensing
appli-cations, MNPs are used through direct application of tagged
supportsto the sensor, being integrated into the transducer
materials, and/or dispersion of the MNPs in the sample followed by
their attractionby an external magnetic eld onto the active
detection surface ofthe (bio)sensor.
Table 1 shows examples of MNP-based sensors and biosensorsfor
the detection of several analytes in different samples
[22,2559],taking into consideration their analytical gures of
merit, such asLOD and linear range. Table 1 shows that these
sensors andbiosensors are based on different transduction
principles (electro-chemical, optical, piezoelectric andmagnetic
eld), whichwe presentand discuss in the following sub-sections
according to their clas-sication.
3.1. Electrochemical
Electrochemical (EC) devicesmeasure EC signals (current,
voltage,and impedance) induced by the interaction of analytes and
elec-trodes that can be coated with chemicals, biochemical
materials orbiological elements to improve their surface activity
[60,61]. ECdevices possess advantages of rapidity, high
sensitivity, low cost andeasy miniaturization and operation, so
being attractive in applica-tions, such as clinical, environmental,
biological and pharmaceutical[13,60]. EC devices can be classied as
amperometric, potentio-metric, voltammetric, chemiresistive, and
capacitive, according totheir working principles [60]. The EC
immunosensors, and enzyme,tissue and DNA biosensors are designed
through immobilizingbiological-recognition elements of antibodies,
enzyme, tissue andDNA, respectively, on the working electrode
surface. To improve thesensitivity of EC devices, signal
amplication has been attemptedusing MNPs. MNPs can be used in EC
devices through their contactwith the electrode surface, transport
of a redox-active species tothe electrode surface, and formation of
a thin lm on the elec-trode 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.
Amongthe sensors, the detection mode most used was
voltammetry[2831].
Due to its superparamagnetic property, biocompatibility with
an-tibodies and enzymes and ease of preparation, Fe3O4 is
mostcommonly used in developing biosensors. However, Fe3O4
magnet-ic dipolar attraction and its large ratio of surface area to
volumemaylead to aggregation in clusters when exposed to biological
solu-tions. Functionalization can overcome this problem and also
enhancebiocompatibility.
A broad variety of functionalized MNPs have been used, such
ascore-shell Au-Fe3O4 [25], core-shell Au-Fe3O4@SiO2 [32],
core-shellFe3O4@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 themost used in biosensors,
sinceit contributes to stabilization of MNPs in solution and
enhances thebinding of ligands at the surface of MNPs. Core-shell
Fe3O4@SiO2 isalso much used in modifying electrode surfaces, since
its charac-teristics, such as good electrical conductivity, large
surface area and
29T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014)
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Table 1Selected examples of sensors and biosensors based on
magnetic nanoparticles
Transductionprinciple
Sensor type Modes of magnetic nanoparticles Detection limit
Detection range Analyte Ref.
Electrochemical Voltammetric immunosensor Core-shell Au-Fe3O4
0.01 ng mL1 0.00550 ng mL1 Carcinoembryonic antigen (N/A)
[25]Voltammetric immunosensor Fe3O4 Au nanoparticles 0.22 ng mL1
0.5200.0 ng mL1 Clenbuterol (pork) [26]Voltammetric enzyme based
biosensor Au-Fe3O4 composite nanoparticles 5.6 104 ng mL1 1.0 10310
ng mL1 Organochloride pesticides (cabbage) [22]Voltammetric enzyme
based biosensor Fe3O4 Au nanoparticles 2.0 105M 2.0 1052.5 103M
H2O2 (contact lens care solution) [27]Voltammetric sensor
Core-shell Fe3O4@SiO2 1.8 108M 5.0 1081.0 106M Metronidazole (milk,
honey) [28]Voltammetric sensor Fe3O4 anchored on reduced graphene
oxide ND 0.20.6 nM Cr(III) (N/A) [29]Voltammetric sensor
Fe3O4@Au-MWCNT-chitosan 1.5 109mol L1 1.0 106-1.0 103mol L1
Streptomycin (N/A) [30]Voltammetric sensor Core-shell
Fe3O4@SiO2/MWCNT 0.13 M 0.60100.0 M Uric acid (blood serum, urine)
[31]Amperometric enzyme based biosensor Core-shell Au-Fe3O4@SiO2
0.01 mM 0.051.0 mM/ 1.0 mM8.0 mM Glucose (human serum)
[32]Amperometric enzyme based biosensor Fe3O4@SiO2/MWCNT 800 nM 1
M30 mM Glucose (glucose solution) [33]Potentiometric immunosensor
Magnetic beads Dynabeads Protein G 0.007 g mL1 ND Zearalenone
(maize certied
reference material, baby food cereal,wheat, rice, maize, barley,
oats, sorghum,rye, soya our)
[34]
Potentiometric enzyme based biosensor Core-shell Fe3O4 0.5 M 0.5
M34 mM Glucose (human serum) [35]Electrochemoluminescent
immunosensor Core-shell Fe3O4 Au nanoparticles 0.2 pg mL1 0.00055.0
ng mL1 -fetoprotein (human serum) [36]Electrochemoluminescent
immunosensor Core-shell Fe3O4@Au 0.25 ng mL1 06 ng mL1 Cry1Ac (N/A)
[37]Electrochemical impedance immunosensor Iron oxide
carboxyl-modied magnetic
nanoparticles0.01 ng mL1 0.015 ng mL1 Ochratoxin A (wine)
[38]
Electrochemical impedance biosensor Fe@Au
nanoparticles-2-aminoethanethiolfunctionalized graphene
nanoparticles
2.0 1015M 1.0 1041.0 108M DNA (N/A) [39]
Optical SPR immunosensor Magnetic nanoparticles (uidMAG-ARA)with
iron oxide core
0.45 pM ND -human chronic gonadotropin (N/A) [40]
SPR immunosensor Fe3O4@Au magnetic nanoparticles 0.65 ng mL1
1.0200.0 ng mL1 -fetoprotein (N/A) [41]SPR immunosensor Fe3O4
magnetic nanoparticles 0.017 nM 0.2727 nM Thrombin (N/A) [42]SPR
immunosensor Fe3O4/Ag/Au magnetic nanocomposites ND 0.1540.00 g mL1
Dog IgG (N/A) [43]SPR immunosensor Fe3O4-Au nanorod ND 0.1540.00 g
mL1 Goat IgM (N/A) [44]SPR immunosensor Core/shell Fe3O4/SiO2 ND
1.2520.00 g mL1 Rabbit IgG (N/A) [45]SPR immunosensor Core/shell
Fe3O4/Ag/SiO2 ND 0.3020.00 g mL1 Rabbit IgG (N/A) [45]SPR
immunosensor Iron oxide carboxyl-modied magnetic
nanoparticles0.94 ng mL1 150 ng mL1 Ochratoxin A (wine) [38]
Fluorescence immunosensor Fe3O4 ND 103108 cfu mL1 Escherichia
coli (N/A) [46]Piezoelectric QCM immunosensor Iron oxide magnetic
nanobeads 0.0128 HA unit 0.12812.8 HA unit Avian inuenza virus H5N1
(chicken
tracheal swab)[47]
QCM biosensor Iron oxide magnetic nanoparticles ND 1.8 1041.8
107 cfu mL1 D. desulfotomaculum (N/A) [48]QCM immunosensor
Fe3O4@SiO2 0.3 pg mL1 0.001100 ng mL1 C-reactive protein (human
serum) [49]Electrochemical QCM immunosensor Core-shell
Fe3O4@Au-MWCNTcomposites 0.3 pg mL1 0.0015 ng mL1 Myoglobin (human
serum) [50]QCM immunosensor Iron oxide magnetic nanoparticles 53
cfu mL1 ND Escherichia coli O157:H7 (Milk) [51]
Magnetic eld Giant magnetoresistive immunosensor Cubic FeCo
nanoparticles 83 fM ND Endoglin (human urine) [52]Giant
magnetoresistive immunosensor Cubic FeCo nanoparticles ND 125
fM41.5 pM Interleukin-6 (human serum) [53]Giant magnetoresistive
sensor Iron oxide with polyethylene glycol coating 8 Oe shift* ND
N/A [54]Magneto-optical ber sensor Fe3O4 nanoparticles 592.8 pm Oe1
** ND N/A [55]Magneto-optical ber sensor Fe3O4 in magnetic uid
162.06 pmmT1 ** ND N/A [56]Superconducting quantuminterference
device sensor
Carboxyl functionalized iron oxide nanoparticles 1.3 106 cells
ND MCF7/Her2-18 breast cancer cells (mice cells) [57]
Hall sensor Manganese-doped ferrite (MnFe2O4) ND 101105 cells
Rare cells: MDA-MB-468 cancer cells (whole blood) [58]Hall sensor
Manganese-doped ferrite (MnFe2O4) ND 101106 counts Staphylococcus
aureus, Enterococcus faecalis and
Micrococcus luteus (spiking cultured bacteriain liquid
media)
[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.
30T.A
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more electroactive interaction sites, can provide enhanced
masstransport and easier accessibility to the active sites, thus
increas-ing the analytical signal and the sensitivity.
Carbon materials, such as carbon nanotubes (CNTs) are alsowidely
used to functionalize MNPs due to their physical proper-ties, such
as large surface area, chemical and thermal stability,controlled
nanoscale structure, and electronic and optical proper-ties [30].
Recently, a nanocomposite of multi-walled CNTs (MWCNTs)decorated
with magnetic core-shell Fe3O4@SiO2 was synthetized andused to
fabricate a modied carbon-paste electrode (CPE) for
thedetermination of uric acid (Fe3O4@SiO2/MWCNT-CPE) [31]. The
EC-sensing characteristics were studied by cyclic voltammetry for
anMNP-modied CPE (Fe3O4@SiO2/MWCNT-CPE), an unmodied CPEand
anMWCNT-CPE. The anodic peak current of MNP-modied CPEwas found to
be 2.7 times higher than that of the MWCNT-CPE and4.6 times higher
than that of the unmodied CPE. The increased sen-sitivity can be
attributed to the core-shell Fe3O4@SiO2/MWCNT thathas fast
electron-transfer kinetics and a larger electroactive surfacearea
compared to the other two electrodes (MWCNT-CPE and un-modied
CPE).
Au-Fe3O4-composite NPs [22] are also used due to their easeof
preparation, large specic surface area, good
biocompatibility,strong adsorption ability and good conductivity,
enhanced by usingAuNPs. As an example, Gan et al. [22] modied a
screen-printedcarbon electrode using a composite of MNPs. Fig. 1
shows the bio-sensor apparatus and the biosensor-detection
principle oforganophosphorous pesticides. In this device,
acetylcholinester-ase (AChE)-coated Fe3O4/Au MNPs were synthetized
and thenabsorbed on the surface of a CNT/nano-ZrO2/Prussian
blue/Naon-modied screen-printed carbon electrode. The biosensor was
appliedto determine dimethoate in cabbage and showed performance
com-parable to gas chromatography coupled to ame
photometricdetector (GC-FPD). The biosensor showed advantages, such
as a fastresponse, adequate linear range (Table 1) and adequate
sensitivityfor the detection of organophosphorous pesticides due to
the con-ductive Fe3O4/Au MNPs that were used to provide a large
electrodesurface area to amplify the current response signal of
thiocholine(TCh) and to enhance sensitivity. Furthermore, the
biosensor surfacecan easily be renewed on removing Fe3O4/Au/AChE
from the bio-sensor by applying an external magnetic eld due to
itssuperparamagnetism. Nevertheless, the easy immobilization
ofenzyme/MNPs (Fe3O4/Au/AChE) on the screen-printed carbon
elec-trode reduces the manufacturing costs, since it has the
advantages
of integration of the electrodes, simple manipulation, low
con-sumption of sample, reduced use of expensive reagents, and
simpleexperimental design.
As another example, Zamr et al. [38] developed an EC-impedance
immunosensor for the detection of ochratoxin-A basedon
anti-ochratoxin-A monoclonal-antibody-iron-oxide carboxyl-modied
MNPs at the surface of an Au working electrode. The useof
iron-oxide carboxyl-modied MNPs for
anti-ochratoxin-Amonoclonal-antibody immobilization allows easy
regeneration ofthe electrode and also reduces the impedance of the
system, thusincreasing its sensitivity.
In both these examples, the MNPs were concentrated
onelectrode-surface materials and have advantages, such as
in-creased sensitivity and stability, besides ease of renewing
theelectrode by releasing theMNPs and replacing themwith
newMNPs.
ECL immunosensors currently use MNPs as labeling agent or
im-mobilization support. The ECL signal is based on a sequence of
stages,such as EC (single electron redox processes of substance),
chemi-cal (biradical combinations) and optical (emission of the ECL
quanta)[62]. The ECL assays can have three main formats (i.e.,
direct inter-action, competition assay and sandwich-type assay)
[62]. Quantumdots, such as CdS, CdSe or core/shell type ZnS/CdSe,
have been ofgreatest interest in ECL applications due to the
quantum conne-ment effect having optical and electronic properties
that make themexcellent labels for improving the sensitivity of
transducer sur-faces coated with MNPs and magnetic capture
probes.
An ECL immunosensor was developed for detecting
-fetoprotein(AFP) based on a sandwich immunoreaction strategy using
mag-netic particles as capture probes and quantum dots as signal
tags[36]. Fig. 2 shows the process used for preparing magnetic
captureprobes Fe3O4-Au/primary AFP antibody (Ab1) and signal tag of
CdS-Au/ secondary AFP antibody (Ab2). The Ab1 was rst anchored
inthe surface of Fe3O4-Au nanospheres by the Au-S bond. The
prod-ucts with an Ab1 immobilized on the surface of Fe3O4-Au
capturedAFP (antigen) from a solution. Finally, the protein-labeled
CdS-AuNPs were introduced to the immunoreaction with the
exposedpart of AFP. The Fe3O4-Au/Ab1/AFP/Ab2/CdS-Au was used to
con-struct the ECL immunosensor. It was observed that the Fe3O4
MNP-modied electrode, in the solution, had almost no ECL signal,
whilethe Fe3O4-Au MNP-modied electrode had a slightly enhanced
ECLsignal. The signal of the immunosensor was therefore further
en-hanced by adding CdS-Au as a label compared to the
non-labeledsystem (Fe3O4-Au/Ab1/AFP). It was also observed that,
when the
Fig. 1. Example of an electrochemical (voltammetric enzyme-type)
biosensor: view of the apparatus from (a) plane and (b) vertical
directions; (c) detection principle forthe 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}.
31T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014)
2836
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CdS-Au composite lm was used instead of CdS NPs, the ECL
signalincreased 2.5 times. This increase can be attributed to the
cata-lytic activity of AuNPs that enhanced electrical conductivity
andsensitivity. The immunosensor showed performance comparable
toELISA in detecting AFP in human serum and therefore potential
forclinical application.
3.2. Optical
Optical devices have been applied to the detection of
severalanalytes in clinical samples [24,63], environmental samples
[6466]and food samples [67] due to their main characteristics, such
as lowsignal-to-noise ratio, reduced interferences, and reduced
costs ofmanufacture. Optical devices can be classied by their
principlesof detection (i.e., uorescence spectroscopy,
interferometry, reec-tance, chemiluminescence (CL), light
scattering and refractive index).CL-detection systems have to be
enhanced in emission intensity andimproved in selectivity for use
in quantitative analysis of complexmatrices, such as biological and
environmental samples. In orderto overcome such limitations, MNPs
can play a useful part in theCL reactions as catalyst, biomolecule
carrier and separation tool [16].Iranifam [16] recently reviewed
and discussed the analytical ap-plications of CL-detection systems
assisted by MNPs, so a detailedpresentation and discussion on such
methods is beyond the scopeof this review.
Table 1 shows that, among the MNP-based optical devices,
thedetection modes used were surface plasmon resonance
(SPR)[38,4045], and uorescence spectroscopy [46]. Fig. 3 shows
animmunosensor that combines SPR technology with MNP assays
fordetection and manipulation of human chorionic gonadotropin
(-hCG) [40]. The approach is based on a grating-coupled SPR
sensorchip that is functionalized by antibodies recognizing the
targetanalyte (-hCG). The MNPs were conjugated with antibodies
andwere used both as labels for enhancing refractive-index changes
due
to the capture of analyte and also as carriers for fast delivery
of theanalyte at the sensor surface, thus enhancing the SPR-sensor
re-sponse. A magnetic eld was used to capture the
MNPs-antibody-analyte on the sensor surface. The use of MNPs
together with itscollection on the sensor surface by applying a
magnetic eld im-proved the sensitivity by four orders of magnitude
with respect toregular SPR using direct detection. This enhancement
was attrib-uted to the larger mass and higher refractive index of
MNPs. An LODof 0.45 pM was achieved for the detection of -hCG. This
workingprinciple should be further investigated for the analysis of
analytes,such as viruses or bacterial pathogens, since it can
overcome theproblems of the low sensitivity of SPR-biosensor
technology due tomass transfer to the sensor surface being strongly
hindered by dif-fusion for these analytes.
The analytical signal associated with uorescence intensity
canalso be enhanced using MNPs, such as Fe3O4. A
microuidicimmunosensor chip was developed having circular
microchannels[46] for detection of Escherichia coli. The
methodology used in-volves, in a rst step, the conjugation of Fe3O4
MNPs with antibodyand, in a second step, the in-ow capture of
antigens in themicrochannels. The captured MNPs create a heap-like
structure atthe detection site under the inuence of a reversed
magnetic owthat increases the retention time of antigens at the
site of captureand the capture eciency of antigens, so enhancing
the intensityof the uorescence signal.
3.3. Piezoelectric
Piezoelectric devices can be quartz-crystal microbalance(QCM)
and surface acoustic wave (SAW). Table 1 shows that theMNP-based
piezoelectric sensors and biosensors are based onQCM transduction
[4751]. The QCM is a quartz-crystal diskwith metal electrodes in
each side of the disk [6870] that vi-brates under the inuence of an
electric eld. The frequency of
Fig. 2. Example of the preparation procedure of an
electrochemiluminescent (ECL) immunosensor. BSA, Bovine serum
albumin; AFP, -fetoprotein; Ab1, Primary antibodyof AFP; Ab2,
CdS-Au labeled secondary antibody. {Reprinted [36] 2012, with
permission from Elsevier}.
32 T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014)
2836
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this oscillation depends on the cut and the thickness of the
disk.This resonant frequency changes as compound(s) adsorb or
desorbfrom the surface of the crystal. A reduction in frequency is
propor-tional to the mass of adsorbed compound. QCMs are small
androbust, inexpensive, and capable of giving a rapid response
downto a mass change of 1 ng. The major drawback of these devices
isthe increase in noise with the decrease in dimensions due to
in-stability as the surface area-to-volume ratio increases.
Moredisadvantages of QCM are the interference from atmospheric
hu-midity and the diculty in using them for the determination
ofanalytes in solution [71].
MNPs with piezoelectric properties can easily eliminate
theseproblems, since they offer an attractive transductionmechanism
andrecognition event with advantages, such as solid-state
construc-tion and cost effectiveness. The frequency enhancement in
thepresence of MNPs can be due to:
(1) the MNPs possessing some inherent piezoelectricity;(2)
theMNPs binding and helping to concentrate the analytemol-
ecules at the QCM surface; and,(3) the MNPs acting as matrix
carriers to load labels.
A QCM immunosensor for detection of C-reactive protein (CRP)in
serum was developed. In a rst step, a sandwich-typeimmunoreaction
was made between the capture probe (silicondioxide-coated magnetic
Fe3O4 NPs) labeled with primary CRP an-tibody (MNs-CRPAb1), CRP and
signal tag [horseradish peroxidase(HRP) coupled with HRP-linked
secondary CRP antibody co-immobilized on AuNPs (AuNPs-HRP/HRP-CRP
Ab2)] [49]. In a secondstep, the immunocomplex was exposed to
3-amino-9-ethylcarbazole(AEC) and hydrogen peroxide. Fig. 4 shows
the preparation proce-dures and the detection principle. The
capture probe containing theMNPs (MNs-CRPAb1) enhanced the
analytical signal due to bothmagnetic separation and immobilization
at the electrode surface.Further, the advantages of the magnetic
beads (Fe3O4@SiO2) for la-beling CRPAb1 include the mono-disperse
size distribution and easypreparation of the labeled conjugates.
The performance of the QCMmethodology was comparable with the ELISA
methodology whendetecting CRP in human serum. Moreover, the
QCM-sensor surfacecan be regenerated easily and used repeatedly due
to the use of theMNPs.
More research is needed on the development of
magneticnanostructures, characterization of their piezoelectric
behavior andtheir application in piezoelectric sensors and
biosensors, since theypromise to overcome the sensitivity and
stability issues character-istic of these kind of devices.
Fig. 3. Example of a surface-plasmon resonance (SPR)
immunosensor: (A) Opticalsensor set-up and (B) a sensor chip of the
magnetic nanoparticle (NP)-enhancedgrating coupled SPR sensor. (C)
The analytical signal before and after immobiliza-tion of the
capture antibody. {Reprinted with permission from [40], 2011,
AmericanChemical Society}.
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-reactiveprotein; 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}.
33T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014)
2836
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3.4. Magnetic eld
Table 1 shows that themagnetic eld devices usingMNPs
[5259]include giant magnetoresistive (GMR), Hall Effect,
magneto-optical and superconducting quantum interference
sensors.
Magnetoresistive sensors are based on the intrinsic
magnetore-sistance of a ferromagnetic material or on
ferromagnetic/non-magnetic heterostructures [72]. Depending on the
nanostructureof the nanomaterial layer, these devices can show the
GMR effector the tunneling magnetoresistance effect. In these
devices, the an-alytical signal (change in electrical resistance)
is measured followingthe analyte binding in the presence of a
magnetic eld. The ana-lytical signal can therefore be obtained by
small changes in themagnetic eld and depends on the magnetic eld
along the sensorarea [73]. When using a GMR device and MNPs for
interleukin-6(analyte) detection, twomethodologies have been
attempted (Fig. 5)[53]. In the rst possible methodology, the GMR
sensor isfunctionalized with capture antibodies and the analyte
binds tothe capture antibody. The detection antibodies labeled with
MNPsbind to the analyte captured. The second detection
methodologyinvolves functionalization of the GMR sensor with
capture anti-bodies, and then the direct capture of the MNP-labeled
analyte onthe GMR biosensor. In both cases, the GMR biosensor
detects thedipole eld generated by the MNPs captured on the sensor
surface,which is sensitive to distance. The quality of the MNPs is
very im-portant for successful magnetoresistive detection, so ideal
probesshould be superparamagnetic, having high magnetic moment
and
large susceptibility, in order to enable their magnetization in
a smallmagnetic eld. The MNPs also need to have uniform size and
shape,since the magnetic signal depends on it, and to be stable in
phys-iological solutions, so that their coupling with biomolecules
canbe controlled [73]. Moreover, the choice of MNPs with
highmagnetic moment leads to increased signal and therefore high
sen-sitivity. Taking this into consideration, for sensitive
magnetoresistivedetection, the ideal candidates have been metallic
Fe, Co, or theiralloy MNPs [73]. According to Li et al. [53],
considering thesame NP volume and an applied eld of 10 Oe, the net
magneticmoment of one FeCo NP is 711 times higher than that of
oneFe3O4 NP.
MNPs can also be used inmicrouidic devices, which, due to
theirpermanent magnetic moment, can be controlled via external
in-homogeneousmagnetic elds and also detected
bymagnetoresistivesensors. There are also two types of
microfabricated magnetic elddevices, which are the magnetoresistive
and the Hall Effect. A micro-Hall sensor was developed for the
enumeration of rare cells ex vivo[58]. The microuidic chip-based
micro-Hall sensor measures themagnetic moments of cells in ow that
have been labeled withMNPs. The micro-Hall sensor integrates
several technological ad-vances for accurate measurements of
biomarkers on individual cellssuch as:
(1) linear response, which enables operation at such high
mag-netic elds (>0.1 T) that MNPs can be completely magnetizedto
generate maximal signal strength;
Fig. 5. Example of the use of magnetic nanoparticles (MNPs) and
giant magneto-resistive (GMR) sensors in two different
methodologies. (A) Sandwich-type approach, wherethe GMR sensor is
functionalized with capture antibodies, for subsequent analyte
binding. The detection antibodies labeled with MNPs are then
applied and bind to thecaptured 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}.
34 T.A.P. Rocha-Santos/Trends in Analytical Chemistry 62 (2014)
2836
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(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
sensorallows less-stringent uidic control than if the cells had
tobe focused over a single sensor; and,
(4) an array that integrates the overall magnetic ux from
eachcell enables measurement of the total magnetic moment ofa
single cell. The micro-Hall sensor is capable of high-throughput
screening and has demonstrated clinical utilityby detecting
circulating tumor cells in whole blood of 20ovarian cancer patients
at higher sensitivity than currentlypossible with clinical
standards.
A magnetic eld sensor was developed combining a magneticuid
(Fe3O4 NPs) and an optical ber Loyt-Sagnac interferometer[55]. The
sensor takes advantage of the magnication of the bire-fringence
effect of themagnetic uid by the properly designed opticalber
Loyt-Sagnac interferometer structure. The sensor demon-strated a
sensitivity enhanced by 13 orders of magnitude, comparedto existing
magnetic uid sensors.
Magnetic eld sensors are not easily extended to the detectionof
multi-analytes since the analytical signal arises from the
mag-netic moment, m, which is a single physical parameter. By
usingsuperparamagnetic NPs with different sizes or different
materials,the analytical signals can be distinguished by their
unique non-magnetization curves, thus enabling multi-analyte
detection bymagnetic eld devices [58].
4. Conclusions and future trends
In the past decade, MNPs have gained much attention and wereused
in several analytical applications, such as sensors andbiosensors.
In (bio)sensing devices, MNPs can be applied in thesensor surface
or as labels. Magnetic labeling of biomolecules is anattractive
proposition, due to the absence of magnetic back-ground in almost
every biological sample. However, implementationof magnetic labels
requires biocompatibility, monodispersion andadequate
functionalization to reduce non-specic binding. Thefunctionalized
MNPs with proper functional groups and the surfaceimmobilization
technique can therefore play a vital role in signif-icant
improvement in the sensitivity of (bio)sensing devices. In
thiscontext, research focused on synthesis and characterization of
MNPcomposites and their behavior in (bio)sensing devices is still
needed.We therefore recommend further work investigating more
suit-able functionalizedmagnetic nanomaterials that will be t for
multi-analyte detection systems in the future.
The majority of the developed devices using MNPs as labels
orintroduced into the transducer material are based on EC
transduc-tion. EC devices were successfully applied to sensitively
quantifyingdifferent multi-analytes in environmental, clinical and
food samples.These devices can be disposable, labeled or
label-free, integratedinto microuidic structures, and
inexpensive.
Optical devices have been developed almost always based on
CLdetection, and a few used detection by SPR and uorescence
spec-troscopy, so more research is needed on the development of
newoptical sensors and biosensors using MNPs.
Concerning piezoelectric devices, more research is needed on
thedevelopment of new sensors and biosensors, since the
magneticnanostructures have the potential to overcome sensitivity
and sta-bility problems.
Magnetic eld sensors have been used as detectors of MNP
labels.In MNP-based magnetic eld sensors, the next step is to take
thetechnology to the micrometer and nanometer scale and extend
theirapplication to a broad range of environmental, food and
clinicalsamples, since MNPs can enhance the analytical signal.
Sensingmul-tiple analytes into a single magnetic eld device also
needs to be
further developed by the use of superparamagnetic NPs with
dif-ferent characteristics, such as size and type of material.
We recommend integration of MNP-based devices andmicrouidic
structures onto single chips, since it will enable the com-bination
of several steps, such as sample preparation, molecularlabeling,
detection and analysis into a single device for multi-analyte
detection.
Acknowledgements
This work was supported by European Funds through COMPETEand by
National Funds through the Portuguese Science Founda-tion (FCT)
within project PEst-C/MAR/LA0017/2013. This work wasalso funded by
FEDER under the Programa de Cooperao Territo-rial Europeia INTERREG
IV B SUDOE within the framework of theresearch project ORQUE SUDOE,
SOE3/P2/F591.
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Sensors and biosensors based on magnetic nanoparticles
Introduction Synthesis, properties and characterization of magnetic
nanoparticles Sensors and biosensors based on magnetic
nanoparticles Electrochemical Optical Piezoelectric Magnetic field
Conclusions and future trends Acknowledgements References