Biosensors Magnetic Nanoparticles Review 2014

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

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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

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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.

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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}.


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

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}.


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}.


(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

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Biosensors Magnetic Nanoparticles Review 2014