Review

pubs.acs.org/CR

Nanoparticle-Based Immunochemical Biosensors and Assays: Recent

Advances and Challenges
Zdeněk Farka,† Tomás ̌ Juřík,†,‡ David Kovár,̌ † Libuše Trnková,§ and Petr Skládal*,†,‡
†
Central European Institute of Technology (CEITEC), ‡Department of Biochemistry, Faculty of Science, and §Department of
Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic

ABSTRACT: We review the progress achieved during the recent five years in
immunochemical biosensors (immunosensors) combined with nanoparticles for
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enhanced sensitivity. The initial part introduces antibodies as classic recognition

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elements. The optical sensing part describes fluorescent, luminescent, and surface
plasmon resonance systems. Amperometry, voltammetry, and impedance spectroscopy
represent electrochemical transducer methods; electrochemiluminescence with photo-
electric conversion constitutes a widely utilized combined method. The transducing
options function together with suitable nanoparticles: metallic and metal oxides,
including magnetic ones, carbon-based nanotubes, graphene variants, luminescent
carbon dots, nanocrystals as quantum dots, and photon up-converting particles. These
sources merged together provide extreme variability of existing nanoimmunosensing
options. Finally, applications in clinical analysis (markers, tumor cells, and pharmaceuticals) and in the detection of pathogenic
microorganisms, toxic agents, and pesticides in the environmental field and food products are summarized.

CONTENTS 4.3.1. Solution-Based LSPR 9991

4.3.2. Surface-Based LSPR 9991
1. Introduction 9974 4.3.3. Plasmonic Nanoparticle Assemblies 9992
2. Antibodies 9974 4.3.4. Controlled Nanoparticle Growth 9992
3. Nanoparticles for Immunosensing 9976 4.4. Surface-Enhanced Raman Scattering 9992
3.1. Metallic Nanoparticles 9976 4.5. Electrochemical Transducers 9994
3.1.1. Gold Nanoparticles 9976 4.5.1. Amperometric and Voltammetric Meas-
3.1.2. Silver Nanoparticles 9977 urements 9995
3.2. Magnetic Nanoparticles 9977 4.5.2. Electrochemical Immunosensors with
3.2.1. Magnetic Preconcentration 9978 Metals or Metal Oxides 9996
3.2.2. Renewable Sensor Surfaces and Mod- 4.5.3. Allotropic Modification 9996
ification Methods 9979 4.5.4. Electrochemical Impedance Spectrosco-
3.2.3. Magnetic Particles as Tags 9979 py 9998
3.3. Carbon-Based Nanomaterials 9980 4.5.5. Field-Effect Transistors 9999
3.3.1. Carbon Nanotubes 9980 4.6. Magnetic Sensors 10001
3.3.2. Graphene 9981 4.6.1. Diagnostic Magnetic Resonance 10001
3.3.3. Other Carbon-Based Nanomaterials 9982 4.6.2. Magnetoresistance 10001
3.4. Luminescent Nanocrystals 9983 4.6.3. Superconducting Quantum Interference
3.4.1. Quantum Dots 9983 Device 10001
3.4.2. Photon-Upconverting Nanoparticles 9984 4.6.4. Other Magnetic Sensors 10002
4. Transduction Mechanisms 9985 4.7. Piezoelectric Systems 10002
4.1. Optical Transducers 9985 5. Applications 10007
4.1.1. Fluorescence 9985 5.1. Clinical Assays 10007
4.1.2. FRET Assays 9985 5.1.1. Proteins and Small Molecules as Markers 10007
4.1.3. Chemiluminescent Nanolabels 9985 5.1.2. Cancer Cells 10007
4.1.4. Electrochemiluminescence 9986 5.1.3. Pharmaceutical Detection 10010
4.1.5. Photoelectrochemical Conversion 9987 5.2. Toxic Substances and Pathogens 10011
4.1.6. Visual Evaluation and Colorimetric Sys- 5.2.1. Detection of Toxins 10011
tems 9988 5.2.2. Pesticides as Environmental Pollutants 10013
4.1.7. Single-Molecule Detection Techniques 9989 5.2.3. Microbial Detection 10014
4.2. Surface Plasmon Resonance 9989
4.2.1. Amplification by Nanoparticles 9989
4.3. Localized Surface Plasmon Resonance 9991 Received: January 15, 2017
Published: July 28, 2017

© 2017 American Chemical Society 9973 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
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6. Conclusion and Outlook 10016 techniques using magnetic nanoparticles modified with target-
Author Information 10019 specific antibodies.
Corresponding Author 10019 The transducing options are combined with all suitable
ORCID 10019 nanoparticles: metallic and metal oxides, with special attention to
Notes 10019 magnetic ones, carbon-based nanotubes, graphene variants, and
Biographies 10019 luminescent carbon dots. Luminescent nanocrystals are
Abbreviations 10019 represented by quantum dots and photon up-converting
References 10020 particles. Individual sensors also often contain other compo-
nents, including enzymes (peroxidase, glucose oxidase, alkaline
phosphatase) generating redox-active donors/acceptors, molec-
ular fluorophores, and electroactive molecules (e.g., ferrocene).
1. INTRODUCTION The above-mentioned groups of transducers and nano-
This review focuses on advances in immunochemical biosensors particles ensure an extremely wide range of potential
(immunosensors) combined with nanoparticles for the combinations, and this precondition is really reflected in the
enhanced sensitivity of the resulting assays. When reading the exceptional variability of the existing nanoimmunosensing
papers published in Chemical Reviews during the recent five years, options. Finally, we have tried to provide an overview of
we noticed a strong interest in various types of nanoparticles and applications aimed especially at clinical analysis, followed by the
other nanomaterials applied for the improvement of biosensors detection of pathogenic organisms and toxic agents; the
as well as other bioanalytical assays. The relevant publications environmental field and food assay then complement the list.
typically concentrated on the type of nano-object being chosen.
On the basis of our long experience in the construction and 2. ANTIBODIES
application of immunosensors, or biosensors based on antibod- Currently, the detection and quantification of different analytes
ies, we find it challenging to set the primary focus on antibodies exhibits an increasing tendency toward broader application. In
and to propose a review of the most promising trends regarding multiple immunoassays, antibodies (Ab’s) are employed as a
the combination with nanoparticles for immunosensing. Despite biorecognition element, and the utilization in biosensors brings
the numerous attempts to replace them with alternative new tools for analysis in the biochemical, clinical, and
recognition molecules (aptamers, biomimetic polymers, artificial environmental fields. It is commonly known that the high
receptors), classic antibodies still remain the most common sensitivity and selectivity of immunosensors to recognize a
recognition elements in research and commercial affinity assays. biomolecular component are ensured by specific interactions and
Thus, we consider it beneficial to aim the attention of the review the extremely high equilibrium association constants (1010 M−1
on this point, summarizing the novel nanotrends to improve the and greater) attainable between an antibody and its correspond-
classic immunoanalytical and, in particular, immunosensing ing antigen.
concepts. We believe that such an approach will be interesting for Antibodies are a unique natural family of (immune system)
not only chemists working in the analytical field but also the large related glycoproteins known as immunoglobulins (Ig’s),
community of immunoassay users within medical (clinical produced by differentiated B cells in response to the attendant
assays) and biological research. of an immunogen during an immune response. The role of Ab is
The targeted scientific resources cover the recent five years, essential to life and plays an unsubstitutable role in the immune
namely, the period from 2012 to 2016 (September). The initial, systems of higher animals. A typical mammalian antibody unit is a
and rather wide, literature search yielded approximately 4500 heterodimer consisting of two identical long heavy chains
hits. After manual preselection, 3300 papers were evaluated as (approximately 450−600 amino acid residues) and two identical
relevant to our field. short light chains (approximately 220 residues).1 The heavy
The critically selected results cover all possible types of chains are a large polypeptide subunit and vary between different
immunosensors and immunoassays applied usually in heteroge- animals. These four chains are joined to form a “Y”-shaped
neous formats; i.e., several separation and washing steps are molecule (Figure 1).
involved. Homogeneous formats, providing simplified working Both Ig chains consist of conserved protein structures called
procedures, were rather rare. The initial part introduces domains corresponding to approximately 110 amino acids. The
antibodies as classic recognition elements, which, however, light chains have two domainsvariable (VL) and constant (CL).
continue to develop and improve the usage of tools from The heavy chains also have one variable domain (VH) and,
molecular biology and protein engineering. The sensing depending on the Ig types, another three (in the case of IgG, IgA,
techniques covered mostly optical and electrochemical trans- and IgD) or four (in the case of IgM and IgE) constant domains
ducers. The former area included classic label-based fluorescence (CH1, CH2, CH3, CH4). The domains are identical between the
and luminescence but only a few chemiluminescence examples; two light and two heavy chains. The heavy chains are connected
advanced label-less surface plasmon resonance was rather with each other by covalent disulfide bridges and noncovalent
common together with its localized variants. One of the chapters bonds. Similarly, the light chains are connected to the heavy
also discusses the promising surface-enhanced Raman scattering. chains. The arms of the “Y” consist of the N-termini of each
Electrochemistry was mainly represented by the simplest heavy chain associated with one of the light chains to create two
amperometric measurements, followed by voltammetric ap- antigen-binding domains. This region is termed the “antigen-
proaches and impedance spectroscopy; potentiometric techni- binding fragment” (Fab fragment or domain). The tail of the “Y”
ques were rare and consisted of miniaturized field-effect is formed by a combination of the C-termini of the two heavy
transducers. Furthermore, combined electro-optical techniques, chains and is termed the “crystallizable fragment” (Fc fragment
namely, electrochemiluminescence and photoelectric conver- or domain). Physiologically, the Fc fragment is responsible for
sion, proved very fruitful. Special examples of magnetic the effector role of the Ig (i.e., the cell receptor interaction,
transduction are focused both on assays and on imaging complement activation, etc.).2
9974 DOI: 10.1021/acs.chemrev.7b00037
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Figure 1. Unique structure of antibodies comprised of four polypeptide units joined together to form a “Y”-shaped moleculetwo identical heavy
chains and two identical light chains. The disulfide bonds depicted between CL and CH1 are relevant for most IgG subclasses. The two Fab’s are antigen-
binding fragments, and Fc is a crystallizable fragment. In the right-hand structure, flexibility is outlined: Fab arm waving (violet), Fab rotation (blue), Fab
elbow bend (orange), and Fc wagging (green).

The chains have another region, known as the hinge region, quaternary molecular structure: IgM has a pentameric structure,
located between the CH1 and CH2 domains The hinge region IgA has a dimeric one, and the others are monomers.
gives flexibilitynamely, arm rotation and wavingto the Fab As mentioned above, the discussed antibodies are glyco-
fragment. The other possible type of flexibility rests in the Fab proteins. The carbohydrates are localized in the constant
elbow bend and Fc wagging.3 The hinge region contains a high domains of the heavy chains, mainly around the CH2 and hinge
amount of proline accountable for the flexibility and sensitivity to regions.8 The share of carbohydrates is 15% of the heavy chains.
proteolytic enzymes. A controlled scission using proteolytic The exact role of the carbohydrate residues is not fully
enzymes (pepsin or papain) leads to the fragmentation of a understood; we can speculate on their relation to catabolism or
molecule; as well as reaction with disulfide reducing agents. The to some of the Ig unknown functions. Experimentally, it was
sensitivity of IgG subclasses to proteolytic cleavage depends on shown that the oxidation or deglycosylation of the Ig does not
the sequence and length of their hinge regions; also, the strength affect the change of the molecular structure; only the effector
of the reducing agents plays a role regarding the position of functionality is affected.9,10
reduced − S−S− bridges.4 The eminent dogma of the structure of antibodies was
A minimal antigen-binding fragment consisting of VH and VL reinterpreted by discovering a new antibody type in the
chains and referred to as the Fv fragment is obtainable by the Camelidae species in the 1990s.11 Camelids (i.e., Camelus
pepsin digestion of F(ab′). A recombinant single-chain Fv (scFv) dromedarius, Lama glama) produce heavy-chain antibodies
fragment contains a small flexible linker between the VH and VL (hcAb’s) missing the light chains; these antibodies are more
chains and is more stable than the native Fv fragment. The stable than classic antibodies and are capable of strongly binding
antigens. The recombinant variable domain (VHH) of hcAb is
progress in the molecular recombinant DNA technology allows
commercially produced and called a “nanobody”.12 The items
scFv fragments retaining the antigen-binding capacity of the
may possess inherent thermal and protease stability and are able
parent immunoglobulin or totally newly designed scFv fragments
to bind epitopes that cannot interact with whole antibodies.13
to be obtained in a routine manner (Figure 2).5,6 Other heavy-chain antibodies have been isolated from
Due to the variability of the VL and VH domains, the Fab cartilaginous fish and termed “IgNAR” or “vNAR” (the variable
fragment determines the specificity and ability to interact and domain of a new antigen receptor in sharks).14,15 Genetic
bind the immunogen. This variability is located in three segments engineering allows making, e.g., recombinant fusion products of
within the domains called hypervariable regions or complemen- nanobodies with the superfolder green fluorescent protein16 or
tarity-determining regions (CDRs).7 These regions exhibit about intraspike cross-linked antibodies for HIV therapy.17
10 amino acids and are usually denoted as CDR1, CDR2, and Antibodies harvested from blood plasma are mixture products
CDR3. Each antibody molecule has two antigen-binding sites of many different plasma cell clones, and they react with many
formed by the regions, localized at the tip of each arm of the “Y”- epitopes. The number of producing clones varies on the inducing
shaped molecule. epitopes. In practice, it is not possible to isolate specific
The classification of antibodies is based on the sequence of the antibodies of one clone from these mixtures known as polyclonal
heavy chains and the content of carbohydrates. The heavy chains antibodies (pAb’s). The immunoglobulins produced by the
are highly conserved and can be separated into isotypes or classes single plasma cell originating clone are specific against one
of Ig (μ, IgM; γ, IgG; ε, IgE; α, IgA; δ, IgD). Similarly, the light epitope of the immunogen. These specific antibodies are called
chains are described as κ and λ, but contrariwise, they are the monoclonal and are mainly produced via the hybridoma
same for all Ig classes. Isotypes α and γ have approximately 450 technique using the fusion of B-cells with the immortal myeloma
amino acids, whereas μ and ε exhibit 550 amino acids. Over this cell line.18 Another in vitro technique, known as the phage
diversity, the individual classes of antibodies differ in the display method, is based on selecting recombinant structures
9975 DOI: 10.1021/acs.chemrev.7b00037
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Figure 2. Fragments of an IgG molecule prepared via the application of protease enzymes and disulfide reducing agents. The image includes
recombinant fragments of classic antibodies, i.e., single-chain Fv (scFv) and camelized single-domain Ab (sdAb), also known as VHH or nanobodies,
which can be prepared in the same form by recombinant engineering.

presented on the bacteriophage surface and tested for the experimental conditions allowed the preparation of Au NPs
interaction with the target antigen.19 with various shapes, such as nanorods,28 nanostars,29 nano-
The specificity and sensitivity of antibodies are crucial clusters,30 core−shell structures,31 and irregularly shaped NPs.32
parameters for the construction of immunosensors.20 Suo et al. Au NPs have drawn the particular focus of scientists in the
reported a comparative study of the efficacy of seven antibodies bioanalytical field due to their distinct physical and chemical
for the binding of the living cells of Salmonella enterica. The properties, including easy preparation and modification, superior
results suggest that an antibody should target a surface antigen biocompatibility, intensive color, and catalytic activity.33,34 Au
extending out from the bacterial surface and closely attaching to NPs enable the conjugation of biological ligands, exploiting the
the bacterial cell wall. In the studied case, the best results were strong affinity of the mercapto35 and amino36 functional groups
achieved using antifimbria antibodies.21 to gold. Au NPs also provide a microenvironment compatible
As regards the immunosensing formats, the most common with biomolecules; thus, their activity remains even after
competitive and sandwich options are shown in Figure 3. immobilization. For this reason, Au NPs are often modified
using different biomolecules, such as antibodies, enzymes, or
3. NANOPARTICLES FOR IMMUNOSENSING DNA, to create specific nanoprobes applicable for detecting
3.1. Metallic Nanoparticles various analytes.37
3.1.1. Gold Nanoparticles. Because of their unique optical, The applications of Au NPs in immunosensing cover the
chemical, electrical, and catalytic properties, Au NPs are the most majority of possible transducers. For example, due to the high
common signal amplification labels for various kinds of molar extinction coefficient and significant color changes during
immunosensors and immunoassays, including lateral flow assays, aggregation, a number of colorimetric immunoassays have been
electrochemistry, colorimetric assays, and plasmonic sensing developed.38 Fluorescence immunoassays can be constructed on
(SPR, LSPR, SERS).22 The particular properties and applications the basis of the energy transfer between fluorophores and Au
of Au NPs are strongly influenced by their sizes and shapes. The NPs, which causes the quenching of the fluorescence signal.39
color of a colloidal Au NP solution is either intense red (particles The plasmonic properties of Au NPs can be used to amplify SPR
smaller than 100 nm) or dirty yellow (larger particles).23 These immunosensing,40 the catalytic properties of Au NPs are
optical properties are caused by localized surface plasmon utilizable for the amplification of optical or electrochemical
resonance. The free electrons of Au NPs undergo oscillation in signals,41 and the electrochemical properties can be exploited in
the presence of an oscillating electromagnetic field, and EIS biosensors.42 Many in vitro studies have demonstrated that
resonance occurs at a specific frequency of the light.24 Au NPs are generally nontoxic for cells, this being in contrast
The currently most common technique for the synthesis of Au with other NPs (e.g., carbon nanotubes and metal oxides).43 The
NPs was developed by Turkevich et al. in 195125 and further precondition then enables the application of Au NPs within in
improved by Frens in 1973.26 This method is based on the vivo diagnostics and imaging.44
chemical reduction of gold salts (e.g., hydrogen tetrachloroau- More details about the amplification of the sensor response by
rate, HAuCl4) by citrate; the products of the reaction are Au NPs are provided in sections devoted to individual
monodisperse spherical Au NPs. The particle size and shape can transducers. Au NPs appear to be quite universal and fully
be controlled by the concentration of the reagents or the selected established; the excellent stability compared to that of other
reducing agent or by using a surfactant (i.e., cetyltrimethylam- metals in combination with routine procedures for bioconjuga-
monium bromide, CTAB).27 Further optimizations of the tion, pronounced colors, and sensitive plasmon changes makes
9976 DOI: 10.1021/acs.chemrev.7b00037
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them typically the first nanomaterial to be considered for

improving the performance of classic immunoassays.
3.1.2. Silver Nanoparticles. Ag NPs embody the most
common commercially produced type of NPs. They are used as
antimicrobials within multiple consumer products, including
cosmetics, clothing, shoes, and detergents, and as surface
coatings in respirators and water filters.45,46 Ag NPs are
characterized by an extinction coefficient higher than that of
Au NPs exhibiting the same size and also provide stronger
Raman and fluorescence enhancement,47 which enables their use
in optical applications.48 Moreover, Ag NPs can be oxidized more
easily and offer improved electrochemical activity compared to
Au NPs, making them excellent candidates for detection tags in
electrochemical sensing. However, the practical applications of
Ag NPs in immunosensing are restricted by their significantly
lower stability, more prominent difficulty to functionalize, and
limited biocompatibility compared to those of Au NPs.49 In
recent years, the application of Ag NPs in immunosensing has
been increasing with the improvement in the relevant methods of
synthesis, stabilization, and functionalization.
Spherical Ag NPs can be synthesized using the Turkevich
method described for spherical Au NPs. Experimentally, due to
its good solubility in polar solvents, AgNO3 is the most Figure 3. Formats suitable for electrochemical immunosensing include
commonly used precursor in the preparation of Ag NPs via the competitive (A, B) and sandwich (C) immunoassays. For competition,
reduction route. The reduction using citrate typically leads to the the immobilized recognition molecule can be either an antibody (A) or
production of particles with larger diameters (50−100 nm) and an antigen (B, antigen, hapten, or their derivatives); the signal-
broad surface plasmon absorption. Smaller spherical nano- generating labeled molecule, or the tracer, includes analyte−NP (A) or
particles (5−20 nm) can be synthesized using NaBH4 as the antibody−NP (B1) conjugates. The latter variant can also employ an
unlabeled primary antibody and a secondary labeled antibody (B2). For
reducing agent.50,51 The Ag NP dispersions are usually stabilized
sandwich assays, the capture (primary) antibody is immobilized (C),
by poly(vinyl alcohol), poly(vinylpyrrolidone), BSA, citrate, or and a signal is generated using the labeled secondary antibody (C1) or
cellulose.34 even the third labeled antibody (C2). The general calibration graphs for
Besides the amplification of traditional immunosensors, Ag both competitive and sandwich assays are shown in the right-hand
NPs are also used in specialized applications. A metalloimmuno- section of the image.
assay based on the dissolution of Ag NPs was developed by
Szymanski et al.52 After the sandwich reaction with the Ag NP
label, the Ag NPs aggregated due to the addition of thiocyanate,
and the negatively charged aggregates were attracted to the
positively charged carbon electrode during pretreatment. Once
in direct contact with the electrode surface, the Ag NPs were
oxidized at +0.6 V to form soluble silver ions, which were
immediately complexed by the thiocyanate and detected via
anodic stripping voltammetry.52
Furthermore, the silver-based enhancement approach is
suitable for the amplification of biosensors based on Au NP
labels. Au NPs can act as a catalyst, reducing silver ions into
metallic silver in the presence of a reducing agent. The reaction
leads to the deposition of silver on the gold surface as the
nucleation site and to the growth of NPs, resulting in signal
enhancement (Figure 4). This approach was originally used to Figure 4. Principle of the enhanced response for sandwich immuno-
improve the properties of microscopic imaging; the applications assays with Au NP-labeled secondary antibodies. Au NPs act as a catalyst
in DNA sensing53 and immunosensing54,55 followed. and help to reduce Ag+ ions into metallic silver with hydroquinone as a
Even though Ag NPs do not typically show fluorescencent reducing agent. Based on ref 54.
properties, very small Ag NPs or nanoclusters56,57 can be used in
fluorescence applications. The fluorescence of these particles is no immunoassays based on the direct exploitation of the
assumed to originate from either the quantum states within the fluorescent properties of Ag NPs have been reported thus far.
metal core or mixed ligand states at the inorganic−organic At present, the secondary signal enhancement step seems to be
interface.58 There are also reports about the preparation of larger the most important role of Ag NPs in the immunoanalytical field,
luminescent Ag NPs. Zheng et al. synthesized fluorescent followed by the important role in the SERS techniques.
polycrystalline Ag NPs with a diameter of 18 nm.59 The 3.2. Magnetic Nanoparticles
luminescence was claimed to arise from small domains, with sizes Magnetic NPs constitute a type of nanomaterial with unique
similar to the Fermi electron wavelength (∼0.5 nm), that provide physicochemical properties and an extremely wide variety of
discrete energy states and permit optical transitions. However, applications. Due to the good biocompatibility, MPs have been
9977 DOI: 10.1021/acs.chemrev.7b00037
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Figure 5. Scanning electron microscopy images of Caco2 cells captured with MB/anti-EpCAM and simultaneously labeled with AuNPs/anti-EpCAM in
the presence of THP-1 cells: (a, b) SEM images (falsely colored with Corel Paint Shop Pro) of a Caco2 cell captured by MBs/anti-EpCAM. (c, d)
Higher magnification backscattered images of the Caco2 cell surface showing AuNPs distributed along the cell plasma membrane. Scale bars: 3 μm (a),
400 nm (b), and 200 nm (c, d). Reprinted from ref 82. Copyright 2012 American Chemical Society.

widely used in biomedical domains such as drug delivery,60,61 al.71 The prepared Fe3O4/TiO2 NPs selectively interacted with
hyperthermia,62,63 and magnetic resonance imaging.64,65 Envi- the phosphorylated moiety, and the complexes were magneti-
ronmental and catalytic applications are no less important.66,67 cally separated from the human serum samples. The secondary
Analytical applications based on magnetic NPs are represented anti-BChE Ab’s with quantum dot tags made an immunosand-
mainly by three strategies. The basic strategy is the magnetic wich that was analyzed using SPR. In addition, Cd2+ ions were
preconcentration of an analyte due to its interaction with measured using square wave voltammetry. The LOD for the
biofunctionalized nanoparticles. In this manner, one can phosphorylated BChE was at a concentration of 10 pM.
preconcentrate the analyte, minimize the effect of a sample Magnetic NPs with a gold shell and antibodies immobilized in
matrix with interferents, or attract the immunocomplex onto the an oriented manner were used for the preconcentration of the
surface of the sensor via an external magnetic field. This is bovine leukemia virus antigen gp51.72 The screening method for
perhaps the most important and unique advantage. Another the clenbuterol in bovine hair was described by Regiart et al.,73
procedure rests in applications where functionalized MPs are who took advantage of a combination between a microfluidic
used as tags for the visualization and sensitive detection of chip and nanogold-modified screen-printed electrodes. The
immunocomplexes with a specific analyte. The third common competitive indirect immunoassay used magnetic microparticles
approach is the integration of magnetic NPs into the transducer with primary Ab’s for the preconcentration of the antigen. The
material or the modification of the sensor surface to improve the microparticles were magnetically entrapped on the Au NP-
analytical signal. In many cases, the aforementioned approaches modified SPE, and a mixture of the analyte and phosphatase-
are combined and improve the final effects, e.g., the sensitivity, modified clenbuterol was injected. This combination minimized
selectivity, signal-to-noise ratio, and limit of detection. the consumption of the reagents and samples to a few microliters
3.2.1. Magnetic Preconcentration. A very attractive, and facilitated an improvement in the detection limit of up to 8
simple, and promising field is magnetic preconcentration, pg/mL. Magnetic preconcentration was also applied on
where one can easily separate the analyte from the matrix of brevetoxin B in a competitive assay with guanine-assembled
the sample using an external magnetic field and, in the second graphene nanoribbons conjugated with brevetoxin B.74 Ru-
step, detect the analyte in the form of an immunosandwich. For (bpy)3Cl2 was electrochemically detected on a magnetic carbon
example, magnetic NPs were used for the preconcentration of paste electrode, and the signal was proportional to the
myeloperoxidase from human plasma and magnetically en- concentration of the brevetoxin. Magnetic NPs with specific
trapped on the electrode surface.68 The activity of the antibodies were used for the preconcentration of hepatitis B
myeloperoxidase was determined via the chronoamperometric surface antibodies.75 Secondary Ab with HRP formed an
detection of converted TMB. The main advantage consisted of immunosandwich, and the produced 2-hydroxy-3-aminophenox-
direct detection without the necessity of any tags. Commercial azine was detected using the DPV technique with a very low
Dynabeads were used for the competitive magneto-immuno- detection limit of 8 ng/L. The strategy of magnetic
assay.69 Ochratoxin A from diluted instant coffee samples preconcentration in combination with an electrochemical
competed with the enzymatic tracer on the immunobeads, and transducer was also used for, e.g., the impedance detection of
after washing, the immunocomplex was measured amperometri- Listeria monocytogenes,76 amperometric detection of iterleukin-
cally. The LOD in the spiked coffee samples corresponded to 6,77 chronoamperometric detection of Alzheimer’s disease
0.26 μg/mL, a value which was, interestingly, comparable to that biomarkers in cerebrospinal fluid, human serum, and plasma,78
of the samples diluted in PBS (an LOD of 0.32 μg/mL). and chronoamperometric detection of the human colon
Magnetic nanoparticles with immobilized primary antibodies adenocarcinoma cell line as a model of cancer circulating cells
against p24 HIV antigen were also used as the capture probe.70 (Figure 5).79 Similarly, the combined detection of cancer cells
The immunocomplex was attracted to the SPE electrode surface, and tumor biomarkers was described by Yang et al.80 Doubly
and the HRP tag consisting of HRP immobilized via the dextrin functionalized magnetic nanobeads with anti-avian influenza A
amine skeleton on the Au NPs amplified the signal via the (H7N9) and alkaline phosphatase were used for the preconcen-
oxidation of catechol by H2O2. The electrochemical response for tration of the target virus.81 These immunocomplexed nano-
the p24 HIV antigen was linear in a wide range, and an LOD of beads were interacted with an mAb-modified GCE to make a
0.5 pg/mL was achieved. An immunosensor for detecting stable immunosandwich. A double electrode signal was measured
phosphorylated butyrylcholinesterase was described by Zhang et during the enzyme-induced metallization reaction. Anodic
9978 DOI: 10.1021/acs.chemrev.7b00037
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stripping voltammetry helped to analyze the H7N9 virus with an The impedimetric behavior of this system was studied using a
LOD of 6.8 pg/mL. ferro/ferricyanide redox probe.93
A comparative study of the immunomagnetic separation and A combination of several different nanomaterials is also
electrochemical detection of Salmonella was proposed by common, bringing new options and improved sensor properties.
Brandão et al.83 The authors realized the separation of Salmonella For example, the GCE was modified using graphene sheets with
enterica in different media, such as BHI broth or diluted and thionine, and the magnetic NPs covered by a silver shell were
whole milk. A slight matrix effect when using mag NPs at a higher immobilized through glutaraldehyde chemistry.94 The anti-
bacteria concentration was shown. Miniaturization and its kanamycin antibodies were thus immobilized on the surface in
combination with nanobiotechnology can provide powerful a significantly higher amount. The improved electrical behavior
and sensitive analytical instruments. Microfluidics combined of the sensor was characterized using cyclic voltammetry and
with nanostructured microelectrodes has been reported.84 square wave voltammetry. The ability of the sensor was also
Otieno et al. described sensitive preconcentration using mag evaluated using real pork samples. Kanamycin was detected in
NPs and the ultralow accurate detection of cancer biomarkers, less than 5 min with an LOD of 15 pg/mL. An electrochemical
which can be helpful for the early detection of cancer. sensor for the CEA tumor marker was prepared with an
Interleukin-6 and interleukin-8 were detected with ultralow enhanced electrode layer.95 The GCE electrode was modified
limits of detection equal to 5 and 7 fg/mL, respectively. with Au NP-functionalized magnetic carbon nanotubes together
β-Amyloid as an Alzheimer’s disease biomarker was magneti- with lead ions (Pb2+/Au/MWCNTs−Fe3O4). This setup
cally separated from the whole blood sample and detected using a enhanced the electrochemical signal, and the CEA was detected
portable SERS probe with an LOD of 100 fg/mL.85 One with an LOD of 1.7 fg/mL.
multifunctional nanoplatform was made of a magnetic core− QCM sensors are mostly used for the direct monitoring of
plasmonic Au shell nanoparticle attached to hybrid graphene emerging immunocomplexes at their surfaces, and magnetic NPs
oxide. can be used beneficially for the amplification of QCM-based
3.2.2. Renewable Sensor Surfaces and Modification bacteria detection. Zhou et al. described a different approach, one
Methods. The reusable sensor layer based on immunomagnetic based on monitoring the insoluble product given by the reaction
particles has several advantages, including magnetic preconcen- of 3-amino-9-ethylcarbazole with H2O2 catalyzed by the HRP
tration, ecological aspects, and automation possibilities. This tag.96 First, a change in the monitored frequency was given by the
kind of assay has been described several times for, e.g., the magnetic attraction of the immunocomplex (CRP and anti-
detection of aminoterminal probrain natriuretic peptides,86 α- CRP@MPs) to the QCM sensor. An additional frequency
fetoprotein,87 and phosphorylated p53 protein.88 Electrochemi- change arose due to the catalytic reaction and formation of the
cally active magnetite NPs were described by Cheng et al.89 The insoluble product. Using this amplification, C-reactive protein
magnetic core was interlayered with Prussian blue and AEAPS. was determined in the serum with an LOD of 0.3 pg/mL.
This cluster was coated with gold nanoparticles supporting the 3.2.3. Magnetic Particles as Tags. An analytical signal can
immobilization of anti-Escherichia coli antibodies. The sophisti- be enhanced using a suitably selected tag. Mag NPs are usable
cated system produced a renewable amperometric immunosen- individually or in combination with other NPs or signal
sor. These four-layer functionalized magnetic NPs were mediators; for example, the simultaneous detection of tumor
entrapped on the electrode using an internal electromagnet. markers was based on the electrochemical determination of two
The final size of these combined particles was approximately 100 mag-particle-based probes on the electrode surface.97 The
nm. The observed detection limit corresponded to 4.3 × 102 cfu/ primary Ab was immobilized on the poly[1-methyl-3-(1-
mL E. coli O157:H7. An amperometric magneto-immunoassay methyl-4-piperidinylmethylene)thiophene-2,5-diyl chloride]-
was also developed using core−shell magnetic particles attached modified GCE electrode. Two electrochemical probes were
to a carbon paste electrode.90 The tracer was used for the specific made via the modification of Fe3O4 nanoparticles with thionine
label of the captured Legionella pneumophila, and the electric and ferrocenecarboxylic acid possessing two separate analytical
current was recorded after the addition of H2O2 in the presence peaks after the sandwich-type interaction of a labeled secondary
of hydroquinone. Ab with tumor markers. The LODs for the squamous cell
The sensing signal can be enhanced by enlargement of the carcinoma-associated antigen (SCCA) and carcinoembryonic
sensor area and thus via increasing its binding capacity. antigen corresponded to 4 and 5 pg/mL, respectively.
Electrochemical impedance spectroscopy with a modified Mag NPs coated with streptavidin were used as a tag for the
magnetic glassy carbon electrode (MGCE) was used for the detection of the PSA using spectral correlation interferometry,
detection of CD146, a biomarker of human malignant where the change of the thickness of the bioactive layer
melanoma.91 Au@Fe3O4@graphene clusters were used to consisting of the primary Ab, PSA, biotinylated second Ab, and
modify the MGCE electrode and thus to produce a conductive mag NPs was monitored.98 Compared to other NPs used in the
and extra-area platform for the immobilization of specific study, interestingly, the MPs were more effective, and an LOD of
antibodies. The sensor was tested with several interferent 92 pg/mL was achieved. Immunomagnetic NPs were also used as
molecules and then applied for detection in real human serum an enhancing tag for the direct competitive immunoassay for
samples. A wide linear range from 5 pg/mL to 500 ng/mL and a okadaic acid monitored using SPR.99 The magnetic preconcen-
detection limit of 2.5 pg/mL showed good specificity of this tration with SPR was used for the enhanced detection of AFP100
label-free immunosensor. A new sensing platform for the and human interleukin 17A.101
ultralow detection (LOD = 0.33 pg/mL) of the CEA was Similarly, the core−shell magnetite@Au NPs were used for the
provided by the modification of the GCE with Fe3O4/porous preconcentration of the human epididymis protein 4 (an ovarian
graphitic carbon nanocomposites and self-polymerized dop- tumor marker) and further SERS detection of this immuno-
amine.92 Mag NPs coated on an ITO electrode were used as the complex with an LOD of 100 fg/mL.102 The same concept was
active layer for the immobilization of mAb anti-Vibrio cholerae. also employed to detect E. coli;103 likewise, the anti-CEA/
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aminothiophenol/Fe3O4−Au tag was used for the improved (Figure 7) seems to be a promising tool for automatic detection
detection of the CEA expressed by A459 lung cancer cells.104 in various applications. A model experiment was presented on
The analytical response can also be enhanced via special tags the detection of the staphylococcal enterotoxin A and toxic shock
affecting the signal or increasing the amount of mediators. A syndrome toxin from milk. The antigens were captured using
controlled release system was developed for the detection of the antibodies covalently attached in the filter, and the immuno-
SCCA.105 Mesoporous magnetite NPs with encapsulated sandwich arose by interaction with the magnetic NPs labeled
toluidine blue (TB) were used as a tag and source of mediator with secondary Ab’s. The mag NPs served as an active signal tag,
molecules. The interaction of conjugated Ab’s led to the release and their nonlinear magnetization indicated the presence of an
of TB, and the released probe was electrochemically detected by antigen in the sample.
CV. The strategy of “huge” molecular tags carrying several Magnetic NPs became indispensable for specific preconcen-
electrochemically active molecules is represented by cadmium tration of analytes present at very low concentrations; the
ion-doped magnetic poly(styrene−acrylic acid) nanospheres and simultaneous sample cleanup represents an additional benefit.
carbon nanospheres with protein cage NPs.106 Unique magnetic properties allowed the proposal of interesting
Enzyme mimic tags are very attractive due to their high sensing mechanisms, though the development and transfer to
stability and resistance against harsh conditions. There are many commercial devices seems to be slow. The applications in
applications of magnetic particles serving as enzyme mimic tags. targeted drug delivery will grow. The highest potential exists in
A nonenzymatic label based on magnetic beads with immobilized the magnetic resonance imaging for specific contrast enhance-
TMB and CEA was used for competitive binding between this ment.
complex and free analyzed CEA.107 CV and DPV were used to
monitor the oxidation of ascorbic acid catalyzed by mag beads@ 3.3. Carbon-Based Nanomaterials
TMB. A low detection limit, 1 pg/mL, was achieved. The 3.3.1. Carbon Nanotubes. Carbon nanotubes (CNTs),
corralite-like nanocomposite Fe3O4/MnO2/Pt mimics perox- discovered by Iijima in 1991,111 can be considered graphite
idase activity and was tested as a tag conjugated on the secondary sheets rolled up into nanoscale tubes. CNTs can be divided into
Ab.108 The amperometric signal was proportional to the two main categories: single-walled carbon nanotubes
concentration of the CEA with an LOD of 0.16 pg/mL. A (SWCNTs) and multiwalled carbon nanotubes (MWCNTs).
hematin-decorated magnetic NiCo2O4 superstructure was used SWCNTs consist of a single sheet of graphene wrapped into a
for the construction of an enzyme-free ultrasensitive photo- cylindrical tube. SWCNTs are typically about 0.4−2 nm in
electrochemical and electrochemical assay to facilitate the diameter and 1−100 μm in length, depending on the method
detection of the CEA.109 used for their synthesis. MWCNTs are composed of concentric
A magnetic immunoassay on porous 3D filters (Figure 6) cylinders of rolled up graphene sheets; the diameter of
made of twisted fibers of polyethylene coated with polypropylene MWCNTs usually ranges between 1 and 10 nm, depending on
the number of sheets. CNTs exhibit metallic or semiconducting
character, according to their chirality and the diameter of the
tubes.112 The chirality can be designated as armchair, zigzag, or
chiral, depending on the axis upon which the CNT was rolled.113
The three main types of CNT synthesis are arc discharge,111
chemical vapor deposition (CVD),114 and laser ablation.115
CNTs were first synthesized using carbon-arc discharge.
Depending upon the catalyst used, this approach provides
MWCNTs or SWCNTs with a high yield (∼90%) and ensures
good control over the dimensions of the synthesized tubes. Due
to the high yield and reproducibility, this technique allows large-
scale commercial production. Chemical vapor deposition is also
catalyst dependent and results in small-diameter CNTs. The
Figure 6. Detection of superparamagnetic nanolabels by their nonlinear yield of the CNTs is lower, but the created CNTs are significantly
response at combinatorial frequencies from the whole volume of the 3D cleaner, and the purification procedures can be simplified. Laser
solid phase located inside a pipet tip. Reprinted from ref 110. Copyright
2013 American Chemical Society. ablation offers the cleanest CNTs, though at a higher price and
lower yield. All these synthesis techniques provide a mixture of
metallic and semiconducting CNTs.113

Figure 7. SEM surface morphology of cylindrical 3D fiber filters obtained with an FEI Quanta 200 scanning electron microscope: left, magnified lateral
surface fragment (500× magnification); center, overview of the lateral surface of the filter (60× magnification); right, top surface fragment (500×
magnification). Reprinted from ref 110. Copyright 2013 American Chemical Society.

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Figure 8. Schematic display of the different steps involved in the preparation of the dual electrochemical immunosensor for multiplexed determination
of IL-1β and TNF-α cytokines. Based on ref 126.

CNTs are often used in immunosensing116 due to their unique hydroquinone as the redox mediator were conducted for each
physical and chemical properties, e.g., the high surface-to-volume cytokine. LODs of 0.38 pg/mL (IL-1β) and 0.85 pg/mL (TNF-
ratio, high electrical conductivity, and rapid electrode α) were achieved, and the application of a sensor was
kinetics.117,118 The functionalization of CNTs can be performed demonstrated in real samples of human serum and saliva.
via covalent or noncovalent binding with different chemical A label-free electrochemical immunosensor based on GCE
groups, which allows high compatibility of CNTs for the modified by MWCNTs and Au−Pt NPs was developed by Liu et
conjugation with biomolecules.119 The large surface area of al.129 The modifications of the electrode increased the surface
CNTs facilitates a massive loading capacity for the conjugation of area for the immobilization of a large amount of antibodies and
biomolecules or incorporation of other nanoparticles; this enhanced the electrochemical performance. The mAb captured
property can improve the sensitivity via amplification of the the analyte (mycotoxin zearalenone), which was subsequently
electrical120 or optical121 signals. The high conductivity of CNTs directly oxidized by DPV. However, this assay scheme can only
was also demonstrated to mediate electron transfer, which be applied in detecting electrochemically active analytes; in other
further enhances the measured current.122 The chemical cases, a sandwich or a competitive assay has to be performed.
functionalization of CNTs also allows us to enhance their 3.3.2. Graphene. Graphene is a two-dimensional single-
solubility and biocompatibility.123 atom-thick planar sheet of sp2-bonded carbon atoms organized in
In electrochemical immunosensing, CNTs can be used either a hexagonal lattice. The first mechanical exfoliation of graphene
to directly modify the electrode surface or as labels in sandwich was demonstrated by Novoselov et al. in 2004;130since then, the
assays. CNTs as an electrode nanomaterial offer improved number of studies on graphene has constantly increased.
sensitivities, wide detection ranges, and lower limits of detection Graphene offers outstanding electrochemical, mechanical, and
compared to traditional carbon electrodes.124 The CNTs in thermal properties, optical transparency (∼97.7%), and
sandwich-based immunoassays can be used as signal labels and to flexibility. Due to these features, graphene embodies an attractive
provide surface enlargement for the immobilization of the candidate for the preparation of biosensors.113 As graphene is
secondary antibodies.125 conductive, transparent, and inexpensive, it constitutes an ideal
Double-walled carbon nanotubes (DWCNTs) were used to material for the development of biosensors based on diverse
modify two-channel SPEs for the simultaneous determination of transducers, from electrochemical to optical ones.131
two cytokines (interleukin-1β (IL-1β) and tumor necrosis factor Various types of graphene have been synthesized and applied
α (TNF-α); relevant details are shown in Figure 8).126 in biosensing.132 Pristine graphene, obtained via the mechanical
DWCNTs offer improved lifetimes and a higher stability cleavage of graphite, is strongly hydrophobic, which heavily
compared to MWCNTs,127 and they also exhibit better reduces its applications in immunosensing. Graphene oxide
electrochemical behavior than SWCNTs; such features then (GO) significantly improves the hydrophilicity of graphene
enhance the electron transfer and allow considerable over- layers, but GO is an electrical insulator, causing the reduction of
potential reduction for various species. After chemical mod- conductivity by several orders of magnitude. When the oxygen-
ification of DWCNTs, the outer cylinder works as a protective containing groups of GO are eliminated, the reduced graphene
sheath to guard the electric properties of the inner tube. Covalent oxide (rGO) achieves a unique combination of high conductivity,
sidewall chemistry can be performed on DWCNTs without any large surface area, high electrochemical activity, and simple
loss of the intrinsic properties.128 Sandwich-type immunoassays functionalization.133
with amperometric signal amplification using poly-HRP− GO is produced using the Hummers method, which is based
streptavidin conjugates, H2O2 as the HRP substrate, and on a treatment by potassium permanganate and concentrated
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sulfuric acid for the simultaneous oxidation and exfoliation of

graphite.134 The acid treatment introduces polar functional
groups, such as epoxy, carbonyl, and hydroxyl, inducing the
hydrophilicity of GO. The colloidal solution of GO can be
reduced by means of various treatments, such as chemical
reduction by directly adding reducing agents (e.g., hydrazine)135
or thermal reduction using high temperatures (200−900 °C).136
Electrochemical reduction based on immobilizing GO on an
electrode surface and performing reducing scans by sweeping the
potential from 0 to 1.5 V is a simple and convenient procedure to
produce rGO-modified electrodes.137
Chemical vapor deposition (CVD) on transition-metal
substrates (typically Cu138) is a promising, cost-effective, and
high-throughput approach for the synthesis of large-area
graphene films. The CVD synthesis of graphene is practically
the subsequent diffusion and surface segregation of the carbon
atoms obtained by the thermal decomposition of hydrocarbons,
upon the cooling of the carbon−metal solid solution. This Figure 9. Schematic illustration of the graphene oxide-labeled sandwich-
technique enables the control of the grain size, crystallinity, and type impedimetric immunoassay with signal enhancement based on in
number of graphene layers via adjustment of the gas flow rate, situ 4-chloro-1-naphthol precipitation. Based on ref 141.
growth time, and cooling rate. CVD allows the integration of
graphene in conventional Si-based electronics and serves as a
platform for the production of miniaturized FET biosensors.113 surface of GO. The remaining FAM-DNA was adsorbed on the
Similarly to the application of CNTs, the applications of surface of GO, and the fluorescence quenching was evaluated.
graphene in electrochemical immunosensing can also be divided 3.3.3. Other Carbon-Based Nanomaterials. Apart from
into direct modifications of the sensor surface and usage as a label CNTs and graphene, other types of carbon-based nanostructures
in sandwich assays. The modifications of electrode surfaces can (such as fullerene, carbon nanohorns, and carbon dots) have also
be performed with graphene directly or by using nanocomposites been recently used for immunosensing applications.144
of graphene with metallic NPs to enhance the sensitivity even Fullerene C60, the smallest stable and most abundant member
further. A simple one-step method for the preparation of a of the fullerene group, is an electroactive nanomaterial
graphene−thionine−Au nanocomposite was demonstrated by characterized by unique properties that make it well suited for
Han et al.139 HAuCl4 was reduced in the presence of GO and the development of electrochemical sensors.145 Fullerene C60
thionine; the formed nanocomposite was then adsorbed to a has multiple redox states in a wide range of potentials undergoing
GCE, and the anti-CEA antibody was immobilized to Au via six different one-electron reversible reductions to form stable
physical adsorption. The binding of the CEA hindered the intermediates. The capability of signal mediation and the simple
functionalization allow applications in the field of immunosen-
electron transfer to the thionine, which was monitored by SWV.
sors.146,147 Electrodes modified by fullerene C60 have an
A low detection limit of 0.05 fg/mL was achieved, even though
increased electroactive surface area and high electric con-
the amount of Au NPs on the surface was not very high; this
ductivity. The disadvantage of fullerene is the hydrophobicity
could restrict the antibody immobilization and, therefore, also
and insolubility in water, which complicates the conjugation of
the binding of the CEA.140 biologically active molecules.144
A sandwich assay based on HRP-modified GO and Single-walled carbon nanohorns (CNHs) are a novel type of
biocatalyzed precipitation was developed by Hou et al.141 The carbon allotrope. CNHs can be produced by vaporizing pure
antigen (CEA) was captured by an antibody immobilized on a Au graphite rods via CO2 laser ablation. Advantageously, no metal
NP-modified GCE followed by the binding of a conjugate of GO catalyst is necessary; the prepared CNHs can thus be essentially
with multiple molecules of HRP and a detection antibody. The metal-free148 and are usable directly, without post-treatment.
HRP catalyzed the precipitation of 4-chloro-1-naphthol, CNHs are convenient as a scaffold for the immobilization of
resulting in increased impedance. The conjugate with GO antibodies or antigens and also for the amplification of the
allowed improvement of the LOD by 3 orders of magnitude (to electrochemical signal.149
0.64 pg/mL) compared to that of a simple conjugate of the Carbon dots (further divided into carbon quantum dots and
antibody with the HRP. The details of the procedure are shown graphene quantum dots) are a type of 0D carbon nanomaterial
in Figure 9. with a size of approximately 10 nm.150 Since the discovery of
Furthermore, graphene is also suitable for fluorescent and carbon dots by Xu et al. in 2004,151 substantial research effort has
chemiluminescent immunoassays, where it acts as the energy been devoted to this material. As carbon dots are characterized by
acceptor to quench the luminescence signal.142 A complex quantum confinement and edge effects, they can exhibit optical
immunosensing strategy based on ssDNA labeled by 6- and electro-optical properties similar to those of conventional
carboxyfluorescein (FAM-DNA) and exonuclease for signal QDs and offer potential for application within.152,153 Recently,
amplification was developed by Liu et al.143 After the formation also the electrochemical properties of carbon dots were exploited
of a sandwich with a biotinylated detection antibody and the to develop electrochemical biosensors.154
subsequent binding of streptavidin, biotin-labeled ssDNA, and Carbon quantum dots and Ag@SiO2 NPs were combined into
FAM-DNA, the FAM-DNA was hydrolyzed by exonuclease. a nanoplatform for sandwich fluorescence and SERS immuno-
Thus, a small amount of the target protein could produce a large assays.155 The Raman reporter 4,4′-dimercaptoazobenzene was
amount of fluorescent fragments that cannot be adsorbed on the generated from the apparent reporter p-aminothiophenol bound
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Figure 10. Illustration of the construction of bifunctional CND-decorated Ag/PATP/SiO2 nanoparticles for fluorescence and SERS immunoassays.
PATP = p-aminothiophenol, MPTMS = (3-mercaptopropyl)trimethoxysilane, TEOS = tetraethyl orthosilicate, and APTMS = (3-aminopropyl)-
trimethoxysilane. Based on ref 155.

on the surfaces of Ag NPs upon the illumination of a laser. The can be carried out by embedding QDs with different sizes into
large Raman scattering cross sections compensated for the polymeric microbeads at precisely controlled ratios.162
reduction of SERS signals resulting from the silica coating Most of the QDs for analytical applications are prepared as
(Figure 10). IgG molecules were detected in a proof-of-concept core−shell structures, with the core nanocrystal coated with
experiment with an LOD of 2.5 ng/mL. another semiconductor material for the protection and improve-
Graphene quantum dots prepared via the autoclaving of ment of the optical properties (Figure 11). QDs with large
graphene oxide were employed for the electrochemilumines- quantum yields and a narrow size distribution are commonly
cence detection of cancer cells.156 Cubic Cu2O was used as a synthesized at a high temperature in organic solvents.163 To
template for the formation of a surface villous Au nanocage, transfer these hydrophobic QDs to an aqueous solution, the
which was then bound to graphene quantum dots. The
hydrophobic ligand layer has to be changed. The two principal
performance of a sandwich ECL sensor was demonstrated on
the detection of MCF-7 breast cancer cells. Similar labels were hydrophilization methods are ligand exchange and encapsulation
used for core−shell NPs combining fluorescence and the SERS
response.
The main role of graphene variants and carbon nanotubes is
enhancement of the electron transfer rate in electrochemical
immunosensors. The higher current density is favorable for an
improved signal-to-noise ratio. At the lowest level, these carbon-
based nanomaterials function as molecular wires interconnecting
redox centers of proteins, conductive metal NPs, and the
electrode surface.
3.4. Luminescent Nanocrystals
3.4.1. Quantum Dots. Quantum dots (QDs) are fluorescent
semiconductor nanocrystals characterized by dimensions
typically in the range of 1−10 nm.157 They enable various
applications, for example, light-emitting devices, photodetectors,
solar cells, field-effect transistors, memory elements, luminescent
biolabels, biosensors, and bioimaging probes.158 QDs show size-
tunable photoluminescence properties, wide excitation spectra,
and a narrower emission bandwidth compared to classic organic
fluorophores.159,160 The fluorescence color can be controlled by
the QD size, i.e., by modifying the temperature during the Figure 11. Schematic view of quantum dots as labels in immunoassays:
synthesis or the duration of the nanocrystal growth. QDs with (A) QDs formed by a single semiconductor material; (B) core−shell
emission wavelengths ranging from 380 to 2000 nm can be QDs; (C) core−shell QDs with a hydrophilic coating and reactive
prepared using an appropriate semiconductor material and groups R for bioconjugation; (D) a polymeric particle containing several
nanocrystal size.161 Furthermore, multiplexed color encoding QDs for signal multiplexing.

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with an amphiphilic polymer.164,165 Most of the hydrophilic the host lattice with its crystal structure ensures a matrix to bring
ligands employed for ligand exchange include mercapto groups these centers into optimal positions.180
since they offer a high binding affinity to the QD surface.166 The progress in nanocrystal research has evoked an increasing
The conjugates of QDs with antibodies are stable and provide interest in the development of synthesis procedures, facilitating
an easily detectable analytical signal, which makes them useful as the preparation of highly efficient, small UCNPs with a narrow
sensitive fluorescent labels in immunoassays167−169 and size distribution that can form transparent solutions in various
bioimaging.170,171 The application of QDs in quantitative LFIA solvents. Unlike commonly used luminescent biological labels
for CRP detection was demonstrated by Hu et al.172 Fluorescent (for example, organic dyes and QDs), UCNPs are advantageous
nanospheres were produced by embedding hydrophobic CdSe/ in many aspects; they are characterized by a practically zero
ZnS QDs into a poly(styrene−acrylamide) copolymer, which autofluorescence background, large anti-Stokes shifts allowing
strongly increased the fluorescence intensities compared to easy separation of the excitation and detection channels, multiple
single QDs. The QD-based assay was more sensitive (an LOD of and narrow emission bands tunable individually for the
34.8 pM in serum) than the conventional LFIA based on Au NPs. multiplexed detection of analytes, and excellent photostability.180
QDs have also become very popular in ECL immunosens- Small and homogeneous lanthanide-doped UCNPs showing
ing.173,174 Zhang et al.175 synthesized CdSe nanocrystals for the high upconversion efficiency are typically synthesized in organic
single-molecule analysis of the CEA (Figure 12). Mercaptopro- solvents. UCNP functionalization methods to ensure a hydro-
philic surface and allow bioconjugation reactions were reviewed
by Sedlmeier and Gorris.181
The unique photophysical properties of UCNPs make them
suitable as reporters in optical biosensors and biomolecular
binding assays. The potential of UCNPs in diagnostics was first
demonstrated by Tanke et al. in 1999.182,183 Since then, UCNPs
have been used in the design of heterogeneous184−186 and
homogeneous187,188 microtiter plate immunoassays and in lateral
flow immunoassays189 for the detection of various analytes.
Competitive upconversion-linked immunosorbent assay
(ULISA; Figure 13) for the detection of the pharmaceutical

Figure 12. Scheme of a sandwich ECL immunosensor for the

determination of the CEA. Reprinted from ref 175. Copyright 2016
American Chemical Society.

pionic acid and sodium hexametaphosphate were used as the

capping agents to facilitate the electrochemically involved hole
(or electron) injecting process and improve the nanocrystal
stability. A very low LOD of ∼6−8 CEA antigen molecules in 20
μL of serum samples was achieved, which could be ascribed to Figure 13. Scheme of the indirect competitive ULISA for the detection
the effective ECL generation of the well-passivated and stable of diclofenac (DCF). (A) A microtiter plate is coated with a BSA−DCF
NPs. conjugate. (B) Dilution series of DCF are prepared in the microtiter
Tasso et al.176 capped QDs with a multidentate dithiol/ plate followed by the addition of an anti-DCF mouse antibody. (C) The
attachment of the anti-DCF antibody is then detected by the antimouse
zwitterion copolymer ligand. This approach exploited the thiol
IgG−UCNP secondary antibody conjugate. Reprinted from ref 190.
groups for both anchoring and the bioconjugation of up to 10 Copyright 2016 American Chemical Society.
protein A molecules per QD while preserving long-term colloidal
stability of QDs. Protein A provides a simple and universal
platform for the immobilization of various antibodies. The diclofenac was developed by Hlavácě k et al.190 The competitive
authors demonstrated the low toxicity of the conjugates and the reaction based on the immobilized BSA−diclofenac conjugate
usage of the QDs for visualizing E-cadherin in fixed MCF-7 cells and free diclofenac and a primary antibody was followed by the
and tracking the cannabinoid CB1 receptor in live HEK cells. detection step involving the binding of the UCNP−secondary
3.4.2. Photon-Upconverting Nanoparticles. Photon- antibody conjugate. The optimized ULISA achieved an LOD of
upconverting nanoparticles (UCNPs) are lanthanide-doped 0.05 ng/mL, which came close to that of the conventional ELISA
nanocrystals that show anti-Stokes emission. The energy transfer without the necessity of the enzyme-mediated signal amplifica-
up-conversion is a nonlinear optical process characterized by the tion step.
absorption of two or more photons and leading to the emission Li et al. developed an immunoassay based on FRET between
of a single photon at the shorter wavelength.177 Unlike other anti- UCNPs and Au NPs191 (Figure 14). The glass slide was
Stokes processes, such as the two-photon excitation and second covalently modified by UCNPs and the capture antibody. A
harmonic generation, up-conversion can be efficiently excited at competition between the free antigen and the antigen conjugated
lower excitation densities. Upconversion has been known since with BSA and Au NPs was performed. When the conjugate was
the 1960s;178 however, the applications of the upconversion bound, FRET occurred, and this was measured as a decrease of
effect were limited to bulk glass or crystalline materials.179 An luminescence compared to that of free UCNPs. The single-step
inorganic upconversion phosphor contains a crystalline host and method offers several advantages against the commonly used
a dopant (typically lanthanide ions) added at a low multistep reactions due to less washing steps and the overall
concentration. The dopant provides luminescent centers, and shorter analysis time.
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CRP.195 The assay was 260× more sensitive compared to

alternative labeling with Au NPs.
The Ag2S QDs (80 nm in diameter) were protected with a
silica shell (45 nm in thickness) providing for label emitting in
the IR region (896 nm).196 This allowed a sensitive sandwich
assay of Cryptosporidium parvum in the microplate format,
ensuring an LOD of 10 oocysts/mL. Fluorescein-loaded porous
silica NPs served as a label in a sandwich assay for the pathogenic
strain of E. coli.197 General aspects of embedding labels inside
silicate and similar nanoparticles were reviewed by Wei.198
An interesting amplification strategy involving the covalent
coupling step was based on CuO NPs labeling a secondary Ab.
The label was dissolved in HCl and reduced to Cu+ ions
catalyzing the click-chemistry-based alkyne−azide cycloaddition
of weak fluorescent 3-azido-7-hydroxycoumarin and propargyl
alcohol to form a strong fluorescent compound.199
Figure 14. Schematic illustration of the one-step in situ immunoassay 4.1.2. FRET Assays. A FRET-based immunosensor for the
based on FRET between the UCNPs covalently immobilized on the detection of troponin using graphene QDs and graphene as the
substrate surface and Au NPs. Reprinted with permission from ref 191. quencher has already been described.200 The capture anti-cardiac
Copyright 2016 Elsevier. troponin I Ab was covalently conjugated with amine-function-
alized graphene quantum dots. This fluorescent nanoprobe
(excitation at 360 nm, emission at 437 nm) was further
The excitation by near-infrared light that is within the optical investigated in the presence of graphene, which resulted in the
transparency window and, therefore, can penetrate tissues makes quenching of the fluorescence intensity due to dipole−dipole
UCNPs helpful also for the visualization of specific markers in interaction. The addition of the target troponin expelled the
optical microscopy.192 Thus far, most UCNP applications in stacked graphene apart from the immunocomplex and recovered
bioimaging were based on UCNPs not labeled by an antibody.193 the fluorescence.
Wang et al.194 applied conjugates of UCNPs with an anti-CEA8 The fluorescence of CdTe modified with the capture Ab was
antibody as fluorescent biolabels for the specific detection of the quenched by the present H2O2. The competitive assay format for
carcinoembryonic antigen (CEA) expressed on the surface of
ochratoxin used the tracer based on an ochratoxin−catalase
HeLa cells. A strong luminescence signal from the UCNPs was
conjugate. Thus, in the absence of ochratoxin, the bound catalase
obtained, and no autofluorescence from the cells was observed
decomposed the H2O2, and the fluorescence was recovered. The
under 980 nm excitation.
achieved LOD of 0.05 pg/mL was 300× lower compared to that
The properties of luminescent NPs can be easily fine-tuned
of the conventional ELISA technique with HRP as the label.201
through simple modifications of the synthetic procedures; the
The optical advantages of QDs were combined with the long-
time-dependent size allows the emission bands of QDs to be
lasting luminescence of lanthanides.202 The amphiphilic polymer
shifted, and the amount of dopants influences the UCNPs. The
backbone was covalently decorated with biotin (future
main optical advantage is high brightness and stability of the
conjugation reactions) and chelate complexes with embedded
derived labels. Additional benefits include a single excitation
atoms of Eu. This was used to coat the surface of CdSe QDs using
wavelength for several types of NPs; this is significant for
trioctylphosphine oxide as a contacting interlayer. The close
multilabel procedures. Quite unique for the future seems to be
proximity of QD and Eu resulted in an efficient FRET transfer,
the anti-Stokes infrared excitation of UCNPs completely
and the overall system exhibited long-lasting luminescence
removing the background fluorescence of biological samples.
suitable for measurement using the time-resolved approach,
4. TRANSDUCTION MECHANISMS which provides an excellent signal-to-noise ratio. Several other
similar approaches based on luminescent terbium complexes
Nanoparticles appeared compatible with almost all transducing were also reviewed and considered for a multiplexed assay when
systems suitable for the affinity types of biosensors. The combined with QDs of different sizes (colors).203 The
technological aspects of the most common types are provided immunosensor based on luminescence resonance energy transfer
in the subsections below, with a focus on the employed used near-infrared (980 nm) excitation of UCNPs NaYF4:Yb3+,
nanoparticles. Er3+ as the donor modified with the capture Ab. The analyte
4.1. Optical Transducers (glycated hemoglobin HbA1c) was bound and functioned as the
4.1.1. Fluorescence. The sensitivity of a fluorescence-based acceptor. HbA1c absorbs at 541 nm, which overlaps with the
(immuno)assay relies primarily on three factors: the brightness UCNP emission, and the signal is quenched.204
of the fluorescent labels, the packing density of the fluorophores, 4.1.3. Chemiluminescent Nanolabels. The common
and the parameters of the detection optics. The two initial option is to prepare nanomaterials loaded with suitable
aspects can be conveniently addressed using novel fluorescent chemiluminescent dyes. Mesoporous silicate NPs were loaded
nanomaterials. with rhodamine 6G and fluorescein and coupled to the detection
The embedding of hydrophobic CdSe/ZnS QDs into antibody.205 The classic microplate heterogeneous format was
poly(styrene−acrylamide) copolymer nanospheres provided used for the sandwich immunoassay of staphyloccocal enter-
labels containing around 330 QDs per NP sized 270 nm. The otoxin C1; the final luminescence was triggered by the addition
surface carboxyls served in antibody coupling using the EDC/ of bis(2,4,6-trichlorophenyl) oxalate, H2O2, and imidazole.
NHS chemistry. The thus obtained fluorescent nanoconjugate Resonant energy transfer occurs onto the internal dyes with an
was used in the lateral flow strip format for the rapid detection of enhanced signal.
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Figure 15. Preparation of the hybrid Ab−NP/luminol/GOD label and the subsequent ECL of luminol using in situ generated ROS radicals. Ce:ZONFs
= ceria-doped zinc oxide nanoflowers. Based on ref 222.

4.1.4. Electrochemiluminescence. The conversion of with PANI nanofibers/graphene sheets and subsequently
electrochemical energy to light at the surface of an electrode is deposited Au NPs on magnetic beads were used for the sensitive
known as electrochemiluminescence (ECL). The relaxation of assay of interferon γ (LOD = 30 fg/mL).212
the excited states of the molecules formed within the Labels based on poly(amidoamine)-dendrimer-functionalized
electrochemical reaction is accompanied by luminescence. The carbon nanodots were combined with an electrode modified
process is initiated by applying a suitable potential on the using the composite consisting of fullerene, graphene oxide (in
electrode, and the intensity of the released light is measured by a situ electroreduced to graphene), and chitosan; the sandwich
photodetector, typically a photomultiplier.206 The simple assay of AFP provided an LOD of 0.33 fg/mL.213
instrumentation and low background signal compared to those For large analytes, such as microbes, ECL blocking assays are
of other luminescent methods resulted in numerous analytical suitable: the signal decreases with the rising amount of the
applications of ECL.207 A high response is often obtained due to surface-bound analyte. The magnetic Fe3O4/graphene oxide
the repeated conversion of such labels, e.g., ruthenium complexes nanocomposite was activated with EDC/NHS and isoluminol
represented by Ru(bpy)32+. (ABEI), and the capture Ab’s were covalently attached. The
The ECL of various NPs is a relatively new technique; suitable product was simply drop-coated on a magnetic electrode; the
variants include the common binary, core−shell, and doped ECL signal decreased with increasing amounts of the target
QDs, single-element NPs (Si, Ge, Ag, Au), metal oxide pathogen Vibrio parahemolyticus (an LOD of 5 cfu/g in seafood
semiconductors, up-converting NPs, molecular nanoaggregates, samples).214 The concept also functioned for N-terminal pro-
and more complex hierarchical assemblies providing several ECL brain natriuretic peptide with an ITO electrode modified with
mechanisms and reaction courses.208 ABEI−Au nanodots/chitosan/MWCNT as the ECL interface.
The composite QDs Cd/ZnSe served as a label for the After activation with glutaraldehyde and the covalent binding of
sandwich assay of AFP. The ECL was carried out on glassy the capture Ab, the presence of the analyte resulted in decreased
carbon via a cathodic pathway with (NH4)2S2O8 as the ECL (LOD = 3.9 fg/mL).215
coreactant. The procedure employed spectral evaluation instead A similar performance was also obtained for a direct assay of
of the common simple light intensity measurement;195 the deoxynivalenol.216 Network-like Co NPs were produced by the
authors proposed this approach for multicolor ECL immuno- alkaline dissolution of Al from the CoAl alloy; Co3O4 was further
assays. The resulting emission spectra were similar for ECL and grown on the surface followed by Au NP functionalization,
photoexcitation, thus confirming the similar mechanism. The deposition of the capture Ab, and further modification with
authors used a comparable approach with CdSe for the assay of Ru(bpy)32+-loaded silicate NPs. This assembly was drop-coated
the CEA; the remarkably low LOD was 0.1 fg/mL, which on glassy carbon and allowed to dry. The ECL signal was
corresponds to few (7) molecules of the CEA in 20 μL of sample, measured in the presence of K2S2O8; it continuously decreased
thus approaching the single-molecule detection capabilities.209 with higher amounts of deoxynivalenol in the solution. However,
For CdTe-based QDs, significantly enhanced ECL was obtained the authors did not explain why the ECL decreases, as the analyte
after deposition of these QDs onto graphene sheets.210 The is a rather small molecule for reasonable blocking of the surface.
multicolor sensing could also be achieved with common band- The novel ECL system was designed by a rather extensive
pass filters and PMT detectors.211 The graphene-modified glassy Mn2+ doping level of the NaYF4:Yb/Er UCNPs.217 The UCNPs
carbon was linked to two different capture antibodies (anti-AFP were coated with an aminosilicate shell, dropped on glassy
and anti-CEA) in the sandwich format; the biotinylated carbon, and Au NPs were bound through interaction with amino
secondary Ab’s were labeled with different streptavidin−QD groups. Eventually, the capture Ab was linked through
conjugates. The achieved LOD was 0.4 fg/mL for both markers. adsorption on the Au surface. The ECL was measured with
The QDs as labels in ECL sandwich assays are usually excited K2S2O8, and it continuously decreased with higher concen-
on differently modified electrodes. Thus, glassy carbon coated trations of the CEA (LOD = 5.2 pg/mL).
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Small analytes, such as mercury ions, are typically measured reaction exhibits a shorter electron transfer path and lower
using competitive assays. The electrode surface was modified energy loss.
with a poly(diallyldimethylammonium chloride)−graphene− 4.1.5. Photoelectrochemical Conversion. A suitable
CdSe composite secured with chitosan, and the assembly photoactive nanomaterial absorbs the photon, and charge
provided a strong ECL signal with cathodically produced separation occurs as the electron−hole pair formed by the
H2O2. The methylmercury−6-mercaptonicotinic acid linked to excitation of the electron from the valence to the conductive
albumin was further immobilized as a coating antigen. This band. An anodic photocurrent occurs when the electrons are
competed with the free mercury ions for the tracer, or a specific transferred to the electrode and the electron donor (D) in the
Ab−Au NP−HRP tracer. After the binding of the tracer, HRP solution replaces the hole (Figure 16). Alternatively, if the
decomposes the H2O2 by the oxidation of o-phenylenediamine,
and the ECL intensity drops.218 Alternatively, ALP as a label
enzymatically produced p-nitrophenol, which was oxidized to p-
benzoquinone acting as the quencher of the surface-deposited
QDs.219
The quenching of ECL also occurs due to the resonance
energy transfer within the sandwich complex.220 The carbon-
ization of diethylenetriaminepentaacetic acid provided N-doped
C-QDs, which, deposited on an electrode, function as a
luminophore. However, the binding of the analyte (AFP) and
its labeling with the secondary Ab linked to aminated graphene
resulted in the resonant loss of excitation and decreased the ECL
signal. A similar principle was employed using ferrocene−
chitosan NPs as labels in a sandwich assay.221
Hybrid luminol/nanoparticles constitute a combination of
organic and inorganic labels. An enhanced response can be Figure 16. Principle of the origin of photocurrents. The nanoparticles
achieved by various combinations of organic and nanocrystal- contain valence and conductive bands (VB and CB, respectively). The
based luminophores. The cerium-doped ZnO nanoflowers were electrons are provided (accepted) by the donors (acceptors) present in
the surrounding solution. Reprinted with permission from ref 227.
prepared by autoclaving Ce3+ and Zn2+ salts with lysine, which Copyright 2015 Elsevier.
afterward served in the EDC/NHS coupling of the sequentially
added luminol, secondary Ab, and GOD enzyme (in excess to
block the surface, Figure 15). The capture Ab was deposited electrons are transferred to the acceptor (A), complementary
through Ag NWs on glassy carbon. After completion of the electrons from the electrode neutralize the holes, yielding a
sandwich immunoassay, the added glucose with GOD generated cathodic photocurrent.227 General applications of QDs for PEC
in situ H2O2, which was, in the presence of Ce4+, electrochemi- systems were recently reviewed by Lisdat.228
cally oxidized to ROS radicals reacting with the embedded CuS (p-type semiconductor) constitutes a suitable PEC
luminol. The application for an assay of the amyloid-β protein material; it was on-site coated to a Au paper electrode (cellulose
resulted in an LOD of 52 fg/mL within about 90 min.222 coated with Au NPs) modified with ZnO nanoflakes, and the
Luminol was also bound to Au NPs, and the product was capture Ab was linked through a chitosan layer.229 The sandwich
coated on magnetic Fe3O4 NPs together with a secondary Ab. with the CEA analyte was labeled with the Au NP/secondary Ab/
The ECL was measured on a Au electrode modified with Au/ GOD enzyme assembly. The H2O2 resulting from the enzymatic
ZnO NPs containing the capture Ab. An LOD of 4.5 fg/mL was oxidation of glucose served as the electron donor for the PEC
achieved for mucin.223 For the analysis of CEA-125, the luminol process. The wide band gap of ZnO allows its excitation with UV
was covalently coupled to the poly- light, and this problem is overcome by the introduction of CuS
(diethylenetriaminepentaacetic acid−ethylene glycol) ester serving as the primary light capture system. Tetracarboxyl
dendrimers.224 naphthalocyanine zinc can serve as an alternative sensitizer; it
The SiO2 NPs were doped with Ru(bpy)32+ and further was covalently linked to ZnO using aminothiophenol as a bridge
combined with Au/graphene and a secondary Ab to form a and the EDC/NHS coupling.230 This brings the option for near-
composite bioconjugate. This approach significantly enhances infrared photoexcitation; ascorbic acid served as the electron
the amount of Ru complexes per molecule of tracer in sandwich donor. The CEA was the analyzed marker, blocking the surface
assays. The other components increase the rate of the electron and thus lowering the photocurrent with its increasing
transfer and provide multiple antibody binding sites. For the concentrations.
HIV-1 p24 antigen in a human serum, the achieved LOD was 1 A similar approach was used with CdS QDs deposited on TiO2
pg/mL.225 and galactosidase as a label, producing p-aminophenol by
Tris(4,4′-dicarboxy-2,2′-bipyridyl)ruthenium(II) was linked enzymatic hydrolysis of p-aminophenyl galactopyranoside.
with cysteine using EDC/NHS coupling chemistry to obtain a Aminophenol as a donor is photooxidized to quinonimine.231
self-enhanced ECL label for reagentless use.226 This makes the A more complex interface consisted of TiO2 nanotubes coated
procedure independent of common coreactants such as sequentially with Mn-doped CdS and CdTe QDs (Figure 17)
peroxydisulfate, oxalate, or tripropylamine and, consequently, suitable for visible light excitation due to the gradual transfer of
more robust. After being linked to Au nanorods and the electron/hole entities.232 The sandwich immunosensing for
attachment of a secondary Ab, it served in a sandwich assay for matrix metalloproteinase brings a secondary Ab linked to silicate
cardiac troponin I with an LOD of 83 fg/mL. Compared to the NPs functioning as a shield for the ascorbic acid donor and
use of free cysteine as the coreactant, the use of Cys@Ru(II) decreasing the photocurrent. This strategy also worked with
provided a much higher ECL signal since the intramolecular ECL ZnO as the primary electrode coating.233
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coated with a carbon layer as the counter electrode from the

other side. The 60 s accumulated charge was evaluated as the
corresponding potential change after the measuring circuit was
switched on with a simple multimeter.
An alternative system employed the CL generated by the
classic HRP-catalyzed luminol reaction.240 The PEC layer was
also obtained using an SWCNT coated with the photovoltaic
polymer poly(m-phenylenevinylene-co-2,5-dioctoxy-p-phenyle-
nevinylene), which forms excitons under the incident light. As
its valence band is aligned with the CNT, the holes in the excitons
are injected into the carbon nanotube, leaving the electrons in the
vicinity of the CNT on a Si wafer and finally resulting in the
Figure 17. System for the sequential transfer of electrons/holes through measured current.241 Illumination resulted from the HRP/
overlapping energy levels. Based on ref 232. luminol reaction within the sandwich complex with troponin
labeled by the secondary Ab−HRP conjugate.
A PEC blocking assay was based on an ITO electrode coated
Alternatively, Fe (0.1%) doping of TiO2 enhanced its using the layer-by-layer technique by CdSe QDs and poly-
photoactivity 10-fold and shifted the excitation toward the (diallyldimethylammonium chloride) layers. A capture Ab was
visible light range. A further 3-fold enhancement was achieved by linked using EDC/NHS chemistry, and a sandwich was formed
CdS QDs; when the coupled capture Ab binds the corresponding with the target analytemodel immunoglobulinlabeled by
squamous cell carcinoma antigen, the photocurrent decreases.234 the secondary Ab−HRP conjugate. After the addition of 4-
Bi2S3 nanorods on an ITO electrode served as the photo- chloro-1-naphthol and H2O2, enzyme conversion produced a
interface for a sandwich-based assay of avian leukosis virus. A precipitating product which blocked the generation of a
secondary Ab linked to ALP provided for the enzymatic photocurrent.242 The precipitation of the product helps to
production of ascorbate from ascorbate phosphate.235 This keep the signaling molecules close to the point of formation and
donor system was applied also to the CdS QD/TiO2 assembly.236 minimizes their loss by diffusion to the surrounding bulk
The SnO2 QD/graphene composite functioned as a label for medium. Thus, this simple approach can be considered an
the sandwich sensing of the CEA; a capture Ab was deposited on amplification strategy.
an ITO through Au NPs. This required near-UV (365 nm) 4.1.6. Visual Evaluation and Colorimetric Systems. The
irradiation.237 A similar format for the CEA used a label based on wide use of colored nanoparticles seems to shift colorimetric
carboxylated MWCNT−Congo red−C60 fullerene nanohybrids immunoassays closer to real clinical applications.243 The intuitive
prepared by mechanical grinding. This photolabel was suitable approach utilizes colored NPs directly as a label for evaluation.
for green laser excitation.238 The use of Au NPs as labels remains the most common option
An interesting and smartly conceived approach employed a for lateral flow immunoassays,244,245 being a convenient format
charge-collecting component in the electronic amplification for the visual evaluation of immunoassays performed out of
interface. The chemiluminescent illumination system was laboratory. A significant sensitivity improvement was obtained
combined with PEC transduction.239 The CL excitation part as when Au NPs were combined with silica nanorods.246
the tracer employed Au NP labels containing attached CEA, Conversely, NPs without any pronounced color can help to
bound isoluminol (ABEI), and GOD for the enzymatic catalyze the conversion of chromogenic substrates. Pt NPs were
generation of H2O2. The PEC surface consisted of TiO2 used in the lateral flow format as a catalytic system mimicking the
nanospheres and CdS QDs and was modified with a capture enzyme action of peroxidase; the evaluation might be realized
Ab (Figure 18). To further enhance the signal, the photocurrent using a colorimetric system or simply visually using TMB and
electrons were collected in a supercapacitor formed by paper H2O2 as substrates, though chemiluminescence with luminol is
suitable too.247 Pt NPs were also combined with magnetic NPs
for convenient manipulation, and the catalytic properties were
enhanced using graphene oxide; in this way, breast cancer cells
can be identified, with short time periods around 5 min.248
The straightforward blue/red color change discrimination
helped to identify food allergies.249 The principle was based on
HRP as the label on a secondary Ab specific against the target IgE
present in the blood of patients suffering from allergies. Bound
HRP decomposes H2O2, and in this way, small blue Au NPs
appear. In the absence of HRP, H2O2 reduces Au3+ to Au, which
increases the size of the NPs, resulting in the red color. The IgE
can be quantified according to the absorbance at 550 nm. A
similar color change allowed the detection of several pathogens
(Salmonella, Listeria, and E. coli O157) in the sample; the
triggered chemical cascade led to a large red to dark blue shift
visible to the naked eye. The breakdown of cysteine-loaded
Figure 18. Principle of CL illumination with a PEC transducer. The nanoliposomes initiated the aggregation of plasmonic gold
response is enhanced by the flow of electrons to the supercapacitor nanoparticles.250
charge collection system. PIP = p-iodophenol, and PWE = paper Ag nanocubes, Au/Ag alloy nanoparticles, and Au/Ag
working electrode. Based on ref 239. nanocages were evaluated for a multiplexed dot immunoassay
9988 DOI: 10.1021/acs.chemrev.7b00037
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Figure 19. Principle of the single-particle photon burst counting applied for homogeneous immunosensing. Based on ref 252.

carried out on a nitrocellulose membrane strip; multicolor NPs and the resonance is spread along the metal/dielectric surface up
were conjugated with specific antibodies. The NPs were prepared to hundreds of micrometers.256 LSPR embodies nonpropagating
via galvanic replacement between the Ag atoms of silver surface plasmon resonance excited on nanostructured metal
nanocubes and AuCl3. Depending on the Ag/Au conversion surfaces; it can be tuned by the size, shape, or composition of
ratio, the particle plasmon resonance was tuned from 450 to 700 nanostructures or nanoparticles.257
nm, and the suspension color changed from yellow to blue, SPR measurements mostly consist of direct detection258 and
suitable for visual evaluation on the sensing strip.251 sandwich259 or competitive inhibition260 assays. Direct detection
4.1.7. Single-Molecule Detection Techniques. Enhanced is appropriate for applications where the direct binding of the
immunoassays have recently been evaluated digitally by single- analyte yields a sufficient response. The detection limits can be
molecule analysis based on counting individual molecular or enhanced using a sandwich or an inhibition assay. In a sandwich
nanoparticle labels instead of measuring the overall (analog) assay, the measurement is carried out in two steps: First, the
signal. The setup typically comprises a microscope, a sensitive analyte is bound to the antibodies on the sensor surface, and in
camera, and suitable software to count the individual spots. The the second step, the sensor surface is incubated with a solution
high brightness of luminescent NPs is a significant advantage. containing secondary antibodies (which can be labeled by
The noise-free digital readout allows the elimination of the nanoparticles or enzymes261 to further improve the signal),
instrumental background, which has a crucial impact on lowering which bind to the previously captured analyte and increase the
the LOD. sensor response. In an inhibition assay, the examined sample is
The single-particle method (Figure 19) combines photon first mixed with respective antibodies (which, again, can be
burst counting with Au NPs as labeling probes.252 The photon labeled to enhance the signals), and then the mixture is brought
bursting of a single NP is generated in a highly focused laser beam into contact with the sensor surface exhibiting immobilized
(<1 fL) due to the plasmon resonance scattering and Brownian analyte molecules. The free antibodies remaining in the solution
motion. A linear relationship was found between the burst counts can subsequently bind to the surface.
and the number of particles in a solution. Upon the 4.2.1. Amplification by Nanoparticles. Various formats
immunoaggregation of NPs through the present molecules of for the detection of chemical and biological analytes have been
the antigen (PSA), the number of counts decreases. The linear used in SPR immunosensing. The detection scheme is chosen
range of the PSA was 1−1000 pmol/L, and the LOD with respect to the analyte size, binding characteristics of the
corresponded to 0.8 pmol/L.
biomolecular recognition element, range of the concentrations to
4.2. Surface Plasmon Resonance be measured, and sample matrix.262 Direct SPR biosensors are
Surface plasmon resonance (SPR) biosensors are based on the applicable in the case of medium and large molecular weight
light-stimulated oscillation of electrons in the conduction band of analytes, which induce measurable refractive index changes upon
metal films (usually gold), called resonant surface plasmons. This their binding on the surface. The typical detection limits are
effect is strongly dependent on the dielectric constant of its above nanograms per milliliter.263
environment253 and is highly advantageous for biosensing The enhancement of the sensor sensitivity via labeling the
applications because the biological receptor−analyte interaction secondary Ab’s in a sandwich assay by latex particles264 and Au
causes a change of the oscillation frequency. The signal can be NPs265 was presented in the 1990s. Throughout the years, Au
measured as a change of the angle, intensity, refractive index, or NPs have become a standard for SPR signal amplification tags
phase of the reflected light.254 and enhanced sensing surfaces. Nevertheless, substantial effort
SPR sensors can be classified into two main categories: was also put into the development of other nanomaterials for
propagating SPRs (PSPRs, also simply referred to as SPRs) and SPR amplification, such as nanoparticles based on Ag,266 CdS,267
localized SPRs (LSPRs).255 PSPR is typically excited on NiO,268 Pd,269 and NPs,270 also including various kinds of
continuous metal thin films through prism couplers or a grating, magnetic NPs.271,272
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The principles of signal enhancement using nanomaterials can LSPR peaks of Au NPs are determined by their size and shape
be divided into three categories: (1) plasmonic NP-based SPR and the dielectric constant of the surrounding medium. The large
sensing, where LSPR is coupled with the surface plasmon wave local electromagnetic field enhancement is closely related to
excited on the sensing film (Au and Ag NPs), (2) large surface metal nanostructures with sharp corners or large curvatures since
mass loading to improve the sensitivity (latex and magnetic electric charges can preferentially accumulate in these regions.277
NPs), and (3) charge transfer from the nanomaterial to the The LSPR of Au NRs can be systematically adjusted from the
metallic sensing film that induces a larger evanescent field visible to the near-infrared wavelengths by manipulating their
enhancement, thereby magnifying the SPR signals (gra- aspect ratios.273
phene).273 Besides the use of Au NPs in a solution, the incorporation of
Au NPs constitute the most common signal-amplification additional plasmonic nanostructures directly in the SPR sensor
labels in SPR immunosensing. It has been shown that electronic chip is one of the perspective ways to enhance SPR signals.273,278
coupling between the localized surface plasmons of Au NPs and The excitation of LSPRs by light is related to the strong
the surface plasmon waves associated with the Au SPR chip can absorption and scattering of light and also high enhancement of
significantly increase the SPR response (Figure 20).274−276 The the electromagnetic field close to the nanostructure.279 Metal
NPs with controlled sizes and lateral distances280 and different
types of plasmonic nanostructures,281 including nanogratings,282
nanoholes,283,284 and nanodots,285 were used in SPR sensors. In
addition, even a single nanohole in a metal layer has been proved
to support LSPRs.286
Ag NP-coated SPR sensors were found to exhibit stronger
enhancement of the SPR response compared to those coated
with Au NPs287 due to the larger negative real part and smaller
imaginary part in their complex dielectric constants.288,289 The
major disadvantage of Ag NPs is their limited stability and
pronounced susceptibility to oxidation. To overcome this
challenge, Au−Ag alloy nanocomposites were applied in SPR
immunoassays.290 The nanocomposites present high resistance
to oxidization and enable high sensitivity enhancement. Using
the Au−Ag alloy, the human IgG was detected with an LOD of
Figure 20. Scheme of the sandwich SPR assay amplified by Au NPs for 150 ng/mL, while the Au NPs provided an LOD of 300 ng/mL.
the detection of bacteria. Based on ref 276. Magnetic NPs have been employed in SPR immunosensing to
increase binding-induced refractive index changes291 and for the
preconcentration and purification of the analyte in complex
samples.292,293 The nanohybrids of Au NPs and magnetic NPs

Figure 21. Functionalization of the graphene layer on a Au SPR chip via (top) the electropolymerization of polypyrrole−NTA and (bottom) the π−π
stacking of pyrene−NTA followed by electropolymerization for the reinforcement of the layer. Based on ref 303.

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offer the advantages of both of the above-mentioned refractive index changes, including those induced by the
amplification approaches.294 Zhang et al.295 synthesized particles biomolecular interactions at the surface of the nanostructures,
consisting of a Au nanorod core and a magnetic shell. The NPs can be observed using the LSPR peak shift.
were assembled on the sensor surface via a magnetic pillar Plasmon-enabled assays are usually performed with stable
without any chemical covalent link; this procedure simplified the colloid plasmonic NPs. The NPs are characterized by a large
immunoassay and facilitated easy regeneration. The authors surface area for sensing because of their small size; the high
demonstrated the detection of IgG with an LOD of 150 ng/mL. diffusion rates of the NPs enable fast analysis. Assays based on the
Carbon-based nanomaterials, such as graphene296 and carbon direct capture of the analyte on the NP surface usually provide
nanotubes,297 have also been used for the enhancement of SPR relatively small shifts in the LSPR peak, and therefore, an
immunosensing. Theoretical models predicted that the incor- absorbance spectroscopy setup is required to allow sensitive
poration of a single layer of graphene can strongly amplify the detection.315
optical sensitivity of SPR sensors.298,299 GO and rGO were Various materials (typically Au316 but also Ag or Cu317) and
introduced on a gold film using the layer-by-layer assembly, and shapes (typically spherical NPs318 or nanorods319,320) of
their effect on the refractive index increase was systematically plasmonic NPs have been recently employed for solution-
investigated by Chung et al.300 The practical applications of based LSPR immunosensing. The NP shape has a significant
graphene in SPR immunosensing were demonstrated by several impact on the detection sensitivity; Au nanorods were
research groups.301,302 Singh et al.303 bound graphene non- significantly more influenced by bulk refractive index changes
covalently to a gold surface to enhance the SPR detection of than spherical Au NPs.321
anticholera toxin antibodies (Figure 21). NTA functional groups LSPR spectroscopy is usually carried out with large ensembles
were attached to the graphene via the electropolymerization of of NPs. However, each nanoparticle in the ensemble can be
polypyrrole or π−π stacking of pyrene. A biotinylated cholera potentially used as an independent sensor. The use of single-
toxin was bound to these layers, and anti-cholera toxin antibodies nanoparticle sensors can ensure improved absolute detection
were detected. The presence of a single graphene sheet increased limits (the evaluation of the total number of molecules in a
the SPR sensor performances by 80% (an LOD of 4 pg/mL) sample) and also increase the spatial resolution in multiplexed
compared to a graphene-devoid setup. assays.322 Moreover, single nanoparticles with especially narrow
The sandwich approach based on the above-mentioned NP bandwidths can be selected from the field of view to enhance the
labels is generally applicable to enhance the detection of any signal-to-noise ratio (S/N) resolution.323 Typically, the LSPR
analyte large enough to allow the binding of two antibodies (the mode of single NPs, inducing absorption and scattering, can be
capture and detection Ab’s). The sandwich NP-enhanced SPR monitored by dark-field microscopy.324
has been used for the detection of various proteins (e.g., cardiac 4.3.2. Surface-Based LSPR. Changes in the ionic strength,
troponin T,304 ErbB2 receptor tyrosine kinase 2,305 or CEA306) pH, or temperature can cause the aggregation of NPs. To prevent
and bacterial pathogens (e.g., Salmonella272,276). such a complication, LSPR immunosensing can be performed
Small chemical compounds with a mass inadequate to cause with nanostructures on solid surfaces. Various approaches to
significant changes in the refractive index that do not possess at preparing surfaces for LSPR have been developed.
least two epitopes are hardly detectable by the direct or sandwich The family of bottom-up techniques is based on capturing NPs
approaches. To enhance the SPR response in these situations, a on the substrate. The assembly can be performed via chemical
competition for binding to the surface between an antigen binding, exploiting the high affinity of Au and Ag to the
conjugated with a high molecular weight label and the unlabeled mercapto325 and amino326 functional groups. Other methods
antigen in the sample can be performed. Another method is include electrostatic interactions between oppositely charged
based on immobilizing the antigen to the sensor surface followed surfaces and metal NPs,327 thermal annealing,328 and the thermal
by the injection of the primary antibody and a sample containing growing of NPs.329
a free antigen. In this case, the signal can be further amplified by Top-down techniques can also be used for the preparation of
the use of the secondary Ab’s labeled by NPs (e.g., Au307−309 or metal nanostructures on solid supports. Photolithography
magnetic292 ones). enables the formation of plasmonic nanostructures with various
shapes.330 Advanced lithographic techniques, such as electron
4.3. Localized Surface Plasmon Resonance
beam lithography (EBL)331 or focused ion beam (FIB),332 allow
LSPR is an optical phenomenon caused by the collective the production of metal nanostructures with accurate control of
oscillations of the electron gas in metal nanostructures (with the size, shape, and spatial distribution. As an alternative way of
dimensions smaller than the wavelength of light) surrounded by LSPR surface preparation, inexpensive and large-scale litho-
a dielectric. Typical materials for plasmonic applications are the graphic methods were established, including nanosphere
nanoparticles or nanostructures of noble metals such as Au or Ag, lithography (NSL),333 colloidal lithography,334 soft lithogra-
which exhibit LSPR in the visible range of the spectrum.310 When phy,335 nanoimprint lithography (NIL),336 and templating by
the nanostructures interact with light, a portion of the incident self-organized nanoporous anodized aluminum oxide (AAO).337
photons are absorbed, while another portion are scattered in A significant benefit of surface-based assays is that the washing
different directions.311 Both the absorption and the scattering are steps can be performed with sequential washes over static sensor
significantly enhanced when the LSPR is excited. The LSPR components, while solution-based nanobiosensors require
resonant frequency depends on the composition, size, and shape nanoparticle capture (e.g., using a magnet) or precipitation
of the NPs as well as on the refractive index of the surrounding followed by washing, which is a time-consuming task. Never-
dielectric medium.312,313 theless, moving from solution-based to surface-based sensing
4.3.1. Solution-Based LSPR. The very strong and highly negates the enlarged sensing surface of small particles dispersed
confined electromagnetic fields induced by LSPR yield a very in a solution.315
sensitive probe for the monitoring of small changes in the The label-free detection based on the immobilization of the
dielectric environment around the nanostructures.314 Local antibody to the sensing surface and direct capture of the antigen
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Figure 22. Plasmonic immunoassay based on the HRP-mediated aggregation of Au NPs that enables naked-eye readout. Based on ref 342.

is performed as a typical procedure. However, enhancing the linked to the growth of Au NPs to obtain blue (or red) solutions
LSPR immunoassay with 400% amplification of the shift upon in the presence (or absence) of the analyte. In the absence of the
antibody binding to the analyte was demonstrated using analyte, the reduction of Au3+ by H2O2 occurred at a fast rate, and
antibodies labeled by Au NPs.338 nonaggregated Au NPs (red color) were formed. In the presence
4.3.3. Plasmonic Nanoparticle Assemblies. The optical of the analyte, the catalase consumed the H2O2, slowing the
properties of plasmonic NPs depend on the organization and crystal growth kinetics and causing the growth of nanocrystals
distances between them. When the NPs are in close proximity, with ill-defined morphology and aggregated NPs (blue). The
the interparticle plasmon coupling causes a red shift in the naked-eye detection of low levels of the PSA and HIV-1 capsid
absorbance peak.339 The ability to functionalize the NPs and link antigen p24 was demonstrated, both with an LOD of 10−18 g/
their aggregation to the presence of the analyte enables the mL.
development of various assays based on color change.340 These
methods demonstrate the potentially simple assay scheme with 4.4. Surface-Enhanced Raman Scattering
easy colorimetric readout. Aggregation-based methods typically Raman spectroscopy is a spectroscopic technique that monitors
provide a larger LSPR shift compared to the direct analyte the vibrational, rotational, and other low-frequency states in a
capture. Because in some of the techniques the color changes can molecule or system. The vibrational mode provides a major
also be seen with the naked eye, this approach is applicable to contribution to the chemical constitution of a specific analyte.
point-of-care diagnosis.341 Aggregation-based colorimetric sens- The Raman spectrum ensures a chemical fingerprint for the
ing also has some disadvantages, including mainly the narrow identification of the analyte. However, Raman signals are
dynamic range and complicated quantification. An additional generally weak because of the very small number of scattered
limitation lies in that the LSPR shifts commonly occur in a region photons (1 in 106 to 1010), which causes serious limitations to
of high absorbance by native proteins, and thus, the sensitivity of identifying analytes at low concentrations.347
measurement in real samples can be restricted.315 A substantial signal enhancement (surface-enhanced Raman
A sandwich assay based on an HRP-labeled detection antibody scattering) was first observed by Fleischmann et al. in 1974,348
and an enzymatic cascade leading to the aggregation of Au NPs when pyridine was adsorbed to a electrochemically roughened
(Figure 22) was developed by Xianyu et al.342 The HRP- Ag surface. Even though the electromagnetic (EM) basis of SERS
catalyzed oxidation of iodide and iodide-catalyzed oxidation of is currently well established, surface enhancement has also been
cysteine were used to modulate the plasmonic signals of Au NPs. connected with the charge transfer (CT) effects in the metal−
The method enabled sensitive naked-eye readout and has a
adsorbate system (chemical enhancement).349
potential for point-of-care applications in resource-constrained
An EM enhancement appears if an EM field is induced by the
settings.
LSPR of a noble-metal surface (e.g., Au and Ag) via the excitation
4.3.4. Controlled Nanoparticle Growth. Large LSPR
shifts are detectable when physical changes, such as the of the electrons on the metal surface by the photons from a laser
nucleation and growth of new particles or controlled growth of source.350 When the analyte molecules are directly on or close to
shell structures on pre-existing core NPs, occur in the the surface of the metallic nanostructures, the number of induced
nanomaterial structure. Ultrasensitive immunoassays can be dipoles increases and subsequently participates in the formation
developed by linking the changes of the nanomaterial structure to of the SERS effect, resulting in the detectable enhancement of
the presence or absence of an analyte.343,344 This approach can otherwise low Raman signals.351 The signals increase in
bring advantages to aggregation assays based on preformed NPs conjunction with enhanced EM fields, usually ranging between
since the complex matricxes of real samples might induce the 104 and 108.352
aggregation of NPs independently from the analyte presence. The CT mechanism can be defined as the grouping of the
The plasmonic ELISA-based enzymatically controlled NP resonant and nonresonant electronic processes that occur
growth was pioneered by the group of Stevens.345,346 The between the metal surface and molecule and are dependent
detection procedure exploited a classic ELISA sandwich with a upon the adsorption of the molecule. Because the incident laser
biotinylated secondary Ab and streptavidin-labeled catalase, causes excited resonance states with the metal surface or
which catalyzes the decomposition of H2O2 to H2O and O2. The molecule, the promoted charge transfer between the two changes
Au NP precursor material (HAuCl4) was added into the ELISA the resonance of the system. This participates in the polarizability
wells, where it reacted to form NPs. The biocatalytic cycle was of the molecule and enhances the Raman signal.353,354 The effect
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Figure 23. Two strategies for a multianalyte SERS immunoassay based on the sandwich approach. Based on ref 363.

of CT interactions is significantly lower (on the order of 101 to nanotag comprises three parts: Raman reporter molecules
102) compared to the discussed EM enhancement.355 providing characteristic Raman signatures, a plasmonic metal
For most of the reported immunosensing applications, SERS- NP (typically Au or Ag) to enhance the Raman signal, and a
active substrates have been prepared using Au or Ag.356 Similarly recognition element to bind the target molecule.315 The Raman
to SPR and LSPR, the factors influencing the preference of Au or reporters that can be used also as a conjugation linker (e.g., p-
Ag are connected with the differences in the surface chemistries mercaptobenzoic acid) have gained significant attention in recent
that allow the desired modifications, for example, surface years due to the simplified nanotag preparation.
passivation or the conjugation of biomolecules. The higher A typical SERS immunoassay is based on a sandwich scheme:
levels of enhancement provided by Ag NPs go together with the the capture antibody is immobilized on the surface, it binds the
deterioration of the optical properties, caused by rapid oxidation antigen from the sample, and SERS nanotags are applied to allow
in air and aqueous solutions.357 To address the particular the detection. The application of extrinsic SERS in cellular and in
limitations, the synthesis of composites comprising Ag coated vivo sensing is extensive because the nanotags associated with the
with Au was demonstrated; the process connects high chemical target biomolecules can stand out in the background signals from
stability and significant enhancement of SERS signals.358,359
a complex biological matrix.
SERS-based immunosensing can be divided into two main
The sandwich approach can also be applied in simultaneous
schemes: label-free intrinsic SERS, where the Raman spectra of
detection of multiple analytes through the use of different Ab’s
the target molecule are directly measured, and extrinsic SERS,
where the metal surface is functionalized with Raman reporter and different Raman reporters to prepare specific nanotags.
molecules and target-specific ligands and an amplified signal from Contrary to the wide emission profiles of fluorescent
the Raman reporter is measured after binding to the target compounds, the individual Raman spectral peaks show a higher
analyte. Extrinsic SERS is typically used for the detection of resolution and are, on the average, 10−100 times narrower in
macromolecules. The complex biochemical composition of width.361 Furthermore, all Raman labels can be excited by a single
biological samples complicates the interpretation of intrinsic laser source, which is not possible in fluorescence-based
SERS spectra, making the identification of a particular multiplex analysis. Another advantage of SERS is the high optical
biomolecule a difficult task. Macromolecules also exhibit a stability of the Raman labels. Contrary to fluorescence,
lower SERS effect compared to smaller molecules.360 Therefore, photobleaching does not occur in Raman spectroscopy. The
different SERS labels or nanotags are used extensively in signal intensities can be improved by increasing the power of the
bioanalytical applications, where the known signature of the tag excitation laser.362 However, due to the strong local heating
allows the identification of the target analyte. A typical SERS induced by the plasmonic nanostructures, the laser power
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Figure 24. Number of studies that have used electrochemical methods combined with immunochemical recognition principles in the past five years.
Combinations containing, in addition, some types of nanoparticles are shown too.

densities at the sample must still be carefully controlled to the noninvasive application of SERS is highly valuable for live
prevent damaging the sample. imaging. SERS also provides a very high resolution for the
Another multiplexing scheme is based on the combination of monitoring of the intracellular environment and the tracking of
identical reporters with different kinds of NPs, arising from the the cellular distribution of extrinsic molecules. While SERS can
fact that the SERS spectrum of one reporter molecule is be used for the direct imaging of Raman fingerprints in single
influenced by the plasmonic NP enhancement (Figure 23). The cells, SERS microscopy mostly depends on extrinsic detection
ability to encode the reporter NPs was presented by the based on nanotags. Various substrates have been adapted for the
application of Au NPs and bimetallic Ag−Au NPs to distinguish conjugation of antibodies for targeted cancer imaging in live
human and mouse antibodies.363 cells.377 For example, Au−Ag core−shell NPs were bound to
A label-free SERS immunoassay based on the frequency shift mAb’s via a poly(ethylene glycol) (PEG) linker and applied for
due to the binding of the analyte was developed by Tang et al.364 the imaging of the expression of phospholipase Cγ1 on the
A Ag NP film for SERS substrates was grown on surface of HEK293 cells.378 A multiplexed mixture of receptor-
mercaptosilanized slides using a high-temperature modification targeted SERS nanotags enabled the rapid quantitative molecular
of Tollen’s method. Poly(dimethylsiloxane) (PDMS) stamps phenotyping of the surface of freshly excised breast cancer tissues
were used to chemisorb two Raman reporters in small square to detect the presence of residual tumors. To reduce the
domains on the substrate via microcontact printing followed by ambiguity caused by nonspecific sources of contrast such as off-
repeating with two antibodies. For the multiplex sensing of AFP
target binding or uneven delivery, a ratiometric method was used
and glypican-3 (GPC3), the patterned antibody-conjugated
for the quantification of the specific vs nonspecific binding. This
substrates were immersed in the sample, and SERS spectra were
technique provides results in less than 15 min and allows the
recorded.
The recent progress in SERS-based immunosensing was potential intraoperative use in guiding breast-conserving
devoted to the development of NPs with different shapes and surgeries.379
compositions to achieve higher SERS enhancement factors. 4.5. Electrochemical Transducers
Compared to conventional nanospheres, nanorods have a Electrochemical immunosensors and immunoassays are gaining
stronger SERS effect due to the more intensive scattering growing attention due to their high sensitivity, selectivity, low
derived from the electromagnetic radiation.365 Other shapes of cost, good portability, reproducibility, and compatibility with
noble-metal nanoparticles include hollow nanospheres,366 nano- micromachining technology. With the development of nano-
cubes,367 nanostars,368,369 nanoprisms,370 nanoflowers,371 and
technology and nanoscience, electrochemical immunosensing
tetrapods.372
not only opened the door to substantial improvement of the
The combination of magnetic beads with SERS nanotags
sensitivity of immunoassays but also led toward implementing
enables some of the limitations of immunoassays on solid
substrates (e.g., the long incubation times and the requirement of further inherent merits, such as miniaturization, portability, and
repeated washing) to be overcome.373,374 A sensor based on a the immense scope of modifications. Together with antibodies
competitive SERS immunoassay and magnetic separation was (the biorecognition element) and electroactive mediators (either
presented by Yang et al.375 Au NPs were labeled by the as carriers or as electroactive labels), these approaches secure low
chloramphenicol−BSA conjugate and a Raman reporter to detection limits with relatively fast responses. While direct
prepare the nanotag. With the addition of free chloramphenicol, immunosensors are able to follow fast electric signals during the
a competitive immune reaction was initiated between free immunocomplex formation, indirect sensors use signal-generat-
chloramphenicol and the nanotag for binding to the antichlor- ing labels incorporated into the immunocomplex during its
amphenicol antibody-modified magnetic NPs. Instead of the formation. The latter allow more sensitive and versatile
solid substrate, the antibody-conjugated magnetic beads were detection. Recently, electrochemical immunosensing has expe-
applied as supporting materials and separation tools. Using a rienced major development, and the application of nanoparticles
magnet, the mixture was removed from the supernatant for in electrochemical techniques contributes to this. The
concentration effects. The SERS signals were recorded directly scientometric data for the past five years (Figure 24) show that
from the supernatant; an LOD of 1 pg/mL was achieved. the most increasing trend is associated with impedimetric
SERS techniques have also progressed toward the use in immunosensors. The second position is then occupied by
microscopy and small-animal in vivo imaging.376 The potential of amperometric immunosensors.
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4.5.1. Amperometric and Voltammetric Measure- a high and targeted surface area allows faster and more complete
ments. The amperometric immunosensor is based on and controlled charge transfer at lower overpotentials, which
measuring the current changes of a conductive material due to lessens the complications associated with electrode fouling. NPs
the interaction of an analyte with the surface functionalized with can guarantee enhancement of biomolecule compatibility and
antibodies (immuno); in other words, the amperometric functionalization. On the basis of the knowledge of electrostatic
immunosensor is a device that transforms chemical information, interactions or the formation of bonds, the NP functionalization
such as the concentration of a specific sample component, into an is able to attach specifically certain biomolecules, allowing their
analytically useful signal. Usually, the current is measured as a efficient immobilization and increased electroanalytical re-
function of the electrode potential (E) or time (t). Both modes sponses.382
are used in immunosensing. With respect to the variation of An electrochemical (amperometric) immunosensor, being a
parameters, amperometric detection in potential-controlled chemical biosensor, contains two basic functional units: a
methods (potentiostatic methods) can be realized by different bioreceptor and a transducer. Some immunosensors may include
techniques (Figure 25, right). These are as follows: (a) a separator consisting of, for example, a membrane. From the
bioreceptor part, the important information is transformed into a
form of energy measurable as electrical work by the transducer.
Thus, in amperometric immunosensors, the response is derived
from the interaction between chemistry and electric current
(Figure 26).

Figure 25. Scheme of the three-electrode setup used in potentiostatic

electrochemical methods (left). Potential-controlled methods suitable
for electrochemical immunosensing (right).

chronoamperometry, in which the current is measured at a

fixed potential in time (usually a short time), (b) single-potential
amperometry, where the direct current (dc) is recorded as a
function of the potential difference between two electrodes
(usually in stirred solutions for a longer time), and (c) multiple-
potential amperometry, in which the potential is swept in time by Figure 26. Scheme of the electrochemical (amperometric) immuno-
the scan rate (dE/dt) and the corresponding current is recorded sensor design, depicting the integration of immunological recognition at
the solid-state surface.
in the whole potential window as a voltammetric curve, i.e., I =
f(E). Then, linear sweep (LSV), cyclic (CV), normal pulse
Undoubtedly, nanotechnology has had a major impact on
(NPV), differential pulse (DPV), and square wave (SWV)
biosensor research. In the field of electrochemical biosensors
voltammetric responses characterize electrochemical systems at
(immunosensors), nanotechnology brings new and varied
different potentials and time together.380
opportunities connected with the modification of a transducer
To control the potential value and to avoid the current load of and/or biomolecules via nanomaterials. This is often related to
the reference electrode, an electrochemical cell containing three the miniaturization of the transducer. Apart from the very specific
electrodes, namely, working (WE), counter or auxiliary (CE or biorecognition reaction, antibodies (Ab’s) and antigens (Ag’s)
AE), and reference (RE) electrodes, is used. The current flows can be produced to obtain a specific binding partner for the target
between the WE and CE electrodes, and the desired potential is of interest.383
controlled between the WE and RE electrodes (Figure 25, left). Finally, it should be noted that electrochemical sensors based
The above-mentioned methods can reveal not only the on enzyme labels produce or consume an electroactive substrate
reduction and/or oxidation potential of an analyte but also its or cofactor which can be monitored at an electrode interface. The
electrochemical activity (adsorption, interaction with modified most common enzyme labelshorseradish peroxidase (HRP),
layers, electrocatalysis, and preceding chemical reactions). The glucose oxidase (GOD), and alkaline phosphatase (ALP),
techniques are sensitive to electrode surface changes, and as such, together with nanomaterials (nanoparticles, nanocompo-
they find application in the electrochemical immunoassay. sites)open up an exceptional potential for powerful electro-
Moreover, they can be regarded as nondestructive since only a chemical immunosensors. For example, ALP cleaves the
very small amount of the analyte is consumed at the surface of the nonelectroactive p-aminophenyl phosphate into p-aminophenol,
working electrode. The explosive development of nanoscience which undergoes reversible oxidation. Moreover, p-aminophenol
and nanotechnology, giving new improved electroanalytical can be recycled thanks to the reduction by p-benzoquinonimine
tools, is also reflected in the area of immunosensors.381 at the second electrode.
As well as nanomaterial-based biosensors, the enhancement of Multiple strategies to enhance the amperometric responses of
the analytical performance of electrochemical immunosensors by immunosensors have been reported; however, no clear
NPs consists of lowering overpotentials (at higher surface area, formulation or optimum procedure has been proposed to date,
the current density tends to be smaller and electrocatalysis and thus, we acquire an attractive topic in the electrochemical
efficiency to be higher) and increasing current yields (redox investigation of immunosensors. The research problems may rest
conversion stemming from the large surface area of NPs). NPs in or be related to (a) the optimization of a suitable interaction or
also improve the reproducibility of nanoimmunosensors because binding mechanism between the analyte and the electrode
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surface, (b) the modification of the electrode surface (nano- silver deposition for anodic stripping analysis. The immuno-
composites, polymers, nanoparticles, self-assembled monolayers sensor was constructed by covalently immobilizing capture Ab
(SAMs)), (c) the immobilization of the antibody, (d) the effect on the Chit/rGO film-modified GCE. The in situ synthesis of Au
of the pH, ionic strength, and temperature on the individual steps NPs led to the enhanced loading of the label on the bead
within electrochemical immunodetection, and (e) the effect of surface.386
the Ab (length), polymers, and nanoparticles on electron transfer Mao et al.387 used the Nafion membrane modified by titanium
processes. In this field, recent research activities have been dioxide (TiO2) nanoparticles for human chorionic gonadotropin
focused on the modification of electrode surfaces by using metal and a Nafion−TiO2−Gr homogeneous composite with a GCE
(prominently gold and silver) or metal oxide nanoparticles, for the detection of CEA.388 To detect sulfamethoxazole, a new
nanocomposites, and allotropic modifications of carbon (e.g., electrochemical immunosensor was based on a CeO2−chitosan
CNTs and graphene). Some papers discuss electrode surface nanocomposite modifying a GCE.389 A detection limit of 0.11
modification performed by means of SAMs, diazonium, or sol− pg/mL CEA was achieved in a sandwich-type immunoassay
gel chemistry. Within the development of electrochemical (anti-horseradish peroxidase bonded to anti-carcinoembryonic
immunosensors, conducting polymers have attracted consid- antigen, HRP−anti-CEA) by using biometallic AuPt nano-
erable attention stemming from a set of crucial reasons. Polymers chains.390 The biometallic nanochains were considered as
embody a suitable (very often also biocompatible) matrix for the promising candidates for the next-generation sandwich-type
entrapment of enzymes, and they can be prepared in situ on electrochemical immunoassays. To determine the prostate-
electrode surfaces via electropolymerization, enabling control specific antigen (PSA) with a low limit of detection (1.16 fg/
over their film thickness. Moreover, electropolymerization can mL in serum), TiO2 NPs and a monoclonal antibody in
establish a direct connection of the polymer layer with the combination with ICP−MS were used.391 The amperometric/
electrode surface, which is important for increasing the coulombimetric signal produced of the CdS NP was employed
robustness of the electrochemical immunosensor. for the detection of sulfonamide antibiotic residues in food
Metallic nanoparticles have become a much-favored tool in samples.392 Au NPs were invented to recognize the trombin
electroanalysis because of their superior physical and chemical captured on the screen-printed carbon electrode.393 For the
properties, including the high surface-to-volume ratio, good electrochemical detection of staphylococcal enterotoxin B, GCEs
electrical qualities, strong adsorption ability, and positive surface were modified with platinum nanoparticles,394 and to facilitate
characteristics. The implementation of metallic or metal oxide the rapid detection of Salmonella pullorum, a system containing
nanoparticles is used also in electrochemical immunosensors. ionic liquids (Au NP/HRP/ILs) was used.395
4.5.2. Electrochemical Immunosensors with Metals or Carbon nanotubes (SWCNTs or MWCNTs) and graphene,
Metal Oxides. Electrochemical applications of nanomaterials graphene oxide (GO), and reduced graphene oxide (rGO)
are predominated by carbon and metallic nanoparticles, which nanosheets all belong to the allotropes of carbon with a two-
are used in modifying active surfaces of conventional macro- and dimensional nanostructure, offering unique chemical, geo-
microelectrodes. A large variety of designs employing metallic metrical, and mechanical properties such as high strength
NPs for immunosensors were reported. For example, one design flexibility and thermal stability. From the perspective of their
was developed for ultrasensitive electrochemical immunoassay of application in electrochemical sensing, we should highlight
small molecules based on a host−guest interaction of adamantine electrical properties such as the high conductivity and electron
with a β-cyclodextrin-functionalized Au/Pd bimetallic nanop- transfer capability.
robe. In that design, the electrocatalysis of Au/Pd NPs toward 4.5.3. Allotropic Modification. Papers on novel electro-
the oxidation of NaBH 4 was employed to produce a chemical immunodetection platforms based on carbon nano-
voltammetric analytical signal. The highly efficient electro- tubes have been published; selected examples describe
catalysis by AuPd nanoparticles for NaBH4 oxidation produced modifications with a thionine−chitosan nanocomposite film,396
an ultrasensitive response (LOD = 4.6 ng/L) to chloramphenicol MWCNTs with graphene sheets and poly(ethylenimine)−
as a model of a small-molecule antigen.384 Au,397 GCE/Bi NPs/Nafion−MWCNTs/GCE,398 and electro-
A highly sensitive electrochemical CEA immunosensor was spun carbon nanotube nanofibers.399
fabricated by covalently immobilizing a monoclonal CEA Advanced electrochemical immunodetection platforms based
antibody (anti-CEA, Ab1) and a mediator (thionine, Th) on on graphene have been presented in many papers. The
the Au NP-encapsulated dendrimer. The highly sensitive electrochemical reduction of GO was chosen for preparing
detection was achieved by the increased HRP-electrocatalyzed rGO-modified ITO surfaces.400 Graphene oxide sheets were
reduction of hydrogen peroxide locally generated by GOD. The initially deposited on amine-terminated benzenediazonium-
immunosensor surface was characterized using EIS, AFM, and modified indium tin oxide (ITO) surfaces through both
QCM; dendrimer-modified NPs and the Ab2/MWCNT/GOx/ electrostatic and π−π interactions between the modified surfaces
HRP bioconjugates were characterized using high-resolution and GO. Using the ultrasensitive detection of an antigen by the
TEM, SEM, and X-ray photoelectron spectroscopy. Cyclic and sandwich ELISA method, a very low limit of detection (ca. 100
square wave voltammetry techniques were used to monitor the fg/mL, which corresponds to ca. 700 aM) was achieved.
increased electrocatalyzed reduction of hydrogen peroxide by Graphene-based immunosensors were fabricated for the
HRP.385 detection of aflatoxin B1, an extremely toxic substance among
In the other voltammetric immunoassay of CEA, a polystyrene mycotoxins in contaminated food products.
microbead was covered with chemically deposited Au NPs, A dual enhancing strategy401 has been employed to develop an
which were also employed as a tracing tag to label the signal electrochemical immunosensor for the ultrasensitive detection of
antibody. A triple signal amplification was achieved using AFP, which is enhanced by a polydopamine-functionalized N-
graphene to modify the immunosensor surface for accelerating doped multiwalled carbon nanotube (PDA-N-MWCNT) and
electron transfer, poly(styrene-co-acrylic acid) microbeads the nanocomposite of graphene-loaded Au/Pt mesoporous
carried Au NPs as a tracing tag on the Ab2, and Au NPs induced nanodendrites.
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Figure 27. Schematic representation of the preparation of an immunosensor. The reticular structures represent rGO−TEPA. Ab1 represents the anti-
TSGF antibody. rGO−TEPA, GA, Ab1, BSA, TSGF, and Ab2−Ag@CeO2 are modified onto the GCE in sequence. Based on ref 402.

Figure 28. Schematic illustration of the fabrication process related to the sandwich-type electrochemical immunosensor for detecting the
carcinoembryonic antigen. CD−NGs = cyclodextrin−nanosheets of graphene. Reprinted from ref 403 with the permission of the Creative Commons
Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). Copyright 2016 Nature Publishing Group.

The application of nanomaterials in electrochemical immu- response. In addition, the good electroconductivity and electron
nosensors of the sandwich ELISA type is presented in many transfer capability of rGO−TEPA can be beneficial for the
variations. For example, one of the referenced papers describes detection of H2O2. Second, Ag@CeO2 exhibits fine catalytic
an ultrasensitive amperometric immunosensor developed to activity toward H2O2, which can improve the immunosensor
detect a tumor-specific grow factorthe endometrial cancer performance significantly. The authors have discussed the effect
marker.402 Reduced graphene oxide−tetraethylenepentamine of the irreversible agglomeration of rGO on the stability of these
(rGO−TEPA) was used to modify the surface of a glassy carbon nanostructured electrochemical sensors and their potential
electrode (GCE), and a Ag (silver)@CeO2 nanocomposite was application in the detection of other cancer biomarkers.
applied as the secondary antibody (Ab2) label (Figure 27). The Tumor markers are highly popular analytes for modified
amperometric response of the immunosensor for the reduction electrochemical immunosensors. The explanation is simple:
of H2O2 was recorded. Thus, the anti-TSGF primary antibody Clinical practice requires an uncomplicated, reliable, low-cost,
(Ab1) was immobilized onto the rGO−TEPA-modified GCE via and sensitive detection method for tumor markers to reveal
cross-linking with glutaraldehyde (GA), and then the tumor- cancer at an early stage. In other words, tumor markers can reflect
specific growth factor antigen and Ab2−Ag@CeO2 were the existence and growth of a tumor. CEA, a widely used tumor
modified onto the electrode surface in sequence. Under optimal marker produced abundantly in essentially all human colon
experimental conditions, this immunosensor exhibited a low carcinomas and in a high proportion of carcinomas at many other
detection limit of 0.2 pg/mL. A possible explanation can be sites, is applied for clinical research and early diagnosis in the
outlined as follows: First, the large specific surface area of rGO− serum. The authors of a referenced source developed a novel and
TEPA can increase the loading capacity of the Ab1 and then raise ultrasensitive sandwich-type electrochemical immunosensor for
the amount of combined antigen and Ab2, leading to a higher the quantitative detection of the CEA (Figure 28).403 This
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immunosensor was developed by using trimetallic NiAuPt V (t ) V0 sin(2πft )

nanoparticles on graphene nanosheets as excellent labels and Z= =
I (t ) I0 sin(2πft + θ )
β-cyclodextrin-functionalized reduced graphene oxide nano-
sheets as the platform. Such an assembly with a high specific where V0 and I0 are the maximum potential and current signals, f
surface area, good biocompatibility, and ideal dispersibility was denotes the frequency, t represents the time, and θ is the phase
used to capture the primary Ab1 efficiently. The trimetallic shift between the voltage−time and current−time functions.
NiAuPt−NG nanocomposites were used as the labels for the Generally, the applied potential is rather small, which provides a
signal amplification, showing improved electrocatalytic activity practical advantage compared to other electrochemical methods
toward the reduction of hydrogen peroxide (H2O2), which is (CV, DPV, SWV). Higher potential values can cause an
substantially better than that of monometallic Pt−NGs, unfavorable disruption of the biomolecular layer, influence the
bimetallic NiPt−NGs, and AuPt−NGs due to the synergetic binding, or oxidize/reduce the attached components.406 In
effect presented in the NiAuPt−NGs. The NiAuPt−NG certain immunosensing assays, EIS is used to monitor particular
nanocomposites consist of tightly coupled nanostructures of immobilization steps and support the data obtained from the
Au, Ni, and Pt, which have neither an alloy nor a core−shell above-mentioned common electrochemical approaches.407 The
structure. Under optimal conditions, a linear range of 0.001−100 central role of EIS is, however, associated with label-free
ng/mL and a low detection limit of 0.27 pg/mL were obtained detection. Since the impedance-based technique exhibits
for the CEA. The proposed electrochemical sandwich-type extreme dependency on the interfacial binding events occurring
immunosensor may have promising application in bioassays and at the electrode surface, the labeling is not required in certain
enriches electrochemical immunoassays. cases.408 Principally, the analyte of interest is bound to a specific
In general, electroactive nanomaterials were used as labels for Ab immobilized on the electrode, and the impedance increment
constructing a sandwich-type immunoassay to enhance the is registered in the solution of the redox probe as a result of the
sensitivity. According to the discussions concerning this accumulated mass hindering the electron transfer.
application, there are some drawbacks related to (a) the activity Various nanomaterials have been used to enlarge the surface
of the biomolecules in the systems after the application of area, to improve the stability of the immobilized biomolecules,
nanoparticles or nanocomposites, (b) the aggregation of and to enhance the sensitivity of the developed sensor.409−411
nanoparticles and the effect of their shells on both the The most frequent items, or Au NPs/nanostructures/nano-
aggregation process and the electrochemical activity of nano- composites412,413 and graphene sheets,414,415 assembled on the
particles, and (c) the electron transfer and its rate influenced by a electrode represent highly effective and biocompatible layers
linker (length, cleavage) between the electrode surface and the providing an extended surface/volume ratio and thus also more
electron transfer mediator. In amperometric immunosensors, the space for antibody immobilization. Moreover, the nanostructure-
main disadvantage of having an indirect sensing system is, designed surface is considered to be an excellent promoter of the
however, compensated for by excellent sensitivity compared to electron transfer between the electrode and the redox
that of classic ELISA. This is due to the linear analyte probe.416,417 Multiple nanocomposites have been fabricated to
concentration range compared to the logarithmic relationship enhance the signal intensity. For instance, Raymundo-Pereira et
in potentiometric systems. Special attention must be directed to al. revealed the synergistic effect of Au and Pt nanostructure-
the system-inherent transport rate limitations for redox partners based electrodes accelerating the electron transfer more
on the electrode surface. efficiently than just bare Au or Pt electrodes.418 The NP-
4.5.4. Electrochemical Impedance Spectroscopy. Elec- modified label-free impedimetric sensor demonstrates an ideal
trochemical impedance spectroscopy (EIS) has received arrangement for point-of-care applications.419 For practical
substantial attention in the field of immunosensors during the purposes and ease of operation, the single-frequency mode of
recent years, especially due to the possibility of ultrasensitive, impedance suggests a desirable alternative, facilitating the data
nondestructive, and rapid electrochemical sensing and character- analysis and excluding the need for equivalent circuit modeling
ization of various biological analytes and interfaces. EIS embodies and fitting of electrochemical parameters.420 In some cases, the
a powerful technique to explore the physicochemical properties label-free approach does not provide satisfactory LODs and is
of the biorecognition events connected to a respective transducer substituted with the sandwich format. Here, the response and
or, generally, an electrode. In the case of biosensors, EIS may selectivity are further improved by the attachment of a detection
provide valuable information about the individual immobilized Ab, ordinarily conjugated to a label. Several NPs402,421 and
layers, polymers, and diverse coatings on the electrode; nanomaterials (carbon nanotubes, graphene)422−424 have been
furthermore, the charge transfer resistances, capacitances, and used to assemble an increased load of antibodies/labels, e.g,
diffusion coefficients can be readily evaluated. The method also enzymes, catalyzing the conversion of the substrate to insoluble
enables us to examine the electrochemical behavior of a products on the electrode, thus amplifying the signal by the
composite electrode, surface roughness, porosity, and eventual extension of the charge transfer resistance.425 Another variant of
adsorption mechanism. As the technical background of EIS has immunosensors, the signal-off group, is based on “electron
been comprehensively described elsewhere,404,405 this section wiring” between the electrode and the highly conductive NPs
will focus especially on the recently utilized approaches conjugated either to the detection Ab or whole cells (Figure
associated with nanoparticle-enhanced immunosensing. The 29).426 It has been reported that the electron transfer (ET) at the
principle of impedimetric measurement rests in the application interface of the AuNPs/insulating barrier/electrode is similar to
of a sinusoidal potential (or current) with a low amplitude or even more efficient than the ET between the bare electrode
through the two- or three-electrode cells containing an and the redox probe.427 In this case, a decrease of the charge
electrolyte solution, mainly ferro/ferricyanide. The resulting transfer resistance is observed with an increased concentration of
current (or potential) is recorded by a potentiostat over a range the nanoparticle-modified analyte. The above principles can be
of frequencies, and the overall impedance is calculated by ranged within faradic impedance spectroscopy: the charge is
appropriate software according to transferred in the presence of a redox probe across the interface.
9998 DOI: 10.1021/acs.chemrev.7b00037
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Chemical Reviews Review

4.5.5. Field-Effect Transistors. Within the effort to achieve

a deeper understanding of both these and the biomolecule−
surface interactions at the atomic level, potentiometric
immunosensors based on the field-effect transistor (FET) have
attracted wide interest.430 Field-effect transistors (FETs) are
active electronic components enabling us to control the current
flowing between the drain (D) and source (S) terminals via the
voltage (charge) on the gate (G) terminal. The principle of the
FET was patented by J. E. Lilienfeld in 1925. Depending on the
architecture, FET devices can be classified into two main
branches: insulated gate FETs (or MOSFETs, metal oxide
semiconductor field-effect transistors) and junction FETs
(JFETs).
Most FET devices applicable in the field of sensing are
MOSFETs. When using MOSFETs as (bio)chemical sensors,
the gate terminal is in direct contact with the measured
environment (samples). Interestingly, the name is now a
misnomer because the previous metal gate material is often
replaced with a layer of polycrystalline Si (Figure 30) due to the
Figure 29. Scheme of the signal-off impedimetric immunosensor. Based capacity of the latter to form self-aligned gates. Typical gate
on ref 42. materials are SiO2, Si3N4, Al2O3, and Ta2O5; the surfaces of these
oxidic materials contain amphoteric hydroxyl groups capable of
both donating and binding protons. The pH changes induce
variations in the surface charge which controls the conductance
Contrariwise, nonfaradic EIS is usually performed in a dielectric of the drain−source channel of the resulting ISFET (ion-
solution, which becomes more conductive when a charged selective FET) devices. ISFETs are easily adaptable for the
material, e.g., a negatively charged cell membrane of bacteria, is measurement of ions other than H+ (e.g., K+ and Ca2+) by
attached to the electrode.428 Then the solution resistance and coating the gate with an additional ion-selective membrane. By
double-layer capacitance are monitored as the most variable coating the ISFET gate with an enzyme layer, a range of enzyme
parameters. Nguyen et al. successfully applied such an approach FET (ENFET) devices can be constructed provided that the
in the detection of Salmonella adhered to magnetic silica corresponding enzymatic reactions involve a pH change. This
nanotubes and achieved a remarkable limit of detection.429 technique can also be applied to immunosensors, and ISFETs are
Although the nanosurfaces provide a large number of good candidates for ultrasensitive immunosensor applications.
advantages within impedimetric immunosensing, the orientation Typical graphene-based field-effect transistors (GFETs) on
of the immobilized antibodies remains questionable. Some Ab’s Si/SiO2 or poly(ethylene terephthalate) (PET) substrates are
may be deeply buried in the branched nanostructures presented in Figure 31. While the output characteristics of FET
inaccessible for larger analytes. These phenomena could result devices correspond to the drain current ID (μA) as a function of
in uneasily reproducible impedance spectra among the individual the drain voltage VD or Vds (V), the transfer characteristics are
sensors. However, multiple reports dealing with EIS illustrate measured as the drain current ID (μA) dependent on the gate
that this technique finds its potential in many bioanalytical voltage VG or Vg (V).431 Then the drain current versus the time
applications. for an FET during the injection of various concentrations of the

Figure 30. Conceptual enhancement mode, n-channel MOSFET: (a) basic MOSFET structure; (b) schematic diagram with the applied voltage; (c)
transfer characteristics of the FET (the drain current ID as a function of the gate voltage VG).

9999 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

in other methods for atrazine detection, and falls within the

working range between 0.001 and 10 ng/mL. Single-walled
carbon nanotubes (SWCNTs), but horizontally aligned, were
applied in a liquid-gated field-effect transistor (FET) of
interleukin-6 (IL-6; from the family of secreted proteins).435
The proposed immunosensor exhibits not only good sensitivity
(the LOD is 1.37 pg/mL) but also improved stability attributed
to the strong adhesion of CNTs to the quartz substrate because
of the good horizontal alignment of these tubes. This facile
approach could be customized to also detect food toxins (e.g.,
Clostridium perfringens) and biomarkers upon appropriate
functionalization of the aligned CNTs.436
The superior physical and electrical properties, including the
high carrier mobility, ambipolar electric field effect, high surface
area, flexibility, and compatibility with microfabrication
techniques, make carbon allotropic nanomaterials such as
Figure 31. Typical back-gate graphene-based field-effect transistors
graphene (G) and carbon nanotubes (CNTs) easy to integrate
(GFETs) on a flexible poly(ethylene terephthalate) (PET) substrate (as
the chemical and biological sensor in an aqueous solution). Based on ref into FET immunosensors. Ramnani et al.437 presented an
431. approach toward integration into these devices using various
fabrication methods, evaluated different sensing platforms that
incorporate biomolecules such as enzymes, antibodies, and
studied analyte is registered (e.g., serum ferritin in the aptamers as the recognition elements, and pointed to problems
concentration range between 50 pg/mL and 500 pg/mL).432 connected with the same properties of GFETs or CNTFETs.
An advantage of FETs as potentiometric sensors is the The discussed issues included, for example, impurities, the
simplicity of operation, which can be suitably used for number of layers, edge structure, substrate, length and diameter
automation; this is complemented with the small size of the of the tubes, or level of agglomeration. In view of our experience,
solid-state FET sensors, which require very little current (usually this evaluation can be supplemented with two aspects: the
less than 1 mA). Possible drawbacks may consist of the amount and distribution of hydroxyl, carbonyl, carboxyl, or other
nonspecific effects of binding or the signaling influences from functionalized groups and their distribution on the surface area
other ions present within the sample. The referenced paper433 with respect to edge effects.
pointed to detecting biomolecules in complex biosamples with Park et al. used a modified FET immunosensor for very
high ionic strength (>100 mM), where screening effects can be sensitive determination of the CEA.438 For this purpose, they
expected. Most sensors operate under low ionic strength fabricated aptamer-functionalized multidimensional conducting
conditions, requiring ex situ biosample manipulation steps polymer (poly(pyrrole-3-carboxylate)) nanotubes (Apt-C-PPy
(desalting processes). The authors demonstrated an effective MNTs). To produce an FET-type biosensor transducer,
approach for the direct detection of the biomolecules in an functionalized NTs were integrated with the CEA-binding
untreated serum, based on the fragmentation of the antibody- aptamer immobilized on an interdigitated array electrode
capturing units. Moreover, the size-reduced antibody fragments substrate by covalent bonding with amide groups. The resulting
permit the biorecognition event to occur in closer proximity to liquid-gated C-PPy MNT-based FET sensors exhibit both a rapid
the nanowire surface, falling within the charge-sensitive Debye response in real time (<1 s) and ultrasensitivity toward the CEA
screening length (the dimensions of macromolecules). with a detection limit of 1 fg/mL.
In FET immunosensors (also EISFET, or the electrolyte− Within the domain of FET immunosensing, another paper439
insulator−semiconductor field-effect transistor), the gate is from the same laboratory examines the highly sensitive and label-
decorated by covalently immobilizing antibodies as binding free detection of cardiac troponin I (cTnI), a biomarker for the
entities that specifically capture the desired analyte. Two diagnosis of acute myocardial infarction. Monoclonal antibodies
proposed basic mechanisms (the intrinsic charge of the for cTnI were covalently immobilized on a silicon nanowire
detectable macromolecule and/or the charge redistribution surface with a honeycomb-like structure, and the attachment of
that follows the intermolecular interaction) were discussed.433 the antibodies is clearly visualized by an atomic force microscope.
Numerous research efforts have been devoted to realizing the The detection limit of the silicon nanowire FETs is about 5 pg/
idea of these approaches; however, most of the reported results mL.
turned out to be disappointing. An alternative solution for recognizing tumor-related proteins
The immunosensor is based on an FET where a network of by using an FET, usually based on antibodies, is presented in a
SWCNTs acts as the conductor channel, constituting carbon corresponding paper.440 Here, the platelet-derived growth factor
nanotube field-effect transistors (CNTFETs). Anti-atrazine (PDGF) was detected via an aptamer (fragment single-stranded
antibodies were adsorbed onto the SWCNTs, and subsequently, DNA), and the LOD equals 8.8 pM.
the SWCNTs were protected with Tween 20 to prevent the Some possible applications of immuno-FETs as quantitative
nonspecific binding of bacteria or proteins.434 The principle of point-of-care devices are presented in the form of next-
the immunoreaction consists of the direct adsorption of atrazine- generation tools for serological disease diagnosis to compete
specific antibodies (anti-atrazine) onto SWCNT networks. After with pathogen serology using enzyme-linked immunosorbent
being exposed to increasing concentrations of atrazine, assay (ELISA). Exploiting the model pathogen bovine herpes
CNTFETs could be used as convenient label-free platforms to virus-1 (BHV-1; a major viral pathogen of bovine respiratory
detect atrazine. Under optimal conditions, a detection limit as disease), this study employs an extended-gate FET for direct
low as 0.001 ng/mL was obtained, which is lower than that found potentiometric serological diagnosis.441 To demonstrate the
10000 DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

capabilities of the FET sensor as a diagnostic instrument, the protein (CRP), a key indicator of infectious/noninfectious
BHV-1 viral protein gE was expressed and immobilized on the diseases or an acute tissue.454 Dextran-coated magnetite
sensor surface to serve as a capture antigen for the BHV-1- nanoparticles were conjugated with specific anti-CRP antibodies.
specific antibody (anti-gE). This FET sensor is significantly faster The interaction of magnetic nanoparticles with CRP was
than ELISA (<10 min). By using another type of FET monitored as a decreasing change of the T2 relaxation time,
immunosensor, one based on a hornlike polycrystalline silicon which corresponds to the concentration of the analyte in the
nanowire (poly-Si NW FET), the intracellular protein ferritin sample. A compact-size DMR system suitable for POC detection
was detected in a microfluidic channel with an LOD of 50 pg/ was constructed and tested using Staphylococcus aureus.455
mL.442 4.6.2. Magnetoresistance. Magnetic particles serving as
FET immunosensors also occupy a significant position within labels interact with an external magnetic field, which induces a
the diagnosis of various diseases. For example, nanowire change in the electrical resistance. Specifically bound antigens
immuno-FETs and ion-sensitive field-effect transistors (ISFETs) can be detected by magnetoresistive (MR) sensors. Various MR-
were used for the real-time and label-free detection of antibodies based sensors have been derived, including the giant (GMR),
from avian influenza (anti-AI)443 and hepatitis B surface tunneling (TMR), colossal (CMR), and anisotropic (AMR)
antigens,444 respectively. Newly developed ISFET-based port- types.456 Since their discovery by Grünberg and simultaneously
able sensors hold a large potential for point-of-care (POC) tools by Fert in 1988,457 GMR sensors have become popular.458,459
in a variety of diseases, without being limited by the need for GMR is a quantum mechanical effect based on spin-polarized
expensive equipment such as spectrophotometers.445 Similarly, electron transport in magnetic/nonmagnetic multilayers.460 A
the label-free, low-cost, and miniaturized silicon nanowire field- detected nonmagnetic layer is sandwiched between two
effect transistor (Si NW FET) chip, detecting the human thyroid- ferromagnetic layers. The upper layer consisting of MPs is
stimulating hormone446 or human immunodeficiency virus referred to as the free layer, and its magnetization can be changed
(HIV),447 has a potential in the point-of-care diagnosis of by an external magnetic field. However, the penetration depth of
thyroid or AIDS diseases. The type of transistor channels may the magnetic field is only approximately 150 nm. The
vary according to the organic molecules used as semiconductors magnetization of the bottom fixed layer remains unchangeable.
(e.g., n channel for pentacene and p channel for naphthalenete- The imbalance of the spin populations results in a magnetic
tracarboxylic diimide); these organic molecules are in con- moment in the film and affects the electric resistivity, and small
junction with a new dielectric layer (fluorinated polymer and changes in the magnetization of the free layer are detected.
vapor-deposited hydrocarbon).448 Organic thin film transistors A GMR sensor arranged in a microfluidic cell was used for
(OTFTs) are able to detect a wide range of analytes, including detecting a D-dimera biomarker of thrombosis.461 Magnetic
gases, chemicals associated with explosives, and biomolecules NPs with an average size of 100 nm were used as the signal probe.
(nucleic acids, proteins). Compared to inorganic semiconduc- The detection limit corresponded to 5 ng/mL, and the results
tors, organic ones are flexible materials promising (a) integration were in good correlation with the applied Sysmex CA1500
into wearable or implantable medical care devices, (b) the commercial analyzer. The use of a GMR sensor for detecting E.
fabrication of thin layers by spin-coating and/or printing coli and E. coli O157:H7 was presented by Kokkinis et al.462 and
procedures, and (c) the modification of the transistor surface Sun et al.,463 respectively. This technique also introduces new
via simple chemical tailoring. possibilities into the study of protein interactions. The
monitoring of the binding affinities of programmed cell death
4.6. Magnetic Sensors
proteins 1 and 2 (PD-1 and PD-2) was described.464 Another
4.6.1. Diagnostic Magnetic Resonance. Magnetic NPs interesting application consists of the multiplexed monitoring of
offer unique possibilities for biosensing methods. Biological food allergens.465 The clinically important peanut allergens Ara h
samples exhibit no magnetic background, and thus, such 1 and Ara h 2 and wheat allergen gliadin were simultaneously
procedures are highly sensitive and can be performed in complex analyzed, with LODs of 7.0, 0.2, and 1.5 ng/mL, respectively. Yet
matrixes without further preprocessing. Several methods have another application of GMR sensors was focused on the
been developed for the analysis of biomolecules and other detection of representative biomarkers for radiation exposure
particles using a magnetic field and MP-based labels.449 Some and cancer, including the phosphorylated structural maintenance
authors referred to functionalized magnetic NPs as magnetic of chromosome 1 (phosphor-SMC1), granulocyte colony
nanosensors.450 Biomolecules and cells labeled with magnetic stimulation factor (GCSF), and interleukin-6.466
nanoparticles can be detected using a technique based on nuclear TMR sensors take advantage from replacing the spacer layer
magnetic resonance effects. This method is termed diagnostic with a thin insulator; NPs are entrapped magnetically.467 The
magnetic resonance (DMR) and has been advanced by designing TMR sensor with an electromagnetic trap of E. coli bound to
a miniaturized chip-based μNMR system.451,452 In a magnetic IMPs was constructed as a miniature device (Figure 32).468 Even
field, MPs induce a change in the proton relaxation rate and the though the LOD was not sufficiently low (6.6 × 106 cfu/mL), the
transverse relaxation time T2 of the measured samples. Two concept seems to be promising.
forms of DMR assays can be used considering the size of the 4.6.3. Superconducting Quantum Interference Device.
target. First, the magnetic relaxation switching (MRS) effect can A superconducting quantum interference device (SQUID) is the
be exploited to detect small molecules making aggregates with most sensitive tool for monitoring a magnetic field at low
MPs and thus changing the magnetic relaxivity. For example, frequencies. In its simplest form, it consists of a superconducting
kanamycin was detected using a competitive MRS immunoassay loop broken by one or two weak links called Josephson junctions.
with an LOD of 0.1 ng/mL and an analysis time of less than 1 Two main types of SQUID sensors are utilized: the direct current
h.453 Furthermore, not only small molecules but also larger (DC-SQUID) variant, which uses two Josephson junctions, and
targets such as bacteria or cells are labeled with MPs; the the radio frequency (RF-SQUID) embodiment, where only one
unbound MPs are removed, and the relaxation time is measured. junction is employed. RF-SQUIDs are cheaper but also less
Liao et al. used dynamic magnetic resonance to detect C-reactive sensitive.469 If the current is below the critical value, these
10001 DOI: 10.1021/acs.chemrev.7b00037
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Chemical Reviews Review

samples containing various amounts of the PSA, and the mixture

was incubated. In the following step, the immunocomplex on the
Dynabeads was magnetically separated, and a small volume was
dropped onto the immunochip. After incubation, the chip was
washed with PBS, and changes in the magnetic field were
measured (Figure 33). The magnetic change correlated with the
concentration of the PSA in the sample, and the LOD
corresponded to 0.1 ng/mL.

Figure 32. (a) Optical image of a microfabricated tunnel magneto-

resistive sensor supplemented by an electromagnetic trap. (b) Schematic
representation of the detection method. Reprinted with permission
from ref 468. Copyright 2014 Elsevier.

junctions allow it to pass with zero voltage; otherwise, the voltage

appears across the junction. In the case of RF-SQUIDs, other
components such as a radio frequency coil and a large antenna
loop are incorporated. The working principle is based on the
interaction of a magnetic field (affected by the analyte labeled
with MPs) and an electric current. A SQUID sensor utilizing
magnetic NPs as a label was constructed and tested on the
streptavidin/biotin system.470 The sensor was capable of
distinguishing between captured and free magnetic markers. A
highly interesting aspect rests in the low detection limit for
biotin, achieving a concentration of 9.5 × 10−16 mol/L. An
original comparison of three different magnetic methods was
presented by a team of Japanese researchers;471 the paper
focused on SQUID, an MR sensor, and a fluxgate sensor. In
addition to this problem, the authors discussed using magnetic
markers with a large magnetic moment to attain a higher signal.
4.6.4. Other Magnetic Sensors. The immunointeractions Figure 33. (a) Block diagram of the microfluxgate-based biosensing
of MP-labeled molecules can be monitored via magnetic particle system. (b) Detection discipline of the microfluxgate-based biosensing
quantification (MPQ). The method uses the nonlinear magnet- system. Reprinted with permission from ref 478. Copyright 2016
ization of particles in a magnetic field at two ac frequencies; the Springer.
particle responses are recorded. Orlov et al. detected the PSA in a
human serum, with a detection limit as low as 25 pg/mL.472
The Dynabeads magnetic particles were used to label the
Grapevine fanleaf virus was captured on an immunofiltration
antigen, and the changes in the magnetic fields generated by two
column via specific monoclonal Ab’s. The viruses were labeled
excitation coils and affected by the presence of an amount of
with a second Ab conjugated to magnetic NPs, and the frequency
Dynabeads were detected by the sensing coil at a minimum
generated by MPs in a magnetic field was recorded.473 A planar
detectable concentration of 1 pg/mL. Planar-frequency mixing
microcoil array was exploited as a sensor of magnetic beads
magnetic detection (p-FMMD) as a technique based on
through the bottom of classic ELISA plates.474 The immuno-
nonlinear magnetization was presented by Kim et al.479 The
sandwich of mouse IgG with magnetically labeled secondary Ab’s
immunocomplexes with superparamagnetic iron oxide (SPIO)
was detected with a sensitivity comparable to that of optical
nanoparticles were measured conveniently in planar microfluidic
detection with an LOD of 100 pg/mL.
channels. The Alzheimer’s disease biomarker amyloid β 42 was
An integrated platform to perform the manipulation with and
detected at a minimal concentration of 23.8 pg/mL.
detection of cells and biomolecules was described.475 Electro-
magnetic microcoils and capacitive biosensors on a CMOS chip 4.7. Piezoelectric Systems
were constructed, and the functionality was characterized on the In 1959, the relationship between quartz resonant frequency and
model interaction between anti-streptavidin antibodies and the mass accumulated on the sensor surface was established by
streptavidin-coated magnetic microbeads. A microfluxgate Sauerbrey, leading to the development of a commonly used
sensor was developed and tested on AFP and the CEA model microgravimetric biosensing technique−quartz crystal micro-
antigen.476 An MEMS477 microfluxgate sensor was described by balance (QCM). Shortly explained, QCM is a mass-sensitive
Sun et al.478 Primary anti-PSA antibodies were immobilized on a instrument detecting binding events by measuring the frequency
small glass plate with a gold film via an SAM and EDC/NHS change of the quartz resonator. The corresponding mass can be
chemistry. Dynabeads with the anti-PSA were mixed with easily deduced from the Sauerbrey equation:480
10002 DOI: 10.1021/acs.chemrev.7b00037
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−2Δmf0 2 results in a frequency decrease; however, a current increase will

Δf = = −Cf Δm be observed during the voltammetric scan because of the wiring
A μq ρq effect of the conducting nanoparticles.
In the domain of immunosensors, QCM apparently
where Δf is a change in the resonant frequency of the crystal constitutes an obsolete technique, but the incorporation of
(Hz), Δm denotes a mass change, f 0 represents the intrinsic various nanoparticles and nanomaterials nevertheless makes it a
crystal frequency (MHz), A is the piezoelectrically active area promising instrument for future applications dealing with the
(cm2), ρq is the density of a quartz (g/cm3), μq denotes the shear fast, sensitive, and real-time detection of many toxins,494
modulus of a quartz (Pa), and Cf is the constant of a crystal. The proteins,495−497 and bacteria.498,499
significance of QCM rests in the possibility of rapid and real-time Typically, different types of nanoparticles are best compatible
monitoring of surface modifications, adsorption/desorption with selected types of transducers. In the field of biosensors,
effects, and biomolecule interactions, e.g., antigen−antibody electrochemical transduction is most popular, as the good
recognition and DNA hybridization. The QCM apparatus often performance can be achieved with rather simple and miniature
suffers from the influence of the surrounding noise and may lack devices. Measuring techniques are the simplest amperometry and
sensitivity, especially in the case of low molecular weight analytes. differential pulsed voltammetry when the highest sensitivity is
Thus, recent approaches propose the application of novel NPs, required. Potentiometric measurements are rare because of
nanomaterials, and nanocomposites.481,482 For instance, highly complications with a reliable reference, and the complex sample
biocompatible Au NPs providing a high surface-to-volume ratio matrixes also limit a wider use of field-effect transistors. The
were used by Chu et al. to improve the sensor performance.483 carbon- and metal-based NPs help to improve the transport of
The surface coverage by Au NPs increased the number of the electrons from traditional enzyme-based labels, though combi-
binding sites for Ab’s and, subsequently, the mass of the target nations of two (or even more) nanomaterials are common. The
analyte. Another way to enhance the signal intensity consists of wide variety of “nano”-modified screen-printed electrodes are
the secondary Ab-functionalized Au NPs bound to the antigen in already easily obtained from several suppliers. Many authors
a sandwich format.484 This additional binding step further favor the impedimetric techniques, which provide the direct
extends the mass on the surface, resulting in a broader shift of the measurement without the need for any labeling. The EIS
frequency.485,486 measurements might appear quite simple and straightforward,
One might assume that the larger the secondary ligand but in real samples, complications with nonspecifically adsorbed
assembled, the higher the signal observed. This, however, is not biomolecules create significant complications and irreproducible
always correct, as the Sauerbrey frequency decrease takes into results.
account only thin films rigidly attached to the surface.487 An Optical techniques have gained interest because of the
interesting option to overcome this limitation was proposed by excellent photochemical stability and brightness of the
Liu et al.;488 a complex of 150 nm magnetic particles, detection luminescent nanocrystal and even the use of some hybrid NPs
antibody, and enzyme catalase was used to amplify the signal. as labels. On the other hand, the high expectations related to
Once this complex was attached to the antigen on the QCM quantum dots are fulfilled only gradually; reliable bioconjugation
surface, hydrogen peroxide was introduced into the system, procedures for often hydrophobic QDs were not readily
initiating the biocatalyzed conversion to water and oxygen. The available, and the simplified adsorption of biomolecules was
generated oxygen influenced the shear modulus of the not robust enough. Currently, the interest in up-converting NPs
immunocomplex layer, with the viscosity and density of the as labels is growing. It was rather surprising that optoelec-
adjacent liquid layer resulting in a significant frequency increase. trochemical combined techniques such as electrochemilumines-
The frequently applied mechanism of the biocatalyzed cence and photoelectrochemical conversion are represented by a
precipitation of an insoluble product on the surface appeared high number of contributions; evidently, this is the field where
to be beneficial for increased signal generation also in the case of optically active NPs have brought significant benefits. For direct
QCM.489 Akter et al. exploited the dual merit of magnetic NPs, assays with real-time data collection, surface plasmon resonance
i.e., the surface enlargement for antibody/enzyme capturing and traditionally serves in immunosensing; noble-metal NPs help to
the possibility of easy sample purification, and developed a moderately increase the measured signals. Due to the very high
sensitive QCM sensor based on the bienzymatic (GOD/HRP) costs of instruments and limited portability, classic SPR functions
conversion of the initial substrateglucoseto a solid product, in biochemical research laboratories and allows more precise
resulting in extended rigidity of the layer and a concomitant screening of drug candidates in pharma industries. Much more
frequency change.490 This approach, however, significantly interest is focused on localized SPR variants, which allow simple
lowers the detection limit, and regeneration is practically evaluation based on a change of color.
impossible, making the sensor disposable. A solution to this Rapid development of Raman spectroscopy and especially the
problem arises from a paper by Zhou et al.,491 who omitted the surface-enhanced variants with nanomaterials and nanoparticles
covalent immobilization of the primary antibody and attracted was also successfully combined with the specific antibodies, and
the MNP−Ab1/antigen/Ab2−HRP immunocomplex to the applications are rapidly growing. Here, the imaging variants are
QCM surface by an external magnet. The surface covered by suitable for living cells and are tested also for specific visualization
the precipitate can be regenerated chemically or electrochemi- of malignant tissues during surgery.
cally.492 The data obtained from the microgravimetric measure- Magnetic transducers are highly variable and often complex;
ments can be promptly verified by employing electrochemical the bioanalytical applications exist rather rarely. The main field
quartz crystal microbalance (EQCM). The assay is ordinarily here will be the magnetic resonance imaging with the help of
performed in an electrochemical cell composed of a gold-coated specifically binding magnetic NPs. Finally, piezoelectric trans-
quartz crystal as a working electrode, a reference electrode, an duction, despite the very long tradition, will most probably
auxiliary electrode, and a certain electrolyte solution.493 For remain a rather exotic laboratory approach; nanoparticles might
instance, the accumulation of the secondary ligand, e.g., Au NPs, shift the sensitivity, but the improvement will be only limited.
10003 DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Table 1. Selected Examples of Immunoassays for Clinical Markers Based on Nanoparticles

marker time year and
sample matrix LOD range (min) surface label(s) procedure ref
α-Fetal Protein (AFP)
serum 0.8 pg/mL 0.001−200 ng/mL 250 mpt−Ab1 PbS NP/Ab2; Ag NP/DNA RCA, DPV FIG− 2013527
RCA
PBS (model) 0.01 pg/mL 0.1−50 pg/mL 150 GCE/Ab1 CdZnSe QD/Ab2 sw, ECL 2016528
serum 0.33 fg/mL 1 fg/mL to 80 ng/mL 180 GCE/grox/chit−fuller- C−QD/PAAD/Ab2 sw, ECL 2016213
ene/Ab1
Amyloid A
serum 43 ng/mL 9.4−600 ng/mL 45 GCE/PPy-COOH/chit/ − (direct) blocked DPV 2015529
MWCNT/Ab1
Amyloid-β
serum 1 pg/mL 1−10000 pg/mL 120 Au/Al2O3 array/Au NP/ − (direct) EIS 2014530
Ab1
serum 50 fg/mL 0.08 to 105 pg/mL 90 GCE/Ag NW/Cys/Ab1 ZnO/CeO2 NP/luminol/GOD/Ab2 sw, ECL 2016222
Apolipoprotein-A1
serum 0.02 pg/mL 0.0001−50 ng/mL 130 SPE−C/Au NP/Ab1 Ag NP/hydroxyapatite/Ab2 sw, stripping SWV 2015531
Apolipoprotein-A2
urine 6.7 pg/mL 20 pg/mL to 2 mg/mL 12 polycrystalline Si NW/ − (direct) FET 2015532
graphene/Ab1
Apoptosis Regulators Bcl-2 and BAX
cell lysate 1 ng/mL 1−300 ng/mL 340 GCE/rGO/Ab1a,Ab1b SiO2/CdSeTe NP/PDDA/Ab2a; dual sw, stripping 2016533
SiO2/Ag NC/PEI/Ab2b SWV
Butyrylcholinesterase, Phosphorylated
plasma 0.01 nM 0.02−10 nM 80 SPE−C; Fe3O4/TiO2 CdS QD/Ab2 sw, mag sep, DPV 2013534
NP/Ab1
Calmodulin
tumor cells 18 pg/mL 0.05−200 ng/mL 240 GCE/chit−thionine/gra- Au NR/HRP/Ab2 sw, DPV 2014535
phene/Au Ag NP/Ab1
Cancer Antigen CA-125
serum 1.6 mU/mL 2−100 mU/mL 65 Au/Au NP/SiO2CdS − (direct) blocked EIS 2015536
QD/Ab1
Carbohydrate Antigen 19-9
PBS (model) 0.04 U/mL 0.01−200 U/mL 130 ITO/TiO2 NWs/Au NP/ (bipyridinium2+)−Ab2 sw, blocked PEC 2016537
CdSe−ZnS/Ab1
serum, urine 0.5 mU/mL 0.001−5 U/mL 60 GCE/grox/Au NP/ABEI/ − (direct) blocked ECL 2015538
Ab1
Carbohydrate Antigen 15-3
serum 14 mU/mL 0.05−120 U/mL 105 GCE/PEI−MWCNT/Au Mn−ZnO NR/Lys/Ru(bpy-di- sw, ECL 2015539
NP/Ab1 COOH)32+/Pt NP/Ab2
Carcinoembryonic Antigen (CEA)
serum 0.1 pg/mL 1 pg/mL to 50 ng/mL 35 Fe3O4/Au NP/Ab1 PANI NF/HRP/Ab2 sw, mag sep, DPV 2012540
in flow
serum 0.36 fg/mL 0.005−10 ng/mL 65 ITO/Au NP/Ab1 graphene−SnO2 NP/PDDA/Ab2 sw, PEC 2013237
serum 0.1 pg/mL 0.0001−10 ng/mL 150 microplate−mAb1 NaEuF4 NP/av/Ab2 Eu3+ dissolution, 2014541
time-resolved
PL
serum 0.86 fg/mL 1 fg/mL to 10 ng/mL 80 Au NR/SiO2/ rhodamine- − (direct) SERS 2014542
6G/Ab2
serum 1 pg/mL 0.05−80 ng/mL ? ITO−Au/Au NP/Ab1 blocked EIS and 2015543
UV spectra
serum 0.1 pg/mL 1.0 pg/mL to 45 Au/PANI−ferricyanide/ − (direct) blocked DPV 2015544
500 ng/mL Au NP/Ab1
serum 3.2 fg/mL 0.01 to 105 pg/mL 150 GCE/ZnO NP/Ab1 Au,Pd NP/Ab2 sw, catalytic, amp 2015545
serum 0.16 fg/mL 1 fg/mL to 200 ng/mL 45 GCE/PPy−phytic acid/ − (direct) blocked DPV 2015546
Au NP/Ab1
serum 0.1 fg/mL 1.0−1000 fg/mL 150 GCE/PABA/Ab1 CdSe QD/Ab2 sw, ECL 2016209
serum 0.65 pg/mL 0.001−80 ng/mL 75 GCE/Au NP/Ab1 GO/HRP/Ab2 sw, precipitation, 2016547
EIS
serum 0.16 pg/mL 0.0005−100 ng/mL 140 microplate/Ab1 Cu NP/Ab2 sw, Cu-click con- 2016199
jugation, F
serum 0.2 pg/mL 0.001−80 ng/mL >45 GCE/GO/Au NP/Ab1 Fe3O4 NP/silicate/ferrocene/HRP/ sw, DPV 2016548
Ab2

10004 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Table 1. continued
marker time year and
sample matrix LOD range (min) surface label(s) procedure ref
Cortisol
saliva 1 pM 1 pM to 100 nM 35 Si/Au/ZnO NR/Ab1 − (direct) CV 2015549
C-Reaction Protein (CRP)
plasma 3.9 ng/mL 0.025−1.6 ng/mL 20 nitrocellulose/mAb1 CdZnSe QD/mAb2 sw, LFIA, F 2016195
C-Terminal Telopeptide
serum 50 pg/mL 50−600 pg/mL 90 CNT (aligned)−epoxy/ − (direct) EIS 2016550
Au NP/Ab1
Cystatin C
serum 0.14 pM 0.72 pM to 3.6 nM 45 Ti/TiO2 NT/rAb − (direct) blocked PEC 2016551
Cytokeratins Antigen 21-1
serum 2.3 pg/mL 0.01−200 ng/mL 45 GCE/rGO/polyhydroqui- − (direct) blocked DPV 2016552
none/Au NP/Ab1
Epidermal Growth Factor Receptor
serum 2 fg/mL 1−14 fg/mL ? SPE−C/SWCNT/Ab1 − (direct) EIS 2014553
Enolase, Neuron-Specific
serum 5 pg/mL 0.01−120 ng/mL 45 GCE/graphene−C nano- Pt NP/HRP/Ab2 sw, DPV 2013554
spheres/poly(thio-
nine)/Ab1
serum 0.2 pg/mL 0.001−100 ng/mL 35 ITO/ZnCdHgSe QD/ − (direct) blocked PEC 2015555
pAb1
Epidermal Growth Factor Receptor 2
serum 10 fg/mL 0.01−100 pg/mL 40 Au/Ab1 Au,Ag NP/SiO2/malachite green/ sw, SERS 2015556
Ab2
cell homoge- 0.05 pg/mL 0.1−1000 pg/mL SPE−Pt/poly(thio- Fe3O4/chit/Au NP/Ab2 sw, mag sep, DPV 2015557
nate phene)/Ab1
Epithelial Cell Adhesion Molecule
blood cells 1.2 pg/mL 2.5−2000 pg/mL 40 glass/ZnO NP/PVA/Ab1 Ab2−HRP sw, fluidics, F 2016558
extract
Erythropoietin
serum 0.0027 mIU/mL 0.01−80 mIU/mL 135 GCE/AuNP/Ab1 fullerene−PAMAM NP/Au NP/Ab2 sw, DPV 2015559
Ethinylestradiol
urine 65 pg/mL 0.1−50 ng/mL 65 GCE/GO/Ag NP/SiO2/ HRP− ethinylestradiol comp, amp 2016560
Ab1
Ferritin
serum 50 pg/mL 0.05−500 ng/mL 5 polycrystalline Si NW/ − (direct) FET 2016561
Ab1
Hemoglobin, Glycated (HbA1c)
blood 2.5% 5.6−11.5% 12 − (in solution) (NaYF4:Yb3+, Er3+) NP/silicate/Ab1 UCNP PL 2016204
quenched by
hemoglobin
Human Chorionic Gonadotrophin
serum 0.0026 mIU/mL 0.005−500 mIU/mL 150 graphene/CNT/Au NP/ silica NP/Au NPs/thionine/HRP/ sw, DPV 2012562
Ab1 Ab2
serum 8.6 pg/mL 0.01−16 ng/mL 65 GCE/sulfographene/thio- − (direct) DPV 2013563
nin/Pd−SiO2 NP/Ab1
urine 0.016 ng/mL 0.1−25 ng/mL 20 SPE−C/graphene/chi/Au − (direct) blocked EIS 2014564
NP/Ab1
Insulin
serum 0.086 nM 1−10000 ng/mL 30 ITO/rGO/Ab1 − (direct) capacitance 2015565
serum 15 pM 1−100 pM 25 PGE/MWCNT−pyrene- Fe3O4 NP/insulin comp, DPV 2015566
butyric acid
Interferon γ
blood cells 30 fg/mL 0.1−500 pg/mL 170 grox/PANI NF/mAb1 CdS QD/pAb2 sw, ECL 2016212
supernatant
blood, serum, 400 fg/mL 1 pg/mL to 10 μg/mL 60 PS/PLL/Au NP/Ab1 − (direct) LSPR 2016567
saliva
Interleukin-6
serum 0.01 fg/mL 0.01−100 fg/mL 45 Si/SiO2/SWCNT/Au − (direct) EIS 2013568
NP/mAb1
serum 0.3 pg/mL 1−40 pg/mL 150 ITO/graphene−Au NP− Au NP/MWCNT/PDOPA/HRP/ sw, amp 2014569
silicate/Ab1 Ab2

10005 DOI: 10.1021/acs.chemrev.7b00037

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Chemical Reviews Review

Table 1. continued
marker time year and
sample matrix LOD range (min) surface label(s) procedure ref
Interleukin-17
serum 50 fg/mL 0.1−1000 pg/mL 125 GCE/graphene/Ab1 PS−Cd/Au NP/Ab2 sw, DPV of re- 2013570
leased Cd2+
Matrix Metalloproteinase-2
serum 3.6 fg/mL 0.01−500 pg/mL 140 TiO2 NT/CdS,Mn,CdTe SiO2 NP/Ab2 sw, blocked PEC 2014232
QD/Ab1
Monocyte Chemotactic Protein-1
serum 0.03 pg/mL 0.09−360 pg/mL 65 Au NP/Au,Pt NW/ − (direct) blocked DPV 2015571
Mucin
cell culture 0.5 nM 1−500 nM 125 GCE/graphene/Ab1 Ag NP/aptamer; Ag deposition sw, SWV 2015572
Natriuretic Peptide
PBS (model) 0.33 fg/mL 0.001−2 pg/mL 55 GCE/PAMAM/Ab1 chit−ferrocene NP/Ab2 sw, blocked ECL 2014221
serum 0.75 fg/mL 1 fg/mL to 1 ng/mL 110 CoFe2O4/Au NP/Ab1 metal−organic frame/Au tetrapods/ sw, SERS 2016573
toluidine blue/Ab2
Netrin-1
serum 30 fg/mL 0.09−1800 pg/mL 50 GCE/MWCNT/chit/thi- − (direct) blocked DPV 2015574
onin/Au NP/pAb1
Osteopontin
serum 0.3 pg/mL 1 pg/mL to 1 μg/mL 65 Au/ITO gap with − (direct) blocked EIS 2015575
SWCNT-COOH/Ab1
Procalcitonin
serum 0.4 pg/mL 0.02−500 ng/mL 120 GCE/Au NP/Ab1 PAMAM−Au NP/β-cyclodextrin− catalytic, DPV 2015576
ferrocene/Ab2
serum 1.2 pg/mL 0.01−100 ng/mL ∼60 GCE/Au NP/Ab1 MWCNT/CoPC NP/choline oxi- sw, DPV 2016577
dase/Ab2
Prostate-Specific Antigen (PSA)
serum 0.4 pg/mL 1−10000 pg/mL 125 Au/MWCNT/Au NP/ MWCNT/HRP/Ab2 sw, precipitation, 2012578
Ab1 SWV
serum 10−18 g/mL − (qualitative) 300 mtp/Ab1 catalase−Ab2 generation of Au 2012579
NP, color, visual
serum 0.3 ng/mL 0.3−100 ng/mL 12 Au/Ab1 Au NP/Ab2 sw, SPR 2012580
serum 0.3 fg/mL 10 fg/mL to 10 ng/mL 12 Au NW/polypyrrole/Ab1 − (direct) blocked DPV 2014581
serum, saliva 0.04 fg/mL 0.04−10 fg/mL 85 Au/Au NP/Ab1 SiO2−Au nanosphere/ABEI/Ab2 sw, ECL 2014582
serum 0.32 pg/mL 0.001−3 ng/mL 140 microplate/Ab1; Ti/TiO2 Au NP/ssDNA primer/Ab2; av-ALP ligase RCA, PEC 2015583
NT/CdS QD
serum 0.05 pg/mL 0.1−1000 pg/mL 50 PGE/SWCNT/Ab1 SiO2 NP/Ru(bpy)32+/Ab2 sw, ECL (CCD 2015584
multiplex)
Protein p53
PBS (model) 1 pg/mL 1−1000 pg/mL 105 GCE/MWCNT−polya- HRP−Ab2 sw, DPV 2015585
mide/polythionine/Ab1
PBS (model) 50 pg/mL 0.05−100 ng/mL ? Ti/TiO2 NT/Au NP/ − (blocked ALP) LSPR-enhanced 2016586
ALP/Ab1 PEC
Selectin-P
0.85 pg/mL 1 pg/mL to 10 μg/mL 90 SPE−C/MWCNT/Au lipo(ferricyanide)/Ab2 sw, DPV 2012587
NP/Ab1
Thrombin
serum 1 aM 1 aM to 200 nM 60 Au/Ab1 Au NP (diff. shapes)/aptamers sw, SPR 2016588
Thyroid-Stimulating Hormone
serum 0.005 μIU/mL 0.01−20 μIU/mL Au/Au NP/Ab1 Au−PANI NP/HRP/Ab2 sw, DPV 2012589
serum 100 zM 100 zM to 100 fM >180 Au dots/Ab1 Ag NP/Ab2 sw, dark field light 2016590
scattering
Thyroxin (T4)
PBS (model) 15 fg/mL 0.05−5000 pg/mL 230 GCE/MWCNT/Nafion/ Fe3O4/graphene/Au NP/PDDA/ sw, mag. sep, hy- 2013591
Ab1 ssDNAAb2; ssDNA/cytochrome bridization,
c/GOD DPV
Tissue Polypeptide Antigen
serum 5 pg/mL 0.01−30 ng/mL 36 GCE/Ab1 Au−PB NP/HRP/Ab2 sw, catalytic, DPV 2014592
serum 0.3 pg/mL 0.001−100 ng/mL 90 GCE/Ab1 Au−PB NP/polytyramine/HRP/Ab2 sw, catalytic, DPV 2015593
3,3′,5-Triiodothyronine (T3)
PBS (model) 30 fg/mL 0.1−10000 pg/mL 85 GCE/PLL/Au NP/Ab1 Fe3O4/GO/Ru(bpy)32+/Ab2 sw, enhanced ECL 2013594
Troponin I, Cardiac (cTnI)
serum 0.08 pg/mL 0.25−100 pg/mL 60 GCE/Au NP/Ab1 Au NR/Ru(dcbpy)32+/Cys/Ab2 sw, enhanced ECL 2014226
plasma 3.1 pg/mL 0.01−50 pg/mL 45 microplate/mAb1 NaYF4:Yb3+, Er3+ NP/PAA/mAb2 sw, UCNP PL 2016595
serum 0.19 pg/mL 0.001−1000 ng/mL ∼15 graphene QD/Ab1 graphene (as FRET quencher) homogen., re- 2016200
stored PL

10006 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Table 1. continued
marker time year and
sample matrix LOD range (min) surface label(s) procedure ref
Trypsin
serum 1.2 pg/mL 20−20000 pg/mL ? GCE/polythionine/ − (direct) blocked DPV 2015596
AuNP/Ab1
Tumor Necrosis Factor α
serum 2 pg/mL 5−5000 pg/mL 125 GCE/MWCNT/Au NP/ chit−PB−CeO2 NP/Ab2 sw, catalytic, amp 2012597
Ab1
serum 2 pg/mL 5 pg/mL to 10 ng/mL 125 GCE/peptide, ferrocene Au NR/GOD/Ab2 sw, DPV 2013598
NW/Au NP/Ab1
Vascular Endothelial Growth Factor
plasma 7 fg/mL 0.1 pg/mL to 10 ng/mL 30 Au triangular nanospots/ Au NP/Ab2 sw, SERS 2016599
Ab1

5. APPLICATIONS immunosensors. The Clearblue pregnancy test based on

This part of the review starts with clinical assays, namely, human chorionic gonadotropin constitutes one of the first
procedures for the determination of markers such as proteins, commercially available personal electrochemical immunosensor
small molecules, tumor cells, and drugs. tests. Other sex hormones are represented by cortisol and
ethinylestradiol.
5.1. Clinical Assays Urgent cardiac states are evaluated using troponin I. CRP is the
5.1.1. Proteins and Small Molecules as Markers. In most important acute phase protein. Neuronal disorders,
medicine, biomarkers indicate the severity or presence of some including Alzheimer’s disease, are studied by means of amyloid
disease or particular physiological state of the organism (https:// fragments. Numerous systems are centered on cancer markers
fnih.org/what-we-do/biomarkers-consortium). Substances such as fetoprotein, cancer and carbohydrate antigens, protein
chosen as clinical markers are currently analyzed in specialized p53, and the prostate-specific and (perhaps the most frequently
central laboratories using large and fully automated analyzers, or assayed) carcinoembryonic antigens. From the technological
“black boxes”, where users introduce the samples and supply point of view, the CEA molecule might serve well for the critical
immunoreagents in the form of disposable kits. Inside, comparison of tens of different sensing approaches. Recent
immunoassays and immunosensors function as independent concern has focused on regulatory factors such as interferon,
modules. The system is well-established, fully sufficient for the interleukins, growth factor receptors, and apoptosis.
clinically relevant levels of analytes, and rather conservative with 5.1.2. Cancer Cells. Cancer constitutes a most serious cause
respect to novel technologies. For less common biomarkers, the of death. Despite the fact that cancer cells emerge from the
classic ELISA kits are supplied. body’s own cells, it is very difficult to analyze cancerous growth at
Thus, the community of researchers in the field should be an early stage. Fortunately, there are many genes overexpressed
initially addressed because the scope of the assays is larger than in a cancerous tissue that offer a potential for analytical and
the options existing in analyzers or as ELISA kits, and new therapeutic exploitation.500 Tumor markers are widely used in
markers are being introduced within the current preventive oncology and play an indispensable role in cancer detection and
medicine trends. The convenient overview of blood tests is clinical screening.501,502 Any effort to detect cancer as early as
available online (https://en.wikipedia.org/wiki/Reference_ possible places increasing demands on the detection methods
ranges_for_blood_tests); a much more comprehensive database and analytical protocols; this is then reflected also in the field of
is maintained by the American Association for Clinical biosensors.503 Another situation arises when the cancer is fully
Chemistry (https://labtestsonline.org). manifested and metastases may occur. Metastatic tumors are
Immunosensors with NPs should be considered for special formed through the spread of cancer cells from the original
situations, especially when new markers not yet used within tumor. From this perspective, circulating tumor cells (CTCs)
analyzer procedures need to be measured. The most promising have assumed a key role in the process, and their early diagnosis
application situations will occur when either a rapid analysis at brings an opportunity to conduct effective treatment.
critical moments or a measurement cycle to be performed CTCs are dissipated populations of tumor cells in the
directly in an ambulance (or generally out of laboratory) bloodstream, characterized by their very rare occurrence,
becomes a priority. For this purpose, the point-of-care plasticity, and heterogeneity. The detection of CTCs is a
immunosensor format is the most appropriate. The performance fundamental prerequisite for the detailed understanding of
is simple, and POC devices are typically portable and suitable for particulars such as the characteristics of CTCs and their
nontrained users. The results are obtained in sufficiently short prognosis, predictive significance, and, above all, use in both
time to make decisions immediately improving the patient’s clinical practice and the development of new drugs. The
state. The POC immunosensors will play a key role also in separation and detection of CTC cells is based on detecting
personalized medicine. epithelial characters. Unfortunately, there are several limitations
Selected applications of immunosensors with nanoparticles to current diagnostic methods; relevant deficiencies include, for
are summarized in Table 1. The examples provided include example, the inability to detect cells with mesenchymal
protein markers indicating the health condition; insulin and also characteristics or the lack of morphological verification of
glycated hemoglobin as indicators of long-term treatment in CTCs, making their isolation and characterization a major
diabetic patients are prominently mentioned in the given context. technological challenge.
Endocrinological markers include thyroid hormones such as On the basis of the aforementioned properties of tumor cells,
the thyroid-stimulating hormone, trijodothyronine, and thyro- numerous platforms for CTC detection have been developed.
xin, which require highly sensitive assays ensured via Generally, one can refer to two major categories:504 (1)
10007 DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
 Table 2. Assays for Cells Related to Malignant Transformations
time year and
marker sample matrix LOD range (min) surface label(s) procedure ref
Basal Cell Carcinoma
skin tissue sections − − 5 skin tissue Au NPs/4-ATP/Ber−EP4 SERS detection of cells via interaction of 2016600
label with EpCAM
Chemical Reviews

Chondroitin Sulfate Proteoglycan 4 (CSPG4), Alias High Molecular Weight Melanoma-Associated Antigen (HMW-MAA)
cell lysate of M14 human − yes/no detection system ∼120 PANI@GO film on ITO label-free EIS 2016601
melanoma line (model)
HepG2 Cells
HepG2 cells (model) 5 cells/mL 10 to 105 cells/mL 60 ITO/CNT/anti/EpCAM label-free EIS 2014602
Human Breast Cancer (MCF-7) Cells and Adriamycin-Resistant MCF-7 (MCF-7/ADR) Cells
MCF-7 and MCF-7/ADR 170 cells/mL 5 × 102 to >180 (Bcl-2)−BSA/PLL/GCE Au NP/Ab EIS detection of cells with expressed Bcl-2 2015603
(model) 1.6 × 106 cells/mL protein
Human Cervical Carcinoma (HeLa) Cells
HeLa cell line (model) 10 cells/mL 10 to 106 cells/mL >30 Au/MPA/PEI−Fc/ label-free DPV detection of cells with expressed folate 2013604
SWCNT/FA receptor
6 cells/mL 6 to 103 and 103 to NA Au/1,6-dimercaptohexane/ label-free EIS detection of cells with expressed folate 2012605
105 cells/mL Au NPs/MUA/FA receptor
Human Epithelial Carcinoma (A431) Cells
detection of EGFR in cell ∼100 pg in a sample NA 150 optical fiber/PLL Au NPs/MGITC/anti-EGFR combination of SERS with hollow core 2012606
lysate (model) volume of ∼10 nL photonic crystal fiber (HCPCF)
Human Ovarian Cancer (SKOV-3) Cells
SKOV-3 cell line (model) 5.2 cells/mL 6.5−65000 cells/mL NA GCE/GO/anti-HER2 ssDNA-labeled anti-HER2 antibody and DPV detection of daunorubicin after 2012607

10008
hybridization with cDNA intercalation
Review

DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Table 3. Assays for Drugs and Other Pharmaceuticals

pharmaceutical sample time year and
matrix LOD range (min) surface label(s) procedure ref
Chloramphenicol
w (environmental; 1 pg/mL 1 pg/mL to 120 MNP/Ab1 Au NP/SERS reporter/ mag sep, sw SERS 2016608
river) 10 ng/mL Ab2
eye drops 4.6 pg/mL 50 pg/mL to 45 GCE/MWCNTs/ Ab−adamantine, AuPd comp LSV 2013609
50 μg/mL chloramphenicol− NP/cyclodextrin
BSA
Clenbuterol
w (model) 6.57 pg/mL 0.01−10 ng/mL NA Au/graphene/Ab − (direct) SPR (and EIS) 2015610
urine 6.8 pg/mL 0.01−10 ng/mL 150 GCE/MWCNT/Ab1 Ag−graphene oxide− comp DPV 2012611
clenbuterol
pork meat, liver 20 pg/mL 50 pg/mL to 240 GCE/QDs/ Ab1, Ab2−HRP comp ECL 2013612
1 μg/mL clenbuterol−OVA
urine 0.35 ng/mL 1.22−6 ng/mL 24 glass/clenbuterol−BSA Au NP/Ab comp capillary 2016613
immunochromatograpy
swine urine 5 pg/mL 0.01−1 ng/mL 90 GCE/Au NP/ Ab−Ru(bpy) comp ECL 2012614
clenbuterol−BSA
pork 1.38 pg/mL 0.01−100 ng/mL 60 SPCE/rGO/clenbuterol AgPd NP/Ab comp LSV 2013615
swine feed 0.25 ng/mL 0.5−1000 ng/mL 60 GCE/MWNCTs/Ab graphene oxide/Au comp enzyme amplified 2013616
NP/GOD/ DPV
clenbuterol
pig urine 5.5 pg/mL 0.01−10 ng/mL NA Au/QD/PANI − (direct) EIS 2016617
nanowire/Ab
Diclofenac
w (environmental; 50 pg/mL 50 pg/mL to 180 microplate/diclofenac− Ab1,Ab2−UCNP comp luminescence 2016618
river, lake, tap 0.5 ng/mL BSA
water)
Doxorubicin
human serum 1.7 pg/mL 2.5−100 pg/mL 60 stainless steel/Au NP/ − (direct) EIS 2013619
Ab
human serum, urine 90 fg/mL 2.5−50 pg/mL 60 Au/Au NP/Ab − (direct) EIS 2014620
Infliximab
human serum 0.3 ng/mL 0.3−100 ng/mL 150 Au/Ab1 Au NP/Ab2 sw SPR 2016621
Kanamycin
milk 2 pg/mL 2 pg/mL to 10 MNP/Ab1 Au@Ag NP/SERS sw SERS 2014622
80 ng/mL reporter/Ab2
chicken liver 5.8 pg/mL 0.01−12 ng/mL NA GCE/graphene/nafion/ − (direct) CV 2012623
thionine/Pt NP/Ab
pork meat 15 pg/mL 0.05−16 ng/mL NA GCE/graphene− − (direct) LSV 2013624
thionin/Ag@Fe3O4/
Ab
Morphine
urine 0.82 ng/mL 2−200 ng/mL NA ITO/Au NP/Ab − (direct) ECL 2015625
Ofloxacin
w (model) 30 pg/mL 0.08−410 ng/mL 180 GCE/Au nanocluster/ Au NR/HRP/Ab2 comp, enzymatic 2013626
ofloxacin−OVA amplification, CV
w (model) 0.15 ng/mL 0.26−25.6 ng/mL 120 GCE/MWCNTs/ Ab1, Ab2−Au comp CV 2015627
ofloxacin nanoflower
Pefloxacin
seafood 1 ng/mL 1−20 ng/mL 120 Au NR/Ab magnetosome/ comp LSPR 2013628
pefloxacin−ova
Ractopamine (Growth Promoter, Feed Additive)
fodder 10 pg/mL 0.01−25 ng/mL 40 Au/MNP/cyclodextrin Ab2−poly-HRP sw QCM, precipitation 2015629
enhancement
pork 1.52 pg/mL 0.01−100 ng/mL 60 SPCE/rGO/ AgPd NP/Ab comp LSV 2013517
ractopamine
pig urine 7.5 pg/mL 0.1−10 ng/mL NA Au/Cu/Cu2O − (direct) EIS 2015630
nanocrystal/rGO/Ab
serum 2.5 pg/mL 0.01−10 ng/mL 20 GCE/magnetic − (direct) SWV 2015631
chitosan/Au@Ag2S
NP/Ab
Salbutamol
pig feed, pork liver 10 ng/mL 20 ng/mL to 30 ITO/Ag nanoprism/Ab − (direct) LSPR 2013632
0.8 μg/mL
animal feed, pork liver 50 ng/mL 50 ng/mL to 30 ITO/hollow Au NP/Ab − (direct) LSPR 2013633
0.8 μg/mL
porcine serum 4 fg/mL 0.1 pg/mL to 60 SPCE/Au NP/Au NS/ − (direct) EIS 2016634
1 μg/mL Ab

10009 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Table 3. continued
pharmaceutical sample time year and
matrix LOD range (min) surface label(s) procedure ref
Salbutamol
pork 1.44 pg/mL 0.01−100 ng/mL 60 SPCE/rGO/salbutamol AgPd NP/Ab comp LSV 2013517
serum 7 pg/mL 0.02−15 ng/mL NA GCE/graphene/Ab1 mesoporous silica/Pd sw amperometry 2012635
NP/Ab2

morphological methods based on the gradient density, size, and cycle, mainly due to their poor degradability in wastewater
deformability of CTCs and (2) immunological methods based treatment plants. Diclofenac has been detected in low microgram
on the interaction between specific Ab’s and expressed epithelial per liter amounts in wastewaters and also in nanogram per liter
cell surface markers such as EpCAM (the epithelial cell adhesion amounts in surface waters, groundwater, and drinking water.190
molecule). Moreover, CellSearch (Janssen Diagnostics) as the Doxorubicin constitutes an anthracycline antibiotic that has
only FDA-approved platform for CTC detection in clinical been extensively used for the chemotherapeutic treatment of a
practice utilizes the magnetic preconcentration of CTCs using variety of cancers, such as lymphoblastic leukemia and
anti-EpCAM antibodies immobilized on magnetic particles. The sarcomas.509 The detection of doxorubicin in biological and
fluorescent detection is provided for by the second anti- clinical samples is important, mainly because of its high
cytokeratin and anti-CD45 antibodies labeled with fluorescent cardiotoxicity effects.510
dyes.505 Kanamycin embodies an aminoglycoside antibiotic produced
A basic prerequisite for the application of CTCs in clinical by the bacterium Streptomyces kanamyceticus; it finds application
practice is the unification of the preanalytical and analytical in the treatment of various bacterial infections by inducing
phases of detection and the ability to implement the current mistranslation and indirectly inhibiting translocation in the
knowledge of liquid biopsy and immunochemical assays. The course of protein synthesis. Analogously to other aminoglyco-
noninvasive detection of CTCs may ideally replace metastatic sides, kanamycin is characterized by a narrow safety margin and
tissue biopsies. An open challenge currently lies within the newly can generate several side effects, e.g., the loss of hearing, damage
emerging area of detecting CTCs for the industry of biosensors. to the kidneys, and allergic reactions to drugs.511 In addition,
Regrettably, biosensor-based detections of cancer cells are very residual amounts of kanamycin in the given foodstuff can cause
rare, and they are usually described on the model cell lines. Table antibiotic resistance of the pathogenic bacterial strains.512
2 provides a summary of representative studies where the Pefloxacin is an antibiotic drug within the group of
nanoparticles are simultaneously utilized. fluoroquinolones. Due to its broad spectrum of activity against
5.1.3. Pharmaceutical Detection. The development and Gram-positive and Gram-negative bacteria, pefloxacin is used in
extensive availability of sensitive analytical techniques enabled a the aquaculture industry to treat and prevent various infectious
rising amount of pharmaceuticals to be detected after medical or diseases. However, overusing the drug generates the risk of
veterinary application. During medical procedures, the drug residues in seafood and contributes to bacterial resistance.513
levels in biological fluids (i.e., urine and blood) often have to be Ofloxacin represents a new generation of fluorinated
monitored to ensure efficient and safe treatment. The quinolones structurally related to nalidixic acid. It has been
pharmaceutical residues in the environment also have to be commonly used against most Gram-negative bacteria, many
controlled due to possible side effects and within the monitoring Gram-positive bacteria, and some anaerobes through the
of the increasing bacterial antibiotic resistance. In livestock inhibition of their DNA gyrase. The drug exhibits rapid
production, veterinary drugs and anabolic steroids (endogenous absorption and potent inhibition ability at a reasonable
or synthetic hormones) are employed to a considerable extent. price.514 Unlike most other wide-spectrum antibacterial
Any inappropriate or unauthorized use of such compounds may pharmaceuticals, ofloxacin can be orally administered as well as
leave residues in edible tissues, which might then be harmful for intravenously transported into body tissues.515 Additionally,
consumers. Overall, there are a wide array of matrixes in which ofloxacin is applied not only in human medicine but also in the
the pharmaceuticals have to be analyzed, ranging from biological treatment and prevention of veterinary diseases in food-
fluids through environmental samples to food products. producing animals, and even as a growth-promoting substance.
Chloramphenicol is a broad-spectrum antibiotic offering The residues of ofloxacin in food products of animal origin are
outstanding antibacterial and pharmacokinetic effects. However, potentially dangerous via, e.g., toxic influence, an allergic
its application is limited since it may cause aplastic anemia and hypersensitivity reaction, and the promotion of bacterial
other adverse reactions.506 The use of chloramphenicol in food- antibiotic resistance.516
producing animals is prohibited in the European Union (EU), Ractopamine, clenbuterol, and salbutamol are a group of β-
and any residues found in a sample are considered a violation adrenergic agonists with comparable chemical structures and
under EU legislation. Nevertheless, chloramphenicol residues effects. Although they were first developed to treat diseases, the
have been detected in a wide variety of foodstuffs, such as prawn, side effects of reducing fat levels and increasing muscle protein
honey, and milk-based products imported from non-EU anabolism were discovered in the drug when administered to
countries.507 animals. Hoewever, the residues accumulating in animal tissues
Diclofenac is an extensively used nonsteroidal anti-inflamma- can induce symptoms of serious poisoning in humans; therefore,
tory drug. In the Indian subcontinent, the widespread use of β-adrenergic agonists have been forbidden as an animal feed
diclofenac for the veterinary treatment of cattle since the 1990s additive in numerous countries worldwide.517
has led to an abrupt decline in the vulture population because the To date, tools such as liquid chromatography (HPLC,518,519
substance can cause renal failure in vultures that feed on LC−MS,520 GC−MS521) capillary electrophoresis,522523 and
contaminated carcasses.508 In Europe, diclofenac belongs to spectroscopic techniques (colorimetry,524 fluorometry,525 chem-
pharmaceuticals most frequently analyzed in relation to the water iluminescence526) have been used for the detection of
10010 DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

pharmaceuticals. The chromatographic and electrophoretic by the cleavage of the proteins associated with the release of
procedures are nevertheless time-consuming and labor-intensive, acetylcholine after targeted binding with nerve cells or
which renders them usable mainly for confirmatory analysis. cholinergic nerve endings; the process induces muscular
Since the pharmaceuticals are a rather heterogeneous group of paralysis, respiratory collapse, or death.637 The fatal dose of
compounds, the immunosensor-based detection methods vary botulinum neurotoxins ranges between 0.1 and 1 ng/kg in
appropriately. Most of the drugs are compounds of relatively low humans, and we thus have to consider the risk that the
molecular weights, and therefore, sandwich assay is not as aerosolized toxin might be also used as a biological weapon.638
common as competitive or direct detection. Brevetoxin B is an efficient neurotoxin produced by the red
The relevant applications of NP-based immunoanalytical tide organism Gymnodinium breve Davis.639 Many filter-feeding
techniques and sensors for the detection of pharmaceuticals are shellfish are known to accumulate brevetoxins with no obvious
provided in Table 3. adverse effects; however, eating brevetoxin-contaminated shell-
5.2. Toxic Substances and Pathogens fish poses a major health hazard. Brevetoxin can bind to voltage-
The assays within this category very often need to be realized out gated sodium channels in nerve cells, which leads to gastro-
of regular laboratories to quickly screen and identify potentially intestinal and neurological symptoms. The lethal dose of
dangerous substances. The rapid immunoassays suitable for field brevetoxins in mice is around 200 μg/kg of body weight for
use are represented by the lateral flow immunoassay format intraperitoneal injection and varies between 520 and 6600 μg/kg
(Figure 34); a drop of the sample spontaneously moves through for oral administration.640 Brevetoxin can also influence
respiratory irritation via aerosol exposure at seashores.641
Cholera toxin constitutes an enterotoxin protein secreted by
the bacterium Vibrio cholerae, a causative agent for diarrhea and
acidosis in humans with high lethality.642 Cholera toxin is
composed of two subunits: cholera toxin subunit A and cholera
toxin subunit B. The latter is responsible for binding to the
ganglioside GM1 receptor on intestinal cell walls, whereas the
former is the active function protein that activates the production
of cyclic AMP, causing a dramatic efflux of ions and water from
the infected enterocytes; the process leads to watery diarrhea.643
Microcystins are the most widespread lethal cyanotoxins. They
are produced by the blooming cyanobacteria Microcystis
aeruginosa in fresh and brackish waters.644 Within over 80
mycrocystin types, microcystin-LR (containing leucin (L) and
arginine (R) as the two variable amino acids) is the most
prevalent and abundant toxin, accounting for 46.0−99.8% of the
overall concentration of microcystins in the toxic cyanobacterial
blooms.645 It is a hepatotoxin capable of inducing functional and
structural disturbances of the liver; the substance can accumulate
Figure 34. Schematic view of the lateral flow immunoassay format in aquatic organisms and transfer to higher trophic levels.646 The
widely used for rapid assays out of the laboratory. LD50 of microcystin-LR in mice and rats is 36−122 μg/kg
through various routes, including aerosol inhalation.647
the porous strip material with the help of capillary forces, Mycotoxins embody secondary metabolites produced by
dissolving the immunoreagents deposited at the beginning of the microfungi having the ability to cause disease and death in
flow path in the tracer release pad. Finally, the concentration level humans and animals. The most important mycotoxins are the
is evaluated in the measuring part embodied in the capture zone, aflatoxins and ochratoxin A produced by the fungi Aspergillus and
and the performance of the assay is confirmed in the control Penicillium. In general terms, aflatoxins are difuranocoumarin
zone. Sophisticated immunosensors should compete with the derivatives produced via a polyketide pathway by many strains of
fast performance of this format. Aspergillus flavus and Aspergillus parasiticus. More than 20
5.2.1. Detection of Toxins. Microbial toxins are the main aflatoxins have been identified, those of major concern being
virulent subunits of many pathogenic microorganisms (bacteria B1, B2, G1, and G2; the classification defines the fluorescence
and fungi); they represent a heterogeneous set of compounds under UV light (blue or green) and relative chromatographic
which can interfere with biochemical processes, including the mobility during thin-layer chromatography.648 AFB1 is normally
membrane function, ion transport, transmitter release, and predominant in amount and also exhibits the highest toxicity.649
macromolecule synthesis. Human exposure to toxins in either When aflatoxin B1 is consumed by cows, it metamorphosizes
food or the environment may cause serious health problems, with into its hydroxylated product, aflatoxin M1, which is secreted
the individual symptoms varying substantially between the through the milk.650 Because of the differences in aflatoxin
toxins.636 Thermal processing methods such as pasteurization or susceptibility in test animals, it is difficult to extrapolate the
heating typically kill only the bacteria and do not affect the toxins. possible effects of aflatoxin on humans. The acute lethal dose for
Thus, the detection of food toxins should be carried out by adults was calculated to lie between approximately 10 and 20 mg
immunological rather than microbiological procedures because of aflatoxins.651 Ochratoxin A is produced by many filamentous
the latter detect only the bacteria. species belonging to the genera Aspergillus and Penicillium.652
Botulinum neurotoxins represent the most potent natural The substance constitutes a potent nephrotoxic mycotoxin
toxins. The group comprises seven different immunogenic linked to kidney problems in both livestock and human
serotypes (A−G) produced by various strains of the spore- populations, and it also exhibits carcinogenic, genotoxic, and
forming bacterium Clostridium botulinum. The toxicity is caused immunotoxic properties.653 The LD50 of ochratoxin A in mice
10011 DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Table 4. Overview of Immunosensors for Toxic Molecules

toxin sample time year and
matrix LOD range (min) surface label(s) procedure ref
Aflatoxin A1
peanuts 8 pg/mL 8 pg/mL to 1 ng/mL 90 Au/aflatoxin−BSA Au NP/Ab2 comp SPRi 2014698
Aflatoxin B1
peanuts 0.16 ng/mL 0.5−50 ng/mL 45 − Au NR/AFB1−BSA comp, optical (reader) 2013699
peanuts 0.6 pg/mL 0.6 pg/mL to 180 microplate/Ab1 biotin/Ab2; sa; sw, commercial 2016700
10 ng/mL nanoliposome/biotin glucometer readout
w (environmental; 0.1 ng/mL 0.1 ng/mL to 30 MNP/Ab1 hollow Au NP/Ab2 sw SERS 2014701
tap water) 100 μg/mL
w (model) 80 pg/mL 0.25−1.4 ng/mL NA ITO/MWCNTs/Ab − (direct) CV 2013702
w (model) 30 pg/mL NA 12 LFIA strip/AFB−BSA Au NP/Ab comp LFIA 2014703
olive oil 0.03 ng/mL 0.1−10 ng/mL 40 GCE/MWCNT/ionic − (direct) EIS 2015704
liquid/Ab
milk, peanut oil 0.2 pg/mL 1 pg/mL to 90 SPCE/Au NP/Ab1 Cu−apatite/AFB−BSA comp ASV 2016705
100 ng/mL
w (model) 1 pg/mL 1 pg/mL to NA Si/PMMA/Pt NP/Ab − (direct) EIS 2016706
10 μg/mL
corn powder 3.5 pg/mL 0.01−100 ng/mL 210 chitosan/SWCNTs/ Ab1, Ab2−ALP comp DPV 2016707
AFB1−BSA
peanuts 5 pg/mL 5 pg/mL to 5 ng/mL 30 GCE/AFB1−BSA graphene oxide/CoTPP/Pt comp peroxidase-like 2016708
NP/Ab DPV
corn 0.2 ng/mL 0.05−200 ng/mL 90 magnetic electrode/ − (direct) ECL 2016709
CNHs/MNPs/Ab
peanuts 2.7 pg/mL 3 pg/mL to 80 GCE/graphene/conA/ Au NP/invertase/AFB1− comp, displacement 2015710
20 ng/mL SiO2 NP/Ab BSA DPV
w (model) 0.12 ng/mL 0.125−1.5 ng/mL NA ITO/rGO/Ab − (direct) CV 2013711
w (model) 0.16 ng/mL 1−8 ng/mL NA ITO/rGO−Ni NP/Ab − (direct) DPV 2016712
corn 10 fg/mL 10 fg/mL to 50 GCE/PPy/PPa/rGO/ − (direct) EIS 2015713
10 pg/mL Ab
Aflatoxin M1
milk 18 pg/mL 18 pg/mL to 55 Au/pHEMA/BSA− Au NPs/Ab2 indirect comp, SPR 2016714
1 μg/mL AFM1
Botulinum Neurotoxin
orange juice, milk 5 pg/mL 10 pg/mL to 65 GCE/graphene/Ab1 Au NP/Ag NP/Ab2/ALP sw LSV of product of 2015715
10 ng/mL enzymatic reaction
orange juice 150 fg/mL 150 fg/mL to 240 nanoporous silica/Ab1 dye-doped NP/Ab2 sw F 2012716
2.5 ng/mL
Brevetoxin
seafood 0.6 pg/mL 1 pg/mL to 75 Au/graphene/ConA/ Au NP/glucoamalyse comp, hydrolytic 2013717
10 ng/mL sa/Ab1 reaction, displacement
QCM
seafood 6 pg/mL 0.01−3.5 ng/mL 80 mesoporous silica methylene blue, aminated controlled release, SWV 2013718
nanocontainer/Ab polystyrene microspheres
seafood 5 pg/mL 0.01−10 ng/mL 50 GCE/brevetoxin−BSA mesoporous enriched comp, DPV 2015719
PdNS/Ab
Cholera Toxin
w (model) 1.1 μg/mL 1.1−6 μg/mL 25 buoyant silica Au NP/Ab2 sw, SERS 2012720
microspheres/Ab1
w (model) 0.6 ng/mL 37−350 ng/mL 30 ITO/NiO NWs/ − (direct) EIS 2013721
(SpA)/Ab
Microcystin-LR
w (drinking water) 0.04 ng/mL 0.05−20 ng/mL 45 Si/MWCNTs/Ab − (direct) EIS 2012722
w (environmental; 4 pg/mL 5−50 pg/mL 150 Au/CNT@Co silicate/ Ab1 and MNP/dopamine/ comp CV 2016723
lake, tap water) Ag NP/microcystin Au NP/Ab2
w (environmental; 4 pg/mL 0.01−100 ng/mL 90 GCE/Au NP/ Ab−HRP comp EIS 2016724
lake) microcystin−BSA
w (environmental; 1.7 ng/mL 2.5 ng/mL to 150 GCE/CNT/Ab1 Au NP/Ab2 comp ASV 2016725
lake) 5 μg/mL
w (environmental; 0.6 pg/mL 1−1000 pg/mL 60 Au/MWCNT/ − (direct) resistivity 2015726
lake, river, tap) microcystin
w (environmental; 0.5 ng/mL 0.5 ng/mL to 180 glass/graphene oxide/ Au NP/aptamer sw F quenching 2012727
lake) 10 μg/mL Ab1
w (environmental) 21 pg/mL 0.1−25 ng/mL 60 fluorine doped tin − (direct) photocurrent decrease 2012728
oxide/QD−
graphene/Ab
w (drinking water) 1.7 ng/mL 5 ng/mL to 1 μg/mL 15 GCE/ionic liquid/ − (direct) EIS 2012729
MWCNTs/Ab

10012 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Table 4. continued
toxin sample time year and
matrix LOD range (min) surface label(s) procedure ref
Ochratoxin
peanuts 30 pg/mL 30 pg/mL to 90 Au/ochratoxin−BSA Au NP/Ab2 comp SPRi 2014308
1 ng/mL
corn, wheat, rice, 10 zg/mL 10 zg/mL to 180 microplate/Ab1 SiO2 NP/catalase/ comp plasmonic ELISA, 2015730
coffee 1 ag/mL ochratoxin naked eye or reader
ground corn 0.2 ng/mL 1 ng/mL to 1 μg/mL 120 GCE/Au NPs/ Ab comp CV 2013731
ochratoxin−OVA
corn, wheat, rice 0.05 pg/mL 0.05−10 pg/mL 195 microplate/Ab1 OTA−CAT and QDs comp F quenching 2016732
milk 2 pg/mL 10 pg/mL to NA ITO/TiO2/QD/Ab − (direct) PEC 2015733
50 ng/mL
instant coffee 0.26 ng/mL 1−104 ng/mL 15 MNP/Ab ochratoxin−HRP comp amperometry 2015734
Staphylococcal Enterotoxin A
milk 10 pg/mL 0.01−10 ng/mL 120 3D fiber/Ab1 MNP/Ab2 sw, mag. Separation, 2013735
mag. detection
Staphylococcal Enterotoxin B
w (model) 1 pg/mL 1 pg/mL to 1 ng/mL 10 LFA strip/Ab1 hollow Au NP/Ab2 sw, LFIA, naked eye 2016736
w (model) 8.15 ng/mL 10 ng/mL to NA sepharose/Ab1 QD/Ab2 comp F 2012737
1 μg/mL
milk 17 pg/mL 50 pg/mL to 45 magnetosome/PANI− − (direct) EIS 2013738
5 ng/mL Au NPs/Ab1
milk 2.5 ng/mL 5−100 ng/mL 15 LFIA strip/Ab1 Au NP/Ab2 LFIA naked eye readout 2016739
w (model) 1 ng/mL NA 20 PMMA/SWCNTs/Ab − (direct) electrical percolation 2013740
Staphylococcal Enterotoxin C1
milk 19 pg/mL 0.025−2 ng/mL 160 microplate/Ab1 SiO2 NP/Ab2 sw CL 2016741
Zearalenon
peanuts 15 pg/mL 15 pg/mL to 90 Au/zearalenon−BSA Au NP/Ab2 comp SPRi 2014742
1 ng/mL
feed sample 1 pg/mL 5 pg/mL to 5 ng/mL 180 glass/zearalenone−BSA Au NP/Ab comp SERS 2014743
pig feed 2.1 pg/mL 5 pg/mL to NA GCE/nitrogen-doped PtCo NP/Ab2 sw, chronoamperometry 2013744
25 ng/mL graphene/Ab1

oscillates within the range of 38−56 mg/kg, depending on the feature of most pesticides is bioaccumulation risk and the
mouse strain.654 Staphylococcal enterotoxins form a category of relatively high toxicity to humans.662 In the EU, pesticides in
toxic proteins produced by Staphylococcus aureus. Enterotoxins drinking water are currently regulated by the Drinking Water
are often found in protein-rich food, such as meat and Directive, which stipulates the maximum allowable concen-
milk,655and they exhibit heat stability, resistance to gut proteases, tration of 0.1 μg/L per pesticide or 0.5 μg/L for the total
and activity over a wide range of pH values.656 Thus far, 20 pesticide concentration.663
serologically distinct staphylococcal enterotoxins have been 2,4-Dichlorophenoxyacetic acid (2,4-D) embodies one of the
discovered; staphylococcal enterotoxin B (SEB) is most often most frequently applied herbicides in agriculture. It is a synthetic
connected with food poisoning. The SEB infection is very rapid plant growth regulator, structurally and functionally akin to
and causes symptoms such as nausea, violent vomiting, and auxin.664 At low concentrations, 2,4-D is a component of the
abdominal cramping that may result in diarrhea even at a dose of plant tissue culture medium; at high ones, however, it functions
less than 1 μg or 100−200 ng in highly sensitive people.657,658 as a herbicide for broadleaf weeds. The compound is potentially
Zearalenone is a mycotoxin produced mainly by fungi toxic to humans, can be accumulated in the human body, and has
belonging to the genus Fusarium. Contaminations by zearale- a certain potential of carcinogenicity and mutagenicity.665,666
none are frequent in agricultural commodities and cereal The oral LD50 of 2,4-D in rats is 375 mg/kg of body weight.667
products such as flour, malt, soybeans, and beer.659 Consuming The U.S. Environmental Protection Agency (EPA) has set the
contaminated products might cause various toxic effects in enforceable regulation for 2,4-D, or the maximum contaminant
humans and animals, including teratogenesis, carcinogenicity, level (MCL), at 70 μg/L.668
neurotoxicity, abortion, and the estrogenic effect.660 The LD50 of Atrazine is a widely used herbicide that enables the control of
zearalenone in mice equals 500 mg/kg of body weight.661 annual grasses and broadleaf weeds in agriculture worldwide. It is
The selected applications of NP-based immunoanalytical persistent in the environment and can thus remain in the
techniques and sensors for the detection of toxins are provided in ecological system, including soil, natural water, and food (e.g.,
Table 4. maize). When accumulated in vivo, atrazine can antagonize,
5.2.2. Pesticides as Environmental Pollutants. Pesticides impair, enhance, or inhibit the actions of endogenous hormones,
constitute significant pollutants as they are constantly spread in leading to abnormalities in growth, reproduction, development,
large amounts into the environment. The negative influence of behavior, immune functions, or malignant tumors.669 The
these compounds on the environment was emphasized by atrazine toxicity (LD50) by oral ingestion in humans is 1000
pesticides being listed as priority hazard agents within European mg/kg.670
water policy. The substances exhibit adverse health effects, and Carbofuran constitutes a broad-spectrum insecticide com-
therefore, most countries have defined maximum residue levels monly applied in agriculture to control insects and nematodes for
(MRLs) of pesticides in food and animal feed. The common the purposes of production enhancement.671 It is highly toxic to
10013 DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

mammals and reportedly embryotoxic and teratogenic. Due to its The relevant applications of immunosensing techniques and
extensive use in agriculture and relatively good solubility in water, sensors used for pesticides are summarized in Table 5.
carbofuran can contaminate surface and ground waters and, 5.2.3. Microbial Detection. The rapid detection and reliable
therefore, poses a risk to consumers and the environment. The identification of hazardous microbial agents constitutes a
U.S. EPA prescribes the maximum contaminant level (MCL) for challenging task. The prevention or early treatment of infectious
carbofuran in drinking water at 40 μg/L.672 diseases is a concern of modern society. Even human deaths due
Chlorpyrifos is an organophosphorus acetylcholinesterase to possible bioterrorist attacks are threats to modern society, and
inhibitor. Exposures to chlorpyrifos can result in a series of it is thus understandable that the growing demands for the
neurotoxic injuries to the central nervous system as well as the detection of bioagents originated from the military, civil rescue,
cardiovascular and respiratory functions.673 The acute and and security services, protection of public buildings, and
chronic reference doses of chlorpyrifos are 5 and 0.3 μg/kg/ homeland security, all of which constitute major domains of
day, respectively, with the oral LD50 amounting to 50−250 mg/ current public interest. The Centers for Disease Control and
kg/day.674 Prevention sorted the critical biological agents for public health
Diuron is a substituted phenylurea herbicide employed for into the three categories.690 The properties of biological agents
wide-spectrum pre-emergence weed control. The compound is a such as lethal dose and infectiveness make these agents suitable
potent photosynthesis inhibitor, interrupting the photosynthetic candidates for use as biological warfare agents (BWAs). The
electron transport chain; the process then leads to reduced most dangerous bacteria are, for example, Francisella tularensis
formation of high-energy substances such as ATP.675 This (tularemia), Yersinia pestis (plague), Clostridium botulinum
herbicide can be classified as an endocrine disruptor.676 It is (botulism), and Bacillus anthracis (anthrax). The last one is
rather persistent in soil, having a half-life in the range between 90 feared because it has already been used. As regards the practical
and 180 days, depending on the type of environment.677 Diuron use, the Department of Homeland Security in the United States
exhibits only slight acute toxicity to mammals; the oral LD50 in requires the sensitivity of field devices in the range from 102 to
rats is 3.4 g/kg.678 105 organisms/L.691 The most dangerous bioagents cannot be
Endosulfan constitutes a broad-spectrum organochlorine easily used in common laboratory conditions; therefore, the safe
pesticide widely used in agriculture to control insects and strains of E. coli (DH5α) and Bacillus atrophaeus are used for the
mites. The substance has been regarded as a relatively development of detection technologies.
environmentally safe pesticide with a short half-life and little Microbial detection is nevertheless indispensable also for the
evidence of bioaccumulation. However, due to its high everyday inspection of potentially contaminated food, including
meat, poultry, and milk products, vegetables, and fruits; possible
application rate (750 g/ha) and relatively high acute toxicity to
contaminants then comprise the strains of Escherichia,
fish (LC50 = 0.1−20 g/L), endosulfan poses a potential
Salmonella, and Listeria. Salmonella was evaluated as a leading
environmental threat.679
cause of foodborne infections in the United States, with
Imidacloprid is an insecticide that kills insects by binding to
approximately 1.2 million illnesses and 450 deaths per year.692
the nicotinic acetylcholine receptors (nAChR’s) in their central
Legionella should be seriously considered too as it occasionally
nervous system. The compound is highly specific for nAChR’s
contaminates water supplies.
and is less harmful to mammals. However, it is soluble in water Viruses and viral antigens are typically assayed in clinical
and has a lifetime greater than 1000 days, which enables it to diagnostics; classic examples are hepatitis surface antigens and
accumulate in soils and water sources.680 The short-term oral human immunodeficiency virus. Each year, outbreaks of viral
LD50 is 450 mg/kg for rats and 150 mg/kg for mice.681 infections (the most common being influenza with potentially
Metolcarb is an N-methylcarbamate pesticide widely used in highly dangerous mutated variants) cause illness, disability,
agricultural production to control rice leafhoppers, planthoppers, death, and economic loss. As learned from past incidents, the
and fruit flies. The compound is based on inhibiting detrimental impact grows exponentially without effective
acetylcholinesterase transmission at nerve endings.682 It is quarantine. Therefore, rapid on-site detection and analysis are
potentially dangerous to mammals; the LD50 equals 268 mg/ highly desired.693 Recently, the lack of laboratory facilities
kg.683 resulted in diagnostic complications during the West African
Paraquat is a widely used and fast-acting organic heterocyclic Ebola virus outbreak in 2013−2015, thus compromising
herbicide. The use of paraquat has been banned in the EU since outbreak control. Nearly 28000 confirmed, probable, and
2007; however, this rule does not apply to non-European suspected cases were reported; owing to limited laboratory
countries exporting to the EU. The maximum residue limit capacity and local transport infrastructure, the delays from
(MRL) of 20 μg/kg has been established for many food products sample collection to test results were often 2 days or more.694
such as barley, wheat, or potato.684 The LD50 of paraquat in rats is Even though suitable analytical procedures (cultivation tests,
79 mg/kg.685 polymerase chain reaction,695 enzyme-linked immunosorbent
Parathion and methyl parathion are organophosphorus assays) and devices (mass spectrometry696) are readily available,
pesticides. The symptoms of poisoning include nausea, vomiting, drawbacks such as slow operation, complicated portability, and
diarrhea, muscle cramping/twitching, and shortness of breath.686 high running costs often limit their applicability. Conventional
The LD50 values of parathion and methyl parathion in mice were microbiological methods are time-consuming and usually require
found to be 13.5 and 11 mg/kg, respectively.687 the collection of samples for subsequent laboratory analysis. The
Among the many pesticides used in agriculture, insecticides complexities of analyzed samples containing interfering (bio)-
from organophosphorus and carbamic groups are often applied substances disadvantage PCR methods, and additional methods
because they exhibit high insecticidal activity and rather small are needed to avoid false conclusions. In the case of MS, extensive
persistence in the environment. The substances are commonly instrumentation limits widespread use for the field detection.
detected by inhibition-based enzymatic sensors, which are not The actual assays of bioagents are further complicated by minor
discussed in this review and were summarized elsewhere.688,689 differences between hazardous and commonly used microbial
10014 DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
 Table 5. Assays for Pesticides and Other Environmental Pollutants
time year and
pesticide sample matrix LOD range (min) surface label(s) procedure ref
2,4-Dichlorophenoxyacetic Acid
w (model) 13 ng/mL 13.3−666.7 ng/mL 70 Au/2,4-D−BSA Ab1, Ab2−Au NP comp QCM 2014745
Atrazine
Chemical Reviews

w (model) 50 pg/mL 50 pg/mL to 5 ng/mL 180 glass/Au NPs/Ab − (direct) LSPR 2012746
maize 1 ng/mL 1−15.6 ng/mL 10 Au/Au NP/Ab − (direct) SPR 2015747
crop 16 pg/mL 0.05−0.5 ng/mL 45 Au/Au NP/Ab − (direct) DPV 2014748
w (model) 0.01 ng/mL 0.01−50 ng/mL 20 SPE/styrene sulfonic acid doped − (direct) EIS 2014749
nanostructured PANI/Ab
orange juice 3.5 pM 0.9−4.5 nM 20 boron doped diamond/Pt NP/magnetic atrazine−HRP mag sep, comp, 2016750
bead/Ab chronoamperometry
w (environmental), feed, corn flakes 1.2 ng/mL 0.01−1000 ng/mL 120 GCE/Au NP/atrazine−BSA Ab1, Ab2−HRP comp CV 2014751
w (environmental) 1 pg/mL 1 pg/mL to 10 ng/mL 15 FET/SWCNTs/Ab − (direct) FET 2016752
w (environmental) 0.2 pg/mL 0.2−20 pg/mL 90 SPCE/magnetic bead/Ab phage particles/HRP mag sep, noncompetitive, 2014753
chronoamperometry
Carbofuran
lettuces, cabbages, green peppers, tomatoes, Chinese 60 pg/mL 0.1 to 106 ng/mL 45 Au/deposited Au nanocrystals/Ab − (direct) DPV 2012754
chives, strawberries
cabbage, lettuce 0.021 ng/mL 0.1−1 μg/mL 15 Au/Au NP/Prussian blue−MWCNT− − (direct) CV 2012755
chitosan/SpA/Ab
cabbages, green peppers, tomatoes, Chinese chives, 0.03 ng/mL 0.5−500 ng/mL 25 GCE/MWCNTs/graphene−PEI−Au/Au − (direct) CV 2013756
peaches NP/Ab

10015
cabbage 0.11 ng/mL 1 ng/mL to 30 GCE/Au NP/thiourea/Au NP/Ab − (direct) amperometry 2012757
200 μg/mL
Chlorsulfuron
w (model) NA 0.1 pg/mL to 1 170 microplate/chlorsulfuron−BSA Au NP/Ab comp ASV (SWV) 2012758
0 ng/mL
Chlorpyrifos
cabbage, pakchoi, lettuce, leek 52 pg/mL 5 ng/mL to 2 mg/mL 30 GCE/NiAl/graphene/hollow Au NP/Ab − (direct) CV 2015759
w (environmental) 6.3 pg/mL 0.01−1000 ng/mL 120 GCE/polydopamine nanospheres/ Ab1, Ab2/CNT/ comp CV enzymatic amplification 2015760
chlorpyrifos−OVA Fe3O4/HRP
Diuron
w (model) 0.01 ng/mL 1 pg/mL to 10 μg/mL 150 microplate/diuron−BSA/Ag NP Ab−FITC comp plasmon enhanced FL 2013761
(blocking)
w (environmental) 0.1 pg/mL 0.01 pg/mL to 185 SPE/MWCNTs/diuron hapten Ab1, Ab2−ALP comp DPV 2012762
10 mg/mL
w (environmental) 5.46 ng/mL 1−1000 ng/mL NA SPCE/Au NP/Ab − (direct) EIS 2012763
w (model) 0.01 pg/mL 0.01 pg/mL to 120 SPCE/functioinalized graphene−GO/ Ab1, Ab2−ALP comp LSV 2013764
10 μg/mL diuron−BSA
Review

DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

species. Evidently, a reliable device suitable for rapid on-site POC

year and

2012765

2016766

2013767

2014768

2016769
detection was missing.
ref Nanoparticles bring important advantages to immunoassays.
Magnetic NPs appeared to be a useful tool providing a favorable
dual benefit for the signal amplification: immunomagnetic
separation, and preconcentration of the sample. Microbial
species captured in the sensing area provide a sufficiently large
surface ideally suited for further binding of “decorating”
procedure

mag sep, comp, ASV

nanoparticle-based labels (Figure 35). The relevant example
applications of NP-based immunoanalytical techniques and
comp SWV

sensors are provided for bacteria (Table 6) and viruses (including

comp SPR

viral antigens, Table 7).

QCM

EIS
label(s)

− (direct)

− (direct)
QD/Ab

Figure 35. Enhanced response of an immunosensor for the detection of

Ab

Ab

microbes. A comparison of the different sizes of the NP labels binding to

E. coli. Based on ref 697.
Al2O3/Ag nanostructures/imidacloprid−

magnetic microparticle/paraquat−BSA
GCE/SWCNTs/endosulfan hapten

6. CONCLUSION AND OUTLOOK

Au/MWCNT−PAMAM/Ab

This review has summarized recent advances, challenges, and

surface

trends in the rapidly developing domain of immunochemical

SPCE/graphene/Ab

biosensing supported and enhanced by nanoparticles. The

research topic represents the interdisciplinary effort to combine
the unique electronic, magnetic, optical, catalytic, and mechan-
ical properties of nanoparticles with the optimized recognition
BSA

function of biomaterials such as antibodies. In the review, nano-

objects were introduced in broad contexts, and the role of
nanoparticles in immunosensing was discussed. Attention was
(min)
time

180

120
20

30

10

paid to not only several applications of nanoparticles in individual

immunomethods but also the architecture and transduction
strategies that have proposed perspectives for further develop-
ment.
0.1−1000 pg/mL
3.1−67.8 μg/kg
0.1−50 μg/mL

The review has demonstrated that NP-based immunosensors

range

0.01−20 ppb

provide very good results with a promising sensitivity and

1−10 ppb

reproducibility and, in combination with novel devices (such as

microfluidic sample delivery, microelectromechanical systems, or
sensors with embedded electronic signal treatment, namely,
concepts well-known from the lab-on-the-chip field), offer an
19 ng/mL

attractive analytical approach for the fast, low-cost, and accessible

1.4 μg/kg

52 fg/mL
LOD

0.01 ppb

detection of trace prognostic biomarkers, drugs, toxins, microbial

1 ppb

pathogens, and environmental pollutants. The key advantages of

immunochemical biosensorssmall size and portability, rea-
sonable assay costs, simplified use, and straightforward
interpretation of resultsare being further enhanced through
incorporation of nanoparticles improving particular steps
completing both the immunorecognition and sensing function.
pesticide sample matrix

The relative complexity of the sensing structures and

procedures should not constitute an obstacle, as the production
technologies for the robust deposition of thin layers and
immobilization of biocomponents are already available. The
Table 5. continued

actual reliability in real situations, however, might pose certain

difficulties, especially if we consider the fact that the results
w (environmental)

obtained from the testing of newly developed bioanalytical

comato, carrot
Imidacloprid

technologies almost invariably appear to be flawless. Thus,

orange juice
Endosulfan

w (model)

Metolcarb

Parathion
Paraquat

extensive, critical test cycles supervised by independent special-

potato

ists should be realized prior to considering any production and

commercialization-related steps. Importantly, what looks ideal in
10016 DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Table 6. Immunosensing for Pathogenic Bacteria

bacteria sample LOD range time year and
matrix (cfu/mL) (cfu/mL) (min) surface label(s) procedure ref
Alexandrium minutum (Microalgae, Shellfish Toxins)
w (sea) 100 100 to 108 30 nitrocellulose/mAb1 mag NP/mAb2 sw, mag sep and reader, 2016770
LFIA
Bacillus anthracis
(spores) milk 400 4 × 103 to 30 nitrocellulose/mAb1 mag NP/mAb2 sw, mag sep and reader, 2013771
powder 106 LFIA
Bacillus cereus
cell culture 10 50 to 104 30 glassy C/chit−Au NP/Ab1 − (direct) blocked chronoamp 2012772
Cryptosporidium parvum (Protozoan Parasite, Oocysts)
w (model) 5 5−100 65 glass/mAb1 Ag2S/SiO2/mAb2 sw, F (NIR) 2014196
Enterobacter sakazakii
w (model) 1000 104 to 1010 45 SPE C/MWCNT−alginate−chit/ − (direct) blocked CV 2013773
HRP/thionin−Ab1
Escherichia coli
w (model) 10 10 to 109 30 Au/cystine flowers/Ab1 − (direct) blocked EIS 2014774
w (model) (DH5α) 210 100 to 107 1 aligned C nanofibers Fe2O3/Au nano-ovals/ dielectrophoretic capture; 2015775
Ab SERS
urine 30 100 to 108 120 Fe3O4/Au NP/Ab1 CdTe QD/chit/Ab2 sw, F 2016776
dairy 50 100 to 106 150 glassy C/PAMAM dendrimer/ MWCNT/HRP/pAb2 enzyme PANI deposition, 2016777
AuNP/mAb1 DPV
Escherichia coli O157:H7
w (model) 250 400 to 45 Au/Au NP/chit−MWCNT−SiO2/ − (direct) blocked CV 2012778
4 × 105 thionine/mAb1
stool (model) 15 30 to 3 × 106 90 C/fullerene, ferrocene/Au, SiO2 Pt NP/GOD/Ab2 sw, CV of GOD− 2013779
NP/Ab1 ferrocene transfer
brassica 430 4 × 103 to 35 Fe3O4/PB/Au NP/Ab1 − (direct) mag sep, catalytic NP, CV 2014780
4 × 108
w (model) 100 100 to 107 10 nitrocellulose/pAb1 Au NP/mAb2 LFIA, color visual/reader 2015244
w (model) 10 10 to 106 60 mag NP/PANI/mAb1 Au NP/Pb NP/mAb2 mag sep, sw, SWV of 2015781
dissolved Pb2+
milk 10 10 30 Fe3O4/Pt/Ab1 − mag sep, catalytic, color 2015782
visual
milk, 3 4 to 4 × 106 75 Fe3O4/SiO2/PAA/Ab1 SiO2/FITC/Ab2 sw, mag sep, F 2016197
orange juice, w
w (model) 100 100 to 106 15 nitrocellulose/pAb1 AuPt NP/Ab2 LFIA, catalytic NP, color 2016783
visual/reader
w (model) 100 300 to 105 150 Au/pAb1 Au NP/pAb2 sw, EIS 201642
food (hamburger) 57 10 to 104 80 Au/PCBAA brush/Ab1 Ab2−bt; Au NP/sav sw, SPR 2016276
food 1−10 104 to 106 24 h Au/Ab1 Au NP/Ab2 sw, QCM, on-chip 2016784
cultivation
Legionella pneumophila
w (preconcentrated 10 10 to 105 180 SPE−C; Fe3O4 NP/PDOPA/pAb1 pAb2−HRP sw, mag sep, amp 2015785
2000×)
Listeria innocua
w (model) 104 104 to 108 20 mag NP/Ab1 Au NP/Ab2 sw, SERS 2016786
Listeria monocytogenes
lettuce 300 300 to 104 150 IDE; Fe3O4 NP/mAb1 Au NP/pAb2/urease sw, urease/urea 2015787
impedance
milk 100 100 to 107 <10 SPE−Au/grox−chit/Ag NP/Ru − (direct) blocked amp 2015788
(bpy)32+/mAb1
Pseudomonas aeruginosa
w 900 10 to 107 90 glassy C/Ca−pectin/Au NP/Ab1 Ab2−HRP sw, DPV 2016789
Salmonella galinarum
chicken 32 100 to 106 120 SPE; Fe3O4/SiO2/Ab1 Ab2−HRP sw, mag sep, CV 2015790
Salmonella pullorum
chicken liver 90 100 to 106 150 SPE; Fe3O4/SiO2/Ab1 grox-r/AuNP/Ab2 sw, mag sep, DPV 2016791
Salmonella typhimurium
milk, egs, sprouts 13 10 to 106 150 SPE−avidin; Fe3O4−latex NP/ pAb2−biotin sw, Ag-enhanced stripping 2013792
ssDNA code/mAb1 DPV
w (model) 100 100 to 105 25 glass/ZnO NR/pAb − (direct) blocked PL (UV) 2014793
milk 5 10 to 105 150 glassy C/chit/Au NP/Ab1 Ab2−HRP sw, DPV 2015413
apple juice <10 10 to 1000 180 polystyrene/mAb1 bt−Ab2, sa, Cys/bt− sw, NP aggreg., SPR color 2015250
lipo, Au NP visual
chicken extract 1000 103 to 106 70 mag NP/Ab1 CdSe/ZnS QDs/Ab2 sw, mag sep, fluidics, F 2015794
w (model) 100 100 to 105 40 − Au NP/Ab SERS; ICP-MS 2015795

10017 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Table 6. continued
bacteria sample LOD range time year and
matrix (cfu/mL) (cfu/mL) (min) surface label(s) procedure ref
Vibrio cholerae
w (model) 100 100 to 104 90 Pt/CeO2 NW/Ab1 − (direct) blocking EIS 2016796
Vibrio parahemolyticus
sea w, seafood 5 10 to 108 65 GCE/grox/ABEI/Ab1 − (direct) blocked ECL 2016214

Table 7. Immunosensors for Viruses and Viral Antigens

virus (antigen) time year and
sample matrix LOD range (min) surface label(s) procedure ref
Avian Leucosis ALVs-J (TCID Is the 50% Tissue Culture Infective Dose)
serum (avian) 102.08 TCID/mL 102.1 to ∼100 ITO/Bi2S3 NR/chit/Ab1 Au NP/ALP/Ab2 sw, generated 2014235
103.7 TCID50/mL ascorbate, PEC
Bacteriophage MS2
w (river) 9 pfu/mL 10 to 1011 pfu/mL 210 SPE−Au/Fe2O3/ Ab2−ALP sw, DPV 2015797
SWCNT/Ab1
Cytomegalovirus pp65 Antigen
saliva 30 pg/mL 0.1−80 ng/mL 60 Pt, Pd NP/SWCNT/HRP/ − (direct) blocking DPV 2016798
thionine/Ab1
Dengue
cell culture 1 pfu/mL 1−900 pfu/mL 45 Al2O3 nanochannels/Ab1 − (direct) blocked EIS 2012799
cell culture 0.04 pfu/mL 3−45 pfu/mL 5 Al2O3 Pt nanochannels/PB − (direct) blocked PB 2012800
nanotubes/Ab1 catalysis, fuel cell
Hepatitis B Aurface Antigen
w (model) 5 mIU/mL 5−1000 mIU/mL 90 Au NP 50 nm/Ab1 Au NP 10 nm/Ab2 sw, enhanced DLS 2012801
serum 0.1 ng/mL 0.5−800 ng/mL 30 CPE/graphene/Au NP/ − (direct) blocked DPV 2012802
Nafion−Cys/Ab1
serum (human) 0.11 pg/mL 1−100 pg/mL 70 Fe3O4 NP/rAb1 PAA−Ru(bpy)32+/SiO2/ mag sep, sw, ECL 2015803
Nafion/pAb2
serum (human) 0.3 pg/mL 0.001−20 ng/mL ? glassy C/Au NP/Ab1 halloysite NT/MnO2−Pd sw, LSV 2016804
NP/Ab2
Hepatitis C Core Antigen
serum (human) 10 fg/mL 0.25−300 pg/mL 90 Au/graphitized C−MB/Au MWCNT/dsDNA−multi- sw, SWV 2013805
NP/Ab1 HRP/Ab2
Human Immunodeficiency
blood 98 pfu/mL 100 to 106 pfu/mL 70 polystyrene/PLL/Au NP/ − (direct) LSPR 2012806
Ab1
Influenza (Avian) Antigen(s)
serum (human) 0.4 pg/mL 1−100 pg/mL 60 glassy C, Au,Pd NP/Ab1 grox/Pt, CeO2 NP/ALP/ sw, DPV 2015807
Ab2
Influenza H1N1 and H5N1 Antigens (Avian)
w (model) 8.3 pM 25−500 pM 45 SPE−C/grox/MB/chit− − (direct) blocked DPV 2016808
protein A−Ab1
Influenza H7 Antigen
w (model) 1.6 pg/mL 1.6 to 80 Au/graphene−chit/Au graphene/Ag NP/pAb2 sw, LSV 2016809
1.6 × 104 pg/mL NP−mAb1
Influenza H7N9 Antigen
w (model) 0.8 pg/mL 8−60 pg/mL 80 glassy C/Au NP/SiO2− MWCNT/oligo- sw, 2015810
ADH/protein A/mAb1 DNazyme/hemin/MB/ electrocatalytic,
pAb2 amp
Orchid (Cymbidium Mosaic or Odontoglossum Ringspot)
plant extract 42 pg/mL 0.04−100 ng/mL 10 fiber/silicate/Au NR/Ab1 − (direct) LSPR 2014811
Rift Valley Fever, West Nile Antigen
serum (fetal 5 fg/mL 0.005−50 pg/mL 60 Fe3O4/SiO2/Ab1 Au NP/IR dye/Ab2 mag separ, SERS 2013812
bovine)
Vaccinia
fruit juice 4000 pfu/mL 104 to 107 pfu/mL 65 ITO/grox/mAb1 Ab2−ALP sw, amp 2015813

a scientific paper or on the Web can be markedly less optimal in lowest detection threshold, ideally at the level of a few molecules.
reality; moreover, the typical end user does not examine the However, it is also vital to stress the aspects that are seldom
principles of the sensing devices but rather focuses on the reliable brought to the limelight, and these prominently include the
performance, fast results, and economical use as his or her central rather long duration of the whole analytical process, starting from
criteria for success. the application of a sample and ending with the reading of the
Researchers involved in the field currently seem to concentrate result. The high sensitivity and very low measured concen-
upon achieving the best possible performance limits, namely, the trations are indeed nice indicators, but they should always be
10018 DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

compared with the practical needs and existing levels of analytes of magnetic nanoparticles. He then joined the group of Prof. Maria
in real samples. Hepel at the State Univeristy of New York (SUNY; Potsdam, NY) as a
We have summarized various strategies and approaches which postdoctoral researcher in physical electrochemistry. His current
can be used for the further development of nanoparticle-based research activities at Masaryk University relate to microfluidic platforms
immunosensors. It is clear that there are still many challenges, but for screening and selection methods in directed enzyme evolution.
one may consider some current issues making the repeatable Libuše Trnková is an Associated Professor in the Faculty of Science,
production of these devices harder: (i) heterogeneity existing at Masaryk University (Brno, Czech Republic). She graduated in physical
the nanoscale level, (ii) stable shape, size, and surface chemistry from the university, receiving her Ph.D. in 1983. She currently
modification of nanomaterials, (iii) high variability of such heads the Laboratories of Biophysical Chemistry and Electrochemistry
produced immunosensors depending on rarely optimized (LABIFEL). Her research interests are focused on the electrochemical
preparation methods and not completely defined properties of properties of biopolymers and their components in solutions, electrode/
the components, and (iv) general problems with immobilization electrolyte interfaces, electrochemical processes, and the development
of antibodies on solid-state surfaces. of biosensors. She is the founder of elimination voltammetry, a novel
In our view, three main requirements have to be taken into electrochemical method.
account with probe immobilization and modification by NPs
because none of the immobilization techniques and NPs used are Petr Skládal is an Associated Professor in the Department of
nowadays optimal for this purpose. First, the immobilization and Biochemistry, Faculty of Science, Masaryk University. He received his
modification processes need to be stable and involve well-defined Ph.D. in the field of amperometric biosensors in 1992. After completing
probes (Ab’s), second, the probes (Ab’s) have to remain research stays (1991, 1993) at the University of Florence, Italy, with
functional, and third, they have to be in appropriate orientation Marco Mascini, he continued to investigate biosensors at Masaryk
and configuration. From the physicochemical point of view, the University. He currently heads the Nanobiotechnology Laboratory at
perspective future can also be supported by the improved the Central European Institute of Technology in Brno. His research is
knowledge of involved transport properties, kinetics of focused on enzyme and immunochemical biosensors using electro-
interactions, reaction mechanism of the used systems, and last chemical and piezoelectric transducers, affinity kinetics with surface
but not least interactions between molecules of antibodies and plasmon resonance systems, and applications of atomic force
nanoparticles. microscopy in life sciences.

AUTHOR INFORMATION ABBREVIATIONS

Corresponding Author Ab antibody (mAb, monoclonal; pAb, polyclonal; rAb,
*E-mail: [email protected]. recombinant; Ab1, primary/capture; Ab2, secon-
ORCID dary/detection)
ABEI N-(4-aminobutyl)-N-ethylisoluminol
David Kovár:̌ 0000-0002-5550-6143 ADH alcohol dehydrogenase
Petr Skládal: 0000-0002-3868-5725 AEAPS [3-[(2-aminoethyl)amino]propyl]trimethoxysilane
Notes AFP α-fetal protein
The authors declare no competing financial interest. ALP alkaline phosphatase
amp amperometric
Biographies av avidin
Zdeněk Farka received his M.Sc. with honors in analytical biochemistry bpy 2,2′-bipyridine
at Masaryk University in 2014; his thesis was focused on the BSA bovine serum albumin
immunosensing of bacteria in bioaerosols. He is currently pursuing his bt biotin
Ph.D. at CEITEC, Masaryk University, Czech Republic, under the CEA carcinoembryonic antigen
supervision of Dr. Petr Skládal. His research interests include the chit chitosan
detection of bacteria and proteins via immunoanalytical techniques. He CL chemiluminescence
is developing label-free point-of-care sensors and examines the CNDs carbon nanodots
amplification of the immunosensor response by means of nanoparticles comp competitive immunoassay
and enzymes. In 2016, he spent an internship at the University of CTCs circulating tumor cells
Regensburg (Germany), working on applications of photon-upconvert- CV cyclic voltammetry
ing nanoparticles under the supervision of Dr. Gorris. DLS dynamic light scattering
DPV differential pulse voltammetry
Tomás ̌ Juřı ́k received his B.Sc. and M.Sc. in biochemistry from Masaryk ECL electrochemiluminescence
University while working in the biosensors laboratory of Dr. Petr EDC 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
Skládal. He is currently a Ph.D. student/researcher at CEITEC, Masaryk hydrochloride
University, Czech Republic. In 2014, he spent an internship at the EIS electrochemical impedance spectroscopy
Autonomous University of Barcelona, investigating magnetic separa- F fluorescence
tion-based immunosensors under the supervision of Dr. Pividori. His FET field-effect transistor
present research concentrates on nanostructured materials and surfaces FITC fluoresceine isothiocyanate
for the detection of clinical markers and microbes via electrochemical FRET fluorescence resonance energy transfer
techniques. GCE glassy carbon electrode
David Kovár ̌ received his Ph.D. in biomolecular chemistry in 2015 under GOD glucose oxidase
the supervision of Dr. Petr Skládal at Masaryk University, Czech GO graphene oxide
Republic. His Ph.D. studies were focused on immunospecific sensors rGO reduced graphene oxide
exploiting nanoparticles and nanostructures with the main applications HRP horseradish peroxidase
10019 DOI: 10.1021/acs.chemrev.7b00037
Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

ICP-MS inductively coupled plasma mass spectrometry (2) Vidarsson, G.; Dekkers, G.; Rispens, T. IgG subclasses and
Ig immunoglobulin allotypes: from structure to effector functions. Front. Immunol. 2014, 5,
ITO indium tin oxide 520.
LFIA lateral flow immunoassay (3) Kontermann, R.; Dübel, S. Antibody Engineering; Springer: Berlin,
lipo liposome 2001.
LSPR localized surface plasmon resonance (4) Hermanson, G. T. Bioconjugate Techniques, 3rd ed.; Elsevier:
Amsterdam, 2013.
mag magnetic
(5) Ahmad, Z. A.; Yeap, S. K.; Ali, A. M.; Ho, W. Y.; Alitheen, N. B. M.;
MB methylene blue Hamid, M. scFv Antibody: Principles and Clinical Application. Clin. Dev.
MEMS microelectromechanical system Immunol. 2012, 2012, 980250.
mtp microtitration plate (6) Jeong, H. J.; Kawamura, T.; Dong, J.; Ueda, H. Q-Bodies from
MWCNTs multiwalled carbon nanotubes Recombinant Single-Chain Fv Fragment with Better Yield and
NC nanocrystal Expanded Palette of Fluorophores. ACS Sensors 2016, 1, 88−94.
NF nanofiber (7) Choi, Y.; Deane, C. M. Predicting Antibody Complementarity
NHS N-hydroxysuccinimide Determining Region Structures without Classification. Mol. BioSyst.
NIR near-infrared 2011, 7, 3327.
NP nanoparticle (8) Gala, F. A.; Morrison, S. L. The Role of Constant Region
NT nanotube Carbohydrate in the Assembly and Secretion of Human IgD and IgA1. J.
NTA nitrilotriacetic acid Biol. Chem. 2002, 277, 29005−29011.
NW nanowire (9) Zheng, K.; Bantog, C.; Bayer, R. The Impact of Glycosylation on
PAA poly(acrylic acid) Monoclonal Antibody Conformation and Stability. mAbs 2011, 3, 568−
PABA poly(aminobenzoic acid) 576.
PAMAM poly(amidoamine) (10) Higel, F.; Seidl, A.; Sörgel, F.; Friess, W. N-Glycosylation
PB Prussian blue Heterogeneity and the Influence on Structure, Function and
Pharmacokinetics of Monoclonal Antibodies and Fc Fusion Proteins.
PBS phosphate-buffered saline
Eur. J. Pharm. Biopharm. 2016, 100, 94−100.
PC phthalocyanine (11) Hamers-Casterman, C.; Atarhouch, T.; Muyldermans, S.;
PCBAA poly(carboxybetaine acrylamide) Robinson, G.; Hammers, C.; Songa, E. B.; Bendahman, N.; Hammers,
PDDA poly(diallyldimethylammonium chloride) R. Naturally Occurring Antibodies Devoid of Light Chains. Nature
PANI poly(aniline) 1993, 363, 446−448.
PDOPA poly(dopamine) (12) Gibbs, W. W. Nanobodies. Sci. Am. 2005, 293, 78−83.
PEC photoelectrochemical conversion (13) Hassanzadeh-Ghassabeh, G.; Devoogdt, N.; De Pauw, P.; Vincke,
PEI poly(ethylenimine) C.; Muyldermans, S. Nanobodies and Their Potential Applications.
PGE pyrolytic graphite electrode Nanomedicine 2013, 8, 1013−1026.
PL photoluminescence (14) Juarez, K.; Dubberke, G.; Lugo, P.; Koch-Nolte, F.; Buck, F.;
PLL poly(lysine) Haag, F.; Licea, A. Monoclonal Antibodies for the Identification and
PMT photomultiplier tube Purification of vNAR Domains and IgNAR Immunoglobulins from the
POC point-of-care detection Horn Shark. Hybridoma 2011, 30, 323−329.
PS poly(styrene) (15) Feige, M. J.; Grawert, M. A.; Marcinowski, M.; Hennig, J.; Behnke,
PVA poly(vinyl alcohol) J.; Auslander, D.; Herold, E. M.; Peschek, J.; Castro, C. D.; Flajnik, M.;
QD quantum dot et al. The Structural Analysis of Shark IgNAR Antibodies Reveals
RCA rolling cycle amplification Evolutionary Principles of Immunoglobulins. Proc. Natl. Acad. Sci. U. S.
ROS reactive oxygen species A. 2014, 111, 8155−8160.
(16) Abbady, A. Q.; Al-Shemali, R.; Mir Assaad, J.; Murad, H.
sav streptavidin
Generation and Characterization of Nanobodies against rhGH
SCCA squamous cell carcinoma-associated antigen Expressed as sfGFP Fusion Protein. Gen. Comp. Endocrinol. 2014, 204,
scFv single-chain variable fragment 33−42.
sep separation (17) Galimidi, R. P.; Klein, J. S.; Politzer, M. S.; Bai, S.; Seaman, M. S.;
SERS surface-enhanced Raman spectroscopy Nussenzweig, M. C.; West, A. P., Jr.; Bjorkman, P. J. Intra-Spike
SPE screen-printed electrode Crosslinking Overcomes Antibody Evasion by HIV-1. Cell 2015, 160,
SPR surface plasmon resonance 433−446.
sw sandwich immunoassay (18) Tomita, M.; Tsumoto, K. Hybridoma Technologies for Antibody
SWCNTs single-walled carbon nanotubes Production. Immunotherapy 2011, 3, 371−380.
SWV square wave voltammetry (19) Hammers, C. M.; Stanley, J. R. Antibody Phage Display:
TMB 3,3′,5,5′-tetramethylbenzidine Technique and Applications. J. Invest. Dermatol. 2014, 134, 1−5.
UCNP up-converting nanoparticle (20) Sharma, S.; Byrne, H.; O’Kennedy, R. J. Antibodies and Antibody-
UV ultraviolet Derived Analytical Biosensors. Essays Biochem. 2016, 60, 9−18.
vis visible (21) Suo, Z.; Yang, X.; Avci, R.; Deliorman, M.; Rugheimer, P.; Pascual,
w water D. W.; Idzerda, Y. Antibody Selection for Immobilizing Living Bacteria.
Anal. Chem. 2009, 81, 7571−7578.
(22) Fenzl, C.; Hirsch, T.; Baeumner, A. J. Nanomaterials as Versatile
REFERENCES Tools for Signal Amplification in (Bio)analytical Applications. TrAC,
(1) Bengtén, E.; Wilson, M.; Miller, N.; Clem, L. W.; Pilström, L.; Trends Anal. Chem. 2016, 79, 306−316.
Warr, G. W. Immunoglobulin Isotypes: Structure, Function, and (23) Murphy, C. J.; Gole, A. M.; Stone, J. W.; Sisco, P. N.; Alkilany, A.
Genetics. In Origin and Evolution of the Vertebrate Immune System; Du M.; Goldsmith, E. C.; Baxter, S. C. Gold Nanoparticles in Biology:
Pasquier, L., Littman, G. W., Eds.; Current Topics in Microbiology and Beyond Toxicity to Cellular Imaging. Acc. Chem. Res. 2008, 41, 1721−
Immunology, Vol. 248; Springer: Berlin, 2000; p 189. 1730.

10020 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(24) Haes, A. J.; Van Duyne, R. P. A Unified View of Propagating and (44) Dinish, U. S.; Balasundaram, G.; Chang, Y.-T.; Olivo, M. Actively
Localized Surface Plasmon Resonance Biosensors. Anal. Bioanal. Chem. Targeted in Vivo Multiplex Detection of Intrinsic Cancer Biomarkers
2004, 379, 920−930. Using Biocompatible SERS Nanotags. Sci. Rep. 2015, 4, 4075.
(25) Turkevich, J.; Stevenson, P. C.; Hillier, J. A Study of the (45) Bondarenko, O.; Juganson, K.; Ivask, A.; Kasemets, K.; Mortimer,
Nucleation and Growth Processes in the Synthesis of Colloidal Gold. M.; Kahru, A. Toxicity of Ag, CuO and ZnO Nanoparticles to Selected
Discuss. Faraday Soc. 1951, 11, 55. Environmentally Relevant Test Organisms and Mammalian Cells in
(26) Frens, G. Controlled Nucleation for the Regulation of the Particle Vitro: A Critical Review. Arch. Toxicol. 2013, 87, 1181−1200.
Size in Monodisperse Gold Suspensions. Nature, Phys. Sci. 1973, 241, (46) Turner, A. P. F. Biosensors: Sense and Sensibility. Chem. Soc. Rev.
20−22. 2013, 42, 3184.
(27) Xia, Y.; Xiong, Y.; Lim, B.; Skrabalak, S. E. Shape-Controlled (47) Nooney, R.; Clifford, A.; LeGuevel, X.; Stranik, O.; McDonagh,
Synthesis of Metal Nanocrystals: Simple Chemistry Meets Complex C.; MacCraith, B. D. Enhancing the Analytical Performance of
Physics? Angew. Chem., Int. Ed. 2009, 48, 60−103. Immunoassays That Employ Metal-Enhanced Fluorescence. Anal.
(28) Baek, S. H.; Wark, A. W.; Lee, H. J. Dual Nanoparticle Amplified Bioanal. Chem. 2010, 396, 1127−1134.
Surface Plasmon Resonance Detection of Thrombin at Subattomolar (48) Liang, A.; Liu, Q.; Wen, G.; Jiang, Z. The Surface-Plasmon-
Concentrations. Anal. Chem. 2014, 86, 9824−9829. Resonance Effect of Nanogold/Silver and Its Analytical Applications.
(29) Nguyen, A. H.; Lee, J.; Il Choi, H.; Seok Kwak, H.; Jun Sim, S. TrAC, Trends Anal. Chem. 2012, 37, 32−47.
(49) Li, H.; Xu, D. Silver Nanoparticles as Labels for Applications in
Fabrication of Plasmon Length-Based Surface Enhanced Raman
Bioassays. TrAC, Trends Anal. Chem. 2014, 61, 67−73.
Scattering for Multiplex Detection on Microfluidic Device. Biosens.
(50) Fang, Y. Optical Absorption of Nanoscale Colloidal Silver:
Bioelectron. 2015, 70, 358−365. Aggregate Band and Adsorbate-Silver Surface Band. J. Chem. Phys. 1998,
(30) Rasheed, P. A.; Sandhyarani, N. A Highly Sensitive DNA Sensor
108, 4315−4318.
for Attomolar Detection of the BRCA1 Gene: Signal Amplification with (51) Austin, L. A.; Mackey, M. A.; Dreaden, E. C.; El-Sayed, M. A. The
Gold Nanoparticle Clusters. Analyst 2015, 140, 2713−2718. Optical, Photothermal, and Facile Surface Chemical Properties of Gold
(31) Chen, H.; Qi, F.; Zhou, H.; Jia, S.; Gao, Y.; Koh, K.; Yin, Y. and Silver Nanoparticles in Biodiagnostics, Therapy, and Drug Delivery.
Fe3O4@Au Nanoparticles as a Means of Signal Enhancement in Surface Arch. Toxicol. 2014, 88, 1391−1417.
Plasmon Resonance Spectroscopy for Thrombin Detection. Sens. (52) Szymanski, M.; Turner, A. P.F.; Porter, R. Electrochemical
Actuators, B 2015, 212, 505−511. Dissolution of Silver Nanoparticles and Its Application in Metal-
(32) Dreaden, E. C.; Alkilany, A. M.; Huang, X.; Murphy, C. J.; El- loimmunoassay. Electroanalysis 2010, 22, 191−198.
Sayed, M. A. The Golden Age: Gold Nanoparticles for Biomedicine. (53) Taton, T. A. Scanometric DNA Array Detection with Nano-
Chem. Soc. Rev. 2012, 41, 2740−2779. particle Probes. Science 2000, 289, 1757−1760.
(33) Jans, H.; Huo, Q. Gold Nanoparticle-Enabled Biological and (54) Yeh, C.-H.; Hung, C.-Y.; Chang, T. C.; Lin, H.-P.; Lin, Y.-C. An
Chemical Detection and Analysis. Chem. Soc. Rev. 2012, 41, 2849−2866. Immunoassay Using Antibody-Gold Nanoparticle Conjugate, Silver
(34) Mody, V.; Siwale, R.; Singh, A.; Mody, H. Introduction to Metallic Enhancement and Flatbed Scanner. Microfluid. Nanofluid. 2009, 6, 85−
Nanoparticles. J. Pharm. BioAllied Sci. 2010, 2, 282. 91.
(35) Lin, H.-Y.; Huang, C.-H.; Lu, S.-H.; Kuo, I.-T.; Chau, L.-K. Direct (55) Omidfar, K.; Khorsand, F.; Darziani Azizi, M. New Analytical
Detection of Orchid Viruses Using Nanorod-Based Fiber Optic Particle Applications of Gold Nanoparticles as Label in Antibody Based Sensors.
Plasmon Resonance Immunosensor. Biosens. Bioelectron. 2014, 51, 371− Biosens. Bioelectron. 2013, 43, 336−347.
378. (56) Díez, I.; Ras, R. H. A. Fluorescent Silver Nanoclusters. Nanoscale
(36) Inci, F.; Filippini, C.; Baday, M.; Ozen, M. O.; Calamak, S.; 2011, 3, 1963.
Durmus, N. G.; Wang, S.; Hanhauser, E.; Hobbs, K. S.; Juillard, F.; et al. (57) Singh, A. K.; Kanchanapally, R.; Fan, Z.; Senapati, D.; Ray, P. C.
Multitarget, Quantitative Nanoplasmonic Electrical Field-Enhanced Synthesis of Highly Fluorescent Water-Soluble Silver Nanoparticles for
Resonating Device (NE2RD) for Diagnostics. Proc. Natl. Acad. Sci. U. S. Selective Detection of Pb(ii) at the Parts per Quadrillion (PPQ) Level.
A. 2015, 112, E4354−E4363. Chem. Commun. 2012, 48, 9047.
(37) Wang, X.; Niessner, R.; Tang, D.; Knopp, D. Nanoparticle-Based (58) Ashenfelter, B. A.; Desireddy, A.; Yau, S. H.; Goodson, T., III;
Immunosensors and Immunoassays for Aflatoxins. Anal. Chim. Acta Bigioni, T. P. Fluorescence from Molecular Silver Nanoparticles. J. Phys.
2016, 912, 10−23. Chem. C 2015, 119, 20728−20734.
(38) Vilela, D.; González, M. C.; Escarpa, A. Sensing Colorimetric (59) Zheng, J.; Ding, Y.; Tian, B.; Wang, Z. L.; Zhuang, X. Luminescent
Approaches Based on Gold and Silver Nanoparticles Aggregation: and Raman Active Silver Nanoparticles with Polycrystalline Structure. J.
Chemical Creativity behind the Assay. A Review. Anal. Chim. Acta 2012, Am. Chem. Soc. 2008, 130, 10472−10473.
(60) Ulbrich, K.; Holá, K.; Šubr, V.; Bakandritsos, A.; Tuček, J.; Zbořil,
751, 24−43.
(39) Mayilo, S.; Kloster, M. A.; Wunderlich, M.; Lutich, A.; Klar, T. A.; R. Targeted Drug Delivery with Polymers and Magnetic Nanoparticles:
Covalent and Noncovalent Approaches, Release Control, and Clinical
Nichtl, A.; Kürzinger, K.; Stefani, F. D.; Feldmann, J. Long-Range
Studies. Chem. Rev. 2016, 116, 5338−5431.
Fluorescence Quenching by Gold Nanoparticles in a Sandwich
(61) Huang, J.; Li, Y.; Orza, A.; Lu, Q.; Guo, P.; Wang, L.; Yang, L.;
Immunoassay for Cardiac Troponin T. Nano Lett. 2009, 9, 4558−4563. Mao, H. Magnetic Nanoparticle Facilitated Drug Delivery for Cancer
(40) Vaisocherová-Lísalová, H.; Víšová, I.; Ermini, M. L.; Špringer, T.; Therapy with Targeted and Image-Guided Approaches. Adv. Funct.
Song, X. C.; Mrázek, J.; Lamačová, J.; Scott Lynn, N., Jr.; Šedivák, P.; Mater. 2016, 26, 3818−3836.
Homola, J. Low-Fouling Surface Plasmon Resonance Biosensor for (62) Obaidat, I.; Issa, B.; Haik, Y. Magnetic Properties of Magnetic
Multi-Step Detection of Foodborne Bacterial Pathogens in Complex Nanoparticles for Efficient Hyperthermia. Nanomaterials 2015, 5, 63−
Food Samples. Biosens. Bioelectron. 2016, 80, 84−90. 89.
(41) Liu, R.; Zhang, Y.; Zhang, S.; Qiu, W.; Gao, Y. Silver Enhancement (63) Salunkhe, A. B.; Khot, V. M.; Pawar, S. H. Magnetic Hyperthermia
of Gold Nanoparticles for Biosensing: From Qualitative to Quantitative. with Magnetic Nanoparticles: A Status Review. Curr. Top. Med. Chem.
Appl. Spectrosc. Rev. 2014, 49, 121−138. 2014, 14, 572−594.
(42) Wan, J.; Ai, J.; Zhang, Y.; Geng, X.; Gao, Q.; Cheng, Z. Signal-off (64) Shin, T.-H.; Choi, Y.; Kim, S.; Cheon, J. Recent Advances in
Impedimetric Immunosensor for the Detection of Escherichia Coli Magnetic Nanoparticle-Based Multi-Modal Imaging. Chem. Soc. Rev.
O157:H7. Sci. Rep. 2016, 6, 19806. 2015, 44, 4501−4516.
(43) Li, N.; Zhao, P.; Astruc, D. Anisotropic Gold Nanoparticles: (65) Busquets, M. A.; Estelrich, J.; Sánchez-Martín, M. J. Nanoparticles
Synthesis, Properties, Applications, and Toxicity. Angew. Chem., Int. Ed. in Magnetic Resonance Imaging: From Simple to Dual Contrast Agents.
2014, 53, 1756−1789. Int. J. Nanomed. 2015, 1727.

10021 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(66) Govan, J.; Gun’ko, Y. Recent Advances in the Application of (82) Maltez-da Costa, M.; de la Escosura-Muñiz, A.; Nogués, C.;
Magnetic Nanoparticles as a Support for Homogeneous Catalysts. Barrios, L.; Ibáñez, E.; Merkoçi, A. Simple Monitoring of Cancer Cells
Nanomaterials 2014, 4, 222−241. Using Nanoparticles. Nano Lett. 2012, 12, 4164−4171.
(67) Pratt, A. Environmental Applications of Magnetic Nanoparticles. (83) Brandão, D.; Liébana, S.; Campoy, S.; Alegret, S.; Isabel Pividori,
Nanomagnetism: Fundamentals and Applications; Elservier: Amsterdam, M. Immunomagnetic Separation of Salmonella with Tailored Magnetic
2014; p 259. Micro and Nanocarriers. A Comparative Study. Talanta 2015, 143,
(68) Barallat, J.; Olivé-Monllau, R.; Gonzalo-Ruiz, J.; Ramírez-Satorras, 198−204.
R.; Muñoz-Pascual, F. X.; Ortega, A. G.; Baldrich, E. Chronoampero- (84) Otieno, B. A.; Krause, C. E.; Latus, A.; Chikkaveeraiah, B. V.;
metric Magneto Immunosensor for Myeloperoxidase Detection in Faria, R. C.; Rusling, J. F. On-Line Protein Capture on Magnetic Beads
Human Plasma Based on a Magnetic Switch Produced by 3D Laser for Ultrasensitive Microfluidic Immunoassays of Cancer Biomarkers.
Sintering. Anal. Chem. 2013, 85, 9049−9056. Biosens. Bioelectron. 2014, 53, 268−274.
(69) Jodra, A.; Hervás, M.; López, M. Á .; Escarpa, A. Disposable (85) Demeritte, T.; Viraka Nellore, B. P.; Kanchanapally, R.; Sinha, S.
Electrochemical Magneto Immunosensor for Simultaneous Simplified S.; Pramanik, A.; Chavva, S. R.; Ray, P. C. Hybrid Graphene Oxide Based
Calibration and Determination of Ochratoxin A in Coffee Samples. Sens. Plasmonic-Magnetic Multifunctional Nanoplatform for Selective
Actuators, B 2015, 221, 777−783. Separation and Label-Free Identification of Alzheimer’s Disease
(70) Gan, N.; Du, X.; Cao, Y.; Hu, F.; Li, T.; Jiang, Q. An Ultrasensitive Biomarkers. ACS Appl. Mater. Interfaces 2015, 7, 13693−13700.
Electrochemical Immunosensor for HIV p24 Based on Fe3O4@SiO2 (86) Liang, W.; Li, Y.; Zhang, B.; Zhang, Z.; Chen, A.; Qi, D.; Yi, W.;
Nanomagnetic Probes and Nanogold Colloid-Labeled Enzyme− Hu, C. A Novel Microfluidic Immunoassay System Based on
Antibody Copolymer as Signal Tag. Materials 2013, 6, 1255−1269. Electrochemical Immunosensors: An Application for the Detection of
(71) Zhang, X.; Wang, H.; Yang, C.; Du, D.; Lin, Y. Preparation, NT-proBNP in Whole Blood. Biosens. Bioelectron. 2012, 31, 480−485.
Characterization of Fe3O4 at TiO2Magnetic Nanoparticles and Their (87) Tsai, H. Y.; Gao, B. Z.; Yang, S. F.; Li, C. S.; Fuh, C. B. Detection
Application for Immunoassay of Biomarker of Exposure to Organo- of Alpha-Fetoprotein in Magnetic Immunoassay of Thin Channels
phosphorus Pesticides. Biosens. Bioelectron. 2013, 41, 669−674. Using Biofunctional Nanoparticles. J. Nanopart. Res. 2014, 16, 2182.
(72) Baniukevic, J.; Hakki Boyaci, I.; Goktug Bozkurt, A.; Tamer, U.; (88) Luo, Y.; Asiri, A. M.; Zhang, X.; Yang, G.; Du, D.; Lin, Y. A
Ramanavicius, A.; Ramanaviciene, A. Magnetic Gold Nanoparticles in Magnetic Electrochemical Immunosensor for the Detection of
SERS-Based Sandwich Immunoassay for Antigen Detection by Well Phosphorylated p53 Based on Enzyme Functionalized Carbon Nano-
Oriented Antibodies. Biosens. Bioelectron. 2013, 43, 281−288. spheres with Signal Amplification. RSC Adv. 2014, 4, 54066−54071.
(73) Regiart, M.; Fernández-Baldo, M. A.; Spotorno, V. G.; Bertolino, (89) Cheng, P.; Huang, Z.-G.; Zhuang, Y.; Fang, L.-C.; Huang, H.;
F. A.; Raba, J. Ultra Sensitive Microfluidic Immunosensor for Deng, J.; Jiang, L.-L.; Yu, K.-K.; Li, Y.; Zheng, J.-S. A Novel
Determination of Clenbuterol in Bovine Hair Samples Using Electro- Regeneration-Free E. Coli O157:H7 Amperometric Immunosensor
deposited Gold Nanoparticles and Magnetic Micro Particles as Bio- Based on Functionalised Four-Layer Magnetic Nanoparticles. Sens.
Affinity Platform. Biosens. Bioelectron. 2013, 41, 211−217. Actuators, B 2014, 204, 561−567.
(74) Tang, J.; Hou, L.; Tang, D.; Zhou, J.; Wang, Z.; Li, J.; Chen, G. (90) Martín, M.; Salazar, P.; Jiménez, C.; Lecuona, M.; Ramos, M. J.;
Magneto-Controlled Electrochemical Immunoassay of Brevetoxin B in Ode, J.; Alcoba, J.; Roche, R.; Villalonga, R.; Campuzano, S.; et al. Rapid
Seafood Based on Guanine-Functionalized Graphene Nanoribbons. Legionella pneumophila Determination Based on a Disposable Core−
Biosens. Bioelectron. 2012, 38, 86−93. shell Fe3O4@poly(dopamine) Magnetic Nanoparticles Immunoplat-
(75) Ding, F. L.; Cheng, Q.; Li, J. F.; Jiang, F. E. Magnetic form. Anal. Chim. Acta 2015, 887, 51−58.
Nanospheres-Based Electrochemical Immunoassay Amplified by (91) Wang, Y.; Guo, Z.; Ma, H.; Li, Y.; Cao, W.; Du, B.; Wei, Q.
Hyperbranched Polymer Conjugate. Chin. J. Anal. Chem. 2012, 40, Magnetic Electrode-Based Label-Free Electrochemical Impedance
1514−1518. Spectroscopy Immunosensor for Sensitive Detection of Human
(76) Chen, Q.; Lin, J.; Gan, C.; Wang, Y.; Wang, D.; Xiong, Y.; Lai, W.; Malignant Melanoma Markers Using Gold Nanoparticles Function-
Li, Y.; Wang, M. A Sensitive Impedance Biosensor Based on alized Magnetic Graphene Sheets as Signal Amplifier. RSC Adv. 2014, 4,
Immunomagnetic Separation and Urease Catalysis for Rapid Detection 59106−59113.
of Listeria mnocytogenes Using an Immobilization-Free Interdigitated (92) Ji, L.; Yan, T.; Li, Y.; Gao, J.; Wang, Q.; Hu, L.; Wu, D.; Wei, Q.;
Array Microelectrode. Biosens. Bioelectron. 2015, 74, 504−511. Du, B. Preparation of Au-Polydopamine Functionalized Carbon
(77) Ojeda, I.; Moreno-Guzmán, M.; González-Cortés, A.; Yáñez- Encapsulated Fe3O4 Magnetic Nanocomposites and Their Application
Sedeño, P.; Pingarrón, J. M. Electrochemical Magnetoimmunosensor for Ultrasensitive Detection of Carcino-Embryonic Antigen. Sci. Rep.
for the Ultrasensitive Determination of Interleukin-6 in Saliva and Urine 2016, 6, 21017.
Using Poly-HRP Streptavidin Conjugates as Labels for Signal (93) Sharma, A.; Baral, D.; Rawat, K.; Solanki, P. R.; Bohidar, H. B.
Amplification. Anal. Bioanal. Chem. 2014, 406, 6363−6371. Biocompatible Capped Iron Oxide Nanoparticles for Vibrio cholerae
(78) de la Escosura-Muñiz, A.; Plichta, Z.; Horák, D.; Merkoçi, A. Detection. Nanotechnology 2015, 26, 175302.
Alzheimer′s Disease Biomarkers Detection in Human Samples by (94) Yu, S.; Wei, Q.; Du, B.; Wu, D.; Li, H.; Yan, L.; Ma, H.; Zhang, Y.
Efficient Capturing through Porous Magnetic Microspheres and Label-Free Immunosensor for the Detection of Kanamycin Using Ag@
Labelling with Electrocatalytic Gold Nanoparticles. Biosens. Bioelectron. Fe3O4 Nanoparticles and Thionine Mixed Graphene Sheet. Biosens.
2015, 67, 162−169. Bioelectron. 2013, 48, 224−229.
(79) Maltez-da Costa, M.; de la Escosura-Muñiz, A.; Nogués, C.; (95) Li, F.; Jiang, L.; Han, J.; Liu, Q.; Dong, Y.; Li, Y.; Wei, Q. A Label-
Barrios, L.; Ibáñez, E.; Merkoçi, A. Simple Monitoring of Cancer Cells Free Amperometric Immunosensor for the Detection of Carcinoem-
Using Nanoparticles. Nano Lett. 2012, 12, 4164−4171. bryonic Antigen Based on Novel Magnetic Carbon and Gold
(80) Yang, H.-W.; Lin, C.-W.; Hua, M.-Y.; Liao, S.-S.; Chen, Y.-T.; Nanocomposites. RSC Adv. 2015, 5, 19961−19969.
Chen, H.-C.; Weng, W.-H.; Chuang, C.-K.; Pang, S.-T.; Ma, C.-C. M. (96) Zhou, J.; Gan, N.; Li, T.; Zhou, H.; Li, X.; Cao, Y.; Wang, L.; Sang,
Combined Detection of Cancer Cells and a Tumor Biomarker Using an W.; Hu, F. Ultratrace Detection of C-Reactive Protein by a Piezoelectric
Immunomagnetic Sensor for the Improvement of Prostate-Cancer Immunosensor Based on Fe3O4@SiO2 Magnetic Capture Nanoprobes
Diagnosis. Adv. Mater. 2014, 26, 3662−3666. and HRP-Antibody Co-Immobilized Nano Gold as Signal Tags. Sens.
(81) Wu, Z.; Zhou, C.-H.; Chen, J.-J.; Xiong, C.; Chen, Z.; Pang, D.- Actuators, B 2013, 178, 494−500.
W.; Zhang, Z.-L. Bifunctional Magnetic Nanobeads for Sensitive (97) Zhang, X.; Ren, X.; Cao, W.; Li, Y.; Du, B.; Wei, Q. Simultaneous
Detection of Avian Influenza A (H7N9) Virus Based on Immuno- Electrochemical Immunosensor Based on Water-Soluble Polythiophene
magnetic Separation and Enzyme-Induced Metallization. Biosens. Derivative and Functionalized Magnetic Material. Anal. Chim. Acta
Bioelectron. 2015, 68, 586−592. 2014, 845, 85−91.

10022 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(98) Orlov, A. V.; Nikitin, M. P.; Bragina, V. A.; Znoyko, S. L.; Zaikina, (117) Baughman, R. H. Carbon Nanotubes–the Route Toward
M. N.; Ksenevich, T. I.; Gorshkov, B. G.; Nikitin, P. I. A New Real-Time Applications. Science 2002, 297, 787−792.
Method for Investigation of Affinity Properties and Binding Kinetics of (118) Jiang, L.; Han, J.; Li, F.; Gao, J.; Li, Y.; Dong, Y.; Wei, Q. A
Magnetic Nanoparticles. J. Magn. Magn. Mater. 2015, 380, 231−235. Sandwich-Type Electrochemical Immunosensor Based on Multiple
(99) Garibo, D.; Campbell, K.; Casanova, A.; de la Iglesia, P.; Signal Amplification for α-Fetoprotein Labeled by Platinum Hybrid
Fernández-Tejedor, M.; Diogène, J.; Elliott, C. T.; Campàs, M. SPR Multiwalled Carbon Nanotubes Adhered Copper Oxide. Electrochim.
Immunosensor for the Detection of Okadaic Acid in Mussels Using Acta 2015, 160, 7−14.
Magnetic Particles as Antibody Carriers. Sens. Actuators, B 2014, 190, (119) Kumar, S.; Ahlawat, W.; Kumar, R.; Dilbaghi, N. Graphene,
822−828. Carbon Nanotubes, Zinc Oxide and Gold as Elite Nanomaterials for
(100) Liang, R.-P.; Yao, G.-H.; Fan, L.-X.; Qiu, J.-D. Magnetic Fabrication of Biosensors for Healthcare. Biosens. Bioelectron. 2015, 70,
Fe3O4@Au Composite-Enhanced Surface Plasmon Resonance for 498−503.
Ultrasensitive Detection of Magnetic Nanoparticle-Enriched α- (120) Chang, Y.-T.; Huang, J.-H.; Tu, M.-C.; Chang, P.; Yew, T.-R.
Fetoprotein. Anal. Chim. Acta 2012, 737, 22−28. Flexible Direct-Growth CNT Biosensors. Biosens. Bioelectron. 2013, 41,
(101) Guo, X. Fe3O4@Au Nanoparticles Enhanced Surface Plasmon 898−902.
Resonance for Ultrasensitive Immunoassay. Sens. Actuators, B 2014, 205, (121) Huang, J.-H.; Hong, Y.-J.; Chang, Y.-T.; Chang, P.; Yew, T.-R.
276−280. Carbon Nanotubes for Highly Sensitive Colorimetric Immunoassay
(102) Ge, M.; Wei, C.; Xu, M.; Fang, C.; Yuan, Y.; Gu, R.; Yao, J. Ultra- Biosensor. J. Mater. Chem. B 2013, 1, 5389.
Sensitive Magnetic Immunoassay of HE4 Based on Surface Enhanced (122) Tu, M.-C.; Chen, H.-Y.; Wang, Y.; Moochhala, S. M.; Alagappan,
Raman Spectroscopy. Anal. Methods 2015, 7, 6489−6495. P.; Liedberg, B. Immunosensor Based on Carbon Nanotube/manganese
(103) Ondera, T. J.; Hamme, A. T., II Magnetic-Optical Nanohybrids Dioxide Electrochemical Tags. Anal. Chim. Acta 2015, 853, 228−233.
for Targeted Detection, Separation, and Photothermal Ablation of (123) Balasubramanian, K.; Burghard, M. Electrochemically Function-
Drug-Resistant Pathogens. Analyst 2015, 140, 7902−7911. alized Carbon Nanotubes for Device Applications. J. Mater. Chem. 2008,
(104) Qiu, Y.; Deng, D.; Deng, Q.; Wu, P.; Zhang, H.; Cai, C. Synthesis 18, 3071.
of Magnetic Fe3O4−Au Hybrids for Sensitive SERS Detection of Cancer (124) Feng, T.; Wang, Y.; Qiao, X. Recent Advances of Carbon
Cells at Low Abundance. J. Mater. Chem. B 2015, 3, 4487−4495. Nanotubes-Based Electrochemical Immunosensors for the Detection of
(105) Gao, J.; Guo, Z.; Yu, S.; Su, F.; Ma, H.; Du, B.; Wei, Q.; Pang, X. Protein Cancer Biomarkers. Electroanalysis 2017, 29, 662−675.
A Novel Controlled Release System-Based Homogeneous Immuno- (125) Lim, W. Q.; Gao, Z. Metal Oxide Nanoparticles in Electro-
assay Protocol for SCCA Using Magnetic Mesoporous Fe3O4 as a analysis. Electroanalysis 2015, 27, 2074−2090.
Nanocontainer and Aminated Polystyrene Microspheres as a Molecular (126) Sánchez-Tirado, E.; Salvo, C.; González-Cortés, A.; Yáñez-
Gate. Biosens. Bioelectron. 2015, 66, 141−145. Sedeño, P.; Langa, F.; Pingarrón, J. M. Electrochemical Immunosensor
(106) Zhang, B.; Cui, Y.; Liu, B.; Chen, H.; Chen, G.; Tang, D. for Simultaneous Determination of Interleukin-1 Beta and Tumor
Cadmium Ion-Doped Magnetic Poly(styrene-Acrylic Acid) Nano-
Necrosis Factor Alpha in Serum and Saliva Using Dual Screen Printed
spheres for Sensitive Electrochemical Immunoassay. Biosens. Bioelectron.
Electrodes Modified with Functionalized Double−walled Carbon
2012, 35, 461−465.
Nanotubes. Anal. Chim. Acta 2017, 959, 66−73.
(107) Akter, R.; Kyun Rhee, C.; Aminur Rahman, M. Sensitivity
(127) Green, A. A.; Hersam, M. C. Properties and Application of
Enhancement of an Electrochemical Immunosensor through the
Double-Walled Carbon Nanotubes Sorted by Outer-Wall Electronic
Electrocatalysis of Magnetic Bead-Supported Non-Enzymatic Labels.
Type. ACS Nano 2011, 5, 1459−1467.
Biosens. Bioelectron. 2014, 54, 351−357.
(108) Wu, D.; Ma, H.; Zhang, Y.; Jia, H.; Yan, T.; Wei, Q. Corallite-like (128) Moore, K. E.; Flavel, B. S.; Ellis, A. V.; Shapter, J. G. Comparison
Magnetic Fe3O4@MnO2@Pt Nanocomposites as Multiple Signal of Double-Walled with Single-Walled Carbon Nanotube Electrodes by
Amplifiers for the Detection of Carcinoembryonic Antigen. ACS Appl. Electrochemistry. Carbon 2011, 49, 2639−2647.
Mater. Interfaces 2015, 7, 18786−18793. (129) Liu, N.; Nie, D.; Tan, Y.; Zhao, Z.; Liao, Y.; Wang, H.; Sun, C.;
(109) Dai, H.; Gong, L.; Zhang, S.; Xu, G.; Li, Y.; Hong, Z.; Lin, Y. All- Wu, A. An Ultrasensitive Amperometric Immunosensor for Zearale-
in-One Bioprobe Devised with Hierarchical-Ordered Magnetic nones Based on Oriented Antibody Immobilization on a Glassy Carbon
NiCo2O4 Superstructure for Ultrasensitive Dual-Readout Immunosen- Electrode Modified with MWCNTs and AuPt Nanoparticles. Micro-
sor for Logic Diagnosis of Tumor Marker. Biosens. Bioelectron. 2016, 77, chim. Acta 2017, 184, 147−153.
928−935. (130) Novoselov, K. S. Electric Field Effect in Atomically Thin Carbon
(110) Orlov, A. V.; Khodakova, J. A.; Nikitin, M. P.; Shepelyakovskaya, Films. Science 2004, 306, 666−669.
A. O.; Brovko, F. A.; Laman, A. G.; Grishin, E. V.; Nikitin, P. I. Magnetic (131) Pumera, M. Graphene in Biosensing. Mater. Today 2011, 14,
Immunoassay for Detection of Staphylococcal Toxins in Complex 308−315.
Media. Anal. Chem. 2013, 85, 1154−1163. (132) Wang, Z.; Dai, Z. Carbon Nanomaterial-Based Electrochemical
(111) Iijima, S. Helical Microtubules of Graphitic Carbon. Nature Biosensors: An Overview. Nanoscale 2015, 7, 6420−6431.
1991, 354, 56−58. (133) Loh, K. P.; Bao, Q.; Eda, G.; Chhowalla, M. Graphene Oxide as a
(112) Wilder, J. W. G.; Venema, L. C.; Rinzler, A. G.; Smalley, R. E.; Chemically Tunable Platform for Optical Applications. Nat. Chem.
Dekker, C. Electronic Structure of Atomically Resolved Carbon 2010, 2, 1015−1024.
Nanotubes. Nature 1998, 391, 59−62. (134) Hummers, W. S.; Offeman, R. E. Preparation of Graphitic Oxide.
(113) Ramnani, P.; Saucedo, N. M.; Mulchandani, A. Carbon J. Am. Chem. Soc. 1958, 80, 1339−1339.
Nanomaterial-Based Electrochemical Biosensors for Label-Free Sensing (135) Stankovich, S.; Dikin, D. A.; Piner, R. D.; Kohlhaas, K. A.;
of Environmental Pollutants. Chemosphere 2016, 143, 85−98. Kleinhammes, A.; Jia, Y.; Wu, Y.; Nguyen, S. T.; Ruoff, R. S. Synthesis of
(114) Kong, J.; Soh, H. T.; Cassell, A. M.; Quate, C. F.; Dai, H. Graphene-Based Nanosheets via Chemical Reduction of Exfoliated
Synthesis of Individual Single-Walled Carbon Nanotubes on Patterned Graphite Oxide. Carbon 2007, 45, 1558−1565.
Silicon Wafers. Nature 1998, 395, 878−881. (136) McAllister, M. J.; Li, J.-L.; Adamson, D. H.; Schniepp, H. C.;
(115) Guo, T.; Nikolaev, P.; Thess, A.; Colbert, D. T.; Smalley, R. E. Abdala, A. A.; Liu, J.; Herrera-Alonso, M.; Milius, D. L.; Car, R.;
Catalytic Growth of Single-Walled Manotubes by Laser Vaporization. Prud’homme, R. K.; Aksay, I. A. Single Sheet Functionalized Graphene
Chem. Phys. Lett. 1995, 243, 49−54. by Oxidation and Thermal Expansion of Graphite. Chem. Mater. 2007,
(116) Oliveira, O. N.; Iost, R. M.; Siqueira, J. R.; Crespilho, F. N.; 19, 4396−4404.
Caseli, L. Nanomaterials for Diagnosis: Challenges and Applications in (137) Zhou, M.; Zhai, Y.; Dong, S. Electrochemical Sensing and
Smart Devices Based on Molecular Recognition. ACS Appl. Mater. Biosensing Platform Based on Chemically Reduced Graphene Oxide.
Interfaces 2014, 6, 14745−14766. Anal. Chem. 2009, 81, 5603−5613.

10023 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(138) Mattevi, C.; Kim, H.; Chhowalla, M. A Review of Chemical (159) Burda, C.; Chen, X.; Narayanan, R.; El-Sayed, M. A. Chemistry
Vapour Deposition of Graphene on Copper. J. Mater. Chem. 2011, 21, and Properties of Nanocrystals of Different Shapes. Chem. Rev. 2005,
3324−3334. 105, 1025−1102.
(139) Han, J.; Ma, J.; Ma, Z. One-Step Synthesis of Graphene oxide− (160) Resch-Genger, U.; Grabolle, M.; Cavaliere-Jaricot, S.; Nitschke,
thionine−Au Nanocomposites and Its Application for Electrochemical R.; Nann, T. Quantum Dots Versus Organic Dyes as Fluorescent Labels.
Immunosensing. Biosens. Bioelectron. 2013, 47, 243−247. Nat. Methods 2008, 5, 763−775.
(140) Han, J.; Ma, J.; Ma, Z. One-Step Synthesis of Graphene oxide− (161) Petryayeva, E.; Algar, W. R.; Medintz, I. L. Quantum Dots in
thionine−Au Nanocomposites and Its Application for Electrochemical Bioanalysis: A Review of Applications Across Various Platforms for
Immunosensing. Biosens. Bioelectron. 2013, 47, 243−247. Fluorescence Spectroscopy and Imaging. Appl. Spectrosc. 2013, 67, 215−
(141) Hou, L.; Cui, Y.; Xu, M.; Gao, Z.; Huang, J.; Tang, D. Graphene 252.
Oxide-Labeled Sandwich-Type Impedimetric Immunoassay with (162) Han, M.; Gao, X.; Su, J. Z.; Nie, S. Nat. Biotechnol. 2001, 19,
Sensitive Enhancement Based on Enzymatic 4-Chloro-1-Naphthol 631−635.
Oxidation. Biosens. Bioelectron. 2013, 47, 149−156. (163) Peng, Z. A.; Peng, X. Formation of High-Quality CdTe, CdSe,
(142) Lee, J. S.; Joung, H.-A.; Kim, M.-G.; Park, C. B. Graphene-Based and CdS Nanocrystals Using CdO as Precursor. J. Am. Chem. Soc. 2001,
Chemiluminescence Resonance Energy Transfer for Homogeneous 123, 183−184.
Immunoassay. ACS Nano 2012, 6, 2978−2983. (164) Medintz, I. L.; Uyeda, H. T.; Goldman, E. R.; Mattoussi, H.
(143) Liu, Y.; Luo, M.; Xiang, X.; Chen, C.; Ji, X.; Chen, L.; He, Z. A Quantum Dot Bioconjugates for Imaging, Labelling and Sensing. Nat.
Graphene Oxide and Exonuclease-Aided Amplification Immuno-Sensor Mater. 2005, 4, 435−446.
for Antigen Detection. Chem. Commun. 2014, 50, 2679. (165) Yu, W. W.; Chang, E.; Drezek, R.; Colvin, V. L. Water-Soluble
(144) Yáñez-Sedeño, P.; González-Cortés, A.; Agüí, L.; Pingarrón, J. Quantum Dots for Biomedical Applications. Biochem. Biophys. Res.
M. Uncommon Carbon Nanostructures for the Preparation of Commun. 2006, 348, 781−786.
Electrochemical Immunosensors. Electroanalysis 2016, 28, 1679−1691. (166) Lees, E. E.; Nguyen, T.-L.; Clayton, A. H. A.; Mulvaney, P. The
(145) Pilehvar, S.; De Wael, K. Recent Advances in Electrochemical Preparation of Colloidally Stable, Water-Soluble, Biocompatible,
Biosensors Based on Fullerene-C60 Nano-Structured Platforms. Semiconductor Nanocrystals with a Small Hydrodynamic Diameter.
Biosensors 2015, 5, 712−735. ACS Nano 2009, 3, 1121−1128.
(146) Afreen, S.; Muthoosamy, K.; Manickam, S.; Hashim, U. (167) Speranskaya, E. S.; Beloglazova, N. V.; Lenain, P.; De Saeger, S.;
Functionalized Fullerene (C60) as a Potential Nanomediator in the Wang, Z.; Zhang, S.; Hens, Z.; Knopp, D.; Niessner, R.; Potapkin, D. V.;
Fabrication of Highly Sensitive Biosensors. Biosens. Bioelectron. 2015, 63, et al. Polymer-Coated Fluorescent CdSe-Based Quantum Dots for
354−364. Application in Immunoassay. Biosens. Bioelectron. 2014, 53, 225−231.
(147) Han, J.; Zhuo, Y.; Chai, Y.-Q.; Xiang, Y.; Yuan, R. New Type of (168) Sun, B.; Chen, L.; Xu, Y.; Liu, M.; Yin, H.; Ai, S. Ultrasensitive
Redox Nanoprobe: C60-Based Nanomaterial and Its Application in Photoelectrochemical Immunoassay of Indole-3-Acetic Acid Based on
Electrochemical Immunoassay for Doping Detection. Anal. Chem. 2015, the MPA Modified CdS/RGO Nanocomposites Decorated ITO
87, 1669−1675.
Electrode. Biosens. Bioelectron. 2014, 51, 164−169.
(148) Shi, L.; Liu, X.; Niu, W.; Li, H.; Han, S.; Chen, J.; Xu, G.
(169) Fan, D.; Wu, D.; Cui, J.; Chen, Y.; Ma, H.; Liu, Y.; Wei, Q.; Du, B.
Hydrogen Peroxide Biosensor Based on Direct Electrochemistry of
An Ultrasensitive Label-Free Immunosensor Based on CdS Sensitized
Soybean Peroxidase Immobilized on Single-Walled Carbon Nanohorn
Fe−TiO2 with High Visible-Light Photoelectrochemical Activity.
Modified Electrode. Biosens. Bioelectron. 2009, 24, 1159−1163.
Biosens. Bioelectron. 2015, 74, 843−848.
(149) Liu, F.; Xiang, G.; Yuan, R.; Chen, X.; Luo, F.; Jiang, D.; Huang,
(170) Gao, X.; Cui, Y.; Levenson, R. M.; Chung, L. W. K.; Nie, S. In
S.; Li, Y.; Pu, X. Procalcitonin Sensitive Detection Based on Graphene−
Vivo Cancer Targeting and Imaging with Semiconductor Quantum
gold Nanocomposite Film Sensor Platform and Single-Walled Carbon
Nanohorns/hollow Pt Chains Complex as Signal Tags. Biosens. Dots. Nat. Biotechnol. 2004, 22, 969−976.
(171) Rakovich, T. Y.; Mahfoud, O. K.; Mohamed, B. M.; Prina-Mello,
Bioelectron. 2014, 60, 210−217.
(150) Wang, Y.; Hu, A. Carbon Quantum Dots: Synthesis, Properties A.; Crosbie-Staunton, K.; Van Den Broeck, T.; De Kimpe, L.;
and Applications. J. Mater. Chem. C 2014, 2, 6921. Sukhanova, A.; Baty, D.; Rakovich, A.; et al. Highly Sensitive Single
(151) Xu, X.; Ray, R.; Gu, Y.; Ploehn, H. J.; Gearheart, L.; Raker, K.; Domain Antibody−Quantum Dot Conjugates for Detection of HER2
Scrivens, W. A. Electrophoretic Analysis and Purification of Fluorescent Biomarker in Lung and Breast Cancer Cells. ACS Nano 2014, 8, 5682−
Single-Walled Carbon Nanotube Fragments. J. Am. Chem. Soc. 2004, 5695.
126, 12736−12737. (172) Hu, J.; Zhang, Z.-L.; Wen, C.-Y.; Tang, M.; Wu, L.-L.; Liu, C.;
(152) Lim, S. Y.; Shen, W.; Gao, Z. Carbon Quantum Dots and Their Zhu, L.; Pang, D.-W. Sensitive and Quantitative Detection of C-
Applications. Chem. Soc. Rev. 2015, 44, 362−381. Reaction Protein Based on Immunofluorescent Nanospheres Coupled
(153) Zou, F.; Zhou, H.; Tan, T. V.; Kim, J.; Koh, K.; Lee, J. Dual- with Lateral Flow Test Strip. Anal. Chem. 2016, 88, 6577−6584.
Mode SERS-Fluorescence Immunoassay Using Graphene Quantum (173) Zhang, X.; Tan, X.; Zhang, B.; Miao, W.; Zou, G. Spectrum-
Dot Labeling on One-Dimensional Aligned Magnetoplasmonic Nano- Based Electrochemiluminescent Immunoassay with Ternary CdZnSe
particles. ACS Appl. Mater. Interfaces 2015, 7, 12168−12175. Nanocrystals as Labels. Anal. Chem. 2016, 88, 6947−6953.
(154) Wang, Z.; Dai, Z. Carbon Nanomaterial-Based Electrochemical (174) Qiu, Y.; Wen, Q.; Zhang, L.; Yang, P. Label-Free and Dynamic
Biosensors: An Overview. Nanoscale 2015, 7, 6420−6431. Evaluation of Cell-Surface Epidermal Growth Factor Receptor
(155) Zhang, X.; Du, X. Carbon Nanodot-Decorated Ag@ Expression via an Electrochemiluminescence Cytosensor. Talanta
SiO2Nanoparticles for Fluorescence and Surface-Enhanced Raman 2016, 150, 286−295.
Scattering Immunoassays. ACS Appl. Mater. Interfaces 2016, 8, 1033− (175) Zhang, X.; Zhang, B.; Miao, W.; Zou, G. Molecular-Counting-
1040. Free and Electrochemiluminescent Single-Molecule Immunoassay with
(156) Liu, F.; Ge, S.; Su, M.; Song, X.; Yan, M.; Yu, J. Dual-Stabilizers-Capped CdSe Nanocrystals as Labels. Anal. Chem.
Electrochemiluminescence Device for in-Situ and Accurate Determi- 2016, 88, 5482−5488.
nation of CA153 at the MCF-7 Cell Surface Based on Graphene (176) Tasso, M.; Singh, M. K.; Giovanelli, E.; Fragola, A.; Loriette, V.;
Quantum Dots Loaded Surface Villous Au Nanocage. Biosens. Regairaz, M.; Dautry, F.; Treussart, F.; Lenkei, Z.; Lequeux, N.; et al.
Bioelectron. 2015, 71, 286−293. Oriented Bioconjugation of Unmodified Antibodies to Quantum Dots
(157) Alivisatos, P. The Use of Nanocrystals in Biological Detection. Capped with Copolymeric Ligands as Versatile Cellular Imaging Tools.
Nat. Biotechnol. 2004, 22, 47−52. ACS Appl. Mater. Interfaces 2015, 7, 26904−26913.
(158) Wu, P.; Yan, X.-P. Doped Quantum Dots for Chemo/biosensing (177) Haase, M.; Schäfer, H. Upconverting Nanoparticles. Angew.
and Bioimaging. Chem. Soc. Rev. 2013, 42, 5489. Chem., Int. Ed. 2011, 50, 5808−5829.

10024 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(178) Auzel, F. Upconversion and Anti-Stokes Processes with f and d Ag2S@silica Core−Shell Nanospheres. RSC Adv. 2014, 4, 62399−
Ions in Solids. Chem. Rev. 2004, 104, 139−174. 62403.
(179) Chamarro, M. A.; Cases, R. Energy up-Conversion in (Yb, Ho) (197) Hu, R.-R.; Yin, Z.-Z.; Zeng, Y.-B.; Zhang, J.; Liu, H.-Q.; Shao, Y.;
and (Yb, Tm) Doped Fluorohafnate Glasses. J. Lumin. 1988, 42, 267− Ren, S.-B.; Li, L. A Novel Biosensor for Escherichia Coli O157:H7 Based
274. on Fluorescein-Releasable Biolabels. Biosens. Bioelectron. 2016, 78, 31−
(180) Li, X.; Zhang, F.; Zhao, D. Lab on Upconversion Nanoparticles: 36.
Optical Properties and Applications Engineering via Designed (198) Wei, W.; Wei, M.; Liu, S. Silica Nanoparticles as a Carrier for
Nanostructure. Chem. Soc. Rev. 2015, 44, 1346−1378. Signal Amplification. Reviews in Analytical Chemistry; De Gruyter: Berlin,
(181) Sedlmeier, A.; Gorris, H. H. Surface Modification and 2012; Vol. 31.
Characterization of Photon-Upconverting Nanoparticles for Bioanalyt- (199) Xie, Q.; Weng, X.; Lu, L.; Lin, Z.; Xu, X.; Fu, C. A Sensitive
ical Applications. Chem. Soc. Rev. 2015, 44, 1526−1560. Fluorescent Sensor for Quantification of Alpha-Fetoprotein Based on
(182) Zijlmans, H. J. M. A. A.; Bonnet, J.; Burton, J.; Kardos, K.; Vail, Immunosorbent Assay and Click Chemistry. Biosens. Bioelectron. 2016,
T.; Niedbala, R. S.; Tanke, H. J. Detection of Cell and Tissue Surface 77, 46−50.
Antigens Using Up-Converting Phosphors: A New Reporter Technol- (200) Bhatnagar, D.; Kumar, V.; Kumar, A.; Kaur, I. Graphene
ogy. Anal. Biochem. 1999, 267, 30−36. Quantum Dots FRET Based Sensor for Early Detection of Heart Attack
(183) Van de Rijke, F.; Zijlmans, H.; Li, S.; Vail, T.; Raap, A. K.; in Human. Biosens. Bioelectron. 2016, 79, 495−499.
Niedbala, R. S.; Tanke, H. J. Up-Converting Phosphor Reporters for (201) Huang, X.; Zhan, S.; Xu, H.; Meng, X.; Xiong, Y.; Chen, X.
Nucleic Acid Microarrays. Nat. Biotechnol. 2001, 19, 273−276. Ultrasensitive Fluorescence Immunoassay for Detection of Ochratoxin
(184) Päkkilä, H.; Ylihärsilä, M.; Lahtinen, S.; Hattara, L.; Salminen, A Using Catalase-Mediated Fluorescence Quenching of CdTe QDs.
N.; Arppe, R.; Lastusaari, M.; Saviranta, P.; Soukka, T. Quantitative Nanoscale 2016, 8, 9390−9397.
Multianalyte Microarray Immunoassay Utilizing Upconverting Phos- (202) Cywinski, P. J.; Hammann, T.; Hühn, D.; Parak, W. J.;
phor Technology. Anal. Chem. 2012, 84, 8628−8634. Hildebrandt, N.; Löhmannsröben, H.-G. Europium-Quantum Dot
(185) Huang, P.; Zheng, W.; Zhou, S.; Tu, D.; Chen, Z.; Zhu, H.; Li, R.; Nanobioconjugates as Luminescent Probes for Time-Gated Biosensing.
Ma, E.; Huang, M.; Chen, X. Lanthanide-Doped LiLuF4 Upconversion J. Biomed. Opt. 2014, 19, 101506.
Nanoprobes for the Detection of Disease Biomarkers. Angew. Chem., Int. (203) Hildebrandt, N.; Wegner, K. D.; Algar, W. R. Luminescent
Ed. 2014, 53, 1252−1257. Terbium Complexes: Superior Förster Resonance Energy Transfer
(186) Sirkka, N.; Lyytikäinen, A.; Savukoski, T.; Soukka, T. Donors for Flexible and Sensitive Multiplexed Biosensing. Coord. Chem.
Upconverting Nanophosphors as Reporters in a Highly Sensitive Rev. 2014, 273−274, 125−138.
Heterogeneous Immunoassay for Cardiac Troponin I. Anal. Chim. Acta (204) Jo, E.-J.; Mun, H.; Kim, M.-G. Homogeneous Immunosensor
2016, 925, 82−87. Based on Luminescence Resonance Energy Transfer for Glycated
(187) Wu, S.; Duan, N.; Zhu, C.; Ma, X.; Wang, M.; Wang, Z. Magnetic Hemoglobin Detection Using Upconversion Nanoparticles. Anal. Chem.
Nanobead-Based Immunoassay for the Simultaneous Detection of 2016, 88, 2742−2746.
Aflatoxin B1 and Ochratoxin A Using Upconversion Nanoparticles as (205) Tao, L.; Zhang, C.; Zhang, J.; Sun, Y.; Li, X.; Yan, K.; Jin, B.;
Multicolor Labels. Biosens. Bioelectron. 2011, 30, 35−42. Zhang, Z.; Yang, K. Sensitive Chemiluminescence Immunoassay for
(188) Arppe, R.; Mattsson, L.; Korpi, K.; Blom, S.; Wang, Q.; Staphylococcal Enterotoxin C1 Based on the Use of Dye-Encapsulated
Riuttamäki, T.; Soukka, T. Homogeneous Assay for Whole Blood Folate Mesoporous Silica Nanoparticles. Microchim. Acta 2016, 183, 2163−
Using Photon Upconversion. Anal. Chem. 2015, 87, 1782−1788. 2168.
(189) Corstjens, P. L. A. M.; van Lieshout, L.; Zuiderwijk, M.; Kornelis, (206) Richter, M. M. Electrochemiluminescence (ECL). Chem. Rev.
D.; Tanke, H. J.; Deelder, A. M.; van Dam, G. J. Up-Converting 2004, 104, 3003−3036.
Phosphor Technology-Based Lateral Flow Assay for Detection of (207) Li, L.; Chen, Y.; Zhu, J.-J. Recent Advances in Electro-
Schistosoma Circulating Anodic Antigen in Serum. J. Clin. Microbiol. chemiluminescence Analysis. Anal. Chem. 2017, 89, 358−371.
2008, 46, 171−176. (208) Deng, S.; Ju, H. Electrogenerated Chemiluminescence of
(190) Hlavácě k, A.; Farka, Z.; Hübner, M.; Horňaḱ ová, V.; Němeček, Nanomaterials for Bioanalysis. Analyst 2013, 138, 43−61.
D.; Niessner, R.; Skládal, P.; Knopp, D.; Gorris, H. H. Competitive (209) Zhang, X.; Zhang, B.; Miao, W.; Zou, G. Molecular-Counting-
Upconversion-Linked Immunosorbent Assay for the Sensitive Detec- Free and Electrochemiluminescent Single-Molecule Immunoassay with
tion of Diclofenac. Anal. Chem. 2016, 88, 6011−6017. Dual-Stabilizers-Capped CdSe Nanocrystals as Labels. Anal. Chem.
(191) Li, C.; Zuo, J.; Li, Q.; Chang, Y.; Zhang, Y.; Tu, L.; Liu, X.; Xue, 2016, 88, 5482−5488.
B.; Zhao, H.; Zhang, H.; Kong, X. One-Step in Situ Solid-Substrate- (210) Gan, N.; Zhou, J.; Xiong, P.; Li, T.; Jiang, S.; Cao, Y.; Jiang, Q. An
Based Whole Blood Immunoassay Based on FRET Between Ultrasensitive Electrochemiluminescence Immunoassay for Carbohy-
Upconversion and Gold Nanoparticles. Biosens. Bioelectron. 2017, 92, drate Antigen 19−9 in Serum Based on Antibody Labeled Fe3O4
335−341. Nanoparticles as Capture Probes and Graphene/CdTe Quantum Dot
(192) Zhou, J.; Sun, Y.; Du, X.; Xiong, L.; Hu, H.; Li, F. Dual-Modality Bionanoconjugates as Signal Amplifiers. Int. J. Mol. Sci. 2013, 14,
in Vivo Imaging Using Rare-Earth Nanocrystals with Near-Infrared to 10397−10411.
Near-Infrared (NIR-to-NIR) Upconversion Luminescence and Mag- (211) Guo, Z.; Hao, T.; Du, S.; Chen, B.; Wang, Z.; Li, X.; Wang, S.
netic Resonance Properties. Biomaterials 2010, 31, 3287−3295. Multiplex Electrochemiluminescence Immunoassay of Two Tumor
(193) Liu, Q.; Yang, T.; Feng, W.; Li, F. Blue-Emissive Upconversion Markers Using Multicolor Quantum Dots as Labels and Graphene As
Nanoparticles for Low-Power-Excited Bioimaging in Vivo. J. Am. Chem. Conductingbridge. Biosens. Bioelectron. 2013, 44, 101−107.
Soc. 2012, 134, 5390−5397. (212) Zhu, M.; Tang, Y.; Wen, Q.; Li, J.; Yang, P. Dynamic Evaluation
(194) Wang, M.; Mi, C.-C.; Wang, W.-X.; Liu, C.-H.; Wu, Y.-F.; Xu, Z.- of Cell-Secreted Interferon Gamma in Response to Drug Stimulation via
R.; Mao, C.-B.; Xu, S.-K. Immunolabeling and NIR-Excited Fluorescent a Sensitive Electro-Chemiluminescence Immunosensor Based on a
Imaging of HeLa Cells by Using NaYF4:Yb,Er Upconversion Nano- Glassy Carbon Electrode Modified with Graphene Oxide, Polyaniline
particles. ACS Nano 2009, 3, 1580−1586. Nanofibers, Magnetic Beads, and Gold Nanoparticles. Microchim. Acta
(195) Hu, J.; Zhang, Z.-L.; Wen, C.-Y.; Tang, M.; Wu, L.-L.; Liu, C.; 2016, 183, 1739−1748.
Zhu, L.; Pang, D.-W. Sensitive and Quantitative Detection of C- (213) Zhang, S.; Zang, L.; Zhang, X.; Dai, H.; Xu, G.; Zhang, Q.; Yang,
Reaction Protein Based on Immunofluorescent Nanospheres Coupled C.; Lin, Y. Signal-on Electrochemiluminescent Immunosensor Based on
with Lateral Flow Test Strip. Anal. Chem. 2016, 88, 6577−6584. Poly(amidoamine) Dendrimer Functionalized Carbon Nanodots
(196) Srinivasan, K.; Thiruppathiraja, C.; Subramanian, K.; Dinakaran, Amplification for Ultrasensitive Detection of α-Fetoprotein. Electrochim.
K. Sensitive Detection of C. Parvum Using near Infrared Emitting Acta 2016, 196, 67−74.

10025 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(214) Sha, Y.; Zhang, X.; Li, W.; Wu, W.; Wang, S.; Guo, Z.; Zhou, J.; (231) Zhao, W.-W.; Chen, R.; Dai, P.-P.; Li, X.-L.; Xu, J.-J.; Chen, H.-Y.
Su, X. A Label-Free Multi-Functionalized Graphene Oxide Based A General Strategy for Photoelectrochemical Immunoassay Using an
Electrochemiluminscence Immunosensor for Ultrasensitive and Rapid Enzyme Label Combined with a CdS Quantum Dot/TiO2 Nanoparticle
Detection of Vibrio Parahaemolyticus in Seawater and Seafood. Talanta Composite Electrode. Anal. Chem. 2014, 86, 11513−11516.
2016, 147, 220−225. (232) Fan, G.-C.; Han, L.; Zhu, H.; Zhang, J.-R.; Zhu, J.-J.
(215) Zhang, H.; Han, Z.; Wang, X.; Li, F.; Cui, H.; Yang, D.; Bian, Z. Ultrasensitive Photoelectrochemical Immunoassay for Matrix Metal-
Sensitive Immunosensor for N-Terminal Pro-Brain Natriuretic Peptide loproteinase-2 Detection Based on CdS:Mn/CdTe Cosensitized TiO2
Based on N-(Aminobutyl)-N-(Ethylisoluminol)-Functionalized Gold Nanotubes and Signal Amplification of SiO2@Ab2Conjugates. Anal.
Nanodots/Multiwalled Carbon Nanotube Electrochemiluminescence Chem. 2014, 86, 12398−12405.
Nanointerface. ACS Appl. Mater. Interfaces 2015, 7, 7599−7604. (233) Li, W.; Sheng, P.; Cai, J.; Feng, H.; Cai, Q. Highly Sensitive and
(216) Lv, X.; Li, Y.; Yan, T.; Pang, X.; Cao, W.; Du, B.; Wu, D.; Wei, Q. Selective Photoelectrochemical Biosensor Platform for Polybrominated
Electrochemiluminescence Modified Electrodes Based on RuSi@ Diphenyl Ether Detection Using the Quantum Dots Sensitized Three-
Ru(bpy)32+ Loaded with Gold Functioned Nanoporous CO/Co3O4 Dimensional, Macroporous ZnO Nanosheet Photoelectrode. Biosens.
for Detection of Mycotoxin Deoxynivalenol. Biosens. Bioelectron. 2015, Bioelectron. 2014, 61, 209−214.
70, 28−33. (234) Fan, D.; Wu, D.; Cui, J.; Chen, Y.; Ma, H.; Liu, Y.; Wei, Q.; Du, B.
(217) Liu, M.; Ye, Y.; Yao, C.; Zhao, W.; Huang, X. Mn2+-Doped An Ultrasensitive Label-Free Immunosensor Based on CdS Sensitized
NaYF4:Yb/Er Upconversion Nanoparticles with Amplified Electro- Fe−TiO2 with High Visible-Light Photoelectrochemical Activity.
generated Chemiluminescence for Tumor Biomarker Detection. J. Biosens. Bioelectron. 2015, 74, 843−848.
Mater. Chem. B 2014, 2, 6626−6633. (235) Sun, B.; Qiao, F.; Chen, L.; Zhao, Z.; Yin, H.; Ai, S. Effective
(218) Cai, F.; Zhu, Q.; Zhao, K.; Deng, A.; Li, J. Multiple Signal Signal-on Photoelectrochemical Immunoassay of Subgroup J Avian
Amplified Electrochemiluminescent Immunoassay for Hg2+Using Leukosis Virus Based on Bi2S3 Nanorods as Photosensitizer and in Situ
Graphene-Coupled Quantum Dots and Gold Nanoparticles-Labeled Generated Ascorbic Acid for Electron Donating. Biosens. Bioelectron.
Horseradish Peroxidase. Environ. Sci. Technol. 2015, 49, 5013−5020. 2014, 54, 237−243.
(219) Yang, M.; Chen, Y.; Xiang, Y.; Yuan, R.; Chai, Y. In Situ Energy (236) Zhao, W.-W.; Ma, Z.-Y.; Yan, D.-Y.; Xu, J.-J.; Chen, H.-Y. In Situ
Transfer Quenching of Quantum Dot Electrochemiluminescence for Enzymatic Ascorbic Acid Production as Electron Donor for CdS
Sensitive Detection of Cancer Biomarkers. Biosens. Bioelectron. 2013, 50, Quantum Dots Equipped TiO2 Nanotubes: A General and Efficient
393−398. Approach for New Photoelectrochemical Immunoassay. Anal. Chem.
(220) Zhou, J.; Han, T.; Ma, H.; Yan, T.; Pang, X.; Li, Y.; Wei, Q. A 2012, 84, 10518−10521.
Novel Electrochemiluminescent Immunosensor Based on the Quench- (237) Wang, Y.; Li, M.; Zhu, Y.; Ge, S.; Yu, J.; Yan, M.; Song, X. A
ing Effect of Aminated Graphene on Nitrogen-Doped Carbon Quantum Visible Light Photoelectrochemical Sensor for Tumor Marker Detection
Dots. Anal. Chim. Acta 2015, 889, 82−89. Using Tin Dioxide Quantum Dot−graphene as Labels. Analyst 2013,
(221) Zhuo, Y.; Han, J.; Tang, L.; Liao, N.; Gui, G.-F.; Chai, Y.-Q.; 138, 7112−7118.
Yuan, R. Quenching of the Emission of Peroxydisulfate System by (238) Hu, C.; Zheng, J.; Su, X.; Wang, J.; Wu, W.; Hu, S. Ultrasensitive
Ferrocene Functionalized Chitosan Nanoparticles: A Sensitive “signal All-Carbon Photoelectrochemical Bioprobes for Zeptomole Immuno-
Off” Electrochemiluminescence Immunosensor. Sens. Actuators, B 2014, sensing of Tumor Markers by an Inexpensive Visible Laser Light. Anal.
192, 791−795. Chem. 2013, 85, 10612−10619.
(222) Wang, J.-X.; Zhuo, Y.; Zhou, Y.; Wang, H.-J.; Yuan, R.; Chai, Y.- (239) Wang, Y.; Liu, H.; Wang, P.; Yu, J.; Ge, S.; Yan, M.
Q. Ceria Doped Zinc Oxide Nanoflowers Enhanced Luminol-Based Chemiluminescence Excited Photoelectrochemical Competitive Im-
Electrochemiluminescence Immunosensor for Amyloid-β Detection. munosensing Lab-on-Paper Device Using an Integrated Paper Super-
ACS Appl. Mater. Interfaces 2016, 8, 12968−12975. capacitor for Signal Amplication. Sens. Actuators, B 2015, 208, 546−553.
(223) Wang, J.-X.; Zhuo, Y.; Zhou, Y.; Yuan, R.; Chai, Y.-Q. (240) Sun, G.; Zhang, Y.; Kong, Q.; Ma, C.; Yu, J.; Ge, S.; Yan, M.;
Electrochemiluminescence Immunosensor Based on Multifunctional Song, X. Chemiluminescence Excited Paper-Based Photoelectrochem-
Luminol-Capped AuNPs@Fe3O4 Nanocomposite for the Detection of ical Competitive Immunosensing Based on Porous ZnO Spheres and
Mucin-1. Biosens. Bioelectron. 2015, 71, 407−413. CdS Nanorods. J. Mater. Chem. B 2014, 2, 7679−7684.
(224) Li, J.; Xu, Q.; Fu, C.; Zhang, Y. A Dramatically Enhanced (241) Shim, J. S.; Ahn, C. H. Optical Immunosensor Using Carbon
Electrochemiluminescence Assay for CA125 Based on Dendrimer Nanotubes Coated with a Photovoltaic Polymer. Biosens. Bioelectron.
Multiply Labeled Luminol on Fe3O4 Nanoparticles. Sens. Actuators, B 2012, 34, 208−214.
2013, 185, 146−153. (242) Zhao, W.-W.; Ma, Z.-Y.; Yu, P.-P.; Dong, X.-Y.; Xu, J.-J.; Chen,
(225) Zhou, L.; Huang, J.; Yu, B.; Liu, Y.; You, T. A Novel H.-Y. Highly Sensitive Photoelectrochemical Immunoassay with
Electrochemiluminescence Immunosensor for the Analysis of HIV-1 Enhanced Amplification Using Horseradish Peroxidase Induced
p24 Antigen Based on P-RGO@Au@Ru-SiO2Composite. ACS Appl. Biocatalytic Precipitation on a CdS Quantum Dots Multilayer Electrode.
Mater. Interfaces 2015, 7, 24438−24445. Anal. Chem. 2012, 84, 917−923.
(226) Zhou, Y.; Zhuo, Y.; Liao, N.; Chai, Y.; Yuan, R. Ultrasensitive (243) Zheng, W.; Jiang, X. Integration of Nanomaterials for
Electrochemiluminescent Detection of Cardiac Troponin I Based on a Colorimetric Immunoassays with Improved Performance: A Functional
Self-Enhanced Ru(II) Complex. Talanta 2014, 129, 219−226. Perspective. Analyst 2016, 141, 1196−1208.
(227) Zhou, H.; Liu, J.; Zhang, S. Quantum Dot-Based Photoelectric (244) Cui, X.; Huang, Y.; Wang, J.; Zhang, L.; Rong, Y.; Lai, W.; Chen,
Conversion for Biosensing Applications. TrAC, Trends Anal. Chem. T. A Remarkable Sensitivity Enhancement in a Gold Nanoparticle-
2015, 67, 56−73. Based Lateral Flow Immunoassay for the Detection of Escherichia coli
(228) Lisdat, F.; Schäfer, D.; Kapp, A. Quantum Dots on Electrodes O157:H7. RSC Adv. 2015, 5, 45092−45097.
new Tools for Bioelectroanalysis. Anal. Bioanal. Chem. 2013, 405, (245) Ge, X.; Asiri, A. M.; Du, D.; Wen, W.; Wang, S.; Lin, Y.
3739−3752. Nanomaterial-Enhanced Paper-Based Biosensors. TrAC, Trends Anal.
(229) Sun, G.; Yang, H.; Ma, C.; Zhang, Y.; Yu, J.; He, W.; Song, X. Chem. 2014, 58, 31−39.
Application of CuS-Functionalized ZnO Nanoflakes for a Paper-Based (246) Xu, H.; Chen, J.; Birrenkott, J.; Zhao, J. X.; Takalkar, S.; Baryeh,
Photoelectrochemical Immunoassay Using an in Situ Electron Donor K.; Liu, G. Gold-Nanoparticle-Decorated Silica Nanorods for Sensitive
Producing Strategy. New J. Chem. 2015, 39, 7012−7018. Visual Detection of Proteins. Anal. Chem. 2014, 86, 7351−7359.
(230) Sun, G.; Wang, P.; Zhu, P.; Ge, L.; Ge, S.; Yan, M.; Song, X.; Yu, (247) Park, J.-M.; Jung, H.-W.; Chang, Y. W.; Kim, H.-S.; Kang, M.-J.;
J. A near-Infrared Light Photoelectrochemical Immunosensor Based on Pyun, J.-C. Chemiluminescence Lateral Flow Immunoassay Based on Pt
a Au-Paper Electrode and Naphthalocyanine Sensitized ZnO Nanorods. Nanoparticle with Peroxidase Activity. Anal. Chim. Acta 2015, 853,
J. Mater. Chem. B 2014, 2, 4811. 360−367.

10026 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(248) Kim, M. I.; Kim, M. S.; Woo, M.-A.; Ye, Y.; Kang, K. S.; Lee, J.; nance Detection of Cocaine Using Supramolecular Aptamer Complexes
Park, H. G. Highly Efficient Colorimetric Detection of Target Cancer and Metallic or Semiconductor Nanoparticles. Anal. Chem. 2009, 81,
Cells Utilizing Superior Catalytic Activity of Graphene Oxide− 9291−9298.
magnetic-Platinum Nanohybrids. Nanoscale 2014, 6, 1529−1536. (268) Chen, H.; Liu, F.; Koh, K.; Lee, J.; Ye, Z.; Yin, T.; Sun, L.
(249) Bose, P. P.; Mandal, G.; Chatterjee, U.; Singh, M.; Chatterjee, B. Sensitive Detection of Tuberculosis Using Nanoparticle-Enhanced
P. Gold Nanoparticle-Based Novel Visual Diagnostic Method for the Surface Plasmon Resonance. Microchim. Acta 2013, 180, 431−436.
Detection of Specific IgE to Test for Food Allergies. Anal. Methods 2016, (269) Lin, K.; Lu, Y.; Chen, J.; Zheng, R.; Wang, P.; Ming, H. Surface
8, 3878−3884. Plasmon Resonance Hydrogen Sensor Based on Metallic Grating with
(250) Bui, M.-P. N.; Ahmed, S.; Abbas, A. Single-Digit Pathogen and High Sensitivity. Opt. Express 2008, 16, 18599.
Attomolar Detection with the Naked Eye Using Liposome-Amplified (270) Golub, E.; Pelossof, G.; Freeman, R.; Zhang, H.; Willner, I.
Plasmonic Immunoassay. Nano Lett. 2015, 15, 6239−6246. Electrochemical, Photoelectrochemical, and Surface Plasmon Reso-
(251) Panfilova, E.; Shirokov, A.; Khlebtsov, B.; Matora, L.; Khlebtsov, nance Detection of Cocaine Using Supramolecular Aptamer Complexes
N. Multiplexed Dot Immunoassay Using Ag Nanocubes, Au/Ag Alloy and Metallic or Semiconductor Nanoparticles. Anal. Chem. 2009, 81,
Nanoparticles, and Au/Ag Nanocages. Nano Res. 2012, 5, 124−134. 9291−9298.
(252) Lan, T.; Wang, J.; Dong, C.; Huang, X.; Ren, J. Homogeneous (271) Pollet, J.; Delport, F.; Janssen, K. P. F.; Tran, D. T.; Wouters, J.;
Immunoassays by Using Photon Burst Counting Technique of Single Verbiest, T.; Lammertyn, J. Fast and Accurate Peanut Allergen
Gold Nanoparticles. Talanta 2015, 132, 698−704. Detection with Nanobead Enhanced Optical Fiber SPR Biosensor.
(253) Wijaya, E.; Lenaerts, C.; Maricot, S.; Hastanin, J.; Habraken, S.; Talanta 2011, 83, 1436−1441.
Vilcot, J.-P.; Boukherroub, R.; Szunerits, S. Surface Plasmon Resonance- (272) Liu, X.; Hu, Y.; Zheng, S.; Liu, Y.; He, Z.; Luo, F. Surface
Based Biosensors: From the Development of Different SPR Structures Plasmon Resonance Immunosensor for Fast, Highly Sensitive, and in
to Novel Surface Functionalization Strategies. Curr. Opin. Solid State Situ Detection of the Magnetic Nanoparticles-Enriched Salmonella
Mater. Sci. 2011, 15, 208−224. enteritidis. Sens. Actuators, B 2016, 230, 191−198.
(254) Guo, X. Surface Plasmon Resonance Based Biosensor (273) Zeng, S.; Baillargeat, D.; Ho, H.-P.; Yong, K.-T. Nanomaterials
Technique: A Review. J. Biophotonics 2012, 5, 483−501. Enhanced Surface Plasmon Resonance for Biological and Chemical
(255) Stewart, M. E.; Anderton, C. R.; Thompson, L. B.; Maria, J.; Sensing Applications. Chem. Soc. Rev. 2014, 43, 3426.
Gray, S. K.; Rogers, J. A.; Nuzzo, R. G. Nanostructured Plasmonic (274) Maurer, T.; Adam, P.-M.; Lévêque, G. Coupling between
Sensors. Chem. Rev. 2008, 108, 494−521. Plasmonic Films and Nanostructures: From Basics to Applications.
(256) Zeng, S.; Yu, X.; Law, W.-C.; Zhang, Y.; Hu, R.; Dinh, X.-Q.; Ho, Nanophotonics 2015, 4, 361−382.
H.-P.; Yong, K.-T. Size Dependence of Au NP-Enhanced Surface (275) Li, R.; Feng, F.; Chen, Z.-Z.; Bai, Y.-F.; Guo, F.-F.; Wu, F.-Y.;
Plasmon Resonance Based on Differential Phase Measurement. Sens. Zhou, G. Sensitive Detection of Carcinoembryonic Antigen Using
Actuators, B 2013, 176, 1128−1133. Surface Plasmon Resonance Biosensor with Gold Nanoparticles Signal
(257) Zeng, S.; Yong, K.-T.; Roy, I.; Dinh, X.-Q.; Yu, X.; Luan, F. A Amplification. Talanta 2015, 140, 143−149.
Review on Functionalized Gold Nanoparticles for Biosensing (276) Vaisocherová-Lísalová, H.; Víšová, I.; Ermini, M. L.; Špringer, T.;
Applications. Plasmonics 2011, 6, 491−506. Song, X. C.; Mrázek, J.; Lamačová, J.; Scott Lynn, N.; Šedivák, P.;
(258) Nakamura, C.; Hasegawa, M.; Nakamura, N.; Miyake, J. Rapid Homola, J. Low-Fouling Surface Plasmon Resonance Biosensor for
and Specific Detection of Herbicides Using a Self-Assembled Photo- Multi-Step Detection of Foodborne Bacterial Pathogens in Complex
synthetic Reaction Center from Purple Bacterium on an SPR Chip. Food Samples. Biosens. Bioelectron. 2016, 80, 84−90.
Biosens. Bioelectron. 2003, 18, 599−603. (277) Pettinger, B.; Ren, B.; Picardi, G.; Schuster, R.; Ertl, G.
(259) Wei, J.; Mu, Y.; Song, D.; Fang, X.; Liu, X.; Bu, L.; Zhang, H.; Nanoscale Probing of Adsorbed Species by Tip-Enhanced Raman
Zhang, G.; Ding, J.; Wang, W.; Jin, Q.; Luo, G. A Novel Sandwich Spectroscopy. Phys. Rev. Lett. 2004, 92, 096101.
Immunosensing Method for Measuring Cardiac Troponin I in Sera. (278) Spackova, B.; Wrobel, P.; Bockova, M.; Homola, J. Optical
Anal. Biochem. 2003, 321, 209−216. Biosensors Based on Plasmonic Nanostructures: A Review. Proc. IEEE
(260) Gobi, K. V.; Tanaka, H.; Shoyama, Y.; Miura, N. Continuous 2016, 104, 2380−2408.
Flow Immunosensor for Highly Selective and Real-Time Detection of (279) Maier, S. A. Plasmonics: Fundamentals and Applications; Springer:
Sub-Ppb Levels of 2-Hydroxybiphenyl by Using Surface Plasmon New York, 2007.
Resonance Imaging. Biosens. Bioelectron. 2004, 20, 350−357. (280) Jang, Y. H.; Chung, K.; Quan, L. N.; Špačková, B.; Šípová, H.;
(261) Farka, Z.; Juřík, T.; Pastucha, M.; Skládal, P. Enzymatic Moon, S.; Cho, W. J.; Shin, H.-Y.; Jang, Y. J.; Lee, J.-E.; Kochuveedu, S.
Precipitation Enhanced Surface Plasmon Resonance Immunosensor for T.; Yoon, M. J.; Kim, J.; Yoon, S.; Kim, J. K.; Kim, D.; Homola, J.; Kim,
the Detection of Salmonella in Powdered Milk. Anal. Chem. 2016, 88, D. H. Configuration-Controlled Au Nanocluster Arrays on Inverse
11830−11836. Micelle Nano-Patterns: Versatile Platforms for SERS and SPR Sensors.
(262) Shankaran, D.; Gobi, K.; Miura, N. Recent Advancements in Nanoscale 2013, 5, 12261.
Surface Plasmon Resonance Immunosensors for Detection of Small (281) Joshi, S.; Segarra-Fas, A.; Peters, J.; Zuilhof, H.; van Beek, T. A.;
Molecules of Biomedical, Food and Environmental Interest. Sens. Sens. Nielen, M. W. F. Multiplex Surface Plasmon Resonance Biosensing and
Actuators, B 2007, 121, 158−177. Its Transferability Towards Imaging Nanoplasmonics for Detection of
(263) Habauzit, D.; Armengaud, J.; Roig, B.; Chopineau, J. Mycotoxins in Barley. Analyst 2016, 141, 1307−1318.
Determination of Estrogen Presence in Water by SPR Using Estrogen (282) Moon, S.; Kim, Y.; Oh, Y.; Lee, H.; Kim, H. C.; Lee, K.; Kim, D.
Receptor Dimerization. Anal. Bioanal. Chem. 2008, 390, 873−883. Grating-Based Surface Plasmon Resonance Detection of Core-Shell
(264) Kubitschko, S.; Spinke, J.; Brückner, T.; Pohl, S.; Oranth, N. Nanoparticle Mediated DNA Hybridization. Biosens. Bioelectron. 2012,
Sensitivity Enhancement of Optical Immunosensors with Nano- 32, 141−147.
particles. Anal. Biochem. 1997, 253, 112−122. (283) Im, H.; Sutherland, J. N.; Maynard, J. A.; Oh, S.-H. Nanohole-
(265) Lyon, L. A.; Musick, M. D.; Smith, P. C.; Reiss, B. D.; Peña, D. J.; Based Surface Plasmon Resonance Instruments with Improved Spectral
Natan, M. J. Surface Plasmon Resonance of Colloidal Au-Modified Gold Resolution Quantify a Broad Range of Antibody-Ligand Binding
Films. Sens. Actuators, B 1999, 54, 118−124. Kinetics. Anal. Chem. 2012, 84, 1941−1947.
(266) Wu, Q.; Song, D.; Zhang, D.; Sun, Y. An Enhanced SPR (284) Im, H.; Shao, H.; Park, Y. I.; Peterson, V. M.; Castro, C. M.;
Immunosensing Platform for Human IgG Based on the Use of Silver Weissleder, R.; Lee, H. Label-Free Detection and Molecular Profiling of
Nanocubes and Carboxy-Functionalized Graphene Oxide. Microchim. Exosomes with a Nano-Plasmonic Sensor. Nat. Biotechnol. 2014, 32,
Acta 2016, 183, 2177−2184. 490−495.
(267) Golub, E.; Pelossof, G.; Freeman, R.; Zhang, H.; Willner, I. (285) Kravets, V. G.; Schedin, F.; Jalil, R.; Britnell, L.; Gorbachev, R. V.;
Electrochemical, Photoelectrochemical, and Surface Plasmon Reso- Ansell, D.; Thackray, B.; Novoselov, K. S.; Geim, A. K.; Kabashin, A. V.;

10027 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Grigorenko, A. N. Singular Phase Nano-Optics in Plasmonic Monolayer Graphene for Sensitivity Enhancement of Surface Plasmon
Metamaterials for Label-Free Single-Molecule Detection. Nat. Mater. Resonance Immunosensors. J. Am. Chem. Soc. 2015, 137, 2800−2803.
2013, 12, 304−309. (304) Pawula, M.; Altintas, Z.; Tothill, I. E. SPR Detection of Cardiac
(286) Degiron, A.; Lezec, H. J.; Yamamoto, N.; Ebbesen, T. W. Optical Troponin T for Acute Myocardial Infarction. Talanta 2016, 146, 823−
Transmission Properties of a Single Subwavelength Aperture in a Real 830.
Metal. Opt. Commun. 2004, 239, 61−66. (305) Eletxigerra, U.; Martinez-Perdiguero, J.; Barderas, R.; Pingarrón,
(287) Lee, Y. H.; Chen, H.; Xu, Q.-H.; Wang, J. Refractive Index J. M.; Campuzano, S.; Merino, S. Surface Plasmon Resonance
Sensitivities of Noble Metal Nanocrystals: The Effects of Multipolar Immunosensor for ErbB2 Breast Cancer Biomarker Determination in
Plasmon Resonances and the Metal Type. J. Phys. Chem. C 2011, 115, Human Serum and Raw Cancer Cell Lysates. Anal. Chim. Acta 2016,
7997−8004. 905, 156−162.
(288) Hutter, E.; Fendler, J. H.; Roy, D. Surface Plasmon Resonance (306) Li, R.; Feng, F.; Chen, Z.-Z.; Bai, Y.-F.; Guo, F.-F.; Wu, F.-Y.;
Studies of Gold and Silver Nanoparticles Linked to Gold and Silver Zhou, G. Sensitive Detection of Carcinoembryonic Antigen Using
Substrates by 2-Aminoethanethiol and 1,6-Hexanedithiol. J. Phys. Chem. Surface Plasmon Resonance Biosensor with Gold Nanoparticles Signal
B 2001, 105, 11159−11168. Amplification. Talanta 2015, 140, 143−149.
(289) Lu, H.; Zhang, H.; Yu, X.; Zeng, S.; Yong, K.-T.; Ho, H.-P. Seed- (307) Jiang, Z.; Qin, Y.; Peng, Z.; Chen, S.; Chen, S.; Deng, C.; Xiang, J.
Mediated Plasmon-Driven Regrowth of Silver Nanodecahedrons The Simultaneous Detection of Free and Total Prostate Antigen in
(NDs). Plasmonics 2012, 7, 167−173. Serum Samples with High Sensitivity and Specificity by Using the Dual-
(290) Wang, J.; Song, D.; Wang, L.; Zhang, H.; Zhang, H.; Sun, Y. Channel Surface Plasmon Resonance. Biosens. Bioelectron. 2014, 62,
Design and Performances of Immunoassay Based on SPR Biosensor 268−273.
with Au/Ag Alloy Nanocomposites. Sens. Actuators, B 2011, 157, 547− (308) Hu, W.; Chen, H.; Zhang, H.; He, G.; Li, X.; Zhang, X.; Liu, Y.;
553. Li, C. M. Sensitive Detection of Multiple Mycotoxins by SPRi with Gold
(291) Wang, J.; Munir, A.; Zhu, Z.; Zhou, H. S. Magnetic Nanoparticle Nanoparticles as Signal Amplification Tags. J. Colloid Interface Sci. 2014,
Enhanced Surface Plasmon Resonance Sensing and Its Application for 431, 71−76.
the Ultrasensitive Detection of Magnetic Nanoparticle-Enriched Small (309) Karczmarczyk, A.; Dubiak-Szepietowska, M.; Vorobii, M.;
Molecules. Anal. Chem. 2010, 82, 6782−6789. Rodriguez-Emmenegger, C.; Dostálek, J.; Feller, K.-H. Sensitive and
(292) Wang, Y.; Dostalek, J.; Knoll, W. Magnetic Nanoparticle-
Rapid Detection of Aflatoxin M1 in Milk Utilizing Enhanced SPR and
Enhanced Biosensor Based on Grating-Coupled Surface Plasmon
p(HEMA) Brushes. Biosens. Bioelectron. 2016, 81, 159−165.
Resonance. Anal. Chem. 2011, 83, 6202−6207.
(310) Caucheteur, C.; Guo, T.; Albert, J. Review of Plasmonic Fiber
(293) Liu, X.; Hu, Y.; Zheng, S.; Liu, Y.; He, Z.; Luo, F. Surface
Optic Biochemical Sensors: Improving the Limit of Detection. Anal.
Plasmon Resonance Immunosensor for Fast, Highly Sensitive, and in
Bioanal. Chem. 2015, 407, 3883−3897.
Situ Detection of the Magnetic Nanoparticles-Enriched Salmonella
(311) Haes, A. J.; Van Duyne, R. P. A Unified View of Propagating and
Enteritidis. Sens. Actuators, B 2016, 230, 191−198.
Localized Surface Plasmon Resonance Biosensors. Anal. Bioanal. Chem.
(294) Torun, Ö .; Hakkı Boyacı, I.̇ ; Temür, E.; Tamer, U. Comparison
2004, 379, 920−930.
of Sensing Strategies in SPR Biosensor for Rapid and Sensitive
(312) Liz-Marzán, L. M. Tailoring Surface Plasmons through the
Enumeration of Bacteria. Biosens. Bioelectron. 2012, 37, 53−60.
(295) Zhang, H.; Sun, Y.; Gao, S.; Zhang, H.; Zhang, J.; Bai, Y.; Song, Morphology and Assembly of Metal Nanoparticles. Langmuir 2006, 22,
D. Studies of Gold Nanorod-Iron Oxide Nanohybrids for Immunoassay 32−41.
Based on SPR Biosensor. Talanta 2014, 125, 29−35. (313) Haes, A. J.; Stuart, D. A.; Nie, S.; Van Duyne, R. P. Using
(296) Sreekanth, K. V.; Zeng, S.; Yong, K.-T.; Yu, T. Sensitivity Solution-Phase Nanoparticles, Surface-Confined Nanoparticle Arrays
Enhanced Biosensor Using Graphene-Based One-Dimensional Pho- and Single Nanoparticles as Biological Sensing Platforms. J. Fluoresc.
tonic Crystal. Sens. Actuators, B 2013, 182, 424−428. 2004, 14, 355−367.
(297) Cui, S.; Pu, H.; Lu, G.; Wen, Z.; Mattson, E. C.; Hirschmugl, C.; (314) Sepúlveda, B.; Angelomé, P. C.; Lechuga, L. M.; Liz-Marzán, L.
Gajdardziska-Josifovska, M.; Weinert, M.; Chen, J. Fast and Selective M. LSPR-Based Nanobiosensors. Nano Today 2009, 4, 244−251.
Room-Temperature Ammonia Sensors Using Silver Nanocrystal- (315) Howes, P. D.; Rana, S.; Stevens, M. M. Plasmonic Nanomaterials
Functionalized Carbon Nanotubes. ACS Appl. Mater. Interfaces 2012, for Biodiagnostics. Chem. Soc. Rev. 2014, 43, 3835−3853.
4, 4898−4904. (316) Byun, J.-Y.; Shin, Y.-B.; Li, T.; Park, J.-H.; Kim, D.-M.; Choi, D.-
(298) Wu, L.; Chu, H. S.; Koh, W. S.; Li, E. P. Highly Sensitive H.; Kim, M.-G. The Use of an Engineered Single Chain Variable
Graphene Biosensors Based on Surface Plasmon Resonance. Opt. Fragment in a Localized Surface Plasmon Resonance Method for
Express 2010, 18, 14395. Analysis of the C-Reactive Protein. Chem. Commun. 2013, 49, 9497.
(299) Gosciniak, J.; Tan, D. T. H. Graphene-Based Waveguide (317) Valdez, J.; Bawage, S.; Gomez, I.; Singh, S. R. Facile and Rapid
Integrated Dielectric-Loaded Plasmonic Electro-Absorption Modula- Detection of Respiratory Syncytial Virus Using Metallic Nanoparticles. J.
tors. Nanotechnology 2013, 24, 185202. Nanobiotechnol. 2016, 14, 13.
(300) Chung, K.; Rani, A.; Lee, J.-E.; Kim, J. E.; Kim, Y.; Yang, H.; Kim, (318) Lee, J. U.; Nguyen, A. H.; Sim, S. J. A Nanoplasmonic Biosensor
S. O.; Kim, D.; Kim, D. H. Systematic Study on the Sensitivity for Label-Free Multiplex Detection of Cancer Biomarkers. Biosens.
Enhancement in Graphene Plasmonic Sensors Based on Layer-by-Layer Bioelectron. 2015, 74, 341−346.
Self-Assembled Graphene Oxide Multilayers and Their Reduced (319) Chen, S.; Zhao, Q.; Zhang, L.; Wang, L.; Zeng, Y.; Huang, H.
Analogues. ACS Appl. Mater. Interfaces 2015, 7, 144−151. Combined Detection of Breast Cancer Biomarkers Based on Plasmonic
(301) Hu, W.; He, G.; Zhang, H.; Wu, X.; Li, J.; Zhao, Z.; Qiao, Y.; Lu, Sensor of Gold Nanorods. Sens. Actuators, B 2015, 221, 1391−1397.
Z.; Liu, Y.; Li, C. M. Polydopamine-Functionalization of Graphene (320) Sun, X.; Wu, L.; Ji, J.; Jiang, D.; Zhang, Y.; Li, Z.; Zhang, G.;
Oxide to Enable Dual Signal Amplification for Sensitive Surface Zhang, H. Longitudinal Surface Plasmon Resonance Assay Enhanced by
Plasmon Resonance Imaging Detection of Biomarker. Anal. Chem. Magnetosomes for Simultaneous Detection of Pefloxacin and Micro-
2014, 86, 4488−4493. cystin-LR in Seafoods. Biosens. Bioelectron. 2013, 47, 318−323.
(302) Zhang, J.; Sun, Y.; Xu, B.; Zhang, H.; Gao, Y.; Zhang, H.; Song, (321) Chen, C.-D.; Cheng, S.-F.; Chau, L.-K.; Wang, C. R. C. Sensing
D. A Novel Surface Plasmon Resonance Biosensor Based on Graphene Capability of the Localized Surface Plasmon Resonance of Gold
Oxide Decorated with Gold Nanorod−Antibody Conjugates for Nanorods. Biosens. Bioelectron. 2007, 22, 926−932.
Determination of Transferrin. Biosens. Bioelectron. 2013, 45, 230−236. (322) McFarland, A. D.; Van Duyne, R. P. Single Silver Nanoparticles
(303) Singh, M.; Holzinger, M.; Tabrizian, M.; Winters, S.; Berner, N. as Real-Time Optical Sensors with Zeptomole Sensitivity. Nano Lett.
C.; Cosnier, S.; Duesberg, G. S. Noncovalently Functionalized 2003, 3, 1057−1062.

10028 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(323) Anker, J. N.; Hall, W. P.; Lyandres, O.; Shah, N. C.; Zhao, J.; Van (341) Nie, X.-M.; Huang, R.; Dong, C.-X.; Tang, L.-J.; Gui, R.; Jiang, J.-
Duyne, R. P. Biosensing with Plasmonic Nanosensors. Nat. Mater. 2008, H. Plasmonic ELISA for the Ultrasensitive Detection of Treponema
7, 442−453. Pallidum. Biosens. Bioelectron. 2014, 58, 314−319.
(324) Choi, I.; Choi, Y. Plasmonic Nanosensors: Review and Prospect. (342) Xianyu, Y.; Chen, Y.; Jiang, X. Horseradish Peroxidase-
IEEE J. Sel. Top. Quantum Electron. 2012, 18, 1110−1121. Mediated, Iodide-Catalyzed Cascade Reaction for Plasmonic Immuno-
(325) Lin, H.-Y.; Huang, C.-H.; Lu, S.-H.; Kuo, I.-T.; Chau, L.-K. assays. Anal. Chem. 2015, 87, 10688−10692.
Direct Detection of Orchid Viruses Using Nanorod-Based Fiber Optic (343) Soh, J. H.; Lin, Y.; Rana, S.; Ying, J. Y.; Stevens, M. M.
Particle Plasmon Resonance Immunosensor. Biosens. Bioelectron. 2014, Colorimetric Detection of Small Molecules in Complex Matrixes via
51, 371−378. Target-Mediated Growth of Aptamer-Functionalized Gold Nano-
(326) Inci, F.; Filippini, C.; Baday, M.; Ozen, M. O.; Calamak, S.; particles. Anal. Chem. 2015, 87, 7644−7652.
Durmus, N. G.; Wang, S.; Hanhauser, E.; Hobbs, K. S.; Juillard, F.; (344) Peng, C.; Duan, X.; Khamba, G. W.; Xie, Z. Highly Sensitive
Kuang, P. P.; Vetter, M. L.; Carocci, M.; Yamamoto, H. S.; Takagi, Y.; “signal on” Plasmonic ELISA for Small Molecules by the Naked Eye.
Yildiz, U. H.; Akin, D.; Wesemann, D. R.; Singhal, A.; Yang, P. L.; Nibert, Anal. Methods 2014, 6, 9616−9621.
M. L.; Fichorova, R. N.; Lau, D. T.-Y.; Henrich, T. J.; Kaye, K. M.; (345) De la Rica, R.; Stevens, M. M. Plasmonic ELISA for the
Ultrasensitive Detection of Disease Biomarkers with the Naked Eye.
Schachter, S. C.; Kuritzkes, D. R.; Steinmetz, L. M.; Gambhir, S. S.;
Nat. Nanotechnol. 2012, 7, 821−824.
Davis, R. W.; Demirci, U. Multitarget, Quantitative Nanoplasmonic
(346) De la Rica, R.; Stevens, M. M. Plasmonic ELISA for the
Electrical Field-Enhanced Resonating Device (NE2RD) for Diagnostics.
Detection of Analytes at Ultralow Concentrations with the Naked Eye.
Proc. Natl. Acad. Sci. U. S. A. 2015, 112, E4354−E4363. Nat. Protoc. 2013, 8, 1759−1764.
(327) Mock, J. J.; Smith, D. R.; Schultz, S. Local Refractive Index (347) Raman, C. V.; Krishnan, K. S. A New Type of Secondary
Dependence of Plasmon Resonance Spectra from Individual Nano- Radiation. Nature 1928, 121, 501−502.
particles. Nano Lett. 2003, 3, 485−491. (348) Fleischmann, M.; Hendra, P. J.; McQuillan, A. J. Raman Spectra
(328) Qiu, G.; Ng, S. P.; Wu, L. C.-M. Dielectric Functionalization for of Pyridine Adsorbed at a Silver Electrode. Chem. Phys. Lett. 1974, 26,
Differential Phase Detecting Localized Surface Plasmon Resonance 163−166.
Biosensor. Sens. Actuators, B 2016, 234, 247−254. (349) Chrimes, A. F.; Khoshmanesh, K.; Stoddart, P. R.; Mitchell, A.;
(329) Liu, C.; Meng, F.; Zheng, W.; Xue, T.; Jin, Z.; Wang, Z.; Cui, X. Kalantar-zadeh, K. Microfluidics and Raman Microscopy: Current
Plasmonic ZnO nanorods/Au Substrates for Protein Microarrays with Applications and Future Challenges. Chem. Soc. Rev. 2013, 42, 5880.
High Sensitivity and Broad Dynamic Range. Sens. Actuators, B 2016, 228, (350) Banholzer, M. J.; Millstone, J. E.; Qin, L.; Mirkin, C. A. Rationally
231−236. Designed Nanostructures for Surface-Enhanced Raman Spectroscopy.
(330) He, J.; Boegli, M.; Bruzas, I.; Lum, W.; Sagle, L. Patterned Chem. Soc. Rev. 2008, 37, 885−897.
Plasmonic Nanoparticle Arrays for Microfluidic and Multiplexed (351) Qian, X.-M.; Nie, S. M. Single-Molecule and Single-Nanoparticle
Biological Assays. Anal. Chem. 2015, 87, 11407−11414. SERS: From Fundamental Mechanisms to Biomedical Applications.
(331) Gunnarsson, L.; Rindzevicius, T.; Prikulis, J.; Kasemo, B.; Käll, Chem. Soc. Rev. 2008, 37, 912−920.
M.; Zou, S.; Schatz, G. C. Confined Plasmons in Nanofabricated Single (352) Jensen, L.; Aikens, C. M.; Schatz, G. C. Electronic Structure
Silver Particle Pairs: Experimental Observations of Strong Interparticle Methods for Studying Surface-Enhanced Raman Scattering. Chem. Soc.
Interactions. J. Phys. Chem. B 2005, 109, 1079−1087. Rev. 2008, 37, 1061−1073.
(332) Brolo, A. G.; Gordon, R.; Leathem, B.; Kavanagh, K. L. Surface (353) Morton, S. M.; Jensen, L. Understanding the Molecule−Surface
Plasmon Sensor Based on the Enhanced Light Transmission through Chemical Coupling in SERS. J. Am. Chem. Soc. 2009, 131, 4090−4098.
Arrays of Nanoholes in Gold Films. Langmuir 2004, 20, 4813−4815. (354) Muehlethaler, C.; Leona, M.; Lombardi, J. R. Review of Surface
(333) Haes, A. J.; Van Duyne, R. P. A Nanoscale Optical Biosensor: Enhanced Raman Scattering Applications in Forensic Science. Anal.
Sensitivity and Selectivity of an Approach Based on the Localized Chem. 2016, 88, 152−169.
Surface Plasmon Resonance Spectroscopy of Triangular Silver Nano- (355) Moskovits, M. Surface-Enhanced Raman Spectroscopy: a Brief
particles. J. Am. Chem. Soc. 2002, 124, 10596−10604. Retrospective. J. Raman Spectrosc. 2005, 36, 485−496.
(334) Larsson, E. M.; Alegret, J.; Käll, M.; Sutherland, D. S. Sensing (356) Willets, K. A.; Van Duyne, R. P. Localized Surface Plasmon
Characteristics of NIR Localized Surface Plasmon Resonances in Gold Resonance Spectroscopy and Sensing. Annu. Rev. Phys. Chem. 2007, 58,
Nanorings for Application as Ultrasensitive Biosensors. Nano Lett. 2007, 267−297.
7, 1256−1263. (357) Driscoll, A. J.; Harpster, M. H.; Johnson, P. A. The Development
(335) Stewart, M. E.; Mack, N. H.; Malyarchuk, V.; Soares, J. A. N. T.; of Surface-Enhanced Raman Scattering as a Detection Modality for
Lee, T.-W.; Gray, S. K.; Nuzzo, R. G.; Rogers, J. A. Quantitative Portable in Vitro Diagnostics: Progress and Challenges. Phys. Chem.
Chem. Phys. 2013, 15, 20415.
Multispectral Biosensing and 1D Imaging Using Quasi-3D Plasmonic
(358) Gutés, A.; Maboudian, R.; Carraro, C. Gold-Coated Silver
Crystals. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 17143−17148.
Dendrites as SERS Substrates with an Improved Lifetime. Langmuir
(336) Jo, N. r.; Lee, K. j.; Shin, Y.-B. Enzyme-Coupled Nanoplasmonic
2012, 28, 17846−17850.
Biosensing of Cancer Markers in Human Serum. Biosens. Bioelectron. (359) Wang, Y.; Vaidyanathan, R.; Shiddiky, M. J. A.; Trau, M.
2016, 81, 324−333. Enabling Rapid and Specific Surface-Enhanced Raman Scattering
(337) Yeom, S.-H.; Han, M.-E.; Kang, B.-H.; Kim, K.-J.; Yuan, H.; Eum, Immunoassay Using Nanoscaled Surface Shear Forces. ACS Nano
N.-S.; Kang, S.-W. Enhancement of the Sensitivity of LSPR-Based CRP 2015, 9, 6354−6362.
Immunosensors by Au Nanoparticle Antibody Conjugation. Sens. (360) Liao, W.; Lu, X. Determination of Chemical Hazards in Foods
Actuators, B 2013, 177, 376−383. Using Surface-Enhanced Raman Spectroscopy Coupled with Advanced
(338) Hall, W. P.; Ngatia, S. N.; Van Duyne, R. P. LSPR Biosensor Separation Techniques. Trends Food Sci. Technol. 2016, 54, 103−113.
Signal Enhancement Using Nanoparticle−Antibody Conjugates. J. Phys. (361) Wang, G.; Park, H.-Y.; Lipert, R. J.; Porter, M. D. Mixed
Chem. C 2011, 115, 1410−1414. Monolayers on Gold Nanoparticle Labels for Multiplexed Surface-
(339) Gunnarsson, L.; Rindzevicius, T.; Prikulis, J.; Kasemo, B.; Käll, Enhanced Raman Scattering Based Immunoassays. Anal. Chem. 2009,
M.; Zou, S.; Schatz, G. C. Confined Plasmons in Nanofabricated Single 81, 9643−9650.
Silver Particle Pairs: Experimental Observations of Strong Interparticle (362) Haisch, C. Raman-Based Microarray Readout: a Review. Anal.
Interactions. J. Phys. Chem. B 2005, 109, 1079−1087. Bioanal. Chem. 2016, 408, 4535−4545.
(340) Gupta, S.; Andresen, H.; Ghadiali, J. E.; Stevens, M. M. Kinase- (363) Cui, Y.; Ren, B.; Yao, J.-L.; Gu, R.-A.; Tian, Z.-Q. Multianalyte
Actuated Immunoaggregation of Peptide-Conjugated Gold Nano- Immunoassay Based on Surface-Enhanced Raman Spectroscopy. J.
particles. Small 2010, 6, 1509−1513. Raman Spectrosc. 2007, 38, 896−902.

10029 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(364) Tang, B.; Wang, J.; Hutchison, J. A.; Ma, L.; Zhang, N.; Guo, H.; (382) Lim, S. A.; Ahmed, M. U. Electrochemical Immunosensors and
Hu, Z.; Li, M.; Zhao, Y. Ultrasensitive, Multiplex Raman Frequency Shift Their Recent Nanomaterial-Based Signal Amplification Strategies: A
Immunoassay of Liver Cancer Biomarkers in Physiological Media. ACS Review. RSC Adv. 2016, 6, 24995−25014.
Nano 2016, 10, 871−879. (383) Borgmann, S.; Schulte, A.; Neugebauer, S.; Schuhmann, W.
(365) Wu, L.; Wang, Z.; Zong, S.; Huang, Z.; Zhang, P.; Cui, Y. A Amperometric Biosensors. In Advances in Electrochemical Science and
SERS-Based Immunoassay with Highly Increased Sensitivity Using Engineering; Alkire, R. C., Kolb, D. M., Lipkowski, J., Eds.; Wiley-VCH:
Gold/silver Core-Shell Nanorods. Biosens. Bioelectron. 2012, 38, 94−99. Weinheim, Germany, 2011.
(366) Hwang, J.; Lee, S.; Choo, J. Application of a SERS-Based Lateral (384) Wang, L.; Lei, J.; Ma, R.; Ju, H. Host−Guest Interaction of
Flow Immunoassay Strip for the Rapid and Sensitive Detection of Adamantine with a β-Cyclodextrin-Functionalized AuPd Bimetallic
Staphylococcal Enterotoxin B. Nanoscale 2016, 8, 11418−11425. Nanoprobe for Ultrasensitive Electrochemical Immunoassay of Small
(367) Jiang, T.; Zhang, L.; Zhou, J. Silver Nanocube-Mediated Molecules. Anal. Chem. 2013, 85, 6505−6510.
Sensitive Immunoassay Based on Surface-Enhanced Raman Scattering (385) Jeong, B.; Akter, R.; Han, O. H.; Rhee, C. K.; Rahman, M. A.
Assisted by Etched Silicon Nanowire Arrays. Analyst 2014, 139, 5893− Increased Electrocatalyzed Performance through Dendrimer-Encapsu-
5900. lated Gold Nanoparticles and Carbon Nanotube-Assisted Multiple
(368) Nguyen, A. H.; Lee, J.; Il Choi, H.; Seok Kwak, H.; Jun Sim, S. Bienzymatic Labels: Highly Sensitive Electrochemical Immunosensor
Fabrication of Plasmon Length-Based Surface Enhanced Raman for Protein Detection. Anal. Chem. 2013, 85, 1784−1791.
Scattering for Multiplex Detection on Microfluidic Device. Biosens. (386) Lin, D.; Wu, J.; Wang, M.; Yan, F.; Ju, H. Triple Signal
Bioelectron. 2015, 70, 358−365. Amplification of Graphene Film, Polybead Carried Gold Nanoparticles
(369) Li, M.; Kang, J. W.; Sukumar, S.; Dasari, R. R.; Barman, I. as Tracing Tag and Silver Deposition for Ultrasensitive Electrochemical
Multiplexed Detection of Serological Cancer Markers with Plasmon- Immunosensing. Anal. Chem. 2012, 84, 3662−3668.
Enhanced Raman Spectro-Immunoassay. Chem. Sci. 2015, 6, 3906− (387) Li, J.; Li, S.; Yang, C. F. Electrochemical Biosensors for Cancer
3914. Biomarker Detection. Electroanalysis 2012, 24, 2213−2229.
(370) Ciou, S.-H.; Cao, Y.-W.; Huang, H.-C.; Su, D.-Y.; Huang, C.-L. (388) Huang, K.-J.; Wu, Z.-W.; Wu, Y.-Y.; Liu, Y.-M. Electrochemical
SERS Enhancement Factors Studies of Silver Nanoprism and Spherical Immunoassay of Carcinoembryonic Antigen Based on TiO2 −
Nanoparticle Colloids in The Presence of Bromide Ions. J. Phys. Chem. C Graphene/Thionine/Gold Nanoparticles Composite. Can. J. Chem.
2009, 113, 9520−9525. 2012, 90, 608−615.
(371) Kamińska, A.; Witkowska, E.; Winkler, K.; Dzięcielewski, I.; (389) Cai, M.; Zhu, L.; Ding, Y.; Wang, J.; Li, J.; Du, X. Determination
Weyher, J. L.; Waluk, J. Detection of Hepatitis B Virus Antigen from of Sulfamethoxazole in Foods Based on CeO2/Chitosan Nano-
Human Blood: SERS Immunoassay in a Microfluidic System. Biosens. composite-Modified Electrodes. Mater. Sci. Eng., C 2012, 32, 2623−
Bioelectron. 2015, 66, 461−467. 2627.
(372) He, Y.; Wang, Y.; Yang, X.; Xie, S.; Yuan, R.; Chai, Y. Metal (390) Cao, X.; Wang, N.; Jia, S.; Guo, L.; Li, K. Bimetallic AuPt
Organic Frameworks Combining CoFe2O4Magnetic Nanoparticles as Nanochains: Synthesis and Their Application in Electrochemical
Highly Efficient SERS Sensing Platform for Ultrasensitive Detection of Immunosensor for the Detection of Carcinoembryonic Antigen. Biosens.
N-Terminal Pro-Brain Natriuretic Peptide. ACS Appl. Mater. Interfaces Bioelectron. 2013, 39, 226−230.
2016, 8, 7683−7690. (391) Cho, H. K.; Lim, H. B. Determination of Prostate-Specific
(373) Li, J.; Skeete, Z.; Shan, S.; Yan, S.; Kurzatkowska, K.; Zhao, W.; Antigen (PSA) Tagged with TiO2 Nanoparticles Using ICP-MS. J. Anal.
Ngo, Q. M.; Holubovska, P.; Luo, J.; Hepel, M.; Zhong, C.-J. Surface At. Spectrom. 2013, 28, 468.
Enhanced Raman Scattering Detection of Cancer Biomarkers with (392) Valera, E.; Muriano, A.; Pividori, I.; Sánchez-Baeza, F.; Marco,
Bifunctional Nanocomposite Probes. Anal. Chem. 2015, 87, 10698− M.-P. Development of a Coulombimetric Immunosensor Based on
10702. Specific Antibodies Labeled with CdS Nanoparticles for Sulfonamide
(374) Zengin, A.; Tamer, U.; Caykara, T. Extremely Sensitive Antibiotic Residues Analysis and Its Application to Honey Samples.
Sandwich Assay of Kanamycin Using Surface-Enhanced Raman Biosens. Bioelectron. 2013, 43, 211−217.
Scattering of 2-Mercaptobenzothiazole Labeled Gold@silver Nano- (393) Yeh, F.-Y.; Liu, T.-Y.; Tseng, I.-H.; Yang, C.-W.; Lu, L.-C.; Lin,
particles. Anal. Chim. Acta 2014, 817, 33−41. C.-S. Gold Nanoparticles Conjugates-Amplified Aptamer Immunosens-
(375) Yang, K.; Hu, Y.; Dong, N. A Novel Biosensor Based on ing Screen-Printed Carbon Electrode Strips for Thrombin Detection.
Competitive SERS Immunoassay and Magnetic Separation for Accurate Biosens. Bioelectron. 2014, 61, 336−343.
and Sensitive Detection of Chloramphenicol. Biosens. Bioelectron. 2016, (394) Sharma, A.; Kameswara Rao, V.; Vrat Kamboj, D.; Jain, R.
80, 373−377. Electrochemical Immunosensor for Staphylococcal Enterotoxin B
(376) Dinish, U. S.; Balasundaram, G.; Chang, Y.-T.; Olivo, M. Actively (SEB) Based on Platinum Nanoparticles-Modified Electrode Using
Targeted In Vivo Multiplex Detection of Intrinsic Cancer Biomarkers Hydrogen Evolution Inhibition Approach. Electroanalysis 2014, 26,
Using Biocompatible SERS Nanotags. Sci. Rep. 2015, 4, 4075. 2320−2327.
(377) Vendrell, M.; Maiti, K. K.; Dhaliwal, K.; Chang, Y.-T. Surface- (395) Wang, D.; Dou, W.; Zhao, G.; Chen, Y. Immunosensor Based on
Enhanced Raman Scattering in Cancer Detection and Imaging. Trends Electrodeposition of Gold-Nanoparticles and Ionic Liquid Composite
Biotechnol. 2013, 31, 249−257. for Detection of Salmonella Pullorum. J. Microbiol. Methods 2014, 106,
(378) Lee, S.; Kim, S.; Choo, J.; Shin, S. Y.; Lee, Y. H.; Choi, H. Y.; Ha, 110−118.
S.; Kang, K.; Oh, C. H. Biological Imaging of HEK293 Cells Expressing (396) Sun, X.; Cao, Y.; Gong, Z.; Wang, X.; Zhang, Y.; Gao, J. An
PLCγ1 Using Surface-Enhanced Raman Microscopy. Anal. Chem. 2007, Amperometric Immunosensor Based on Multi-Walled Carbon Nano-
79, 916−922. tubes-Thionine-Chitosan Nanocomposite Film for Chlorpyrifos
(379) Wang, Y.; Kang, S.; Khan, A.; Ruttner, G.; Leigh, S. Y.; Murray, Detection. Sensors 2012, 12, 17247−17261.
M.; Abeytunge, S.; Peterson, G.; Rajadhyaksha, M.; Dintzis, S.; Javid, S.; (397) Zhu, Y.; Cao, Y.; Sun, X.; Wang, X. Amperometric
Liu, J. T. C. Quantitative Molecular Phenotyping with Topically Applied Immunosensor for Carbofuran Detection Based on MWCNTs/GS-
SERS Nanoparticles for Intraoperative Guidance of Breast Cancer PEI-Au and AuNPs-Antibody Conjugate. Sensors 2013, 13, 5286−5301.
Lumpectomy. Sci. Rep. 2016, 6, 21242. (398) Sharma, M. K.; Narayanan, J.; Upadhyay, S.; Goel, A. K.
(380) Bard, A. J.; Faulkner, L. R. Electrochemical Methods: Electrochemical Immunosensor Based on Bismuth Nanocomposite
Fundamentals and Applications, 2nd ed.; Wiley: Hoboken, NJ, 2001. Film and Cadmium Ions Functionalized Titanium Phosphates for the
(381) Merkoci, A.; Ambrosi, A.; de la Escosura-Muniz, A.; Perez- Detection of Anthrax Protective Antigen Toxin. Biosens. Bioelectron.
Lopez, B.; Guix, M.; Maltez, M.; Marin, S. Nanomaterials for 2015, 74, 299−304.
Electroanalysis. In Encyclopedia of Analytical Chemistry; Meyer, R. A., (399) Dai, H.; Xu, G.; Zhang, S.; Gong, L.; Li, X.; Yang, C.; Lin, Y.;
Ed.; John Wiley & Sons Ltd.: Hoboken, NJ, 2010. Chen, J.; Chen, G. Carbon Nanotubes Functionalized Electrospun

10030 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Nanofibers Formed 3D Electrode Enables Highly Strong ECL of Nanoparticles Biocompatible Film on Au Microelectrode for Determi-
Peroxydisulfate and Its Application in Immunoassay. Biosens. Bioelectron. nation of Aflatoxin B1 in Maize. Biosens. Bioelectron. 2016, 80, 222−229.
2014, 61, 575−578. (418) Raymundo-Pereira, P. A.; Shimizu, F. M.; Coelho, D.; Piazzeta,
(400) Haque, A.-M. J.; Park, H.; Sung, D.; Jon, S.; Choi, S.-Y.; Kim, K. M. H. O.; Gobbi, A. L.; Machado, S. A. S.; Oliveira, O. N., Jr. A
An Electrochemically Reduced Graphene Oxide-Based Electrochemical Nanostructured Bifunctional Platform for Sensing of Glucose
Immunosensing Platform for Ultrasensitive Antigen Detection. Anal. Biomarker in Artificial Saliva: Synergy in Hybrid Pt/Au Surfaces.
Chem. 2012, 84, 1871−1878. Biosens. Bioelectron. 2016, 86, 369−376.
(401) Jiao, L.; Mu, Z.; Zhu, C.; Wei, Q.; Li, H.; Du, D.; Lin, Y. (419) Kavosi, B.; Hallaj, R.; Teymourian, H.; Salimi, A. Au
Graphene Loaded Bimetallic Au@Pt Nanodendrites Enhancing Ultra- Nanoparticles/PAMAM Dendrimer Functionalized Wired Ethylene-
sensitive Electrochemical Immunoassay of AFP. Sens. Actuators, B 2016, amine−viologen as Highly Efficient Interface for Ultra-Sensitive α-
231, 513−519. Fetoprotein Electrochemical Immunosensor. Biosens. Bioelectron. 2014,
(402) Yu, S.; Zou, G.; Wei, Q. Ultrasensitive Electrochemical 59, 389−396.
Immunosensor for Quantitative Detection of Tumor Specific Growth (420) Ramanathan, M.; Patil, M.; Epur, R.; Yun, Y.; Shanov, V.; Schulz,
Factor by Using Ag@CeO2 Nanocomposite as Labels. Talanta 2016, M.; Heineman, W. R.; Datta, M. K.; Kumta, P. N. Gold-Coated Carbon
156−157, 11−17. Nanotube Electrode Arrays: Immunosensors for Impedimetric
(403) Tian, L.; Liu, L.; Li, Y.; Wei, Q.; Cao, W. Ultrasensitive Detection of Bone Biomarkers. Biosens. Bioelectron. 2016, 77, 580−588.
Sandwich-Type Electrochemical Immunosensor Based on Trimetallic (421) Li, L.; Feng, D.; Zhang, Y. Simultaneous Detection of Two
Nanocomposite Signal Amplification Strategy for the Ultrasensitive Tumor Markers Using Silver and Gold Nanoparticles Decorated
Detection of CEA. Sci. Rep. 2016, 6, 30849. Carbon Nanospheres as Labels. Anal. Biochem. 2016, 505, 59−65.
(404) Randviir, E. P.; Banks, C. E. Electrochemical Impedance (422) Akter, R.; Jeong, B.; Choi, J.-S.; Rahman, M. A. Ultrasensitive
Spectroscopy: An Overview of Bioanalytical Applications. Anal. Methods Nanoimmunosensor by Coupling Non-Covalent Functionalized
2013, 5, 1098. Graphene Oxide Platform and Numerous Ferritin Labels on Carbon
(405) Lisdat, F.; Schäfer, D. The Use of Electrochemical Impedance Nanotubes. Biosens. Bioelectron. 2016, 80, 123−130.
Spectroscopy for Biosensing. Anal. Bioanal. Chem. 2008, 391, 1555− (423) Wang, G.; He, X.; Chen, L.; Zhu, Y.; Zhang, X. Ultrasensitive IL-
1567. 6 Electrochemical Immunosensor Based on Au Nanoparticles-
(406) Daniels, J. S.; Pourmand, N. Label-Free Impedance Biosensors: Graphene-Silica Biointerface. Colloids Surf., B 2014, 116, 714−719.
Opportunities and Challenges. Electroanalysis 2007, 19, 1239−1257. (424) Sun, B.; Gou, Y.; Ma, Y.; Zheng, X.; Bai, R.; Ahmed Abdelmoaty,
(407) Ma, H.; Li, Y.; Wang, Y.; Hu, L.; Zhang, Y.; Fan, D.; Yan, T.; Wei, A. A.; Hu, F. Investigate Electrochemical Immunosensor of Cortisol
Q. Cubic Cu2O Nanoframes with a Unique Edge-Truncated Structure Based on Gold Nanoparticles/Magnetic Functionalized Reduced
and a Good Electrocatalytic Activity for Immunosensor Application.
Graphene Oxide. Biosens. Bioelectron. 2017, 88, 55−62.
Biosens. Bioelectron. 2016, 78, 167−173.
(425) Hou, L.; Tang, Y.; Xu, M.; Gao, Z.; Tang, D. Tyramine-Based
(408) Katz, E.; Willner, I. Probing Biomolecular Interactions at
Enzymatic Conjugate Repeats for Ultrasensitive Immunoassay Accom-
Conductive and Semiconductive Surfaces by Impedance Spectroscopy:
panying Tyramine Signal Amplification with Enzymatic Biocatalytic
Routes to Impedimetric Immunosensors, DNA-Sensors, and Enzyme
Precipitation. Anal. Chem. 2014, 86, 8352−8358.
Biosensors. Electroanalysis 2003, 15, 913−947.
(426) Wan, J.; Ai, J.; Zhang, Y.; Geng, X.; Gao, Q.; Cheng, Z. Signal-off
(409) Yagati, A. K.; Choi, Y.; Park, J.; Choi, J.-W.; Jun, H.-S.; Cho, S.
Impedimetric Immunosensor for the Detection of Escherichia Coli
Silver Nanoflower−reduced Graphene Oxide Composite Based Micro-
Disk Electrode for Insulin Detection in Serum. Biosens. Bioelectron. 2016, O157:H7. Sci. Rep. 2016, 6, 19806.
(427) Shein, J. B.; Lai, L. M. H.; Eggers, P. K.; Paddon-Row, M. N.;
80, 307−314.
(410) Wang, X.; Deng, W.; Shen, L.; Yan, M.; Yu, J. A 3D Gooding, J. J. Formation of Efficient Electron Transfer Pathways by
Electrochemical Immunodevice Based on an Au Paper Electrode and Adsorbing Gold Nanoparticles to Self-Assembled Monolayer Modified
Using Au Nanoflowers for Amplification. New J. Chem. 2016, 40, 2835− Electrodes. Langmuir 2009, 25, 11121−11128.
2842. (428) Mihailescu, C.-M.; Stan, D.; Iosub, R.; Moldovan, C.; Savin, M. A
(411) Wang, Y.; Li, Y.; Hu, L.; Ren, X.; Du, B.; Ma, H.; Wei, Q. Sensitive Capacitive Immunosensor for Direct Detection of Human
Application of Three-Dimensional Flower-like Nanomaterials in the Heart Fatty Acid-Binding Protein (h-FABP). Talanta 2015, 132, 37−43.
Fabrication of Sandwich-Type Electrochemical Immunosensors. RSC (429) Nguyen, P.-D.; Tran, T. B.; Nguyen, D. T. X.; Min, J. Magnetic
Adv. 2015, 5, 88160−88165. Silica Nanotube-Assisted Impedimetric Immunosensor for the Separa-
(412) Raghav, R.; Srivastava, S. Core−shell Gold−silver Nanoparticles tion and Label-Free Detection of Salmonella Typhimurium. Sens.
Based Impedimetric Immunosensor for Cancer Antigen CA125. Sens. Actuators, B 2014, 197, 314−320.
Actuators, B 2015, 220, 557−564. (430) Shalev, G.; Rosenwaks, Y.; Levy, I. The Interplay between pH
(413) Xiang, C.; Li, R.; Adhikari, B.; She, Z.; Li, Y.; Kraatz, H.-B. Sensitivity and Label-Free Protein Detection in Immunologically
Sensitive Electrochemical Detection of Salmonella with Chitosan−gold Modified Nano-Scaled Field-Effect Transistor. Biosens. Bioelectron.
Nanoparticles Composite Film. Talanta 2015, 140, 122−127. 2012, 31, 510−515.
(414) Yu, S.; Zou, G.; Wei, Q. Ultrasensitive Electrochemical (431) He, Q.; Wu, S.; Yin, Z.; Zhang, H. Graphene-Based Electronic
Immunosensor for Quantitative Detection of Tumor Specific Growth Sensors. Chem. Sci. 2012, 3, 1764.
Factor by Using Ag@CeO2 Nanocomposite as Labels. Talanta 2016, (432) Yen, L.-C.; Pan, T.-M.; Lee, C.-H.; Chao, T.-S. Label-Free and
156−157, 11−17. Real-Time Detection of Ferritin Using a Horn-like Polycrystalline-
(415) Tuteja, S. K.; Chen, R.; Kukkar, M.; Song, C. K.; Mutreja, R.; Silicon Nanowire Field-Effect Transistor Biosensor. Sens. Actuators, B
Singh, S.; Paul, A. K.; Lee, H.; Kim, K.-H.; Deep, A.; et al. A Label-Free 2016, 230, 398−404.
Electrochemical Immunosensor for the Detection of Cardiac Marker (433) Elnathan, R.; Kwiat, M.; Pevzner, A.; Engel, Y.; Burstein, L.;
Using Graphene Quantum Dots (GQDs). Biosens. Bioelectron. 2016, 86, Khatchtourints, A.; Lichtenstein, A.; Kantaev, R.; Patolsky, F.
548−556. Biorecognition Layer Engineering: Overcoming Screening Limitations
(416) Jia, X.; Chen, X.; Han, J.; Ma, J.; Ma, Z. Triple Signal of Nanowire-Based FET Devices. Nano Lett. 2012, 12, 5245−5254.
Amplification Using Gold Nanoparticles, Bienzyme and Platinum (434) Belkhamssa, N.; Justino, C. I. L.; Santos, P. S. M.; Cardoso, S.;
Nanoparticles Functionalized Graphene as Enhancers for Simultaneous Lopes, I.; Duarte, A. C.; Rocha-Santos, T.; Ksibi, M. Label-Free
Multiple Electrochemical Immunoassay. Biosens. Bioelectron. 2014, 53, Disposable Immunosensor for Detection of Atrazine. Talanta 2016,
65−70. 146, 430−434.
(417) Ma, H.; Sun, J.; Zhang, Y.; Bian, C.; Xia, S.; Zhen, T. Label-Free (435) Chen, H.; Choo, T. K.; Huang, J.; Wang, Y.; Liu, Y.; Platt, M.;
Immunosensor Based on One-Step Electrodeposition of Chitosan-Gold Palaniappan, A.; Liedberg, B.; Tok, A. I. Y. Label-Free Electronic

10031 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Detection of Interleukin-6 Using Horizontally Aligned Carbon Relaxation Switch and Biotin−streptavidin System for the Detection of
Nanotubes. Mater. Des. 2016, 90, 852−857. Kanamycin in Milk. Biosens. Bioelectron. 2013, 39, 112−117.
(436) Palaniappan, Al.; Goh, W. H.; Fam, D. W. H.; Rajaseger, G.; (454) Liao, S.-H.; Chen, K.-L.; Wang, C.-M.; Chieh, J.-J.; Horng, H.-E.;
Chan, C. E. Z.; Hanson, B. J.; Moochhala, S. M.; Mhaisalkar, S. G.; Wang, L.-M.; Wu, C.; Yang, H.-C. Using Bio-Functionalized Magnetic
Liedberg, B. Label-free electronic detection of bio-toxins using aligned Nanoparticles and Dynamic Nuclear Magnetic Resonance to Character-
carbon nanotubes. Biosens. Bioelectron. 2013, 43, 143−147. ize the Time-Dependent Spin-Spin Relaxation Time for Sensitive Bio-
(437) Ramnani, P.; Saucedo, N. M.; Mulchandani, A. Carbon Detection. Sensors 2014, 14, 21409−21417.
Nanomaterial-Based Electrochemical Biosensors for Label-Free Sensing (455) Issadore, D.; Min, C.; Liong, M.; Chung, J.; Weissleder, R.; Lee,
of Environmental Pollutants. Chemosphere 2016, 143, 85−98. H. Miniature Magnetic Resonance System for Point-of-Care Diag-
(438) Park, J. W.; Na, W.; Jang, J. One-Pot Synthesis of Multidimen- nostics. Lab Chip 2011, 11, 2282−2287.
sional Conducting Polymer Nanotubes for Superior Performance Field- (456) Jogschies, L.; Klaas, D.; Kruppe, R.; Rittinger, J.; Taptimthong,
Effect Transistor-Type Carcinoembryonic Antigen Biosensors. RSC P.; Wienecke, A.; Rissing, L.; Wurz, M. Recent Developments of
Adv. 2016, 6, 14335−14343. Magnetoresistive Sensors for Industrial Applications. Sensors 2015, 15,
(439) Kim, K.; Park, C.; Kwon, D.; Kim, D.; Meyyappan, M.; Jeon, S.; 28665−28689.
Lee, J.-S. Silicon Nanowire Biosensors for Detection of Cardiac (457) Ennen, I.; Albon, C.; Weddemann, A.; Auge, A.; Hedwig, P.;
Troponin I (cTnI) with High Sensitivity. Biosens. Bioelectron. 2016, Wittbracht, F.; Regtmeier, A.; Akemeier, D.; Dreyer, A.; Peter, M.; et al.
77, 695−701. From Magnetic Nanoparticles to Magnetoresistive Biosensors. Acta
(440) Lin, M.-Y.; Hsu, W.-Y.; Yang, Y.-S.; Huang, J.-W.; Chung, Y.-L.; Phys. Pol., A 2012, 121, 420−425.
Chen, H. Immobilized Rolling Circle Amplification on Extended-Gate (458) Manteca, A.; Mujika, M.; Arana, S. GMR Sensors: Magneto-
Field-Effect Transistors with Integrated Readout Circuits for Early resistive Behaviour Optimization for Biological Detection by Means of
Detection of Platelet-Derived Growth Factor. Anal. Bioanal. Chem. Superparamagnetic Nanoparticles. Biosens. Bioelectron. 2011, 26, 3705−
2016, 408, 4785−4797. 3709.
(441) Tarasov, A.; Gray, D. W.; Tsai, M.-Y.; Shields, N.; Montrose, A.; (459) Wang, W.; Wang, Y.; Tu, L.; Feng, Y.; Klein, T.; Wang, J.-P.
Creedon, N.; Lovera, P.; O’Riordan, A.; Mooney, M. H.; Vogel, E. M. A Magnetoresistive Performance and Comparison of Supermagnetic
Potentiometric Biosensor for Rapid on-Site Disease Diagnostics. Nanoparticles on Giant Magnetoresistive Sensor-Based Detection
Biosens. Bioelectron. 2016, 79, 669−678. System. Sci. Rep. 2015, 4, 5716.
(442) Brince Paul, K.; Kumar, S.; Tripathy, S.; Vanjari, S. R. K.; Singh, (460) Chu, Y. W.; Engebretson, D. A.; Carey, J. R. Bioconjugated
V.; Singh, S. G. A Highly Sensitive Self Assembled Monolayer Modified Magnetic Nanoparticles for the Detection of Bacteria. J. Biomed.
Copper Doped Zinc Oxide Nanofiber Interface for Detection of Nanotechnol. 2013, 9, 1951−1961.
Plasmodium Falciparum Histidine-Rich Protein-2: Targeted towards (461) Gao, Y. Z.; Zhang, L.; Huo, W. S.; Shi, S.; Lian, J.; Gao, Y. H. An
Rapid, Early Diagnosis of Malaria. Biosens. Bioelectron. 2016, 80, 39−46. Integrated Giant Magnetoresistance Microfluidic Immuno-Sensor for
(443) Ahn, J.-H.; Im, M.; Park, T. J.; Lee, S. Y.; Choi, Y.-K. Label-Free Rapid Detection and Quantification of D-Dimer. Chin. J. Anal. Chem.
and Real-Time Detection of Avian Influenza Using Nanowire Field 2015, 43, 802−807.
Effect Transistors. J. Biomed. Nanotechnol. 2015, 11, 1640−1643. (462) Kokkinis, G.; Jamalieh, M.; Cardoso, F.; Cardoso, S.; Keplinger,
(444) Lee, I.-K.; Jeun, M.; Jang, H.-J.; Cho, W.-J.; Lee, K. H. A Self- F.; Giouroudi, I. Magnetic-Based Biomolecule Detection Using Giant
Amplified Transistor Immunosensor under Dual Gate Operation: Magnetoresistance Sensors. J. Appl. Phys. 2015, 117, 17B731.
Highly Sensitive Detection of Hepatitis B Surface Antigen. Nanoscale (463) Sun, X.; Lei, C.; Guo, L.; Zhou, Y. Separable Detecting of
2015, 7, 16789−16797. Escherichia Coli O157H:H7 by a Giant Magneto-Resistance-Based Bio-
(445) Jang, H.-J.; Ahn, J.; Kim, M.-G.; Shin, Y.-B.; Jeun, M.; Cho, W.-J.; Sensing System. Sens. Actuators, B 2016, 234, 485−492.
Lee, K. H. Electrical Signaling of Enzyme-Linked Immunosorbent (464) Lee, J.-R.; Bechstein, D. J. B.; Ooi, C. C.; Patel, A.; Gaster, R. S.;
Assays with an Ion-Sensitive Field-Effect Transistor. Biosens. Bioelectron. Ng, E.; Gonzalez, L. C.; Wang, S. X. Magneto-Nanosensor Platform for
2015, 64, 318−323. Probing Low-Affinity Protein−protein Interactions and Identification of
(446) Lu, N.; Dai, P.; Gao, A.; Valiaho, J.; Kallio, P.; Wang, Y.; Li, T. a Low-Affinity PD-L1/PD-L2 Interaction. Nat. Commun. 2016, 7,
Label-Free and Rapid Electrical Detection of hTSH with CMOS- 12220.
Compatible Silicon Nanowire Transistor Arrays. ACS Appl. Mater. (465) Ng, E.; Nadeau, K. C.; Wang, S. X. Giant Magnetoresistive
Interfaces 2014, 6, 20378−20384. Sensor Array for Sensitive and Specific Multiplexed Food Allergen
(447) Kim, J.-Y.; Ahn, J.-H.; Moon, D.-I.; Park, T. J.; Lee, S. Y.; Choi, Detection. Biosens. Bioelectron. 2016, 80, 359−365.
Y.-K. Multiplex Electrical Detection of Avian Influenza and Human (466) Kim, D.; Lee, J.-R.; Shen, E.; Wang, S. X. Modeling and
Immunodeficiency Virus with an Underlap-Embedded Silicon Nano- Experiments of Magneto-Nanosensors for Diagnostics of Radiation
wire Field-Effect Transistor. Biosens. Bioelectron. 2014, 55, 162−167. Exposure and Cancer. Biomed. Microdevices 2013, 15, 665−671.
(448) Huang, W.; Besar, K.; LeCover, R.; Dulloor, P.; Sinha, J.; (467) Li, F.; Kosel, J. A Magnetic Biosensor System for Detection of E.
Martínez Hardigree, J. F.; Pick, C.; Swavola, J.; Everett, A. D.; Frechette, coli. IEEE Trans. Magn. 2013, 49, 3492−3495.
J.; et al. Label-Free Brain Injury Biomarker Detection Based on Highly (468) Li, F.; Kosel, J. An Efficient Biosensor Made of an
Sensitive Large Area Organic Thin Film Transistor with Hybrid Electromagnetic Trap and a Magneto-Resistive Sensor. Biosens.
Coupling Layer. Chem. Sci. 2014, 5, 416−426. Bioelectron. 2014, 59, 145−150.
(449) Issadore, D.; Park, Y. I.; Shao, H.; Min, C.; Lee, K.; Liong, M.; (469) Pizzella, V.; Penna, S. D.; Gratta, C. D.; Romani, G. L. SQUID
Weissleder, R.; Lee, H. Magnetic Sensing Technology for Molecular Systems for Biomagnetic Imaging. Supercond. Sci. Technol. 2001, 14,
Analyses. Lab Chip 2014, 14, 2385−2397. R79−R114.
(450) Syed, M. A. Advances in Nanodiagnostic Techniques for (470) Uchida, S.; Higuchi, Y.; Ueoka, Y.; Yoshida, T.; Enpuku, K.;
Microbial Agents. Biosens. Bioelectron. 2014, 51, 391−400. Adachi, S.; Tanabe, K.; Tsukamoto, A.; Kandori, A. Highly Sensitive
(451) Shao, H.; Min, C.; Issadore, D.; Liong, M.; Yoon, T.-J.; Liquid-Phase Detection of Biological Targets With Magnetic Markers
Weissleder, R.; Lee, H. Magnetic Nanoparticles and microNMR for and High SQUID. IEEE Trans. Appl. Supercond. 2014, 24, 1−5.
Diagnostic Applications. Theranostics 2012, 2, 55−65. (471) Bhuiya, A. K.; Asai, M.; Watanabe, H.; Hirata, T.; Higuchi, Y.;
(452) Haun, J. B.; Yoon, T.-J.; Lee, H.; Weissleder, R. Magnetic Yoshida, T.; Enpuku, K. Characterization of Magnetic Markers and
Nanoparticle Biosensors. Wiley Interdisciplinary Reviews: Nanomedicine Sensors for Liquid-Phase Immunoassays Using Brownian Relaxation.
and Nanobiotechnology 2010, 2, 291−304. IEEE Trans. Magn. 2012, 48, 2838−2841.
(453) Chen, Y. P.; Zou, M. q.; Qi, C.; Xie, M.-X.; Wang, D.-N.; Wang, (472) Orlov, A. V.; Bragina, V. A.; Nikitin, M. P.; Nikitin, P. I. Rapid
Y.-F.; Xue, Q.; Li, J.-F.; Chen, Y. Immunosensor Based on Magnetic Dry-Reagent Immunomagnetic Biosensing Platform Based on Volu-

10032 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

metric Detection of Nanoparticles on 3D Structures. Biosens. Bioelectron. Nanoprobes and HRP-Antibody Co-Immobilized Nano Gold as Signal
2016, 79, 423−429. Tags. Sens. Actuators, B 2013, 178, 494−500.
(473) Rettcher, S.; Jungk, F.; Kühn, C.; Krause, H.-J.; Nölke, G.; (492) Juřík, T.; Skládal, P. Detection of Hydrogen Peroxide and
Commandeur, U.; Fischer, R.; Schillberg, S.; Schröper, F. Simple and Glucose by Enzyme Product Precipitation on Sensor Surface. Chem.
Portable Magnetic Immunoassay for Rapid Detection and Sensitive Papers 2015, 69, 167−175.
Quantification of Plant Viruses. Appl. Environ. Microbiol. 2015, 81, (493) Chauhan, R.; Singh, J.; Solanki, P. R.; Basu, T.; O’Kennedy, R.;
3039−3048. Malhotra, B. D. Electrochemical Piezoelectric Reusable Immunosensor
(474) Zheng, Y.; Shang, N.; Haddad, P. S.; Sawan, M. A Microsystem for Aflatoxin B1 Detection. Biochem. Eng. J. 2015, 103, 103−113.
for Magnetic Immunoassay Based on Planar Microcoil Array. IEEE (494) Chauhan, R.; Singh, J.; Solanki, P. R.; Manaka, T.; Iwamoto, M.;
Trans. Biomed. Circ. Syst 2016, 10, 477−486. Basu, T.; Malhotra, B. D. Label-Free Piezoelectric Immunosensor
(475) Chang, A.-Y.; Lu, M. S.-C. A CMOS Magnetic Microbead-Based Decorated with Gold Nanoparticles: Kinetic Analysis and Biosensing
Capacitive Biosensor Array with on-Chip Electromagnetic Manipu- Application. Sens. Actuators, B 2016, 222, 804−814.
lation. Biosens. Bioelectron. 2013, 45, 6−12. (495) Ly, T. N.; Park, S.; Park, S. J. Detection of HIV-1 Antigen by
(476) Yang, Z.; Lei, J.; Sun, X.; Lei, C.; Zhou, Y.; Liu, Y. A Dynabeads- Quartz Crystal Microbalance Using Gold Nanoparticles. Sens. Actuators,
Labeled Immunoassay Based on a Fluxgate Biosensor for the Detection B 2016, 237, 452−458.
of Biomarkers. Anal. Methods 2015, 7, 2391−2398. (496) Ding, P.; Liu, R.; Liu, S.; Mao, X.; Hu, R.; Li, G. Reusable Gold
(477) Bogue, R. Recent developments in MEMS sensors: a review of Nanoparticle Enhanced QCM Immunosensor for Detecting C-Reactive
applications, markets and technologies. Sens. Rev. 2013, 33, 300−304. Protein. Sens. Actuators, B 2013, 188, 1277−1283.
(478) Sun, X.; Lei, C.; Guo, L.; Zhou, Y. Sandwich Immunoassay for (497) Reddy, S. B.; Mainwaring, D. E.; Al Kobaisi, M.; Zeephongsekul,
the Prostate Specific Antigen Using a Micro-Fluxgate and Magnetic P.; Fecondo, J. V. Acoustic Wave Immunosensing of a Meningococcal
Bead Labels. Microchim. Acta 2016, 183, 2385−2393. Antigen Using Gold Nanoparticle-Enhanced Mass Sensitivity. Biosens.
(479) Kim, C.-B.; Lim, E.-G.; Shin, S. W.; Krause, H. J.; Hong, H. Bioelectron. 2012, 31, 382−387.
Magnetic Immunoassay Platform Based on the Planar Frequency (498) Salam, F.; Uludag, Y.; Tothill, I. E. Real-Time and Sensitive
Mixing Magnetic Technique. Biosens. Bioelectron. 2016, 83, 293−299. Detection of Salmonella Typhimurium Using an Automated Quartz
(480) Sauerbrey, G. Verwendung von Schwingquarzen Zur Wägung Crystal Microbalance (QCM) Instrument with Nanoparticles Ampli-
Dünner Schichten Und Zur Mikrowägung. Eur. Phys. J. A 1959, 155, fication. Talanta 2013, 115, 761−767.
206−222. (499) Masdor, N. A.; Altintas, Z.; Tothill, I. E. Sensitive Detection of
(481) Ramos-Jesus, J.; Pontes-de-Carvalho, L. C.; Melo, S. M. B.; Campylobacter Jejuni Using Nanoparticles Enhanced QCM Sensor.
Alcântara-Neves, N. M.; Dutra, R. F. A Gold Nanoparticle Piezoelectric Biosens. Bioelectron. 2016, 78, 328−336.
Immunosensor Using a Recombinant Antigen for Detecting Leishmania (500) Kohn, K. W.; Zeeberg, B. M.; Reinhold, W. C.; Pommier, Y.
Infantum Antibodies in Canine Serum. Biochem. Eng. J. 2016, 110, 43− Gene Expression Correlations in Human Cancer Cell Lines Define
50. Molecular Interaction Networks for Epithelial Phenotype. PLoS One
(482) Ding, J.; Lu, Z.; Wang, R.; Shen, G.; Xiao, L. Piezoelectric
2014, 9 (6), e99269.
Immunosensor with Gold Nanoparticles Enhanced Competitive
(501) Duffy, M. J. Tumor Markers in Clinical Practice: A Review
Immunoreaction Technique for 2,4-Dichlorophenoxyacetic Acid
Focusing on Common Solid Cancers. Med. Princ. Pract. 2013, 22, 4−11.
Quantification. Sens. Actuators, B 2014, 193, 568−573.
(502) Wu, L.; Qu, X. Cancer biomarker detection: recent achievements
(483) Chu, P.-T.; Lin, C.-S.; Chen, W.-J.; Chen, C.-F.; Wen, H.-W.
and challenges. Chem. Soc. Rev. 2015, 44 (10), 2963−2997.
Detection of Gliadin in Foods Using a Quartz Crystal Microbalance
(503) Topkaya, S. N.; Azimzadeh, M.; Ozsoz, M. Electrochemical
Biosensor That Incorporates Gold Nanoparticles. J. Agric. Food Chem.
Biosensors for Cancer Biomarkers Detection: Recent Advances and
2012, 60, 6483−6492.
Challenges. Electroanalysis 2016, 28, 1402−1419.
(484) Kleo, K.; Schäfer, D.; Klar, S.; Jacob, D.; Grunow, R.; Lisdat, F.
(504) Yu, M.; Stott, S.; Toner, M.; Maheswaran, S.; Haber, D. A.
Immunodetection of Inactivated Francisella Tularensis Bacteria by
Using a Quartz Crystal Microbalance with Dissipation Monitoring. Anal. Circulating Tumor Cells: Approaches to Isolation and Characterization.
Bioanal. Chem. 2012, 404, 843−851. J. Cell Biol. 2011, 192, 373−382.
(485) Yan, Z.; Yang, M.; Wang, Z.; Zhang, F.; Xia, J.; Shi, G.; Xia, L.; Li, (505) Riethdorf, S.; Fritsche, H.; Muller, V.; Rau, T.; Schindlbeck, C.;
Y.; Xia, Y.; Xia, L. A Label-Free Immunosensor for Detecting Common Rack, B.; Janni, W.; Coith, C.; Beck, K.; Janicke, F.; Jackson, S.; Gornet,
Acute Lymphoblastic Leukemia Antigen (CD10) Based on Gold T.; Cristofanilli, M.; Pantel, K. Detection of Circulating Tumor Cells in
Nanoparticles by Quartz Crystal Microbalance. Sens. Actuators, B 2015, Peripheral Blood of Patients with Metastatic Breast Cancer: A
210, 248−253. Validation Study of the CellSearch System. Clin. Cancer Res. 2007, 13,
(486) Luo, Y.; Liu, T.; Zhu, J.; Kong, L.; Wang, W.; Tan, L. Label-Free 920−928.
and Sensitive Detection of Thrombomodulin, a Marker of Endothelial (506) Yang, K.; Hu, Y.; Dong, N. A Novel Biosensor Based on
Cell Injury, Using Quartz Crystal Microbalance. Anal. Chem. 2015, 87, Competitive SERS Immunoassay and Magnetic Separation (for
11277−11284. Accurate and Sensitive Detection of Chloramphenicol. Biosens.
(487) Voinova, M. V.; Jonson, M.; Kasemo, B. Missing Mass” Effect in Bioelectron. 2016, 80, 373−377.
Biosensor’s QCM Applications. Biosens. Bioelectron. 2002, 17, 835−841. (507) Ashwin, H. M.; Stead, S. L.; Taylor, J. C.; Startin, J. R.;
(488) Liu, W.; Huang, R.; Qi, W.; Wang, M.; Su, R.; He, Z. A Gas-Phase Richmond, S. F.; Homer, V.; Bigwood, T.; Sharman, M. Development
Amplified Quartz Crystal Microbalance Immunosensor Based on and Validation of Screening and Confirmatory Methods for the
Catalase Modified Immunoparticles. Analyst 2015, 140, 1174−1181. Detection of Chloramphenicol and Chloramphenicol Glucuronide
(489) Chen, S.; Pan, D.; Gan, N.; Wang, D.; Zhu, Y.; Li, T.; Cao, Y.; Using SPR Biosensor and Liquid Chromatography−tandem Mass
Hu, F.; Jiang, S. A QCM Immunosensor to Rapidly Detect Ractopamine Spectrometry. Anal. Chim. Acta 2005, 529, 103−108.
Using Bio-Polymer Conjugate and Magnetic β-Cyclodextrins. Sens. (508) Oaks, J. L.; Gilbert, M.; Virani, M. Z.; Watson, R. T.; Meteyer, C.
Actuators, B 2015, 211, 523−530. U.; Rideout, B. A.; Shivaprasad, H. L.; Ahmed, S.; Iqbal Chaudhry, M. J.;
(490) Akter, R.; Rhee, C. K.; Rahman, M. A. A Highly Sensitive Quartz Arshad, M.; Mahmood, S.; Ali, A.; Ahmed Khan, A. Diclofenac Residues
Crystal Microbalance Immunosensor Based on Magnetic Bead- as the Cause of Vulture Population Decline in Pakistan. Nature 2004,
Supported Bienzymes Catalyzed Mass Enhancement Strategy. Biosens. 427, 630−633.
Bioelectron. 2015, 66, 539−546. (509) Rezaei, B.; Askarpour, N.; Ensafi, A. A. A Novel Sensitive
(491) Zhou, J.; Gan, N.; Li, T.; Zhou, H.; Li, X.; Cao, Y.; Wang, L.; Doxorubicin Impedimetric Immunosensor Based on a Specific
Sang, W.; Hu, F. Ultratrace Detection of C-Reactive Protein by a Monoclonal Antibody−Gold Nanoaprticle−Sol−Gel Modified Elec-
Piezoelectric Immunosensor Based on Fe3O4@SiO2 Magnetic Capture trode. Talanta 2014, 119, 164−169.

10033 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(510) Zhang, Y.-W.; Shi, J.; Li, Y.-J.; Wei, L. Cardiomyocyte Death in (530) Wu, C. C.; Ku, B. C.; Ko, C. H.; Chiu, C. C.; Wang, G. J.; Yang, Y.
Doxorubicin-Induced Cardiotoxicity. Arch. Immunol. Ther. Exp. 2009, H.; Wu, S. J. Electrochemical impedance spectroscopy analysis of A-beta
57, 435−445. (1−42) peptide using a nanostructured biochip. Electrochim. Acta 2014,
(511) Finegold, S. M. Toxicity of Kanamycin in Adults. Ann. N. Y. Acad. 134, 249−257.
Sci. 1966, 132, 942−956. (531) Wang, H.; Li, G.; Zhang, Y.; Zhu, M.; Ma, H.; Du, B.; Wei, Q.;
(512) Zengin, A.; Tamer, U.; Caykara, T. Extremely Sensitive Wan, Y. Nanobody-Based Electrochemical Immunoassay for Ultra-
Sandwich Assay of Kanamycin Using Surface-Enhanced Raman sensitive Determination of Apolipoprotein-A1 Using Silver Nano-
Scattering of 2-Mercaptobenzothiazole Labeled Gold@silver Nano- particles Loaded Nanohydroxyapatite as Label. Anal. Chem. 2015, 87,
particles. Anal. Chim. Acta 2014, 817, 33−41. 11209−11214.
(513) Sun, X.; Wu, L.; Ji, J.; Jiang, D.; Zhang, Y.; Li, Z.; Zhang, G.; (532) Chen, H. C.; Chen, Y. T.; Tsai, R. Y.; Chen, M. C.; Chen, S. L.;
Zhang, H. Longitudinal Surface Plasmon Resonance Assay Enhanced by Xiao, M. C.; Chen, C. L.; Hua, M. Y. A Sensitive and Selective Magnetic
Magnetosomes for Simultaneous Detection of Pefloxacin and Micro- Graphene Composite-Modified Polycrystalline-Silicon Nanowire Field-
cystin-LR in Seafoods. Biosens. Bioelectron. 2013, 47, 318−323. Effect Transistor for Bladder Cancer Diagnosis. Biosens. Bioelectron.
(514) Monk, J. P.; Campoli-Richards, D. M. Ofloxacin. Drugs 1987, 33, 2015, 66, 198−207.
346−391. (533) Zhou, S. W.; Wang, Y. Y.; Zhu, J. J. Simultaneous Detection of
(515) Todd, P. A.; Faulds, D. Ofloxacin. Drugs 1991, 42, 825−876. Tumor Cell Apoptosis Regulators Bcl-2 and Bax through a Dual-Signal-
(516) Zang, S.; Liu, Y.; Lin, M.; Kang, J.; Sun, Y.; Lei, H. A Dual Marked Electrochemical Immunosensor. ACS Appl. Mater. Interfaces
Amplified Electrochemical Immunosensor for Ofloxacin: Polypyrrole 2016, 8, 7674−7682.
Film-Au Nanocluster as the Matrix and Multi-Enzyme-Antibody (534) Zhang, X.; Wang, H.; Yang, C.; Du, D.; Lin, Y. Preparation,
Functionalized Gold Nanorod as the Label. Electrochim. Acta 2013, Characterization of Fe3O4 at TiO2 magnetic nanoparticles and their
90, 246−253. application for immunoassay of biomarker of exposure to organo-
(517) Wang, H.; Zhang, Y.; Li, H.; Du, B.; Ma, H.; Wu, D.; Wei, Q. A phosphorus pesticides. Biosens. Bioelectron. 2013, 41, 669−674.
Silver−Palladium Alloy Nanoparticle-Based Electrochemical Biosensor (535) Geng, P.; Fu, Y.; Yang, M.; Sun, Q.; Liu, K.; Zhang, X.; Xu, Z.;
for Simultaneous Detection of Ractopamine, Clenbuterol and Zhang, W. Amplified Electrochemical Immunosensor for Calmodulin
Salbutamol. Biosens. Bioelectron. 2013, 49, 14−19. Detection Based on Gold-Silver-Graphene Hybrid Nanomaterials and
(518) Alhareth, K.; Vauthier, C.; Gueutin, C.; Ponchel, G.; Moussa, F. Enhanced Gold Nanorods Labels. Electroanalysis 2014, 26, 2002−2009.
HPLC Quantification of Doxorubicin in Plasma and Tissues of Rats (536) Johari-Ahar, M.; Rashidi, M. R.; Barar, J.; Aghaie, M.;
Treated with Doxorubicin Loaded Poly(alkylcyanoacrylate) Nano- Mohammadnejad, D.; Ramazani, A.; Karami, P.; Coukos, G.; Omidi,
particles. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2012, 887− Y. An Ultra-Sensitive Impedimetric Immunosensor for Detection of the
888, 128−132. Serum Oncomarker CA-125 in Ovarian Cancer Patients. Nanoscale
(519) Morales-Trejo, F.; León, S. V.; Escobar-Medina, A.; Gutiérrez- 2015, 7, 3768−3779.
Tolentino, R. Application of High-Performance Liquid chromatog- (537) Zhu, H.; Fan, G. C.; Abdel-Halim, E. S.; Zhang, J. R.; Zhu, J. J.
raphy−UV Detection to Quantification of Clenbuterol in Bovine Liver Ultrasensitive Photoelectrochemical Immunoassay for CA19−9 Detec-
Samples. J. Food Drug Anal. 2013, 21, 414−420. tion Based on CdSe@ZnS Quantum Dots Sensitized TiO2 NWs/Au
(520) Impens, S.; Reybroeck, W.; Vercammen, J.; Courtheyn, D.; Hybrid Structure Amplified by Quenching Effect of Ab(2)@V2+
Ooghe, S.; De Wasch, K.; Smedts, W.; De Brabander, H. Screening and Conjugates. Biosens. Bioelectron. 2016, 77, 339−346.
Confirmation of Chloramphenicol in Shrimp Tissue Using ELISA in (538) Sha, Y.; Guo, Z.; Chen, B.; Wang, S.; Ge, G.; Qiu, B.; Jiang, X. A
Combination with GC−MS2 and LC−MS2. Anal. Chim. Acta 2003, One-Step Electrochemiluminescence Immunosensor Preparation for
483, 153−163. Ultrasensitive Detection of Carbohydrate Antigen 19−9 Based on
(521) He, L.; Su, Y.; Zeng, Z.; Liu, Y.; Huang, X. Determination of Multifunctionalized Graphene Oxide. Biosens. Bioelectron. 2015, 66,
Ractopamine and Clenbuterol in Feeds by Gas Chromatography−mass 468−473.
Spectrometry. Anim. Feed Sci. Technol. 2007, 132, 316−323. (539) Zhang, L.; He, Y.; Wang, H.; Yuan, Y.; Yuan, R.; Chai, Y. A Self-
(522) Lu, H.; Yuan, G.; He, Q.; Chen, H. Rapid Analysis of Enhanced Electrochemiluminescence Immunosensor Based on L-Lys-
Anthracycline Antibiotics Doxorubicin and Daunorubicin by Microchip Ru(dcbpy)(3)(2+) Functionalized Porous Six Arrises Column Nano-
Capillary Electrophoresis. Microchem. J. 2009, 92, 170−173. rods for Detection of CA15−3. Biosens. Bioelectron. 2015, 74, 924−930.
(523) Horstkötter, C.; Blaschke, G. Stereoselective Determination of (540) Cui, Y.; Tang, D.; Liu, B.; Chen, H.; Zhang, B.; Chen, G.
Ofloxacin and Its Metabolites in Human Urine by Capillary Electro- Biofunctionalized Dendritic Polyaniline Nanofibers for Sensitive
phoresis Using Laser-Induced Fluorescence Detection. J. Chromatogr., Electrochemical Immunoassay of Biomarkers. Analyst 2012, 137,
Biomed. Appl. 2001, 754, 169−178. 1656−1662.
(524) He, P.; Shen, L.; Liu, R.; Luo, Z.; Li, Z. Direct Detection of β- (541) Zhou, S.; Zheng, W.; Chen, Z.; Tu, D.; Liu, Y.; Ma, E.; Li, R.;
Agonists by Use of Gold Nanoparticle-Based Colorimetric Assays. Anal. Zhu, H.; Huang, M.; Chen, X. Dissolution-Enhanced Luminescent
Chem. 2011, 83, 6988−6995. Bioassay Based on Inorganic Lanthanide Nanoparticles. Angew. Chem.,
(525) Martínez Ferreras, F.; Wolfbeis, O. S.; Gorris, H. H. Dual Int. Ed. 2014, 53, 12498−12502.
Lifetime Referenced Fluorometry for the Determination of Doxorubicin (542) Quyen, T. T. B.; Chang, C.-C.; Su, W.-N.; Uen, Y.-H.; Pan, C.-J.;
in Urine. Anal. Chim. Acta 2012, 729, 62−66. Liu, J.-Y.; Rick, J.; Lin, K.-Y.; Hwang, B.-J. Self-Focusing Au@SiO2
(526) Francis, P. S.; Adcock, J. L. Chemiluminescence Methods for the Nanorods with Rhodamine 6G as Highly Sensitive SERS Substrate for
Determination of Ofloxacin. Anal. Chim. Acta 2005, 541, 3−12. Carcinoembryonic Antigen Detection. J. Mater. Chem. B 2014, 2, 629−
(527) Zhang, B.; Liu, B.; Zhou, J.; Tang, J.; Tang, D. Additional 636.
Molecular Biological Amplification Strategy for Enhanced Sensitivity of (543) Zeng, H.; Agyapong, D. A. Y.; Li, C.; Zhao, R.; Yang, H.; Wu, C.;
Monitoring Low-Abundance Protein with Dual Nanotags. ACS Appl. Jiang, Y.; Liu, Y. A Carcinoembryonic Antigen Optoelectronic
Mater. Interfaces 2013, 5, 4479−4485. Immunosensor Based on Thiol-Derivative-Nanogold Labeled Anti-
(528) Zhang, X.; Tan, X.; Zhang, B.; Miao, W.; Zou, G. Spectrum- CEA Antibody Nanomaterial and Gold Modified ITO. Sens. Actuators, B
Based Electrochemiluminescent Immunoassay with Ternary CdZnSe 2015, 221, 22−27.
Nanocrystals as Labels. Anal. Chem. 2016, 88, 6947−6953. (544) He, S.; Wang, Q.; Yu, Y.; Shi, Q.; Zhang, L.; Chen, Z. One-Step
(529) Xia, C.; Li, Y.; Yuan, G.; Guo, Y.; Yu, C. Immunoassay for serum Synthesis of Potassium Ferricyanide-Doped Polyaniline Nanoparticles
amyloid A using a glassy carbon electrode modified with carboxy- for Label-Free Immunosensor. Biosens. Bioelectron. 2015, 68, 462−467.
polypyrrole, multiwalled carbon nanotubes, ionic liquid and chitosan. (545) Wang, Y.; Li, Y.; Hu, L.; Ren, X.; Du, B.; Ma, H.; Wei, Q.
Microchim. Acta 2015, 182, 1395−1402. Application of Three-Dimensional Flower-Like Nanomaterials in the

10034 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Fabrication of Sandwich-Type Electrochemical Immunosensors. RSC (562) Lu, J.; Liu, S.; Ge, S.; Yan, M.; Yu, J.; Hu, X. Ultrasensitive
Adv. 2015, 5, 88160−88165. Electrochemical Immunosensor Based on Au Nanoparticles Dotted
(546) Rong, Q.; Han, H.; Feng, F.; Ma, Z. Network Nanostructured Carbon Nanotube-Graphene Composite and Functionalized Meso-
Polypyrrole Hydrogel/Au Composites as Enhanced Electrochemical porous Materials. Biosens. Bioelectron. 2012, 33, 29−35.
Biosensing Platform. Sci. Rep. 2015, 5, 11440. (563) Wu, D.; Zhang, Y.; Shi, L.; Cai, Y.; Ma, H.; Du, B.; Wei, Q.
(547) Hou, L.; Cui, Y.; Xu, M.; Gao, Z.; Huang, J.; Tang, D. Graphene Electrochemical Immunosensor for Ultrasensitive Detection of Human
Oxide-Labeled Sandwich-Type Impedimetric immunoassay with Chorionic Gonadotropin Based on Pd@SBA-15. Electroanalysis 2013,
sensitive Enhancement Based on Enzymatic 4-Chloro-1-naphthol 25, 427−432.
oxidation. Biosens. Bioelectron. 2013, 47, 149−156. (564) Teixeira, S.; Ferreira, N. S.; Conlan, R. S.; Guy, O. J.; Sales, M. G.
(548) Feng, T.; Qiao, X.; Wang, H.; Sun, Z.; Hong, C. A Sandwich- F. Chitosan/AuNPs Modified Graphene Electrochemical Sensor for
Type Electrochemical Immunosensor for Carcinoembryonic Antigen Label-Free Human Chorionic Gonadotropin Detection. Electroanalysis
Based on Signal Amplification Strategy of Optimized Ferrocene 2014, 26, 2591−2598.
Functionalized Fe3O4@SiO2 as Labels. Biosens. Bioelectron. 2016, 79, (565) Yagati, A. K.; Park, J.; Cho, S. Reduced Graphene Oxide
48−54. Modified the Interdigitated Chain Electrode for an Insulin Sensor.
(549) Vabbina, P. K.; Kaushik, A.; Pokhrel, N.; Bhansali, S.; Pala, N.
Sensors 2016, 16, 109.
Electrochemical Cortisol Immunosensors Based on Sonochemically (566) Singh, V.; Krishnan, S. Voltammetric Immunosensor Assembled
Synthesized Zinc Oxide 1D Nanorods and 2D Nanoflakes. Biosens.
on Carbon-Pyrenyl Nanostructures for Clinical Diagnosis of Type of
Bioelectron. 2015, 63, 124−130.
Diabetes. Anal. Chem. 2015, 87, 2648−2654.
(550) Ramanathan, M.; Patil, M.; Epur, R.; Yun, Y.; Shanov, V.; Schulz,
(567) Inci, F.; Filippini, C.; Baday, M.; Ozen, M. O.; Calamak, S.;
M.; Heineman, W. R.; Datta, M. K.; Kumta, P. N. Gold-Coated Carbon
Nanotube Electrode Arrays: Immunosensors for Impedimetric Durmus, N. G.; Wang, S. Q.; Hanhauser, E.; Hobbs, K. S.; Juillard, F.;
Detection of Bone Biomarkers. Biosens. Bioelectron. 2016, 77, 580−588. et al. Multitarget, Quantitative Nanoplasmonic Electrical Field-
(551) Mi, L.; Wang, P. Y.; Yan, J. R.; Qian, J.; Lu, J. S.; Yu, J. C.; Wang, Enhanced Resonating Device ((NERD)-R-2) for Diagnostics. Proc.
Y. Z.; Liu, H.; Zhu, M.; Wan, Y. K.; Liu, S. Q. A Novel Natl. Acad. Sci. U. S. A. 2015, 112, E4354−E4363.
Photoelectrochemical Immunosensor by Integration of Nanobody (568) Yang, T.; Wang, S.; Jin, H.; Bao, W.; Huang, S.; Wang, J. An
and TiO2 Nanotubes for Sensitive Detection of Serum Cystatin C. Anal. Electrochemical Impedance Sensor for the Label-Free Ultrasensitive
Chim. Acta 2016, 902, 107−114. Detection of Interleukin-6 Antigen. Sens. Actuators, B 2013, 178, 310−
(552) Wang, H. Q.; Rong, Q. F.; Ma, Z. F. Polyhydroquinone- 315.
Graphene Composite as New Redox Species for Sensitive Electro- (569) Wang, G.; He, X.; Chen, L.; Zhu, Y.; Zhang, X. Ultrasensitive IL-
chemical Detection of Cytokeratins Sntigen 21-1. Sci. Rep. 2016, 6, 6 Electrochemical Immunosensor Based on Au Nanoparticles-
30623. Graphene-Silica Biointerface. Colloids Surf., B 2014, 116, 714−719.
(553) Asav, E.; Sezginturk, M. K. A Novel Impedimetric Disposable (570) Jiang, W.; Li, T.; Qu, F.; Ding, L.; Shen, Z.; Yang, M.
Immunosensor for Rapid Detection of a Potential Cancer Biomarker. Electrochemical Immunosensor for the Detection of Interleukin-17
Int. J. Biol. Macromol. 2014, 66, 273−280. Based on Cd2+ Incorporated Polystyrene Spheres. Sens. Actuators, B
(554) Zhang, Y.; Ren, W. Carbon Nanosphere-Functionalized 2013, 185, 658−662.
Graphene Nanosheets for Sensing Biomolecules Based on Platinum (571) Li, Y.; He, J.; Xia, C.; Gao, L.; Yu, C. Ultrasensitive
Nanoflower Labeling. Anal. Methods 2013, 5, 3379−3385. Electrochemical Immunosensor Based on Orderly Oriented Conductive
(555) Yu, X.; Wang, Y.; Chen, X.; Wu, K.; Chen, D.; Ma, M.; Huang, Z.; Wires for the Detection of Human Monocyte Chemotactic Protein-1 in
Wu, W.; Li, C. White-Light-Exciting, Layer-by-Layer-Assembled Serum. Biosens. Bioelectron. 2015, 70, 392−397.
ZnCdHgSe Quantum Dots/Polymerized Ionic Liquid Hybrid Film (572) Guo, Q.; Li, X.; Shen, C.; Zhang, S.; Qi, H.; Li, T.; Yang, M.
for Highly Sensitive Photoelectrochemical lmmunosensing of Neuron Electrochemical Immunoassay for the Protein Biomarker Mucin 1 and
Specific Enolase. Anal. Chem. 2015, 87, 4237−4244. for MCF-7 Cancer Cells Based on Signal Enhancement by Silver
(556) Wang, Y.; Vaidyanathan, R.; Shiddiky, M. J. A.; Trau, M. Nanoclusters. Microchim. Acta 2015, 182, 1483−1489.
Enabling Rapid and Specific Surface-Enhanced Raman Scattering (573) He, Y.; Wang, Y.; Yang, X.; Xie, S. B.; Yuan, R.; Chai, Y. Q. Metal
Immunoassay Using Nanoscaled Surface Shear Forces. ACS Nano Organic Frameworks Combining CoFe2O4 Magnetic Nanoparticles as
2015, 9, 6354−6362. Highly Efficient SERS Sensing Platform for Ultrasensitive Detection of
(557) Omidfar, K.; Darzianiazizi, M.; Ahmadi, A.; Daneshpour, M.; N-Terminal Pro-Brain Natriuretic Peptide. ACS Appl. Mater. Interfaces
Shirazi, H. A High Sensitive Electrochemical Nanoimmunosensor Based 2016, 8, 7683−7690.
on Fe3O4/TMC/Au Nanocompo Dite and Pt-Modified Electrode for (574) Xu, W.; He, J.; Gao, L.; Zhang, J.; Yu, C. Immunoassay for Netrin
the Detection of Cancer Biomarker Epidermal Growth Factor Receptor. 1 via a Glassy Carbon Electrode Modified with Multi-Walled Carbon
Sens. Actuators, B 2015, 220, 1311−1319.
Nanotubes, Thionine and Gold Nanoparticles. Microchim. Acta 2015,
(558) Fernandez-Baldo, M. A.; Ortega, F. G.; Pereira, S. V.; Bertolino,
182, 2115−2122.
F. A.; Serrano, M. J.; Lorente, J. A.; Raba, J.; Messina, G. A.
(575) Sharma, A.; Hong, S.; Singh, R.; Jang, J. Single-Walled Carbon
Nanostructured Platform Integrated into a Microfluidic Immunosensor
Coupled to Laser-Induced Fluorescence for the Epithelial Cancer Nanotube Based Transparent Immunosensor for Detection of a
Biomarker Determination. Microchem. J. 2016, 128, 18−25. Prostate Cancer Biomarker Osteopontin. Anal. Chim. Acta 2015, 869,
(559) Han, J.; Zhuo, Y.; Chai, Y. Q.; Xiang, Y.; Yuan, R. New Type of 68−73.
Redox Nanoprobe: C-60-Based Nanomaterial and Its Application in (576) Shen, W. J.; Zhuo, Y.; Chai, Y. Q.; Yang, Z. H.; Han, J.; Yuan, R.
Electrochemical Immunoassay for Doping Detection. Anal. Chem. 2015, Enzyme-Free Electrochemical Immunosensor Based on Host-Guest
87, 1669−1675. Nanonets Catalyzing Amplification for Procalcitonin Detection. ACS
(560) Cincotto, F. H.; Martinez-Garcia, G.; Yanez-Sedeno, P.; Appl. Mater. Interfaces 2015, 7, 4127−4134.
Canevari, T. C.; Machado, S. A. S.; Pingarron, J. M. Electrochemical (577) Yang, Z. H.; Zhuo, Y.; Yuan, R.; Chai, Y. Q. Electrochemical
Immunosensor for Ethinylestradiol using Diazonium Salt Grafting onto Activity and Electrocatalytic Property of Cobalt Phthalocyanine
Silver Nanoparticles-Silica-Graphene Oxide Hybrids. Talanta 2016, Nanoparticles-Based Immunosensor for Sensitive Detection of
147, 328−334. Procalcitonin. Sens. Actuators, B 2016, 227, 212−219.
(561) Yen, L. C.; Pan, T. M.; Lee, C. H.; Chao, T. S. Label-Free and (578) Akter, R.; Rahman, Md. A.; Rhee, C. K. Amplified Electro-
Real-Time Detection of Ferritin using a Horn-Like Polycrystalline- chemical Detection of a Cancer Biomarker by Enhanced Precipitation
Silicon Nanowire Field-Effect Transistor Biosensor. Sens. Actuators, B Using Horseradish Peroxidase Attached on Carbon Nanotubes. Anal.
2016, 230, 398−404. Chem. 2012, 84, 6407−6415.

10035 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(579) de la Rica, R.; Stevens, M. M. Plasmonic ELISA for the Au Nanocomposites as Enhanced Sensing Signal for Selective Detection
Ultrasensitive Detection of Disease Biomarkers with the Naked Eye. of Biomarker with High Isoelectric Point. Sens. Actuators, B 2015, 216,
Nat. Nanotechnol. 2012, 7, 821−824. 307−315.
(580) Uludag, Y.; Tothill, I. E. Cancer Biomarker Detection in Serum (597) Li, T.; Si, Z.; Hu, L.; Qi, H.; Yang, M. Prussian Blue-
Samples Using Surface Plasmon Resonance and Quartz Crystal Functionalized Ceria Nanoparticles as Label for Ultrasensitive
Microbalance Sensors with Nanoparticle Signal Amplification. Anal. Detection of Tumor Necrosis Factor-alpha. Sens. Actuators, B 2012,
Chem. 2012, 84, 5898−5904. 171-172, 1060−1065.
(581) Moon, J.-M.; Kim, Y. H.; Cho, Y. A nanowire-Based Label-Free (598) Sun, Z.; Deng, L.; Gan, H.; Shen, R.; Yang, M.; Zhang, Y.
Immunosensor: Direct Incorporation of a PSA Antibody in Electro- Sensitive Immunosensor for Tumor Necrosis Factor alpha Based on
polymerized Polypyrrole. Biosens. Bioelectron. 2014, 57, 157−161. Dual Signal Amplification of Ferrocene Modified Self-Assembled
(582) Du, S.; Guo, Z.; Chen, B.; Sha, Y.; Jiang, X.; Li, X.; Gan, N.; Peptide Nanowire and Glucose oxidase Functionalized Gold Nanorod.
Wang, S. Electrochemiluminescence Immunosensor for Tumor Biosens. Bioelectron. 2013, 39, 215−219.
Markers Based on Biological Barcode Mode with Conductive (599) Li, M.; Cushing, S. K.; Zhang, J.; Suri, S.; Evans, R.; Petros, W. P.;
Nanospheres. Biosens. Bioelectron. 2014, 53, 135−141. Gibson, L. F.; Ma, D.; Liu, Y.; Wu, N. Three-Dimensional Hierarchical
(583) Zhuang, J.; Tang, D.; Lai, W.; Xu, M.; Tang, D. Target-Induced Plasmonic Nano-Architecture Enhanced Surface-Enhanced Raman
Nano-Enzyme Reactor Mediated Hole-Trapping for High-Throughput Scattering Immunosensor for Cancer Biomarker Detection in Blood
Immunoassay Based on a Split-Type Photoelectrochemical Detection Plasma. ACS Nano 2013, 7, 4967−4976.
Strategy. Anal. Chem. 2015, 87, 9473−9480. (600) Quynh, L. M.; Nam, N. H.; Kong, K.; Nhung, N. T.; Notingher,
(584) Kadimisetty, K.; Malla, S.; Sardesai, N. P.; Joshi, A. A.; Faria, R. I.; Henini, M.; Luong, N. H. Surface-Enhanced Raman Spectroscopy
C.; Lee, N. H.; Rusling, J. F. Automated Multiplexed ECL Study of 4-ATP on Gold Nanoparticles for Basal Cell Carcinoma
Immunoarrays for Cancer Biomarker Proteins. Anal. Chem. 2015, 87, Fingerprint Detection. J. Electron. Mater. 2016, 45, 2563−2568.
4472−4478. (601) Fu, J.; Shi, Z.; Li, M.; Wang, Y.; Yu, L. Label-Free Detection of
(585) Wang, X.; Gao, C.; Shu, G.; Wang, Y.; Liu, X. The Enzyme Chondroitin Sulphate Proteoglycan 4 by a Polyaniline/Graphene
Electrocatalytic Immunosensor Based on Functional Composite Nanocomposite Functionalized Impedimetric Immunosensor. J. Nano-
Nanofibers for Sensitive Detection of Tumor Suppressor Protein p53. mater. 2016, 2016, 7834657.
J. Electroanal. Chem. 2015, 756, 101−107. (602) Liu, Y.; Zhu, F.; Dan, W.; Fu, Y.; Liu, S. Construction of Carbon
(586) Zhu, Y. C.; Zhang, N.; Ruan, Y. F.; Zhao, W. W.; Xu, J. J.; Chen, Nanotube Based Nanoarchitectures for Selective Impedimetric
H. Y. Alkaline Phosphatase Tagged Antibodies on Gold Nanoparticles/ Detection of Cancer Cells in Whole Blood. Analyst 2014, 139, 5086−
TiO2 Nanotubes Electrode: A Plasmonic Strategy for Label-Free and 5092.
Amplified Photoelectrochemical Immunoassay. Anal. Chem. 2016, 88, (603) Chen, L.; Luo, Y.; Liu, T.; Yuan, Y.; Gu, H.; Yang, Y.; Li, L.; Tan,
5626−5630. L. Label-Free Electrochemical Immunoassay of Bcl-2 Protein
(587) Ho, J. A.; Jou, A. F.; Wu, L.; Hsu, S. L. Development of an Expression on Tumor Cells. Talanta 2015, 132, 479−485.
Immunopredictor for the Evaluation of the Risk of Cardiovascular (604) Liu, J.; Qin, Y.; Li, D.; Wang, T.; Liu, Y.; Wang, J.; Wang, E.
Diseases Based on the Level of Soluble P-selectin. Methods 2012, 56, Highly Sensitive and Selective Detection of Cancer Cell with a Label-
223−229. Free Electrochemical Cytosensor. Biosens. Bioelectron. 2013, 41, 436−
(588) Kwon, M. J.; Lee, J.; Wark, A. W.; Lee, H. J. Nanoparticle- 441.
Enhanced Surface Plasmon Resonance Detection of Proteins at (605) Wang, R.; Di, J.; Ma, J.; Ma, Z. Highly Sensitive Detection of
Attomolar Concentrations: Comparing Different Nanoparticle Shapes Cancer Cells by Electrochemical Impedance Spectroscopy. Electrochim.
and Sizes. Anal. Chem. 2012, 84, 1702−1707. Acta 2012, 61, 179−184.
(589) Cui, Y.; Chen, H.; Hou, L.; Zhang, B.; Liu, B.; Chen, G.; Tang, D. (606) Dinish, U. S.; Fu, C. Y.; Soh, K. S.; Ramaswamy, B.; Kumar, A.;
Nanogold-Polyaniline-Nanogold Microspheres-Functionalized Molec- Olivo, M. Highly Sensitive SERS Detection of Cancer Proteins in Low
ular Tags for Sensitive Electrochemical Immunoassay of Thyroid- Sample Volume Using Hollow Core Photonic Crystal Fiber. Biosens.
Stimulating Hormone. Anal. Chim. Acta 2012, 738, 76−84. Bioelectron. 2012, 33, 293−298.
(590) Lee, S.; Nan, H.; Yu, H.; Kang, S. H. Quantitative Nano- (607) Xia, Y.; Gao, P.; Bo, Y.; Wang, W.; Huang, S. Immunoassay for
immunosensor Based on Dark-Field Illumination with Enhanced SKOV-3 Human Ovarian Carcinoma Cells using a Graphene Oxide-
Sensitivity and On-Off Switching using Scattering Signals. Biosens. Modified Electrode. Microchim. Acta 2012, 179, 201−207.
Bioelectron. 2016, 79, 709−714. (608) Yang, K.; Hu, Y.; Dong, N. A Novel Biosensor Based on
(591) Han, J.; Zhuo, Y.; Chai, Y.; Yu, Y.; Liao, N.; Yuan, R. Competitive SERS Immunoassay and Magnetic Separation for Accurate
Electrochemical Immunoassay for Thyroxine Detection using Cascade and Sensitive Detection of Chloramphenicol. Biosens. Bioelectron. 2016,
Catalysis as Signal Amplified Enhancer and Multi-Functionalized 80, 373−377.
Magnetic Graphene Sphere as Signal Tag. Anal. Chim. Acta 2013, (609) Wang, L.; Lei, J.; Ma, R.; Ju, H. Host−Guest Interaction of
790, 24−30. Adamantine with a β-Cyclodextrin-Functionalized AuPd Bimetallic
(592) Li, Q.; Lou, F.; Tang, D. Biofunctional Nanogold Microsphere Nanoprobe for Ultrasensitive Electrochemical Immunoassay of Small
Doped with Prussian Blue Nanoparticles for Sensitive Electrochemical Molecules. Anal. Chem. 2013, 85, 6505−6510.
Immunoassay of Cancer Marker. Anal. Methods 2014, 6, 3442−3448. (610) Yan, F.; Zhang, Y.; Zhang, S.; Zhao, J.; Liu, S.; He, L.; Feng, X.;
(593) Xu, T.; Zhang, H.; Li, X.; Xie, Z.; Li, X. Enzyme-Triggered Zhang, H.; Zhang, Z. Carboxyl-Modified Graphene for Use in an
Tyramine-Enzyme Repeats on Prussian Blue-Gold Hybrid Nanostruc- Immunoassay for the Illegal Feed Additive Clenbuterol Using Surface
tures for Highly Sensitive Electrochemical Immunoassay of Tissue Plasmon Resonance and Electrochemical Impedance Spectroscopy.
Polypeptide Antigen. Biosens. Bioelectron. 2015, 73, 167−173. Microchim. Acta 2015, 182, 855−862.
(594) Liao, N.; Zhuo, Y.; Chai, Y. Q.; Xiang, Y.; Han, J.; Yuan, R. (611) Bai, J.; Lai, Y.; Jiang, D.; Zeng, Y.; Xian, Y.; Xiao, F.; Zhang, N.;
Reagentless Electrochemiluminescent Detection of Protein Biomarker Hou, J.; Jin, L. Ultrasensitive Electrochemical Immunoassay Based on
using Graphene-Based Magnetic Nanoprobes and Poly-L-lysine as Co- Graphene oxide−Ag Composites for Rapid Determination of
Reactant. Biosens. Bioelectron. 2013, 45, 189−194. Clenbuterol. Analyst 2012, 137, 4349.
(595) Sirkka, N.; Lyytikainen, A.; Savukoski, T.; Soukka, T. (612) Yao, X.; Yan, P.; Tang, Q.; Deng, A.; Li, J. Quantum Dots Based
Upconverting Nanophosphors as Reporters in a Highly Sensitive Electrochemiluminescent Immunosensor by Coupling Enzymatic
Heterogeneous Immunoassay for Cardiac Troponin I. Anal. Chim. Acta Amplification for Ultrasensitive Detection of Clenbuterol. Anal. Chim.
2016, 925, 82−87. Acta 2013, 798, 82−88.
(596) Weng, S.; Liu, Q.; Zhao, C.; Hong, G.; Jiang, Z.; Lin, L.; Chen, Y.; (613) Qu, X.; Lin, H.; Du, S.; Sui, J.; Zhang, X.; Cao, L. Development of
Lin, X. Sensitive Electrochemical Immunoassay Based on Polythionine- a Nano-Gold Capillary Immunochromatographic Assay for Rapid and

10036 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Semi-Quantitative Detection of Clenbuterol Residues. Food Anal. Sensitively Detecting Ractopamine. Electrochim. Acta 2015, 182, 668−
Methods 2016, 9, 2531−2540. 675.
(614) Li, Z.; Wang, Y.; Kong, W.; Wang, Z.; Wang, L.; Fu, Z. (631) Zhang, Y.; Ma, H.; Wu, D.; Li, Y.; Du, B.; Wei, Q. Label-Free
Ultrasensitive Detection of Trace Amount of Clenbuterol Residue in Immunosensor Based on Au@Ag2S Nanoparticles/magnetic Chitosan
Swine Urine Utilizing an Electrochemiluminescent Immunosensor. Matrix for Sensitive Determination of Ractopamine. J. Electroanal. Chem.
Sens. Actuators, B 2012, 174, 355−358. 2015, 741, 14−19.
(615) Wang, H.; Zhang, Y.; Li, H.; Du, B.; Ma, H.; Wu, D.; Wei, Q. A (632) Wu, Y.; Dong, P.; Deng, A.; Di, J. Development of a Label-Free
Silver−palladium Alloy Nanoparticle-Based Electrochemical Biosensor and Reagentless Plasmonic Immunosensor for the Detection of
for Simultaneous Detection of Ractopamine, Clenbuterol and Salbutamol. Anal. Methods 2013, 5, 5222.
Salbutamol. Biosens. Bioelectron. 2013, 49, 14−19. (633) Yan, Z.; Hu, T.; Guo, W.; Deng, A.; Di, J. A Label-Free
(616) Lai, Y.; Bai, J.; Shi, X.; Zeng, Y.; Xian, Y.; Hou, J.; Jin, L. Graphene Immunosensor for Determination of Salbutamol Based on Localized
Oxide as Nanocarrier for Sensitive Electrochemical Immunoassay of Surface Plasmon Resonance Biosensing. Bioprocess Biosyst. Eng. 2014,
Clenbuterol Based on Labeling Amplification Strategy. Talanta 2013, 37, 651−657.
107, 176−182. (634) Lin, C.-H.; Wu, C.-C.; Kuo, Y.-F. A High Sensitive Impedimetric
(617) Zhang, Z.; Duan, F.; He, L.; Peng, D.; Yan, F.; Wang, M.; Zong, Salbutamol Immunosensor Based on the Gold Nanostructure-
W.; Jia, C. Electrochemical Clenbuterol Immunosensor Based on a Gold Deposited Screen-Printed Carbon Electrode. J. Electroanal. Chem.
Electrode Modified with Zinc Sulfide Quantum Dots and Polyaniline. 2016, 768, 27−33.
Microchim. Acta 2016, 183, 1089−1097. (635) Cui, Z.; Cai, Y.; Wu, D.; Yu, H.; Li, Y.; Mao, K.; Wang, H.; Fan,
(618) Hlavácě k, A.; Farka, Z.; Hübner, M.; Horňaḱ ová, V.; Němeček, H.; Wei, Q.; Du, B. An Ultrasensitive Electrochemical Immunosensor
D.; Niessner, R.; Skládal, P.; Knopp, D.; Gorris, H. H. Competitive for the Detection of Salbutamol Based on Pd@SBA-15 and Ionic Liquid.
Upconversion-Linked Immunosorbent Assay for the Sensitive Detec- Electrochim. Acta 2012, 69, 79−85.
tion of Diclofenac. Anal. Chem. 2016, 88, 6011−6017. (636) Scognamiglio, V.; Arduini, F.; Palleschi, G.; Rea, G. Biosensing
(619) Rezaei, B.; Havakeshian, E.; Ensafi, A. A. Stainless Steel Modified Technology for Sustainable Food Safety. TrAC, Trends Anal. Chem.
with an Aminosilane Layer and Gold Nanoparticles as a Novel 2014, 62, 1−10.
Disposable Substrate for Impedimetric Immunosensors. Biosens. (637) Narayanan, J.; Sharma, M. K.; Ponmariappan, S.; Sarita; Shaik,
Bioelectron. 2013, 48, 61−66. M.; Upadhyay, S. Electrochemical Immunosensor for Botulinum
(620) Rezaei, B.; Askarpour, N.; Ensafi, A. A. A Novel Sensitive Neurotoxin Type-E Using Covalently Ordered Graphene Nanosheets
Doxorubicin Impedimetric Immunosensor Based on a Specific Modified Electrodes and Gold Nanoparticles-Enzyme Conjugate.
Monoclonal Antibody−gold Nanoaprticle−sol−gel Modified Elec- Biosens. Bioelectron. 2015, 69, 249−256.
trode. Talanta 2014, 119, 164−169. (638) Arnon, S. S.; Schechter, R.; Inglesby, T. V.; Henderson, D. A.;
(621) Lu, J.; Van Stappen, T.; Spasic, D.; Delport, F.; Vermeire, S.; Gils,
Bartlett, J. G.; Ascher, M. S.; Eitzen, E.; Fine, A. D.; Hauer, J.; Layton, M.;
A.; Lammertyn, J. Fiber Optic-SPR Platform for Fast and Sensitive
Lillibridge, S.; Osterholm, M. T.; O’Toole, T.; Parker, G.; Perl, T. M.;
Infliximab Detection in Serum of Inflammatory Bowel Disease Patients.
Russell, P. K.; Swerdlow, D. L.; Tonat, K.; for the Working Group on
Biosens. Bioelectron. 2016, 79, 173−179.
Civilian Biodefense.. Botulinum Toxin as a Biological Weapon: Medical
(622) Zengin, A.; Tamer, U.; Caykara, T. Extremely Sensitive
and Public Health Management. JAMA 2001, 285, 1059−1070.
Sandwich Assay of Kanamycin Using Surface-Enhanced Raman
(639) Kadota, I.; Takamura, H.; Nishii, H.; Yamamoto, Y. Total
Scattering of 2-Mercaptobenzothiazole Labeled Gold@silver Nano-
particles. Anal. Chim. Acta 2014, 817, 33−41. Synthesis of Brevetoxin B. J. Am. Chem. Soc. 2005, 127, 9246−9250.
(623) Wei, Q.; Zhao, Y.; Du, B.; Wu, D.; Li, H.; Yang, M. Ultrasensitive (640) Plakas, S. M.; Dickey, R. W. Advances in Monitoring and
Detection of Kanamycin in Animal Derived Foods by Label-Free Toxicity Assessment of Brevetoxins in Molluscan Shellfish. Toxicon
Electrochemical Immunosensor. Food Chem. 2012, 134, 1601−1606. 2010, 56, 137−149.
(624) Yu, S.; Wei, Q.; Du, B.; Wu, D.; Li, H.; Yan, L.; Ma, H.; Zhang, Y. (641) Lin, Y.; Zhou, Q.; Lin, Y.; Lu, M.; Tang, D. Mesoporous Carbon-
Label-Free Immunosensor for the Detection of Kanamycin Using Ag@ Enriched Palladium Nanostructures with Redox Activity for Enzyme-
Fe3O4 Nanoparticles and Thionine Mixed Graphene Sheet. Biosens. Free Electrochemical Immunoassay of Brevetoxin B. Anal. Chim. Acta
Bioelectron. 2013, 48, 224−229. 2015, 887, 67−74.
(625) Ya, Y.; Xiaoshu, W.; Qing, D.; Lin, J.; Yifeng, T. Label-Free (642) Solanki, P. R.; Ali, M. A.; Agrawal, V. V.; Srivastava, A. K.;
Immunosensor for Morphine Based on the Electrochemiluminescence Kotnala, R. K.; Malhotra, B. D. Highly Sensitive Biofunctionalized
of Luminol on Indium−tin Oxide Coated Glass Functionalized with Nickel Oxide Nanowires for Nanobiosensing Applications. RSC Adv.
Gold Nanoparticles. Anal. Methods 2015, 7, 4502−4507. 2013, 3, 16060.
(626) Zang, S.; Liu, Y.; Lin, M.; Kang, J.; Sun, Y.; Lei, H. A Dual (643) Bunyakul, N.; Promptmas, C.; Baeumner, A. J. Microfluidic
Amplified Electrochemical Immunosensor for Ofloxacin: Polypyrrole Biosensor for Cholera Toxin Detection in Fecal Samples. Anal. Bioanal.
Film-Au Nanocluster as the Matrix and Multi-Enzyme-Antibody Chem. 2015, 407, 727−736.
Functionalized Gold Nanorod as the Label. Electrochim. Acta 2013, (644) Han, C.; Doepke, A.; Cho, W.; Likodimos, V.; de la Cruz, A. A.;
90, 246−253. Back, T.; Heineman, W. R.; Halsall, H. B.; Shanov, V. N.; Schulz, M. J.;
(627) He, Z.; Zang, S.; Liu, Y.; He, Y.; Lei, H. A Multi-Walled Carbon Falaras, P.; Dionysiou, D. D. A Multiwalled-Carbon-Nanotube-Based
Nanotubes-Poly(l-Lysine) Modified Enantioselective Immunosensor Biosensor for Monitoring Microcystin-LR in Sources of Drinking Water
for Ofloxacin by Using Multi-Enzyme-Labeled Gold Nanoflower as Supplies. Adv. Funct. Mater. 2013, 23, 1807−1816.
Signal Enhancer. Biosens. Bioelectron. 2015, 73, 85−92. (645) Hou, L.; Ding, Y.; Zhang, L.; Guo, Y.; Li, M.; Chen, Z.; Wu, X.
(628) Sun, X.; Wu, L.; Ji, J.; Jiang, D.; Zhang, Y.; Li, Z.; Zhang, G.; An Ultrasensitive Competitive Immunosensor for Impedimetric
Zhang, H. Longitudinal Surface Plasmon Resonance Assay Enhanced by Detection of Microcystin-LR via Antibody-Conjugated Enzymatic
Magnetosomes for Simultaneous Detection of Pefloxacin and Micro- Biocatalytic Precipitation. Sens. Actuators, B 2016, 233, 63−70.
cystin-LR in Seafoods. Biosens. Bioelectron. 2013, 47, 318−323. (646) Gan, C.; Ling, L.; He, Z.; Lei, H.; Liu, Y. In-Situ Assembly of
(629) Chen, S.; Pan, D.; Gan, N.; Wang, D.; Zhu, Y.; Li, T.; Cao, Y.; Biocompatible Core−shell Hierarchical Nanostructures Sensitized
Hu, F.; Jiang, S. A. QCM Immunosensor to Rapidly Detect Immunosensor for Microcystin-LR Detection. Biosens. Bioelectron.
Ractopamine Using Bio-Polymer Conjugate and Magnetic β-Cyclo- 2016, 78, 381−389.
dextrins. Sens. Actuators, B 2015, 211, 523−530. (647) Dawson, R. M. The Toxicology of Microcystins. Toxicon 1998,
(630) Wang, M.; Kang, M.; Guo, C.; Fang, S.; He, L.; Jia, C.; Zhang, G.; 36, 953−962.
Bai, B.; Zong, W.; Zhang, Z. Electrochemical Biosensor Based on Cu/ (648) Bennett, J. W.; Klich, M. Mycotoxins. Clin. Microbiol. Rev. 2003,
Cu2O Nanocrystals and Reduced Graphene Oxide Nanocomposite for 16, 497−516.

10037 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(649) Xu, X.; Liu, X.; Li, Y.; Ying, Y. A Simple and Rapid Optical (669) Liu, X.; Yang, Y.; Mao, L.; Li, Z.; Zhou, C.; Liu, X.; Zheng, S.; Hu,
Biosensor for Detection of Aflatoxin B1 Based on Competitive Y. SPR Quantitative Analysis of Direct Detection of Atrazine Traces on
Dispersion of Gold Nanorods. Biosens. Bioelectron. 2013, 47, 361−367. Au-Nanoparticles: Nanoparticles Size Effect. Sens. Actuators, B 2015,
(650) Stroka, J.; Anklam, E. New Strategies for the Screening and 218, 1−7.
Determination of Aflatoxins and the Detection of Aflatoxin-Producing (670) Ghosh, P. K.; Philip, L. Environmental Significance of Atrazine
Moulds in Food and Feed. TrAC, Trends Anal. Chem. 2002, 21, 90−95. in Aqueous Systems and Its Removal by Biological Processes: An
(651) Pitt, J. I. Toxigenic Fungi: Which Are Important? Med. Mycol. Overview. Global NEST J. 2006, 8, 159−178.
2000, 38 (Suppl. 1), 17−22. (671) Sun, X.; Zhu, Y.; Wang, X. Amperometric Immunosensor Based
(652) El Khoury, A.; Atoui, A. Ochratoxin A: General Overview and on Deposited Gold Nanocrystals/4,4′-Thiobisbenzenethiol for Deter-
Actual Molecular Status. Toxins 2010, 2, 461−493. mination of Carbofuran. Food Control 2012, 28, 184−191.
(653) Cabañes, F. J.; Bragulat, M. R.; Castellá, G. Ochratoxin A (672) Brkić, D. V.; Vitorović, S. L.; Gašić, S. M.; Nešković, N. K.
Producing Species in the Genus Penicillium. Toxins 2010, 2, 1111− Carbofuran in Water: Subchronic Toxicity to Rats. Environ. Toxicol.
1120. Pharmacol. 2008, 25, 334−341.
(654) Creppy, E. E.; Chiarappa, P.; Baudrimont, I.; Borracci, P.; (673) Sun, Z.; Wang, W.; Wen, H.; Gan, C.; Lei, H.; Liu, Y. Sensitive
Moukha, S.; Carratù, M. R. Synergistic Effects of Fumonisin B1 and Electrochemical Immunoassay for Chlorpyrifos by Using Flake-Like
Ochratoxin A: Are in Vitro Cytotoxicity Data Predictive of in Vivo Acute Fe3O4 Modified Carbon Nanotubes as the Enhanced Multienzyme
Toxicity? Toxicology 2004, 201, 115−123. Label. Anal. Chim. Acta 2015, 899, 91−99.
(655) Blaiotta, G.; Ercolini, D.; Pennacchia, C.; Fusco, V.; Casaburi, A.; (674) Schwartz, R.; Lahav, O.; Ostfeld, A. Integrated Hydraulic and
Pepe, O.; Villani, F. PCR Detection of Staphylococcal Enterotoxin Organophosphate Pesticide Injection Simulations for Enhancing Event
Genes in Staphylococcus Spp. Strains Isolated from Meat and Dairy Detection in Water Distribution Systems. Water Res. 2014, 63, 271−
Products. Evidence for New Variants of seG and seI in S. Aureus AB- 284.
8802. J. Appl. Microbiol. 2004, 97, 719−730. (675) Bazot, S.; Bois, P.; Joyeux, C.; Lebeau, T. Mineralization of
(656) Wang, W.; Liu, L.; Xu, L.; Kuang, H.; Zhu, J.; Xu, C. Gold- Diuron [3-(3,4-Dichlorophenyl)-1, 1-Dimethylurea] by Co-Immobi-
Nanoparticle-Based Multiplexed Immunochromatographic Strip for lized Arthrobacter Sp. and Delftia Acidovorans. Biotechnol. Lett. 2007,
Simultaneous Detection of Staphylococcal Enterotoxin A, B, C, D, and 29, 749−754.
E. Part. Part. Sys. Charact. 2016, 33, 388−395. (676) Tixier, C.; Sancelme, M.; Sancelme, M.; Bonnemoy, F.; Cuer, A.;
(657) Vinayaka, A. C.; Thakur, M. S. An Immunoreactor-Based Veschambre, H. Degradation Products of a Phenylurea Herbicide,
Competitive Fluoroimmunoassay for Monitoring Staphylococcal Enter- Diuron: Synthesis, Ecotoxicity, and Biotransformation. Environ. Toxicol.
otoxin B Using Bioconjugated Quantum Dots. Analyst 2012, 137, 4343. Chem. 2001, 20, 1381−1389.
(658) Ricci, F.; Volpe, G.; Micheli, L.; Palleschi, G. A Review on Novel (677) Sharma, P.; Bhalla, V.; Tuteja, S.; Kukkar, M.; Suri, C. R. Rapid
Developments and Applications of Immunosensors in Food Analysis. Extraction and Quantitative Detection of the Herbicide Diuron in
Anal. Chim. Acta 2007, 605, 111−129. Surface Water by a Hapten-Functionalized Carbon Nanotubes Based
(659) Schatzmayr, G.; Streit, E. Global Occurrence of Mycotoxins in Electrochemical Analyzer. Analyst 2012, 137, 2495.
the Food and Feed Chain: Facts and Figures. World Mycotoxin J. 2013, 6, (678) Giacomazzi, S.; Cochet, N. Environmental Impact of Diuron
213−222. Transformation: A Review. Chemosphere 2004, 56, 1021−1032.
(660) Liu, J.; Hu, Y.; Zhu, G.; Zhou, X.; Jia, L.; Zhang, T. Highly (679) Lee, N.; Beasley, H. L.; Kimber, S. W. L.; Silburn, M.; Woods, N.;
Sensitive Detection of Zearalenone in Feed Samples Using Competitive Skerritt, J. H.; Kennedy, I. R. Application of Immunoassays to Studies of
Surface-Enhanced Raman Scattering Immunoassay. J. Agric. Food Chem. the Environmental Fate of Endosulfan. J. Agric. Food Chem. 1997, 45,
2014, 62, 8325−8332. 4147−4155.
(661) Abbès, S.; Ouanes, Z.; ben Salah-Abbès, J.; Houas, Z.; Oueslati, (680) Lee, K.-L.; You, M.-L.; Tsai, C.-H.; Lin, E.-H.; Hsieh, S.-Y.; Ho,
R.; Bacha, H.; Othman, O. The Protective Effect of Hydrated Sodium M.-H.; Hsu, J.-C.; Wei, P.-K. Nanoplasmonic Biochips for Rapid Label-
Calcium Aluminosilicate Against Haematological, Biochemical and Free Detection of Imidacloprid Pesticides with a Smartphone. Biosens.
Pathological Changes Induced by Zearalenone in Mice. Toxicon 2006, Bioelectron. 2016, 75, 88−95.
47, 567−574. (681) Proença, P.; Teixeira, H.; Castanheira, F.; Pinheiro, J.;
(662) Arduini, F.; Cinti, S.; Scognamiglio, V.; Moscone, D. Monsanto, P. V.; Marques, E. P.; Vieira, D. N. Two Fatal Intoxication
Nanomaterials in Electrochemical Biosensors for Pesticide Detection: Cases with Imidacloprid: LC/MS Analysis. Forensic Sci. Int. 2005, 153,
Advances and Challenges in Food Analysis. Microchim. Acta 2016, 183, 75−80.
2063−2083. (682) Pan, M.; Kong, L.; Liu, B.; Qian, K.; Fang, G.; Wang, S.
(663) Dolan, T.; Howsam, P.; Parsons, D. J.; Whelan, M. J. Is the EU Production of Multi-Walled Carbon Nanotube/poly(aminoamide)
Drinking Water Directive Standard for Pesticides in Drinking Water Dendrimer Hybrid and Its Application to Piezoelectric Immunosensing
Consistent with the Precautionary Principle? Environ. Sci. Technol. 2013, for Metolcarb. Sens. Actuators, B 2013, 188, 949−956.
47, 4999−5006. (683) Sun, J.; Dong, T.; Zhang, Y.; Wang, S. Development of Enzyme
(664) Grossmann, K. Auxin Herbicides: Current Status of Mechanism Linked Immunoassay for the Simultaneous Detection of Carbaryl and
and Mode of Action. Pest Manage. Sci. 2010, 66, 113−120. Metolcarb in Different Agricultural Products. Anal. Chim. Acta 2010,
(665) Park, K.; Park, J.; Kim, J.; Kwak, I.-S. Biological and Molecular 666, 76−82.
Responses of Chironomus Riparius (Diptera, Chironomidae) to (684) Valera, E.; García-Febrero, R.; Pividori, I.; Sánchez-Baeza, F.;
Herbicide 2,4-D (2,4-Dichlorophenoxyacetic Acid). Comp. Biochem. Marco, M.-P. Coulombimetric Immunosensor for Paraquat Based on
Physiol., Part C: Toxicol. Pharmacol. 2010, 151, 439−446. Electrochemical Nanoprobes. Sens. Actuators, B 2014, 194, 353−360.
(666) Ding, J.; Lu, Z.; Wang, R.; Shen, G.; Xiao, L. Piezoelectric (685) Melchiorri, D.; Reiter, R. J.; Sewerynek, E.; Hara, M.; Chen, L.;
Immunosensor with Gold Nanoparticles Enhanced Competitive Nisticò, G. Paraquat Toxicity and Oxidative Damage. Biochem.
Immunoreaction Technique for 2,4-Dichlorophenoxyacetic Acid Pharmacol. 1996, 51, 1095−1099.
Quantification. Sens. Actuators, B 2014, 193, 568−573. (686) Mehta, J.; Vinayak, P.; Tuteja, S. K.; Chhabra, V. A.; Bhardwaj,
(667) Seiler, J. P. The Genetic Toxicology of Phenoxy Acids Other N.; Paul, A. K.; Kim, K.-H.; Deep, A. Graphene Modified Screen Printed
Than 2,4,5-T. Mutat. Res., Rev. Genet. Toxicol. 1978, 55, 197−226. Immunosensor for Highly Sensitive Detection of Parathion. Biosens.
(668) Fusco, G.; Gallo, F.; Tortolini, C.; Bollella, P.; Ietto, F.; De Mico, Bioelectron. 2016, 83, 339−346.
A.; D’Annibale, A.; Antiochia, R.; Favero, G.; Mazzei, F. AuNPs- (687) Benke, G. M.; Cheever, K. L.; Mirer, F. E.; Murphy, S. D.
Functionalized PANABA-MWCNTs Nanocomposite-Based Impedi- Comparative Toxicity, Anticholinesterase Action and Metabolism of
metric Immunosensor for 2,4-Dichlorophenoxy Acetic Acid Detection. Methyl Parathion and Parathion in Sunfish and Mice. Toxicol. Appl.
Biosens. Bioelectron. 2017, 93, 52−56. Pharmacol. 1974, 28, 97−109.

10038 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(688) Scognamiglio, V.; Arduini, F.; Palleschi, G.; Rea, G. Biosensing (706) Mondal, K.; Ali, M. A.; Srivastava, S.; Malhotra, B. D.; Sharma, A.
Technology for Sustainable Food Safety. TrAC, Trends Anal. Chem. Electrospun Functional Micro/nanochannels Embedded in Porous
2014, 62, 1−10. Carbon Electrodes for Microfluidic Biosensing. Sens. Actuators, B 2016,
(689) Arduini, F.; Cinti, S.; Scognamiglio, V.; Moscone, D. 229, 82−91.
Nanomaterials in Electrochemical Biosensors for Pesticide Detection: (707) Zhang, X.; Li, C.-R.; Wang, W.-C.; Xue, J.; Huang, Y.-L.; Yang,
Advances and Challenges in Food Analysis. Microchim. Acta 2016, 183, X.-X.; Tan, B.; Zhou, X.-P.; Shao, C.; Ding, S.-J.; Qiu, J.-F. A Novel
2063−2083. Electrochemical Immunosensor for Highly Sensitive Detection of
(690) Rotz, L. D.; Khan, A. S.; Lillibridge, S. R.; Ostroff, S. M.; Hughes, Aflatoxin B1 in Corn Using Single-Walled Carbon Nanotubes/chitosan.
J. M. Public Health Assessment of Potential Biological Terrorism Food Chem. 2016, 192, 197−202.
Agents. Emerging Infect. Dis. 2002, 8, 225−230. (708) Shu, J.; Qiu, Z.; Wei, Q.; Zhuang, J.; Tang, D. Cobalt-Porphyrin-
(691) Sabelnikov, A.; Zhukov, V.; Kempf, R. Probability of Real-Time Platinum-Functionalized Reduced Graphene Oxide Hybrid Nanostruc-
Detection versus Probability of Infection for Aerosolized Biowarfare tures: A Novel Peroxidase Mimetic System For Improved Electro-
Agents: A Model Study. Biosens. Bioelectron. 2006, 21, 2070−2077. chemical Immunoassay. Sci. Rep. 2015, 5, 15113.
(692) Scallan, E.; Hoekstra, R. M.; Angulo, F. J.; Tauxe, R. V.; (709) Xu, G.; Zhang, S.; Zhang, Q.; Gong, L.; Dai, H.; Lin, Y. Magnetic
Widdowson, M. A.; Roy, S. L.; Jones, J. L.; Griffin, P. M. Foodborne Functionalized Electrospun Nanofibers for Magnetically Controlled
Illness Acquired in the United States - Major Pathogens. Emerging Infect. Ultrasensitive Label-Free Electrochemiluminescent Immune Detection
Dis. 2011, 17, 7−15. of Aflatoxin B1. Sens. Actuators, B 2016, 222, 707−713.
(693) Weidemaier, K.; Carrino, J.; Curry, A.; Connor, J. H.; Liebmann- (710) Lin, Y.; Zhou, Q.; Lin, Y.; Tang, D.; Niessner, R.; Knopp, D.
Vinson, A. Advancing Rapid Point-of-Care Viral Diagnostics to a Enzymatic Hydrolysate-Induced Displacement Reaction with Multi-
Clinical Setting. Future Virol. 2015, 10, 313−28. functional Silica Beads Doped with Horseradish Peroxidase−Thionine
(694) Nouvellet, P.; Garske, T.; Mills, H. L.; Nedjati-Gilani, G.; Conjugate for Ultrasensitive Electrochemical Immunoassay. Anal.
Hinsley, W.; Blake, I. M.; Van Kerkhove, M. D.; Cori, A.; Dorigatti, I.; Chem. 2015, 87, 8531−8540.
Jombart, T.; Riley, S.; Fraser, C.; Donnelly, C. A.; Ferguson, N. M. The (711) Srivastava, S.; Kumar, V.; Ali, M. A.; Solanki, P. R.; Srivastava, A.;
Role of Rapid Diagnostics in Managing Ebola Epidemics. Nature 2015, Sumana, G.; Saxena, P. S.; Joshi, A. G.; Malhotra, B. D. Electrophoreti-
528, S109−16. cally Deposited Reduced Graphene Oxide Platform for Food Toxin
(695) Hospodsky, D.; Yamamoto, N.; Peccia, J. Accuracy, Precision, Detection. Nanoscale 2013, 5, 3043.
and Method Detection Limits of Quantitative PCR for Airborne (712) Srivastava, S.; Kumar, V.; Arora, K.; Singh, C.; Ali, M. A.; Puri, N.
Bacteria and Fungi. Appl. Environ. Microbiol. 2010, 76, 7004−7012. K.; Malhotra, B. D. Antibody Conjugated Metal Nanoparticle Decorated
(696) van Wuijckhuijse, A. L.; Stowers, M. A.; Kleefsman, W. A.; van Graphene Sheets for a Mycotoxin Sensor. RSC Adv. 2016, 6, 56518−
Baar, B. L. M.; Kientz, C. E.; Marijnissen, J. C. M. Matrix-Assisted Laser 56526.
Desorption/Ionisation Aerosol Time-of-Flight Mass Spectrometry for (713) Wang, D.; Hu, W.; Xiong, Y.; Xu, Y.; Li, C. M. Multi-
the Analysis of Bioaerosols: Development of a Fast Detector for functionalized Reduced Graphene Oxide-Doped Polypyrrole/pyrrole-
Airborne Biological Pathogens. J. Aerosol Sci. 2005, 36, 677−687. propylic Acid Nanocomposite Impedimetric Immunosensor to Ultra-
(697) Jiang, X.; Wang, R.; Wang, Y.; Su, X.; Ying, Y.; Wang, J.; Li, Y. Sensitively Detect Small Molecular Aflatoxin B1. Biosens. Bioelectron.
Evaluation of Different Micro/Nanobeads used as Amplifiers in QCM 2015, 63, 185−189.
Immunosensor for More Sensitive Detection of E. coli O157:H7. Biosens. (714) Karczmarczyk, A.; Dubiak-Szepietowska, M.; Vorobii, M.;
Bioelectron. 2011, 29, 23−28. Rodriguez-Emmenegger, C.; Dostálek, J.; Feller, K.-H. Sensitive and
(698) Hu, W.; Chen, H.; Zhang, H.; He, G.; Li, X.; Zhang, X.; Liu, Y.; Rapid Detection of Aflatoxin M1 in Milk Utilizing Enhanced SPR and
Li, C. M. Sensitive Detection of Multiple Mycotoxins by SPRi with Gold p(HEMA) Brushes. Biosens. Bioelectron. 2016, 81, 159−165.
Nanoparticles as Signal Amplification Tags. J. Colloid Interface Sci. 2014, (715) Narayanan, J.; Sharma, M. K.; Ponmariappan, S.; Sarita; Shaik,
431, 71−76. M.; Upadhyay, S. Electrochemical Immunosensor for Botulinum
(699) Xu, X.; Liu, X.; Li, Y.; Ying, Y. A Simple and Rapid Optical Neurotoxin Type-E Using Covalently Ordered Graphene Nanosheets
Biosensor for Detection of Aflatoxin B1 Based on Competitive Modified Electrodes and Gold Nanoparticles-Enzyme Conjugate.
Dispersion of Gold Nanorods. Biosens. Bioelectron. 2013, 47, 361−367. Biosens. Bioelectron. 2015, 69, 249−256.
(700) Tang, J.; Huang, Y.; Liu, H.; Zhang, C.; Tang, D. Novel (716) Bok, S.; Korampally, V.; Darr, C. M.; Folk, W. R.; Polo-Parada,
Glucometer-Based Immunosensing Strategy Suitable for Complex L.; Gangopadhyay, K.; Gangopadhyay, S. Femtogram-Level Detection
Systems with Signal Amplification Using Surfactant-Responsive Cargo of Clostridium Botulinum Neurotoxin Type A by Sandwich Immuno-
Release from Glucose-Encapsulated Liposome Nanocarriers. Biosens. assay Using Nanoporous Substrate and Ultra-Bright Fluorescent
Bioelectron. 2016, 79, 508−514. Suprananoparticles. Biosens. Bioelectron. 2013, 41, 409−416.
(701) Ko, J.; Lee, C.; Choo, J. Highly Sensitive SERS-Based (717) Tang, D.; Zhang, B.; Tang, J.; Hou, L.; Chen, G. Displacement-
Immunoassay of Aflatoxin B1 Using Silica-Encapsulated Hollow Gold Type Quartz Crystal Microbalance Immunosensing Platform for
Nanoparticles. J. Hazard. Mater. 2015, 285, 11−17. Ultrasensitive Monitoring of Small Molecular Toxins. Anal. Chem.
(702) Singh, C.; Srivastava, S.; Ali, M. A.; Gupta, T. K.; Sumana, G.; 2013, 85, 6958−6966.
Srivastava, A.; Mathur, R. B.; Malhotra, B. D. Carboxylated Multiwalled (718) Zhang, B.; Liu, B.; Liao, J.; Chen, G.; Tang, D. Novel
Carbon Nanotubes Based Biosensor for Aflatoxin Detection. Sens. Electrochemical Immunoassay for Quantitative Monitoring of Biotoxin
Actuators, B 2013, 185, 258−264. Using Target-Responsive Cargo Release from Mesoporous Silica
(703) Urusov, A. E.; Zherdev, A. V.; Dzantiev, B. B. Use of Gold Nanocontainers. Anal. Chem. 2013, 85, 9245−9252.
Nanoparticle-Labeled Secondary Antibodies to Improve the Sensitivity (719) Lin, Y.; Zhou, Q.; Lin, Y.; Lu, M.; Tang, D. Mesoporous Carbon-
of an Immunochromatographic Assay for Aflatoxin B1. Microchim. Acta Enriched Palladium Nanostructures with Redox Activity for Enzyme-
2014, 181, 1939−1946. Free Electrochemical Immunoassay of Brevetoxin B. Anal. Chim. Acta
(704) Yu, L.; Zhang, Y.; Hu, C.; Wu, H.; Yang, Y.; Huang, C.; Jia, N. 2015, 887, 67−74.
Highly Sensitive Electrochemical Impedance Spectroscopy Immuno- (720) Schmit, V. L.; Martoglio, R.; Carron, K. T. Lab-on-a-Bubble
sensor for the Detection of AFB1 in Olive Oil. Food Chem. 2015, 176, Surface Enhanced Raman Indirect Immunoassay for Cholera. Anal.
22−26. Chem. 2012, 84, 4233−4236.
(705) Wang, H.; Zhang, Y.; Chu, Y.; Ma, H.; Li, Y.; Wu, D.; Du, B.; (721) Solanki, P. R.; Ali, M. A.; Agrawal, V. V.; Srivastava, A. K.;
Wei, Q. Disposable Competitive-Type Immunoassay for Determination Kotnala, R. K.; Malhotra, B. D. Highly Sensitive Biofunctionalized
of Aflatoxin B1 via Detection of Copper Ions Released from Cu-Apatite. Nickel Oxide Nanowires for Nanobiosensing Applications. RSC Adv.
Talanta 2016, 147, 556−560. 2013, 3, 16060.

10039 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(722) Han, C.; Doepke, A.; Cho, W.; Likodimos, V.; de la Cruz, A. A.; (740) Bruck, H. A.; Yang, M.; Kostov, Y.; Rasooly, A. Electrical
Back, T.; Heineman, W. R.; Halsall, H. B.; Shanov, V. N.; Schulz, M. J.; Percolation Based Biosensors. Methods 2013, 63, 282−289.
Falaras, P.; Dionysiou, D. D. A Multiwalled-Carbon-Nanotube-Based (741) Tao, L.; Zhang, C.; Zhang, J.; Sun, Y.; Li, X.; Yan, K.; Jin, B.;
Biosensor for Monitoring Microcystin-LR in Sources of Drinking Water Zhang, Z.; Yang, K. Sensitive Chemiluminescence Immunoassay for
Supplies. Adv. Funct. Mater. 2013, 23, 1807−1816. Staphylococcal Enterotoxin C1 Based on the Use of Dye-Encapsulated
(723) Gan, C.; Ling, L.; He, Z.; Lei, H.; Liu, Y. In-Situ Assembly of Mesoporous Silica Nanoparticles. Microchim. Acta 2016, 183, 2163−
Biocompatible Core−shell Hierarchical Nanostructures Sensitized 2168.
Immunosensor for Microcystin-LR Detection. Biosens. Bioelectron. (742) Hu, W.; Chen, H.; Zhang, H.; He, G.; Li, X.; Zhang, X.; Liu, Y.;
2016, 78, 381−389. Li, C. M. Sensitive Detection of Multiple Mycotoxins by SPRi with Gold
(724) Hou, L.; Ding, Y.; Zhang, L.; Guo, Y.; Li, M.; Chen, Z.; Wu, X. Nanoparticles as Signal Amplification Tags. J. Colloid Interface Sci. 2014,
An Ultrasensitive Competitive Immunosensor for Impedimetric 431, 71−76.
Detection of Microcystin-LR via Antibody-Conjugated Enzymatic (743) Liu, J.; Hu, Y.; Zhu, G.; Zhou, X.; Jia, L.; Zhang, T. Highly
Biocatalytic Precipitation. Sens. Actuators, B 2016, 233, 63−70. Sensitive Detection of Zearalenone in Feed Samples Using Competitive
(725) Zhang, J.; Sun, Y.; Dong, H.; Zhang, X.; Wang, W.; Chen, Z. An Surface-Enhanced Raman Scattering Immunoassay. J. Agric. Food Chem.
Electrochemical Non-Enzymatic Immunosensor for Ultrasensitive 2014, 62, 8325−8332.
Detection of Microcystin-LR Using Carbon Nanofibers as the Matrix. (744) Feng, R.; Zhang, Y.; Ma, H.; Wu, D.; Fan, H.; Wang, H.; Li, H.;
Sens. Actuators, B 2016, 233, 624−632. Du, B.; Wei, Q. Ultrasensitive Non-Enzymatic and Non-Mediator
(726) Tan, F.; Saucedo, N. M.; Ramnani, P.; Mulchandani, A. Label- Electrochemical Biosensor Using Nitrogen-Doped Graphene Sheets for
Free Electrical Immunosensor for Highly Sensitive and Specific Signal Amplification and Nanoporous Alloy as Carrier. Electrochim. Acta
Detection of Microcystin-LR in Water Samples. Environ. Sci. Technol. 2013, 97, 105−111.
2015, 49, 9256−9263. (745) Ding, J.; Lu, Z.; Wang, R.; Shen, G.; Xiao, L. Piezoelectric
(727) Shi, Y.; Wu, J.; Sun, Y.; Zhang, Y.; Wen, Z.; Dai, H.; Wang, H.; Li, Immunosensor with Gold Nanoparticles Enhanced Competitive
Z. A Graphene Oxide Based Biosensor for Microcystins Detection by Immunoreaction Technique for 2,4-Dichlorophenoxyacetic Acid
Fluorescence Resonance Energy Transfer. Biosens. Bioelectron. 2012, 38, Quantification. Sens. Actuators, B 2014, 193, 568−573.
31−36. (746) Jia, K.; Bijeon, J. L.; Adam, P. M.; Ionescu, R. E. Sensitive
(728) Tian, J.; Zhao, H.; Zhao, H.; Quan, X. Photoelectrochemical Localized Surface Plasmon Resonance Multiplexing Protocols. Anal.
Immunoassay for Microcystin-LR Based on a Fluorine-Doped Tin Chem. 2012, 84, 8020−8027.
Oxide Glass Electrode Modified with a CdS-Graphene Composite. (747) Liu, X.; Yang, Y.; Mao, L.; Li, Z.; Zhou, C.; Liu, X.; Zheng, S.; Hu,
Microchim. Acta 2012, 179, 163−170. Y. SPR Quantitative Analysis of Direct Detection of Atrazine Traces on
(729) Sun, X.; Guan, L.; Shi, H.; Ji, J.; Zhang, Y.; Li, Z. Determination Au-Nanoparticles: Nanoparticles Size Effect. Sens. Actuators, B 2015,
of Microcystin-LR with a Glassy Carbon Impedimetric Immunoelec-
218, 1−7.
trode Modified with an Ionic Liquid and Multiwalled Carbon (748) Liu, X.; Li, W.-J.; Li, L.; Yang, Y.; Mao, L.-G.; Peng, Z. A Label-
Nanotubes. Microchim. Acta 2013, 180, 75−83. Free Electrochemical Immunosensor Based on Gold Nanoparticles for
(730) Huang, X.; Chen, R.; Xu, H.; Lai, W.; Xiong, Y. Nanospherical
Direct Detection of Atrazine. Sens. Actuators, B 2014, 191, 408−414.
Brush as Catalase Container for Enhancing the Detection Sensitivity of
(749) Deep, A.; Saraf, M.; Neha; Bharadwaj, S. K.; Sharma, A. L.
Competitive Plasmonic ELISA. Anal. Chem. 2016, 88, 1951−1958.
Styrene Sulphonic Acid Doped Polyaniline Based Immunosensor for
(731) Liu, X.; Yang, Z.; Zhang, Y.; Yu, R. A Novel Electrochemical
Highly Sensitive Impedimetric Sensing of Atrazine. Electrochim. Acta
Immunosensor for Ochratoxin A with Hapten Immobilization on
2014, 146, 301−306.
Thionine/gold Nanoparticle Modified Glassy Carbon Electrode. Anal.
(750) Medina-Sánchez, M.; Mayorga-Martinez, C. C.; Watanabe, T.;
Methods 2013, 5, 1481.
(732) Huang, X.; Zhan, S.; Xu, H.; Meng, X.; Xiong, Y.; Chen, X. Ivandini, T. A.; Honda, Y.; Pino, F.; Nakata, K.; Fujishima, A.; Einaga, Y.;
Ultrasensitive Fluorescence Immunoassay for Detection of Ochratoxin Merkoçi, A. Microfluidic Platform for Environmental Contaminants
A Using Catalase-Mediated Fluorescence Quenching of CdTe QDs. Sensing and Degradation Based on Boron-Doped Diamond Electrodes.
Nanoscale 2016, 8, 9390−9397. Biosens. Bioelectron. 2016, 75, 365−374.
(733) Yang, J.; Gao, P.; Liu, Y.; Li, R.; Ma, H.; Du, B.; Wei, Q. Label- (751) Giannetto, M.; Umiltà, E.; Careri, M. New Competitive
Free Photoelectrochemical Immunosensor for Sensitive Detection of Dendrimer-Based and Highly Selective Immunosensor for Determi-
Ochratoxin A. Biosens. Bioelectron. 2015, 64, 13−18. nation of Atrazine in Environmental, Feed and Food Samples: The
(734) Jodra, A.; Hervás, M.; López, M. Á .; Escarpa, A. Disposable Importance of Antibody Selectivity for Discrimination Among Related
Electrochemical Magneto Immunosensor for Simultaneous Simplified Triazinic Metabolites. Anal. Chim. Acta 2014, 806, 197−203.
Calibration and Determination of Ochratoxin A in Coffee Samples. Sens. (752) Belkhamssa, N.; Justino, C. I. L.; Santos, P. S. M.; Cardoso, S.;
Actuators, B 2015, 221, 777−783. Lopes, I.; Duarte, A. C.; Rocha-Santos, T.; Ksibi, M. Label-Free
(735) Orlov, A. V.; Khodakova, J. A.; Nikitin, M. P.; Shepelyakovskaya, Disposable Immunosensor for Detection of Atrazine. Talanta 2016,
A. O.; Brovko, F. A.; Laman, A. G.; Grishin, E. V.; Nikitin, P. I. Magnetic 146, 430−434.
Immunoassay for Detection of Staphylococcal Toxins in Complex (753) González-Techera, A.; Zon, M. A.; Molina, P. G.; Fernández, H.;
Media. Anal. Chem. 2013, 85, 1154−1163. González-Sapienza, G.; Arévalo, F. J. Development of a Highly Sensitive
(736) Hwang, J.; Lee, S.; Choo, J. Application of a SERS-Based Lateral Noncompetitive Electrochemical Immunosensor for the Detection of
Flow Immunoassay Strip for the Rapid and Sensitive Detection of Atrazine by Phage Anti-Immunocomplex Assay. Biosens. Bioelectron.
Staphylococcal Enterotoxin B. Nanoscale 2016, 8, 11418−11425. 2015, 64, 650−656.
(737) Vinayaka, A. C.; Thakur, M. S. An Immunoreactor-Based (754) Sun, X.; Zhu, Y.; Wang, X. Amperometric Immunosensor Based
Competitive Fluoroimmunoassay for Monitoring Staphylococcal Enter- on Deposited Gold Nanocrystals/4,4′-Thiobisbenzenethiol for Deter-
otoxin B Using Bioconjugated Quantum Dots. Analyst 2012, 137, 4343. mination of Carbofuran. Food Control 2012, 28, 184−191.
(738) Wu, L.; Gao, B.; Zhang, F.; Sun, X.; Zhang, Y.; Li, Z. A Novel (755) Sun, X.; Du, S.; Wang, X. Amperometric Immunosensor for
Electrochemical Immunosensor Based on Magnetosomes for Detection Carbofuran Detection Based on Gold Nanoparticles and PB-
of Staphylococcal Enterotoxin B in Milk. Talanta 2013, 106, 360−366. MWCNTs-CTS Composite Film. Eur. Food Res. Technol. 2012, 235,
(739) Wang, W.; Liu, L.; Xu, L.; Kuang, H.; Zhu, J.; Xu, C. Gold- 469−477.
Nanoparticle-Based Multiplexed Immunochromatographic Strip for (756) Zhu, Y.; Cao, Y.; Sun, X.; Wang, X. Amperometric
Simultaneous Detection of Staphylococcal Enterotoxin A, B, C, D, and Immunosensor for Carbofuran Detection Based on MWCNTs/GS-
E. Part. Part. Sys. Charact. 2016, 33, 388−395. PEI-Au and AuNPs-Antibody Conjugate. Sensors 2013, 13, 5286−5301.

10040 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

(757) Sun, X.; Li, Q.; Wang, X. Amperometric Immunosensor Based (775) Madiyar, F. R.; Bhana, S.; Swisher, L. Z.; Culbertson, C. T.;
on Gold Nanoparticles and Saturated Thiourea for Carbofuran Huang, X.; Li, J. Integration of a Nanostructured Dielectrophoretic
Detection. IEEE Sens. J. 2012, 12, 2071−2076. Device and a Surface-Enhanced Raman Probe for Highly Sensitive
(758) Nangia, Y.; Bhalla, V.; Kumar, B.; Suri, C. R. Electrochemical Rapid Bacteria Detection. Nanoscale 2015, 7, 3726−3736.
Stripping Voltammetry of Gold Ions for Development of Ultra-Sensitive (776) Dogan, Ü .; Kasap, E.; Cetin, D.; Suludere, Z.; Boyaci, I. H.;
Immunoassay for Chlorsulfuron. Electrochem. Commun. 2012, 14, 51− Türkyılmaz, C.; Ertas, N.; Tamer, U. Rapid Detection of Bacteria Based
54. on Homogenous Immunoassay Using Chitosan Modified Quantum
(759) Qiao, L.; Guo, Y.; Sun, X.; Jiao, Y.; Wang, X. Electrochemical Dots. Sens. Actuators, B 2016, 233, 369−378.
Immunosensor with NiAl-Layered Double Hydroxide/graphene Nano- (777) Zhang, X.; Shen, J.; Ma, H.; Jiang, Y.; Huang, C.; Han, E.; Yao, B.;
composites and Hollow Gold Nanospheres Double-Assisted Signal He, Y. Optimized Dendrimer-Encapsulated Gold Nanoparticles and
Amplification. Bioprocess Biosyst. Eng. 2015, 38, 1455−1468. Enhanced Carbon Nanotube Nanoprobes for Amplified Electro-
(760) Sun, Z.; Wang, W.; Wen, H.; Gan, C.; Lei, H.; Liu, Y. Sensitive chemical Immunoassay of E. Coli in Dairy Product Based on
Electrochemical Immunoassay for Chlorpyrifos by Using Flake-Like Enzymatically Induced Deposition of Polyaniline. Biosens. Bioelectron.
Fe3O4 Modified Carbon Nanotubes as the Enhanced Multienzyme 2016, 80, 666−673.
Label. Anal. Chim. Acta 2015, 899, 91−99. (778) Li, Y.; Cheng, P.; Gong, J.; Fang, L.; Deng, J.; Liang, W.; Zheng, J.
(761) Sharma, P.; Kukkar, M.; Ganguli, A. K.; Bhasin, A.; Suri, C. R. Amperometric Immunosensor for the Detection of Escherichia Coli
Plasmon Enhanced Fluoro-Immunoassay Using Egg Yolk Antibodies O157:H7 in Food Specimens. Anal. Biochem. 2012, 421, 227−233.
for Ultra-Sensitive Detection of Herbicide Diuron. Analyst 2013, 138, (779) Li, Y.; Fang, L.; Cheng, P.; Deng, J.; Jiang, L.; Huang, H.; Zheng,
4312. J. An Electrochemical Immunosensor for Sensitive Detection of
(762) Sharma, P.; Bhalla, V.; Tuteja, S.; Kukkar, M.; Suri, C. R. Rapid Escherichia Coli O157:H7 Using C60 Based Biocompatible Platform
Extraction and Quantitative Detection of the Herbicide Diuron in and Enzyme Functionalized Pt Nanochains Tracing Tag. Biosens.
Surface Water by a Hapten-Functionalized Carbon Nanotubes Based Bioelectron. 2013, 49, 485−491.
Electrochemical Analyzer. Analyst 2012, 137, 2495. (780) Cheng, P.; Huang, Z.-G.; Zhuang, Y.; Fang, L.-C.; Huang, H.;
(763) Bhalla, V.; Sharma, P.; Pandey, S. K.; Suri, C. R. Impedimetric Deng, J.; Jiang, L.-L.; Yu, K.-K.; Li, Y.; Zheng, J.-S. A Novel
Label-Free Immunodetection of Phenylurea Class of Herbicides. Sens. Regeneration-Free E. Coli O157:H7 Amperometric Immunosensor
Actuators, B 2012, 171−172, 1231−1237. Based on Functionalised Four-Layer Magnetic Nanoparticles. Sens.
(764) Sharma, P.; Tuteja, S. K.; Bhalla, V.; Shekhawat, G.; Dravid, V. P.; Actuators, B 2014, 204, 561−567.
Suri, C. R. Bio-Functionalized Graphene−graphene Oxide Nano- (781) Wang, Y.; Fewins, P. A.; Alocilja, E. C. Electrochemical
composite Based Electrochemical Immunosensing. Biosens. Bioelectron. Immunosensor Using Nanoparticle-Based Signal Enhancement for
2013, 39, 99−105. Escherichia Coli O157:H7 Detection. IEEE Sens. J. 2015, 15, 4692−
(765) Liu, G.; Wang, S.; Liu, J.; Song, D. An Electrochemical 4699.
Immunosensor Based on Chemical Assembly of Vertically Aligned (782) Kwon, D.; Lee, S.; Ahn, M. M.; Kang, I. S.; Park, K.-H.; Jeon, S.
Carbon Nanotubes on Carbon Substrates for Direct Detection of the Colorimetric Detection of Pathogenic Bacteria Using Platinum-Coated
Pesticide Endosulfan in Environmental Water. Anal. Chem. 2012, 84, Magnetic Nanoparticle Clusters and Magnetophoretic Chromatogra-
3921−3928. phy. Anal. Chim. Acta 2015, 883, 61−66.
(766) Lee, K.-L.; You, M.-L.; Tsai, C.-H.; Lin, E.-H.; Hsieh, S.-Y.; Ho, (783) Jiang, T.; Song, Y.; Wei, T.; Li, H.; Du, D.; Zhu, M.-J.; Lin, Y.
M.-H.; Hsu, J.-C.; Wei, P.-K. Nanoplasmonic Biochips for Rapid Label- Sensitive Detection of Escherichia coli O157:H7 Using Pt−Au Bimetal
Free Detection of Imidacloprid Pesticides with a Smartphone. Biosens. Nanoparticles with Peroxidase-like Amplification. Biosens. Bioelectron.
Bioelectron. 2016, 75, 88−95. 2016, 77, 687−694.
(767) Pan, M.; Kong, L.; Liu, B.; Qian, K.; Fang, G.; Wang, S. (784) Guo, X.; Lin, C.-S.; Chen, S.-H.; Ye, R.; Wu, V. C. H. A
Production of Multi-Walled Carbon Nanotube/poly(aminoamide) Piezoelectric Immunosensor for Specific Capture and Enrichment of
Dendrimer Hybrid and Its Application to Piezoelectric Immunosensing Viable Pathogens by Quartz Crystal Microbalance Sensor, Followed by
for Metolcarb. Sens. Actuators, B 2013, 188, 949−956. Detection with Antibody-Functionalized Gold Nanoparticles. Biosens.
(768) Valera, E.; García-Febrero, R.; Pividori, I.; Sánchez-Baeza, F.; Bioelectron. 2012, 38, 177−183.
Marco, M.-P. Coulombimetric Immunosensor for Paraquat Based on (785) Martín, M.; Salazar, P.; Jiménez, C.; Lecuona, M.; Ramos, M. J.;
Electrochemical Nanoprobes. Sens. Actuators, B 2014, 194, 353−360. Ode, J.; Alcoba, J.; Roche, R.; Villalonga, R.; Campuzano, S.; et al. Rapid
(769) Mehta, J.; Vinayak, P.; Tuteja, S. K.; Chhabra, V. A.; Bhardwaj, Legionella Pneumophila Determination Based on a Disposable Core−
N.; Paul, A. K.; Kim, K.-H.; Deep, A. Graphene Modified Screen Printed shell Fe3O4@poly(dopamine) Magnetic Nanoparticles Immunoplat-
Immunosensor for Highly Sensitive Detection of Parathion. Biosens. form. Anal. Chim. Acta 2015, 887, 51−58.
Bioelectron. 2016, 83, 339−346. (786) Uusitalo, S.; Kögler, M.; Välimaa, A.-L.; Popov, A.; Ryabchikov,
(770) Gas, F.; Baus, B.; Queré, J.; Chapelle, A.; Dreanno, C. Rapid Y.; Kontturi, V.; Siitonen, S.; Petäjä, J.; Virtanen, T.; Laitinen, R.; et al.
Detection and Quantification of the Marine Toxic Algae, Alexandrium Detection of Listeria Innocua on Roll-to-Roll Produced SERS
Minutum, Using a Super-Paramagnetic Immunochromatographic Strip Substrates with Gold Nanoparticles. RSC Adv. 2016, 6, 62981−62989.
Test. Talanta 2016, 147, 581−589. (787) Chen, Q.; Lin, J.; Gan, C.; Wang, Y.; Wang, D.; Xiong, Y.; Lai,
(771) Wang, D.-B.; Tian, B.; Zhang, Z.-P.; Deng, J.-Y.; Cui, Z.-Q.; W.; Li, Y.; Wang, M. A Sensitive Impedance Biosensor Based on
Yang, R.-F.; Wang, X.-Y.; Wei, H.-P.; Zhang, X.-E. Rapid Detection of Immunomagnetic Separation and Urease Catalysis for Rapid Detection
Bacillus Anthracis Spores Using a Super-Paramagnetic Lateral-Flow of Listeria Monocytogenes Using an Immobilization-Free Interdigitated
Immunological Detectionsystem. Biosens. Bioelectron. 2013, 42, 661− Array Microelectrode. Biosens. Bioelectron. 2015, 74, 504−511.
667. (788) Veerapandian, M.; Neethirajan, S. Graphene Oxide Chemically
(772) Kang, X.; Pang, G.; Chen, Q.; Liang, X. Fabrication of Bacillus Decorated with Ag−Ru/Chitosan Nanoparticles: Fabrication, Electrode
Cereus Electrochemical Immunosensor Based on Double-Layer Gold Processing and Immunosensing Properties. RSC Adv. 2015, 5, 75015−
Nanoparticles and Chitosan. Sens. Actuators, B 2013, 177, 1010−1016. 75024.
(773) Dou, W.; Tang, W.; Zhao, G. A Disposable Electrochemical (789) Krithiga, N.; Viswanath, K. B.; Vasantha, V. S.; Jayachitra, A.
Immunosensor Arrays Using 4-Channel Screen-Printed Carbon Specific and Selective Electrochemical Immunoassay for Pseudomonas
Electrode for Simultaneous Detection of Escherichia coli O157:H7 and aeruginosa Based on Pectin−gold Nano Composite. Biosens. Bioelectron.
Enterobacter sakazakii. Electrochim. Acta 2013, 97, 79−85. 2016, 79, 121−129.
(774) Mouli Pandey, C.; Sumana, G.; Tiwari, I. Nanostructuring of (790) Fei, J.; Dou, W.; Zhao, G. A Sandwich Electrochemical
Hierarchical 3D Cystine Flowers for High-Performance Electrochemical Immunoassay for Salmonella pullorum and Salmonella Gallinarum
Immunosensor. Biosens. Bioelectron. 2014, 61, 328−335. Based on a AuNPs/SiO2/Fe3O4 adsorbing Antibody and 4 Channel

10041 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042
Chemical Reviews Review

Screen Printed Carbon Electrode Electrodeposited Gold Nanoparticles. Functionalized CeO2 Nanocomposites as Signal Enhancer. Biosens.
RSC Adv. 2015, 5, 74548−74556. Bioelectron. 2015, 69, 321−327.
(791) Fei, J.; Dou, W.; Zhao, G. Amperometric Immunoassay for the (808) Veerapandian, M.; Hunter, R.; Neethirajan, S. Dual
Detection of Salmonella pullorum Using a Screen - Printed Carbon Immunosensor Based on Methylene Blue-Electroadsorbed Graphene
Electrode Modified with Gold Nanoparticle-Coated Reduced Graphene Oxide for Rapid Detection of the Influenza A Virus Antigen. Talanta
Oxide and Immunomagnetic Beads. Microchim. Acta 2016, 183, 757− 2016, 155, 250−257.
764. (809) Huang, J.; Xie, Z.; Xie, Z.; Luo, S.; Xie, L.; Huang, L.; Fan, Q.;
(792) Pratiwi, F. W.; Rijiravanich, P.; Somasundrum, M.; Zhang, Y.; Wang, S.; Zeng, T. Silver Nanoparticles Coated Graphene
Surareungchai, W. Electrochemical Immunoassay for Salmonella Electrochemical Sensor for the Ultrasensitive Analysis of Avian
Typhimurium Based on Magnetically Collected Ag-Enhanced DNA Influenza Virus H7. Anal. Chim. Acta 2016, 913, 121−127.
Biobarcode Labels. Analyst 2013, 138, 5011. (810) Yang, J.; Xiang, Y.; Song, C.; Liu, L.; Jing, X.; Xie, G.; Xiang, H.
(793) Viter, R.; Khranovskyy, V.; Starodub, N.; Ogorodniichuk, Y.; Quadruple Signal Amplification Strategy Based on Hybridization Chain
Gevelyuk, S.; Gertnere, Z.; Poletaev, N.; Yakimova, R.; Erts, D.; Reaction and an Immunoelectrode Modified with Graphene Sheets, a
Smyntyna, V.; et al. Application of Room Temperature Photo- Hemin/G-Quadruplex DNAzyme Concatamer, and Alcohol Dehydro-
luminescence From ZnO Nanorods for Salmonella Detection. IEEE genase: Ultrasensitive Determination of Influenza Virus Subtype H7N9.
Sens. J. 2014, 14, 2028−2034. Microchim. Acta 2015, 182, 2377−2385.
(794) Kim, G.; Moon, J.-H.; Moh, C.-Y.; Lim, J. A Microfluidic Nano- (811) Lin, H.-Y.; Huang, C.-H.; Lu, S.-H.; Kuo, I.-T.; Chau, L.-K.
Biosensor for the Detection of Pathogenic Salmonella. Biosens. Direct Detection of Orchid Viruses Using Nanorod-Based Fiber Optic
Bioelectron. 2015, 67, 243−247. Particle Plasmon Resonance Immunosensor. Biosens. Bioelectron. 2014,
(795) Lin, Y.; Hamme, A. T., II Gold Nanoparticle Labeling Based 51, 371−378.
(812) Neng, J.; Harpster, M. H.; Wilson, W. C.; Johnson, P. A. Surface-
ICP-MS Detection/Measurement of Bacteria, and Their Quantitative
Enhanced Raman Scattering (SERS) Detection of Multiple Viral
Photothermal Destruction. J. Mater. Chem. B 2015, 3, 3573−3582.
Antigens Using Magnetic Capture of SERS-Active Nanoparticles.
(796) Tam, P. D.; Thang, C. X. Label-Free Electrochemical
Biosens. Bioelectron. 2013, 41, 316−321.
Immunosensor Based on Cerium Oxide Nanowires for Vibrio cholerae
(813) Park, S.; Kim, J.; Ock, H.; Dutta, G.; Seo, J.; Shin, E.-C.; Yang, H.
O1 Detection. Mater. Sci. Eng., C 2016, 58, 953−959. Sensitive Electrochemical Detection of Vaccinia Virus in a Solution
(797) Prieto-Simón, B.; Bandaru, N. M.; Saint, C.; Voelcker, N. H. Containing a High Concentration Of l-Ascorbic Acid. Analyst 2015, 140,
Tailored Carbon Nanotube Immunosensors for the Detection of 5481−5487.
Microbial Contamination. Biosens. Bioelectron. 2015, 67, 642−648.
(798) Huang, W.; Xiang, G.; Jiang, D.; Liu, L.; Liu, C.; Liu, F.; Pu, X.
Electrochemical Immunoassay for CytomegalovirusAntigen Detection
with Multiple Signal Amplification Using HRP and Pt-Pd Nanoparticles
Functionalized Single-Walled Carbon Nanohorns. Electroanalysis 2016,
28, 1126−1133.
(799) Nguyen, B. T. T.; Peh, A. E. K.; Chee, C. Y. L.; Fink, K.; Chow, V.
T. K.; Ng, M. M. L.; Toh, C.-S. Electrochemical Impedance
Spectroscopy Characterization of Nanoporous Alumina Dengue Virus
Biosensor. Bioelectrochemistry 2012, 88, 15−21.
(800) Wei, Y.; Wong, L. P.; Toh, C.-S. Fuel Cell Virus Sensor Using
Virus Capture within Antibody-Coated Nanochannels. Anal. Chem.
2013, 85, 1350−1357.
(801) Wang, X.; Li, Y.; Quan, D.; Wang, J.; Zhang, Y.; Du, J.; Peng, J.;
Fu, Q.; Zhou, Y.; Jia, S.; et al. Detection of Hepatitis B Surface Antigen
by Target-Induced Aggregation Monitored by Dynamic Light
Scattering. Anal. Biochem. 2012, 428, 119−125.
(802) Huang, K.-J.; Li, J.; Liu, Y.-M.; Cao, X.; Yu, S.; Yu, M. Disposable
Immunoassay for Hepatitis B Surface Antigen Based on a Graphene
Paste Electrode Functionalized with Gold Nanoparticles and a Nafion-
Cysteine Conjugate. Microchim. Acta 2012, 177, 419−426.
(803) Ge, Z.-L.; Song, T.-M.; Chen, Z.; Guo, W.-R.; Xie, H.-P.; Xie, L.
Polyelectrolyte-Based Electrochemiluminescence Enhancement for
Ru(bpy)32+ Loaded by SiO2 Nanoparticle Carrier and Its High Sensitive
Immunoassay. Anal. Chim. Acta 2015, 862, 24−32.
(804) Li, Y.; Tian, L.; Liu, L.; Liu, L.; Li, J.; Wei, Q.; Cao, W. An
Ultrasensitive Sandwich-Type Electrochemical Immunosensor Based
on δ-MnO2and Palladium Nanoparticles Covered Natural Halloysite
Nanotubes for the Detection of Hepatitis B Surface Antigen. New J.
Chem. 2016, 40, 558−563.
(805) Ma, C.; Liang, M.; Wang, L.; Xiang, H.; Jiang, Y.; Li, Y.; Xie, G.
Multi sHRP-DNA-Coated CMWNTs as Signal Labels for an Ultra-
sensitive Hepatitis C Virus Core Antigen Electrochemical Immuno-
sensor. Biosens. Bioelectron. 2013, 47, 467−474.
(806) Inci, F.; Tokel, O.; Wang, S.; Gurkan, U. A.; Tasoglu, S.;
Kuritzkes, D. R.; Demirci, U. Nanoplasmonic Quantitative Detection of
Intact Viruses from Unprocessed Whole Blood. ACS Nano 2013, 7,
4733−4745.
(807) Yang, Z.-H.; Zhuo, Y.; Yuan, R.; Chai, Y.-Q. An Amplified
Electrochemical Immunosensor Based on in Situ-Produced 1-Naphthol
as Electroactive Substance and Graphene Oxide and Pt Nanoparticles

10042 DOI: 10.1021/acs.chemrev.7b00037

Chem. Rev. 2017, 117, 9973−10042