Talanta 214 (2020) 120716

Contents lists available at ScienceDirect

Talanta
journal homepage: www.elsevier.com/locate/talanta

Aptamer-based biosensor for detecting carcinoembryonic antigen T

a a b c,∗∗ a,∗
Wenwen Xiang , Qiuxiang Lv , Haixia Shi , Bing Xie , Li Gao
a
Institute of Life Sciences, Jiangsu University, Zhenjiang, 212013, PR China
b
P. E. Department of Jiangsu University, Zhenjiang, 212013, PR China
c
Department of Obstetrics and Gynecology, The Fourth People's Hospital of Zhenjiang, Zhenjiang, 212000, PR China

ARTICLE INFO ABSTRACT

Keywords: Carcinoembryonic antigen (CEA), as one of the common tumor markers, is a human glycoprotein involved in cell
Aptamer adhesion and is expressed during human fetal development. Since the birth of human, CEA expression is largely
Biosensor inhibited, with only low levels in the plasma of healthy adults. Generally, CEA will overexpressed in many
Carcinoembryonic antigen cancers, including gastric, breast, ovarian, lung, and pancreatic cancers, especially colorectal cancer. As one of
Tumor marker
the important tumor markers, the detection of CEA has great significance in differential diagnosis, condition
Nanoparticle
monitoring and therapeutic evaluation of diseases. Conventional CEA testing typically uses immunoassay
methods. However, immunoassay methods require complex and expensive instruments and professional per-
sonnel to operate. Moreover, radioactive element may cause certain damage to the human body, which limits
their wide application. In the past few years, biosensors, especially aptamer-based biosensors, have attracted
extensive attention due to their high sensitivity, good selectivity, high accuracy, fast response and low cost. This
review briefly classifies and describes the advance in optical and electrochemical aptamer biosensors for CEA
detection, also explains and compares their advantages and disadvantages.

1. Introduction differential diagnosis, condition monitoring and therapeutic evaluation

of diseases [17–20]. In recent years, sensor analysis and detection of
Tumor markers have great practical value in tumor screening, di- CEA has attracted widespread attention.
agnosis and efficacy evaluation [1–4]. Tumor markers are considered to Most of reported medical practices for CEA detection was based on
be substances that can be attributed to the development of normal cells immunoassay techniques, including enzyme-linked immunosorbent
or carcinogenesis at different stages of cell development [5]. It is most assays (ELISAs) [21,22], electrochemical immunoassays [23], radio-
commonly proteins and sugar lipids, but also includes DNA, RNA and immunoassay (RIA) and immunoradiometric assay (IRMA) [24],
microRNA (miRNA) [6–9]. Since its first description in 1965, carci- fluorescence immunoassay [25] etc.. Although immunoassay has good
noembryonic antigen (CEA) is the most thoroughly studied tumor selectivity, most developed immunoassays rely on specific markers,
marker [10]. such as fluorescent molecules, radioactive elements or enzymes, in
CEA is a human glycoprotein that is involved in cell adhesion and order to translate the binding information of antigen-antibody pairs
expressed during human fetal development. It is produced by normal into readable signals [26]. In addition, immunoassay methods require
fetal intestinal tissue and epithelial tumors, and its serum level can also complex and expensive instruments that require professional operating,
be increased in non-malignant diseases such as inflammatory bowel and radioactive elements can cause damage to body, thus limiting its
disease [11,12]. Following birth, CEA expression has been largely in- wide application [27–29]. Therefore, developing rapid, high-sensi-
hibited, with very low plasma CEA levels in healthy adults [13]. tivity, high-selectivity, cost-effective methods for detecting CEA is cri-
However, CEA is abnormally expressed in many human cancers, such as tical for the detection of human diseases.
gastric cancer, breast cancer, ovarian cancer, lung cancer, and pan- With the development of biosensor technology, biosensor has at-
creatic cancer, especially colorectal cancer (CRC) [10,14,15]. It is tracted great attention as a tool for analysis and diagnosis. It is an
abundantly expressed in approximately 95% of CRC, and some studies evolving field that meets the needs of people for fast, simple, selective
have extensively demonstrated the association between serum CEA (s- and low-cost analysis. Biosensor is a three-part analysis device: a bio-
CEA) levels and CRC [16]. So, detecting CEA has great significance in sensing (or biorecognition) component, a transducer, and a signal

∗
Corresponding author.
∗∗
Corresponding author.
E-mail address: [email protected] (L. Gao).

https://doi.org/10.1016/j.talanta.2020.120716
Received 25 August 2019; Received in revised form 30 December 2019; Accepted 3 January 2020
Available online 11 January 2020
0039-9140/ © 2020 Elsevier B.V. All rights reserved.
W. Xiang, et al. Talanta 214 (2020) 120716

processing unit [30,31]. A key part of the biosensor is the transducer, chloride and aggregates, causing a color change from red to blue. A
which takes advantage of the physicochemical changes that accompany sensitive linear range and detection limit for CEA was received via
the reaction [31]. Biosensors can be divided into electrochemical, op- adjusting the addition of the aptamer and NaCl, which were helpful and
tical, piezoelectric, magnetoelectric, etc. By their signal transduction convenient to meet different detection needs. This method had a linear
methods [32,33]. Optical and electrochemical biosensors are two range between the CEA concentrations of 0–120 ng mL−1 with the limit
widely used biosensing platforms [34,35]. of detection (LOD) 3 ng mL−1 [55].
In the last few decades of research, aptamer-based biosensors have Shahbazi et al. designed a simple colorimetric aptamer biosensor
been applied to CEA detection due to their good sensitivity and se- based on two unlabeled oligonucleotides, including CEA aptamer and
lectivity, high accuracy, fast response, and low cost [36–38]. An ap- split peroxidase-mimicking DNAzyme. In the absence of CEA, DNAzyme
tamer is a single-stranded RNA or DNA molecule selected in vitro from interacted with the aptamer, and there was no restriction on the for-
the nucleic acid molecular library by systematic evolution of ligands by mation of G-quadruplex, which could efficiently catalyzed H2O2-
exponential enrichment (SELEX) to specifically combine targets with mediated oxidation of 2, 2-azino-bis (3-ethylbenzothiazoline-6-sulfo-
high affinity (nucleic acids, small molecules, proteins, etc.) [39–41]. It nicacid) diammonium salt (ABTS) with an output signal of colorimetric.
can be considered functional analogs of antibodies and has a wide range Control experiments had shown that other existing proteins did not
of charge and structure combinations for a wide variety of biomedical, interfere with CEA signals. In addition, the aptamer biosensor in this
diagnostic, in vitro or in vivo biological imagings and therapeutic ap- strategy could detect CEA in saliva [57]. It is worth noting that the
plications [42]. Due to the limitations of immunosensors, they are not oxidation product of ABTS is unstable and rapidly decomposes into
suitable for a wide range of applications in detection. For example, colorless in an aqueous medium. This problem needs to be solved [79].
some very small molecules cannot react and antibodies are unstable in
extreme environments. The aptamer is flexible, repeatable, easy to fix 2.2. Surface plasmon resonance-based CEA aptamer biosensor
and regenerate, no difference between batches, which has been widely
used in the sensor field [43–48]. Since aptamers exhibited many ben- Surface plasmon resonance (SPR) biosensor is attractive for bio-
eficial aspects, aptamer-based biosensor systems have been developed sensing applications because of the high sensitivity of the resulting
to date for analysis of various classes of detectors. evanescent field to local refractive index (RI) changes. SPR was first
This review summarizes the application of aptamers in CEA bio- successfully used to build SPR-based biosensors to detect interactions of
sensors, and provides a detailed introduction in two aspects: aptamer- biomolecular in 1983 [83]. SPR is a strong electron-electron oscillation
based optical biosensors and aptamer-based electrochemical biosensors. that can occur at the metal/dielectric interface [84]. This technology
has attracted widespread attention due to its label-free, high selectivity,
2. Aptamer-based optical CEA biosensor direct and real-time detection [85,86]. Because it is extremely sensitive
to the refractive index of materials near the thin metal film, it is pos-
To date, optical biosensors are used in food safety, life sciences, sible to detect the combination of biochemical molecules with high
environmental monitoring and medical testing, and have made great sensitivity on the surface in real time [87–89]. Direct detection of SPR is
progress [49–51]. Optical biosensor includes transducers that can only applicable to analyte detection with molecular weights greater
capture signals generated by the interactions of biometric element with than 5000 Da, which is difficult to detect for low molecular weight
target analyte and convert them into optical signals [52,53]. It is widely analytes, but it can be improved by competitive and sandwich analysis
used in CEA biosensors due to its high specificity and sensitivity, direct [90]. At present, SPR has been widely used in the field of cancer de-
and rapid quantification, easy miniaturization, and label-free detection tection [91,92]. Guo et al. reported a novel bifunctional electro-
[52,54]. This section highlights optical biosensor platforms that have chemical and SPR biosensor based on metal-organic framework (MOF)
been widely used to date, such as colorimetric, surface plasmon re- nanocomposites (Fig. 1). The composite material was embedded in a
sonance, fluorescence, chemiluminescence and electro- zirconium metal-organic framework (Zr-MOF, UiO-66) of silver na-
chemiluminescence biosensors. Table 1 summarizes the studies of op- noclusters (AgNCs) (AgNCs @ Apt @ UIO-66) using aptamers as tem-
tical biosensors used to determine CEA. plates. The synthesized AgNCs @ Apt @ UiO-66 had well biocompat-
ibility and bioaffinity, and it was used as scaffold of SPR and
2.1. Colorimetric-based CEA aptamer biosensor electrochemical, which shown good selectivity, excellent stability and
wide applicability in real human serum samples. This sensor showed a
In aptamer-based optical technology, colorimetry has attracted little higher LOD of 0.3 ng mL−1 at a concentration of 1.0–250 ng mL−1
great attention due to its low readout cost and visual inspection cap- [58].
abilities. The colorimetric biosensor is label-free which can be quickly
observed color changes through the naked eye [77,78]. Colorimetric 2.3. Fluorescence-based CEA aptamer biosensor
aptamer sensors mainly contain gold nanoparticles (AuNPs) sensors and
HRP-mimicking DNAzyme sensors [79]. Due to their simple operation Fluorescence is one of the most commonly used methods for optical
and portability without other measuring devices, it has the potential of sensors with versatility, simplicity, sensitivity, multi-analyte detection,
commercial detection. non-destructive and reproducible [93,94]. By combining fluorescence
Gold nanoparticles (AuNPs) have many attractive properties, in- technology into the sensing probe, the biometric process is converted to
cluding unique optical properties and high molar extinction coeffi- an optical signal because many targets and biosensing elements have no
cients, which makes them sensitive probes for detecting biological inherent spectral features [95]. Using fluorescence technology and
analytes [80,81]. AuNPs are commonly used as colorimetric indicators aptamers, various aptamer-based fluorescence methods have been de-
owing to their strong distance-dependent optical properties [82]. veloped for CEA detection. According to the type of signal output, the
However, colorimetric biosensor based on AuNPs still has some lim- design of fluorescent biosensor is mainly divided into two categories:
itations. AuNPs have a tendency to non-specific aggregation in complex turn-on and turn-off [96,97]. Turn-on and turn-off represent the en-
biological fluids. And the colorimetric biosensor requires AuNPs to have hancement and attenuation of the fluorescent signal, respectively.
a uniform size and shape [78]. These problems require scholars to Signal changes can reflect the degree of the combining process, per-
consider and explore in sensor design. Luo et al. developed a colori- mitting quantitative measurement of analyte concentration.
metric biosensor for CEA detection based on a salt-induced aggregation
of AuNPs and conformational changes in CEA single-stranded DNA 2.3.1. Turn-off type of CEA biosensor
aptamers. AuNPs were not stable in high concentrations of sodium In the turn-off type, the binding of analyte to the aptamer results in

2
 W. Xiang, et al.

Table 1
Optical aptamer biosensors for CEA determination.
Method Assay strategy Nanomaterial Donor, Sensor Recognition motif Linear range LOD Ref
Exc/Em detection buffer
(nm)

Colorimetric Salt-induced AuNPs aggregation AuNPs – PBS ssDNA 0–120 ng mL−1 3 ng mL−1 [55]
Hyperbranched rolling circle amplification (HRCA) AuNPs – Tris–HCl ssDNA 5–500 pM 2 pM [56]
Label-free optical strategy – – Tris ssDNA 1–50 ng mL −1 1 ng mL−1 [57]
SPR AgNCs @ Apt @ UiO-66－SPR AgNCs @ Apt @ – PBS ssDNA 1.0–250 ng mL−1 0.3 ng mL−1 [58]
UIO-66
Fluorescence Visual fluorescence detection CdTe/CdSe CdTe/CdSe PBS dsDNA 0.05–20 ng mL−1 6.7 pg mL−1 [59]
365/550
Surface-enhanced fluorescence (SEF) AgNCs and AuNP AgNCs purified water ssDNA 0.01–1 ng mL−1 3 pg mL−1 [60]
473/540
−1 −1 −1
Synthesize the blue-fluorescent carbon dots with tomato CD CD PBS ssDNA 1 ng mL to 0.5 mg mL 0.3 ng mL [61]
juice 367/440
−1 −1
“Mix-and-detect” procedure – PFN PBS ssDNA 0.4–100 ng mL 0.316 ng mL [62]
−/−
Polymer point based FRET PFO dots and AuNPs PFO HEPES dsDNA 0.1–10 ng mL−1 – [63]
380/440
FRET between upconversion nanoparticles (UCNPs) and UCNP and GO UCNP HEPES UCNPs ssDNA 0.03–6 ng mL−1 7.9 pg mL−1 [64]

3
graphene oxide (GO) 980/500
−1 −1
FRET between UCPs and palladium nanoparticles (PdNPs) UCPs and PdNPs UCPs Tris-HCl UCPs ssDNA 2–100 pg mL 0.8 pg mL [65]
980/480
The combination of GO and aptamer labeled QDs by CE. CdSe/ZnS and GO CdSe/ZnS PBS QD ssDNA - 0.257–12.9 ng mL−1 5 pg mL−1 [66]
–/634
The combined effects of FRET and internal filter effect (IFE) CdTe-MSN and MoS2 CdTe-MSN PBS ssDNA 0.001–10 pg mL−1 0.7 fg mL−1 [67]
NSs 365/590
and 731
A four-color fluorescent nanoprobe for multiplexed detection GO Cy3 Tris-HCl ssDNA 1.0–200 nM 0.62 nM [68]
and imaging 543/553
Single oligonucleotide- GO FAM 480/ Tris-HCl hairpin ssDNA 50 fg mL−1 to 50 ng mL−1 28.5 fg mL−1 [69]
mediated isothermal quadratic amplification (SOIQA) 490
A cascade nucleic acid amplification strategy – NMM Tris-HCl dsDNA 0.001–2 ng mL−1 0.3 pg mL−1 [70]
399/610
−1 −1 −1
A smart DNA walker – NMM Tris/Mg/K stem–loop structure 10 pg mL to 100 ng mL 1.2 pg mL [71]
399/610 buffer DNA
−1 −1
Chemiluminescence (CL) Capillary electrophoresis-chemiluminescence (CE-CL) GO – PBS HRP-ssDNA 0.0654–6.54 ng mL 4.8 pg mL [72]
detection system
All-in-one dual-aptasensor – – PBS CEA aptamer-linker- 0–200 ng mL−1 0.58 ng mL−1 [38]
hemin aptamer
Electrochemiluminescence (ECL) Surface-enhanced ECL Ru @ SiO 2 -AuNPs – PBS ssDNA 0.005–50 pg mL−1 1.52 fg mL−1 [73]
Label-free ECL ZnS–CdS/MoS 2 – PBS ssDNA 0.05–20 ng mL−1 0.031 ng mL−1 [74]
Signal amplification CdS-GR and AuNP – PBS ssDNA 0.01–10.0 ng mL−1 3.8 pg mL−1 [75]
paper-based bipolar electrode PG-Fe 3 O 4 NPs and – PBS ssDNA 0.1 pg mL−1 to 15 ng mL−1 0.03 pg mL−1 [76]
AuNPs
Talanta 214 (2020) 120716
W. Xiang, et al. Talanta 214 (2020) 120716

Fig. 1. Schematic diagram of CEA aptamer sensor using SPR technique based on the AgNCs@Apt@UiO-66 nanocomposite. Reprinted with permission from Ref. [58].
Copyright 2017 American Chemical Society.

a change in the structural conformation, causing the quencher to be in CEA detection with CdTe/CdSe quantum dot (QD)-enzyme-im-
intimate contact with the fluorophore, thereby reducing fluorescence. pregnated paper (Fig. 2). Upon introduction of the CEA target in the
The most important consideration in such scheme is the degree to detection cells, the target reacted specifically with an aptamer im-
which conformational changes of aptamers affect the distance between mobilized on a mesoporous silica nanocontainers (MSN), which opened
the quencher and fluorophore in the presence of targets [98]. Although the pore and resulted in glucose release. The immobilized glucose
biosensors based on turn-off type are generally not as sensitive as oxidase (GOD) oxidized the released glucose on paper to generate
sensors based on the turn-on type, they can sometimes result in better gluconic acid and hydrogen peroxide, which quenched the fluorescence
targets detection by low-affinity aptamers. Importantly, simpler designs of CdTe/CdSe QD [59]. However, the sensitivity of this method was
with fewer steps are required to “turn-off” biosensor that is both con- relatively low due to the lack of enzyme amplification. Interestingly,
venient and low-cost [99]. For example, Qiu et al. proposed an in- based on complementary DNA hybridization, Yang et al. used AuNP to
tegrated paper-based analytical device (PAD) for visible fluorescence of strengthen the fluorescence intensity of silver nanoclusters (AgNCs),

Fig. 2. A schematic diagram of a visually fluorescent integrated paper based analysis device (PAD) for CEA detection by coupling with a bioresponsive controlled-
release system from DNA-gated mesoporous silica nanocontainers (MSNs). Reprinted with permission from Ref. [59]. Copyright 2017 American Chemical Society.

4
W. Xiang, et al. Talanta 214 (2020) 120716

Fig. 3. A schematic diagram of CEA detection based on Surface-enhanced fluorescence (SEF): (A) schematic illustration of SEF occurring. (B) schematic illustration of
the creative strategy for assaying CEA. Reprinted with permission from Ref. [60].

and successfully established a surface enhanced fluorescence (SEF) 2.3.2.1. FRET-based CEA biosensor. When fluorescence spectra of the
system to detect CEA (Fig. 3). AgNCs provided the original fluorescent donor molecules overlapped with the excitation spectra of receptor
signal, and DNA-modified AuNP was also used as a fluorescence en- molecules, excitation of the donor fluorescent molecule induced
hancer. This method, which combined of nanoparticles and na- fluorescence of the receptor molecule while the fluorescence intensity
noclusters by virtue of aptamer, supplied a worthy model for sensitive was decreased for the donor fluorescent molecule. This phenomenon is
detection of other trace targets in bioanalytical fields. The linear range FRET. The extent of FRET is related to the distance between the donor
was from 0.01 ng mL−1 to 1 ng mL−1 and LOD was down to 3 pg mL−1 and receptor molecules, which was typically 7–10 nm [100,101]. Xu
[60]. et al. designed a four-color fluorescent nanoprobe for multiplex
determination and imaging of tumor-related proteins in living cells.
This was the first example of the coinstantaneous imaging of four
2.3.2. Turn-on type of CEA biosensor intracellular protein biomarkers via nanoprobes. The fluorescence
In general, fluorescence quenching, compared with the fluorescence intensity was linear with CEA concentration from 1.0 nM to 200 nM,
opening method, caused an erroneous signal by accidental quenching of and the CEA detection limit was 0.62 nM [63]. However, traditional
interfering substances. Therefore, turn-on type biosensors had the ad- organic dyes have limitations such as narrow absorption, wide emission
vantage of being easy to detect low concentration analytes and reducing and photobleaching and the appearance of nanomaterials with
false positive signals. Recently, Bao et al. designed a label-free bio- fluorescent emission function solves these problems well [102–104].
sensor using polyfluorene-based cationic conjugated polyelectrolytes The distinguishing feature of upconversion nanoparticles (UCNP) is
(PFN+) for the detection of two tumor markers (CEA and AFP). The the emission of shorter wave luminescence in near-infrared (NIR) ra-
aptamer effectively quenched the fluorescence of PFN+ by forming a diation (anti-Stokes emission), where the inherent bioluminescent
PFN+-DNA complex. Aptamers formed a tighter and folded formation fluorophore cannot be excited and has no light scattering background
through specific protein-aptamer interactions, causing increased fluor- [105–107]. Due to its near-infrared excitation and visible emission
escence intensity of PFN+ when CEA presented. In addition, the sensor properties, the appearance of lanthanide-doped UCNP successfully de-
could quickly detect the target protein within 5 min without the need creased the background interference and significantly improved the
for complicated processing procedures and expensive instruments [62]. signal-to-noise ratio [108,109]. Wang et al. reported a FRET aptamer
There are many methods for detecting CEA for turn-on type, which biosensor using UCNP and graphene oxide (GO) for determination of
is mainly divided into two aspects: one is based on fluorescence re- CEA [64]. Similarly, the aptamer was modified with upconverting na-
sonance energy transfer (FRET), and the other is signal amplification noparticles, but li et al. used palladium nanoparticles (PdNPs) as the
technology. quenching agent to construct the FRET system (Fig. 4). The interaction

5
W. Xiang, et al. Talanta 214 (2020) 120716

Fig. 4. Schematic diagram of FRET between UCP and palladium nanoparticles (PdNPs). Reprinted with permission from Ref. [65].

between suitable CEA and nitrogen functional groups of PdNPs brought and a wider detection range. As a conventional amplification technique,
the UCNP and PdNPs close together, resulting in a fluorescence although PCR has been widely used in various fields, the requirements
quenching of 85% [65]. However, related studies have shown that of thermal cyclers have largely limited the use of PCR in resource-
water has a strong light absorption at 980 nm, resulting in a heating constrained environments and real-time measurements [114–116]. The
effect. This will cause 99% of the UC luminescence signal to be quen- development of isothermal amplification technology effectively avoids
ched due to non-radiative relaxation of the sensitizer and activator ions. the shortcomings of PCR and enables amplification of targets at a
This should be considered in the preparation of biosensors [105,110]. constant temperature in a fast, simple and efficient manner, which is a
Quantum dots (QDs) are common fluorescence molecules that are promising alternative to PCR [117,118]. Xu et al. constructed a single
generally used as fluorescent labeling for aptamers due to their oligonucleotide-mediated isothermal quadratic amplification (SOIQA)
broadband light absorption, low toxicity, resistance against photo- technology for FRET-based fluorescent aptamer biosensors. (Fig. 6).
bleaching and strong photoluminescence emission [111,112]. Zhou CEA bound to the aptamer and unfolded the aptamer hairpin probe
et al. proposed a CEA content analysis strategy based on the combi- labeled fluorophore to build a new DNA hairpin, resulting in catalytic
nation of capillary electrophoresis (CE) and aptamer-labeled QD recycling of the CEA and DNA sequence to carry out SOIQA. The large
(Fig. 5). Combined with CE, the aptamer biosensor had advantages in number of fluorophore-labeled single nucleotides produced by SOIQA
dosage of samples and efficiency of separation was high. In this de- were not adsorbed on GO, leading to a marked increase in the
tection method, the fluorescence intensity had a linear relationship fluorescence intensity of target molecule amplification. This assay
with CEA concentration from 0.257 to 12.9 ng mL−1. Based on S/ provided a low detection limit of 28.5 fg mL−1 for CEA
N = 3, the detection limit was approximately 5 pg mL−1 [66]. It is concentration, ranging from 50 fg mL−1 to 50 ng mL−1, with good
worth noting that the main problem of QDs is that the presence of specificity and a wide detection range of 6 orders of magnitude [69].
cadmium in the core which has a certain toxicity, but this can be solved
with an additional silicon shell coating [113].
Recently, another new type of fluorescent nanomaterial, polymer 2.4. Chemiluminescence-based CEA aptamer biosensor
dots, has attracted wide attention due to the strong fluorescence
emission caused by abundant p-electrons. Lin et al. introduced polymer Chemiluminescence (CL) is an optical strategy that refers to the
dots into FRET-based biosensors to analyze specific proteins, while luminescence energy produced by a chemical reaction without using
AuNPs were used as effective quenchers. CEA was quantitatively de- external light sources or optics. Compared to the fluorescence and other
tected by changes in fluorescence intensity. There was a good linear optical techniques, CL does not require an external light source and
range of CEA between 0.1 and 10 ng mL−1 [68]. optical filters, avoiding the influence of stray light and the instability of
light source [119–121]. In addition, the lifetime of the CL luminescent
material is much longer than the fluorescent material [122]. However,
2.3.2.2. Nucleic acid amplification technologies-based CEA biosensor. In due to the small CL reaction system and poor selectivity, the application
order to improve sensitivity and enhance signal readout, signal of CL is limited. So it is often associated with separation technology to
amplification strategy that is based on nucleic acid amplification has make up for its shortcomings. Zhou et al. designed a novel CEA de-
been investigated and applied to CEA detection. Its purpose is to termination method based on aptamer/graphene oxide (Apt/GO)
improve the performance of biosensors, resulting in higher sensitivity combined with capillary electrophoresis-chemiluminescent (CE-CL).

6
W. Xiang, et al. Talanta 214 (2020) 120716

Fig. 5. Schematic diagram of CE combined with GO and aptamer-labeled QD for CEA detection. Reprinted with permission from Ref. [66].

When CEA existed, HRP-Apt-CEA complex was formed by HRP-Apt and increased the ECL intensity by 30 times [73]. In another study, Wang
CEA, leaving from GO, and then the CL signal catalyzed by this complex et al. used ZnS–CdS nanoparticle (NP) modified molybdenum disulfide
could be detected without any chemiluminescence resonance energy (MoS2) nanocomposite electrodes as a sensing system and aptamers as
transfer (CRET). CL intensity was linear with the CEA concentration, identification molecules to prepare a sensitive ECL biosensor for CEA
ranging from 0.0654 to 6.54 ng mL−1 with a detection limit of ap- determination. The layered MoS2 modified on the electrode greatly
proximately 4.8 pg mL−1 [72]. In another study, Khang et al. used a increased the surface area of the sensing interface, which largely in-
dual DNA aptamer (CEA aptamer combined with hemin aptamer) to creased the loading number of ZnS–CdS, generating more ECL signals.
develop a dual aptamer biosensor based on 1,1′-oxalyldiimidazole This strategy had a good application prospect and was successfully
(ODI) CL detection. The detection of all-in-one aptamer biosensor can applied to the detection of CEA in human serum with a recovery rate of
be completed in a short single incubation time without the need for 80–111% [74].
time-consuming washing operations, thereby eliminating the waste and
interference required by conventional ELISA [38]. 3. Aptamer-based electrochemical CEA biosensor

2.5. Electrochemiluminescence-based CEA aptamer biosensor Electrochemical biosensors are based on selective interactions be-
tween a target compound and a recognition element (enzyme, antibody,
Electrogenerated chemiluminescence (ECL) is the light produced by DNA/RNA, tissue or other biomolecules) to generate an electrical signal
an electron transfer reaction between electrochemically generated re- proportional to the concentration of the analyte compound. A typical
agents [123]. ECL combines the characteristics of electrochemical electrochemical biosensor consists of three parts: working, reference and
controllability and low chemiluminescence background and has ad- auxiliary electrodes [126,127]. A series of electrochemical techniques
vantage of cost-effective, simple optical setup and fast measurement, have been applied to biosensing applications, including impedimetric,
considering as a powerful analytical technique produced by electro- amperometric, voltammetric, potentiometric, etc. [127–129].
chemical reactions [124,125]. Wang et al. designed a surface enhanced One of the key advantages of electrochemical transduction com-
ECL (SEECL) biosensor for ultra-sensitive detection of target in human pared to fluorescence analysis is that it does not contain labels and the
serum (Fig. 7). Researchers used Ru (bpy)32+ doped SiO2 nanoparticles conversion phenomenon is simple. Cheap electrodes can be integrated
(Ru@SiO2) as ECL luminophores, and AuNPs acted as surface en- with simple electronic devices for fast detections in a compact, easy-to-
hancement sources for ECL signal amplification. In the presence of CEA, use portable system. In general, electrochemical biosensors offer ad-
Ru@SiO2 and AuNP formed a network of nanostructures, which vantages such as high specificity of their biometric processes, low

7
W. Xiang, et al. Talanta 214 (2020) 120716

Fig. 6. Schematic diagram of single oligonucleotide-mediated isothermal secondary amplification (SOIQA). Reprinted with permission from Ref. [69].

Fig. 7. Schematic diagram of CEA detection in human serum based on localized surface plasmon resonance (LSPR) enhanced electrochemiluminescence (ECL) of Ru
(bpy)32+. Reprinted with permission from Ref. [73]. Copyright 2015 American Chemical Society.

8
 W. Xiang, et al.

Table 2
Electrochemical aptamer biosensors for CEA determination.
Method Assay strategy nanomaterial Sensor detection Recognition motif Linear range LOD Ref
buffer

EIS Glucose oxidase (GOx)-initiated cascade catalysis amplification Pt@CuMOFs-hGq-GOx PBS ssDNA 0.05 pg mL −1 to 20 ng mL−1 0.023 pg mL −1 [133]
MnTMPyP-dsDNA assisted by HCR PtPd nanowires PBS dsDNA 0.1 pg mL−1 to 0.5 ng mL−1 and 1 ng mL−1 0.030 pg mL−1 [134]
to 40 ng mL−1.
Amperometric Sandwich complexes AuNPs PBS ssDNA 1–200 ng mL−1 0.5 ng mL−1 [135]
Aptamer-initiated on-particle template-independent enzymatic AuNP PBS ssDNA 50 fM–500 pM 5 fM [136]
polymerization (aptamer-OTEP)
Voltammetric A dual-target electrochemical Au PBS dsDNA 0.01 pM to 100 nM 3.33 fM [36]
Dual-analyte detection system AuNPs PBS integrated signal probe 1 ng mL−1 to 1 μg mL−1 0.517 ng mL−1 [137]
(ISP)
A nanocomposite of multi-walled carbon nanotubes, hemin and HGNs-MWCNTs PBS ssDNA 1 × 10−15 to 1 × 10−8 g mL−1 0.82 fg m L−1 [138]

9
graphene nanosheets (HGNs-MWCNTs)
−1 −1
Lead ion (Pb2+)-dependent DNAzyme-assisted signal GQDs-IL-NF PBS hairpin DNA 0.5 to 500 fg mL 0.34 fg mL [139]
amplification
A shell-encoded Au NPs Au@Cu2O and Au@Ag core- PBS dsDNA 5 pg mL−1 to 10 ng mL−1 1.8 pg mL−1 [140]
shell NPs
Enzymatically catalytic signal tracing pAu NS Tris-HCl ssDNA 1.0 pg mL −1 to 100 ng mL−1 0.45 pg mL−1 [141]
Ag NCs-HRP signal probe Ag NCs PB ssDNA 1 pg to 10 ng mL−1 0.5 pg mL−1 [142]
A ternary nanocomposite of AuNPs-HGNs AuNPs-HGNs PBS ssDNA 0.0001–10 ng mL−1 40 fg mL−1 [143]
Potentiometric Field-effect transistor (FET) biosensors C-PPy MNTs PBS ssDNA – 1 fg mL−1 [144]
PEC Enzyme-free cascaded quadratic amplification CdS/TiO2 TBE dsDNA 8.0 fg mL−1 to 50.0 pg mL−1 – [145]
RET between P–TiO2 NA and CNTs-Au nanocomposites CNTs-Au and P–TiO 2 NA Tris-HCl dsDNA 0.001–2.5 ng mL−1 0.39 pg mL−1 [146]
RET between CdTe QDs and RGO-AuNPs RGO-AuNPs and CdTe QDs Tris-HCl dsDNA 0.001–2.0 ng mL−1 0.47 pg mL−1 [147]
NaYF4:Yb, Er UCN coupling with target-triggered HCR NaYF4:Yb, Er UCN and Ag 2 S HEPES ssDNA 0.005–5.0 ng mL−1 1.9 pg mL−1 [148]
NaYF4:Yb,Tm@TiO2 upconversion microrods with RCA NaYF 4：Yb，Tm @ TiO 2 PBS ssDNA 10 pg mL−1 to 40 ng mL−1 3.6 pg mL−1 [149]
Dual signal readout NaYF 4：Yb，Er UCNPs @ PBS dsDNA 10.0 pg mL−1 to 5.0 ng mL−1 4.8 pg mL−1 [150]
CdTe and AuNPs
ZnO flower-rods (ZnO FRs) modified with g-C3N4-AuNP g-C3N4-AuNPs and CuS NCs Tris-HCl dsDNA 0.01–2.5 ng mL−1 1.9 pg mL−1 [27]
nanohybrids
Talanta 214 (2020) 120716
W. Xiang, et al. Talanta 214 (2020) 120716

background noise, and better signal to noise ratio [127,130]. However, nanoprobe formed a sandwich structure with CEA, causing the nanop-
the main problem limiting the development of electrochemical sensor is robe being attached to the electrode surface. Thereafter, high-efficiency
the detection limit which is much higher than the polymerase chain amplification by terminal deoxynucleotidyl transferase (TdT) and
reaction (PCR) or fluorescence measurement [131]. In addition, there avidin modified horseradish peroxidase (Av-HRP) dramatically in-
are some issues for electrochemical methods that deserve researchers' creased the electrochemical signal [136].
attention, such as reproducibility of preparations, difficulty in re-
generating sensing surfaces, and often indirect sensing systems [132]. 3.3. Voltammetric-based CEA aptamer biosensor
This chapter introduces electrochemical aptamer biosensors for
CEA, such as electrochemical impedance spectroscopy (EIS), ampero- The use of voltammetric sensors is of particular interest in electro-
metric, voltammetric, potentiometric, and photoelectrochemical (PEC) chemical sensors. They use several different techniques including cyclic
biosensor. Table 2 summarizes the published researchs on the devel- voltammetry (CV), square wave voltammetry (SWV), differential pulse
opment of electrochemical biosensors for CEA detection. voltammetry (DPV), etc. to detect low concentrations of tumor markers
with high sensitivity, high specificity, and good suitability [161,162].
3.1. EIS-based CEA aptamer biosensor The voltammetric biosensor can sense low correlation noise, which can
provide credible and repeatable data for quantification of analytes. This
EIS biosensor measures the change in the electrical impedance data in higher sensitivity and specificity of the voltammetric biosensor.
spectrum produced by the interaction between the analyte and the re- In addition, voltammetric sensor can detect multiple analytes with
ceptor. The region for receptor fixation is mainly on the surface of the different peak potentials in a single electrochemical experiment (or
electrode or in the gap between the electrodes. And it can measure scan), thus providing the possibility to detect multiple substances si-
changes in electrical properties caused by interactions between apta- multaneously [36,137,140].
mers and analytes [151,152]. EIS is not only an effective method for Mazloum-Ardakani et al. developed an aptamer biosensor based on
characterizing functionalized substrates of biomolecules, but also a multi-walled carbon nanotubes, hemin and graphene nanosheets
sensitive technique for monitoring aptamer-ligand binding that occurs (HGNs-MWCNTs) for sensitive detection of CEA. The nanocomposite
on the surface of electrodes. An important advantage of EIS biosensors could provide a comprehensive set of the main excellent properties of
is that the stimulus sinusoidal voltage is small and does not damage or three nanomaterials. Due to its well-defined redox properties, Hemin
interfere with most biorecognition layers [153]. Owing to its large was used as an in situ probe, providing a good interface between the
amount of information, nondestructive, simple, and unmarked, EIS aptamers and the surface electrode. And multi-walled carbon nanotubes
biosensor platform has received considerable attention and wide ap- in nanocomposites improved electrical conductivity and accelerated
plication [49,154,155]. Zhou et al. proposed a sensitive electrochemical electron transfer between hemin and glassy carbon electrodes. When
impedimetric aptamer biosensor for CEA detection based on glucose CEA was captured at the interface by CEA binding aptamers (CBA), the
oxidase (GOx)-driven cascade catalyzed amplification, using Pt nano- signal of hemin was further reduced because of the thickening of
particles, aptamers, hemin, and GOx constitutes a functionalized Cu- electron transfer. The concentration of CEA detected by the electro-
based metal-organic (Pt @ CuMOFs-hGq-GOx) (Fig. 8). Pt @ CuMOFs chemical aptamer biosensor with a wide linear range of
and hemin/G-quadruplex (hGq) synergistically catalyzed the decom- 1.0 × 10−15 g mL−1 to 1.0 × 10−8 g mL−1, and the detection limit
position of H2O2 produced by the cascade reaction. It was accompanied was 0.82 fg mL−1. This low-cost, high sensitivity and selectivity bio-
by oxidizing the 3,3-diaminobenzidine (DAB) and forming a non-con- sensor could be a hopeful means for CEA detection in clinical applica-
ductive insoluble precipitate (IP). It resulted in a remarkable in- tions [138].
creasement in the electrochemical impedance signal. The LOD of this In another study, Huang et al. proposed an electrochemical aptamer
biosensor was 0.023 pg mL−1 with the range of 0.05 pg mL −1 to biosensor using lead ion (Pb2+)-dependent DNAzyme-assisted signal
20 ng mL−1 [133]. Unfortunately, this technology is still not fully un- amplification and graphene quantum dot-ionic liquid-nafion (GQDs-IL-
derstood. By using EIS as a means of supporting voltamperance evi- NF) composite film for CEA electrochemical measurement (Fig. 10).
dence for electrochemical work, rather than the primary technique This was the first time that GQDs-IL-NF composite film had been pre-
[156]. pared on an electrode. When CEA presented, hairpin DNA recognized
CEA and triggered DNAzyme-assisted signal amplification reaction to
3.2. Amperometric -based CEA aptamer biosensor produce a large amount of single-stranded DNA which could adsorbed
on the GQDs-IL-NF modified GCE by a π-π stacking interaction. Thus,
The amperometric biosensor gauges the magnitude of current gen- The methylene blue-abeled substrate DNA (MB-substrate) is im-
erated by a constant reduction or oxidation potential applied to the mobilized on the electrode and generated a large initial electrochemical
working electrode [157]. Therefore, amperometric biosensor is well signal [139].
suited for detecting electroactive substances involved in chemical or Zhao et al. prepared shell-encoded AuNPs containing Au@Cu2O and
biometric processes [158]. Due to the inherent simplicity of the trans- Au@Ag core-shell NP by depositing different amounts of Cu and Ag
ducer, it is suitable for low-cost portable devices that often used for precursors. The AuNPs encoded by the Cu2O shell and the Ag shell
disease diagnosis and environmental monitoring [128]. exhibited two independent DPV peaks at −0.08 V and 0.26 V, re-
AuNPs have excellent electrical conductivity, high surface area, and spectively. The shell-encoded AuNP exhibited an amplified peak cur-
good catalytic properties, so they are ideal materials for preparing rent with an adjustable shell thickness. Electrochemical aptamer sen-
electrochemical biosensors [159,160]. Shu et al. proposed a new elec- sors using shell-encoded AuNPs could double screen CEA and alpha-
trochemical aptamer biosensor based on signal amplification of AuNPs. fetoprotein (AFP) [140].
They used two different aptamers for CEA identification. Compared
with single aptamer, two different CEA aptamers produced better re- 3.4. Potentiometric based CEA aptamer biosensor
cognition accuracy, resulting in a lower background signal and good
selectivity [135]. In another study, Wang et al. constructed an elec- The potentiometric biosensor measures the potential difference
trochemical detection system based on aptamer-initiated on-particle between the working electrode and the reference electrode caused by a
template-independent enzymatic polymerization (aptamer-OTEP) change in the concentration of charged species. In this measurement,
(Fig. 9). The aptamer 1 connected to a gold electrode was used as a the potential difference is determined by the voltammeter when no
capture probe, and aptamer 2 modified on the surface of gold nano- significant current flows [163,164]. Field effect transistors (FET) are a
particles was used as a nanoprobe. The capture probe and the special type of potentiometric biosensor [128]. When zero or negligible

10
W. Xiang, et al. Talanta 214 (2020) 120716

Fig. 8. Schematic diagram of EIS detection based on Glucose oxidase (GOx)-initiated cascade catalysis amplification: (A) Preparation process of Pt@CuMOFs-hGq-
GOx, (B) Schematic illustration of fabrication of the impedimetric aptasensor, and (C) Cascade catalysis amplification to form nonconductive insoluble precipitates
(IPs). Reprinted with permission from Ref. [133].

current flows through the electrode, the potential difference accumu- selectivity, and repetitive properties [166–168]. Park et al. used ap-
lates during the identification process in the electrochemical cell [165]. tamer-functionalized polydimensional conductive-polymer (3-carbox-
The combination of charged targets induces changes in the intrinsic ylate polypyrrole) nanotubes (Apt-C-PPy MNT) to fabricate a FET bio-
carrier concentration of the FET channel, which allows the FET to be sensor to detect CEA (Fig. 11). A C-PPy MNT multidimensional system
biometrically identified, with no labeling, high sensitivity, high was synthesized by a solution-based temperature control technique and

Fig. 9. Schematic diagram of an aptamer-initiated on-particle template-independent enzymatic polymerization (aptamer-OTEP) amperometric biosensor. Reprinted
with permission from Ref. [136].

11
W. Xiang, et al. Talanta 214 (2020) 120716

Fig. 10. Schematic diagram of CEA detection based on lead ion (Pb2+)-dependent DNAzyme assisted signal amplification strategy. Reprinted with permission from
Ref. [139].

Fig. 11. Schematic diagram of a field effect transistor (FET) biosensor based aptamer-functionalized multidimensional conducting-polymer (3-carboxylate poly-
pyrrole) nanotubes (Apt–C-PPy MNTs). Reprinted with permission from Ref. [144].

fixed to the surface of the electrode. It was then bound to the amine photoactive material by photoexcitation to transfer it to the electrode
modified CEA aptamer via an amide covalent bond. The FET biosensor interface, resulting in a change in the output photocurrent signal
based on C-PPy MNT exhibited a fast response (< -1s) for CEA detec- [169,170]. PEC biosensors, combining the advantages of optical and
tion, which had a good electrical conductivity. This was the first de- electrochemical methods, have a low background signal, which is more
monstration of CEA detection using a multi-dimensional CPNT-based sensitive than traditional electrochemical methods and does not require
FET biosensor with a detection limit of approximately 1 fg mL−1 [144]. the complicated and expensive instrument cost of optical biosensors
[171–173].
3.5. Photoelectrochemical based CEA aptamer biosensor Ge et al. developed a PEC biosensor with an enzyme-free cascaded
quadratic signal amplification method using catalytic hairpin assembly
Photoelectrochemical (PEC) biosensors are highly efficient sensing (CHA) and hybridization chain reaction (HCR) for CEA detection. CEA
technologies coupled with electrochemistry and photochemistry which recognized the CEA-aptamer @ sstDNA (single-stranded trigger) com-
have attracted more and more attention. The detection process of PEC plex, which caused sstDNA released from the complex, thereby trig-
biosensor is the opposite of ECL biosensor: light serves as the excitation gering the upstream CHA recycling loop. The dsDNA complex produced
source and photocurrent serves as the detection signal. It typically rely by CHA further induced downstream HCR amplification, resulting in
on the introduction of photoinduced electrons/holes into the forming many hemin/G-quadruplex DNases. This would stimulate the

12
W. Xiang, et al. Talanta 214 (2020) 120716

insoluble/insulating products formed by the biocatalytic precipitation 5. Conclusion

of 4-chloro-1-naphthol (4-CN), leading to a significant reduction in
photocurrent signals [145]. As one of the common tumor markers, CEA has important clinical
In another study, Deng et al. proposed a PEC biosensor based on value in the differential diagnosis, disease monitoring and therapeutic
resonance energy transfer (RET) between pinnate titanium dioxide evaluation of malignant tumors. In the past few decades, biosensor
nanorods array (P–TiO2 NA) and carbon nanotubes-gold nanoparticles technology has attracted the attention of scientists due to its simple,
(CNTs-Au) nanocomposites for highly sensitive detection of CEA. As fast, low-cost detection, high sensitivity and good selectivity. The ap-
the quenching efficiency of excitons generated in P–TiO2 NA de- tamer is relatively fast and inexpensive to produce and can be chemi-
creases, the energy transfer efficiency decreased resulting in an in- cally synthesized. It is extremely accurate and repeatable, with flexible
crease in PEC response. The PEC aptamer sensor had a linear range of marking and good stability. Also, aptamer targets are less restrictive
0.001–2.5 ng mL−1 with a detection limit of 0.39 pg mL−1 and was than antibodies, so they have a wide range of applications in biosensors
satisfactory for clinical sample testing [146]. and medicine. It becomes a suitable substitute for antibodies.
Qiu et al. constructed three sensitive filters based on near-infrared This article outlines the use of aptamers in CEA biosensors. It is
(NIR) light-driven PEC aptamer biosensors for CEA. One of the bio- introduced from two aspects of aptamer-based optical and electro-
sensors amplified the signal by coupling with the HCR under the illu- chemical biosensors. We analyzed the characteristics of each sensor and
mination of near-infrared light and the formation of Ag2S nanoparticles. introduced their advantages and disadvantages. Some biosensors com-
The PEC aptamer platform had high sensitivity to the determination of bined excellent nanomaterials such as graphene, metal nanoparticles,
CEA in the dynamic linear range of 0.005–5.0 ng mL−1 with a detection quantum dots, etc., which are widely used in optical and electro-
limit of 1.9 pg mL−1 [148]. Another biosensor was based on core–shell chemical biosensors. Nanomaterials have a large surface-volume ratio
NaYF4: Yb, Tm@TiO2 upconversion micro rods by coupling with target- which can achieve efficient target interaction. In addition, the devel-
triggered rolling circle amplification (RCA). The working range was opment of nanocomposites can combine the advantages of multiple
10 pg mL−1 to 40 ng mL−1 allowed for the detection of CEA as low as nanomaterials to develop new assays with ultra-sensitivity and multi-
3.6 pg mL−1 [149]. parameter functionality. After combining nanomaterials, biosensor
performance has been greatly optimized and improved, which can
improve the sensitivity and specificity of detection. Due to the existence
4. Other CEA testing methods of multiple tumor markers in cancer patients, some researchers have
been working on the development of biosensors that can detect multiple
In addition to aptamer-based detection methods, other detection tumor markers at the same time. Although some efforts have been made
methods are also used in the detection of CEA, for instance immuno- to design biosensors for detecting multiple biomarkers simultaneously,
based optical and electrochemical biosensor [174,175], biochip functional verification is still limited. Complex biological sample en-
[176,177], radioimmunoassay (RIA) and immunoradiometric assay vironments can interfere with the results of the analysis and there may
(IRMA) [24], portable biosensor [178], mass change-based piezo- be false positive signals. Some of the sensors that have been developed
electric [179] and flexural plate-wave (FPW) biosensor [180] etc.. still require dilution of the serum for sensory analysis. For mass-based
To date, scientists are still improving the ELISA method to achieve piezoelectric and magnetoelectric biosensors, the related article has not
a high sensitivity and better stability. Zhou et al. developed a sand- yet been proposed based on the aptamer detection scheme.
wich format ELISA based on gold nanoparticle layer (GNPL), which Furthermore, current CEA aptamer biosensors lack the research for real-
used IgG as a single protein solution and CEA in human plasma as a time quantitative portable biosensors. Although conventional bio-
measurement system. The GNPL-based sandwich ELISA amplified the sensors have been miniaturized and cost-effective, they have not yet
signal and reduced the LOD compared to the ELISA of the modified achieved in vitro detection of easy-to-use, home-use, and most bio-
plate and the commercial ELISA kit. The results indicated that GNPL sensors lack relevant research for complex environmental detection. To
modified plates could be used in sandwich format ELISA in complex date, commercial CEA biosensors are still in their infancy. These
media [181]. questions still need to be explored by researchers.
The development of imaging equipment allowed high sensitivity
and selective quantitative analysis to be applied at the single molecule Declaration of competing interest
level [182,183] Ahn et al. combined a total internal reflection scat-
tering microscope based on transmission grating (TG) with a plasma The authors declare that there are no conflicts of interest regarding
nano-immunosensor to improve the detection sensitivity of CEA. Scat- the publication of this paper.
tering signals of silver nanoparticles (SNP) nanoprobes bound to CEA in
EFL were collected and spectrally separated using a TG beam splitter. Acknowledgments
The combination of the two techniques minimized the interference of
spectroscopic and background noise. The LOD was as low as 19.75 zM This work is supported by the Jiangsu University (No.13JDG005),
and the linear dynamic range was 19.75 zM to 39.50 nM. Especially, Natural Science Foundation of Liaoning Province and Jiangsu Province
this strategy could be used to directly test multiple protein biomarkers (201601268 and BK20181444 ) .
at the level of a single molecule in a human biological sample by simply
altering the antibody of the target protein [183]. References
Label-free atomic spectrometric bioassays has attracted extensive
research interest due to its low cost, simple design and ease of op- [1] D. Di Gioia, I. Blankenburg, D. Nagel, V. Heinemann, P. Stieber, Tumor markers in
eration. Chen et al. proposed a novel chemical vapor generation- the early detection of tumor recurrence in breast cancer patients: CA 125, CYFRA
21-1, HER2 shed antigen, LDH and CRP in combination with CEA and CA 15-3,
atomic fluorescence spectrometry (CVG-AFS)/inductively coupled Clin. Chim. Acta 461 (2016) 1–7.
plasma-mass spectrometry (ICP-MS) label-free sensing method for the [2] M.J. Duffy, R. Lamerz, C. Haglund, A. Nicolini, M. Kalousova, L. Holubec,
detection of nucleic acids and proteins (CEA). This assay retained the C. Sturgeon, Tumor markers in colorectal cancer, gastric cancer and gastro-
intestinal stromal cancers: European group on tumor markers 2014 guidelines
advantages of label-free atomic spectroscopy bioassay and combineed update, Int. J. Cancer 134 (2014) 2513–2522.
with selective cation exchange reaction and simple filtration separa- [3] H. Shimada, T. Noie, M. Ohashi, K. Oba, Y. Takahashi, Clinical significance of
tion to improve the detection performance. The LOD was 0.2 ng mL−1 serum tumor markers for gastric cancer: a systematic review of literature by the
Task Force of the Japanese Gastric Cancer Association, Gastric Cancer 17 (2014)
for CEA detection with a linear dynamic range of 0.5–20 ng mL−1
26–33.
[184].

13
W. Xiang, et al. Talanta 214 (2020) 120716

[4] Y. Lai, L. Wang, Y. Liu, G. Yang, C. Tang, Y. Deng, S. Li, Immunosensors based on [32] S. Dehghani, R. Nosrati, M. Yousefi, A. Nezami, F. Soltani, S.M. Taghdisi,
nanomaterials for detection of tumor markers, J. Biomed. Nanotechnol. 14 (2018) K. Abnous, M. Alibolandi, M. Ramezani, Aptamer-based biosensors and nano-
44–65. sensors for the detection of vascular endothelial growth factor (VEGF): a review,
[5] G. Lech, R. Slotwinski, M. Slodkowski, I.W. Krasnodebski, Colorectal cancer tu- Biosens. Bioelectron. 110 (2018) 23–37.
mour markers and biomarkers: recent therapeutic advances, World J. [33] N. Verma, A. Bhardwaj, Biosensor technology for pesticides–a review, Appl.
Gastroenterol. 22 (2016) 1745–1755. Biochem. Biotechnol. 175 (2015) 3093–3119.
[6] E. Wieczorek, E. Reszka, mRNA, microRNA and lncRNA as novel bladder tumor [34] I. Willner, M. Zayats, Electronic aptamer-based sensors, Angew Chem. Int. Ed.
markers, Clin. Chim. Acta 477 (2018) 141–153. Engl. 46 (2007) 6408–6418.
[7] X. Han, J. Wang, Y. Sun, Circulating tumor DNA as biomarkers for cancer detec- [35] J. Ali, J. Najeeb, M. Asim Ali, M. Farhan Aslam, A. Raza, Biosensors: their fun-
tion, Genom. Proteom. Bioinform. 15 (2017) 59–72. damentals, designs, types and most recent impactful applications: a review, J.
[8] B.K. Banin Hirata, J.M. Oda, R. Losi Guembarovski, C.B. Ariza, C.E. de Oliveira, Biosens. Bioelectron. 8 (2017).
M.A. Watanabe, Molecular markers for breast cancer: prediction on tumor beha- [36] C. Ma, H. Liu, L. Zhang, H. Li, M. Yan, X. Song, J. Yu, Multiplexed aptasensor for
vior, Dis. Markers (2014) (2014) 513158. simultaneous detection of carcinoembryonic antigen and mucin-1 based on metal
[9] M.H. Tan, H.Y. Wang, C.H. Hsieh, C.N. Wen, Y.H. Wen, C.H. Chen, J.J. Lu, Cancers ion electrochemical labels and Ru(NH3)6(3+) electronic wires, Biosens.
screening in an asymptomatic population by using multiple tumour markers, PLoS Bioelectron. 99 (2018) 8–13.
One 11 (2016). [37] M. Ahmadzadeh-Raji, E. Ghafar-Zadeh, G. Amoabediny, An optically-transparent
[10] P. Gold, S.O. F, Specific carcinoembryonic antigens of the human digestive system, aptamer-based detection system for colon cancer applications using gold nano-
J. Exp. Med. 122 (1965) 467–481. particles electrodeposited on indium tin oxide, Sensors (2016) 16.
[11] C.H. Chen, M.C. Hsieh, C.C. Lai, C.Y. Yeh, J.S. Chen, P.S. Hsieh, J.M. Chiang, [38] H. Khang, K. Cho, S. Chong, J.H. Lee, All-in-one dual-aptasensor capable of rapidly
W.S. Tsai, R. Tang, C.R. Changchien, J.Y. Wang, Lead time of carcinoembryonic quantifying carcinoembryonic antigen, Biosens. Bioelectron. 90 (2017) 46–52.
antigen elevation in the postoperative follow-up of colorectal cancer did not affect [39] T. Hermann, D.J. Pate1, Adaptive recognition by nucleic acid aptamers, Science
the survival rate after recurrence, Int. J. Colorectal Dis. 25 (2010) 567–571. 287 (2000) 820–825.
[12] A. Chiaravalloti, A. Fiorentini, E. Palombo, D. Rinino, A. Lacanfora, R. Danieli, [40] L. Wen, L. Qiu, Y. Wu, X. Hu, X. Zhang, Aptamer-modified semiconductor
C. Di Russo, D. Di Biagio, E. Squillaci, O. Schillaci, Evaluation of recurrent disease quantum dots for biosensing applications, Sensors 17 (2017).
in the re-staging of colorectal cancer by (18)F-FDG PET/CT: use of CEA and CA 19- [41] P. Kalra, A. Dhiman, W.C. Cho, J.G. Bruno, T.K. Sharma, Simple methods and
9 in patient selection, Oncol Lett 12 (2016) 4209–4213. rational design for enhancing aptamer sensitivity and specificity, Front Mol Biosci
[13] J.A. Hensel, V. Khattar, R. Ashton, S. Ponnazhagan, Recombinant AAV-CEA tumor 5 (2018) 41.
vaccine in combination with an immune adjuvant breaks tolerance and provides [42] J. Bala, S. Chinnapaiyan, R.K. Dutta, H. Unwalla, Aptamers in HIV research di-
protective immunity, Mol Ther Oncolytics 12 (2019) 41–48. agnosis and therapy, RNA Biol. 15 (2018) 327–337.
[14] R.D. Blumenthal, E. Leon, H.J. Hansen, D.M. Goldenberg, Expression patterns of [43] S. Catuogno, C.L. Esposito, V. de Franciscis, Aptamer-mediated targeted delivery
CEACAM5 and CEACAM6 in primary and metastatic cancers, BMC Canc. 7 of therapeutics: an update, Pharmaceuticals (2016) 9.
(2007) 2. [44] M. Yüce, N. Ullah, H. Budak, Trends in aptamer selection methods and applica-
[15] J. Marshall, Carcinoembryonic antigen-based vaccines, Semin. Oncol. 30 (2003) tions, Analyst 140 (2015) 5379–5399.
30–36. [45] C. Perez-Gonzalez, D.A. Lafontaine, J.C. Penedo, Fluorescence-based strategies to
[16] K.M. Yang, I.J. Park, C.W. Kim, S.A. Roh, D.H. Cho, J.C. Kim, The prognostic investigate the structure and dynamics of aptamer-ligand complexes, Front Chem
significance and treatment modality for elevated pre- and postoperative serum 4 (2016) 33.
CEA in colorectal cancer patients, Ann Surg Treat Res 91 (2016) 165–171. [46] N. Duan, S. Wu, S. Dai, T. Miao, J. Chen, Z. Wang, Simultaneous detection of
[17] C.O. Sahlmann, K. Homayounfar, M. Niessner, J. Dyczkowski, L.C. Conradi, pathogenic bacteria using an aptamer based biosensor and dual fluorescence re-
F. Braulke, B. Meller, T. Beissbarth, B.M. Ghadimi, J. Meller, D.M. Goldenberg, sonance energy transfer from quantum dots to carbon nanoparticles, Microchimica
T. Liersch, Repeated adjuvant anti-CEA radioimmunotherapy after resection of Acta 182 (2014) 917–923.
colorectal liver metastases: safety, feasibility, and long-term efficacy results of a [47] S.C. Gopinath, T. Lakshmipriya, Y. Chen, W.M. Phang, U. Hashim, Aptamer-based
prospective phase 2 study, Cancer 123 (2017) 638–649. 'point-of-care testing, Biotechnol. Adv. 34 (2016) 198–208.
[18] G. Saito, S. Sadahiro, K. Okada, A. Tanaka, T. Suzuki, A. Kamijo, Relation between [48] S.M. Nimjee, R.R. White, R.C. Becker, B.A. Sullenger, Aptamers as therapeutics,
carcinoembryonic antigen levels in colon cancer tissue and serum carcinoem- Nat. Rev. Drug Discov. 57 (2017) 61–79.
bryonic antigen levels at initial surgery and recurrence, Oncology 91 (2016) [49] V.-T. Nguyen, Y. Kwon, M. Gu, Aptamer-based Environmental Biosensors for Small
85–89. Molecule Contaminants, (2017).
[19] K.G. Spindler, C. Demuth, B.S. Sorensen, J.S. Johansen, D. Nielsen, N. Pallisgaard, [50] L. Gao, Q. Li, R. Li, Z. Deng, B. Brady, N. Xia, G. Chen, Y. Zhou, H. Xia, K. Chen,
E. Hoegdall, P. Pfeiffer, B. Vittrup Jensen, Total cell-free DNA, carcinoembryonic H. Shi, Protein determination using graphene oxide-aptamer modified gold na-
antigen, and C-reactive protein for assessment of prognosis in patients with me- noparticles in combination with Tween 80, Anal. Chim. Acta 941 (2016) 80–86.
tastatic colorectal cancer, Tumour Biol 40 (2018) 1010428318811207. [51] L. Lan, Y. Yao, J. Ping, Y. Ying, Recent progress in nanomaterial-based optical
[20] E. Tan, N. Gouvas, R.J. Nicholls, P. Ziprin, E. Xynos, P.P. Tekkis, Diagnostic pre- aptamer assay for the detection of food chemical contaminants, ACS Appl. Mater.
cision of carcinoembryonic antigen in the detection of recurrence of colorectal Interfaces 9 (2017) 23287–23301.
cancer, Surg Oncol 18 (2009) 15–24. [52] P. Damborsky, J. Svitel, J. Katrlik, Optical biosensors, Essays Biochem 60 (2016)
[21] S. Yokoyama, A. Takeuchi, S. Yamaguchi, Y. Mitani, T. Watanabe, K. Matsuda, 91–100.
T. Hotta, J.E. Shively, H. Yamaue, Clinical implications of carcinoembryonic an- [53] L. Lan, Y. Yao, J. Ping, Y. Ying, Recent advances in nanomaterial-based biosensors
tigen distribution in serum exosomal fraction-Measurement by ELISA, PLoS One for antibiotics detection, Biosens. Bioelectron. 91 (2017) 504–514.
12 (2017) e0183337. [54] F. Long, A. Zhu, H. Shi, Recent advances in optical biosensors for environmental
[22] W. Yang, T. Huang, M. Zhao, F. Luo, W. Weng, Q. Wei, Z. Lin, G. Chen, High monitoring and early warning, Sensors 13 (2013) 13928–13948.
peroxidase-like activity of iron and nitrogen co-doped carbon dots and its appli- [55] C. Luo, W. Wen, F. Lin, X. Zhang, H. Gu, S. Wang, Simplified aptamer-based
cation in immunosorbent assay, Talanta 164 (2017) 1–6. colorimetric method using unmodified gold nanoparticles for the detection of
[23] X. Gu, Z. She, T. Ma, S. Tian, H.B. Kraatz, Electrochemical detection of carci- carcinoma embryonic antigen, RSC Adv. 5 (2015) 10994–10999.
noembryonic antigen, Biosens. Bioelectron. 102 (2018) 610–616. [56] K. Liang, S. Zhai, Z. Zhang, X. Fu, J. Shao, Z. Lin, B. Qiu, G.-n. Chen, Ultrasensitive
[24] B.D. Nicholson, B. Shinkins, N.W. Roberts, T.J. James, S. Mallett, R. Perera, colorimetric carcinoembryonic antigen biosensor based on hyperbranched rolling
J.N. Primrose, D. Mant, Blood CEA levels for detecting recurrent colorectal cancer, circle amplification, The Analyst 139 (2014) 4330–4334.
Cochrane Database Syst. Rev. (2015) (2015) CD011134. [57] N. Shahbazi, S. Hosseinkhani, B. Ranjbar, A facile and rapid aptasensor based on
[25] L. Guo, Y. Shi, X. Liu, Z. Han, Z. Zhao, Y. Chen, W. Xie, X. Li, Enhanced fluores- split peroxidase DNAzyme for visual detection of carcinoembryonic antigen in
cence detection of proteins using ZnO nanowires integrated inside microfluidic saliva, Sens. Actuators B Chem. 253 (2017) 794–803.
chips, Biosens. Bioelectron. 99 (2018) 368–374. [58] C. Guo, F. Su, Y. Song, B. Hu, M. Wang, L. He, D. Peng, Z. Zhang, Aptamer-tem-
[26] L. Xiao, A. Zhu, Q. Xu, Y. Chen, J. Xu, J. Weng, Colorimetric biosensor for de- plated silver nanoclusters embedded in zirconium metal-organic framework for
tection of cancer biomarker by Au nanoparticle-decorated Bi2Se3 nanosheets, ACS bifunctional electrochemical and SPR aptasensors toward carcinoembryonic an-
Appl. Mater. Interfaces 9 (2017) 6931–6940. tigen, ACS Appl. Mater. Interfaces 9 (2017) 41188–41199.
[27] Z. Han, M. Luo, Q. Weng, L. Chen, J. Chen, C. Li, Y. Zhou, L. Wang, ZnO flower- [59] Z. Qiu, J. Shu, D. Tang, Bioresponsive release system for visual fluorescence de-
rod/g-C3N4-gold nanoparticle-based photoelectrochemical aptasensor for detec- tection of carcinoembryonic antigen from mesoporous silica nanocontainers
tion of carcinoembryonic antigen, Anal. Bioanal. Chem. 410 (2018) 6529–6538. mediated optical color on quantum dot-enzyme-impregnated paper, Anal. Chem.
[28] T.Y. Xing, J. Zhao, G.J. Weng, J. Zhu, J.J. Li, J.W. Zhao, Specific detection of 89 (2017) 5152–5160.
carcinoembryonic antigen based on fluorescence quenching of hollow porous gold [60] X. Yang, Y. Zhuo, S. Zhu, Y. Luo, Y. Feng, Y. Xu, Selectively assaying CEA based on
nanoshells with roughened surface, ACS Appl. Mater. Interfaces 9 (2017) a creative strategy of gold nanoparticles enhancing silver nanoclusters' fluores-
36632–36641. cence, Biosens. Bioelectron. 64 (2015) 345–351.
[29] R. Li, F. Feng, Z.Z. Chen, Y.F. Bai, F.F. Guo, F.Y. Wu, G. Zhou, Sensitive detection [61] H. Miao, L. Wang, Y. Zhuo, Z. Zhou, X. Yang, Label-free fluorimetric detection of
of carcinoembryonic antigen using surface plasmon resonance biosensor with gold CEA using carbon dots derived from tomato juice, Biosens. Bioelectron. 86 (2016)
nanoparticles signal amplification, Talanta 140 (2015) 143–149. 83–89.
[30] V. Crivianu-Gaita, M. Thompson, Aptamers, antibody scFv, and antibody Fab' [62] B. Bao, P. Su, J. Zhu, J. Chen, Y. Xu, B. Gu, Y. Liu, L. Wang, Rapid aptasensor
fragments: an overview and comparison of three of the most versatile biosensor capable of simply detect tumor markers based on conjugated polyelectrolytes,
biorecognition elements, Biosens. Bioelectron. 85 (2016) 32–45. Talanta 190 (2018) 204–209.
[31] M. Singh, N. Verma, A. Garg, N. Redhu, Urea biosensors, Sens. Actuators B Chem. [63] J. Xu, W. Chen, M. Shi, Y. Huang, L. Fang, S. Zhao, L. Yao, H. Liang, An aptamer-
134 (2008) 345–351. based four-color fluorometic method for simultaneous determination and imaging

14
W. Xiang, et al. Talanta 214 (2020) 120716

of alpha-fetoprotein, vascular endothelial growth factor-165, carcinoembryonic Nanomaterials based surface plasmon resonance signal enhancement for detection
antigen and human epidermal growth factor receptor 2 in living cells, Mikrochim. of environmental pollution, Biosens. Bioelectron. 127 (2019) 72–84.
Acta 186 (2019) 204. [91] C. Liu, X. Zeng, Z. An, Y. Yang, M. Eisenbaum, X. Gu, J.M. Jornet, G.K. Dy,
[64] Y. Wang, Z. Wei, X. Luo, Q. Wan, R. Qiu, S. Wang, An ultrasensitive homogeneous M.E. Reid, Q. Gan, Y. Wu, Sensitive detection of exosomal proteins via a compact
aptasensor for carcinoembryonic antigen based on upconversion fluorescence re- surface plasmon resonance biosensor for cancer diagnosis, ACS Sens. 3 (2018)
sonance energy transfer, Talanta 195 (2019) 33–39. 1471–1479.
[65] H. Li, L. Shi, D.E. Sun, P. Li, Z. Liu, Fluorescence resonance energy transfer bio- [92] H. Chen, Y. Hou, F. Qi, J. Zhang, K. Koh, Z. Shen, G. Li, Detection of vascular
sensor between upconverting nanoparticles and palladium nanoparticles for ul- endothelial growth factor based on rolling circle amplification as a means of signal
trasensitive CEA detection, Biosens. Bioelectron. 86 (2016) 791–798. enhancement in surface plasmon resonance, Biosens. Bioelectron. 61 (2014)
[66] Z.M. Zhou, J. Zhou, J. Chen, R.N. Yu, M.Z. Zhang, J.T. Song, Y.D. Zhao, Carcino- 83–87.
embryonic antigen detection based on fluorescence resonance energy transfer [93] Y. Jeong, Y.M. Kook, K. Lee, W.G. Koh, Metal enhanced fluorescence (MEF) for
between quantum dots and graphene oxide, Biosens. Bioelectron. 59 (2014) biosensors: general approaches and a review of recent developments, Biosens.
397–403. Bioelectron. 111 (2018) 102–116.
[67] Y. Sun, J. Fan, L. Cui, W. Ke, F. Zheng, Y. Zhao, Fluorometric nanoprobes for [94] O. Tagit, N. Hildebrandt, Fluorescence sensing of circulating diagnostic bio-
simultaneous aptamer-based detection of carcinoembryonic antigen and prostate markers using molecular probes and nanoparticles, ACS Sens. 2 (2017) 31–45.
specific antigen, Mikrochim. Acta 186 (2019) 152. [95] N. Razmi, B. Baradaran, M. Hejazi, M. Hasanzadeh, J. Mosafer, A. Mokhtarzadeh,
[68] Z. Lin, G. Zhang, W. Yang, B. Qiu, G. Chen, CEA fluorescence biosensor based on M. de la Guardia, Recent advances on aptamer-based biosensors to detection of
the FRET between polymer dots and Au nanoparticles, Chem Commun (Camb) 48 platelet-derived growth factor, Biosens. Bioelectron. 113 (2018) 58–71.
(2012) 9918–9920. [96] A.B. Chinen, C.M. Guan, J.R. Ferrer, S.N. Barnaby, T.J. Merkel, C.A. Mirkin,
[69] J. Xu, M. Shi, H. Huang, K. Hu, W. Chen, Y. Huang, S. Zhao, A fluorescent apta- Nanoparticle probes for the detection of cancer biomarkers, cells, and tissues by
sensor based on single oligonucleotide-mediated isothermal quadratic amplifica- fluorescence, Chem. Rev. 115 (2015) 10530–10574.
tion and graphene oxide fluorescence quenching for ultrasensitive protein detec- [97] Y. Han, J. Chen, Z. Li, H. Chen, H. Qiu, Recent progress and prospects of alkaline
tion, Analyst 143 (2018) 3918–3925. phosphatase biosensor based on fluorescence strategy, Biosens. Bioelectron. 148
[70] W. Yang, X. Zhou, J. Zhao, W. Xu, A cascade amplification strategy of catalytic (2019) 111811.
hairpin assembly and hybridization chain reaction for the sensitive fluorescent [98] M. Citartan, T.H. Tang, Recent developments of aptasensors expedient for point-
assay of the model protein carcinoembryonic antigen, Microchimica Acta 185 of-care (POC) diagnostics, Talanta 199 (2019) 556–566.
(2018). [99] R.E. Wang, Y. Zhang, J. Cai, W. Cai, T. Gao, Aptamer-based fluorescent biosensors,
[71] M.Q. He, K. Wang, W.J. Wang, Y.L. Yu, J.H. Wang, Smart DNA machine for car- Curr. Med. Chem. 18 (2011).
cinoembryonic antigen detection by exonuclease III-assisted target recycling and [100] N. Xia, F. Feng, C. Liu, R. Li, W. Xiang, H. Shi, L. Gao, The detection of mercury ion
DNA walker cascade amplification, Anal. Chem. 89 (2017) 9292–9298. using DNA as sensors based on fluorescence resonance energy transfer, Talanta
[72] Z.M. Zhou, Z. Feng, J. Zhou, B.Y. Fang, X.X. Qi, Z.Y. Ma, B. Liu, Y.D. Zhao, X.B. Hu, 192 (2019) 500–507.
Capillary electrophoresis-chemiluminescence detection for carcino-embryonic [101] V.T. Forster, Zwischenmolekulare energiewanderung und fluoreszenz, Ann Phys-
antigen based on aptamer/graphene oxide structure, Biosens. Bioelectron. 64 Berlin 437 (1948) 55–75.
(2015) 493–498. [102] A.A. Jamali, M. Pourhassan-Moghaddam, J.E.N. Dolatabadi, Y. Omidi,
[73] D. Wang, Y. Li, Z. Lin, B. Qiu, L. Guo, Surface-enhanced electrochemiluminescence Nanomaterials on the road to microRNA detection with optical and electro-
of Ru@SiO2 for ultrasensitive detection of carcinoembryonic antigen, Anal. Chem. chemical nanobiosensors, Trac. Trends Anal. Chem. 55 (2014) 24–42.
87 (2015) 5966–5972. [103] M. Fernandez-Suarez, A.Y. Ting, Fluorescent probes for super-resolution imaging
[74] Y.L. Wang, J.T. Cao, Y.H. Chen, Y.M. Liu, A label-free electrochemiluminescence in living cells, Nat. Rev. Mol. Cell Biol. 9 (2008) 929–943.
aptasensor for carcinoembryonic antigen detection based on electrodeposited [104] K. Mao, H. Zhang, Z. Wang, H. Cao, K. Zhang, X. Li, Z. Yang, Nanomaterial-based
ZnS–CdS on MoS2 decorated electrode, Analytical Methods 8 (2016) 5242–5247. aptamer sensors for arsenic detection, Biosens. Bioelectron. 148 (2019) 111785.
[75] G.F. Shi, J.T. Cao, J.J. Zhang, K.J. Huang, Y.M. Liu, Y.H. Chen, S.W. Ren, [105] H.H. Gorris, U. Resch-Genger, Perspectives and challenges of photon-upconversion
Aptasensor based on tripetalous cadmium sulfide-graphene electro- nanoparticles - Part II: bioanalytical applications, Anal. Bioanal. Chem. 409 (2017)
chemiluminescence for the detection of carcinoembryonic antigen, Analyst 139 5875–5890.
(2014) 5827–5834. [106] X. Wang, R.R. Valiev, T.Y. Ohulchanskyy, H. Agren, C. Yang, G. Chen, Dye-sen-
[76] X. Zhang, N. Bao, X. Luo, S.N. Ding, Patchy gold coated Fe3O4 nanospheres with sitized lanthanide-doped upconversion nanoparticles, Chem. Soc. Rev. 46 (2017)
enhanced catalytic activity applied for paper-based bipolar electrode-electro- 4150–4167.
chemiluminescence aptasensors, Biosens. Bioelectron. 114 (2018) 44–51. [107] Z. Xue, Y. Zhang, W. Yu, J. Zhang, J. Wang, F. Wan, Y. Kim, Y. Liu, X. Kou, Recent
[77] F. Qu, T. Li, M. Yang, Colorimetric platform for visual detection of cancer bio- advances in aflatoxin B1 detection based on nanotechnology and nanomaterials-A
marker based on intrinsic peroxidase activity of graphene oxide, Biosens. review, Anal. Chim. Acta 1069 (2019) 1–27.
Bioelectron. 26 (2011) 3927–3931. [108] M. Wu, Q. Lai, Q. Ju, L. Li, H.D. Yu, W. Huang, Paper-based fluorogenic devices for
[78] H. Aldewachi, T. Chalati, M.N. Woodroofe, N. Bricklebank, B. Sharrack, in vitro diagnostics, Biosens. Bioelectron. 102 (2018) 256–266.
P. Gardiner, Gold nanoparticle-based colorimetric biosensors, Nanoscale 10 [109] Z. Zhang, S. Shikha, J. Liu, J. Zhang, Q. Mei, Y. Zhang, Upconversion nanoprobes:
(2017) 18–33. recent advances in sensing applications, Anal. Chem. 91 (2019) 548–568.
[79] C. Feng, S. Dai, L. Wang, Optical aptasensors for quantitative detection of small [110] D. Mendez-Gonzalez, E. Lopez-Cabarcos, J. Rubio-Retama, M. Laurenti, Sensors
biomolecules: a review, Biosens. Bioelectron. 59 (2014) 64–74. and bioassays powered by upconverting materials, Adv. Colloid Interface Sci. 249
[80] C. Yang, Y. Wang, J.L. Marty, X. Yang, Aptamer-based colorimetric biosensing of (2017) 66–87.
Ochratoxin A using unmodified gold nanoparticles indicator, Biosens. Bioelectron. [111] L. Wang, R. Wang, H. Wei, Y. Li, Selection of aptamers against pathogenic bacteria
26 (2011) 2724–2727. and their diagnostics application, World J. Microbiol. Biotechnol. 34 (2018) 149.
[81] J. Liu, Y. Lu, A colorimetric lead biosensor using DNAzyme-directed assembly of [112] C.T. Matea, T. Mocan, F. Tabaran, T. Pop, O. Mosteanu, C. Puia, C. Iancu,
gold nanoparticles, J. Am. Chem. Soc. 125 (2003) 6642–6643. L. Mocan, Quantum dots in imaging, drug delivery and sensor applications, Int. J.
[82] F. Sang, X. Zhang, J. Liu, S. Yin, Z. Zhang, A label-free hairpin aptamer probe for Nanomed. 12 (2017) 5421–5431.
colorimetric detection of adenosine triphosphate based on the anti-aggregation of [113] R. Shandilya, A. Bhargava, N. Bunkar, R. Tiwari, I.Y. Goryacheva, P.K. Mishra,
gold nanoparticles, Spectrochim. Acta A Mol. Biomol. Spectrosc. 217 (2019) Nanobiosensors: point-of-care approaches for cancer diagnostics, Biosens.
122–127. Bioelectron. 130 (2019) 147–165.
[83] B. Liedberg, C. Nylander, I. Lunström, Surface plasmon resonance for gas detection [114] T.H. Fang, N. Ramalingam, D. Xian-Dui, T.S. Ngin, Z. Xianting, A.T. Lai Kuan,
and biosensing, Sens. Actuators 4 (1983) 299–304. E.Y. Peng Huat, G. Hai-Qing, Real-time PCR microfluidic devices with concurrent
[84] C. Lertvachirapaiboon, A. Baba, S. Ekgasit, K. Shinbo, K. Kato, F. Kaneko, electrochemical detection, Biosens. Bioelectron. 24 (2009) 2131–2136.
Transmission surface plasmon resonance techniques and their potential biosensor [115] L. Liu, D. Yang, G. Liu, Signal amplification strategies for paper-based analytical
applications, Biosens. Bioelectron. 99 (2018) 399–415. devices, Biosens. Bioelectron. 136 (2019) 60–75.
[85] C. Esseghaier, G.A.R.Y. Suaifan, A. Ng, M. Zourob, One-step assay for optical [116] H. Qi, S. Yue, S. Bi, C. Ding, W. Song, Isothermal exponential amplification
prostate specific antigen detection using magnetically engineered responsive thin techniques: from basic principles to applications in electrochemical biosensors,
film, J. Biomed. Nanotechnol. 10 (2014) 1123–1129. Biosens. Bioelectron. 110 (2018) 207–217.
[86] E. Wijaya, C. Lenaerts, S. Maricot, J. Hastanin, S. Habraken, J.-P. Vilcot, [117] J. Li, J. Macdonald, Advances in isothermal amplification: novel strategies in-
R. Boukherroub, S. Szunerits, Surface plasmon resonance-based biosensors: from spired by biological processes, Biosens. Bioelectron. 64 (2015) 196–211.
the development of different SPR structures to novel surface functionalization [118] M.C. Giuffrida, G. Spoto, Integration of isothermal amplification methods in mi-
strategies, Curr. Opin. Solid State Mater. Sci. 15 (2011) 208–224. crofluidic devices: recent advances, Biosens. Bioelectron. 90 (2017) 174–186.
[87] H. Wang, X. Wang, J. Wang, W. Fu, C. Yao, A SPR biosensor based on signal [119] A. Roda, M. Mirasoli, E. Michelini, M. Di Fusco, M. Zangheri, L. Cevenini, B. Roda,
amplification using antibody-QD conjugates for quantitative determination of P. Simoni, Progress in chemical luminescence-based biosensors: a critical review,
multiple tumor markers, Sci. Rep. 6 (2016). Biosens. Bioelectron. 76 (2016) 164–179.
[88] Y. Wang, S. Zhang, C. Zhang, Z. Zhao, X. Zheng, L. Xue, J. Liu, X.C. Yuan, [120] Z. Liu, F. Zhao, S. Gao, J. Shao, H. Chang, The applications of gold nanoparticle-
Investigation of an SPR biosensor for determining the influence of connexin 43 initialed chemiluminescence in biomedical detection, Nanoscale Res Lett 11
expression on the cytotoxicity of cisplatin, Analyst 141 (2016) 3411–3420. (2016) 460.
[89] Q. Wang, Q. Li, X. Yang, K. Wang, S. Du, H. Zhang, Y.J.B. Nie, Bioelectronics, [121] N. Li, D. Liu, H. Cui, Metal-nanoparticle-involved chemiluminescence and its ap-
Graphene oxide–gold nanoparticles hybrids-based surface plasmon resonance for plications in bioassays, Anal. Bioanal. Chem. 406 (2014) 5561–5571.
sensitive detection of microRNA, Biosens. Bioelectron. 77 (2016) 1001–1007. [122] J. Ping, Y. Zhou, Y. Wu, V. Papper, S. Boujday, R.S. Marks, T.W. Steele, Recent
[90] M. Mahmoudpour, J. Ezzati Nazhad Dolatabadi, M. Torbati, A. Homayouni-Rad, advances in aptasensors based on graphene and graphene-like nanomaterials,

15
W. Xiang, et al. Talanta 214 (2020) 120716

Biosens. Bioelectron. 64 (2015) 373–385. [150] Z. Qiu, J. Shu, J. Liu, D. Tang, Dual-channel photoelectrochemical ratiometric
[123] L. Hu, G. Xu, Applications and trends in electrochemiluminescence, Chem. Soc. aptasensor with up-converting nanocrystals using spatial-resolved technique on
Rev. 39 (2010) 3275–3304. homemade 3D printed device, Anal. Chem. 91 (2) (2018) 1260–1268.
[124] Y. Nasiri Khonsari, S. Sun, Recent trends in electrochemiluminescence aptasensors [151] K.S. Shin, J.H. Ji, K.S. Hwang, S.C. Jun, J.Y. Kang, Sensitivity enhancement of
and their applications, Chem. Commun. 53 (2017) 9042–9054. bead-based electrochemical impedance spectroscopy (BEIS) biosensor by electric
[125] K. Muzyka, Current trends in the development of the electrochemiluminescent field-focusing in microwells, Biosens. Bioelectron. 85 (2016) 16–24.
immunosensors, Biosens. Bioelectron. 54 (2014) 393–407. [152] G. Liang, Y. Man, X. Jin, L. Pan, X. Liu, Aptamer-based biosensor for label-free
[126] M.R. Saidur, A.R. Aziz, W.J. Basirun, Recent advances in DNA-based electro- detection of ethanolamine by electrochemical impedance spectroscopy, Anal.
chemical biosensors for heavy metal ion detection: a review, Biosens. Bioelectron. Chim. Acta 936 (2016) 222–228.
90 (2017) 125–139. [153] H. Li, X. Liu, L. Li, X. Mu, R. Genov, A.J. Mason, CMOS electrochemical in-
[127] J.M. Moon, N. Thapliyal, K.K. Hussain, R.N. Goyal, Y.B. Shim, Conducting strumentation for biosensor microsystems: a review, Sensors 17 (2016).
polymer-based electrochemical biosensors for neurotransmitters: a review, [154] R. Elshafey, A.C. Tavares, M. Siaj, M. Zourob, Electrochemical impedance im-
Biosens. Bioelectron. 102 (2018) 540–552. munosensor based on gold nanoparticles-protein G for the detection of cancer
[128] J.L. Hammond, N. Formisano, P. Estrela, S. Carrara, J. Tkac, Electrochemical marker epidermal growth factor receptor in human plasma and brain tissue,
biosensors and nanobiosensors, Essays Biochem. 60 (2016) 69–80. Biosens. Bioelectron. 50 (2013) 143–149.
[129] S. Uniyal, R.K. Sharma, Technological advancement in electrochemical biosensor [155] E.B. Bahadir, M.K. Sezginturk, A review on impedimetric biosensors, Artif Cells
based detection of Organophosphate pesticide chlorpyrifos in the environment: a Nanomed Biotechnol 44 (2016) 248–262.
review of status and prospects, Biosens. Bioelectron. 116 (2018) 37–50. [156] E.P. Randviir, C.E. Banks, Electrochemical impedance spectroscopy: an overview
[130] Y. Huang, J. Xu, J. Liu, X. Wang, B. Chen, Disease-related detection with elec- of bioanalytical applications, Analytical Methods 5 (2013).
trochemical biosensors: a review, Sensors 17 (2017). [157] A. Hayat, G. Catanante, J. Marty, Current trends in nanomaterial-based ampero-
[131] T.H. Ho, F.X. Guillon, P. Bigey, F. Bedioui, M. Lazerges, Analysis of the evolution metric biosensors, Sensors 14 (2014) 23439–23461.
of the detection limits of electrochemical nucleic acid biosensors II, Anal. Bioanal. [158] J. Rick, M.C. Tsai, B.J. Hwang, Biosensors incorporating bimetallic nanoparticles,
Chem. 409 (2017) 4335–4352. Nanomaterials (2015) 6.
[132] D. Grieshaber, R. Mackenzie, J. Vörös, E.J.S. Reimhult, Electrochemical biosensors [159] S. Azzouzi, L. Rotariu, A.M. Benito, W.K. Maser, M. Ben Ali, C. Bala, A novel
- sensor principles and architectures, Sensors 8 (2008) 1400–1458. amperometric biosensor based on gold nanoparticles anchored on reduced gra-
[133] X. Zhou, S. Guo, J. Gao, J. Zhao, S. Xue, W. Xu, Glucose oxidase-initiated cascade phene oxide for sensitive detection of l-lactate tumor biomarker, Biosens.
catalysis for sensitive impedimetric aptasensor based on metal-organic frame- Bioelectron. 69 (2015) 280–286.
works functionalized with Pt nanoparticles and hemin/G-quadruplex as mi- [160] W. Zhou, X. Gao, D. Liu, X. Chen, Gold nanoparticles for in vitro diagnostics,
micking peroxidases, Biosens. Bioelectron. 98 (2017) 83–90. Chem. Rev. 115 (2015) 10575–10636.
[134] X. Zhou, S. Xue, P. Jing, W. Xu, A sensitive impedimetric platform biosensing [161] S.G. Meirinho, L.G. Dias, A.M. Peres, L.R. Rodrigues, Voltammetric aptasensors for
protein: insoluble precipitates based on the biocatalysis of manganese(III) meso- protein disease biomarkers detection: a review, Biotechnol. Adv. 34 (2016)
tetrakis (4-N-methylpyridiniumyl)-porphyrinin in HCR-assisted dsDNA, Biosens. 941–953.
Bioelectron. 86 (2016) 656–663. [162] F.S. Felix, L. Angnes, Electrochemical immunosensors - a powerful tool for ana-
[135] H. Shu, W. Wen, H. Xiong, X. Zhang, S. Wang, Novel electrochemical aptamer lytical applications, Biosens. Bioelectron. 102 (2018) 470–478.
biosensor based on gold nanoparticles signal amplification for the detection of [163] E.B. Bahadir, M.K. Sezginturk, Poly (amidoamine) (PAMAM): an emerging mate-
carcinoembryonic antigen, Electrochem. Commun. 37 (2013) 15–19. rial for electrochemical bio(sensing) applications, Talanta 148 (2016) 427–438.
[136] P. Wang, Y. Wan, S. Deng, S. Yang, Y. Su, C. Fan, A. Aldalbahi, X. Zuo, Aptamer- [164] E.B. Bahadir, M.K. Sezginturk, Electrochemical biosensors for hormone analyses,
initiated on-particle template-independent enzymatic polymerization (aptamer- Biosens. Bioelectron. 68 (2015) 62–71.
OTEP) for electrochemical analysis of tumor biomarkers, Biosens. Bioelectron. 86 [165] V. Perumal, U. Hashim, Advances in biosensors: principle, architecture and ap-
(2016) 536–541. plications, J. Appl. Biomed. 12 (2014) 1–15.
[137] J. Xiang, X. Pi, X. Chen, L. Xiang, M. Yang, H. Ren, X. Shen, N. Qi, C. Deng, [166] A. Kim, C.S. Ah, C.W. Park, J.H. Yang, T. Kim, C.G. Ahn, S.H. Park, G.Y. Sung,
Integrated signal probe based aptasensor for dual-analyte detection, Biosens. Direct label-free electrical immunodetection in human serum using a flow-
Bioelectron. 96 (2017) 268–274. through-apparatus approach with integrated field-effect transistors, Biosens.
[138] M. Mazloum-Ardakani, Z. Tavakolian-Ardakani, N. Sahraei, S.M. Moshtaghioun, Bioelectron. 25 (2010) 1767–1773.
Fabrication of an ultrasensitive and selective electrochemical aptasensor to detect [167] Z. Bao, J. Sun, X. Zhao, Z. Li, S. Cui, Q. Meng, Y. Zhang, T. Wang, Y. Jiang, Top-
carcinoembryonic antigen by using a new nanocomposite, Biosens. Bioelectron. down nanofabrication of silicon nanoribbon field effect transistor (Si-NR FET) for
129 (2019) 1–6. carcinoembryonic antigen detection, Int. J. Nanomed. 12 (2017) 4623–4631.
[139] J.Y. Huang, L. Zhao, W. Lei, W. Wen, Y.J. Wang, T. Bao, H.Y. Xiong, X.H. Zhang, [168] J. Li, G. He, H. Ueno, C. Jia, H. Noji, C. Qi, X. Guo, Direct real-time detection of
S.F. Wang, A high-sensitivity electrochemical aptasensor of carcinoembryonic single proteins using silicon nanowire-based electrical circuits, Nanoscale 8 (2016)
antigen based on graphene quantum dots-ionic liquid-nafion nanomatrix and 16172–16176.
DNAzyme-assisted signal amplification strategy, Biosens. Bioelectron. 99 (2018) [169] W.W. Zhao, J.J. Xu, H.Y. Chen, Photoelectrochemical enzymatic biosensors,
28–33. Biosens. Bioelectron. 92 (2017) 294–304.
[140] Y. Zhao, Y. Yang, Y. Sun, L. Cui, F. Zheng, J. Zhang, Q. Song, C. Xu, Shell-encoded [170] H. Wang, Y. Wang, Y. Zhang, Q. Wang, X. Ren, D. Wu, Q. Wei,
Au nanoparticles with tunable electroactivity for specific dual disease biomarkers Photoelectrochemical immunosensor for detection of carcinoembryonic antigen
detection, Biosens. Bioelectron. 99 (2018) 193–200. based on 2D TiO2 nanosheets and carboxylated graphitic carbon nitride, Sci. Rep.
[141] H. Cheng, L. Xu, H. Zhang, A. Yu, G. Lai, Enzymatically catalytic signal tracing by 6 (2016) 27385.
a glucose oxidase and ferrocene dually functionalized nanoporous gold nanoprobe [171] J. Li, Y. Zhang, X. Kuang, Z. Wang, Q. Wei, A network signal amplification strategy
for ultrasensitive electrochemical measurement of a tumor biomarker, The Analyst of ultrasensitive photoelectrochemical immunosensing carcinoembryonic antigen
141 (2016) 4381–4387. based on CdSe/melamine network as label, Biosens. Bioelectron. 85 (2016)
[142] H. Quan, C. Zuo, T. Li, Y. Liu, M. Li, M. Zhong, Y. Zhang, H. Qi, M. Yang, 764–770.
Electrochemical detection of carcinoembryonic antigen based on silver na- [172] W.W. Zhao, J.J. Xu, H.Y. Chen, Photoelectrochemical DNA biosensors, Chem. Rev.
nocluster/horseradish peroxidase nanocomposite as signal probe, Electrochim. 114 (2014) 7421–7441.
Acta 176 (2015) 893–897. [173] X. Zeng, J. Bao, M. Han, W. Tu, Z. Dai, Quantum dots sensitized titanium dioxide
[143] Z. Liu, Y. Wang, Y. Guo, C. Dong, Label-free electrochemical aptasensor for car- decorated reduced graphene oxide for visible light excited photoelectrochemical
cino-embryonic antigen based on ternary nanocomposite of gold nanoparticles, biosensing at a low potential, Biosens. Bioelectron. 54 (2014) 331–338.
hemin and graphene, Electroanalysis 28 (2016) 1023–1028. [174] J. Wang, Y. Cao, Y. Xu, G. Li, Colorimetric multiplexed immunoassay for se-
[144] J.W. Park, W. Na, J. Jang, One-pot synthesis of multidimensional conducting quential detection of tumor markers, Biosens. Bioelectron. 25 (2009) 532–536.
polymer nanotubes for superior performance field-effect transistor-type carci- [175] L. Tian, L. Liu, Y. Li, Q. Wei, W. Cao, Ultrasensitive sandwich-type electrochemical
noembryonic antigen biosensors, RSC Adv. 6 (2016) 14335–14343. immunosensor based on trimetallic nanocomposite signal amplification strategy
[145] L. Ge, W. Wang, T. Hou, F. Li, A versatile immobilization-free photoelec- for the ultrasensitive detection of CEA, Sci. Rep. 6 (2016) 30849.
trochemical biosensor for ultrasensitive detection of cancer biomarker based on [176] L. Pan, J. Zhao, Y. Huang, S. Zhao, Y.M. Liu, Aptamer-based microchip electro-
enzyme-free cascaded quadratic amplification strategy, Biosens. Bioelectron. 77 phoresis assays for amplification detection of carcinoembryonic antigen, Clin.
(2016) 220–226. Chim. Acta 450 (2015) 304–309.
[146] W. Deng, L. Shen, X. Wang, C. Yang, J. Yu, M. Yan, X. Song, Using carbon na- [177] C. Zong, J. Wu, M. Liu, L. Yang, F. Yan, H. Ju, Chemiluminescence imaging for a
notubes-gold nanocomposites to quench energy from pinnate titanium dioxide protein assay via proximity-dependent DNAzyme formation, Anal. Chem. 86
nanorods array for signal-on photoelectrochemical aptasensing, Biosens. (2014) 9939–9944.
Bioelectron. 82 (2016) 132–139. [178] Q. Fu, Z. Wu, F. Xu, X. Li, C. Yao, M. Xu, L. Sheng, S. Yu, Y. Tang, A portable smart
[147] X. Zeng, S. Ma, J. Bao, W. Tu, Z. Dai, Using graphene-based plasmonic nano- phone-based plasmonic nanosensor readout platform that measures transmitted
composites to quench energy from quantum dots for signal-on photoelec- light intensities of nanosubstrates using an ambient light sensor, Lab Chip 16
trochemical aptasensing, Anal. Chem. 85 (2013) 11720–11724. (2016) 1927–1933.
[148] Z. Qiu, J. Shu, D. Tang, NaYF4:Yb, Er Upconversion nanotransducer with in situ [179] G.Y. Shen, H. Wang, T. Deng, G.L. Shen, R.Q. Yu, A novel piezoelectric im-
fabrication of Ag2S for near-Infrared light responsive photoelectrochemical bio- munosensor for detection of carcinoembryonic antigen, Talanta 67 (2005)
sensor, Anal. Chem. 90 (2018) 12214–12220. 217–220.
[149] Z. Qiu, J. Shu, D. Tang, Near-infrared-to-ultraviolet light-mediated photoelec- [180] J.W. Lan, I.Y. Huang, Y.C. Lin, C.Y. Lin, J.L. Chen, C.H. Hsieh, Development of an
trochemical aptasensing platform for cancer biomarker based on core-shell FPW biosensor with low insertion loss and high fabrication yield for detection of
NaYF4:Yb,Tm@TiO2 upconversion microrods, Anal. Chem. 90 (2018) 1021–1028. carcinoembryonic antigen, Sensors 16 (2016).

16
W. Xiang, et al. Talanta 214 (2020) 120716

[181] F. Zhou, M. Wang, L. Yuan, Z. Cheng, Z. Wu, H. Chen, Sensitive sandwich ELISA antigen on a plasmonic nanoimmunosensor by transmission grating-based total
based on a gold nanoparticle layer for cancer detection, Analyst 137 (2012) internal reflection scattering microscopy, Biosens. Bioelectron. 96 (2017)
1779–1784. 159–166.
[182] S. Lee, S.K. Chakkarapani, E.S. Yeung, S.H. Kang, Direct quantitative screening of [184] P. Chen, K. Huang, R. Dai, E. Sawyer, K. Sun, B. Ying, X. Wei, J. Geng, Sensitive
influenza A virus without DNA amplification by single-particle dual-mode total CVG-AFS/ICP-MS label-free nucleic acid and protein assays based on a selective
internal reflection scattering, Biosens. Bioelectron. 87 (2017) 842–849. cation exchange reaction and simple filtration separation, Analyst 144 (2019)
[183] S. Ahn, H. Yu, S.H. Kang, Enhanced detection sensitivity of carcinoembryonic 2797–2802.

17