Trends in Analytical Chemistry 133 (2020) 116067

Contents lists available at ScienceDirect

Trends in Analytical Chemistry

journal homepage: www.elsevier.com/locate/trac

Biosensing based on field-effect transistors (FET): Recent progress and

challenges
Deniz Sadighbayan a, b, Mohammad Hasanzadeh b, *, Ebrahim Ghafar-Zadeh a, c, **
a
Biologically Inspired Sensors and Actuators (BioSA), Faculty of Science, Dept. of Biology, York University, Toronto, Canada
b
Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
c
Dept. of Elecrical Engineering and Computer Science, Lassonde School of Engineering, York University, Toronto, Canada

a r t i c l e i n f o a b s t r a c t

Article history: The use of field-Effect-Transistor (FET) type biosensing arrangements has been highlighted by re-
Available online 9 October 2020 searchers in the field of early biomarker detection and drug screening. Their non-metalized gate di-
electrics that are exposed to an electrolyte solution cover the semiconductor material and actively
Keywords: transduce the biological changes on the surface. The efficiency of these novel devices in detecting
Cancer different biomolecular analytes in a real-time, highly precise, specific, and label-free manner has been
Biomarkers
validated by numerous research studies. Considerable progress has been attained in designing FET de-
Biomedical analysis
vices, especially for biomedical diagnosis and cell-based assays in the past few decades. The exceptional
Biotechnology
Advanced nanomaterial
electronic properties, compactness, and scalability of these novel tools are very desirable for designing
Field-effect-transistor rapid, label-free, and mass detection of biomolecules. With the incorporation of nanotechnology, the
Biosensor performance of biosensors based on FET boosts significantly, particularly, employment of nanomaterials
such as graphene, metal nanoparticles, single and multi-walled carbon nanotubes, nanorods, and
nanowires. Besides, their commercial availability, and high-quality production on a large-scale, turn
them to be one of the most preferred sensing and screening platforms. This review presents the basic
structural setup and working principle of different types of FET devices. We also focused on the latest
progression regarding the use of FET biosensors for the recognition of viruses such as, recently emerged
COVID-19, Influenza, Hepatitis B Virus, protein biomarkers, nucleic acids, bacteria, cells, and various ions.
Additionally, an outline of the development of FET sensors for investigations related to drug development
and the cellular investigation is also presented. Some technical strategies for enhancing the sensitivity
and selectivity of detection in these devices are addressed as well. However, there are still certain
challenges which are remained unaddressed concerning the performance and clinical use of transistor-
based point-of-care (POC) instruments; accordingly, expectations about their future improvement for
biosensing and cellular studies are argued at the end of this review.
© 2020 Elsevier B.V. All rights reserved.

1. Introduction transducing layers, and readout systems) necessitates specializa-

tion in various topics, constructing an efficient biosensor requires
Compact analytical tools that turn a biological response into a the active cooperation of scientists from diverse fields, including
measurable electrical signal are called biosensors [1]. These mini- chemistry, biology, and engineering [3]. There are different types of
aturized devices must be sensitive, selective, rapid, cost-effective, biosensors that are being studied by researchers from all over the
and simple [2]. Besides, they should act independently of external globe, such as, electrical, electrochemical, optical, photonic, mag-
factors such as temperature and pH. Since assembling different netic, piezoelectric, etc. [4]. Among a wide range of electrical
parts of a biosensor (biological elements, biocompatible materials, sensing devices, field-effect transistor (FET) biosensors appeared to
be one of the most promising alternatives due to their advantages
like being fast, low-cost, and simple [5]. The very first FET biosensor
* Corresponding author. was generated by Bergveld fifty years ago [6]. This novel technology
** Corresponding author. has been evolving since 1970 in different forms and is an ideal
E-mail addresses: [email protected] (M. Hasanzadeh), [email protected] approach for swift and precise detection of various analytes and
(E. Ghafar-Zadeh).

https://doi.org/10.1016/j.trac.2020.116067
0165-9936/© 2020 Elsevier B.V. All rights reserved.
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

also drug discovery [7]. Although conventional sensing techniques alternative solution for expensive, time-consuming, and labor-
have the capability of specific detection of biomolecules, they entail intensive cell-based drug screening studies [19]. High-throughput
complicated instrumentations with complex protocols that make screening (HTS) systems based on cell and tissue culture are
them expensive, labor-intensive, and time-consuming [4]. These among the most promising methods for both drug discovery and
restrictions can be conquered by fabricating novel and reliable FET- identifying biologically active small molecules or genes rapidly.
based biosensors which are modified by specific probes on their They reflect the intricacies of actual living systems by imitating
conducting channel, offering real-time and label-free analyses [8]. their microenvironment [20]. The more advanced the biological
Generally, a solid-state device in which the electroconductivity assays the more accurate they will perform in assessing the prob-
of the semiconductor between the source and drain terminals is able biological response of living cells to a controlled stimulus.
regulated by a third gate electrode through an insulator is called a Characterizing localization, protein expression, cellular
FET [9]. Since constructing most of these devices is done according morphology, and other phenotypic attributes of cells are necessary
to standard protocols, they require almost no post-processing, for these assays which need sophisticated biochemical and mo-
however, to modify their surface and increase their sensitivity, lecular biology tools. FET-based screening systems are one of the
some other materials such as nanostructures are fabricated and most ideal choices for implementing such research works [11].
added to their structure. Since, they are already commercialized, In this regard, the chief intention of this review is to describe
mass-produced, and widely used, they are very promising in the different applications of FET-based devices such as early detection
future of medical diagnostics principally for POC applications [10]. of different diseases, including, recently increasing pandemic
Over the years, there has been an outstanding development in the coronavirus disease 2019, influenza, hepatitis B virus, Alzheimer's
design and fabrication of FETs employing nanostructures [11]. Their disease, cancer, acute myocardial infarction, malaria, bacterial
exclusive electronic characteristics, small size, dynamic range, and infection, and cell-based assays for studying dose-dependent
real-time biological detection with LODs down to zeptomolar levels cytotoxic effects of drugs, ion efflux, dopamine, and identify spe-
and even in some cases enabling the evaluation of single molecules cific ligands of cells.
or particles, turn them to be one of the most powerful diagnostic
platforms [12]. 2. Field effect transistor-based biosensors
To recognize specific analytes, biological receptors, such as,
antibodies, nucleic acids, aptamers, enzymes, cells, microorgan- Field-effect transistor biosensors have appeared as the most
isms, or artificial biomaterials are immobilized on the sensing developed alternatives between various types of biosensors
channels, which are linked to the source and drain electrodes [13]. because of several advantages they offer. There are different cate-
After exposing the biosensor to target analytes, and forming spe- gories of transistor-based sensing platforms, however, the most
cific biological complexes such as antigen-antibody, enzyme-sub- used structures for biological applications are ion-sensitive field-
strate, DNA structures, etc. the transducer system converts effect transistors (ISFETs) and metal-oxide-semiconductor field-
biochemical changes into a measurable signal. Attachment of effect transistors (MOSFETs), which are separated based on the
charged biomolecules to the surface of gate dielectric is equivalent technique of applying the gate voltage, design, and material of the
to applying a voltage by the use of a gate electrode and results in the gate and the channel region. The preliminary basis of regulating the
threshold voltage variations. Therefore, the strategy underneath channel conductance is analogous in all FETs, thus, the method of
the FET biosensors is the reliance of the conductance on the the gate coupling can vary considerably (See Fig. 1).
adsorbed species [14].
Two major categories of FETs are n-type and p-type devices in 2.1. Ion-sensitive field-effect transistors (ISFETs)
which electrons and holes are the prime charge carriers, respec-
tively [10]. If the target molecule is positively charged, the response ISFETs are the most common types of integrated devices for
of an n-type FET sensor will be an upsurge in the conductance, micro electrochemical LOC arrangements [14]. Their use as a
because of aggregation of electrons. Reversely, if the target is a transducer signifies a favorable tool for biological applications.
molecule with a negative charge, the conductance will be Their configuration is very similar to the normal MOSFETs. The only
decreased. The opposite trend is applicable regarding the p-type difference is their sensitive area or transistor gate that transduces
FET system [15]. ion concentration to a measurable voltage. In other words, a sample
One of the most important factors to take into account is the solution with an immersed reference electrode and an insulating
type of semiconductor in designing a successful biosensor. There is layer which is sensitive to ions are representing the metal gate and
a wide range of materials such as SiO2, Si3N4, and Ta2O5 which are gate oxide of a MOSFET [22]. The sensitivity and capability of an
being used in the structure of FET biosensing devices [16]. The ISFET sensor are highly dependable on the nature of the insulating
integration of nanotechnology paves the way for the use of nano layer [23]. It isolates the channel of the FET from the liquid and
transducers like nanowires, carbon nanotubes, nanoparticles, couples the surface layer charge into the channel electrostatically
nanorods, etc. in the fabrication of novel biosensors [17]. Some [16]. This dielectric layer can be made of different materials such as
nanostructures like silicon nanowires, graphene, and carbon Si3N4, Al2O3, or Ta2O5 on SiO2, which act selectively particularly for
nanotubes are among the most popular and functional alternatives Hþ ions owing to their active groups on the oxide surface [24].
when fabricating sensitive, specific, label-free, rapid, and cost- These types of ISFETs are pH-ISFET that is the most common
effective devices [11]. Superior mechanical stamina, high surface category [25]. To enhance the specificity of the device and enable
to volume ratio, extraordinary chemical and thermal firmness, and identifying other analytes, ion-sensing or ion-blocking membranes
superior semiconductivity of these materials make them the ideal such as ionophores can be employed [26]. By regulating the current
choice for immobilizing biorecognition elements (BREs) [18]. flowing between the two semiconductors (S and D), the measure-
Numerous pioneering studies have used these strategies to fabri- ment is done. Source and drain are linked together by a third
cate high-tech devices for POC diagnoses of different diseases electrode (gate terminal) that is directly contacted to the sample to
which are discussed thoroughly in the following sections. be measured [27]. To make them sensitive towards biomolecules, a
Another important application of FETs is cell-based screening. bio-recognition layer is introduced at their surface. In this case, the
To overcome the burden of treating some lethal diseases and conventional ISFET is called a biologically-sensitive field-effect
address the patients' urgent needs, scientists are trying to find an transistor (BioFET) [10]. This layer which provides selective
2
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

Fig. 1. Schematic representation of a MOSFET and an ISFET structure. (Ug: gate voltage, Ud: the source-drain voltage) [21].

interaction with analytes decreases non-specific binding and, en- making the MOSFET' input resistance exceptionally high. Therefore,
ables a charge transfer, binds to the transducer surface by either no current flows into the gate and the device acts like a voltage-
chemical or electrostatic interactions [28]. If an attachment takes controlled resistor [39]. MOSFETs can easily become damaged due
place between targets and BREs, a variation will be seen in the to the accumulation of large amounts of static charge resulting from
surface charge. Accordingly, the potential in the semiconductor and high input resistance. Thus, they need to be used carefully [40]. For
the conductivity of the channel will change. By measuring the example, a commercial biosensing device based on MOSFET for the
change in conductance, the binding of the analytes can be detected recognition of C-reactive protein (CRP) was created by Lyu and
[29]. For instance, Synhaivska et al. used silicon nanoribbon ISFET colleagues. The binding of the CRP to its specific antibody was
structures amended with a Gly-Gly-His peptide for the identifica- sensed by quantifying the drain current of the system. The manu-
tion of copper ions in a wide range of concentrations. The attach- factured MOSFET biosensor paved the way for the emergence of
ment of copper ions results in a structural alteration of the ligand, cheap and simple FET-based biosensors [41]. Or in another research
and also a loss of proton in the secondary amine assemblies [30]. work done by Mostafa et al., MOSFET-fixed cantilevers were
These devices can be developed through complementary metal designed to spot Bacillus thuringiensis. Attachment of this target to
oxide semiconductor technology (CMOS). CMOS is a commonly the cantilever which is modified by gold caused variations in the
used technology for producing integrated circuits that are being current of MOSFET drain as a result of the flexing of the cantilever. It
exploited in a wide range of electronic apparatuses such as, digital is important to mention that the electronic attributes of the target
cameras, batteries, and microprocessors [31]. The “MOS” in CMOS were also accountable for the alteration in the current of the drain.
denotes the MOSFET transistors in a CMOS. Although recently Their reported limit of detection was 10 mL [42].
developed MOSFETs usually employ polysilicon as a substitute for
aluminum as the conductive material, we still call them metal oxide
3. Selective adhesion on FET for biosensing applications
semiconductor transistors. Whereas, the N-doped or P-doped
semiconductors represent the “complementary” part in CMOS [32].
One of the most common uses of FET-based biosensors is the
These devices are well-known for their efficient consumption of
early detection of diseases rapidly and reliably. Since the majority of
electrical power [33]. No electrical current is needed excluding
biomolecules transmit electrical charges. The FET biosensors can
when they are shifting from one state to another. The fact that
act as capable candidates intended for utilizations necessitating
complementary semiconductors work together results in the con-
high preciseness and speed. Also, novel CMOS manufacturing
trol of output voltage and the design of low-power devices that
strategies offer the advantages of miniaturization and concurrent
emit negligible heat [34]. Consequently, these transistors
sensing. To demonstrate competencies of FET biosensing systems, a
substituted other former structures and been utilized in most up-
wide range of biological analytes were studied during the last few
to-date processors [35]. This unique technology facilitates the
years. To illustrate, they were exploited to sense different viruses
development of inexpensive, extensive, and mass-produced de-
such as recently emerged COVID-19, influenza, hepatitis B virus
vices capable of detecting tiny amounts of analytes on miniaturized
(HBV), or biomarkers of diseases such as Alzheimer's, cancer, acute
chips [36]. For example, Malpartida-Cardenas and coworkers used
myocardial infarction (AMI), bacteria-related disorders, etc. Be-
an ISFET, manufactures in standard CMOS technology for instan-
sides, they have been utilized for designing nucleic acid sensors
taneous DNA sensing. This fully-electronic Lab-on-Chip platform
that are dependent on DNA hybridization. Considering these im-
was designed to detect plasmodium falciparum [37].
provements, FET biosensing platforms have been highlighted as a
perfect choice for the pioneering class of point-of-care diagnostics.
2.2. Metal-oxide field-effect transistors (MOSFETs)
3.1. Coronavirus disease 2019 (COVID-19)
MOSFETs are the most frequent form of insulated gate FETs
(IGFET) which are exploited in various types of electronic circuits The COVID-19 that has made more than a billion people stay in
for switching and amplifying electronic signals. They are the core of quarantine and has brought much of global economic activity to a
integrated circuits and are capable of being used in a single chip halt, is a recently emerged contagious malady instigated by the
because of their small sizes [38]. The key characteristic of MOSFETs severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
is their metal oxide gate electrode. An ultra-thin layer of insulating [43]. In the last months of 2019, several unknown pneumonia cases
material (usually SiO2) insulates this controlling gate from the main occurred in China. As person-to-person transfer augmented
channel which is located in the middle of the drain and source, promptly, the outbreak was acknowledged by the World Health
3
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

Organization (WHO) to be a global health hazard [44]. There is not a selectivity, cost, and ease of use have been designed. To reduce the
reliable and accurate source of information regarding the actual number of patients suffering from adverse effects of inappropriate
morbidity and mortality rates that have given rise to vagueness in drugs and attain accurate results in a short time, it is necessary to
assessing and envisaging the degree of this pandemic [45]. Thus, to use ultra-sensitive and selective methods [54]. The novel technol-
effectively monitor patients and control new infections, it is vital to ogy of FET-based biosensors is highly capable of detecting any
design accurate COVID-19 recognition assays [46]. There is a wide nano-sized object, like an antibody, biomolecules, pathogens, and
range of available diagnostic tests, however, FET biosensors offer even viruses [55]. Owing to a large amount of hemagglutinin (HA)
many benefits, in particular, high speed, sensitivity, and specificity and neuraminidase (NA) on a viral particle, these glycoproteins are
which are required in COVID-19 detection. As it is demonstrated in an ideal target for virus detection [56]. Additionally, the nucleo-
Fig. 2, Seo and colleagues presented a FET-based biosensor for protein (NP) of influenza types A and B are different, so, it can be a
identifying SARS-CoV-2 in biological fluids. The device was fabri- perfect target in antigen-detection type assays [57]. Table 1 in-
cated by modifying sheets of graphene as sensing materials with a dicates various characteristics of lately projected biosensors for
monoclonal antibody specific for the SARS-CoV-2 spike protein. identifying of influenza virus. The most efficient device is an
This approach was successful to sense SARS-CoV-2 in culture me- immunosensor fabricated by Chiang and coworkers, which had a
dium and clinical samples with LODs of 1.6  101 pfu/ml and LOD of 1017 M. Whereas, the least sensitivity which is 100 pM is
2.42  102 copies/ml, respectively. Therefore, this device with an reported by Lee and colleagues. The first system was a reusable
off-chip readout system is a promising immunosensing strategy for SiNW-FET as an ultrasensitive biosensor to detect avian influenza
COVID-19 that necessitates no sample pre-processing [47]. Besides, virus (AIV) in buffer solution. The employment of nanowires on the
designing customized biosensing tools for controlling the trans- surface of this device boosted the available surface area for
mission rate of this pandemic-causing virus is possible through immobilizing the receptors. They used a disulfide linker to func-
using the already developed immuno-, or genosensors which are tionalize the surface of SiNW-FET. After the immobilization of BREs,
proposed for detecting other proteins or nucleic acids. In addition, the final immunosensor was successful to identify 1017 M of H5N2
utilizing nanomaterials in the structure of these sensors will further AIVs [58]. As it is demonstrated in Fig. 3, the latter device was a
improve their efficiency and sensitivity. genosensor for measuring the electrical potential on electrodes
amended by an oligonucleotide. It was designed to repeatedly
measure the charges provoked in the working electrode. The
3.2. Influenza reference electrode, working electrodes, and readout circuits were
arranged in one package via CMOS technology. It was acknowl-
Influenza is a contagious viral respiratory sickness caused by the edged that the system was able to recognize down to 100 pM of
influenza virus that is responsible for up to 1 billion contagions, oligonucleotide sequences derived from the H5N1 avian influenza
around 4 million serious cases [48]. The main reason for this high virus [59].
morbidity and mortality rate of pandemic disease is the alterations
in the surface antigens that happen occasionally [49]. Everyone is
indeed in danger of being affected by influenza, but, the major 3.3. Hepatitis B virus (HBV)
proportion of influenza-related deaths are related to the elderly and
especially to those with cardiovascular and respiratory disorders HBV infection is one of the most critical universal public health
[50]. Influenza viruses are separated into different subtypes based burdens [62]. According to global estimates over one-third of the
on surface viral glycoproteins [51]. The infection initiates after the World's population have been diseased with HBV, and about 5% of
virus links to the sialic acid receptors on host respiratory epithelial this population are infected recurrently and around 25% of these
cells via H proteins [52]. Despite the significant number of re- chronic carriers have severe liver diseases like cirrhosis, hepatic
searchers working on influenza prevention, the death rate is still carcinoma, and chronic hepatitis [63]. There is a high risk of
high. Thus rapid diagnostic approaches may be the solution [53]. Up emerging chronic infection and following complications if the
until now, a wide range of tests with different sensitivity, infection happens before birth [64]. Perinatal transmission at birth,

Fig. 2. Outline of COVID-19 FET sensor functioning method [47].

4
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

Table 1
FET-base biosensors for early detection of influenza.

Application Target RE Linker Surface Sensor Readout LOD Sample Ref.

IV diagnosis GST-tagged-HA CMP-NANA/Biotin- APTES SiO2/SiNW CMOS- Off-chip 1 fM Buffer [60]

tagged GST antibody GA compatible solution
Gold-labeled FET (PBS)
streptavidin
AIV diagnosis AIa antibody SBP SiO2/CYTOPTM FET Off-chip 1.9 fM Buffer [61]
(hydrophobic) and Si3N4 0.19 pM solution
(hydrophilic) (PBS)
AIV detection AIV mAbH5 MPTMS SiNW SiNW-FET Off-chip 1017 M Buffer [58]
DTT biotin-HPDP solution
(PBS)
Detection of DNA oligonucleotide sequences 18-mer ssDNA Thiol chain Al/Au FET On-chip 100 pM Buffer [59]
Hybridization derived from the H5N1AIV mercaptohexanol solution
(PBS)

APTES: (3-Aminopropyl) triethoxysilane, GST: glutathione S-transferase, CMP-NANA: Cytidine-50-monophosphate-N-acetylneuraminic acid, AIa: avian influenza antigen,
SBP: silica binding protein, MPTMS: 3-mercaptopropyltrimethoxysilane, Biotin-HPDP: N-(6-(biotinamido)hexyl)-3’-(20 -pyridyldithio)-propionamide, DTT: dithiothreitol.

Fig. 3. (a) A conceptual view of the proposed device. (b) The operation procedure with a top-notch model [59].

horizontal transmission between youngsters, sexual interaction, immobilized bioreceptor. Accordingly, the number of interactions
and injecting drug use are among the most prevalent infections in between BREs and the target analytes augmented considerably
most of the countries [65]. For that reason, it is of high importance which further amplified the signal.
to prevent and control this viral disease by implementing strategies
such as promoting consciousness via public education, vaccination, 3.4. Alzheimer's disease (AD)
blood transfusion safety policies, early identification, and effectual
medical care [66]. Lately, there is an extensive focus on the HBV AD is the most prevalent type of dementia, representing over
early detection and evaluation systems improvement [67]. The 60% of cases of dementia in people over 65 [71]. This neurode-
nanoscience-based approaches have been very successful in HBV generative disease causes advanced damage to cognitive functions
detection biosensor structures [68]. Amongst the recently devel- such as language, attention, visuospatial orientation, memory,
oped FET-based biosensors for detecting HBV, Shariati designed a comprehension, judgment, and reasoning [72]. Irreparable and
FET genosensor for sensing HBV founded on indium tin oxide gradual molecular processes that occur in the brain of AD patients
nanowires (ITO NWs) modified by gold. Owing to ITONWs are resulting in fatal outcomes generally [73]. Therefore, it is a very
extraordinary conductivity, the immobilization of BREs (SS-DNA) crucial health disorder especially for aged people [74]. Much
and target attachment were enhanced intensely. The reported LOD research has been conducted to determine risk factors along with
of the genosensor was about 1 fM [69]. In another work done by finding the most important processes that give rise to the
Gao and coworkers, a novel biosensor was fabricated for DNA commencement and progression of AD [75]. Studies supported by
detection based on silicon nanowire (SiNW) FET. According to Fig. 4, clinical trials related to early detection and treatment of AD include
the surface of SiNW was modified by probe DNA, succeeded by targeting aggregations of amyloid-beta (Ab) plaques [76]. It is
hybridization with the complementary target DNA and rolling cir- approved that the existence of these biomarkers is interconnected
cle amplification (RCA) primer. A limit of detection of 1 fM was with the pathological changes taking place in the brain throughout
achieved [70]. Using nanostructures like nanowires on the topmost AD progress [77]. So, it is essential to measure the concentration of
layer of the FET devices increased the surface to volume ratio Ab-42 to recognize AD in the early stages [78]. Its level in the serum
significantly which paved the way for enhancing the number of of healthy people is in the range of 20 pg/ml, whereas, this amount
5
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

Fig. 4. Schema of SiNW detection of DNA after functionalizing it with APTES, N-ethyl-N0 -dimethyl aminopropyl carbodiimide (EDC), and N-hydroxysuccinimide (NHS) [70].

in AD or pre-AD patients is over 40 pg/ml [78]. For this reason, or epigenetic conversions which cause cellular signaling disruption
designing novel biosensors with lower limits of detection for swift and tumorigenic alteration and malignancy [84]. Biomarkers are
and reliable detection of Ab is of high importance [79]. Up to now, the molecules which experience conspicuous modifications during
several techniques have been presented for the measurement of cancer. These molecules which may be nucleic acids, proteins,
Ab-42. As it is depicted in Fig. 5, Kutovyi and coworkers developed metabolites, isoenzymes, or hormones have high clinical impor-
an innovative strategy for detecting Ab peptides by immobilizing tance [85]. The presence, absence, or variation in the concentration
aptamers onto the SiO2 surface of the manufactured sensors via of a particular biomarker in a cell usually demonstrates cancer
GPTS (3- glycidyloxypropyltrimethoxysilane). To target the Ab-40 progression [86]. Recognition and measurement of these oncobio-
(amyloid beta-40) sequence, ssDNA aptamer was designed, syn- markers could help in early detection and monitoring disease
thesized, and immobilized on silicon (Si) nanowire (NW) FETs development [87]. Recently, there is increasing attention to FET-
altered with a thin layer of SiO2. The binding of Ab peptides of based cancer biosensors as they show superb analytical efficiency
different concentrations in the buffer solution to the sensors' sur- and real-time measurement. A wide range of cancer biomarkers has
face was in the range from 0.1 pg/ml to 10 mg/ml [80]. been monitored by these kinds of biosensors, including, CEACAM,
PSA, cDNA, SSAT, CEA, DTC, miRNA, IL-8, TNF-a, AFP, VEGF, CRP,
3.5. Cancer CYFRA21-1, IP-10, APOA2, and ALCAM. Table 2 shows a list of
recently developed biosensors for early cancer detection. Between
Cancer is the second dominant fatal disease globally with above diverse approaches of assembling biosensing systems, geno and
200 known categories and more than 1600 deaths taking place aptasensors display advanced preciseness as compared to immu-
each day [81]. Despite the ever-growing technology, the number of nosensing assays. The stated LODs vary between 12.5 aMe0.2 mM. It
survived cancer patients is still low as a consequence of detection at is demonstrated in Fig. 6 that, Lu et al. proposed a SiNW-FET
advanced levels and the unsatisfactory prognosis of cancer [82]. biosensor for detecting miR-21 and miR-205, which offers high
The common diagnostic approaches, including ultrasound, CT scan, sensitivity along with lower manufacturing cost. The response time
PET, magnetic resonance imaging, and biopsy are incompetent for of this nanosensor was less than 1 min and its LOD was 1 zmol [88].
early cancer detection [83]. The outset and development of this In another research work done by Bao et al. a pioneering method
multilevel disease, are connected with an intricate series of genetic was used to detect a specific cancer biomarker (CEA). The top-down

Fig. 5. (a) Illustration of a SiNW-FET biosensor. (b) Transfer curves of SiNW-FET before and after modification with Ab-40-specific aptamers. The dashed circle demonstrates the
range of voltages at which noticeable RTS noise was detected [80].

6
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

Table 2
FET-base biosensors for early cancer detection.

Application Target RE Linker Surface Sensor Readout LOD Sample Ref.

Disease antigen CEACAM5 Antibody GTA SiO2/SiNW Potentiometric Off-chip 18 ng/mL Buffer solution [92]
detection CEACAM1 and 21.6 ng/
mL
Prostate cancer PSA PSA antibodiesAPTES SiO2/SiNW Potentiometric Off-chip 90 pg/mL Serum [93]
diagnosis GA
AuNPs
Oncological diseases oDNA Complementary APTES a stack of h-k PEALD Amperometric Off-chip 1016 M Buffer solution [94]
diagnosis oDNA probe DTSSP cross-linker dielectrics, HfO2 and (potassium
molecule Al2O3 phosphate buffer)
CEA detection CEA Antibody APTES SiNx/SiNRs CMOS- Off-chip 10 pg/mL Buffer solution (PBS) [95]
GA compatible
FET
Lung cancer diagnosis miRNA126 probe DNA and APTES SiNW CMOS- Off-chip 0.1 fM and Buffer solution (PBS) [96]
and CEA anti-CEA GA compatible 1 fg/ml
antibody FET
PSA detection PSA DNA aptamers PYCOOH SiO2/graphene FET FET Off-chip 1 nM Buffer solution (PBS) [97]
EDC/NHS channel/Si3N4
PEG
ETA
Lung cancer diagnosis CYFRA21-1 Antibody ETA SiNW CMOS- Off-chip 12.5 aM Serum sample [98]
compatible
SiNW-TFET
Colorectal Cytokeratin-19 Anti-KRT APTES SiO2/Si3N4/p-type CMOS- On-chip 83 fM (~1.3 10% serum [99]
Cancer Diagnosis as a marker of antibodies GA SiNWs compatible cancer cells/
DTC FET mL)
Bladder cancer APOA2 APOA2 antibody Biotin SiNx/MGLA poly-SiNW- Off-chip 6.7 pgmL1 Urine sample [100]
diagnosis APTES FET
GA
EDC/NHS
Prostate cancer PSA Antibody APTES P-type SiNW SiNW-FET Off-chip 10 nM Buffer solution (PBS) [101]
diagnosis GA silane-PEG
Cancer diagnosis CYFRA21-1 and Antibody APTES SiNW CMOS- Off-chip 1 fg/mL- Buffer solution (PBS) [102]
PSA GA compatible 10 fg/mL ehuman serums
FET
Cancer diagnosis ALCAM Antibody APTES SiO2/Si3N4 CMOS- Off-chip 15.5 pg/ml Serum [103]
GA compatible
FET
OSCC diagnosis IL-8 and TNF-a Antibody APTES SiO2/Si3N4/SiNW CMOS- Off-chip 10 fg/mL- Buffer solution (PBS) [104]
GA compatible 100 fg/mL eartificial saliva
FET
Cancer diagnosis AFP Antibody APTES SiO2/SiN x/SiNW SiNW-FET Off-chip 0.1 ng/mL Buffer solution (PBS) [105]
GA
Cervical carcinoma VEGF Avastin APTES n-type polycrystalline SiNW-FET Off-chip 1.25 pg/mL Serum samples [106]
diagnosis GA silicon nanowire EIS
EDC/NHS
SPAnH- Fe3O4
Early cytokine IL-10 Anti- IL-10 Hydroxyl group Si/Al2O3/multi- FET Off-chip 0.5 pg/mL standard samples [107]
detection OTS walled carbon
APTES nanotubeseCOOH
EDC/NHS
Cancer diagnosis miR-21 and Probe DNA APTES P-type SiNW CMOS- Off-chip 1 zmol Human serum [88]
miR-205 (Prb21) EDC/NHS compatible samples
SiNWFET
Prostatic hyperplasia MMP-2 Synthetic peptide O2 P-type SiNW FET Off-chip 1 pM Standard sample [108]
and prostate cancer Plasma
diagnosis TESBA
SH-PEG
Prostatic hyperplasia MMP-2 Synthetic peptide O2 PeSiNW/AuNP FET Off-chip 100 fM Standard sample [109]
and prostate cancer Plasma
diagnosis TESBA
SH-PEG
Streptavidin
CRP detection CRP Anti-CRP SBP protein A SiO2 nanogap- On-chip 0.1 ng/ml Human serum [110]
6-His embedded FET
CMOS
Multiplexed detection CRP and PSA Anti-CRP and APTES silicate SiNW SiNW FET Off-chip 0.12 ng/ml Serum [111]
of protein markers anti-PSA monomer, buffer and 0.18 ng/
solution, and SolB ml
reagent mixture
to form sol-gel

CEACAM: carcinoembryonic antigen-related cell adhesion molecule, GTA: Glutaraldehyde, oDNA: DNA oligonucleotide, PYCOOH: pyrene butyric acid, DTC: disseminated
tumor cell, APOA2: apolipoprotein A-II, MGLA: magnetic graphene with long-chain acid groups, ALCAM: Activated leukocyte cell adhesion molecule, IL-8: interleukin-8, TNF-
a: tumor necrosis factor a, OSCC: oral squamous cell carcinoma, AFP: Alpha-fetoprotein, VEGF: vascular endothelial growth factor, SPAnH- Fe3O4: Magnetic nanoparticles with
poly(aniline-co-N-(1-one-butyric acid) aniline)- Fe3O4, EIS: electrochemical impedance spectroscopy, IL-10: interleukin-10, MMP-2: Matrix metalloproteinases, SH-PEG:
polyethylene glycol functionalized thiol group, TESBA: 3-(triethoxysilyl)butyl aldehyde, 6-His: six-histidine, OTS: Octadecyltrichlorosilane.

7
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

Fig. 6. Illustration of detecting miRNA by SiNW which is functionalized by APTES, EDC, and NHS [88].

construction technique of this FET-based biosensor made the (SPR) are not cost-effective, and swift since they necessitate using
researcher have control over its electrical characteristics. Further- highly sophisticated instruments and skilled laboratory personal
more, this approach is CMOS-compatible which enables mass [121]. So, they lack the capacity of being used as point-of-care (POC)
production of the proposed biosensor for high throughput, real- testing [122]. Hitherto, several different strategies based on FET
time, cheap, and precise assays. The surface of the device was have been developed for detecting AMI, which is listed in Table 3.
modified with APTES, GA, and anti-CEA, and a microfluidic channel Amongst different approaches, the most proficient method is
was added on top of it. This approach was successful enough to established by Arshad and coworkers who developed an alternative
detect down to 10 pg/mL of the analyte [89]. Or Gao and colleagues technique for signal amplification. As it is illustrated in Fig. 7, they
designed a microfluidic sensing platform based on CMOS- designed a FET biosensor for achieving a boosted sensitivity and
compatible SiNW-FET for the identification of lung cancer bio- lower limit of detection. In this regard, a silicon-on-insulator wafer
markers ((miRNA)126 and CEA). Utilizing nanowires enabled with top silicon and buried oxide (BOX) layers, and titanium di-
single-molecule level detection with high sensitivity and specificity oxide (TiO2) nanomaterial were used to facilitate an efficient
in biofluids [90]. The other CMOS-compatible silicon nanowire immobilization of specific antibody to selectively bind to cardiac
tunneling field-effect transistor (SiNW-TFET) biosensor was re- troponin I (cTnI). The fabricated device presented a high capability
ported by Gao et al. for pH and cytokeratin 19 fragment (CYFRA21- in detecting lower levels (LOD ¼ 1 fg/ml) of cTnI [123]. However,
1) detection. It was capable of recognizing down to 12.5 aM of the Kong et al. assembled a biosensing technique for identifying cTnI,
target protein in the serum sample. These successful studies using SiNW-based FETs. This way, monoclonal antibodies against
demonstrate the power of FET-based platforms for a wide range of CTnI were successfully immobilized on the surfaces of nanowires.
POC applications [91]. The designed arrangement displayed a fast and sensitive response
to target analytes which was recorded by a homemade biosensor
measurement system. Additionally, its construction process en-
3.6. Acute myocardial infarction (AMI) ables its mass-production which paves the way for practical ap-
plications [124].
AMI is the primary reason for demise worldwide among heart-
related disorders [112]. It is usually initiated by a decrease or
blockage of blood flow to a section of the heart, resulting in necrosis 3.7. Malaria
of heart muscle [113]. This is generally the result of a blood clot or
fat that obstructs cardiac muscle, which contains a coronary artery Malaria is among the serious infectious maladies in over 100
that carries oxygenated blood [114]. Accordingly, due to the insuf- countries in the tropical and subtropical regions [127]. Each year,
ficient circulation of the oxygenated blood within the organ itself, about 500 million people especially children under 5 years become
the cardiac muscle gradually damages and it secretes a protein- infected and 1 to 3 million people lose their lives [128]. The path-
based molecule called cardiac troponin I (cTnI) [115]. Therefore, ogenesis of human malaria clinical illness is complicated since it
cTnI is an excellent biomarker for AMI detection and its concen- has several settings, and possible outcomes [129]. Generally, the
tration level can be associated with the stage of AMI [116]. Its main cause of Malaria is the Plasmodium parasite known to pass on
durability and response capability after interaction with its com- a disease to the human population [130]. Plasmodium falciparum is
plementary antibody turn it to be the reference point for early the most predominant of them all [131]. Plasmodium falciparum
diagnosis of AMI [117]. To treat AMI early and prevent permanent malaria parasites' biology, is definite, foreseeable, and simply dis-
damage to the heart, early detection is necessary [118]. Conven- tressed during their life cycle [132]. Furthermore, by the appear-
tional detection methods like electrocardiogram (ECG) are not ance of some strains that are not sensitive to drugs, the efficacy of
efficient enough because of their low sensitivity. Also, they require existing malaria medications is decreasing [133]. Accordingly, the
capturing the unusual signal and therefore, cannot be considered as need to precisely spot this disorder for appropriate medicament
early detection [119]. But detecting cTnI as a biomarker of AMI of- and monitoring cannot be denied [134]. To control transmission
fers higher sensitivity, and selectivity [120]. Commonly used assays dynamics, it is necessary to detect this disease early even in pa-
to detect this biomarker, including ELISA, fluorescence, electro- tients without any symptoms [135]. Up to the present time, a large
chemiluminescence immunoassay, and surface plasmon resonance number of researchers have tried to overcome the difficulties in

8
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

Table 3
FET-base biosensors for early detection of AMI.

Application Target RE Linker Surface Sensor Readout LOD Sample Ref.

Acute myocardial infarction disease cTn1 Anti-cardiac troponin I APTES TiO2 FET Off-chip 1 fg/ml Blood [123]
diagnosis antibody GA
CTnI detection cTnI Anti-cTnI APTES Poly-SiNW CMOS-compatible On-chip 7.6 pg/ml Serum samples [125]
GA SiNWFET
AMI diagnosis cTnT Anti-cTnT APTES Si/SiO2/SiNW P-type Off-chip 27pM serum [126]
GA SiNW-FET
AMI diagnosis cTnI Anti- cTnI APTES SiNW/SiO2/ CMOS-compatible Off-chip 0.092 ng/ Buffer solution [124]
GA SiNx SiNW FET mL (PBS)

cTnT: cardiac Troponin T.

Fig. 7. Surface functionalization process involving binding of linkers ((a)APTES and (B)GA) and (c) immobilizing antibody (d) Ab-Ag interaction [123].

malaria diagnostics with technologies that consider point-of-care [138]. These types of contagious or transmittable illnesses are most
demands and early-stage detection [136]. But amongst these challenging in poor nations, such as African countries, where
novel techniques, biosensors seem to be the most sensitive and therapeutic amenities and diagnostic methods are not at an
rapid ones. Specifically, Lab-on-Chip (LOC) platforms based on advanced level [139]. However, in wealthy and developed countries
CMOS are precise and efficient for targeting this goal. Fig. 8 depicts such as western nations, food-borne pathogens are considered a
a particular, and quantifiable detection method for this parasite, major risk as well [140]. So it is vital to detect these bacteria early to
using a LOC system proposed by Malpartida-Cardenas and co- prevent disease development and subsequent treatment. A time-
workers. They established reliable detection of a single-nucleotide consuming process, lack of sensitivity and selectivity, the need for
related to drug-resistant strain of malaria. This DNA sensing was specialized laboratory equipment, expert personnel, and high cost
enabled by utilizing ISFETs, which were constructed through of conventional methods of bacterial detection, made scientists
standard CMOS technology. This research study is capable of being look for a more efficient alternative [141]. A rapid investigation that
developed to a handy and assessable POC assay of malaria [37]. could sense and identify the cause of bacterial infection within
minutes is needed immediately. Recently developed FET-based
3.8. Bacteria-related disease biosensors are very appropriate for handy POC and LOC devices
[10]. Table 4 summarizes the recently fabricated biosensors for
Rapid and reliable detecting bacterial pathogens are imperative bacterial infections. For instance, Nikkhoo and coworkers, an
in different fields such as public health, medicine, food poisoning, innovative all-electronic biosensor that can detect bacteria in
bioterrorism, and security [137]. Bacterial infections are causing below ten minutes was introduced. They selected bacteriocins as
millions of deaths and hospitalizations yearly all around the world the potential BREs were which were incorporated with potassium-
9
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

carbon nanotubes for speedy and precise detection of specific an-

tigen of Lyme disease. They were successful to effectively detect
this antigen with a LOD of 1 ng/ml [143].

3.9. Other potential diseases

3.9.1. Nucleic acid detection

Nucleic acid diagnostics are of significant importance in
numerous areas, such as early detection of genetic diseases, iden-
tifying pathogens, and drug development studies [144]. DNA hy-
bridization is the key strategy of most DNA detection methods, in
which a particular single-stranded DNA (ssDNA) molecules identify
the reciprocal strand mediated by typically Watson and Crick base
pairing procedures [145]. By immobilizing probe DNAs onto the
sensor's surface, this hybridization is generally sensed [146]. DNA's
phosphate backbone is the reason for the shift in-charge near the
sensor's surface yielding a response after attachment [147]. One of
Fig. 8. Transverse profile of an ISFET manufactured in standard CMOS technology and
the most essential features to take into consideration is the DNA
the analogous circuit macro model [37]. probe density on the sensing area that should be high enough to
produce measurable hybridized charge and boosted sensor signal.
But to prevent electrostatic repulsions and the resulting reduction
selective sensors in CMOS technology to offer a cost-effective bio- in hybridization efficacy, it should not be too high [148]. In recent
sensing tool [142]. As can be seen in Fig. 9, Lerner and colleagues years, FET devices have attracted attention amid the abundance of
evaluated the capability of a FET device based on single-walled electrical DNA detection platforms, owing to their several benefits,

Table 4
FET-base biosensors for early detection of bacteria-related diseases.

Application Target RE Linker Surface Sensor Readout LOD Sample Ref.

Grampositive and Gram- E. coli, S. aureus Bacteriocins potassium Valinomycin- SiO2/Al/methylene blue/ CMOS On-chip 107 Buffer [142]
Negative bacteria or P. aeruginosa ions polyvinylchloride potassium-sensitive integrated bacteria/ solution
detection (PVC) electrode ISFETs mL
Lyme disease diagnosis B. burgdorferi Borrelia burgdorferi Diazonium salts Si/SiO2/single-wall SWNT FET Off-chip 1 ng/ml Buffer [143]
flagellar antigen (Lyme) flagellar Histidine nanotube (SWNT) solution
antibody EDC/NHS

Fig. 9. Modification chemistry for Lyme antibody and its interaction with a flagellar antigen [143].
10
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

including reduced size, rapid response, incorporation into arrays, Transplanting isolated islets from a donor pancreas into another
and the probability of affordable large-scale manufacture [149]. The person is a form of treatment for type 1 diabetes. After trans-
capability of concurrent analysis of several DNA/RNA targets in plantation, the islets start producing insulin and regulating the
down-sized analytical structures has paved the way for the level of glucose in the blood. The average concentration of
improvement of all-inclusive LOC platforms [150]. Between the pancreatic insulin is ~10 mM. This value is contingent upon several
currently developed FET-based genosensors that are presented in parameters such as the number and size of islets, extent, and length
Table 5, the device fabricated by Hu and coworkers showed an of glucose stimulation, etc. Thus, it is important to monitor the level
extraordinary performance. They functionalized the surface of of insulin secreted from islets [162]. Thyroid-stimulating hormone
polycrystalline silicon nanowire FET devices with DNA probes and (TSH), is a glycoprotein secreted from the pituitary gland, which
attained a LOD of 0.1 fM [151]. In another successful work con- controls the endocrine role of the thyroid gland. Its level is an in-
ducted by Hwang et al. FETs with a monolayer of graphene channel dicator of the metabolic actions in the human body [163]. That is
were utilized for the detection of DNA. Fig. 10 demonstrates that why TSH biosensors are being developed in recent years. To have a
these miniaturized devices showed exceptional sensitivity in both successful treatment without side effects, it is imperative to
buffer and human serum samples. The reported LODs were 600 zM maintain the drug's proper concentration in the blood. For this
and 20 aM, respectively [152]. These results depict that FET bio- reason, tracking the drug level and regulating its effective dosage is
sensors are offering a favorable methodology sensitive and specific of considerable importance [164]. A list of these newly developed
for nucleic acid detection. FET biosensors is summarized in Table 6. For example, Lee et al.
came up with a pioneering recognizing method for FSH using
3.9.2. Other biomarkers SiNW-FET devices modified with boronic acid. The detection pro-
FET biosensors are used for some other applications as well. For cess was effectively done in both buffer solution and 20% serum
instance, measuring the amount of L-carnitine [156]. Its deficiency condition with a LOD of 0.72 fM and 1.1 fM, respectively [165].
that is caused by chronic disorders is generally associated with Fig. 11 clarifies the functionalization process of the SiNW-FET
genetic diseases, cardiomyopathy, and hypoglycemia in newborns, device.
isovaleric acidaemia, chronic fatigue syndrome, methylmalonic,
and hypoketotic hypoglycaemic encephalopathy [157]. So, 4. Non- selective adhesion for cell-based screening
measuring the serum concentration of L-carnitine for monitoring applications
anomalies in the oxidation of fatty acid is significantly imperative in
therapeutic applications. Or follicle-stimulating hormone (FSH) It can be inferred from Table 7 that a wide variety of cell-based
which is secreted by the pituitary gland and has a part in body biosensing platforms are designed and used for different applica-
growth [158]. By planning a sensor sensitive to sialic acids, one can tions in recent years. For example, Anand et al. established a FET
directly measure the concentration of FSH. Another target analyte is device based on SiNW for the instantaneous sensing of the cultured
phosphate -one of the most fundamental nourishing materials. Its cortical neurons' Kþ efflux. They functionalized the surface of the
normal physiological range is between 0.80 and 1.45 mM. To system by Kþ-specific DNA-aptamers. After introducing the cells
maintain a healthy body, an average human must consume over the FET in a buffer free of Naþ/Kþ ions, the extracellular level of
700e1250 mg phosphorus every day. It is noteworthy that, exces- Kþ varied according to the environmental status. The results vali-
sive consumption accelerates the aging processes [159]. Hence, dated the sensitivity of the arrangement for detecting cations and
checking phosphate levels in nutrients is necessary to avoid unfa- measuring the intra- and extracellular concentrations of the Kþ
vorable effects. Real-time inspection of glycemic levels can affect [172]. Or in another work done by Li and colleagues, a bottom-up
diabetic outcomes, such as amended hemoglobin A1C levels and technique was used to detect the secreted dopamine from
lower long term complications [160]. Therefore, glucose-sensitive PC12 cells. They modified the surface of Si NWs with APTMS. The
biosensors are amongst the most popular and well-established selective surface-modified SiNW-FETs presented favorable elec-
FET devices. In brain tissue, the neurotransmitter acetylcholine trical properties such as high trans-conductance. It was confirmed
which is one of the neurochemically active molecules is engaged in that employing the interaction between biotin and avidin in the
a variety of behavioral aspects such as, reasoning, attention, moti- surface amendment of the SiNW-FETs significantly boosted the
vation, and reward in the central nervous system. As a result, its detection sensitivity [171]. The same research group designed
monitoring is vital for revealing brain disorders [161]. another multiple-parallel-connected SiNW-FET device for

Table 5
FET-base biosensors for early detection of nucleic acids.

Application Target RE Linker Surface Sensor Readout LOD Sample Ref.

Optimize the ionic strength and the debye Target DNA APTES Poly-Si NW FET Off-chip 0.1 fM Buffer [151]
length of the detection oligomers oligomers GA solution
(BTP)
DNA detection DNA PNA APTES SiO2/Ti/Au/PMMA/SLG/copper/ G-FET Off-chip 10 fM Buffer [153]
GA CVD-grown SLG solution
PASE (PBS)
ETA
Nucleic acid analysis Target Probe APTES SiO2/Si3N4/SWNT CMOS-compatible Off-chip 1 fM Buffer [154]
DNA DNA EDC/ SiNW-FET solution
NHS (PBS)
DNA hybridization sensing Target Probe APTES SiO2/Poly SiNW CMOS-compatible Off-chip 1 fM Buffer [155]
DNA DNA GA poly-Si NW FET solution
(PBS)
DNA detection Target Probe PASE PS/Graphene/PMMA/Silicone FET Off-chip 20 aM Serum [152]
DNA DNA ETA rubber

ETA: ethanolamine, SLG: single-layer graphene, PNA: peptide nucleic acid, PASE: 1-Pyrenebutanoic acid succinimidyl ester, PS: polystyrene.

11
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

Fig. 10. Illustration of the flat and crumpled graphene FET genosensor. b fabrication of FETs and investigational flow of the procedure [152].

Table 6
FET-base biosensors for early detection of other biomarkers.

Application Target RE Linker Surface Sensor Readout LOD Sample Ref.

Direct protein sensing beyond the Streptavidin Biotin Magnetic Ta2O5/SiO2 ISFET Off-chip 2.3 mM Buffer solution [166]
debye length limit beads
Screening disorders in fatty acid L-carnitine Carnitine APTES Ta2O5 ISFET Off-chip 0.2 mM Artificial urine [167]
oxidation acetyltransferase GA
FSH detection Sialic acids Boronic acid SB-ester SiNW FET Off-chip 0.72 fM Buffer solution (PBS) and 20% [165]
NaIO4 1.1 fM serum solution
Phosphate detection Phosphate Pyruvate oxidase ZnO NRs Si/SiO2 FET Off-chip 0.5 mM Buffer solution (HEPES) [168]
Thyroid diagnosis hTSH Anti-hTSH APTES SiNW/SiO2 CMOS-compatible Off-chip 0.11 pM Buffer solution (PBS) [169]
GA SiNWFET
Lead and potassium ions detection Kþ and TBA MB Si/SiO2/ FET-like Off-chip 100 mM Standard sample [170]
Pb2þ graphene e10 mM
Biomolecular recognition Avidin Biotin APTMS SiNW SiNW-FET Off-chip 15 ± 1 fM Buffer solution (PBS) [171]

ZnO NRs: ZnO nanorods, hTSH: human thyroid-stimulating hormone, TBA: thrombin binding aptamer, APTMS: 3-Aminopropyl)trimethoxysilane.

identifying dopamine by utilizing DNA-aptamers as BREs. It was designing an olfactory receptor (OR) genes screening test. The ORs
demonstrated that the LOD improved to below 1011 M in com- on the surface membrane of nanovesicles induced the increase of
parison with conventional electrochemical approaches. Also, the calcium ions. Consequently, a variation in the current occurred
high selectivity of the device was such that it could differentiate alongside the carbon nanotube which was monitored by the
dopamine from its other chemical analogs. This FET aptasensor was fabricated biosensor [175]. These successful research works
also used to screen the release of dopamine from living cells in a confirm the significant potential of FET-base devices for cell-based
milieu which had poor oxygen concentration [173]. In a different screening applications. Despite the improvements in this field, re-
research work conducted by Susloparova et al., open-gate FET de- searchers face many challenges that should address in future
vices were employed to investigate the cancerous cells' adhesion studies. For example, to solve packaging issues, upcoming designs
status in the presence of an anti-cancer drug. The proposed can have a more compact structure. Besides, a shared readout
approach has the potential to be used for the examination of the system can be huge save in power consumption and area. It is
effectiveness of new medications in concurrent evaluations [174]. imperative to keep the power factor as low as possible to prevent
Another application can be seen in Lim and coworkers' research, temperature increase and accordingly cell death. Or to construct a
which used SWCNT-FET systems coupled with nanovesicles for wide-ranging biological micro-device that can identify cellular

12
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

Fig. 11. Illustration of the functionalization process of the SiNW-FET sensor using SB-ester [165].

Table 7
FET-base biosensors for cell-based screening applications.

Application Cell AL Surface Sensor Readout Specification Culture? Sample Ref

Detection of dopamine Living Boronic SiNW SiNW-FET Off-chip 33 ± 8 fM Yes Buffer [171]
released from PC12 cells PC12 cells acid/ solution
dopamine (PBS)
APTMS
EDC/NHS
Detection of the Kþ efflux Cortical Aptamers SiNW/ FET Off-chip AMPA stimulation boosted the Kþ level to Yes Tris buffer [172]
neurons APTM/ ~800 nM (EC50 ¼ 10.3 mM) solution
DSC
Detection of dopamine Living APTMS SiNW SiNW-FET Off-chip <10e11 M Yes Buffer [173]
released from PC12 cells PC12 cells PTMS solution
BMS (PBS)
DNA-
aptamers
OR screening assay HEK-293 PDL SWNT FET Off-chip Calcium influx (1 mM Ca2þ ions) Yes Buffer [175]
solution
(PBS)
Anti-cancer drug (topotecan HEK293 Fibronectin SiO2 Impedance Off-chip 20% change in the amplitude of the Yes Buffer [174]
hydrochloride) action H441 spectroscopy (open impedance spectra in the presence of the solution
analysis gate FET) drug (PBS)
Detection of the Kþ-efflux Chromaffin VAL-PVC SiO2 SiNW-FET Off-chip Increase of the Kþ level under the Yes Buffer [180]
cells stimulation of nicotine solution (Tris
buffer)

HEK-293: human embryonic kidney cells, AMPA: a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, DSC: N, N0 -disuccinimidyl carbonate, OR: Olfactory receptor genes,
PDL: Poly- D elysine, PTMS: propyltrimethoxysilane, BMS: 3-maleimidobenzoic acid, H441: human lung adenocarcinoma epithelial cells.

13
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

reactions and process the gathered data, digitization of blocks in References

conjunction with multi-array electrode systems might be needed
[176,177]. In addition, implantable systems that are capable of real- [1] N. Bhalla, P. Jolly, N. Formisano, P. Estrela, Essays Biochem. 60 (2016) 1.
[2] A.C. Carpenter, I.T. Paulsen, T.C. Williams, Genes (Basel) 9 (2018).
time reporting of cellular activities set the stage for the emergence [3] S. Patel, R. Nanda, S. Sahoo, E. Mohapatra, Biochem. Res. Int. 2016 (2016),
of a new category of sensing platforms. Compactness and flexibility 3130469.
are the two important features of theses novel sensors. Tackling [4] P. Mehrotra, J. Oral Biol. Craniofac. Res. 6 (2016) 153.
[5] L. Syedmoradi, A. Ahmadi, M.L. Norton, K. Omidfar, Mikrochim. Acta 186
these problems requires the collaboration of researchers from (2019) 739.
different backgrounds. If the abovementioned confrontations are [6] P. Bergveld, IEEE Tran. Biomed. Eng. BME-17 (1970) 70.
resolved, FET-based devices may be expected to function as an [7] P. Duroux, C. Emde, P. Bauerfeind, C. Francis, A. Grisel, L. Thybaud,
D. Arstrong, C. Depeursinge, A.L. Blum, Gut 32 (1991) 240.
efficient platform for biological and biomedical applications [8] X. Liu, H. Jiang, Sensors (Basel) 17 (2017).
[178,179]. [9] X. Dai, R. Vo, H.H. Hsu, P. Deng, Y. Zhang, X. Jiang, Nano Lett. 19 (2019) 6658.
[10] C.A. Vu, W.Y. Chen, Sensors (Basel) 19 (2019).
[11] V. Pachauri, S. Ingebrandt, Essays Biochem. 60 (2016) 81.
5. Conclusion
[12] T. Wadhera, D. Kakkar, G. Wadhwa, B. Raj, J. Electron. Mater. 48 (2019) 7635.
[13] W. Huang, A.K. Diallo, J.L. Dailey, K. Besar, H.E. Katz, J. Mater. Chem. C Mater.
The most recent and innovative approaches in the field of bio- 3 (2015) 6445.
[14] C.S. Lee, S.K. Kim, M. Kim, Sensors (Basel) 9 (2009) 7111.
logically sensitive field-effect transistors for early diagnosis of dis-
[15] L. Mu, Y. Chang, S.D. Sawtelle, M. Wipf, X. Duan, M.A. Reed, IEEE Access 3
eases and cell-based assays for drug screening studies were (2015) 287.
highlighted in this article. Since the past few decades, several [16] B.M. Lowe, K. Sun, I. Zeimpekis, C.K. Skylaris, N.G. Green, Analyst 142 (2017)
research works have focused on FET-based biosensors owing to 4173.
[17] N.K. Rajan, X. Duan, M.A. Reed, Wiley Interdiscipl. Rev. Nanomed. Nano-
their favorable potentials including, sensitivity, specificity, biotechnol. 5 (2013) 629.
compactness, portability, speed, cost-effectiveness, ease of use, and [18] R. Ahmad, T. Mahmoudi, M.S. Ahn, Y.B. Hahn, Biosens. Bioelectron. 100
the possibility of high-throughput analysis. The fact that most of (2018) 312.
[19] O.M. Lage, M.C. Ramos, R. Calisto, E. Almeida, V. Vasconcelos, F. Vicente, Mar.
them are constructed using standard, commercialized, and mass- Drugs 16 (2018).
produced devices, turn them into one of the most preferred and [20] A. Carnero, Clin. Transl. Oncol. 8 (2006) 482.
successful approaches. Furthermore, the feasibility to study low [21] A. Hierlemann, H. Baltes, Analyst 128 (2003) 15.
[22] K. Nakazato, Sensors (Basel) 9 (2009) 8831.
volumes of samples makes them exceptionally efficient. It cannot [23] K. Risveden, J.F. Ponten, N. Calander, M. Willander, B. Danielsson, Biosens.
be denied that the constant enhancement of nanotechnology and Bioelectron. 22 (2007) 3105.
amendment of readout systems further improve the biosensing [24] A.M. Dinar, A.S.M. Zain, F. Salehuddin, Int. J. Electr. Comput. Eng. 9 (2019).
[25] C. Jimenez-Jorquera, J. Orozco, A. Baldi, Sensors (Basel) 10 (2010) 61.
platforms that facilitate high throughput screening for biomole-
[26] K.B. Parizi, X. Xu, A. Pal, X. Hu, H.S. Wong, Sci. Rep. 7 (2017) 41305.
cular assays and address the need for rapid, robust, and economical [27] M. Meyyappan, J.-S. Lee, (2014) 225.
POC detection. However, there are still numerous important chal- [28] M.A. Morales, J.M. Halpern, Bioconjugate Chem. 29 (2018) 3231.
[29] J.J. Xu, X.L. Luo, H.Y. Chen, Front. Biosci. 10 (2005) 420.
lenges that need to be addressed before they become validated as
[30] O. Synhaivska, Y. Mermoud, M. Baghernejad, I. Alshanski, M. Hurevich,
POC assessments. For instance, BREs should be immobilized in a S. Yitzchaik, M. Wipf, M. Calame, Sensors 19 (2019) 4022.
firm and reproducible manner onto the functionalized FET channel. [31] H. Li, X. Liu, L. Li, X. Mu, R. Genov, A.J. Mason, Sensors (Basel) 17 (2016).
Also, the ability to be massively produced with high accuracy of [32] A.Y. Chang, M.S. Lu, Conf. Proc. IEEE Eng. Med. Biol. Soc. 2013 (2013) 4102.
[33] A.M. Hussain, M.M. Hussain, Adv. Mater. 28 (2016) 4219.
fundamental representative properties, including rate, reliability, [34] Y. Adiguzel, H. Kulah, Sensors (Basel) 12 (2012) 10042.
and shelf-life is of high significance. In addition, a FET type [35] H.H. Radamson, X. He, Q. Zhang, J. Liu, H. Cui, J. Xiang, Z. Kong, W. Xiong, J. Li,
biosensor should be highly selective to have a minimum amount of J. Gao, H. Yang, S. Gu, X. Zhao, Y. Du, J. Yu, G. Wang, Micromachines (Basel) 10
(2019).
cross-reactions, in order to be functional as a POC tool. Though, [36] K.M. Lei, P.I. Mak, M.K. Law, R.P. Martins, Lab Chip 16 (2016) 3664.
recently done research works such as the ones studied here [37] K. Malpartida-Cardenas, N. Miscourides, J. Rodriguez-Manzano, L.S. Yu,
acknowledge that FET-based biosensors will soon find their way N. Moser, J. Baum, P. Georgiou, Biosens. Bioelectron. 145 (2019) 111678.
[38] I. Ferain, C.A. Colinge, J.P. Colinge, Nature 479 (2011) 310.
from the laboratory to the market specifically for applications in the [39] M. Sridhar, D. Xu, Y. Kang, A.B. Hmelo, L.C. Feldman, D. Li, D. Li, J. Appl. Phys.
early detection of disease biomarkers. Integrating nanomaterials 103 (2008) 104701.
and nanostructures such as SiNWs, CNTs, graphene, and metal [40] T. Kudo, T. Ito, A. Nakajima, J. Vac. Sci. Technol. B 31 (2013).
[41] B.M. Cullum, H.-K. Lyu, D.M. Porterfield, Y.-S. Choi, J.-K. Shin, J.-H. Kim, 7313
nanoparticles as sensing channels improve the performance of FET
(2009) 73130S.
type biosensing devices considerably owing to high surface to [42] S. Mostafa, I. Lee, S.K. Islam, S.A. Eliza, G. Shekhawat, V.P. Dravid, F.S. Tulip,
volume ratio, chemical firmness, and biocompatibility. Standard IEEE Electron. Device Lett. 32 (2011) 408.
[43] H. Li, S.M. Liu, X.H. Yu, S.L. Tang, C.K. Tang, Int. J. Antimicrob. Agents (2020)
biosensing tools like SiNWFETs are predicted to contribute signifi-
105951.
cantly to the improvement of biomedical applications and provide [44] F. He, Y. Deng, W. Li, J. Med. Virol. 92 (2020) 719e725.
extraordinary sensitivity and specificity for identifying bio- [45] H. Ge, X. Wang, X. Yuan, G. Xiao, C. Wang, T. Deng, Q. Yuan, X. Xiao, Eur. J.
molecules binding acts or metabolic reactions at the touchpoint of Clin. Microbiol. Infect. Dis. 39 (6) (2020) 1011e1019.
[46] P. Zhai, Y. Ding, X. Wu, J. Long, Y. Zhong, Y. Li, Int. J. Antimicrob. Agents
living organisms and electronics. But, it is not easy to judge which (2020) 105955.
one is the most appropriate choice for further progression due to [47] G. Seo, G. Lee, M.J. Kim, S.H. Baek, M. Choi, K.B. Ku, C.S. Lee, S. Jun, D. Park,
the discrepancy in results from one lab to another. In addition, it is H.G. Kim, S.J. Kim, J.O. Lee, B.T. Kim, E.C. Park, S.I. Kim, ACS Nano 14 (2020)
5135.
noteworthy that, incorporation of microfluidics with biosensing [48] J. Paget, P. Spreeuwenberg, V. Charu, R.J. Taylor, A.D. Iuliano, J. Bresee,
devices will be vital for constructing channelized integrated L. Simonsen, C. Viboud, N. Global, Seasonal influenza-associated mortality
analytical arrangements. Consequently, there is a laborious way in collaborator, G.L.C. Teams*, J Glob Health 9 (2019), 020421.
[49] S. Ghebrehewet, P. MacPherson, A. Ho, BMJ 355 (2016) i6258.
front of researchers to come up with advanced policies for [50] J.H. Beigel, Crit. Care Med. 36 (2008) 2660.
improving the efficacy of FET devices. [51] S. Pleschka, Curr. Top. Microbiol. Immunol. 370 (2013) 1.
[52] S. Fukuyama, Y. Kawaoka, Curr. Opin. Immunol. 23 (2011) 481.
[53] C.C. Otto, S.E. Kaplan, J. Stiles, A. Mikhlina, C. Lee, N.E. Babady, Y.W. Tang, J.
Declaration of competing interest
Vis. Exp. 119 (2017) e54312.
[54] P.I. Kontou, G.G. Braliou, N.L. Dimou, G. Nikolopoulos, P.G. Bagos, Diagnostics
The authors declare that they have no known competing (Basel) 10 (2020).
[55] T. Lee, J.H. Ahn, S.Y. Park, G.H. Kim, J. Kim, T.H. Kim, I. Nam, C. Park, M.H. Lee,
financial interests or personal relationships that could have
Micromachines (Basel) 9 (2018).
appeared to influence the work reported in this paper.
14
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

[56] D.K. Kim, B. Poudel, Yonsei Med. J. 54 (2013) 560. [108] J.H. Choi, H. Kim, H.S. Kim, S.H. Um, J.W. Choi, B.K. Oh, J. Biomed. Nano-
[57] K.S. George, Methods Mol. Biol. 865 (2012) 53. technol. 9 (2013) 732.
[58] P.L. Chiang, T.C. Chou, T.H. Wu, C.C. Li, C.D. Liao, J.Y. Lin, M.H. Tsai, C.C. Tsai, [109] J.H. Choi, H. Kim, J.H. Choi, J.W. Choi, B.K. Oh, ACS Appl. Mater. Interfaces 5
C.J. Sun, C.H. Wang, J.M. Fang, Y.T. Chen, Chem. Asian J. 7 (2012) 2073. (2013) 12023.
[59] K.H. Lee, J.O. Lee, S. Choi, J.B. Yoon, G.H. Cho, Biosens. Bioelectron. 31 (2012) [110] C.H. Kim, J.H. Ahn, J.Y. Kim, J.M. Choi, K.C. Lim, T.J. Park, N.S. Heo, H.G. Lee,
343. J.W. Kim, Y.K. Choi, Biosens. Bioelectron. 41 (2013) 322.
[60] M. Uhm, J.M. Lee, J. Lee, J.H. Lee, S. Choi, B.G. Park, D.M. Kim, S.J. Choi, H.S. Mo, [111] M.H. Lee, K. Lee, S.W. Jung, Conf Proc IEEE Eng Med Biol Soc 2012 (2012) 570.
Y.J. Jeong, D.H. Kim, Sensors (Basel) 19 (2019). [112] T. Lee, J.H. Ahn, J. Choi, Y. Lee, J.M. Kim, C. Park, H. Jang, T.H. Kim, M.H. Lee,
[61] J.Y. Kim, K. Choi, D.I. Moon, J.H. Ahn, T.J. Park, S.Y. Lee, Y.K. Choi, Biosens. Micromachines (Basel) 10 (2019).
Bioelectron. 41 (2013) 867. [113] L. Lu, M. Liu, R. Sun, Y. Zheng, P. Zhang, Cell Biochem. Biophys. 72 (2015) 865.
[62] J. Si, C. Yu, Y. Guo, Z. Bian, R. Meng, L. Yang, Y. Chen, J. Jin, J. Liu, Z. Guo, [114] R. Bruyninckx, B. Aertgeerts, P. Bruyninckx, F. Buntinx, Br. J. Gen. Pract. 58
J. Chen, Z. Chen, J. Lv, L. Li, G. China Kadoorie Biobank Collaborative, BMJ (2008) 105.
Open 9 (2019), e027696. [115] E. Braunwald, Eur Heart J Acute Cardiovasc Care 1 (2012) 9.
[63] C. Stasi, C. Silvestri, F. Voller, J Clin Transl Hepatol 5 (2017) 272. [116] S. Aydin, K. Ugur, S. Aydin, I. Sahin, M. Yardim, Vasc. Health Risk Manag. 15
[64] T. Kushner, M. Sarkar, Clin. Liver Dis. (Hoboken) 12 (2018) 24. (2019) 1.
[65] M.H. Chang, D.S. Chen, Cold Spring Harb. Perspect. Med. 5 (2015) a021493. [117] K.C. Park, D.C. Gaze, P.O. Collinson, M.S. Marber, Cardiovasc. Res. 113 (2017)
[66] E.J. Aspinall, G. Hawkins, A. Fraser, S.J. Hutchinson, D. Goldberg, Occup. Med. 1708.
(Lond.) 61 (2011) 531. [118] R.P. Tiwari, A. Jain, Z. Khan, V. Kohli, R.N. Bharmal, S. Kartikeyan, P.S. Bisen,
[67] T. Wilkins, R. Sams, M. Carpenter, Am. Fam. Physician 99 (2019) 314. Mol. Diagn. Ther. 16 (2012) 371.
[68] C.Y. Yao, W.L. Fu, World J. Gastroenterol. 20 (2014) 12485. [119] J. Boeddinghaus, T. Reichlin, T. Nestelberger, R. Twerenbold, Y. Meili,
[69] M. Shariati, Biosens. Bioelectron. 105 (2018) 58. K. Wildi, P. Hillinger, M.R. Gimenez, J. Cupa, L. Schumacher, M. Schubera,
[70] A. Gao, N. Zou, P. Dai, N. Lu, T. Li, Y. Wang, J. Zhao, H. Mao, Nano Lett. 13 P. Badertscher, S. Corbiere, K. Grimm, C. Puelacher, Z. Sabti, D.F. Widmer,
(2013) 4123. N. Schaerli, N. Kozhuharov, S. Shrestha, T. Burge, P. Machler, M. Buchi,
[71] A. Kumar, J. Sidhu, A. Goyal, J.W. Tsao, Alzheimer Disease, StatPearls Pub- K. Rentsch, O. Miro, B. Lopez, F.J. Martin-Sanchez, E. Rodriguez-Adrada,
lishing StatPearls Publishing LLC. Treasure Island (FL), 2020. B. Morawiec, D. Kawecki, E. Ganovska, J. Parenica, J. Lohrmann, A. Buser,
[72] A.S. Schachter, K.L. Davis, Dialogues Clin. Neurosci. 2 (2000) 91. D.I. Keller, S. Osswald, C. Mueller, Clin. Res. Cardiol. 106 (2017) 457.
[73] M.W. Bondi, E.C. Edmonds, D.P. Salmon, J. Int. Neuropsychol. Soc. 23 (2017) [120] S. Hasic, E. Kiseljakovic, R. Jadric, J. Radovanovic, M. Winterhalter-Jadric,
818. Bosn. J. Basic Med. Sci. 3 (2003) 41.
[74] L.G. Apostolova, Continuum (Minneap Minn) 22 (2016) 419. [121] Y. Freund, C. Chenevier-Gobeaux, P. Bonnet, Y.E. Claessens, J.C. Allo,
[75] J. Neugroschl, S. Wang, Mt. Sinai J. Med. 78 (2011) 596. B. Doumenc, F. Leumani, C. Cosson, B. Riou, P. Ray, Crit. Care 15 (2011) R147.
[76] J. Weller, A. Budson, F1000Res 7 (2018). [122] P. Garg, P. Morris, A.L. Fazlanie, S. Vijayan, B. Dancso, A.G. Dastidar, S. Plein,
[77] J. Rasmussen, H. Langerman, Degener. Neurol. Neuromuscul. Dis. 9 (2019) C. Mueller, P. Haaf, Intern Emerg Med 12 (2017) 147.
123. [123] M.K.M. Arshad, R. Adzhri, M.F.M. Fathil, S.C.B. Gopinath, M.N. N, J. Nanosci.
[78] M. Lee, J.P. Guo, K. Kennedy, E.G. McGeer, P.L. McGeer, J Alzheimers Dis 55 Nanotechnol. 18 (2018) 5283.
(2017) 1175. [124] T. Kong, R. Su, B. Zhang, Q. Zhang, G. Cheng, Biosens. Bioelectron. 34 (2012)
[79] J.C. Lee, S.J. Kim, S. Hong, Y. Kim, Exp. Mol. Med. 51 (2019) 1. 267.
[80] Y. Kutovyi, H. Hlukhova, N. Boichuk, M. Menger, A. Offenhausser, [125] Y. Pei-Wen, H. Che-Wei, H. Yu-Jie, C. Min-Cheng, L. Hsin-Hao, L. Shey-Shi,
S. Vitusevich, Biosens. Bioelectron. 154 (2020) 112053. L. Chih-Ting, Biosens. Bioelectron. 61 (2014) 112.
[81] R.L. Siegel, K.D. Miller, A. Jemal, CA cancer, J Clin 70 (2020) 7. [126] R. Elnathan, M. Kwiat, A. Pevzner, Y. Engel, L. Burstein, A. Khatchtourints,
[82] J.T. Loud, J. Murphy, Semin. Oncol. Nurs. 33 (2017) 121. A. Lichtenstein, R. Kantaev, F. Patolsky, Nano Lett. 12 (2012) 5245.
[83] J.D. Schiffman, P.G. Fisher, P. Gibbs, Am Soc Clin Oncol Educ Book (2015) 57. [127] S.I. Hay, C.A. Guerra, A.J. Tatem, A.M. Noor, R.W. Snow, Lancet Infect. Dis. 4
[84] S. Sarkar, G. Horn, K. Moulton, A. Oza, S. Byler, S. Kokolus, M. Longacre, Int. J. (2004) 327.
Mol. Sci. 14 (2013) 21087. [128] B. Autino, A. Noris, R. Russo, F. Castelli, Mediterr J Hematol Infect Dis 4
[85] E.R. Sauter, Eur. J. Breast Health 13 (2017) 162. (2012), e2012060.
[86] W.D. Hazelton, E.G. Luebeck, Sci. Transl. Med. 3 (2011) 109fs9. [129] A.R. Mawson, Pathog. Glob. Health 107 (2013) 122.
[87] T.O. Tobore, Future Sci. OA 6 (2019) FSO439. [130] D.D. Laishram, P.L. Sutton, N. Nanda, V.L. Sharma, R.C. Sobti, J.M. Carlton,
[88] N. Lu, A. Gao, P. Dai, S. Song, C. Fan, Y. Wang, T. Li, Small 10 (2014) 2022. H. Joshi, Malar. J. 11 (2012) 29.
[89] Z. Bao, J. Sun, X. Zhao, Z. Li, S. Cui, Q. Meng, Y. Zhang, T. Wang, Y. Jiang, Int. J. [131] B. Autino, Y. Corbett, F. Castelli, D. Taramelli, Mediterr J Hematol Infect Dis 4
Nanomed. 12 (2017) 4623. (2012), e2012061.
[90] A. Gao, X. Yang, J. Tong, L. Zhou, Y. Wang, J. Zhao, H. Mao, T. Li, Biosens. [132] K.P. Day, R.E. Hayward, M. Dyer, Parasitology 116 (Suppl) (1998) S95.
Bioelectron. 91 (2017) 482. [133] F. Castelli, L.R. Tomasoni, A. Matteelli, Mediterr J Hematol Infect Dis 4 (2012),
[91] A. Gao, N. Lu, Y. Wang, T. Li, Sci. Rep. 6 (2016). e2012064.
[92] D.S. Su, P.Y. Chen, H.C. Chiu, C.C. Han, T.J. Yen, H.M. Chen, Biosens. Bio- [134] K.V. Ragavan, S. Kumar, S. Swaraj, S. Neethirajan, Biosens. Bioelectron. 105
electron. 141 (2019) 111209. (2018) 188.
[93] S. Mirsian, A. Khodadadian, M. Hedayati, A. Manzour-Ol-Ajdad, [135] W. Ittarat, S. Chomean, C. Sanchomphu, N. Wangmaung, C. Promptmas,
R. Kalantarinejad, C. Heitzinger, Biosens. Bioelectron. 142 (2019) 111527. W. Ngrenngarmlert, Clin. Chim. Acta 419 (2013) 47.
[94] K.A. Malsagova, T.O. Pleshakova, A.F. Kozlov, I.D. Shumov, M.A. Ilnitskii, [136] F.D. Krampa, Y. Aniweh, P. Kanyong, G.A. Awandare, Sensors (Basel) 20
A.V. Miakonkikh, V.P. Popov, K.V. Rudenko, A.V. Glukhov, I.N. Kupriyanov, (2020).
N.D. Ivanova, A.E. Rogozhin, A.I. Archakov, Y.D. Ivanov, Biosensors (Basel) 8 [137] L. Varadi, J.L. Luo, D.E. Hibbs, J.D. Perry, R.J. Anderson, S. Orenga,
(2018). P.W. Groundwater, Chem. Soc. Rev. 46 (2017) 4818.
[95] Z. Bao, J. Sun, X. Zhao, Z. Li, S. Cui, Q. Meng, Y. Zhang, T. Wang, Y. Jiang, Int. J. [138] T.S. Murray, M.E. Groth, C. Weitzman, M. Cappello, Clin. Microbiol. Rev. 18
Nanomed. 12 (2017) 4623. (2005) 510.
[96] A. Gao, X. Yang, J. Tong, L. Zhou, Y. Wang, J. Zhao, H. Mao, T. Li, Biosens. [139] F. Fenollar, O. Mediannikov, New Microbes New Infect 26 (2018) S10.
Bioelectron. 91 (2017) 482. [140] E.J. Toone, Adv. Enzymol. Relat. Area Mol. Biol. 77 (2011) xi.
[97] N. Gao, T. Gao, X. Yang, X. Dai, W. Zhou, A. Zhang, C.M. Lieber, Proc. Natl. [141] E.L. Tsalik, R.A. Bonomo, V.G. Fowler Jr., Annu. Rev. Med. 69 (2018) 379.
Acad. Sci. U. S. A. 113 (2016) 14633. [142] N. Nikkhoo, N. Cumby, P.G. Gulak, K.L. Maxwell, PloS One 11 (2016),
[98] A. Gao, N. Lu, Y. Wang, T. Li, Sci. Rep. 6 (2016) 22554. e0162438.
[99] D.P. Tran, M.A. Winter, B. Wolfrum, R. Stockmann, C.T. Yang, M. Pourhassan- [143] M.B. Lerner, J. Dailey, B.R. Goldsmith, D. Brisson, A.T. Johnson, Biosens. Bio-
Moghaddam, A. Offenhausser, B. Thierry, ACS Nano 10 (2016) 2357. electron. 45 (2013) 163.
[100] H.C. Chen, Y.T. Chen, R.Y. Tsai, M.C. Chen, S.L. Chen, M.C. Xiao, C.L. Chen, [144] J. Wang, Nucleic Acids Res. 28 (2000) 3011.
M.Y. Hua, Biosens. Bioelectron. 66 (2015) 198. [145] F. Teles, L. Fonseca, Talanta 77 (2008) 606.
[101] N. Gao, W. Zhou, X. Jiang, G. Hong, T.M. Fu, C.M. Lieber, Nano Lett. 15 (2015) [146] J. Ping, R. Vishnubhotla, A. Vrudhula, A.T. Johnson, ACS Nano 10 (2016) 8700.
2143. [147] M. Kaisti, A. Kerko, E. Aarikka, P. Saviranta, Z. Boeva, T. Soukka,
[102] N. Lu, A. Gao, P. Dai, H. Mao, X. Zuo, C. Fan, Y. Wang, T. Li, Anal. Chem. 87 A. Lehmusvuori, Sci. Rep. 7 (2017) 15734.
(2015) 11203. [148] Z. Gao, H. Xia, J. Zauberman, M. Tomaiuolo, J. Ping, Q. Zhang, P. Ducos, H. Ye,
[103] D.P. Tran, B. Wolfrum, R. Stockmann, J.H. Pai, M. Pourhassan-Moghaddam, S. Wang, X. Yang, F. Lubna, Z. Luo, L. Ren, A.T.C. Johnson, Nano Lett. 18 (2018)
A. Offenhausser, B. Thierry, Anal. Chem. 87 (2015) 1662. 3509.
[104] Y. Zhang, R. Chen, L. Xu, Y. Ning, S. Xie, G.J. Zhang, Anal. Sci. 31 (2015) 73. [149] B. Veigas, E. Fortunato, P.V. Baptista, Sensors (Basel) 15 (2015) 10380.
[105] F. Zhou, Z. Li, Z. Bao, K. Feng, Y. Zhang, T. Wang, Scand. J. Clin. Lab. Invest. 75 [150] B.R. Li, C.C. Chen, U.R. Kumar, Y.T. Chen, Analyst 139 (2014) 1589.
(2015) 578. [151] W.P. Hu, C.C. Tsai, Y.S. Yang, H.W. Chan, W.Y. Chen, Sci. Rep. 8 (2018) 12598.
[106] H.C. Chen, J.T. Qiu, F.L. Yang, Y.C. Liu, M.C. Chen, R.Y. Tsai, H.W. Yang, C.Y. Lin, [152] M.T. Hwang, M. Heiranian, Y. Kim, S. You, J. Leem, A. Taqieddin, V. Faramarzi,
C.C. Lin, T.S. Wu, Y.M. Tu, M.C. Xiao, C.H. Ho, C.C. Huang, C.S. Lai, M.Y. Hua, Y. Jing, I. Park, A.M. van der Zande, S. Nam, N.R. Aluru, R. Bashir, Nat. Com-
Anal. Chem. 86 (2014) 9443. mun. 11 (2020).
[107] M. Lee, A. Baraket, N. Zine, M. Zabala, F. Campabadal, R. Caruso, M.G. Trivella, [153] C. Zheng, L. Huang, H. Zhang, Z. Sun, Z. Zhang, G.J. Zhang, ACS Appl. Mater.
N. Jaffrezic-Renault, A. Errachid, Methods Mol. Biol. 1172 (2014) 49. Interfaces 7 (2015) 16953.

15
D. Sadighbayan, M. Hasanzadeh and E. Ghafar-Zadeh Trends in Analytical Chemistry 133 (2020) 116067

[154] N. Lu, A. Gao, P. Dai, T. Li, Y. Wang, X. Gao, S. Song, C. Fan, Y. Wang, Methods [168] R. Ahmad, M.S. Ahn, Y.B. Hahn, J. Colloid Interface Sci. 498 (2017) 292.
63 (2013) 212. [169] N. Lu, P. Dai, A. Gao, J. Valiaho, P. Kallio, Y. Wang, T. Li, ACS Appl. Mater.
[155] G. Wenga, E. Jacques, A.C. Salaun, R. Rogel, L. Pichon, F. Geneste, Biosens. Interfaces 6 (2014) 20378.
Bioelectron. 40 (2013) 141. [170] K. Xu, X. Meshik, B.M. Nichols, E. Zakar, M. Dutta, M.A. Stroscio, Nanotech-
[156] G.C. Ferreira, M.C. McKenna, Neurochem. Res. 42 (2017) 1661. nology 25 (2014) 205501.
[157] J. Pekala, B. Patkowska-Sokola, R. Bodkowski, D. Jamroz, P. Nowakowski, [171] B.R. Li, C.W. Chen, W.L. Yang, T.Y. Lin, C.Y. Pan, Y.T. Chen, Biosens. Bio-
S. Lochynski, T. Librowski, Curr. Drug Metabol. 12 (2011) 667. electron. 45 (2013) 252.
[158] M. Zaidi, D. Lizneva, S.M. Kim, L. Sun, J. Iqbal, M.I. New, C.J. Rosen, T. Yuen, [172] A. Anand, C.R. Liu, A.C. Chou, W.H. Hsu, R.K. Ulaganathan, Y.C. Lin, C.A. Dai,
Endocrinology 159 (2018) 3503. F.G. Tseng, C.Y. Pan, Y.T. Chen, ACS Sens. 2 (2017) 69.
[159] E. Takeda, Y. Taketani, N. Sawada, T. Sato, H. Yamamoto, Biofactors 21 (2004) 345. [173] B.R. Li, Y.J. Hsieh, Y.X. Chen, Y.T. Chung, C.Y. Pan, Y.T. Chen, J. Am. Chem. Soc.
[160] P. Mergenthaler, U. Lindauer, G.A. Dienel, A. Meisel, Trends Neurosci. 36 135 (2013) 16034.
(2013) 587. [174] A. Susloparova, D. Koppenhofer, X.T. Vu, M. Weil, S. Ingebrandt, Biosens.
[161] M.R. Picciotto, M.J. Higley, Y.S. Mineur, Neuron 76 (2012) 116. Bioelectron. 40 (2013) 50.
[162] E.A. Ryan, J.R. Lakey, R.V. Rajotte, G.S. Korbutt, T. Kin, S. Imes, A. Rabinovitch, [175] J.H. Lim, J. Park, S. Hong, T.H. Park, Methods Mol. Biol. 1272 (2015) 189.
J.F. Elliott, D. Bigam, N.M. Kneteman, G.L. Warnock, I. Larsen, A.M. Shapiro, [176] A. Matsumoto, Y. Miyahara, Nanoscale 5 (2013) 10702.
Diabetes 50 (2001) 710. [177] S. Rollo, D. Rani, W. Olthuis, C. Pascual Garcia, Biophys Rev 11 (2019) 757.
[163] R. Mullur, Y.Y. Liu, G.A. Brent, Physiol. Rev. 94 (2014) 355. [178] S.A. Pullano, C.D. Critello, I. Mahbub, N.T. Tasneem, S. Shamsir, S.K. Islam,
[164] K.S. McKeating, A. Aube, J.F. Masson, Analyst 141 (2016) 429. M. Greco, A.S. Fiorillo, Sensors (Basel) 18 (2018).
[165] M. Lee, S. Palanisamy, B.H. Zhou, L.Y. Wang, C.Y. Chen, C.Y. Lee, S.F. Yuan, [179] A. Zhang, G. Zheng, C.M. Lieber, (2016) 255.
Y.M. Wang, ACS Appl. Mater. Interfaces 10 (2018) 36120. [180] K.S. Chang, C.J. Sun, P.L. Chiang, A.C. Chou, M.C. Lin, C. Liang, H.H. Hung,
[166] H. Yang, T. Sakata, Sensors (Basel) 19 (2019). Y.H. Yeh, C.D. Chen, C.Y. Pan, Y.T. Chen, Biosens. Bioelectron. 31 (2012)
[167] M.S. Andrianova, E.V. Kuznetsov, V.P. Grudtsov, A.E. Kuznetsov, Biosens. 137.
Bioelectron. 119 (2018) 48.

16