REVIEW

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Field-Effect Transistor-Based Biosensor for pH Sensing and

Mapping
Huihui Ren, Kun Liang, Dingwei Li, Yitong Chen, Yingjie Tang, Yan Wang, Fanfan Li,
Guolei Liu, and Bowen Zhu*

signaling, tumor growth, protein ac-

It is vital to acquire real-time pH signals with high resolution as pH variation tivity, DNA deprotection, and viral
can reflect important information regarding health status and physiological infection.[1–7] The regulation of pH in
environment. Field-effect transistor (FET)-based biosensors (bio-FETs), a kind the human body is crucial for maintain-
of potentiometric sensor, are being rapidly developed for pH detection due to ing a healthy balance in the biological
environments, which can reflect health,
their advantages of high sensitivity, low temperature dependence, and high physiological, and biological status of
portability. More importantly, the high scalability of bio-FETs renders them a person. The normal pH of the skin
applicable for achieving high spatial resolution in pH sensing. In this review surface of most human body sites is
paper, the design, operation principle, and critical characteristics of the acidic with pH value between 4.1 to 5.8,
FET-based pH sensor are introduced. Then, the recent progress in pH while an abnormal pH environment
demonstrates skin lesions, such as acne
mapping with FET sensor arrays, including static array where a sensor pixel is
vulgaris, irritant contact dermatitis, and
directly addressed by wiring, and active-matrix array where a sensor pixel is atopic dermatitis.[8–10] It is reported
accessed by additional switching FETs, is presented. Last, typical examples of that inflammatory skin diseases, itchy,
pH sensor arrays in biomedical applications, such as health monitoring and dry, and aged skin show increased skin
DNA sequencing and elongation are presented. pH.[8] In addition, dysregulated pH is
an adaptive feature of many cancers.
In the normal differentiated adult cell,
1. Introduction intracellular pH is ≈7.2, lower than
extracellular pH. However, most cancer cells have higher intracel-
pH, defined as the H+ activity in the aqueous solution, has lular pH of > 7.4 and a lower intracellular pH of ≈6.7–7.1.[5,11–13]
a profound impact on biomedical applications, including cell This “reversed” pH variation leads to a storm for cancer progres-
sion.
H. Ren, K. Liang, D. Li, Y. Chen, Y. Tang, Y. Wang, F. Li, G. Liu, B. Zhu It has also been reported that pH in normal and tumor cells
Key Laboratory of 3D Micro/Nano Fabrication and Characterization of are different. The hypoxic phenomenon is often obtained during
Zhejiang Province
the development of tumors, resulting in intracellular and extra-
School of Engineering
Westlake University cellular acidosis, which has been a trigger in the early stage of
Hangzhou 310024, China apoptosis.[14,15] It is found that many cellular processes and enzy-
E-mail: [email protected] matic reactions rely on pH. When the pH of body fluid decreases
H. Ren, Y. Chen, F. Li from 6.9 to 6.5, living cells are destroyed, potentially promoting
School of Materials Science and Engineering tumor formation.[16] Acidic environment has been proven to in-
Zhejiang University
Hangzhou 310027, China flame blood cells and lower oxygen levels, which can impair the
K. Liang, D. Li, Y. Tang, Y. Wang, G. Liu function of DNA and hinder the metabolic state of living cells,
College of Information Science and Electronic Engineering causing liver, sweat glands, and liver exhaustion.[17] pH is also
Zhejiang University central in other fields, such as environmental science, chemistry,
Hangzhou 310027, China agriculture, and food processing. Therefore, it is essential to ex-
B. Zhu ploit suitable technologies for accurate detection of pH.
Institute of Advanced Technology
Methods for monitoring pH with highly complex biological
Westlake Institute for Advanced Study
Hangzhou 310024, China systems; however, rely on situational restrictions and needs. Con-
sidering the importance and tight regulation of pH in biologi-
The ORCID identification number(s) for the author(s) of this article cal systems, pH sensors nowadays have attracted immense re-
can be found under https://doi.org/10.1002/adsr.202200098
search attention. Several approaches involving electronic sen-
© 2023 The Authors. Advanced Sensor Research published by
sors have been employed to record pH values, consisting of
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution License, which permits use, distribution capacitive, chemiresistive, amperometric, and potentiometric
and reproduction in any medium, provided the original work is properly technologies.[18] Besides, other transduction techniques, includ-
cited. ing optical, mass-sensitive, and cantilever-based pH sensors have
DOI: 10.1002/adsr.202200098 also been applied to determine pH.[19–21] In this review article,

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we focus on the potentiometric pH sensor strategy, whose de-

velopment has undergone considerable effort over the past few
decades.
Potentiometric sensors provide information about the analyte
in the electrolyte by recording the potential difference between
the two electrodes, that is, the potential difference between a
reference electrode and a working/sensing electrode. Typically,
Ag/AgCl electrode is one of the most popular references to pro-
vide stable potential relative to the working electrode. Ideally,
no current flows between the two electrodes during the elec-
trical measurements, establishing a local equilibrium with the
sensor interface.[22] Potentiometric sensors for pH recording are
widely spread on account of their advantages, including simplic-
ity, low-cost, excellent electrical performance, as well as real-time
monitoring. In addition, they are easy to integrate with read-
out circuits. In this regard, monitoring pH of human body flu-
ids has attracted increasing attention for promoting biomedical
applications.[23]
Field-effect transistor (FET)-based biosensors (bio-FETs), a
kind of potentiometric sensors, have been rapidly developed for
pH detection due to a milieu of advantages, including lower tem-
perature dependence, high portability and scalability, less bias Figure 1. Schematic illustration of pH sensor array including static and
at extreme pH, and significant durability, rendering it promis- active-matrix array as well as corresponding applications, such as periph-
ing for biomedical applications.[24–27] FET-based biosensor is a eral arterial disease (PAD), ischemia, e-skin, brain healthy management,
kind of FET where the conventional dielectric structure and gate high-throughput DNA sequencing, and elongation. Healthcare manage-
are replaced by sensitive membrane, reference electrode, and ment: Reproduced with permission.[29] Copyright 2015, American Chemi-
electrolyte.[25,28] Different from traditional electrical sensors in- cal Society. Reproduced with permission.[164] Copyright 2014, Wiley-VCH.
DNA sequencing and elongation: Reproduced with permission.[1] Copy-
volving redox reactions with certain electroactive species, bio- right 2022, American Association for the Advancement of Science. Re-
FETs depend on the effective charge of the binding biological an- produced with permission.[178] Copyright 2015, IEEE. Smart e-skin: Re-
alyte at the surface, which leads to the variation in effective carrier produced with permission.[39] Copyright 2022, American Association for
concentrations in the semiconductor channel through capacitive the Advancement of Science. Reproduced with permission.[154] Copyright
coupling.[29,30] By functionalizing bio-FET surface with a sensi- 2020, Wiley-VCH.
tive membrane, site binding event to targeted molecules such as
proton in electrolyte can be achieved. Thus, FET-based biosensor FET technologies lie at the heart of the sensor array, and there
could provide an excellent pH sensing platform. are high demands on the switch FET components’ performance
Recently, with breakthroughs in artificial intelligence, an in- when integrated into the active-matrix array. For instance, the sig-
telligent system is rapidly progressing, which needs pH sensor nal crosstalk issue between adjacent pixels and power consump-
arrays with the function of real-time collecting of data and trans- tion can be promoted by increasing current on/off ratio of FET. To
mitting it to the cloud serves for artificial intelligence and big achieve a fast readout of the detection pH signal, the FETs should
data analysis.[32] The rapid enhancement of intelligent systems exhibit high electrical performance, for example, high mobility.
has promoted the requirement for pH sensors from individual For a stable operation of the active-matrix array, the variation of
devices to sensor arrays with high spatiotemporal resolution, low the electrical characteristics needs to be suppressed, in which
power consumption, and improved performance. Sensor array threshold voltage is the core point. Herein, we present a review
adds new dimension to measurement, making it possible for spa- of the recent progress on FET-based biosensor array for pH map-
tiotemporal mapping of signals and real-time information feed- ping; discuss the basic information of FET-based pH sensors in-
back. cluding principle, device structure, and characteristics; empha-
FET-based pH sensor array can achieve real-time pH mapping size on the static and active-matrix array for pH mapping; and
with high sensitivity and resolution. So far, two sensor array tech- introduce their applications in healthcare management, high-
nologies, namely, static and active-matrix arrays, have been ex- throughput DNA sequencing, and elongation (Figure 1).
plored for pH sensor systems. The static array exhibits simple de-
sign and fabrication process but suffers from redundant driving
components and leading wires, as well as low device density.[31] 2. FET-Based Biosensor
As for active-matrix array, the individual pixel could be active ex-
clusively for the signal record, while other pixels are in the off 2.1. Device Principle
state, which is an effective approach to achieve accurate read-
out, less electrode wires, and improved spatiotemporal resolu- In 1970, P. Bergveld first proposed the ion sensitive FET (ISFET)
tion. The active-matrix array tenders a potential platform for in- based on metal oxide semiconductor FET (MOSFET) with the liq-
tegrating multi-sensing elements possessing high pixel density, uid gate replacing the metal gate electrode.[32] The typical device
equipping with intelligence system with enhanced functionality. structure of ISFET is depicted in Figure 2a, where the ISFET can

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Figure 2. Mechanism of FET-based biosensor for pH sensing. a) Schematic diagram of typical FET-based pH sensor. b) Electrolyte–insulator–
semiconductor model in electrical potential model. Reproduced with permission.[191] Copyright 2020, Elsevier. c) Site-binding model. Reproduced with
permission.[35] Copyright 2021, Wiley-VCH.

be converted into the bio-FET by modification of the sensing sur- tion and gate voltage is applied through the reference electrode,
face over the surface with specific receptor molecules. The poten- the threshold voltage for the bio-FET (VTH * ) is expressed by:
tial distribution and electrostatic interaction can be modulated by
the binding events referring to charged targets. ΦS QOX + QSS + QB
For the conventional MOSFET, when the device is operated in ∗
VTH = EREF − Ψ0 + 𝜒 sol − − + 2Φf (3)
q COX
the linear region, the equation of drain-to-source (Ids ) is given by:

[ ] Compared to Equation (2), the metal work function (ΦM ) is re-

W ( ) 1 placed by the voltage applied to the reference electrode (EREF ), 𝜒 sol
IDS = COX 𝜇 VG − VTH VD − VD2 (1)
L 2 is the dipole potential of the solution, which is often regarded as
a constant, and Ψ0 is the interfacial potential between the insula-
where COX is the insulator capacitance per unit area, μ is the car- tor and electrolyte, which varies with pH. In this case, if we apply
rier mobility in the channel, VG and VD represent the applied gate fixed VD and a suitable voltage in the reference (VREF ) simulta-
voltage and drain voltage, and L and W are the length and width neously, IDS is pH dependent. It is also essential to ensure that
of the FET, respectively. VTH is the threshold voltage, which can EREF remains constant during the measurement by choosing an
be expressed by: applicable reference electrode.
Considering that Ψ0 changes with proton concentration, the
concepts of the electrical double layer are needed to be discussed.
ΦM − ΦS QOX + QSS + QB Figure 2b shows ion distribution at the dielectric/solution in-
VTH = − + 2Φf (2) terface. There are surface hydroxyl groups in the gate dielectric
q COX
layer, which could adsorb anions and cations and create the net
charge on the surface. According to the Gouy–Chapman–Stern
where the (ΦM− ΦS ) represents the difference between the metal (GCS) model, most anions tend to be close to gate dielectric be-
work function (ΦM ) and semiconductor work function (ΦS ); QOX , cause cations are willing to keep their hydrated molecules.[33] The
QSS , and QB represent charge in the oxide layer, charge at the in- charged ions will present near the surface in an aqueous solu-
terface between oxide and semiconductor layers, and depletion tion environment. Thus, the route from the center of adsorbed
charge in semiconductor, respectively; and Φf is the fermi poten- charged ions to the surface is known as Inner Helmholtz Plane
tial. In the case of the bio-FET, as the gate is exposed to the solu- (IHP). The locus of centers from hydrate ions to IHP is called

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Outer Helmholtz Plan (OHP). The interfacial potential drop is 2.2. Mode of the Signal Acquisition of FET-Based Biosensor
owing to the GCS double layer at the insulator and electrolyte.
On the other hand, the theory of pH sensing is based on the Over the last a few decades, biosensors have gained much atten-
site-binding model, which can be described by potential distribu- tion owing to their well-characterized behaviors, which generally
tion at the electrolyte–insulator (E–I) interface.[34] Figure 2c illus- combine two basic components: biological recognition and trans-
trates the model of pH-induced surface charge states on the (3- ducer. The biosensor system can convert biological recognition
aminopropyl)triethoxysilane (APTES)-modified Al2 O3 /In2 O3 in- events, such as antigen-antibody binding, nucleic acid hybridiza-
terface. The potential difference at the E–I interface is generated tions, enzyme-substrate reactions, and ions response, directly
by the interaction of the insulating layer with ions in the elec- into detectable signals using bio-transducers. Recently, much at-
trolyte. The distance required for intermolecular chemical reac- tention has been paid to FET-based biosensor, a kind of bio-
tions can be carried out only at one molecular distance. However, transducer, due to its excellent sensitivity, miniaturization, and
salt ions will form hydrates with H2 O molecules in the electrolyte, portability.[36] The biological recognition information acquired
which cannot approach the E–I interface, and many sites appear from the sample corresponding to either analyte concentration
at the interface. These sites can only bind with hydrogen or hy- or activity can be transduced to electrical signals via bio-FETs.
droxyl groups. Thus, the existence of terminating group (hydroxyl Subsequently, the electrical signals can be illustrated, amplified,
group or amino group) on the gate insulator surface allows for post-processed, and displayed or sent to the data center for back-
deprotonation or protonation in various pH electrolyte environ- end applications (Figure 3a).[37]
ment, resulting in negative (high pH), neutral, or positive surface To demonstrate the mode of signal acquisition, it is impor-
charge (low pH). The total amount of surface charge (negative or tant to understand the operation mechanism of the FET-based
positive) will influence the dependence of the surface potential of biosensor. As depicted in Figure 3b, a typical FET-based biosen-
the bio-FET on the pH value in the electrolyte, depending on the sor is constructed, where the liquid gate electrode is away from
material properties, interface potential, and hydrogen ions near the dielectric with the intervening electrolyte.[38] The conductivity
the surface.[35] of the FET-based biosensor can be modulated by the electric po-
The equilibrium involves the surface hydroxyl group and the tential or charge density at the channel layer. The biological recog-
corresponding reaction: nition events upon the channel region facilitate the electric field
modulation of devices, which is analogous to change the gate volt-
A − OH ⇌ A − O− + H+B (4) age through the reference electrode. N-type device shows an im-
provement in conductance when binding biomolecules with pos-
and itive charges at the device surface owing to the accumulated elec-
trons in the channel region. However, p-type FET binding with
A − OH + H+B ⇌ A − OH+2 (5) molecules with positive charges will deplete the holes, resulting
in a corresponding decrease in conductance.
HB + are hydrogen ions near the interface. In this case, a
charged layer 𝜎 0 formed on the gate insulator surface. At the 2.3. Electrical Data Analysis
same time, an equal amount of reverse space charges 𝜎 dl are
induced in the solution, which could be explained by the GCS After obtaining a large amount of experimental data, it is essen-
model. The relationship between the pH at the surface interface tial to process the electrical data with appropriate analysis meth-
(HS + ) and bulk (HB + ) could be described by the following equa- ods. In this section, two approaches to analyze the relationship
tion: between the concentration of the analyte and device response will
be introduced. Figure 4a depicts the transfer curves (Ids −VAg/AgCl )
qΨ0
pHS = pHB + (6) of the bio-FET at various pH ranging from 3 to 10 with drain volt-
2.3kT age (Vds ) fixed at 0.05 V. In order to understand the relationship
between the response signal and pH, Ren et al. extracted thresh-
Therefore, the sensitivity (SV ) is defined as:
old voltage (Vth ) from the transfer curves of every pH value, which
𝜕Ψ0 is demonstrated in Figure 4b. As a result, the device illustrated a
SV = 𝜕pHB
= − 2.3kT
q
𝛼 (7) linear dependence between pH values and Vth with the linearity
of 99.7% and the sensitivity of 61.9 mV pH−1 (Figure 4c).[35] On
and the other hand, Wang et al. reported another analysis approach
to further calibrate FET responses, which is used to minimize
1
𝛼= 2.3kTCdiff
(8) the device-to-device variations.[24,39] Figure 4d shows the transfer
1+ 𝜕B curves in sweat samples at different concentrations of cortisol.
q2 𝜕pH
S
During the measurements, the drain voltage (Vds ) was fixed at
where 𝜎 is dimensionless sensitivity parameter, which changes 10 mV when sweeping the gate voltage (Vgs ). The calibrated re-
from 0 to 1; 𝜕pH 𝜕B
is the variation of net groups with the surface sponse (ΔV) was determined by absolute sensor response (ΔIds )
S and the variation in source-drain current with gate voltage sweep
pH; and Cdiff is differential double-layer capacitance. Assuming
𝜕B (dIds /dVgs ).[40] The equation is shown below:
that 𝜕pH is infinite, when the pHB changes, pHS remains original
S
state; at this time, 𝛼 = 1. The sensitivity reaches the Nernst limit ΔIds
Calibratedresponse(ΔV) = (9)
about 59.2 mVpH−1 at room temperature. dIds∕dVgs

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Figure 3. Mode of the signal acquisition for FET-based biosensor. a) Schematic setup of the biosensor, consisting of biological recognition events,
transducer, and electronic system. Reproduced with permission.[37] Copyright 2017, Elsevier. b) Operation schematic of the bio-FET. Reproduced with
permission.[38] Copyright 2015, IEEE.

Figure 4. Electrical data analysis for FET-based biosensor. a) Transfer curves of bio-FET at various pH ranging from 3 to 10. b) The method to extract
threshold voltage (Vth ). c) The linear relationship between the Vth and pH, showing excellent sensitivity and linearity. Reproduced with permission.[35]
Copyright 2021, Wiley-VCH (a–c). d) Transfer characteristics of device with different concentrations of cortisol. e) The approach to acquire the value of
calibrate response. f) Calibrated responses to cortisol concentrations for bio-FET functionalized with aptamer. Reproduced with permission.[39] Copyright
2022, American Association for the Advancement of Science (d-f).

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Figure 5. Basic architectures and materials for FET-based biosensor. a) Top-gated architecture with the bio-layer on the transistor channel. b) Top-gated
architecture with the bio-layer on the gate electrode. c) Side-gated FET-based biosensor. d) Double-gated architecture. e) Extend-gated architecture.
f–o) Typical semiconductor and corresponding devices of FET-based biosensor. 0D material (quantum dots) and quantum dots-based bio-FET (f,g).
Reproduced with permission.[53] Copyright 2022, American Chemical Society (f). Reproduced with permission.[54] Copyright 2020, American Chemical
Society (g). 1D material (nanowire) and corresponding bio-FET. Reproduced with permission.[56] Copyright 2021, American Association for the Advance-
ment of Science (h,i). 2D material (graphene) and corresponding device (j,k). Reproduced with permission.[64] Copyright 2009, American Association
for the Advancement of Science (j). Reproduced with permission.[62] Copyright 2013, American Chemical Society (k). Bulk material (thin film) and corre-
sponding sensor (m). Reproduced with permission.[35] Copyright 2021, Wiley-VCH (l,m). Hybrid material and corresponding bio-FET. Reproduced with
permission.[66] Copyright 2021, Springer Nature, Ltd. (n,o).

In this setup, the calibrated response was calculated when gate the separation of dry and liquid environments, where the device
voltage (Vgs ) was fixed at 200 mV (Figure 4e). Therefore, the re- isolates the electronics part (FET) from the electrolyte sensing
lationship between the calibrated response and cortisol concen- part, preventing possible ion corrosion and making the device
trations is obtained in Figure 4f, illustrating reduced device-to- more stable during long-term measurement.[49] The extended
device variations. gate geometry is commonly used to detect pH, extracellular ions
concentration, and enzyme-linked immunosorbent assay.[37,50] A
special architecture of dual-gate geometry with additional gate di-
2.4. FET-Based Biosensor Architectures electrics is shown in Figure 5d. The capacitive coupling of the two
gate dielectrics significantly enhances sensitivity, even surpass-
FET-based biosensors could be constructed to distinguish de- ing the Nernstian Limit (59 mV pH−1 ).
vice architecture, which depends on the sensing mechanism. As
shown in Figure 5a, the gate is positioned over the channel, where
the devices with sensing films placed on the top of the channel
layer are classical designs that can be used to monitor the prop- 2.5. Materials for FET-Based Biosensor
erties of cells, such as pH variation. Compared with other struc-
tures, it is deemed a convenient method by bio-functionalization An overview of typical semiconductor materials used for FET-
of semiconductor channels.[41–44] There is another design with a based biosensors is presented in this section, focusing on 0D, 1D,
top gate structure, where the sensing films are embedded on the and 2D, bulk, and hybrid materials. A comprehensive overview
gate electrodes, which is applicable for peptides, enzymes, anti- of these materials and correlated devices is shown in Figure 5.
bodies, and genomic probes (Figure 5b).[45] A third FET-based Considering the advantages of quantum dots (QDs) with low
biosensor architecture is the side-gate geometry, in which the cost, high biocompatibility, and ease of fabrication, QDs have
gate is placed in the same platform as the channel layer (Fig- been widely used in biosensing.[51,52] The TEM image of QDs
ure 5c).[46,47] It is commonly utilized in the neuromorphic ap- shows the aspherical nanoparticle morphology with uniformly
plication, where the biocompatible channel lies in direct contact distributed particles (Figure 5f).[53] Fan et al. introduced the QD-
with human tissue to record electrophysiological signals.[48] An- modified gating electrodes in a FET-based biosensor, demon-
other device structure is the extended gate, in which the sens- strating high sensitivity and selectivity (Figure 5g).[54] The sens-
ing electrolyte compartment extends off the FET chip (Figure 5e). ing mechanism of the device is that the coordination of QDs and
One of the main advantages of the extended gate configuration is analytes induces the change in capacitance of the double electri-

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cal layer close to the gate electrode, causing the shift in channel FET-based biosensor configuration. The operation of the FET-
current. based biosensor is determined by the bioreactions between the
It is commonly known that 1D nanowire has enhanced elec- recognition element modified on the device surface and analyte
trical performance, where the conductance of nanowire-based in the solution. The interaction will lead to either an increase
FETs could be restrained by changing channel density and or decrease in the transconductance of the device, which modu-
electric potential, making bio-FETs to be potential candidates lates the carriers transport of semiconductor layer.[67] Therefore,
for biosensing.[55] The transduction behavior in the nanowire- proper surface modification is imperative for enhancing both
based biosensor is similar to the planar sensor, except that the sensitivity and specificity of target detection, preventing interfer-
nanowire-based FETs have ballistic properties of small size with ing substance reactions and minimizing the noise. An essential
a bulk transport of carriers.[56] Thus, nanowire-based FETs, al- step in fabricating a FET-based biosensor device is to anchor a
lowing direct conversion of biological features such as binding, specific recognition group with highly specific binding affinities
enzymatic reactions, and charge transfer, ultimately lead to the to the analyte on the FET surface. Before that, the bifunctional
detection of biomolecular based on an effortless approach.[57] Fig- linker molecules providing binding sites are often utilized to help
ure 5h shows the SEM image of silicon nanowire, reported by Hu anchor the bioreceptor elements to the surface. The modification
et al. The prepared nanowire-based sensor has been proven to layer at the gate or channel surface may also electrically passivate
detect ions with single charge resolution. The events of emitting the device by changing local electrical field and refuse the other
and capturing a single hydrogen ion at the liquid/solid interface interactions of ions or non-specific molecules with the device
are directly recorded by sub-10 nm electrical double layer-gated surface.
nanowire-based bio-FETs (Figure 5i).[56] For silicon and metal-oxide surfaces, covalent modification
As the first case for exploration of graphene in 2004, cur- of the specific bioreceptors through chemical agents is com-
rently, researchers have developed a broad application of 2D monly used. Prior to surface modification, silicon and metal-
materials.[58] The 2D semiconductor materials with single-atom oxide surfaces are often treated with oxygen plasma or ultraviolet-
or few-atom thickness are commonly less than 5 nm, and the ozone (UV-O3 ), generating ─OH groups on the device sur-
lateral size ranges from sub-micrometers to centimeters.[59,60] face, which facilitates the reaction with chemical agents. In this
Graphene is one of the most heavily researched ones, whose lat- regard, organosilanes such as (3-aminopropyl)trimethoxysilane
tice is composed of six-membered rings and sp2 -hybridized car- (APTMS), APTES, and 3-(trimethoxysilyl)propyl aldehyde are
bons with a honeycomb structure (Figure 5j) and the basic struc- widely used. As shown in Figure 6a, a 1:9 (v/v) solution of
ture of 2D bio-FET is shown in Figure 5k.[61–64] The working prin- APTMS and propyltrimethoxysilane (PTMS) were incubated on
ciple of 2D bio-FET is the amplification effect of effective signal the surface by vapor deposition for 1 h at 40 °C.[68] 90% PTMS
transduction close to the 2D material surface. deposited on the SiNW surface not only adjusted to the den-
Bulk materials, such as metal oxide thin films typically serve as sity of APTMS to decrease the steric hindrance of following
sensing materials for pH sensors owing to their excellent chem- bioreceptors but also to prevent non-specific reactions by form-
ical resistance and mechanical strength. Previous reports for dif- ing a chemically insert surface. Functional linkers such as 3-
ferent metal oxides, such as In2 O3 , SnO2 , and PtO2 , have proven maleimidobenzoic acid N-hydroxysuccinimide ester (MBS) could
optimized pH sensitivity.[65] In these materials, hydroxy groups be subsequently reacted with APTES with the amine group,
are formed on the electrolyte’s sensing surface, followed by disso- and maleimide group introduced to incubate DNA-aptamer with
ciating, causing electrochemical equilibrium. Based on this equi- sulfhydryl group. On the other hand, phosphonic acids with
librium, the potential at the interface of solid and liquid is stable ─COOH groups are also available for metal-oxide or SiNWs cova-
and varies with the hydrogen ion concentration. Figure 5l shows lent binding.[69] Phosphonic acid-based modification is less sen-
the HRTEM image of the In2 O3 semiconductor layer and the cor- sitive to moisture and less self-condensing than organosilane
responding device for pH sensing is depicted in Figure 5m. The to facilitate storage and following reaction.[70] Figure 6b depicts
device offers a high sensitivity of 62.4 mV pH−1 with good linear- that In2 O3 , NWs have been modified by 3-phosphonopropionic
ity of 99.3%.[35] acid with ─COOH groups, which were subsequently activated us-
The hybrid structure, such as WSe2 /MoS2 heterostructure, tak- ing carbodiimide chemistry to covalently functionalize antibod-
ing advantage of the interface, exhibits excellent electrical per- ies with amino groups.[71] In the case of the Au surface, one of
formance. The hybrid structure-based device can modulate gate the most optimum linker molecules is the sulfhydryl compound,
transconductance by introducing a screening layer of the inter- such as cysteamine. As shown in Figure 6c, a self-assembled
face and channel charges. This enables super-Nernst pH sensitiv- monolayer of cysteamine with ─SH group was deposited on the
ity by decreasing effective back gate capacitance without improv- Au surface. Through a chemical linker (4-formylphenyl boronic
ing the sensor dimension.[66] Figure 5n shows the HRTEM image acid), biomolecule-like dopamine can successfully bind to device
of the WSe2 /MoS2 heterostructure, demonstrating excellent in- surface.[72]
terface quality. Bio-FET device with the WSe2 (top)/MoS2 (bottom) In addition, the noncovalent modification approach has been
vertical heterostructure is depicted in Figure 5o. widely used to functionalize bioreceptors. For example, 1-
pyrenebutyric acid N-hydroxysuccinimide ester (PASE) molecule
as the linker can noncovalently couple to graphene surface
2.6. Surface Modification for FET-Based Biosensor through 𝜋–𝜋 interactions. Subsequently, the spike S1 proteins are
deposited on the graphene surface through the reaction between
Besides sensing principle, device architectures, channel materi- the amine groups on spike S1 protein and hydroxyl-free succin-
als, and surface modification are also significant parameters in imide ester on PASE (Figure 6d). Different types of substances,

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Figure 6. Surface modification for FET-based biosensor. a) SiNWs surface of the covalent reaction with alkoxysilane derivatives, such as APTMS.
Reproduced with permission.[68] Copyright 2013, American Chemical Society. b) In2 O3 NW-based biosensor’s surface modification route involves 3-
phosphonopropionic acid deposition, carbodiimide chemistry activation, and antibodies incubation. Reproduced with permission.[71] Copyright 2005,
American Chemical Society. c) Reaction sequence for the functionalization of Au surface by a self-assembled monolayer of cysteamine with ─SH groups.
Reproduced with permission.[72] Copyright 2013, Elsevier. d) Schematic diagram of graphene-based biosensor. PASE molecules as the linker can
noncovalently couple to graphene surface through 𝜋–𝜋 interactions. Reproduced with permission.[192] Copyright 2021, American Chemical Society.
e,f) Hydrogel film with functional groups and ion selective membrane can be deposited on the device surface by non-covalent bonding. Reproduced
with permission.[67] Copyright 2023, Elsevier (e). Reproduced according to the terms of the CC BY license.[73] Copyright 2022, The authors, published
by MDPI (f).

such as hydrogel and ion-selective membrane, can also be non- a slower response time in the alkaline buffer compared to the
covalently modified on the device surface (Figure 6e,f).[67,73] acidic region. Libu et al. reported a potentiometric RuO2 –Ta2 O5
pH sensor measured in various pH solutions. They observed that
in the acid solution, the sensor shows a shorter response time
2.7. Characteristics of FET pH Sensor (less than 8 s) and slightly longer in the alkaline buffer (less than
15 s), which is related to H+ ions diffusion and dominant in the
In this section, we introduce the vital parameters such as stability, acidic buffer.[80] The response time performances of FET-based
response time, sensitivity, reproducibility, hysteresis, and drift, pH sensors based on different influencing factors are compared
which influence the sensing performance of bio-FETs. in Table 1.

2.7.1. Response Time 2.7.2. Stability

Response time is one of the most critical factors for poten- The stability of various FET-based sensors is one of the most cru-
tiometric sensors, regarded as the time required for its open cial features requiring continuous measurement or long incuba-
circuit potential (OCP) equilibrium.[74] Some factors influence tion. The devices often suffer from instability when operating in
the signal response time of the potentiometric sensor, includ- the liquid environment such as buffer solution, pure water, or di-
ing thickness, device structure, morphology, pore size, and pH rectly real biofluids, which makes it practically difficult to acquire
range. It is reported that improved surface area-to-volume ratios stable signals. The stability could be influenced by many param-
would reduce response time, owing to the biomolecule binding eters including channel materials, liquid gate electrodes, device
kinetics.[75] On the other hand, nanoscale geometric structure architecture, bias conditions, and pH level. As a result, in the pro-
facilitates great potential for device miniaturization, providing cess of creating biosensors, the transducers need to be adjusted
fast response time.[76] Channel materials with high capacitance, to guarantee their stability and multiple efforts have been taken
distinguished electrical conductivity, and low contact resistance to boost their stability.
will increase the electron transfer rate, resulting in dropping re- One of the current approaches to address the stability of FET-
sponse time. The response time of pH sensors also depends based biosensor focuses on choosing proper channel materials.
on the pH range during the measurement, where most sensors Metal-oxide based biosensor such as IrOx shows promising sta-
demonstrate a shorter time at low and high pH values but slower bility when immersed in various pH electrolytes for a long time.
in between.[74,77–79] Typically, the pH sensor sometimes depicts It illustrates a fast and stable response in corrosive, nonaqueous,

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Table 1. Summary of the response time for pH sensors.

Sensing material Fabrication method Reference material Response time [s] Ref.

ZnO Radio frequency sputter Ag/AgCl 240 [197]

ZnO nanorods Solvothermal route Au 150 [198]
SWCNTs functionalized with poly Dielectrophoresis (DEP) technique Ag/AgCl 3–7 [199]
(acrylic acid) (PAA)
RuO2 /Ta2 O5 Screen printing Ag/AgCl/KCl Acidic: <8 [80]
Basic: <15
RuO2 –SnO2 Screen printing Ag/AgCl/KCl Acidic to basic: <5 [200]
Basic to acidic: <9

or aqueous media.[18] However, most metal-oxide materials, such injection of defects from the solution to the insulator layer.[87]
as In2 O3 and ZnO always suffer from corrosion in liquid envi- The summarized solutions to ameliorate signal drift are: choos-
ronment with extremely high or low pH values, owing to their ing a suitable passivation layer to prevent ions in solution from
chemical instability, which results in a shift of the electric signal. the channel layer, designing special compensative readout cir-
Besides metal-oxide pH sensors, the conductive polymers cuits, and using the proper structure of the device with metal
with the ability of ion-exchanging serve well for developing pH oxide as the gate contact.[35,88,89] Signal drift behavior of insu-
sensors.[81] A popular polymer material is polyaniline (PANI). To lator films based bio-FET has been reported; According to Ren
evaluate the stability characteristics of PANI-based biosensors, et al., In2 O3 -based bio-FET after Al2 O3 deposition using solution-
Rahimi et al. immersed the devices into the various buffers at processed approach shows a low current drift (0.35 mV h−1 ), com-
pH 6, 7, and 8 at the sampling frequency of 1 Hz over 24 h.[82] pared to bared In2 O3 device (12.5 mV h−1 ), because Al2 O3 di-
There was no significant output voltage change during the first electric layer effectively passivates In2 O3 channel layer.[35] For 2D
5 h, and the total voltage change was less than 12 mV over 24 h bio-FETs with a high-k insulator layer, the trapping/de-trapping
monitoring, showing good stability at long time measurement. model of carriers from the channel at the high-k insulator oxide
However, the conducting and semiconducting polymer as active layer is the main reason for signal drift. Thus, the excellent qual-
channel materials would react with the molecular oxygen under ity sensing layer with low defects and ions diffusion is essential
the device operation, resulting in electrochemical side reactions. to achieve a low signal drift on 2D material-based bio-FET. Wei
Such side redox reactions can produce hydrogen peroxide (H2 O2 ) et al. depicted that extended gate (EG) ISFET with top gate molyb-
that may influence the device’ stability.[83] denum disulfide (MoS2 ) FET and EG Al2 O3 /h-BN sensing stack
In comparison, carbon-based materials such as carbon nan- with 5 nm Al2 O3 by ALD method provides a drift value of ≈4 mV
otubes gained much attention for pH sensing owing to their h−1 .[90] Another type of setup is FinFET in liquid gate configura-
high surface-to-volume ratio and environmental stability. How- tion. Rigante et al. reported a FinFET with 20 nm critical features,
ever, the stability performance of carbon nanotube-based bio- using HfO2 as gate dielectric and silicon nanowire as channel.
FETs always suffers from interference by the inhomogeneous in- The device showed excellent stability after 105 h test in the aque-
terface between carbon nanotubes and metallic source and drain ous environment at pH 6, where the single wire FinFET exhibited
electrodes.[84] a drift of 0.13 mV h−1 , a three-wire FinFET was 0.1 mV h−1 , and
In addition, most ISFET configurations and glass-based elec- a five-wire FinFET illustrated 0.12 mV h−1 .[91] The experimental
trodes exhibit poor long-term stability, while EGFET has demon- temperature also could change the drift, where signal drift was
strated better performance.[85] One often neglected issue in FET- obvious at the first few days and later became stable quickly if
based biosensors is the requirement for a proper reference the fixed temperature was relatively high. Table 2 illustrates the
electrode. The electrode should maintain a consistent potential influence of several paraments on stability, such as type of setup,
throughout the operation as any fluctuation could overshadow quality and composition of the sensing film, method of fabrica-
the real biological or chemical signals. tion, and reference materials.

2.7.3. Signal Drift 2.7.4. Hysteresis

Threshold voltage (VTH ) instability of nanomaterial-based poten- Hysteresis is a parameter to evaluate the devices’ reproducibility,
tiometric pH sensors, commonly known as drift, is another chal- which also limits the accuracy of the bio-FET during the measure-
lenge and has become one of the main factors for FET-based ment. While it is generally regarded as a memory effect, the de-
biosensors to be difficult to apply in the marketplace.[86] The drift vice will suffer from serious errors if not considered. The hystere-
is defined as the potential difference over time where the bio- sis behavior refers to the fluctuation of the corresponding current
FETs are immersed in the buffer of permanent pH value. Dif- performed by titration in both acidic and basic loops, which are
ferent factors affect the device drift, including electrochemical correlated with surface defects of interaction between the gate in-
non-equilibrium situation at the insulator/electrolyte interface, sulator and solution ions at the liquid/solid interface.[92,93] Three
ion diffusion at the gate insulator layer, slow surface effect, and possible reasons may influence the hysteresis: one is the design

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Table 2. Summary of the drift effect/stability for pH sensors.

Setup Sensing material Fabrication method Reference material Drift effect Ref.

Bio-FET Al2 O3 /In2 O3 Solution process Ag/AgCl pH 7.4: 0.35 mV h−1 over 1 h [35]
Bio-FET Indium tin oxide — Ti/Au/Ag/AgCl/PVB pH neutral: 1.7 mV h−1 over 8 h [185]
(ITO)/polyethylene
terephthalate
EGFET Al2 O3 /h-BN Atomic layer deposition Ag/AgCl pH 7.6: 4.0 mV h−1 over 600 s [90]
(ALD)
EGFET Aluminum-doped zinc Hydrothermal Ag/AgCl pH 7: 1.27 mV h−1 over 12 h [85]
oxide (AZO) growth/sputter
FinFET HfO2 /SiNW ALD Ag/AgCl pH 6: [91]
Single wire FinFET: 0.13 mV h−1
Three-wire FinFET: 0.10 mV h−1
Five-wire FinFET: 0.12 mV h−1 all over 105 h

Table 3. Summary of the hysteresis for FET-based pH sensors.

Sensing material Fabrication method Setup pH loop Hysteresis [mV] Ref.

Si3 N4 /SiO2 Low-pressure chemical vapor ISFET with periodic-groove channels 7–4–7–10–7 for 1500 s 16.0 [95]
deposition (LPCVD) (PG-ISFET)
SiO2 LPCVD Electrolyte–insulator–semiconductor 7–4–7–10–7 for 1500 s 9.0 [94]
(EIS)
APTES/SiO2 Immersion/thermal oxidation Bio-FET 7–4–7–10–7 for 1500 s 4.0 [97]
SnO2 Radio frequency sputter Bio-FET 7–2–7–12–7 for 1260, 2520, 6.0, 12.7, and 24.8 mV for 1260, [99]
and 5040 s 2520, and 5040 s
CuS/glass Solution process EGFET 7–4–7–10–7 for 300 s CuS/glass: 0.48 [201]
CuS/W CuS/W: 11.72
CuS/Si CuS/Si: 11.05

of a new structure device. There are abundant corners and side- tance of gate dielectrics. A sensor with high sensitivity is always
walls in the channel layer, where ions diffusing to the sensing desirable, and the possible solutions are presented for sensitivity
film constitute a high local electric field and forbid the ions to enhancement. The sensitivity can be improved by using a proper
close the surface.[94–96] In this case, the extraneous ions of the dielectric layer and modification of the semiconductors’ prop-
sensing film are dropping, resulting in improved hysteresis. An- erties. Nowadays, SiO2 , Ta2 O5 , Al2 O3 , Si3 N4 , HfO2 , and other
other is the “passivation” parameter, in which the passivation high-k dielectric as sensing layer have been used in ISFET. Al-
layer could safeguard the semiconductor channel from extrinsic though intensive studies have been applied to various materials,
ions to build up religious hysteresis. Compared to ISFET with their own drawbacks with signal drift, memory effect, and com-
30 nm SiO2 (−54 mV), hysteresis of device with APTES/SiO2 patibility with CMOS technology limit further application.[102,103]
stack-sensing membrane (21 mV) significantly improved, owing Considering the disadvantages of SiO2 films with low interface
to the well-ordered amino groups (−NH2 ).[97,98] The third one is states that are easy to be damaged by the ions in the solution,
“pH loop” factor. It was found that the hysteresis width in the multilayered sensing materials have been implanted in the de-
FET-based sensor is dependent on measurement pH loop time, vice. Meanwhile, high-k dielectric films such as HfO2 have gor-
where the hysteresis increases with the improvement of loop geous signal-to-noise ratios but suffer from non-ideal effects.
time.[99] On the other hand, post-processing of the measured sig- Conversely, Al2 O3 layers have strong power against non-ideal
nal by a given correction algorithm could also address the error performance.[104–106] Thus, Al2 O3 /HfO2 stacking sensing layer
from the hysteresis effect.[100,101] For comparison, Table 3 sum- achieves good sensitivity, enhanced chemical stability, and high
marizes the measured potential values for different pH loop val- output current owing to its rigid band structure.[107]
ues to demonstrate hysteresis width in different FET-based pH However, for traditional ISFET, the maximum achievable sen-
sensors. Hence, the hysteresis width strongly depends on the de- sitivity is 59 mV pH−1 due to the Nernstian limit, whereas DG-
vice configuration, pH measurement loop, and passivation. ISFET has overcome the situation of higher sensitivity beyond
the Nernstian limit tuned by transforming the capacitance of di-
2.7.5. Sensitivity electrics. The sensitivity of DGISFT relies on the surface elec-
trolyte capacity of the top gate (TG) and the dielectric layers’ cou-
Sensitivity is one of the most vital factors of FET-based sensors, pling constant.[108] Bae et al. reported a DGISFET for pH sensing,
which is determined by surface potential as well as the capaci- where Si was utilized as a semiconductor layer, SiO2 as the back

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Table 4. Summary of the sensitivity for FET-based biosensors.

Sensing material Fabrication method Setup pH range Sensitivity Ref.

ZnO Solution process EGFET 2–12 38 mV pH−1 [202]

Aluminum-doped ZnO (AZO) Hydrothermal growth / sputter EGFET 1–3 57.95 mV pH−1 [85]
Al2 O3 /HfO2 ALD Bio-FET 3–11 Al2 O3 : 54.7 mV pH−1 [107]
HfO2 :57.4 mV pH−1
Al2 O3 /HfO2 :57.1 mV pH−1
Ta2 O5 Electron-beam evaporation/dry Bio-FET 3–10 57 mV pH−1 [203]
oxygen atmosphere
Al2 O3 Solution process Double gate ISFET (DGISFET) 3–11 407 mV pH−1 [109]
PEDOT:PSS/poly (benzimida- Solution process Complementary inverter based — 2300 mV dec−1 [110]
zobenzophenanthroline) on OECT
(BBL)

Figure 7. Circuit schematics of static and active-matrix arrays. a) Schematic diagram of a conventional static array. b) The circuit schematic of an
active-matrix array consists of the switch FET and the sensor FET.

gate (BG), and Al2 O3 was regarded as TG as well as the sensing the active-matrix array shows enhanced functionality, in which
film. Compared to the single gate (SG) operation model (48 mV the active component in the array is referred to switch FET.[112]
pH−1 ), the sensitivity of the double gate (DG) was up to 407 mV The circuit schematic of the active-matrix array is shown in Fig-
pH−1 .[109] On the other hand, by integrating signal amplification, ure 7b, demonstrating diminutive cross-talk issue; simple read-
a complementary inverter based on OECTs illustrated an ultra- out circuit as well as less power consumption.[113–115] In addition,
high sensitivity of 2300 mV dec−1 , which overcame the funda- each individual cell of the active-matrix array can be controlled,
mental limit.[110] Table 4 summarizes the sensitivity of various leading to high spatiotemporal resolution. In terms of the wired
FET-based biosensors under different conditions. connection, the number of wires for N × N pixel active-matrix ar-
ray only needs 2N wires. As a result, compared to the static array,
active-matrix array has the advantage of minimizing the whole
3. FET-Based Biosensor Array Configurations size of the device due to the reduction of the number of load-
ing wires, which allows for higher device density. Therefore, the
FET-based biosensor array is an essential implement used to ac-
static and active-matrix arrays are inspiring approaches, which
quire biological electrochemical signals. The two main categories
have been developed for various biomedical fields such as bio-
of biosensor arrays are static and active-matrix geometry, making
electronics, sensors, actuators, memory, and electronic skins (e-
it possible for high-throughput data processing and image map-
skin) far beyond the display industry.[116,117]
ping. The schematic circuit diagram of the static array is shown in
Figure 7a, which is an approach by connecting the outputs of all
individual devices to each pixel for signal transmission. Each de- 3.1. Typical Fabrication Process for Array
vice is individually wired for multiple sensor arrays, so the load-
ing wired design requires N2 wires for an N × N array.[111] On During the past decades, the motivation for fabricating large-
the other hand, the active-matrix array consists of switch FET and area and high-definition sensor arrays has driven the develop-
sensor FET. By putting an active element in each cell of the device, ment of microfabrication technologies. Although many fabrica-

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tion toolkits in modern semiconductor techniques have been pro- hibits a magnified view of one chip containing four subgroups
posed, the low-cost and large-area manufacturing method is re- of six FET devices. The fabrication process is illustrated in Fig-
quired for applications.[118] Figure 8 illustrates the state-of-the-art ure 9b, in which 500 nm Si3 N4 is first deposited on silicon
sensor system fabrication approaches, including inkjet-printed substrate served as dielectric, followed by deposition patterned
technologies, direct light pattern strategy, and photolithography source and drain electrodes (5/45 nm Ti/Au) using photolithog-
method. raphy and e-beam evaporation. Then, the nanoribbon-sharped
In recent years, inkjet-printed technology has been exten- mask is defined by the photolithography step, and In2 O3 is de-
sively explored to fabricate sensor systems.[119–121] Different from posited by sputtering. Thus, In2 O3 nanoribbons are formed af-
traditional photolithography, inkjet-printed technology directly ter the lift-off process. After fabrication of multiple single de-
deposits patterned layers onto the substrates without complex vices on the same substrate by the above method, the static ar-
chemical processes and expensive instruments for construct- ray is created. Owing to the bind-site model, hydroxy groups on
ing the microelectronic device. Due to these advantages, inkjet- the In2 O3 nanoribbon film will deprotonate or protonate, which
printed technology has been employed to fabricate large-area could successfully detect pH value. In2 O3 nanoribbon FET ar-
sensor systems, and the fabrication process is shown in Fig- ray shows excellent sensitivity in both physiological pH rang-
ure 8a.[119] The direct light pattern is a resistance-free pattern- ing from 6.7 to 8.2 and a wide range between 4 to 9 with good
ing method where the semiconductor channel can be patterned long-term stability and uniform electrical performance. How-
through masks and deep ultraviolet (DUV) processing (Fig- ever, with the rapid development of precision medicine, design-
ure 8b). The source and drain electrode also could be evapo- ing flexible and wearable platform for continuous monitoring is
rated and deposited onto the substrate via the shadow masks, demanded.[26]
providing opportunities to obtain low-temperature and low-cost Flexible biosensor array is an intelligent electronic device
roll-to-roll printing of non-silicon-based devices. Low electrical worn on human bodies as an accessory.[127–131] Recent improve-
performance and high-temperature processing of devices, espe- ments in the microelectronics and biosensor domain offer the
cially for solution-based amorphous metal oxide semiconduc- possibility of employing wearable sensor arrays to continu-
tors, are among the most significant trade-off issues because ously monitor personal physical status without restricting user’s
high temperature is not suitable for roll-up, flexible, and confor- movement.[132–134] However, the wearable bio-FET array with the
mal electronics.[122] Here, direct light pattern technology provides function of detecting physiological signals remains a challenge.
the potential power to balance it. Although the direct light pat- To meet the requirements above, new flexible systems based on
tern and inkjet-printed strategies decrease multiple steps com- the FET biosensor array are introduced. Recently, a highly sen-
pared to the photolithographic process, they always suffer from sitive and conformal In2 O3 nanoribbon FET array was proposed
nonideal layer registration and low pattern resolution.[25,30] Pho- by Liu et al. Figure 9c depicts the flexible In2 O3 FET individual
tolithographic process is one of the leading fabrication strate- sensor array fabricated on polyethylene terephthalate (PET) sub-
gies for high-performance sensor systems. Figure 8c shows the strate with 5 × 5 cm, demonstrating the wearability and bendabil-
typical steps for photolithographic technology, in which the ma- ity of the device. The scanning electron microscope (SEM) image
terials are deposited on the whole surface and then etched to of an individual device exhibiting channel and electrode region is
form patterns with the assistance of photoresists.[123] Photolitho- shown in Figure 9d. The single In2 O3 nanoribbon device is fabri-
graphic technologies can achieve high-resolution patterns down cated following Aroonyadet et al., demonstrated in Figure 9b.[126]
to the nanometer scale, but the trade-off is needed to be con- The device reflects an improved conductivity when the pH value
sidered, including complicated instruments and multiple steps, of the buffer decreases (pH range from 10 to 5) because hydroxyl
such as spin-coating photoresists, light exposure, development, groups on the In2 O3 nanoribbon surface are protonated owing to
and stripping photoresists.[124,125] After repeating the photolitho- more H+ ions in the solution, which results in the positive gating
graphic process, the integrated device with excellent pattern reg- effect on semiconductor channel.
istration can be formed. Rim et al. also demonstrated a flexible static array on ultra-
thin polyimide (PI) films, and the schematic view of the array is
shown in Figure 9e.[29] First, the ultrathin PI films (2 μm) are
3.2. Static Array for pH Sensing spin-coated on glass substrates, followed by spin-coating In2 O3
films patterned by direct light pattern technology. The interdig-
Static arrays have advantages in terms of reducing measurement ital electrodes are deposited on the patterned In2 O3 films by e-
time and testing errors, as well as facilitating the analysis of ana- beam evaporation using shadow masks. Next, the prepared de-
lytes compared to the single device. The regulation of pH is vital vices are delaminated underwater; then, transferred to artificial
to keep a healthy balance in the biological environment for sus- polydimethylsiloxane (PDMS) substrate, where an ultrathin flex-
taining a lifestyle, which is the reason for dysfunction or severe ible PI-based array conformably contacts the PDMS. The cross-
disease within a physical system. Thus, the fundamental param- section view of the individual device is shown in Figure 9f, where
eter of pH is of significant interest in the biomedical domain. the device structure is bottom-gate and top-contact; meanwhile,
This section will focus on recent progress in pH sensing using In2 O3 serves as a semiconductor layer. This flexible array exhibits
the static array. good sensitivity with a linear range from 5.5 to 9.0, and the rate
Aroonyadet et al. reported a top–down fabricated In2 O3 of linear pH response is ≈8.6 ± 0.4 μA pH−1 .
nanoribbon FET sensor array using radio frequency (RF) Wearable sensing technology that detects biological signals
sputtering.[126] Figure 9a shows the wafer-scale photo of In2 O3 such as pH in human skin or biofluids provides specific person-
nanoribbon FET array with 100% yield, and the inset image ex- alized physiological and psychological information.[135,136] How-

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Figure 8. Flow diagram of typical fabrication processing to construct sensor system. a) Illustration of inkjet-printing technology. Reproduced with
permission.[119] Copyright 2021, Springer Nature, Ltd. b) Illustration of direct light pattern strategy. Reproduced with permission.[122] Copyright 2014,
American Chemical Society. c) Illustration of the photolithographic process. Reproduced with permission.[123] Copyright 2022, American Chemical So-
ciety.

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Figure 9. Summary of reported researchers for static arrays. a) Optical image of In2 O3 nanoribbon sensor array fabricated on a 3-in. wafer. Inset exhibits
a magnified image of four individual devices consisting of six nanoribbon devices. b) Fabrication process of In2 O3 nanoribbon device. Reproduced
with permission.[126] Copyright 2015, American Chemical Society (a,b). c) Photograph of flexible In2 O3 pH sensor array. d) SEM image of an individual
In2 O3 nanoribbon sensor (L/W = 500/25 μm). Scale bar is 1 cm. Reproduced with permission.[193] Copyright 2018, American Chemical Society (c,d).
e) The schematic image of the flexible In2 O3 array. f) Cross-section view of individual device. Reproduced with permission.[29] Copyright 2015, American
Chemical Society (e,f). g) Expanded image of the wearable sensing system in which the sensor array, microfluidic system, liquid crystal display (LCD),
and flexible printed circuit board (FPCB) components are integrated to form pH sensing smartwatch. h) Photography of the FET-based pH sensor
array with In2 O3 semiconductor layer based on a flexible polyimide substrate. i) Unknow pH solution compared by FET sensor array and the pH meter.
Reproduced with permission.[39] Copyright 2022, American Association for the Advancement of Science (g–i).

ever, the existing wearable system lacks the wireless and dy- posited to form source and drain electrodes. By functionaliz-
namic capabilities to capture physiological changes accurately ing with (3-aminopropyl) triethoxysilane (APTES) diluted with
and seamlessly. Owing to the weakness mentioned above, FET- trimethoxy(propyl)silane (PTMS) (1:9 v/v ratio), a pH-sensitive
based pH sensor is currently unavailable to advance personalized film is self-assembled on an In2 O3 channel, and pH can be suc-
precision medicine. Wang et al. designed a flexible In2 O3 FET cessfully detected through protonation/deprotonation of amine
array-based smartwatch equipped with a multichannel, custom, group in APTES, which changes the conductivity of semicon-
autonomous, and self-referencing measurement unit, achiev- ductor channel. Subsequently, the FET array is embedded in a
ing seamless and real-time data acquisition, where FET arrays thin-film microfluidic system and a liquid crystal display pow-
are modular and generalizable.[39] They could be straightfor- ered by a 110-mAh lithium battery to produce a skin-adherable
wardly applied in mobile and wearable formats for pH detec- “smartwatch” (Figure 9g). The device performs pH measure-
tion in sweat or body fluids. As shown in Figure 9h, thin- ments ranging from 4.6 to 7.6 via implementing calibrated re-
film In2 O3 is deposited on a flexible substrate (polyimide) via sponse method,[137] which shows a high linearity of 99%. As
the solution-processed method and then patterned by the pho- shown in Figure 9i, the pH value of the FET-based sensor is con-
tolithography approach. Interdigitated Ti/Au electrodes are de- siderably close to the pH meter with r = 0.999, P < 0.001.

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Figure 10. Summary of previous reports for active-matrix arrays. a) The layout of the 3600 × 3600 ISFET chip. b) The simplified illustration of an
individual ISFET. Reproduced with permission.[194] Copyright 2017, IEEE (a,b). c) A 256 × 256 implantable measurement setup for pH sensing.
d) Operating principle of a single device with two transistors by converting proton change in electrolyte to the electrical potential variation. Repro-
duced with permission.[195] Copyright 2019, IEEE (c,d). e) The cross-section view of individual ISFET structure for H+ , Na+ , K+ , and Ca2+ detection.
f) Ion mapping image including H+ , Na+ , K+ , and Ca2+ . Reproduced with permission.[145] Copyright 2020, American Chemical Society (e,f). g) Im-
age of pH sensor array based on packaged CMOS integrated circuit consisting of 64 × 64 = 4096 Al pads and 16 × 16 = 256 electrochemical cells.
Inset image is the magnified view of the individual cell consisting of an outer cathodic Pt ring electrode combined with four underlying Al pads, an
inner anodic Pt ring combined with another four Al pads, and a center OCP sensor with the circular Pt electrode combined with one underlying Al pad.
h) Principle of the device to produce acids and bases by oxidation–reduction reaction on the surface of chip. i) pH localization in an individual concentric
pixel, showing nonexplosive diffusion as time goes by. j) Array-wide pH localization for selected pixel. Reproduced with permission.[1] Copyright 2022,
American Association for the Advancement of Science (g–j). k) Schematic of 5 × 5 flexible active-matrix array consisting of IGZO switch FET and sensor
FET. l) Mapping image of pH distribution after dropping pH 2.5 solution to pH 6.5 mother liquor bath. Reproduced with permission.[154] Copyright
2020, Wiley-VCH (k,l).

3.3. Active-Matrix Array for pH Sensing in which the polysilicon gate is combined with the passivation
layer through the intermediate metal layer. Typically, Si3 N4 is a
Recently, the active-matrix array has attracted much attention in pH-sensitive film that prevents the metal top gate from the mea-
pH sensing, which allows individual and random access to each sured buffer and is highly sensitive to the analyte’s proton. Thus,
pixel with fast addressing speed and keeps a high device density the drain current and the threshold voltage of the device change
owing to shared electrode wires and active components.[138] The with various pH values. This active matrix-array achieves high
circuit diagram of the active-matrix array is shown in Figure 7b, pH sensitivity (73.56 mv pH−1 ), large-area (3600 × 3600), and
where the drain electrodes of each wire are connected to the data high-throughput (26 frame per s) properties, which have great
line, gate electrodes are coupled with a scan line, and source elec- potential in the biological application.
trodes are grounded. As the malfunction or breakdown of the in- While active-matrix sensor arrays for detecting in vitro electro-
dividual device will lead to an entire row or column failing, the physiology, such as pH, have been developed, signal recording
reliability requirements of the cross-point insulation, gate dielec- technology in vivo remains limited. The electrophysiological sig-
tric, and electrodes in the active-matrix array are needed to be nal recording methods based on neural interfacing devices, such
considerably improved than the static array as microelectrode array and multichannel probe array, have been
Ion-sensitive field-effect transistors (ISFETs) have gained ex- proposed for various biomedical applications.[139,140] In addition,
tensive research interests since their invention by Bergveld in an implantable neural recording probe has been employed as
1972. Cong et al. designed a 3600 × 3600-pixel ISFET array and formidable technology to monitor brain activities with high spa-
corresponding readout circuitry using a conventional 0.18 μm tiotemporal resolution.[141,142] However, the neuroimaging tools
CMOS process, which proposes a large-scale and dense pH sen- with a low spatial resolution for neurochemical detection, such as
sor array with a simple architecture. Figure 10a shows the layout protons, have limited the accurate measurement. An implantable
of the ISFET array chip, consisting of ISFET array and periph- 256 × 256 active-matrix array with an integrated readout circuitry
eral circuits. The extended gate ISFET is depicted in Figure 10b, for pH recording and imaging is reported by Lee et al. Figure 10c

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demonstrates the block diagram of the active-matrix array sys- arrays are noncapable of in situ regulation of pH by simulation
tem, where the 256 × 256-pixel arrays are integrated with the but only address the pH values. In addition, owing to the fast
readout circuit and the entire chips are 512 × 512 μm and 10.42 diffusion of protons in water, achieving pH localization by ar-
× 3.55 mm, respectively. The proposed sensor array structure is ray remains challenging.[148] In a traditional pH sensor array,
fabricated based on CMOS technology, including the deposition due to the diffusion effect, the pH values between pixels will
of Ta2 O5 as the ion-sensitive film. The critical point of this array affect each other; so, only the pH value of the whole solution
with the high resolution is achieved by employing two transis- can be measured, and the solution in each pixel cannot be ac-
tors (2-T) in each pixel circuit. This 2-T in-pixel structure makes curately localized.[149,150] Aside from these issues, few previous
it possible to reduce pixel pitch to 2 μm, which is smaller than studies have realized an on-chip pH sensor that can localize the
previous work using seven transistors.[143] Figure 10d shows the pH across the array in real time, except a pH indicator based on
cross-section view of a single pixel. The operation mechanism is a fluorescence approach with off-chip optics.[151] Here, Jung et al.
that the threshold voltage (VTH ) shift of the device changes with proposed a fully electrochemical and high-density array for pH lo-
different concentrations of hydrogen ions when the constant gate calization constructed on the CMOS microelectrode array.[1] As
voltage is applied to the reference electrode. VTH shifts mean that shown in Figure 10g, the CMOS integrated array consists of an
the potential depth beneath the sensing area changes, and these array of 64 × 64 = 4096 aluminum (Al) pads electrodes and an
vibrations are read out by the peripheral circuit. In order to re- electrochemical array of 16 × 16 = 256 cells with a single pad di-
alize the implantable function, the pixel array is willing to be on mension of 10.5 × 10.5 μm and a pad-to-pad pitch of 20 μm.[152]
the side near the edge. This sensor array could detect pH dis- Each pixel consists of an inner andic platinum (Pt) ring con-
tribution change during the inserting trials in brain-like objects nected to four underlying Al pads, as well as an outer cathodic
and then realize 2D image mapping in real-time measurement. Pt ring connected to another four underlying Al pads, arranged
Therefore, we confirm that the implemental active-matrix array in the concentric geometry, and also an open circuit potential
could visualize spatial pH distribution successfully. (OCP) sensor with a circular Pt electrode localized in the cen-
Although large-scale hydrogen ions mapping has been ter that connected to one underlying Al pad. The OCP sensor in
achieved, high-resolution, real-time, and simultaneous monitor- the device is regarded as a variant of ISFET with pH-sensing ca-
ing of multiple ions and image mapping using sensing learning pabilities. Each pixel can not only electrochemically produce pro-
are still challenges with existing spectrophotometric, chromato- tons with a positive stimulus current via the inner anodic ring
graphic, and potentiometric techniques.[144] Moser et al. designed but also electrochemically generate the basic wall with the neg-
an active-matrix array of 1024 ISFETs employing sensor-learning ative stimulus current via the outer cathodic ring, as well as a
technology to perform multi-functional mapping for concurrent central OCP sensor to monitor pH. The mechanism is depicted
detection of hydrogen, calcium, sodium, and potassium ions.[145] in Figure 10h, where the anodic Pt ring is applied to a positive
The ISFET array as the solid-state sensor is based on unmodi- current to oxidize 2,5-dimethyl-1,4-hydroquinone (H2 Q) into 2,5-
fied CMOS technology, eliminating the requirement for unique dimethyl-1,4-benzoquinone (Q) for generating protons, and the
fabrication processes while providing the advantages of scalable cathodic Pt ring is injected to the negative current to generate
and ease of integration.[146] The mechanism of the array is de- quinone dianions (Q2− ) and base molecules that could neutral-
pendent on the modulation of the threshold voltage by generat- ize protons. Thus, the base molecules produced by the outer ring
ing electric field when ions are bonded to the ion-sensitive mem- act as an electrochemical wall that limits the number of protons
brane. Analyte-specific ions sensitivity membrane is incubated generated from the inner ring, resulting in the pH being con-
on the surface of an ISFET array chip, which yields pixels with fined to the pixel and not diffusing. As shown in Figure 10i, an
quasi-Nernstian sensitivity to ions to train array and discriminate acidic pH of 5.26 is observed and remains within the pixel of cur-
species. Taking advantage of the pH sensitivity of Si3 N4 passiva- rent stimulation, while the pH measured outside the activated
tion film in CMOS technology, ISFET operation toward proton pixel is more than 7 during the stimulation, demonstrating that
sensing is demonstrated.[147] Then, the sensor learning of the IS- the pH inside the pixel maintains localized rather than bursting.
FET array depending on back-end offline algorithms is applied Figure 10j shows pH can be localized in any position and any
in the device to process data and generate a sensitivity matrix number of chosen pixels activated with the corresponding cur-
for accurate monitoring functions via ion mapping. Figure 10e rent.
shows the basic structure of the individual pixel emphasizing that Although there have been enormous efforts of active-matrix
both MOSFET and ISFET sensors can be integrated to the same arrays aimed at enhancing pixel density, device size, cross-talk is-
substrate. The device is based on standard CMOS technology us- sues, and electrical performance, the flexible sensor still needs to
ing the extended-gate method, consisting of extending the ISFET be considered due to the requirement of the Internet of Things
gate to the top metal through the vias. The sensing area is consid- (IoT) system.[153] Honda et al. designed a macroscale detachable
ered the top metal region that is combined with the solution via pH sensor array that consists of a reusable, flexible ISFET array
the passivation layer. As shown in Figure 10f, this 32 × 32 ISFET and a disposable flexible pH-sensitive membrane array through
array achieves real-time ions mapping, including H+ , K+ , Na+ , the flexible electrical connector, where ISFET is proposed to be
and Ca2+ . The notion of sensing learning based on offline train- extended gate geometry.[154] Figure 10k illustrates the optical im-
ing algorithms is also introduced to multi-functional ISFET array age of a flexible 5 × 5 pH sensor array, in which polyaniline
to accommodate the versatility through training the platform for (PANI) is employed for a flexible pH-sensitive membrane be-
acquiring more accurate mapping results. cause it has the capacity of low environment toxicity and can also
The pH sensor array, a potential platform for pH mapping, detect protons by protonation/deprotonation effect on its film.
has been extensively studied. However, most previously reported The reaction between PANI and protons serves as potential pro-

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duction, leading to a variation of the transistor potential because Figure 11a. The microneedles are fabricated with epoxy siloxane
PANI electrodes are combined with gate electrode through the polymer, showing excellent biocompatibility. The cross-section
flexible connectors. Thus, by observing the change of drain cur- view of the flexible microneedle pH sensor array is depicted in the
rent, the pH value of the buffer can be detected successfully. Fig- insect of Figure 11a, where the Au electrode is deposited on the
ure 10l shows the pH mapping results when adding a pH 2.5 device via a shadow mask and perylene serves as the passivation
solution into a pH 6.5 electrolyte bath after 6 s, demonstrating layer. To evaluate the pH values, Ag/AgCl and polyaniline (PANI)
that this flexible array offers a potential platform for flexible elec- are electrochemically deposited on the microneedle. The average
tronic domain. sensitivity of 5 × 5 pH sensor array is as high as 82 mV pH−1
after covering with poly(3-methoxypropyl acrylate) (PMC3A) that
is a kind of blood-compatible material, demonstrating large-area
4. Applications of pH Sensor Array sensitivity and high yield. Then, conformable microneedle pH
sensor array is used to monitor the dermal pH in a rat model
This section describes applications of relevant FET-based pH with PAD, to validate the biomedical application. To mimic PAD
sensor arrays in healthcare management, high-throughput DNA in the rat, the femoral artery is chosen to be ligated and the pH
elongation, and sequencing. The application proposed highlights value of the lower extremity is recorded one week after surgery
specific features of the pH sensor array. (Figure 11b). As shown in Figure 11c, the microneedle array ex-
hibits gradual pH variation of the lower extremity from the thigh
to the perineal region in a PAD rat model, while the control group
4.1. Healthcare shows a constant pH value over the whole recording area. The dis-
tal acidity is higher than the proximal region, demonstrating that
The pH regulation in the human body is critical to maintaining the damage of ischemic tissue is more abominable with incre-
a healthy balance in biological environments to sustain life. Vari- ment distal distance from obstructive lesions. Thus, this flexible
ations and disturbances in pH may predict dysfunction or dis- microneedle pH sensor array is a potential platform to provide
ease, including peripheral artery disease, ischemia, atheroscle- reliable data and timely treatments for patients.
rotic plaque development, tumor growth, cancerization, brain Another disease requiring intervention at an early stage is is-
dysfunction, and inflammation.[79,155–158] Nowadays, FET-based chemia. Ischemia is defined as the restriction in blood supply to
biosensor arrays are reported to predict the physiological alter- tissues, muscle groups or organs, especially the heart muscles,
ation mentioned above. Hence, long-term and continuous em- leading to the shortage of oxygen of cells that only generates ATP
ployment of a non-invasive FET-based pH sensor array could via glycolysis and creates H+ as the outgrowth, which impairs cel-
greatly help assess personal health and early disease prediction, lular metabolism. The accumulation of lactic acid explains this
allowing for timely and effective treatment. This part focuses on myocardial acidosis of cells during anaerobic glycolysis. These
pH regulation in healthcare management, specifically ischemia, electrophysiological changes are the electrical substrate for de-
peripheral artery disease, and brain health management. veloping ventricular arrhythmias, causing the high mortality as-
Peripheral arterial disease (PAD) is the third most common sociated with cardinal ischemia.[163] Instability in pH level is
atherosclerotic vascular disease, second only to stroke and coro- known to indicate the abnormality of metabolism, and it does al-
nary artery disease. It triples the risk of cardiovascular disease, low to assist clinicians by providing available cardiac information
leading to amputation in severe cases.[159] However, most pa- through the advanced implantable platform or specialized surgi-
tients with chronic or mild PAD do not experience uncomfort- cal tools.[164] However, it is hard to develop technology for record-
able clinical symptoms that make them unaware of the onset ing and addressing pH in cardiac due to its curvilinear shape,
or progression of the disease, where the PAD will induce dis- heterogeneous surface, and continuous chattering. Previous re-
rupted blood flow, causing ischemic symptoms such as intermit- search reports printed circuit board electrodes showing good sen-
tent claudication.[160] Although ankle-brachial index (ABI) with sitivity and repeatability in buffer solution; however, the electrical
high sensitivity and specificity provides effective monitoring, it is performance tends to fluctuate under in vivo animal models.[165]
unable to assess tissue damage caused by blood flow disturbances Besides, traditional pH sensor, such as glass electrodes are bulky,
and hypoxic injury.[161] As hypoxia enhances anaerobic glycolysis rigid and easy to break, thereby, difficult to be miniaturized for
causing lactic acidosis, observation of pH values can fully reflect application. Currently, Chung et al. have developed a confor-
tissue damage resulting from ischemic injury.[162] Thus, using mal matrix-addressed pH sensor array based on IrOx for record-
pH sensor array can effectively prevent PAD occurrence. How- ing the signals of cardiac ischemia-reperfusion.[164] The sens-
ever, there are disadvantages to the lack of accuracy of pH mon- ing setup divides into miniaturized sensor array and a reference
itoring in human skin owing to the presence of pollutants such electrode. The fabrication of devices exploits various techniques
as cosmetics, sweat, and oil contamination. In addition, skin with including conventional microfabrication, printing, and electro-
inflammation or infection will change the skin pH level, hamper- chemical approaches. Figure 11d shows the basic structure of a
ing accurate measurements.[8] The microneedle system is a great typical IrOx matrix where the magnified views in the lower state
candidate for satisfactory penetration, which can access dermal depict Au electrodes before and after electroplating IrOx . The sen-
sites, cover large skin areas without surgery, and record physio- sor arrays consist of Au traces encapsulated by polyimide (PI),
logical signals such as pH with high accuracy. Therefore, Lee et al. and the interconnections are designed by thin and filamentary
developed a flexible microneedle array for recording pH distribu- serpentine to reduce material strains during mechanical defor-
tion in rats of a PAD model. 5 × 5 flexible multipoint microneedle mation. Then, after employing transfer printing technology, the
pH sensor arrays fabricated on 15 μm-thick PDMS are shown in array can integrate onto the elastomer sheet or inflatable balloon

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Figure 11. Application of pH sensor arrays for healthcare management. a) Structural image of flexible pH array with microneedles. b) Optical image
of the operation performed with peripheral artery disease (PAD) model. Scale bar is 2.5 mm. c) Image demonstrates location and pH distribution with
pH sensor array in a PAD model rat. Reproduced with permission.[196] Copyright 2021, American Association for the Advancement of Science (a–c).
d) Photography of IrO2 pH sensor array fabricated on flexible substrate. e) Human right ventricular wedge in contact with pH array. f) Time against
pH curve with no-flow ischemia, reperfusion, and baseline. g) pH maps after 18 min of ischemia. Reproduced with permission.[164] Copyright 2014,
Wiley-VCH (d–g). h) Optical image of proton image sensor array consisting of sensor chip packaged with printed circuit board (PCB). i) Visual stimuli of
eight different directions, positioned 13 cm away from the eye of mice. j) Visibility of changes in pH by visual stimuli. Reproduced with permission.[167]
Copyright 2020, Springer Nature, Ltd (h–j).

catheter, following which IrOx layer is successfully deposited on of pH changes with brain function is increased under physio-
the Au electrodes by electrochemical method. The minimized logical and pathological conditions.[167] A 128 × 32 pixel proton
sensing area of 1 mm, sub-millimeter-scale arrays, and precision active-matrix sensor array applied for analyzing the brain in vivo
pH sensor distribution make it possible for in vivo testing. As is reported by Horiuchi et al. Figure 11h shows the photograph
IrOx is sensitive to pH, the device matrix array shows an average of complete proton active-matrix pH sensor array, consisting of a
sensitivity of 69.9 mV pH−1 with a linearity of 99.7% and a re- sensor chip integrated with printed circuit board (PCB), in which
sponse time as low as 0.5 s. The linear response of the device to the sensor chip is used to record pH variation and is combined
temperature is ≈1.6 mV C−1 , and minimal influence of the ex- with PCB by wire bonds passivated by black epoxy. The dimen-
tracellular ions is <3.5 mV. Figure 11e shows the IrOx -based pH sion of the sensing area in the sensor chip possesses a length
sensor arrays are tested on human right ventricle (RV) in open of 11.47 mm, a width of 1.76 mm, and a thickness of 0.1 mm.
circuit potential (OCP) configuration. Time against pH curve is The reduced scale of the sensor array minimizes the damage to
plotted in Figure 11f, indicating a decrease in pH from 7.4 to 6.55 surrounding brain tissues for living animals. The temporal and
during the cardiac ischemic episodes and the pH mapping result spatial resolution of the proton sensor array are 50 frames s−1
of array is shown in Figure 11g. and 23.55 × 23.55 um per pixel. The mechanism of the sensor
The regulation of pH level is also essential for the human brain array to detect proton concentration is based on chemical equi-
to maintain normal function. When the brain is in healthy status, librium in terms of Si3 N4 membrane that alters the surface po-
extracellular pH is maintained between 7.2 to 7.4, while intracel- tential at each cell.[168] The pH sensor array with high sensitivity
lular pH ranges from 6.8 to 7.0.[166] Besides, protons can directly (51.6 mV pH−1 ) and excellent spatial-temporal resolution is used
participate in neurotransmission, illustrating that the correlation to record localized pH change in the brain of live mouse, specif-

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Figure 12. Application of pH sensor arrays for high-throughput DNA sequencing and elongation. a,b) ISFET array for high-throughput DNA sequenc-
ing. c) Packaged array with molded fluidic lid to allow sequencing reagents. d) The mechanism of DNA sequencing. Reproduced with permission.[178]
Copyright 2015, IEEE (a). Reproduced with permission.[177] Copyright 2020, Springer Nature, Ltd (b–d). e,f) pH sensor array and mechanism for high-
throughput DNA elongation. g) The mapping results after Cy5-labeled ddATP incorporated into the deprotected substrate single-stranded DNA. Repro-
duced with permission.[1] Copyright 2022, American Association for the Advancement of Science (e–g).

ically in the primary visual cortex (VI) region. As shown in Fig- opened up new domains, including human genetics, infectious
ure 11i, the researchers evoke brain activity in the V1 of mouse by diseases, personal genomes, as well as ecological and cancer
visual stimulation, causing changes in pH and the visual stimuli studies.[172–176] Nowadays, researchers design a DNA sequenc-
consists of drifting gratings in different orientations. Figure 11j ing technique based on a low-cost and scalable semiconductor
shows the changes in pH caused by visual stimuli, in which di- fabrication technique in which the integrated circuit is engi-
verse spatial patterns of pH variations in V1 region of living mice neered to directly perform non-optical DNA sequencing of the
are observed in response to visual stimuli of eight drift gratings in genome.[177,178] The most widely used technology of the CMOS
different directions. These results illustrate that the sub-second process is employed to fabricate high-density and large-scale pro-
order temporal variation in brain pH can be observed by the pro- duction arrays. The device consists of ISFETs in perfect register
ton pH sensor array, and further confirm that pH change of the with plenty of wells, providing parallel and simultaneous inde-
array can reflect actual variation in brain pH. Thus, the pH sen- pendent sequencing. As shown in Figure 12a, each individual
sor array has potential to seek the relationship between different site pixel of the sensor array contains a primary FET-based sensor
pathologies and cellular pH dysfunction. aligned with the upper well so that the sensing areas of transistors
take up the majority of the bottom of the wells, and the adjacent
pixel select transistor is utilized to capture and for the readout
4.2. High-Throughput DNA Sequencing and Elongation sensor signal.[178,179] Figure 12b shows the array chips manufac-
tured on wafers, and the device passivated with a flow cell is de-
Massively parallel DNA sequencing has been one of the most picted in Figure 12c, in which fluid above the sensor is isolated
successful and widespread applications for pH sensor arrays, with the supporting electronics to protect electronics and offer
which has a profound impact on life science, biotechnology, fluidic sample loading during DNA sequencing.[177] The cross-
and medicine for a lower-cost and more scalable solution.[169–171] section image of the individual pixel of the array is shown in Fig-
The decrease in the time and cost of DNA sequencing has ure 12d, where each sensor element with an individual floating

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gate is connected to the underlying ISFET. The device with tan- a mild solution medium, applied to the storage and archiving of
talum oxide layer provides the sensitivity of 58 mV pH−1 . The DNA data, as well as providing access to numerous molecular
sequencing process starts when the DNA is cut up into millions biology tools.[181–184]
of fragments, and each fragment then attaches to its own bead.
These beads flow across the chip, depositing into the well. DNA
polymerase and sequencing primers are then bound to the tem-
5. Conclusion and Outlook
plate and pipetted into the loading port. Protons are released, a Recent advances in FET-based biosensor arrays for pH sens-
nucleotide is incorporated into the growing DNA strands, chang- ing, including static and active-matrix arrays, have been sum-
ing the pH of the solution in the wells. This induces a variation marized in this review. pH sensor array has received consider-
in the surface potential of the ISFET beneath the well, convert- able attention owing to its unique features and various applica-
ing pH into voltage. Thus, this voltage change is recorded, indi- tions. Nowadays, the developments of novel materials, promis-
cating that the nucleotide was incorporated. For example, cyto- ing device geometry, and semiconductor processing technology
sine is a polymerase of C nucleotide in DNA strand, if a comple- have led to virtual improvements in pH sensor arrays. In this
mentary G is present. If the nucleotide is not complementary to review, recent advances in pH sensor arrays are introduced, in-
the next base, there are no ions released, and no voltage changes cluding geometry design, working principle, advanced electrical
recorded. If there are two identical bases next to each other, two performance, and progressive applications. The structure con-
nucleotides are incorporated: the voltage doubles and the chip figurations of sensor arrays primarily consisting of static arrays
will record two identical bases . This process happens simultane- and active-matrix arrays are concluded above. The recent achieve-
ously in millions; that’s why it’s often described as a massively ments of pH sensor arrays with various mechanisms, structures,
parallel sequencing. The pH sensor platform is touched by cre- and fabrication processes are sorted out in this work. Differences
ating a direct connection between chemical and digital informa- between FET-based sensor arrays including static and active-
tion, providing a fast, simple, scalable sequencing solution that matrix array are demonstrated, where static arrays with simple
is less expensive and more reliable. fabrication approaches and lower cost always suffer from redun-
The second example employing pH sensor array is high dant driving components and leading wires, as well as low de-
throughout DNA elongation by the pH-regulated enzyme at vice density, while active-matrix array containing switch FET and
any selected cells. The utility of synthetic biology has yielded sensor FET has accurate readout, low power consumption, less
numerous chemical substitutes for natural DNA and RNA, electrode wires, high device density, and improved spatiotempo-
supporting the development of diagnostic and therapeutic ral resolution, but more complex craft and expensive technol-
applications.[180] Synthetic DNA is an attractive long-term date ogy. In addition, FET-based pH sensor arrays can be widely em-
storage medium owing to sustainability, longevity, density, and ployed in extensive domains due to the achievement of real-time
ease of replication.[181] The array provides the DNA synthe- pH mapping, including human healthcare management, high-
sis parallelism in which each sequence is elongated at any throughput DNA sequencing, and elongation. Thus, based on the
site simultaneously for high throughout DNA elongation. Jung unique intrinsic characteristics and structure geometries, FET-
et al. used pH sensor array to execute DNA elongation, com- based sensor arrays provide promising platforms to satisfy the
bining dideoxyadenosine triphosphate (ddATP) to the substrate requirements of human society.
of single-stranded DNA molecules by employing pH-regulated Despite the significant progresses that have been made in FET-
enzymes of chain-terminating nucleotides at any locations in based pH sensor array in real-time mapping, excellent sensitiv-
parallel.[1] The optical image of packaged sensor array featur- ity, large-area, and high-density integration to CMOS technol-
ing 64 × 64 = 4096 Al pads and 16 × 16 = 256 electrochemi- ogy, several factors in sensing characteristics are still required
cal cells, is shown in Figure 12f, and the detailed geometry and to be further considered for future advanced pH-sensing appli-
electrical performance were described previously (Figure 10g–j). cations:
As shown in Figure 12e, the substrate DNA molecules are in-
cubated on the glass ceiling, facing the sensor array with a dis- 1) Devices suffer from potential drift along with time, making it
tance of 14 μm. Only when the substrate DNA strands are de- challenging to acquire consistent potential, leading to insta-
protected in an acidic environment can they selectively incorpo- bility, which will be influenced by the passivation layer, test-
rate nucleotide molecules in solution. A local acidic microenvi- ing setup, reference electrode, sensing electrode material, and
ronment is created by applying an appropriate current to stim- fabrication method. Such issues could be addressed by using
ulate the sensor array to form a local pH of ≈5.5. Subsequently, EGFET configurations, which can separate the sensing layer
Cy5-labeled ddATP is added to the electrolyte, which could enzy- from the transistor and protect the device from electrolyte cor-
matically incorporate with deprotected DNA strands, where Cy5 rosion. Deposition of a high-k dielectric layer such as Al2 O3
is a kind of fluorescence pattern. As depicted in Figure 12g, after to the semiconductor layer can also improve long-term stabil-
enzymatic binding of Cy5-labeled ddATP to the selective depro- ity and signal drift.[35] In addition, results of alternative refer-
tection site, epifluorescence imaging demonstrating that fluores- ence electrode materials based on Ti/Au/Ag/AgCl show fur-
cence pattern (Figure 12g right) is identical to the random pixel ther improvements.[185]
activation (Figure 12g left), confirming that the nucleotides are 2) In addition to the challenge mentioned above, efficient sam-
incorporated with the spatial selectively deprotected sites by en- pling and interfaces between fluids and solid surfaces are vital
zyme and pH localized at the ceiling successfully. The highly par- in continuous health monitoring, ensuring high repeatability
allelized and densified pH-regulated enzymatic DNA elongation and preventing contamination.[186,187] Moreover, considering
may enable high-throughput synthesis of DNA enzymatically in that analyte concentration in the real sample is not as reliable

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as that of buffer, a simple purification approach is commonly Acknowledgements

adopted, requiring the device to resist contamination.
3) Fabrication of transparent, flexible, high-density, less cross- This work is supported by the National Natural Science Foundation of
China (Grant No. 62174138), the Westlake Multidisciplinary Research Ini-
talk, and the stable active-matrix array is challenging. Al- tiative Center (MRIC) Seed Fund (Grant No. MRIC20200101), and the
though ISFET array with high-integration is demonstrated by Leading Innovative and Entrepreneur Team Introduction Program of Zhe-
CMOS technology, the current CMOS fabricated process can- jiang (Grant No. 2020R01005). The authors thank Westlake Center for Mi-
not be applied to transparent and flexible substrates due to cro/Nano Fabrication, the Instrumentation and Service Center for Physical
the limitations of crafts. Static arrays with a more straightfor- Sciences (ISCPS), and the Instrumentation and Service Center for Molec-
ward process and low cost have been illustrated to acquire the ular Sciences (ISCMS) at Westlake University for the facility support and
technical assistance.
flexible device, but they suffer from low resolution. Consid-
ering that emerging IoT technologies require massive wear-
able sensor arrays, flexible and large-scale integrated device Conflict of Interest
platforms with low-cost fabrication methods should be inves-
tigated. A new approach, such as a solution-processed method The authors declare no conflict of interest.
using metal oxide semiconductors, has been proposed, which
makes it possible to achieve a flexible and transparent active-
Keywords
matrix array for pH sensing. At the same time, crosstalk prob-
lems are minimized. Owing to the complexity of techniques biomonitoring, biosensor arrays, field-effect transistors, healthcare, pH
and nonuniformity by spin coating, there are few available de- sensors
vices; thus, efforts need to be concentrated on addressing the
abovementioned issues. Received: December 15, 2022
Revised: February 13, 2023
4) The resolution of the array should be improved further, in-
Published online: March 3, 2023
cluding less response time, and higher temporal and spatial
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Huihui Ren received her B.S. degree in applied chemistry from the Zhejiang A&F University (China) in
2017. She obtained her M.S. degree in nano-chemistry in 2019 from the Gachon University, Korea. She
then joined Dr. Bowen Zhu’s research group and is currently pursuing her Ph.D. degree in materials
science and engineering at the Westlake University and Zhejiang University, China. Her research is
focused on thin-film transistors-based biosensors.

Bowen Zhu received his B.S. degree in chemistry from the Jilin University (China) in 2010. He obtained
his Ph.D. degree in materials science in 2016 from the Nanyang Technological University, Singapore.
After his postdoctoral training in the Department of Materials Science & Engineering, UCLA, he joined
the Monash University in 2017, Australia, as a Discovery Early Career Researcher Award (DECRA)
fellow. He joined the School of Engineering at Westlake University, China, as a Principal Investigator in
August 2019 and started his independent research career. His current research is focused on solution-
processed thin-film transistors for flexible active-matrix sensor arrays.

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