sensors

Review
Recent Progress on Semiconductor-Interface Facing
Clinical Biosensing
Mingrui Zhang 1 , Mitchell Adkins 2 and Zhe Wang 2, *

1 School of Engineering, University of Manchester, Manchester M13 9PL, UK;

[email protected]
2 Chemistry Department, Oakland University, Rochester, MI 48309, USA; [email protected]
* Correspondence: [email protected]; Tel.: +1-248-370-2086

Abstract: Semiconductor (SC)-based field-effect transistors (FETs) have been demonstrated as amaz-
ing enhancer gadgets due to their delicate interface towards surface adsorption. This leads to their
application as sensors and biosensors. Additionally, the semiconductor material has enormous
recognizable fixation extends, high affectability, high consistency for solid detecting, and the ability
to coordinate with other microfluidic gatherings. This review focused on current progress on the
semiconductor-interfaced FET biosensor through the fundamental interface structure of sensor design,
including inorganic semiconductor/aqueous interface, photoelectrochemical interface, nano-optical
interface, and metal-assisted interface. The works that also point to a further advancement for the
trademark properties mentioned have been reviewed here. The emergence of research on the organic
semiconductor interface, integrated biosensors with Complementary metal–oxide–semiconductor
(CMOS)-compatible, metal-organic frameworks, has accelerated the practical application of biosen-
sors. Through a solid request for research along with sensor application, it will have the option to



move forward the innovative sensor with the extraordinary semiconductor interface structure.



Citation: Zhang, M.; Adkins, M.; Keywords: biosensor; semiconductor; interface; nanomaterial; field-effect transistor
Wang, Z. Recent Progress on
Semiconductor-Interface Facing
Clinical Biosensing. Sensors 2021, 21,
3467. https://doi.org/10.3390/
1. Introduction
s21103467
The larger part of current biosensors are classified by four distinctive standards.
Academic Editor: Huangxian Ju
Refinement is a rule determined by affinity, catalytic, transmembrane, and cell sensors.
However, the transmembrane and cell sensors are based on affinity or catalytic standards
Received: 26 January 2021 as well. Current investigation and improvement has made strides in sensitivity, selectivity,
Accepted: 6 April 2021 and stability of biosensors. In particular, there is an expanding drift towards scaling down
Published: 16 May 2021 those spectrometers, chromatographs, and detectors, which are customarily utilized in
bioanalytical chemistry, by applying smaller scale- and nano-fabrication procedures. The
Publisher’s Note: MDPI stays neutral current biosensors are equipped with miniaturized instruments for clinical application
with regard to jurisdictional claims in which can be progressively hard to use and, in certain cases, this poses a major challenge,
published maps and institutional affil- especially, in the study of optical and electroanalytical biosensors. The clinical application
iations. of any sensor requires the utilization of total analytic frameworks and consequently inte-
gration with t sample handling, separation, and even sample conditioning. For designing
biosensors, the analysis takes place by coordinate conversion of biochemical information
to electronic signal through appropriate transducers and interface. There is a common bot-
Copyright: © 2021 by the authors. tleneck within the advancement of biosensors facing clinical applications that is deficient
Licensee MDPI, Basel, Switzerland. stability, reproducibility, and sensitivity of their interface properties within the complex
This article is an open access article clinical samples. Designing the interfaces is the key for next-generation biosensors. Due to
distributed under the terms and a large amount of electrical and optical transducers accessible in thin-film innovation, most
conditions of the Creative Commons improvements of innovative biosensors aim at the arrangement of a controlled interface
Attribution (CC BY) license (https:// structure in which the biomolecular units were organized and packed in a reproducible
creativecommons.org/licenses/by/ and controlled manner [1].
4.0/).

Sensors 2021, 21, 3467. https://doi.org/10.3390/s21103467 https://www.mdpi.com/journal/sensors

Sensors 2021, 21, 3467 2 of 25

Semiconductor-based field-effect transistors (FETs) have attracted critical consider-

ation because of their high delicate interface with fluids, which makes them viable as
biosensors [2]. A semiconductor additionally has a few qualities, for example, warm af-
fectability, photosensitivity, negative resistivity temperature, rectifiable, etc. In this manner,
semiconductor materials can be utilized for control gadgets, optoelectronic gadgets, pres-
sure sensors, thermoelectric refrigeration, and different applications other than assembling
enormous scale coordinated circuits. There are numerous orders for sensors, yet there
are two usually utilized groupings: one is arranged by the deliberate physical material
tested, the other is characterized by the working rule of sensors [3]. Sensors arranged by
estimated physical amounts are usually temperature sensor, moistness sensor, pressure
sensor, uprooting sensor, stream sensor, fluid level sensor, power sensor, speeding up
sensor, torque sensor, and so on [4–16].
Nanobiosensors dependent on semiconductor materials are appropriate for wear-
able biosensor applications on account of the speedy reaction time, enormous perceivable
fixation run, high affectability, high consistency for solid detecting, and the ability to coor-
dinate with other microfluidic and electronic useful groups. In particular, one-dimensional
(1D) nanomaterials have huge surface-to-volume proportions and tunable physical prop-
erties [17,18]. These qualities can be utilized to accomplish better execution over mass
materials in an assortment of utilizations, including hardware, optics and photonics, vitality
stockpiling and change gadgets, natural and concoction sensors, intracellular conveyance
of bioactive atoms, and restorative gadgets. To date, another class of natural semiconductor
gadgets functionalized by the quick ionic movement in the room temperature liquid salts
has been identified. This new sort of strong to-fluid interface is framed between natural
semi-conductor single precious stones and ionic fluids so that the structures fill in as quick
exchanging organic field-effect transistors (OFETs) with the most noteworthy transcon-
ductance gm = ID/VG per square channel sheet, i.e., the most proficient reaction of the
yield channel current ID to the information entryway voltage VG among the OFETs at
any point. OFETs are possible for cutting edge minimal effort de-indecencies that can be
created by straightforward manufacturing forms [19]. Be that as it may, performance is
constrained by the poor authority over the quantities of utilitarian nanowires present in
gadgets. Top-down systems experience the ill effects of significant gear and use costs. In
recent years, the interest for profoundly touchy and reusable biosensors has expanded
in light of the fact that the applications dependent on biosensors have evolved gotten
different, with the range including medicinal, rural, modern, and ecological fields [20].
Many review papers summarized a concessive overview on the recent achievements
regarding the implementation of a metal oxide semiconductor (MOS) in biosensors used in
biological and environmental systems [21–49]. So far there have been few works on the
point of view of the unique interface semiconductor formed to oversee its application in
the biosensor. The properties of FET sensors have been dramatically elevated by using the
new sensor structure design and novel surface engineering enabled the sensor functions.
In this review, we summarized the current progress on the semiconductor-based interface
for the biosensor facing the application under the clinical environment. Besides traditional
semiconductor/aqueous interfaces, the designs with new materials and fabrications in-
cluding metal-assisted sensing material, membrane-less interface, and ionic liquid-based
biosensor designs have been noted here (Scheme 1).
Sensors 2021, 21, 3467 3 of 25
Sensors 2021, 21, x FOR PEER REVIEW 3 of 28

Scheme 1.
Scheme 1. Summary
Summary framework
framework of
of interface
interface structure
structure for
for sensor
sensor development.
development.

2.
2. Current
CurrentProgress
ProgressSemiconductor
SemiconductorInterfaced-Based Field-Effect
Interfaced-Based Transistor
Field-Effect (FET) Biosensors
Transistor (FET) Bio-
sensors
2.1. Inorganic Semiconductor/Aqueous Interface
2.1. Inorganic
The many Semiconductor/Aqueous
pathways of enhancing Interface
the sensing characteristics of metal oxides and
metalThesulfide
many by pathways
optimizingofvarious
enhancingparameters, such characteristics
the sensing as synthesis methods,
of metalmorphology,
oxides and
composition,
metal sulfide by andoptimizing
structure, various
have been explored such
parameters, in theaslast 10 years.
synthesis For example,
methods, TiO2 ,
morphology,
ZnO, SnO
composition, 2 , and WO , has
and structure,
3 been presented based on several aspects: synthesis
have been explored in the last 10 years. For example, TiO method, mor-2,
phology, functionalizing molecules, detection target, and limit of
ZnO, SnO2, and WO3, has been presented based on several aspects: synthesis method, detection (LOD) [50–52].
Various developments
morphology, have been
functionalizing made regarding
molecules, detectionapplications
target, and of a metal
limit oxide semicon-
of detection (LOD)
ductor
[50–52].(MOS)-based biosensorshave
Various developments for environmental
been made regardingand biological systems.
applications The recent
of a metal oxide
developments
semiconductorhave been summarized
(MOS)-based biosensors byfor
theenvironmental
Enesca group and in a concessive overviewThe
biological systems. of
the applications of metal oxides [53]. This describes the optimization
recent developments have been summarized by the Enesca group in a concessive over- of certain parame-
ters
viewforof enhancing the sensing
the applications property
of metal oxidesof MOS.
[53]. The
This parameters
describes discussed include
the optimization the
of certain
method of synthesis, composition, structure, and morphology. Based
parameters for enhancing the sensing property of MOS. The parameters discussed include on the aspects such as
optimization of synthesis protocols, functionalizing agents, morphology,
the method of synthesis, composition, structure, and morphology. Based on the aspects target detection,
and
suchlimit of detection of
as optimization (LOD), the new
synthesis representative
protocols, metal oxides
functionalizing agents,including TiO2 , MoS
morphology, 2,
target
graphene, and WSe 2 with novel engineered methods are presented
detection, and limit of detection (LOD), the new representative metal oxides including in this work. For the
interface
TiO2, MoS characterization, X-ray photoelectron spectroscopy (XPS) and ultraviolet pho-
2, graphene, and WSe2 with novel engineered methods are presented in this
toelectron spectroscopy (UPS)
work. For the interface characterization,have beenX-raywidely used for investigating
photoelectron spectroscopy a wider
(XPS)range of
and ul-
organic–organic and metal–organic semiconductor interfaces [53].
traviolet photoelectron spectroscopy (UPS) have been widely used for investigating aHill et al. [54], reported
the
wideruserange
of UPS of for the determination
organic–organic of binding energies
and metal–organic associated
semiconductor with vacuum
interfaces level
[53]. Hill et
position and highest occupied molecular orbital. Furthermore, they used UPS confirmation
al. [54], reported the use of UPS for the determination of binding energies associated with
of possible chemical interaction that occurred at heterointerfaces. They found that most
vacuum level position and highest occupied molecular orbital. Furthermore, they used
organic–organic interfaces exhibited the aligned vacuum level (with some exceptions),
UPS confirmation of possible chemical interaction that occurred at heterointerfaces. They
while all metal–organic interfaces exhibited strong interface dipoles which were respon-
found that most organic–organic interfaces exhibited the aligned vacuum level (with some
sible for an abrupt offset of the vacuum level. Moreover, the presence of dipoles in the
exceptions), while all metal–organic interfaces exhibited strong interface dipoles which
metal–organic semiconductor interfaces where the Fermi level was completely unpinned
were responsible for an abrupt offset of the vacuum level. Moreover, the presence of di-
within the gaps of semiconductors. This suggested that dipoles were not dependent on
poles in the metal–organic semiconductor interfaces where the Fermi level was com-
emptying or populating Fermi level-pinning gap states [54].
pletely unpinned within the gaps of semiconductors. This suggested that dipoles were not
Here we summarize recent progress in this field with different engineering and
dependent on emptying or populating Fermi level-pinning gap states [54].
material aspects.
Here we summarize recent progress in this field with different engineering and ma-
terial Nanofabrication-Affiliated
2.1.1. aspects. FET
For the biosensor application, other than blood, other organic liquids are employed,
2.1.1. Nanofabrication-Affiliated FET
for example, sweat, tears, and spit likewise contain gigantic biochemical analytes that can
For the biosensor
give significant data and application, otherpromptly
are all the more than blood, other organic
available liquids
contrasted withare employed,
blood [55,56].
for example, sweat, tears, and spit likewise contain gigantic biochemical analytes
For PET-based biosensors, the entryway anode just needs to supply stable door inclination that can
give significant data and are all the more promptly available contrasted with
to the gadgets, which can be accomplished by an on-chip metal side cathode. For example,blood [55,56].
aFor PET-basedconformal
profoundly biosensors,In2the
O3entryway
nanoribbon anode
FETjust needs to
biosensor supply
with stable door
a completely inclination
coordinated
to the gadgets,
on-chip which
gold side canwhich
door, be accomplished by an on-chip
has been overlaid metal sidesurfaces,
onto different cathode.was
For example,
recently
a profoundly
exhibited conformal
[57–59]. They haveIn2Oadded
3 nanoribbon FET biosensor
side entryway exampleswith a source/channel
to the completely coordinated
shadow
on-chip
cover gold
and side
have door,awhich
utilized has been overlaid
5 µm ultra-flexible onto different
PET substrate and thesurfaces, wasshadow
subsequent recentlyveil
ex-
hibited [57–59]. They have added side entryway examples to the source/channel shadow
Sensors 2021, 21, 3467 4 of 25

was then overlaid onto the PET substrate for the accompanying metal statement. Moreover,
the chitosan ink was imprinted on PET In2 O3 and the source and channel cushions utilizing
an inkjet printing procedure. Also, the gold side door was utilized rather than the Ag/AgCl
anode which expands the means and difficulty creating this. For affirming the detecting
capacity of the biosensor the creators test the ionic affectability of the biosensor chip with a
gold side or an Ag/AgCl cathode by PH detecting test [60].

glucose oxidase
D − glucose + O2 −−−−−−−−→ gluconic acid + H2 O2 (1)

H2 O2 → O2 + 2H + + 2e− (2)

Nanostructured Arrays and Hierarchical Structure

In contrast to more traditional lithographical fabrication techniques, the template-
based monolayer colloid crystal synthesis was considered as the promising alternative
approach to the synthesis of microstructured and nanostructured arrays with varying mor-
phology [61–63]. Using these approaches, researchers have been able to develop 2D ordered
arrays including nanoring, nanoparticle, and pore arrays. In some cases, 1D nanostruc-
tures composed of the ordered nanorod, nanowire, and nanopillar arrays have also been
developed. By reviewing recent progress in this field, synthesis strategies and morphology-
related properties were presented as the association with these micro/nanostructured
arrays, including their wettability, optical properties, photonic bandgap, and surface-
enhanced Raman scattering [64].
The Johnson group report on the creation of a huge region In2 O3 nanoribbon exhibits
improved sensor properties, yet without utilizing bosses produced by means of electron
beam lithography (EBL) [65]. The gathering utilized high-definition digital versatile discs
(HD-DVD) for chemical lift-off lithography plasma-activated polydimethylsiloxane (CLL
PDMS) stamps. These stamps are reusable and can be utilized for rehashed, wafer-scale
CLL designing. Nuclear power micrographs of designed PDMS surfaces affirmed exact
replication of HD-DVD highlights with profundities of ~60 nm. Filtering electron mi-
croscopy of CLL-designed self-assembled monolayer (SAMs) affirmed the nearness of 1D
highlights (200 nm linewidths) over huge zones, coordinating those on the stamps. The
widths (~200 nm) and statures (~3 nm) of the metal oxide nanoribbons are the smallest, as
far as anyone is concerned, and created by means of top-down approaches. To assess the
exhibition of In2 O3 in gadgets, FETs were built in a base door, top-contact arrangement.
Three thousand to 200-nm-wide In2 O3 nanoribbon were consolidated into every FET de-
vice. This exhibited superior FETs created utilizing In2 O3 nanoribbons having transporter
mobilities up to 13.7 cm2 V−1 s−1 and on/off current proportions >10. These nanoribbon
FETs have comparable electronic properties to In2 O3 slim film transistors, however, they
have higher surface-to-volume proportions. The presentation of these gadgets, for exam-
ple, current on/off proportion, surpassed those recently detailed for 1D nanowire-based
gadgets manufactured by means of a base-up approach. The nanostructures, for example,
In2 O3 nanoribbons and others, will be helpful in nanoelectronics and biosensors. The
method shown here will empower these applications and require minimal effort, with
huge zone designing methodologies to empower an assortment of materials and structure
geometries in nanoelectronics [31].
Yang et al. [66] have discussed physical properties, rational growth, and integration of
nanowires using the previously reported results from their laboratory. They proposed that
vapor–solid-liquid (VLS) crystal growth mechanism can be used for controlling the growth
position, diameter, composition, and orientation of nanowires. These nanowires were also
investigated for their thermal stability and optical characteristic. They conclude that ZnO
nanowires having defined surfaces can particularly act as ultraviolet nanolasers at room
temperature. Furthermore, they reported the development of a novel microfluidic assisted
nanowire integration (MANI) method for hierarchically assembling the building blocks of
nanowires into desired functional systems and devices [66] (Figure 1).
2021, 21, x FOR PEER REVIEW 5 of 28

Sensors 2021, 21, 3467 5 of 25

assisted nanowire integration (MANI) method for hierarchically assembling the building
blocks of nanowires into desired functional systems and devices [66] (Figure 1).

Figure 1. (A) Target recycling and self-assembly amplification. Reprinted with permission from ref. [65]. 2018 American
Chemistry Society (B) The epitaxial growth of ZnO nanowires on the plane of a (110) sapphire substrate can be readily seen
Figure 1. (A) Target recycling and self-assembly amplification. Reprinted with permission from
by examination of the crystal structures of ZnO and sapphire). Reprinted with permission from ref. [66]. 2002 Wiley-VCH.
ref. [65]. 2018 American Chemistry Society (B) The epitaxial growth of ZnO nanowires on the
plane of a (110) Graphene
sapphire substrate can beField-Effect
Engineered readily seen Biosensors
by examination of the crystal structures of
ZnO and sapphire). Reprinted with permission from ref. [66]. 2002 Wiley-VCH.
Due to its special nanostructure, excellent optical and electrical properties, and good
biocompatibility,
Graphene Engineered Field-Effect graphene has rapidly become a hot material in biosensor research and has
Biosensors
successfully detected a variety of small biological molecules, DNA, enzymes, proteins, and
Due to its special nanostructure, excellent optical and electrical properties, and good
cells. Detecting DNA hybridization is critically dependent upon the scalable production of
biocompatibility, graphene has rapidly become a hot material in biosensor research and
all-electronic DNA biosensors. The current developed fabrication approach enables the
has successfully detected a variety of small biological molecules, DNA, enzymes, proteins,
production of label-free DNA biosensors in a highly reproducible and scalable manner with
and cells. Detecting
>90% DNA yield. hybridization
These biosensors is critically
were baseddependent upon the field-effect
upon graphene scalable produc- transistors (GFETs)
tion of all-electronic DNA biosensors. The current developed fabrication
that had been functionalized using single-stranded probe DNA. GFET approach enables
sensor Dirac point
the productionvoltage
of label-free
variedDNA biosensors
in proportion toin a highly
target DNA reproducible
concentrations andon scalable manner
these biosensors, which had
with >90% yield. a 1 fMThese
limitbiosensors
of detectionwere based DNA
for 60-mer upon oligonucleotides.
graphene field-effect transistorsconfirmed that
It additionally
(GFETs) that had been functionalized
mismatch using single-stranded
positioning altered the strength of DNA probehybridization
DNA. GFET sensor in their Di-control studies.
rac point voltage varied in proportion to target DNA concentrations on these
Overall, these highly sensitive DNA biosensors offer promise as an approach to rapidly biosensors,
which had a 1 andfM limit of detection
accurately detectingfor 60-mer DNA oligonucleotides.
DNA hybridization It additionally
and cost-effectively con- sequencing.
conducting
firmed that mismatch positioning altered the strength of DNA hybridization
Johnson’s group [65] reported a method to overcome the length-dependent in their con- property
trol studies. Overall, these DNA
of the GFET highlycorrosivity
sensitive DNA sensorbiosensors
which depends offer promise as an approach
on single-strand DNA testing. The test
to rapidly andshowed
accuratelythat detecting
comparedDNA with thehybridization and cost-effectively
traditional single-strand conducting
DNA testing, the clasp DNA test-
sequencing. ing has a higher specificity for incomplete DNA. A large area of graphene (10 cm × 15 cm)
Johnson’swasgroup [65] reported
incorporated a method
into the copper to overcome
foil through the the
length-dependent
low-pressure mixing property smoke affidavit
of the GFET DNA corrosivity sensor which depends on single-strand
and transferred to the Si/SiO2 substrate through the recently manufactured DNA testing. The Cr/Au an-
test showed that ode.compared
GFET DNA withwasthe traditional
functionalized single-strand
by incubationDNA testing, the clasp
with 1-pyrene DNA acid (base) in
butyric
testing has a higher specificity for incomplete
N, N-dimethylformamide (DMF). DNA.AfterA functionalization,
large area of graphene GFETs (10were
cm ×incubated
15 with a
cm) was incorporated
water sample into the copper
array foil through
of aminated DNA the low-pressure
fragments. mixing
Barrette testsmoke
DNA isaffida-
metastable and can
vit and transferred to the explicitly
be opened Si/SiO2 substrate through
by the target DNA,the thus
recently manufactured
triggering Cr/Au an- reaction. In
the self-aggregation
ode. GFET DNA thewas
sodiumfunctionalized
citrate (SSC) byhybrid
incubation with
vector, GFET1-pyrene butyric
biosensor acid (base)
clusters in N, with known
were mixed
N-dimethylformamide
target DNA (DMF).
in theAfter functionalization,
presence of H 2, H 3, and GFETs were
H 4 (all incubated
with with a of
a convergence wa- 1 µm), and I-Vg
ter sample arrayproperties
of aminated wereDNA estimated in theBarrette
fragments. dry state.testTo explain
DNA the factors
is metastable and of can
self-polymerization
be
opened explicitlyamplification,
by the target a scientific
DNA, thus model is established,
triggering which reflectsreaction.
the self-aggregation the key biochemical
In the reaction,
sodium citratewhich
(SSC) connects the target
hybrid vector, GFET DNA oligomer
biosensor to thewere
clusters start mixed
of an amplification
with known reaction tar- mediated
get DNA in the bypresence
cycling H1 of Hand2, H2.
H 3,The
andmodel
H 4 (allalso
withanticipates that exploratory
a convergence of 1 μm), and dose-response
I-Vg bending
is an element of incubation time: at low targets (fm-run),
properties were estimated in the dry state. To explain the factors of self-polymerization considering that the target DNA
reused will open additional H1 bands over time, thus
amplification, a scientific model is established, which reflects the key biochemical reac- increasing the number of H1 · H2
· H3 · H4
tion, which connects thebuildings,
target DNA it isoligomer
expectedto that
theDirac
start voltage movement will
of an amplification develop if the test
reaction
is conducted
mediated by cycling H1 and in aH2.
longer
The time
model (>1also
h). The model is
anticipates expected
that to be approved
exploratory dose-re- temporarily.
sponse bending Under
is an the same of
element experimental
incubation conditions,
time: at lowthe incubation
targets timeconsidering
(fm-run), was extended thatto 100 h instead
of 1 h by three methods (100 pm, 100 fM, 100 am).
the target DNA reused will open additional H1 bands over time, thus increasing the num- The biosensor was immersed in 1 h
ber of H1 · H2 · H3 · H4 buildings, it is expected that Dirac voltage movement will develop fM, 100 am),
and the polymerization degree was 100 PM. For the lower focal length (100
the reaction will gradually expand after a while. To verify the feasibility of identification
methods based on target reuse and self-aggregation enhancement, GFET experiments were
carried out on some positive controls [65,67] (Figure 2).
Sensors 2021, 21, x FOR PEER REVIEW 6 of 28

if the test is conducted in a longer time (>1 h). The model is expected to be approved tem-
porarily. Under the same experimental conditions, the incubation time was extended to
Sensors 2021, 21, 3467 6 of 25
100 h instead of 1 h by three methods (100 pm, 100 fM, 100 am). The biosensor was im-
mersed in 1 h and the polymerization degree was 100 PM. For the lower focal length (100
fM, 100 am), the reaction will gradually expand after a while. To verify the feasibility of
identification methods based on target reuse and self-aggregation enhancement, GFET
By contrast with the above work, the Long group developed a GFET biosensor that
experiments were carried out on some positive controls [65,67](Figure 2).
could be used to detect alanine aminotransferase (ALT) under a low operative voltage
By contrast with the above work, the Long group developed a GFET biosensor that
could be usedintoadetect
singlealanine
reaction step. Chemical
aminotransferase (ALT)vapor
underdeposition
a low operativewas voltage
used toinfabricate this device
using large-area thin graphene films. The resultant
a single reaction step. Chemical vapor deposition was used to fabricate this device biosensors operated
using with a 0.1 V drain
voltage and − 0.1 to 0.3 V sweep gate voltage and
large-area thin graphene films. The resultant biosensors operated with a 0.1 V drain volt-exhibited significant pH sensitivity
age and −0.1 (23.12
to 0.3 VmV/pH),
sweep gate a low hysteresis
voltage voltage
and exhibited (1.2 mV),
significant pH and a small
sensitivity drift rate (4.74 mV/h).
(23.12
mV/pH), a low The authorsvoltage
hysteresis were able to successfully
(1.2 mV), and a small detect ALT
drift rate (4.74based
mV/h). upon the hybrid configuration of
The authors
were able to successfully
l-alanine and detect ALT based upon
α-ketoglutarate the hybrid configuration
immobilized on the grapheneof l-alanine and
membrane, achieving good
α-ketoglutarate linearity (R2 = 0.99)
immobilized on theingraphene
the 10–100 membrane,
U/L ALT achieving good linearity
concentration range. (R 2 =
Detection of cancer in its
0.99) in the 10–100
early U/L ALT
stages isconcentration
associated with range. Detection
better patientof cancer
outcomes,in its and
earlymiRNAs
stages is represent excellent
associated with better patient
biomarkers thatoutcomes, and miRNAs
can be leveraged for represent
early-stage excellent
cancerbiomarkers
detection that
[68].
can be leveraged for early-stage cancer detection [68].
The Zhang group designed a gold nanoparticle (AuNP)-decorated GFET biosensor
The Zhang group designed a gold nanoparticle (AuNP)-decorated GFET biosensor
that was able to accurately, sensitively, and selectively detect specific miRNAs in a label-free
that was able to accurately, sensitively, and selectively detect specific miRNAs in a label-
free manner. manner. This was
This biosensor biosensor wasvia
fabricated fabricated via adrop-casting
drop-casting reduced graphene a reduced graphene oxide (R-GO)
oxide (R-
GO) suspension onto a sensor surface, after which AuNPs were applied to this R-GO sur-to this R-GO surface.
suspension onto a sensor surface, after which AuNPs were applied
face. Next, a Next,
peptide a peptide nucleic
nucleic acid (PNA) acid (PNA)
probe was probe
affixedwas affixed
to this AuNPtosurface,
this AuNP
and surface, and PNA-
PNA-miRNAmiRNA hybridization
hybridization was thenwas usedthen
as aused
meansas of
a means
detectingof detecting
miRNAs inmiRNAssample in sample solutions.
solutions. This This biosensor
biosensor had ahad
10 fM a 10 fM
limit of limit of detection
detection and was able andtowas able to
effectively effectively differentiate
differ-
entiate between target target
between miRNAs of interest,
miRNAs miRNAsmiRNAs
of interest, bearing abearing
single mismatched base,
a single mismatched base, and non-
and non-complementary
complementary miRNAs.miRNAs.The authors were able
The authors to use
were ablethis
tobiosensor to detect to detect miRNAs
use this biosensor
miRNAs in serum in serumsamples while maintaining
samples while maintaininghigh sensitivity and selectivity,
high sensitivity andunderscor-
selectivity, underscoring the
ing the diagnostic
diagnostic potential of these biosensors for the detection ofcancer
potential of these biosensors for the detection of early-stage and
early-stage cancer and other
other diseases associated with miRNA dysregulation [69].
diseases associated with miRNA dysregulation [69].

Figure 2. (A) (a) Schematic of DNA biosensor based upon a graphene field-effect transistor funct-ionalized with comple-
mentary probe DNA. (b) Raman spectrum of the channel region of a graphene field-effect transistor (GFET) after processing.
Inset: Optical micrograph of an array of 52 GFETs. (c) I-Vg characteristics for an array of 52 GFET devices showing excellent
reproducibility. (d) Histogram of the Dirac voltage extracted from the I-Vg characteristics of the panel (b) along with
a Gaussian fit to the data (red curve) [70]. Reprinted with permission from ref. [67]. 2016 American Chemistry Society.
(B) Biosensor response to positive and negative controls. (a) Relative Dirac voltage shifts for various positive control
experiments based upon concentrations of 1 µm for the target DNA and the specified helper DNAs. (b) Relative Dirac
voltage shifts for 10 nm target DNA and negative controls with base mismatches at the ends; detailed DNA sequences are
listed in Table S1. Error bars are the standard deviation of the mean. Helper DNAs were 1 µm. Reprinted with permission
from ref. [65]. 2018 American Chemistry Society.
 with a Gaussian fit to the data (red curve) [70]. Reprinted with permission from ref. [67]. 2016
American Chemistry Society. (B) Biosensor response to positive and negative controls. (a) Relative
Dirac voltage shifts for various positive control experiments based upon concentrations of 1 μm
for the target DNA and the specified helper DNAs. (b) Relative Dirac voltage shifts for 10 nm tar-
get DNA and negative controls with base mismatches at the ends; detailed DNA sequences are
Sensors 2021, 21, 3467 7 of 25
listed in Table S1. Error bars are the standard deviation of the mean. Helper DNAs were 1 μm.
Reprinted with permission from ref. [65]. 2018 American Chemistry Society

MoS22 Nano-Interface
MoS Nano-Interface
Typically,
Typically, bulkbulk 3D
3D structures
structures of of FET
FET biosensors
biosensors presented
presented thethe low
low sensitivity,
sensitivity, which
which
could be overcome by using 1D or 2D structures (nanotubes/nanowires),
could be overcome by using 1D or 2D structures (nanotubes/nanowires), the latter face the latter face
severe fabrication challenges, impairing their practical applications As mentioned
severe fabrication challenges, impairing their practical applications. As mentioned above, above,
graphene is
graphene is aa promising
promising 2D 2D material
material for
for biosensors, currently,MoS
biosensors, currently, MoS22-based
-based FET
FET biosensors
biosensors
were reported
were reported the the compatible
compatiblesensitivity
sensitivityof ofthat
thatbased
basedon ongraphene.
graphene. MoS advantageous
MoS22 is advantageous
scaling without
for biosensor device scaling without compromising
compromising its its sensitivity.
sensitivity. Additionally,
Additionally, MoS
MoS22 is
is
highly flexible and transparent which offers opportunities in medical prostheses.
highly flexible and transparent which offers opportunities in medical prostheses. Moreover, Moreo-
ver,theoretical
the the theoretical analysis
analysis demonstrated
demonstrated thatthat
MoSMoS 2 was
2 was highly
highly advantageous
advantageous in biosen-
in biosensor
sor device
device scaling
scaling without
without altering
altering its sensitivity
its sensitivity and capability
and capability for single
for single molecular
molecular de-
detection.
tection.
The The concluded
authors authors concluded that the
that the high high flexibility
flexibility and transparent
and transparent nature of nature of MoS
MoS2 could be2
could be exploited
exploited for severalfor several
novel novel opportunities
opportunities in the fieldin
ofthe field ofand
diagnosis diagnosis
medicaland medical
prostheses.
The results show
prostheses. that a show
The results combination of these unique
that a combination characteristics
of these makes MoS2 makes
unique characteristics an ex-
tremely
MoS2 an extremely potential candidate for the fabrication of low-cost next-generation[71]
potential candidate for the fabrication of low-cost next-generation biosensors bi-
(Figure
osensors3).[71] (Figure 3).

Morphological and
Figure 3. Morphological and structural
structuralevolution
evolutionof ofisolated
isolatedmonolayer
monolayerMoSMoS crystalswith
2 2crystals withdifferent
differ-
ent dissolution
dissolution times
times in phosphate-buffered
in phosphate-buffered saline
saline (PBS)solution.
(PBS) solution. An
An image
image ofof an
anAPCVD-grown
APCVD-grown
polycrystalline monolayer
polycrystalline monolayer MoSMoS22crystal
crystalon
ona aSU-8/sapphire
SU-8/sapphire substrate, showing
substrate, showing the the
distribution
distribution
regions. (b) Schematic illustration of the MoS2 GB marked in the dotted box of (a) before and after
regions. (b) Schematic illustration of the MoS2 GB marked in the dotted box of (a) before and after
dissolution in PBS solution. (c–e) OM (c), Raman A1g intensity mapping (d), and atomic force mi-
dissolution in PBS solution. (c–e) OM (c), Raman A1g intensity mapping (d), and atomic force
croscopy (AFM) (e) images of monolayer MoS2 crystals, immersed in a PBS solution (pH 7.4) at 75
microscopy (AFM)
°C with different (e) images
dissolution of monolayer
times (0–8 days) MoS 2 crystals,
[. Reprinted immersed
with in afrom
permission PBS ref.
solution (pH 7.4)
[71]. 2019
at 75 ◦ C with different dissolution times (0–8 days) [. Reprinted with permission from ref. [71].
Springer.
2019 Springer.

To uncover the science and concoction energy of disintegration of monolayer MoS2

in a phosphate-buffered saline (PBS) arrangement, the Chen bunch originally explored
secluded precious stones with few grain limits. The general end is that the disintegration
of monolayer MoS2 precious stones in PBS happens as an imperfection actuated scratching
process. In this work, the disintegration qualities and conduct of both confined precious
stones and constant movies of CVD-developed monolayer MoS2 in PBS arrangements
at different temperatures and with various pH levels. Chen’s collective studied the cy-
totoxicity of MoS2 during the disintegration process, using the starting material of the
continuous film, the separated chip, and the pre decomposition in a PBS arrangement,
and then analyzed the long-range biocompatibility of MoS2 membrane in vitro. As well
as the non-toxic nature of instantaneous MoS2 bioelectronics, the rationality of its long-
term use in the human body is recommended. These findings of the biocompatibility and
 process. In this work, the disintegration qualities and conduct of both confined precious
stones and constant movies of CVD-developed monolayer MoS2 in PBS arrangements at
different temperatures and with various pH levels. Chen’s collective studied the cytotox-
icity of MoS2 during the disintegration process, using the starting material of the continu-
Sensors 2021, 21, 3467 ous film, the separated chip, and the pre decomposition in a PBS arrangement, and then 8 of 25
analyzed the long-range biocompatibility of MoS2 membrane in vitro. As well as the non-
toxic nature of instantaneous MoS2 bioelectronics, the rationality of its long-term use in
the human body is recommended. These findings of the biocompatibility and bioabsorb-
bioabsorbability
ability of MoS2 make of MoS 2 makein
it applied it implantable
applied in implantable and short biomedical
and short biomedical sensors. Chen sensors.
col-
Chen collected and described many MoS -based bioabsorbable sensors,
lected and described many MoS2-based bioabsorbable sensors, which are used to accu-
2 which are used
to accurately
rately estimate estimate weight, temperature,
weight, temperature, strain,
strain, and andThe
motion. motion.
sensorsThe sensors implanted
implanted in the in-
in the intracranial space of the biological model (mouse) allow displaying
tracranial space of the biological model (mouse) allow displaying the important theutilization
important
utilization
methods of methods
observing of patients
observinginpatients in the rehabilitation
the rehabilitation period
period after after amental
a terrible terribleinjury.
mental
injury.
The The show
results resultsthat
showthethat the results
results of continuous
of continuous in vivoinexamination
vivo examination and traditional
and traditional small
small tools of organic markers by fully bioabsorbable sensors
tools of organic markers by fully bioabsorbable sensors (Figure 4). (Figure 4).

Figure 4. Optical images of a MoS2 -based bioabsorbable sensor implanted in a rat together with a
Figure 4. Optical
commercial one images of aafter
before and MoSsuture.
2-based Reprinted
bioabsorbable
withsensor implanted
permission from in
ref.a [71].
rat together with a
2019 Springer.
commercial one before and after suture. Reprinted with permission from ref. [71]. 2019 Springer.
The Banerjee group has demonstrated FET biosensors based on 2D molybdenum
disulfide (MoS2 ), group
The Banerjee which hasprovides high sensitivity
demonstrated and easy based
FET biosensors patternability. The MoS2 -based
on 2D molybdenum di-
pH sensor can achieve sensitivity as high as 713 for a pH change by
sulfide (MoS2), which provides high sensitivity and easy patternability. The MoS2-based 1 unit. Specific protein
sensing
pH sensoriscan
achieved
achievewith a sensitivity
sensitivity as highofas196,
713even
for a at
pH100 femtomolar
change by 1 unit.concentration
Specific protein[26].
According
sensing to the Banerjee
is achieved group, FETs
with a sensitivity ofbased on 3D
196, even at structures
100 femtomolar are associated with lower
concentration [26].
sensitivitytotowards
According the analytes.
the Banerjee group, FETsThus, alternative
based methods should
on 3D structures be explored
are associated for ad-
with lower
dressing the
sensitivity issuesthe
towards of lower sensitivity
analytes. associated methods
Thus, alternative with 3D structures.
should be One-dimensional
explored for ad-
(1D) structures such as nanowires and nanotubes efficiently address
dressing the issues of lower sensitivity associated with 3D structures. One-dimensional the issue of lower
sensitivity towards the target analytes; however, they face
(1D) structures such as nanowires and nanotubes efficiently address the issue certain challenges during their
of lower
fabrication which in turn limit their practical applications for biosensing.
sensitivity towards the target analytes; however, they face certain challenges during their Owing to the 2D
structure of the designed FET biosensor based
fabrication which in turn limit their practical applicationson MoS , it offered easy patternability
2 for biosensing. Owing to the 2D and
device fabrication
structure and exhibited
of the designed high sensitivity.
FET biosensor based onThe MoSsensitivity of MoSpatternability
2, it offered easy 2
-based pH sensorsand
was determined by performing the analysis in the range of pH
device fabrication and exhibited high sensitivity. The sensitivity of MoS2-based pH sen-3–9 and the described
pH was
sors sensor achieved by
determined elevated sensitivity
performing of 713 with
the analysis in thearange
change of of
pHpH 3–9byand1-unit in a wider
the described
pH sensor achieved elevated sensitivity of 713 with a change of pH by 1-unit in aspecific
pH range of 3–9. Furthermore, the fabricated sensor was also used for sensing wider
proteins,
pH range resulting in its ultrasensitive
of 3–9. Furthermore, sensing.sensor
the fabricated At a lowwasconcentration
also used forofsensing
100 femtomolar
specific
concentration,
proteins, a sensitivity
resulting of 196 was sensing.
in its ultrasensitive achievedAt fora the
lowspecific protein of
concentration used
100asfemtomolar
the analyte.
concentration, a sensitivity of 196 was achieved for the2specific protein used as thegraphene,
The authors also compared the efficiency of their MoS -based FET biosensor with analyte.
a 2D material. They found that their MoS -based FET biosensor exhibits almost 74-folds
The authors also compared the efficiency 2of their MoS2-based FET biosensor with gra-
higher sensitivity as compared to graphene [26].
phene, a 2D material. They found that their MoS2-based FET biosensor exhibits almost 74-
To advance this technique, the Yu group [72] reported label-free highly sensitive
folds higher sensitivity as compared to graphene [26].
FET biosensors based on 2D MoS2 avoiding additional absorption layers. Fibroblast
growth factor 21 (FGF21) is considered a vital biomarker and has been reported to be
used in the early detection of non-alcoholic fatty acid liver disease (NAFLD). Currently,
this growth factor is getting wider scientific attention and efforts have been made to
develop the most effective method to detect its extremely low-level in the biological system.
They investigated the biosensor for the detection of FGF21 present in a non-aqueous
environment. Through immobilization on the surface of MoS2 , the designed biosensor
was capable of detecting as low as 10 fg mL−1 of the target FGF21. Multiple sets of
parallel experiments were conducted to demonstrate the consistency and reproducibility
of MoS2 FETs. Moreover, the biosensor was also highly sensitive to detect FGF21 in
complex samples (i.e., serum sample), authenticating its potential to be used in NAFLD
diagnosis. Generally, this study demonstrated the alternative platform based on thin-
 effective method to detect its extremely low-level in the biological system. They investi-
gated the biosensor for the detection of FGF21 present in a non-aqueous environment.
Through immobilization on the surface of MoS2, the designed biosensor was capable of
detecting as low as 10 fg mL−1 of the target FGF21. Multiple sets of parallel experiments
Sensors 2021, 21, 3467 were conducted to demonstrate the consistency and reproducibility of MoS2 FETs. More- 9 of 25
over, the biosensor was also highly sensitive to detect FGF21 in complex samples (i.e.,
serum sample), authenticating its potential to be used in NAFLD diagnosis. Generally,
this study demonstrated the alternative platform based on thin-layered transition-metal
layered
dichalcogenides transition-metal
(TMDs) dichalcogenides
for highly selective (TMDs)
and sensitive forbiosensors
novel highly selective and sensitive novel
development
biosensors development [26] (Figure 5).
[26] (Figure 5).

Figure 5. MoSFigure 5. MoS2-based field-effect transistor (FET) biosensor device. (a) Schematic diagram of MoS2-
2 -based field-effect transistor (FET) biosensor device. (a) Schematic diagram of MoS2 -based FET biosensor.
based FET biosensor. For biosensing, the dielectric layer covering the MoS2 channel is functional-
For biosensing, the dielectric layer covering the MoS2 channel is functionalized with receptors for specifically capturing the
ized with receptors for specifically capturing the target biomolecules. The charged biomolecules
target biomolecules. The charged biomolecules after being captured induce a gating effect, modulating the device current.
after being captured induce a gating effect, modulating the device current. An electrolyte gate in
An electrolyte gate in theofform
the form of an Ag/AgCl
an Ag/AgCl referencereference
electrodeelectrode
is usedisfor
used for applying
applying the biasthetobias
the to the electrolyte.
electrolyte. The The source
and drain contacts are also covered with a dielectric layer to protect them from the electrolyte
source and drain contacts are also covered with a dielectric layer to protect them from the electro- (not shown in this figure).
(b) Optical image
lyteof a MoS
(not shown2 flake on 270
in this nm SiO
figure). grown image
(b) 2Optical on degenerately doped
of a MoS2 flake onSi270
substrate.
nm SiOScale2 grownbar,on
10degen-
µm. (c) Optical
image of the MoS 2 FET
erately biosensor
doped deviceScale
Si substrate. showing
bar, the extended
10 μm. electrodes
(c) Optical image made
of the of
MoSTi/Au.
2 FET Scale bar, 10
biosensor µm. (d) Image
device
and schematicshowing
diagramthe extended
(inset figure)electrodes
of the chip made
withofthe
Ti/Au. Scale bar,
biosensor 10 μm.
device and (d) Image andchannel
microfluidic schematicfor dia-
containing the
gram (inset figure) of the chip with the biosensor device and microfluidic channel for containing
electrolyte. Inlet and outlet pipe for transferring the fluid and the reference electrode are not shown in the figure. Reprinted
with permission thefrom
electrolyte.
ref. [26].Inlet
2014and outlet pipe
American for transferring
Chemistry Society. the fluid and the reference electrode are not
shown in the figure . Reprinted with permission from ref. [26]. 2014 American Chemistry Society
2.1.2. Membraneless Field-Effect Transistor (FET) Biosensors
2.1.2. Membraneless Field-Effect Transistor (FET) Biosensors
The membraneless FET can be used as an alternative platform for developing electrical
The membraneless FET high
biosensors with can be used as an
sensitivity. alternative
They platform
have received for developing
considerable electri-
attention in their efforts
cal biosensors with high sensitivity. They have received considerable attention in
to develop an effective method that detects low levels of the biomarker. FET-type their biosensors
efforts to develop an effective
(BioFETs) have beenmethod that
a topic of detects low interest
increasing levels ofinthe biomarker.
recent FET-type
years owing to their ability
biosensors (BioFETs)
to detect have beenofa topic
analytes of increasing
interest interest
in a selective, in recent
sensitive, years
rapid, owing
and to theirmanner, and
label-free
owing to the fact that these biosensors are amenable to miniaturization. To date, however,
the sensitivity of BioFETs has been limited by their need for an insulating membrane
that prevents nonspecific binding from occurring as a consequence of dangling surface
bonds associated with typical semiconductors. The Park group [19] developed a reusable,
sensitive, and membrane-free BioFET by leveraging tungsten diselenide (WSe2 ) as a defect-
free van der Waals material. By using oxygen plasma treatment to generate a limited
number of surface defects, the authors were additionally able to incorporate additional
bioreceptor immobilization binding sites on the surface of these BioFETs, thus increasing
their sensitivity to 2.87 × 105 A/A for 10 mM glucose. Even after several rounds of glucose
application and subsequent washing, these WSe2 -based BioFETS maintained their excellent
sensitivity (Figure 6).
 bonds associated with typical semiconductors. The Park group [19] developed a reusable,
sensitive, and membrane-free BioFET by leveraging tungsten diselenide (WSe2) as a de-
fect-free van der Waals material. By using oxygen plasma treatment to generate a limited
number of surface defects, the authors were additionally able to incorporate additional
bioreceptor immobilization binding sites on the surface of these BioFETs, thus increasing
Sensors 2021, 21, 3467 10 of 25
their sensitivity to 2.87 × 105 A/A for 10 mM glucose. Even after several rounds of glucose
application and subsequent washing, these WSe2-based BioFETS maintained their excel-
lent sensitivity (Figure 6).

Figure 6. (A) Membraneless FET-type tungsten diselenide (WSe2) biosensors Reprinted with per-
Figure 6. (A) Membraneless FET-type tungsten diselenide (WSe2 ) biosensors Reprinted with permis-
mission from ref. [19]. 2018 American Chemistry Society (B) (a) Schematic representation of the
sion from ref. [19]. 2018 American Chemistry Society (B) (a) Schematic representation of the label-free
label-free MoS2 FET as a biosensor to electrically detect FGF21. (b) Optical and (c) AFM images of
MoS FET2 FET
the2MoS as a transistor.
biosensor Inset
to electrically detect
in (c) shows FGF21.
the MoS (b) Optical and (c) AFM images of the MoS2
2 thickness. (d) Experimental process of surface
FET transistor.
chemistry Inset inanti-FGF21
to prepare (c) shows the MoS2 2surface
on MoS thickness. (d)reaction
and its Experimental process
with FGF21 of surface
Reprinted chemistry
with per-
tomission
preparefrom ref. [71].on
anti-FGF21 2019
MoSSpringer..
2 surface and its reaction with FGF21 Reprinted with permission from
ref. [71]. 2019 Springer.
Parker’s gathering showcases an extremely refined, reusable, film-free biofilm of
tungsten disselenium
Parker’s gathering (WSe 2), one of an
showcases theextremely
channeled refined,
materials,reusable,
WSe2, which has a biofilm
film-free layered of
structuredisselenium
tungsten of progressive (WSemetal
2 ), dihalides
one of thedependent
channeledonmaterials,
van der Waals
WSe2(VDW), whichinteractions.
has a layered
There is of
structure noprogressive
catenary bond metal deformation on the surface
dihalides dependent on van of der
WSeWaals
2, considering the deep
(VDW) interactions.
touching
There is noactivity
catenaryof the
bondmembraneless
deformation WSe on2 biofilm. It is not
the surface subject
of WSe 2 , to fuzzy
considering authority.
the deep
They extended
touching activitytheoffalsifiability
the membraneless of Wse2 biofilms by generating
WSe2 biofilm. It is nota subject
small numberto fuzzyof defects
authority.
on the
They non-defective
extended surface as of
the falsifiability a restrictive destination
Wse2 biofilms for the biological
by generating a small numberreceiver. ofThey
defects
treated WSe slices of silicon dioxide/silicon substrate with oxygen plasma
on the non-defective surface as a restrictive destination for the biological receiver. They
2 for 15 and 30
s. As indicated by XPS results, aggregation speculates that O 2 plasma treatment destroys
treated WSe2 slices of silicon dioxide/silicon substrate with oxygen plasma for 15 and 30 s.
Astheindicated
security ofbyw-Se, thus generating
XPS results, Se opportunities
aggregation and O
speculates that w-oplasma
bonds treatment
on the surface of
destroys
2
the security of w-Se, thus generating Se opportunities and w-o bonds on the surface of
WSe2 . The biological receptor (glucose oxidase: GO) was fixed on the surface after WSe2 ,
O2 plasma treatment. We arranged the control, 15 and 30 s plasma treatment WSe2 test
and incubated the example in the APTES (3-aminopropyl triethoxysilane) response for
30 min. Fill in the form of a synthetic linker to anchor the gox biosector atoms to the WSe2
biosensor. The non-membrane WSe2 biofilm was tested and rinsed with glucose more than
once to analyze its reusability [19] (Figure 6).

Glucose (C6 H12 O6 ) + Glucose oxidase(ox) → gluconolactone(C6 H12 O6 ) + glucose oxidase(red) (3)

Glucose oxidase(red) + O2 → glucose oxidase(ox) + H2 O2 (4)

The group of Yu group reported label-free highly sensitive FET biosensors based on
2D molybdenum disulfide (MoS2 ) avoiding additional absorption layers. They investigated
Sensors 2021, 21, 3467 11 of 25

the biosensor for the detection of FGF21 present in a non-aqueous environment. Through
immobilization on the surface of MoS2 , the designed biosensor was capable of detecting
as low as 10 fg mL−1 of the target FGF21. Multiple sets of parallel experiments were
conducted to demonstrate the consistency and reproducibility of MoS2 FETs. Moreover, the
biosensor was also highly sensitive to detect FGF21 in complex samples (i.e., serum sample),
authenticating its potential to be used in NAFLD diagnosis. Generally, this study demon-
strated the alternative platform based on thin-layered transition-metal dichalcogenides
(TMDs) for highly selective and sensitive novel biosensors development [72].

2.2. Photoelectrochemical Biosensors

In photoelectrochemistry, light is utilized to produce electron/opening sets in a pho-
toactive material, and these electron/gap sets, when isolated, are utilized to drive redox
responses. Contingent upon the responses happening in the photoelectric compound
(PEC) cell, light is then changed over to electrical or synthetic energy. Recently, PEC signal
transduction has been exhibited for organic detecting. In PEC biosensors, light is utilized
to create charge transporters in photoactive materials, and the transduced electrochemical
current is estimated for examining naturally significant targets. Since signal readout is
electrochemical, this technique acquires the advantages of electrochemical biosensing:
1. The sign is perused utilizing economical and simple to-utilize instrumentation.
2. Multiplexed location is accomplished utilizing multielectrode microchips.
3. Due to optical excitation, PEC estimations are performed at lower inclination possibil-
ities contrasted with their electrochemical partners.
4. This brings down the deliberate electrochemical foundation flows and builds the sign-
to-foundation proportion. PEC readout has been utilized to identify biomolecules,
for example, DNA, RNA, and proteins. In any case, when utilizing these creation
techniques, the compromise must be made between the level of auxiliary tunability,
throughput, and cost.
The gathering utilized surface wrinkling to upgrade the proficiency of photocurrent
age in detecting PEC cells. Surface wrinkling is a simple and economical technique for
bringing tunable smaller scale and nanostructuring into dainty movies, permeable systems,
and get together of nanoparticles. In this work, The Soleymani group devised a strategy for
stacking photoactive quantum dots (QDs) into a wrinkled platform of a straightforward
conductive oxide to improve the produced photocurrent (Figure 7). By functionalizing the
photoactive QDs implanted in the wrinkled film, we built up a sensor for distinguishing
DNA targets. The wrinkles were made legitimately on polystyrene by shaping a hardened
oxidized surface layer and contracting the substrate. The indium tin oxide (ITO) and QDs
were then sputtered and stacked into the wrinkled polystyrene framework, separately. The
distinctions in surface geology and progression between the three classes of photoelectrodes.
The standard photoelectrodes are planar, and their ITO layer was free of breaks. These
components, which the article talked about, additionally empowered the oxidized layer
to adjust instead of break in light of the applied strain, making a continuous wrinkled
layer, and afterward, PEC current for the scaffolded-wrinkled surface (at 3 layers) was
around multiple times bigger than the current accomplished in the planar surface. The stem
was utilized to think about the PEC current pattern and as the charges travel through the
system of QDs and the PDDA (poly (diallyl dimethylammonium chloride)) spacer, resistive
misfortunes, dispersion misfortunes, and recombination decline their gathering rate by
the ITO anode, further lessening the photograph current. The gathering explored the
progressions in PEC current when the scaffolded-wrinkled photoelectrodes were interfaced
with test and target DNA strands. The upgraded PEC current acquired utilizing the
wrinkled materials design empowered us to build up a delicate and mark-free DNA
biosensor with a picomolar limit-of-location [20].
 the charges travel through the system of QDs and the PDDA (poly (diallyl dime-
thylammonium chloride)) spacer, resistive misfortunes, dispersion misfortunes, and re-
combination decline their gathering rate by the ITO anode, further lessening the photo-
graph current. The gathering explored the progressions in PEC current when the scaf-
Sensors 2021, 21, 3467 folded-wrinkled photoelectrodes were interfaced with test and target DNA strands.
12 of The
25
upgraded PEC current acquired utilizing the wrinkled materials design empowered us to
build up a delicate and mark-free DNA biosensor with a picomolar limit-of-location [20].

Figure 7. Photoelectric compound (PEC) measurements at planar and scaffolded-wrinkled photoe-

Figure 7. Photoelectric compound (PEC) measurements at planar and scaffolded-wrinkled pho-
lectrodes. (a) Visible light (470 nm) induces electron/hole pairs in CdTe quantum dots (QDs).
toelectrodes. (a) Visible light (470 nm) induces electron/hole pairs in CdTe quantum dots (QDs).
Holes oxidize ascorbic acid, generating an anodic redox current. (b) PEC current densities meas-
Holes
uredoxidize ascorbic
on planar (left) acid, generating an anodic(right)
and scaffolded-wrinkled redox devices
current. using
(b) PEC100current densities
mM ascorbic measured
acid at 0 V
onwith
planar (left)toand
respect scaffolded-wrinkled
Ag/AgCl. The QD layers (right) devicesbyusing
are increased 100 mM
depositing ascorbic
alternate acidofatQDs
layers 0 V and
with
respect to Ag/AgCl.
poly (diallyl The QD layerschloride)
dimethylammonium are increased by depositing
(PDDA). The 470 nmalternate layers diode
light-emitting of QDs is and poly
turned on
at 3 s and
(diallyl turned off at 23 s. (c)
dimethylammonium The average
chloride) PECThe
(PDDA). current
470 nmdensities measureddiode
light-emitting on planar (left)on
is turned andat
3 s and turned off at 23 s. (c) The average PEC current densities measured on planar (left) and
scaffolded-wrinkled (right) devices for different numbers of QD layers. (d) Scanning transmission
electron micrographs of cross-sections of planar (left) and scaffolded-wrinkled (right) devices. The
imaged devices contain three QD layers Reprinted with permission from ref. [20]. 2018 American
Chemistry Society.
Zhang et al. [69], reported the design and development of a self-operating photo-
cathode which was based on the CdS quantum dots sensitized with 3D nanoporous-NiO
(Figure 8). The photocathode reversibly exhibited high selectivity towards dissolved oxy-
gen (working as electron donor) in the electrolyte solution. Employing the photocathode, a
novel photoelectrochemical sensor was developed for the detection of glucose while using
glucose oxidase (GOD) as a biocatalyst. The use of various competing substances such as
dopamine (DA), cysteine (Cys), ascorbic acid (AA), and H2 O2 revealed that they did not
 Zhang et al. [69] , reported the design and development of a self-operating photocathode
which was based on the CdS quantum dots sensitized with 3D nanoporous-NiO (Figure 8).
The photocathode reversibly exhibited high selectivity towards dissolved oxygen (work-
Sensors 2021, 21, 3467 ing as electron donor) in the electrolyte solution. Employing the photocathode, a13novel of 25
photoelectrochemical sensor was developed for the detection of glucose while using glu-
cose oxidase (GOD) as a biocatalyst. The use of various competing substances such as
dopamine (DA), cysteine (Cys), ascorbic acid (AA), and H2O2 revealed that they did not
affect
affectthe
thecathodic
cathodicphotocurrent
photocurrentofofthethe3D
3DNiO/CdS
NiO/CdSelectrode.
electrode.However,
However,theytheysignificantly
significantly
influenced
influenced the photocurrent of the photocathode, thus authenticating the selectivityofofthe
the photocurrent of the photocathode, thus authenticating the selectivity the
described
describedmethod.
method.

Figure8.8. (A)
Figure (A) Schematic diagrams
diagrams for
forenergy
energybands
bandsofofn-CdS
n-CdSand
andp-NiO and
p-NiO andphotocurrent
photocurrent genera-
gen-
tion mechanism of NiO/CdS in the presence of oxygen. (B) The assembly of glucose oxidase
eration mechanism of NiO/CdS in the presence of oxygen. (B) The assembly of glucose oxidase
(GOD)on
(GOD) onindium
indiumtin
tinoxide
oxide (ITO)/NiO/Cd
(ITO)/NiO/Cd Selectrode.
Selectrode.Reprinted
Reprintedwith permission
with from
permission ref.ref.
from [69].
[69].
2014 ScienceDirect.
2014 ScienceDirect.

Theapplicability
The applicabilityofofthe themethod
methodwas wasinvestigated
investigatedfor forthe
thedetection
detectionofofglucose
glucosepresent
present
in real samples including glucose injection and blood serum. The
in real samples including glucose injection and blood serum. The obtained results showedobtained results showed
theywere
they werehighly
highlysatisfactory
satisfactoryininterms
termsofofaccuracy.
accuracy.The Theauthors
authorsofofthethestudy
studyconcluded
concluded
thatthese
that thesefindings
findingscould
couldopen
opennewnewavenues
avenuesfor fordesigning
designingand anddeveloping
developingphotochemical
photochemical
biosensorsbased
biosensors basedon onself-operating
self-operatingphotocathode,
photocathode,and andthis
thiswould,
would,ininturn,
turn,promote
promotethe the
applications of semiconductor nanomaterials in photoelectrochemistry.
applications of semiconductor nanomaterials in photoelectrochemistry. The further report The further report
showedthe
showed thedesign
design and
and development
development of of a self-operating
a self-operating photocathode
photocathode which
which was was
basedbased
on
on CdS
the the CdS quantum
quantum dotsdots sensitized
sensitized withwith 3D nanoporous-NiO.
3D nanoporous-NiO. The The photocathode
photocathode revers-
reversibly
ibly exhibited
exhibited high selectivity
high selectivity towardstowards dissolved
dissolved oxygen oxygen (working
(working as electron
as electron donor)donor)
in thein
the electrolyte
electrolyte solution.
solution. Employing
Employing the photocathode,
the photocathode, a novelaphotoelectrochemical
novel photoelectrochemicalsensor wassen-
sor was developed
developed for the detection
for the detection of glucose ofwhile
glucose while
using usingoxidase
glucose glucose (GOD)
oxidaseas(GOD) as a bio-
a biocatalyst.
catalyst.
The use ofThe use of
various various competing
competing substancessubstances such as dopamine
such as dopamine (DA),(Cys),
(DA), cysteine cysteine (Cys),
ascorbic
ascorbic
acid (AA),acidand(AA),
H2 Oand H2O2 revealed
2 revealed that they that
didthey
notdid not the
affect affect the cathodic
cathodic photocurrent
photocurrent of theof
3D
theNiO/CdS
3D NiO/CdS electrode. However,
electrode. However, they significantly
they significantly influenced
influenced the photocurrent
the photocurrentofofthe the
photocathode,
photocathode,thus thusauthenticating
authenticatingthe the selectivity
selectivity of the described method [69]. [69].
Zheng
Zhengetetal.al.[73]
[73]reported
reportedthethesynthesis
synthesisofofaanovel
novelsensor
sensorforforthe
thedetection
detectionofofglucose
glucose
(Figure
(Figure9).9).The
Thesensor
sensorwas based
was on single-crystalline
based on single-crystalline TiO2TiO
nanowires that were
2 nanowires synthesized
that were synthe-
through a hydrothermal synthetic route. The nanowires were further
sized through a hydrothermal synthetic route. The nanowires were further surface-func- surface-functionalized
with glucose
tionalized oxidase,
with glucoseand enzymes
oxidase, andresponsible for the oxidation
enzymes responsible for theof glucose of
oxidation to glucose
gluconicto
acid. Theacid.
gluconic development of the sensor
The development of the was
sensor based
was on the on
based photogenerated
the photogenerated holes holes
on the on
TiO anode
the2 TiO surface
2 anode that that
surface could generate
could O2 . OThus,
generate 2. Thus,thethe
O2Owas
2 was considered
consideredresponsible
responsible
for
forthe
the efficient
efficient shuttling
shuttling mediator
mediator of of electron
electronbetween
betweenthe thesurface
surfaceofofthethe sensor
sensor andand
the
the redox center of glucose oxidase. This in turn resulted in significant photocurrent
enhancement. The surface-functionalized nanowire-based sensor was found to be highly
sensitive towards glucose in buffer with an as low as ~0.9 nM lower limit of detection.
The sensor was further investigated for its glucose detection capability in complex system
mouse serum. The authors concluded the novel nanowire-based photoelectrochemical
sensor as an efficient, convenient, and cost-effective diagnostic for the detection of disease
biomarkers [73]. The Tang report that PEC biosensors have been used for mycotoxin
detection due to their properties. Photoactive materials like this have important roles in
converting chemical information into detectable PEC signal. Specific recognition elements
also affect the analytical performance of PEC biosensors [74].
 towards glucose in buffer with an as low as ~0.9 nM lower limit of detection. The sensor was
further investigated for its glucose detection capability in complex system mouse serum.
The authors concluded the novel nanowire-based photoelectrochemical sensor as an effi-
cient, convenient, and cost-effective diagnostic for the detection of disease biomarkers [73].
The Tang report that PEC biosensors have been used for mycotoxin detection due to their
Sensors 2021, 21, 3467 14 of 25
properties. Photoactive materials like this have important roles in converting chemical
information into detectable PEC signal. Specific recognition elements also affect the ana-
lytical performance of PEC biosensors [74].

Figure 9. (a) Schematic of glucose oxidase (GOx) functionalization on the TiO2 nanowire surface
Figure 9. (a) Schematic of glucose oxidase (GOx) functionalization on the TiO2 nanowire surface via
via silane/glutaraldehyde linkage chemistry. APTES: 3-aminopropyl triethoxysilane. The green
silane/glutaraldehyde
and pink colors of GOx indicate linkage thechemistry.
flavin group APTES: 3-aminopropyl
(FAD) redox center and thetriethoxysilane. The green and pink
external insulating
proteinofshell,
colors GOx respectively.
indicate the (b) flavin
Schematic of the
group TiO2–GOx
(FAD) redox NW-based
center and PECthe
sensor for glucose
external de-
insulating protein shell,
tection. Under sunlight illumination, the photogenerated holes oxidize H2O or H2O2 over the
respectively. (b) Schematic of the TiO2 –GOx NW-based PEC sensor for glucose detection. Under
TiO2NW anode to form O2, which serves as an efficient electron acceptor of FAD/FADH2. Glucose
sunlight
is oxidized illumination,
to gluconic acid the photogenerated
during holes
this cycle. On the oxidize
cathode (Pt), H
the2 O or H2 O2 over
photogenerated the TiO2 NW anode to
electrons
form
reduceOwater
2 , which
to serves
form H 2 . Theas an
currentefficient
flowing electron
through acceptor
the circuit isof FAD/FADH2.
recorded as the Glucose
sensing signal. is oxidized to
Reprinted with permission from ref. [73]. 2013 The Royal Society of Chemistry.
gluconic acid during this cycle. On the cathode (Pt), the photogenerated electrons reduce water to
form H2 . The current flowing through the circuit is recorded as the sensing signal. Reprinted with
Photoelectrochemical detection of analytes is greatly preferred as it presents an in-
permission fromtransduction
teresting signal ref. [73]. 2013 The Royal
modality. Society of
Modulation ofChemistry.
the charge carriers in such sensing
systems occurs as a result of the redox reactions of molecular targets that take place on the
Photoelectrochemical
surface of the electrode. Owing detection of analytes
to the superior propertiesis
of greatly preferred
PEC biosensors, theyas
areitcon-
presents an in-
teresting
sidered tosignal
be usedtransduction
as a promisingmodality.
tool for the Modulation of the charge
detection of mycotoxin. When carriers
employedininsuch sensing
the fabrication
systems occurs of as
biosensing
a result systems, photoactive
of the redox materials
reactions work as transducers,
of molecular targets thatthustake place on
theysurface
the convertof thethe
chemical information
electrode. Owing into
todetectable signals.
the superior The analytical
properties performance
of PEC biosensors, they are
of biosensors based on PEC materials is greatly influenced by the signal strategies of the
considered to be used as a promising tool for the detection of mycotoxin. When employed
specific recognition element. A review by Tang et al. extensively reviewed the photoactive
in the fabrication of biosensing systems, photoactive materials work as transducers, thus
materials and their signal strategies employed for the fabrication of PEC biosensors used
they
for the detection of mycotoxin.information
convert the chemical into detectable
They also discussed the future signals.
aspects ofThe
theseanalytical
biosensorsperformance
of
in biosensors
detail. based on PEC materials is greatly influenced by the signal strategies of the
specific recognition element. A review by Tang et al. extensively reviewed the photoactive
2.3. Nano Optical
materials Biosensor
and their signal strategies employed for the fabrication of PEC biosensors used
for the detection of mycotoxin. They also discussed the future aspects of these biosensors
in detail.

2.3. Nano Optical Biosensor

Nanoscale optical biosensors are currently attracting greater scientific interest due
to their easy fabrication, characterization, and cost-effectiveness. The Duyne group [75]
reported the usage of nano-sphere lithography (NSL) for the fabrication of gold and silver
nano-triangles and the resulting localized surface plasmon resonance (LSPR) spectra were
recorded by using ultraviolet (UV)–Visible extinction spectroscopy. They found that the
short-range distance dependence (almost 0–2 nm) of electromagnetic fields surrounding the
resonantly excited nanoparticles can be modulated through varying their structure, com-
position, and size. The measurement was based on shifting of LSPR spectra wavelengths
(ìmax) that appeared due to the absorption of hexadecane-thiol as a function of nanoparticle
shape (truncated tetrahedron versus hemisphere), size (in-plane width, out-of-plane height,
and aspect ratio) and composition (silver versus gold). It was observed that hexadecane-
thiol-induced LSPR shift for silver triangles decreased with an increase in width (in-plane)
at a fixed height (out-of-plane) or vice versa. The described trends were in contrast to the
findings of the previously published report which studied long-range distance dependence
examining layers with 30 nm thickness [75]. However, the confirmation of these results for
Sensors 2021, 21, 3467 15 of 25

both short and long-range analysis was based on theoretically using finite element electro-
dynamics. Findings of the study revealed that short-range distance-dependence results
were found sensitive to hot spots (these are the regions having highly induced electric
fields) located in peripheries of the triangles, and hence they suggested the involvement of
enhanced local fields for the generation of extinction spectra. The results also exhibited
the appearance of larger hexadecane thiol-induced LSPR peak shifts in the case of nano
triangles as compared to hemispheres of the same volume. Similarly, a larger peak shift
was observed for the silver nano-triangles as compared to gold nano-triangles having the
same out-of-plane heights and in-plane widths. It was also found that alkane-thiol-induced
LSPR peak shift of chain-length present in silver nano triangles was independent of the size.
A better understanding of the reported short-range dependence of the adsorbate-induced
LSPR peak shift associated with nanoparticle composition as well as structure will provide
knowledge to improve the sensitivity of nanosensors based on refractive-index [76].
Nano-silicon photonics is an ideal stage to realize high orthodontic and selective
recognition of organic atoms under complex fluid conditions. In this case, luminescent
silicon-based nanostructures are very encouraging materials because their large uncoated
surfaces and their optical properties are due to the most innovative conduction techniques.
In the aspect of DNA recognition, the basic detection of Si-nws was carried out by using
the electric conduction strategy based on DNA hybridization conductance variation and
the explicit detection method fixed on the surface of nanowires (NWs), and 220 atoms
(about 6600 DNA target duplicates per 50 mL) that were low fracture points were found.
SSDNA, by using a variety of crystal silicon nano-FETs with measurements of less than
20 nm, another interesting approach relies on fluorescent labeling of DNA. In particular,
his collection demonstrates the high performance of Si NWs biochemical sensors to reduce
the identification of various named genome sequences to as low quality as possible. Sabri-
nas’ [77] collections reported major cases of direct genomic identification in Si-NWs optical
biosensors without enhancement steps (sans-pcr) and markers (unlabeled) (Figure 10). The
proposed approach utilizes a hybrid approach that combines Si NWS with satisfactory in
situ hybridization from two explicit experiments and synthesizes it on the surface with a
genomic double strand. We tried to demonstrate sensors that take advantage of the hepati-
tis b virus (HBV) genome. Figure 10a the concentrations range from 20 cps to 2000 cps for
the Photoluminescence (PL) spectra of the NWs sensor that was tested in HBV genome
extraction from infected human blood. The PL reference of the sensor without any copies
of HBV is depicted in black. Figure 10b shows that the PL integrated peak of the NWs
PL emission is obtained by the buffer solution without any real HBV copy. Lastly, the PL
signal is used as a detection mechanism.
Sensors 2021, 21, x FOR PEER REVIEW 16 of 28

Figure 10. (a) Photoluminescence (PL) spectra of the NWs sensor tested in hepatitis b virus (HBV)
Figure
real genome (a) Photoluminescence
10.extracted (PL)
from infected human blood andspectra of the
spiked in buffer NWsforsensor
reported different tested
con- in hepatitis b virus (HBV)
centrations ranging from 20 cps up to 2000 cps. The PL reference of the sensor without any copies
real genome extracted from infected human blood and spiked in
of HBV is shown in black. (b) The trend of the PL integrated peak of the deconvolved NWs PL
buffer reported for different concen-
trations
emission asranging from
a function of 20 cps
real HBV genomeupconcentration
to 2000 cps. The PL
normalized to itsreference of (red
reference signal the sensor without any copies of
bar) obtained by the buffer solution without any real HBV copy. Reprinted with permission from
HBV is 2018
ref. [77]. shown in black.
American (b)Society
Chemistry The trend of the PL integrated peak of the deconvolved NWs PL emission
as a function of real HBV genome concentration normalized to its reference signal (red bar) obtained
The impact of a natural network and its potential impedances can be evaluated by
by the the
testing buffer
Si NWssolution
sensor withwithout
HBV cloneanygenome
real HBVbroke copy. Reprinted
up in human withthan
serum rather permission from ref. [77]. 2018
American
the support Chemistry
arrangement. Society.
To affirm this theory, a Si wafer (without NWs) was tried with
an answer made by human serum without HBV, and a similar wide multipeaked band
400–600 nm was watched and verified that the PL signal variety of the NWs sensor as a
component of HBV focus is the equivalent in the two grids. The presentation evaluation
of the Si NWs sensor with genuine examples is a significant point to be tended to. To
further explore this point, we tried the gadget by utilizing a genuine HBV genome re-
moved from a blood test. It was affirmed that this Si NWs sensor can distinguish the gen-
Sensors 2021, 21, 3467 16 of 25

The impact of a natural network and its potential impedances can be evaluated by
testing the Si NWs sensor with HBV clone genome broke up in human serum rather than
the support arrangement. To affirm this theory, a Si wafer (without NWs) was tried with
an answer made by human serum without HBV, and a similar wide multipeaked band
400–600 nm was watched and verified that the PL signal variety of the NWs sensor as a
component of HBV focus is the equivalent in the two grids. The presentation evaluation of
the Si NWs sensor with genuine examples is a significant point to be tended to. To further
explore this point, we tried the gadget by utilizing a genuine HBV genome removed from
a blood test. It was affirmed that this Si NWs sensor can distinguish the genuine HBV
genome separated from human blood with an effectiveness similar to the constant PCR
(20 cps/response), regardless of whether its length is about the portion of the analytical
sample [78].
The Duyne group reported the usage of NSL for the fabrication of gold and silver
nano-triangles and the resulting LSPR spectra were recorded by using UV-Visible extinction
spectroscopy. They found that the short-range distance dependence (almost 0–2 nm) of
electromagnetic fields surrounding the resonantly excited nanoparticles can be modulated
through varying their structure, composition, and size. The measurement was based on
shifting of LSPR spectra wavelength (ìmax) appeared due to the absorption of hexadecane-
thiol as a function of nanoparticle shape (truncated tetrahedron versus hemisphere), size
(in-plane width, out-of-plane height, and aspect ratio) and composition (silver versus gold).
It was observed that hexadecane-thiol-induced LSPR shift for silver triangles decreased
with an increase in width (in-plane) at a fixed height (out-of-plane) or vice versa. The
described trends were in contrast to the findings of the previously published report which
studied long-range distance dependence examining layers with 30 nm thickness [75].
However, the confirmation of these results for both short and long-range analysis was
based on theoretically using finite element electrodynamics. Findings of the study revealed
that short-range distance-dependence results were found to be sensitive to hot spots (these
are the regions having highly induced electric fields) located in peripheries of the triangles,
hence suggested the involvement of enhanced local fields for the generation of extinction
spectra. The results also exhibited the appearance of larger hexadecane thiol-induced LSPR
peak shifts in the case of nano triangles as compared to hemispheres of the same volume.
Similarly, a larger peak shift was observed for the silver nano-triangles as compared to
gold nano-triangles having the same out-of-plane heights and in-plane widths. It was
also found that the alkane-thiol-induced LSPR peak shift of chain-length present in silver
nano triangles was independent of the size. A better understanding of the reported short-
range dependence of the adsorbate-induced LSPR peak shift associated with nanoparticle
composition as well as structure will provide knowledge to improve the sensitivity of
nanosensors based on refractive-index [76].

2.4. Metal-Assisted Interface

Plasma biosensors are widely used in logic and medicine research, medical diagnosis,
veterinary practice, nutrition, and health control. Stebunovs et al. [79] collects copper as
a plasma material for constructing biosensor interfaces.(Figure 11) One potential way to
overcome this problem is to protect the hidden metal surface with a graphene-covered
barrier while having a negligible effect on the optical properties of the interface between
the sensor surface and the substance to be tested or the organic frame. Stebunovs’ team pro-
posed the SPR sensor chip, which relies on plasma-copper membranes fixed with different
dielectric layers (Figure 12). The disappearance of the electron column is an essential part
of the standard process, which stores thin copper film on the surface of the glass substrate.
The optical properties of the metal film determine the probability of SPR excitation in a
specific structure, the reverberation quality, and the feasibility of SPR biosensors. The
ellipsoidal model shows that the dielectric constants of copper and gold films are directly
determined by the ellipsoidal information. The variation of copper SPR sensor chips with
different protective layers is hypothesized and preliminarily tested. Improvement with the
 barrier while having a negligible effect on the optical properties of the interface between
the sensor surface and the substance to be tested or the organic frame. Stebunovs’ team
proposed the SPR sensor chip, which relies on plasma-copper membranes fixed with dif-
ferent dielectric layers (Figure 12). The disappearance of the electron column is an essen-
tial part of the standard process, which stores thin copper film on the surface of the glass
Sensors 2021, 21, 3467 17 of 25
substrate. The optical properties of the metal film determine the probability of SPR exci-
tation in a specific structure, the reverberation quality, and the feasibility of SPR biosen-
sors. The ellipsoidal model shows that the dielectric constants of copper and gold films
are directly determined by the ellipsoidal information. The variation of copper SPR sensor
ligand-specific interface in SPR biosensing applications analysis is important because 2D
chips with different protective layers is hypothesized and preliminarily tested. Improve-
material has large surface area and different material properties, and the interface can be
ment with the ligand-specific interface in SPR biosensing applications analysis is im-
applied to a wide range of biological chemical association study, no matter under what
portant because 2D material has large surface area and different material properties, and
thecircumstances,
interface can becompared
applied to with
a wide sulfur
rangeconnection
of biologicallayer, increasing
chemical thestudy,
association limit immobilized.
no
This recent report showed the progress of the go connection layer
matter under what circumstances, compared with sulfur connection layer, increasing the covering the dielectric
layer
limit outside the
immobilized. SPR
This biosensor
recent chip [78].
report showed The Chang
the progress of thegroup proposed
go connection and
layer cov-validated a
highly
ering sensitivelayer
the dielectric metal layer-assisted
outside guide mode
the SPR biosensor resonance
chip [78]. The Chang (MaGMR) device for use in
group proposed
andbioanalytical
validated a contexts. These metal
highly sensitive researchers found that
layer-assisted guidereflection spectra (MaGMR)
mode resonance associated with this
device for usepresented
approach in bioanalytical contexts.
a unique inverse These researchers
response, andfound that reflection
were able to explorespectra
the underlying
associated
mechanisticwithbasis
this approach presented
for observed a unique
resonance. inverse
The response, and
high sensitivity were able
of their MaGMRto ex-device was
plore
foundthe to
underlying mechanistic
be attributable to itsbasis for observed
asymmetric resonance.
resonance modelTheprofile
high sensitivity
and the lowof propaga-
their MaGMR device was found to be attributable to its asymmetric resonance model pro-
tion angle inside the waveguide. Relative to typical GMR, these researchers observed a
file and the low propagation angle inside the waveguide. Relative to typical GMR, these
1-fold enhancement of the evanescent waves within the analyte region. In experimental
researchers observed a 1-fold enhancement of the evanescent waves within the analyte
analyses, they found that the MaGMR was able to achieve a bulk sensitivity of 376.78 nm in
region. In experimental analyses, they found that the MaGMR was able to achieve a bulk
fundamental
sensitivity TMnm
of 376.78 mode while resonating
in fundamental TM mode at 0.809µm with theatfirst
while resonating diffraction
0.809μm with theangle. They
observed a 264.78% enhancement in the sensitivity relative to typical
first diffraction angle. They observed a 264.78% enhancement in the sensitivity relative to GMR sensors under
identical TM mode resonance conditions [80].
typical GMR sensors under identical TM mode resonance conditions [80].

Sensors 2021, 21, x FOR PEER REVIEW 18 of 28

Figure 11. Schematic representation of the surface plasmon resonance (SPR) biosensor comprising
Figure 11. Schematic representation of the surface plasmon resonance (SPR) biosensor comprising
thethe
SPRSPR sensor
sensor chipchip based
based on plasmonic
on plasmonic coppercopper films coated
films coated with a dielectric
with a dielectric layer to protect against
layer to protect
oxidation. The prism and sensor chip substrates are made of the same type of glass, which allows for
against oxidation. The prism and sensor chip substrates are made of the same type of glass, which
an efficient optical connection. The immobilization of biomolecules on the biosensor surface can be
allows for an efficient optical connection. The immobilization of biomolecules on the biosensor
achieved
surface canusing a graphene
be achieved using aoxide linking
graphene layer
oxide deposited
linking atop the
layer deposited dielectric
atop layer.layer.
the dielectric Reprinted with
Reprinted with
permission permission
from ref. [79].from
2018ref. [79]. 2018Chemistry
American American Chemistry
Society. Society.

Figure 12. (a) Covalent immobilization of neutravidin on the surface of the graphene oxide (GO)
linking layer deposited on the copper surface plasmon resonance (SPR) sensor chip protected by
Figure 12. (a) Covalent immobilization of neutravidin on the surface of the graphene oxide (GO)
15 nm thick Al2 O3 film.
linking layer deposited Thecopper
on the immobilization procedure
surface plasmon includes
resonance the activation
(SPR) sensor of carboxyl
chip protected by groups
15 GO
of nm thick
by the O3 film. The
Al2mixture immobilization
of 0.4 procedure includes the activation
M 1-ethyl-3-(3-(dimethylamino) of carboxyl groups
propyl) carbodiimide hydrochloride
of GO by
(EDC) the0.1
and mixture of 0.4 M 1-ethyl-3-(3-(dimethylamino)
M N-hydroxysuccinimide (NHS) solutions propyl)
and carbodiimide
deactivation hydrochloride
of carboxyl groups after
(EDC) and 0.1 M N-hydroxysuccinimide (NHS) solutions and deactivation of carboxyl groups
neutravidin adsorption by 1 M Tris solution. (b) Adsorption of oligonucleotides D1 and D2 on
after neutravidin adsorption by 1 M Tris solution. (b) Adsorption of oligonucleotides D1 and D2
the surface
on the surfaceofofneutravidin–GO copper
neutravidin–GO copper SPR
SPR chip.
chip. D1 isD1 is biotinylated
biotinylated and complementary
and complementary to non- to non-
biotinylated D2.
biotinylated D2. PBS:
PBS: phosphate-buffered
phosphate-buffered saline saline Reprinted
Reprinted with permission
with permission from
from ref. [79]. 2018ref. [79]. 2018
American Chemistry Society.
American Chemistry Society.

3. Perspectives and Future Direction

There have been key developments in the rapidly evolving field of organic electron-
ics over the past two decades as these materials have increasingly been explored as an
alternative to inorganic semiconductors. Owing to their ability to detect nanoscale mate-
Sensors 2021, 21, 3467 18 of 25

3. Perspectives and Future Direction

There have been key developments in the rapidly evolving field of organic electron-
ics over the past two decades as these materials have increasingly been explored as an
alternative to inorganic semiconductors. Owing to their ability to detect nanoscale ma-
terials, organic distributed feedback lasers represent a potentially ideal tool for sensing
applications in biomedical and biological contexts. We note the current developmental
and commercialization status of organic light-emitting diodes, photovoltaics, and thin-film
transistors. Here we focus on a discussion of organic transistors and their recent application
in the field of biosensor development. By presenting numerous examples and relevant
citations, this will provide a comprehensive overview of the properties and principles of
these biosensors.

3.1. Organic Semiconductor Interface for Biosensor

According to the specific material framework, various strategies are used to create
extremely light crystalline layers, including various stripping methods and material manu-
facturing methods [81–84]. These programs play a very good role in most van der Waals
layered materials, because the absence of a covalent bond between adjacent layers improves
the strength of the mixture, and eliminates the problems caused by the hanging bond on the
surface of the material so that the thickness of the “defect-free” gem is reduced to the core
thickness. It is reported that the electronic properties of the materials can be quantitatively
measured by the ion fluid gate field-effect transistor (FET) which is prepared on the large
drop point gem.
Morpurgo’s group presented WS2 type sensor with ionic liquid as electrolyte. [85]
(Figure 13) WS2 is a kind of ring gap semiconductor (∆WS2 1.35 eV), which consists of
two-dimensional (2D) covalently enhanced s-w-slayer and van der Waals gap isolation
(Figure 13). It is found that by coupling WS2 microchip with ionic liquid medium, stable,
non-sluggish, electronic, and gap conductance adjustable bipolar transistors can be ob-
tained. It can be imagined that the bandgap of WS2 can be reasonably determined with high
accuracy (10%) by the dependence of the currently active channel’s input voltage, and the
careful use of the ion fluid gate transistor provides a great asset for the quantitative study
of the electronic characteristics of fragile gemstones. Slim crystalline pieces of WS2 were
acquired by mechanical peeling of a mass single precious stone developed by synthetic
fume transport and afterward moved on an exceptionally doped Si/SiO2 substrate. Chips
appropriate for electrical portrayal were distinguished under an optical magnifying lens
and their thickness was estimated by atomic force microscopy (AFM). Electrical contacts
were manufactured by electron-bar lithography, trailed by metal (Ti/Au) dissipation and
lift-off. The gadget yield attributes, estimated for the two polarities of VG and VD, affirm
the high-caliber of the ambipolar transistor activity. The gathering can absolutely decide
the bandgap of WS2 from basic vehicle estimations on a nanofabricated FET and ionic fluid
gated FETs made on WS2 slim drops are demonstrated to be perfect ambipolar gadgets on
account of an essentially ideal electrostatic coupling between the ionic fluid door and the
transistor channel and to the high caliber of the utilized semiconductor.
Takeya’s work revealed another class of natural semiconductor gadgets functionalized
by the quick ionic movement in the room temperature liquid salts [78]. In this work, strong
to-fluid interfaces are framed between natural semi-conductor single gems and ionic fluids
so the structures fill in as quick exchanging natural field-impact transistors, OFETs, with
the most elevated transconductance gm = ID/VG per square channel sheet, i.e., the most
proficient reaction of the yield channel current ID to the information door voltage VG
among the OFETs so far constructed. OFETs offer the possibility for cutting -edge minimal
effort de-indecencies that can be delivered by straightforward creation forms. There have
been an account of the utilization of such polymer electrolytes as LiClO4 disintegrated
in polyethylene oxide or ionic fluid continued in a polymer gel. However, these gadgets
experience the ill effects of either more unfortunate versatility or moderate reaction to VG
as a result of generally moderate ionic dispersion in the polymer grid. The OFETs most
Sensors 2021, 21, 3467 19 of 25

Sensors 2021, 21, x FOR PEER REVIEW 19 of 28

regularly comprise natural polycrystalline structure and dielectric protectors, for example,
silicon
(10%) dioxide. With common
by the dependence thicknesses
of the currentlyofactive
the door dielectric
channel’s protectors
input voltage,ofandtwotheor careful
three
hundred nanometers, many volts are expected to apply adequate EG for enough Q
use of the ion fluid gate transistor provides a great asset for the quantitative study of the so down
toelectronic
earth flow intensificationofisfragile
characteristics accomplished.
gemstones. Takeya’s gathering use
Slim crystalline room
pieces of temperature
WS2 were ac-
ionic liquids (RTILs) for the door protecting layer and natural single precious
quired by mechanical peeling of a mass single precious stone developed by synthetic stones forfume
the
semiconductor
transport andlayer (Figure
afterward 14). The
moved onelectrical double layer
an exceptionally (EDL)
doped capacitance
Si/SiO of 1-ethyl-3-
2 substrate. Chips ap-
methylimidazolium
propriate for electrical portrayal were distinguished under an optical magnifyingutilizing
bis(trifluoromethylsulfonyl)imide [emim][TFSI] is estimated lens and
a their
test gadget comprising
thickness of the equivalent
was estimated PDMSmicroscopy
by atomic force structure, where
(AFM). the top terminal
Electrical is made
contacts were
out of gold slimby
manufactured movies. The EDL
electron-bar capacitance
lithography, of the
trailed byRTILs
metal stays
(Ti/Au)huge even at 1and
dissipation MHz,
lift-
showing the quick ionic dispersion because of the voltage application. Thus, the EDL OFETs
off. The gadget yield attributes, estimated for the two polarities of VG and VD, affirm the
fusing the RTILs permit exchanging activity at such a high frequency. After presenting
high-caliber of the ambipolar transistor activity. The gathering can absolutely decide the
legitimate measures of RTIL, the fluid-filled in the gap is continued steadily by the capillary
bandgap of WS2 from basic vehicle estimations on a nanofabricated FET and ionic fluid
force. Owing to the high charge carrier mobility in rubrene single crystals and the high
gated FETs made on WS2 slim drops are demonstrated to be perfect ambipolar gadgets on
capacitance of EDLs in the electrolyte, the device realizes the highest transconductance
account of an essentially ideal electrostatic coupling between the ionic fluid door and the
ever achieved for organic transistors.
transistor channel and to the high caliber of the utilized semiconductor.

Sensors 2021, 21, x FOR PEER REVIEW 20 of 28

enough Q so down to earth flow intensification is accomplished. Takeya’s gathering use

room temperature ionic liquids (RTILs) for the door protecting layer and natural single
Figure 13.stones
precious (a) Crystal structure
for structure
the of layered WS
semiconductor 2; the purple balls correspond to W atoms and the
layer (Figure 14). The electrical double layer (EDL)
Figure 13. (a) Crystal of layered WS 2 ; the purple balls correspond to W atoms and the
yellow balls to S atoms. (b) Optical microscope image of a six-terminal Hall bar fabricated on a
capacitance of 1-ethyl-3-methylimidazolium
yellow balls to S atoms. (b) Optical microscope image of a six-terminal bis(trifluoromethylsulfonyl)imide
Hall bar fabricated on a
crystalline WS2 thin flake (the scale bar is 10 μm long). (c) Molecular structure of the ionic liquid
[emim][TFSI]
crystalline WS 2
is
thin estimated
flake (the utilizing
scale bar is a
10 test
µm gadget
long). comprising
(c) Molecular of the − equivalent
structure of the PDMS
ionic(d)
liquid
employed as an electrolyte–gate dielectric. Both cation [P14] and anion [FAP] are + shown.
structure,
employed as where
Cross-section anof the top terminal
electrolyte–gate
a WS2 ionic liquid-gated
is made
dielectric. Both out of
FET.cation
A large
goldofslim
[P14] +
area and
movies.
anion
gold [FAP]
mesh
−The
and are
EDL
shown.capacitance
an oxidized (d) Cross-
Ag/AgO
of the
section RTILs
of a WS stays
ionic huge even
liquid-gated at 1 MHz,
FET. A showing
large area of the
gold quick
mesh ionic
and dispersion
an
wire are used 2as a gate electrode and quasi-reference electrode, respectively. When the gate elec-oxidized because
Ag/AgO of the
wire
voltage
trode
are used application.
is as
biased,
a gatetwo Thus,
electrical
electrode the EDL
anddouble OFETs fusing
layers are electrode,
quasi-reference the RTILs
formed at respectively. permit
the gate/electrolyte exchanging
andgate
When the electrode isat
activity
semiconduc-
such a high
tor/electrolyte frequency.
interfaces, After
enabling presenting
charge legitimate
accumulation at measures
the of RTIL,
semiconductor
biased, two electrical double layers are formed at the gate/electrolyte and semiconductor/electrolyte the
surface.fluid-filled
Reprinted in
the
with gap is continued
permission from steadily
ref. [85]. by
2012 the capillary
American force.
Chemistry Owing
Society. to the
interfaces, enabling charge accumulation at the semiconductor surface. Reprinted with permission high charge carrier mo-
bility
from ref.in[85].
rubrene single crystals
2012 American ChemistryandSociety.
the high capacitance of EDLs in the electrolyte, the
device Takeya’s
realizeswork revealed
the highest another class ofever
transconductance natural semiconductor
achieved for organicgadgets functional-
transistors.
ized by the quick ionic movement in the room temperature liquid salts [78]. In this work,
strong to-fluid interfaces are framed between natural semi-conductor single gems and
ionic fluids so the structures fill in as quick exchanging natural field-impact transistors,
OFETs, with the most elevated transconductance gm = ID/VG per square channel sheet,
i.e., the most proficient reaction of the yield channel current ID to the information door
voltage VG among the OFETs so far constructed. OFETs offer the possibility for cutting -
edge minimal effort de-indecencies that can be delivered by straightforward creation
forms. There have been an account of the utilization of such polymer electrolytes as LiClO4
disintegrated in polyethylene oxide or ionic fluid continued in a polymer gel. However,
these gadgets experience the ill effects of either more unfortunate versatility or moderate
Figure
reaction 14. Color online (a) Structure of organic crystal/ionic liquid transistors.
in the (b) [emim][TFSI]. (c)
Figure 14. to VGonline
Color as a result of generally
(a) Structure moderate
of organic ionic dispersion
crystal/ionic liquid transistors. polymer grid. The
(b) [emim][TFSI].
Optical view of a rubrene crystal/emimTFSI transistor [76]. Reprinted with permission from ref.
(c)OFETs
Optical most
viewregularly
of a rubrenecomprise natural polycrystalline
crystal/emimTFSI transistor [76]. structure
Reprintedandwith
dielectric protectors,
permission from
[78]. 2012 American Institute of Physics.
for example, silicon dioxide.
ref. [78]. 2012 American Institute of Physics.With common thicknesses of the door dielectric protectors of
two or three hundred nanometers, many volts are expected to apply adequate EG for
The Forrest’s group [86] introduced a class of non-metallic cathodes with unique
properties of high-transparency and low-reflectivity having useful applications in a vari-
ety of organic devices (Figure 15). The metal-free cathode was fabricated via employing
thin copper phthalocyanine (CuPc) which was further surface coated with radio-fre-
Sensors 2021, 21, 3467 20 of 25

The Forrest’s group [86] introduced a class of non-metallic cathodes with unique
properties of high-transparency and low-reflectivity having useful applications in a variety
of organic devices (Figure 15). The metal-free cathode was fabricated via employing thin
copper phthalocyanine (CuPc) which was further surface coated with radio-frequency
and low-power sputtered ITO film. The purpose of (CuPc) film was to protect the or-
ganic layers from possible damage during the process of ITO sputtering. A model was
established which proposes that the damage-induced states at the interface of non-metallic
cathode/organic film result in efficient electron injection properties of the cathode. Because
of the low reflectivity of the metal-free cathode, a non-antireflection-coated, metal-free
transparent organic light-emitting device (MF-TOLED) was developed having almost 85%
visible transmission. Results showed that almost the same amount of light was emitted in
both forward and backscattered direction. It was observed that the performance of MF-
TOLED was almost identical to the performance of conventionally used TOLEDs which
employ a cathode having significant reflective and absorptive characteristics based on21the
Sensors 2021, 21, x FOR PEER REVIEW of 28
semitransparent thin film of Mg: Ag capped with ITO [86].

Figure15.
Figure 15.Current-voltage
Current-voltagecharacteristics
characteristicsofof a 0.4
a 0.4 mmmm diameter
diameter metal-free
metal-free transparent
transparent organic
organic light-
light-emitting device (MF-TOLED) and TOLED has grown in the same vacuum cycle.
emitting device (MF-TOLED) and TOLED has grown in the same vacuum cycle. Inset: schematic Inset: sche-
matic illustration of the MF-TOLED structure. Reprinted with permission from ref. [86]. 1998
illustration of the MF-TOLED structure. Reprinted with permission from ref. [86]. 1998 American
American Institute of Physics.
Institute of Physics.
TheLaurand
The Laurand group
group [87]
[87] generated
generated a model
a model for for
the the optimization
optimization of laser-based
of laser-based sen-
sensors.
sors.
The The authors
authors furtherfurther
explored explored the relative
the relative advantages advantages
of usingof using semiconductors
organic organic semiconduc- as a
tors as a laser material rather than dyes in a matrix. This study
laser material rather than dyes in a matrix. This study additionally outlines the additionally outlines
generalthe
structure and operative principles of this sensor, and the authors were able to demonstrateto
general structure and operative principles of this sensor, and the authors were able
demonstrate
that experimental that experimental
bulk and surface bulksensing
and surface
datasensing
utilizing data utilizing oligofluorene
oligofluorene truxene macro-trux-
ene macromolecules and a conjugated polymer for the gain region
molecules and a conjugated polymer for the gain region were consistent with model-based were consistent with
model-based
predictions, predictions,theunderscoring
underscoring utility of thisthe utility Finally,
biosensor. of this these
biosensor. Finally,
researchers these re-
compared
searchers
organic compared organic
semiconductor semiconductor
and dye-doped and dye-doped
laser sensitivity, lasertheoretical
generated sensitivity, andgenerated
experi-
theoretical and experimental biosensing data, and provided methods
mental biosensing data, and provided methods for the improvement of the sensitivity of for the improve-
mentbiosensors
these of the sensitivity
[87]. of these biosensors [87].
Biorecognition isisa akey
Biorecognition keybiological
biologicalprocess
processthat thatisiscommonly
commonlyleveraged
leveragedfor forhealthcare
healthcare
andtechnological
and technologicalapplications.
applications.In Inthis
thisstudy,
study,thetheBiscarini
Biscarinigroup
groupwaswasableabletotodevelop
developanan
electrolytegated
electrolyte gatedfield
fieldeffect
effecttransistor
transistor(EGOFET).
(EGOFET).This Thisdevice
devicewas
wasshown
showntotobebehighly
highly
sensitiveand
sensitive andspecific,
specific,enabling
enablingthe theefficient
efficientandandquantitative
quantitativeassessment
assessmentofofthermody-
thermody-
namicsassociated
namics associatedwithwithinteractions
interactions between
between a human antibody antibody and
and its
itscognate
cognateantigen
antigenat
a solid/liquid interface. At TNFα levels <1 nm, this EGOFET biosensor
at a solid/liquid interface. At TNFα levels <1 nm, this EGOFET biosensor exhibited exhibited a super-
a
exponential response,
super-exponential and itand
response, hadita had
100 pma 100limit
pmof detection.
limit EGOFET
of detection. sensitivity
EGOFET was ul-
sensitivity
timately
was dependent
ultimately upon analyte
dependent concentrations,
upon analyte with maximal
concentrations, sensitivity
with maximal being achieved
sensitivity being
in clinically-relevant
achieved TNFα concentration
in clinically-relevant TNFα concentrationrangesranges
provided the sensor
provided was was
the sensor undergoing
under-
sub-threshold regime operations. When TNFα levels were >1 nm, EGOFET biosensor re-
sponses were found to scale linearly with analyte concentration. Gate voltage was also
found to impact the dynamic range and sensitivity of these biosensors. The mechanism
was proposed to explain the correlations between sensitivity and the density of states
Sensors 2021, 21, 3467 21 of 25

going sub-threshold regime operations. When TNFα levels were >1 nm, EGOFET biosensor
responses were found to scale linearly with analyte concentration. Gate voltage was also
found to impact the dynamic range and sensitivity of these biosensors. The mechanism
was proposed to explain the correlations between sensitivity and the density of states
(DOS). Through their analyses of gate voltage-dependent responses, the authors were able
to define the binding constants for these interactions and to assess surface charges and
effective capacitance related to biorecognition reactions on the surface of their biosensor.
Importantly, the authors were able to use this biosensor to detect TNFα in human plasma,
underscoring the potential utility of this sensor in healthcare settings [70].

3.2. Integrated Biosensor with Complementary Metal-Oxide-Semiconductor (CMOS) Compatible

Dominguez’s group demonstrated the design, development, and evaluation of nano/mi-
crobiosensors which were based on optical waveguides in a highly sensitive interferometric
configuration and by using evanescent wave detection [88]. To achieve elevated sensitivity
for the designed biosensors, they were first precisely designed. Fabrication of the designed
biosensors was then achieved through standard silicon CMOS microelectronics technology.
Employing two different technologies, two integrated interferometric devices (Mach–Zehnder
interferometrics (MZI)) were developed which include (a) MZI micro-device developed
through the Anti Resonant Reflecting Optical Waveguide (ARROW) waveguide, and (b) MZI
micro-device developed through TIR waveguide. The developed biosensors were then sub-
jected to testing for their capability of direct biosensing after the coupling of the surface device
with specific receptors through the nano-scale immobilization technique. The authors con-
cluded that a laboratory-on-a-chip micro-system can be developed through further integration
of the micro-optical sensors, photodetectors, microfluidics, and CMOS electronics.

3.3. Metal-Organic Frameworks as Biosensors for Luminescence-Based Detection and Imaging

In this article, the Fairen-Jimenez’s group [89] describes metal-organic frameworks
(MOFs) generated through the self-assembly of organic linkers and metal clusters or centers.
These MOFs exhibit important chemical and structural properties that make them ideally
suited for use in biomedical, chemical, and environmental biosensing applications. Notably,
these MOFs are highly porous, exhibit significant crystallinity, have a tunable composition,
possess a large surface area, and are amenable to molecular modifications. Through a
review of the relevant literature, these authors discuss classes of MOF-based biosensors
that have been designed for qualitative sensing (including materials designed for MRI
contrast and fluorescence microscopy) and quantitative sensing (including luminescence-
based sensors that can be leveraged to directly assess analyte concentrations). Through
summaries of the pertinent literature, these authors underscore the promise of the MOF
field as a platform for the development of novel biosensors and imaging technologies [89].

4. Conclusions and Perspectives

We have surveyed in this article utilizing semiconductor structures for biosensor
application by explicitly concentrating on the application as the detecting interface for
wide bio identification and therapeutic analysis.
The quantity of production on those points is rapidly expanding mirroring the solid
interest in a clinical application. Because of trademark properties, for example, high
affectability, strength, and unwavering quality, semiconductors seem to satisfy a solid
need. In any case, for further improvement, explicit applications for which these par-
ticular applications become novel (not effectively accomplished by other material) must
be investigated.
The In2 O3 FET-included wearable biosensors with respect to chip gold side entryway
cathodes can be utilized for very touch-sensitive recognition of glucose with a location limit
down to 10 nm. In2 O3 nanoribbon exhibits showed here will empower these applications
and extend minimal effort, huge region designing methodologies to empower an assort-
ment of materials, and structure geometries in nanoelectronics. Self-assembled graphene
Sensors 2021, 21, 3467 22 of 25

FET biosensors beat the coupling partiality subordinate affectability of nucleic corrosive
biosensors and offer a pathway toward multiplexed and mark-free nucleic corrosive testing
with high precision and selectivity.
Monolayer MoS2 interfaces depicted here yield a wide accumulation of results identi-
fied with materials, gadgets, and applications parts of the utilization of MoS2 as separated
precious stones and huge zone polycrystalline movies in biodegradable electronic frame-
works. Membraneless FET biosensors recommend a compelling stage for future touchy
and reusable biosensors dependent on deformity-free VDW materials. The upgraded PEC
current acquired utilizing the wrinkled materials design empowered us to build up a
delicate and mark-free DNA biosensor with a picomolar limit-of-discovery [84].
GFETs defeat the current 2 D sensor shortage upon the ability of biosensors and offer
a platform toward multiplexed and marker-free testing with high precision and selectivity.
The significance of bio-detection and clinical determination will increasingly be upgraded.
Despite the fact that there are solid requests for research of semiconductors’ interesting
properties, we will be ready to recognize new applications for these semiconductors.

Author Contributions: Conceptualization, Z.W.; writing—original draft preparation, M.Z.; writing—

review and editing, Z.W., and M.A.; supervision, Z.W. All authors have read and agreed to the
published version of the manuscript.
Funding: This publication was made possible by the supports from the Army Research Office under
Grant Number W911NF-18-1-0458, National Science Foundation (CHE-1832167, HRD-1700429).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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