2021 3rd International Academic Exchange Conference on Science and Technology Innovation (IAECST)
Recent Advances in DNA Biosensors
2021 3rd International Academic Exchange Conference on Science and Technology Innovation (IAECST) | 978-1-6654-0267-5/21/$31.00 ©2021 IEEE | DOI: 10.1109/IAECST54258.2021.9695697
Weiye Bao*
Jiaxing Senior High School
Jiaxing, China
*
Corresponding author: guanghua.ren@gecacdemy.cn
Shuze Peng*
College of Chemical Engineering
Beijing University of Chemical Technology
Beijing, China
* Corresponding author: 2018010322@mail.buct.edu.cn
Abstract-Traditional DNA sequencing technologies are
complicated and expensive, which greatly hinders its application.
With the development of DNA biosensors, different biosensors
based on different mechanisms have been put into use in DNA
sequencing, biomacromolecule detecting and many other fields.
In this review, three different kinds of biosensing methods
including solid-state nanopores, fluorescent biosensors and
electrochemical biosensors, will be given respectively. Specifically,
their advantages, mechanism, applications and existing problems
are discussed in detail. And also, prospects for future
development will be outlined in this paper.
Keywords-DNA biosensors; solid-state nanopores; fluorescent
biosensors; electrochemical biosensors; detection
I.INTRODUCTION
DNA is a distinctive genetic material for all different
creatures, which regulates the production of proteins with
various functions. As viruses invade humans, they carry their
identifiable DNA. By detecting the occurrence of specific
DNA and analyzing the information, people can determine the
viruses or causative agents, and therefore giving an accurate
diagnosis. In addition to the pathogens, human genes could
also be changed accidentally by radiation or some harmful
chemicals, resulting in serious diseases such as cancer, heart
diseases, and neurodegenerative diseases [1]. For monitoring
DNA information including DNA sequence and concentration,
we have a better understanding of those carriers of genetic
information, which helps in the evaluation of the physical
condition, prevention and clinical diagnosis of various
diseases at an early stage.
A diverse range of DNA detection methods have been
developed in the past till now, such as conventional methods
and novel biosensing methods. Biochemical detection,
chromosome analysis and DNA electrophoresis gradient
method are three representative conventional DNA detection
methods. Biochemical methods are about the detection of
abnormal enzymes in the body by using chemical methods to
detect actual samples to check whether related or sheep
material exists, and to determine whether there is a genetic
defect. The drawback of such method is the lack of sensitivity,
and interestingly it can be tackled by solid-state nanopores that
will be discussed more in this paper. For chromosome analysis,
978-1-6654-0267-5/21/$31.00 ©2021 IEEE
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Jiayi Chen*
Department of Chemistry
University of Manchester
Manchester, UK
* Corresponding author: Jiayi.Chen-6@student.manchester.ac.uk
Bian He*
Saint John's High School
Shrewsbury, United Stares
*
Corresponding author: heb23@stjohnshigh.org
it directly detects abnormalities in the number and structure of
chromosomes, rather than detecting mutations or abnormalities
in a certain gene on a certain chromosome. The shortcoming
of chromosome analysis seems to be limitation on the
application, and its lack of specificity and functionality. In this
case, fluorescent detection has this advantage on the ability to
detect detailed genetic problems rather than vague counting.
Conventional methods are thus gradually replaced by new
biosensing methods with more prominent sensitivity, stability
and other factors.
Application of biosensors for DNA detection has become
popular for 20 years [2]. Biosensors, in general, are tiny
devices that use biological recognition properties to do
selective bioanalysis. Biosensors are quick, simple, and low
cost, and can be used in small hospitals and laboratories in
remote regions where sophisticated instrument facilities are
not available to use. There are several types of DNA
biosensors, like surface plasmon resonance (SPR) biosensors,
electrochemical biosensors. Electrochemical biosensors play a
great role in design of biosensors as they are high sensitivity
and rapid response. This leads to the devices are vital for
sequence-specific biosensing of DNA. The most common
electrochemical method for detecting DNA hybridization
concludes a current at a fixed potential. The immobilization of
the nucleic acid probe onto the transducer surface is critical for
DNA biosensors and gene chips. Solid-state nanopores
biosensors have the advantages of high flux, flexibility, ultra-
long read length, low cost, and does not require polymerase
chain reaction (PCR) amplification and sample chemical
labeling, which greatly simplifies the sequencing process.
Fluorescent biosensors have high sequencing flux and simple
library construction. These three biosensors have very broad
application prospects.
This article will focus on the development process, basic
mechanism, main problems and solutions, and application
examples of above three new biosensing methods, and will
speculate on the future development direction.
II.SOLID-STATE NANOPORE
Solid-state nanopore originated from the invention of the
Coulter counter and single-channel current recording
technology. Li et al. opened a new field of solid-state
nanopore in 2001 [3]. After more than ten years of
development, solid-state nanopore has become increasingly
mature, because of its high flux, low-cost, and lossless
characteristics.
A.Mechanism
Mechanism of solid-state nanopore will be discussed here.
A constant bias voltage applied astride the membrane will
induce a steady-state ionic current through the pore. DNA
molecules added in the negatively biased chamber will drive
the self-charged DNA molecule passing through the nanopore
by electrophoresis force. Different bases cause base-specific
ionic blockage current which provides corresponding
information of DNA sequence [4]. The distribution of
observed molecular event durations and blockade currents
shows that a significant fraction of the events obeys a rule of
constant event charge deficit indicating that they correspond to
molecules translocating through the nanopore in a distribution
of folded and unfolded configurations. A unique property of
solid-state nanopore is that mass transport is affected
significantly by the properties of the solid-liquid interface at
the wall surface as the space is confined to the length scale of
forces derived from coulombic, van der Waals and
hydrophobic interactions [5]. The imbalance between cations
and counterions results in an electrically charged solution
within the channels which gives rise to anomalous transport
behavior such as electrical current polarization and reverse
electrodialysis.
B.Methods
As a new single-molecular technique, it does so by
monitoring the ion flow through pores. [6]. The operation
steps and methods for DNA detection using solid-state
nanopore are present here. The fabrication of artificial solid-
state nanopores in specified insulating membranes. Several
methods to fabricate nanopores in electrolyte solutions have
been invented and demonstrated, the most representative one
being the in-situ fabrication methods, delivering pores with
diameters down to a single nanometer [7]. Silicon is generally
used as the substance due to its mechanical stability, high
resistivity and dielectric strength. On the silicon wafer, thin
layers of SiNx are deposited by low-pressure chemical vapor
deposition with thermally grown SiO2 covering both surfaces,
followed by the etching of exposed Si surface with KOH after
removing the thin film. As shown in Figure 1, five fabrication
processes are illustrated [8].
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Figure 1. The fabrication processes to solid-state nanopore [9].
C.Applications
Hall et al. designed a solid-state nanopore to discriminate
bare double-strand DNA (dsDNA) and RecA-dsDNA complex
[10]. Besides, solid-state nanopore can be used to fabricate
drug screening using antigen-antibody interactions. The ability
of antibodies to immunoprecipitated virus was detected and
the number of antibodies with single virus particles was
measured by a resistance pulse sensor using a submicrometer
pore. Also, charge, size, shape and sequence of amino acid can
be detected by solid-state nanopore by reflection in signal
when proteins translocate across solid state nanopore [11]. In
addition to monitoring molecular interactions, solid-state
nanopore have made development in auspicious application
nucleic acid detection. Zahid and his team presented an assay
for identifying particular sequences in solution based on the
solid-state nanopore platform [12].
D.Drawbacks
Admittedly, solid-state nanopore has a variety of
advantages, including durability, adjustable shape, and the
comprehension to work with other technologies. However,
there are still two significant problems: low temporal and
spatial resolution [13]. On one hand, due to the thickness of
the solid-state nanopore, a minimum of 4 DNA bases passes
through the pore at the same time, which made it hard to
distinguish the different bases. On the other hand, the fast
translocation of the DNA through the pore in the electric field
and the slow data collection increased the difficulty of
discrimination between the bases.
A high temporal resolution to control DNA translocation is
necessary. Two DNA manipulation methods, called voltage-
driven counter-pressure (V-P) method and pressure-driven
counter-voltage (P-V) method, are applied by using both
pressure gradient and voltage [14]. To do the V-P and P-V
methods an instrument is constructed by dividing two
chambers with opposite charges using a solid-state nanopore
chip, as shown in Figure 2. A nitrogen tank with one side open
is connected to the trans chamber to conduct changeable
pressure against the driving voltage. With the precise control
of DNA translocation using the V-P method, the speed of 3kbp
double-strand DNA passing through the pore has gone through
a decrease of 125~200%, providing a better single-molecule
manipulation method.
Figure 2. The schematic diagram of apparatus for V-P method [14].
For improving low spatial resolution, the current resolution
must be improved first. Transverse tunneling current is
believed to be one of the most effective way because of the
following reasons. The tunneling current upward or downward
spike can be acquired simultaneously with the ionic current
blockage, which can support the effectiveness of the
translocation signal [15]. Due to the tiny gap, strong
interaction appears between DNA and the surface of the
nanopore, which is believed to generate a resonance curve
serving for the discrimination of the four nucleotides. The
current chemical modification can be applied to fabricate the
functionalized probes to enlarge the difference between the
probe and four bases.
In order to increase the spatial resolution, atomically thin
nanopore membranes was put into use. Liu et al. proved that
monolayer or few-layer thick exfoliated MoS2 with
subnanometer thickness can be placed at a predesigned
location on the SiNx membranes to make atomically thin
nanopore membranes [16].
III.FLUORESCENT BIOSENSORS
Fluorescent biosensors refer to a technology that completes
molecular recognition by receiving changes in fluorescent
signals. It is widely used in individualized treatment, food
safety, environmental monitoring, material chemistry and other
fields because of its fast speed, simple operation, high
sensitivity, high stability, and high specificity,
The sensor based on fluorescence resonance energy transfer
can detect the target substance by changing the fluorescence
intensity without any separation and washing [17]. The
constant breakthroughs in nanotechnology have opened up the
application of nanomaterials as fluorophores and quenchers in
fluorescence resonance energy transfer systems. Therefore,
most sensors use carboxyfluorescein (FAM), anthocyanin 5
(Cy5), up-conversion luminescent materials, quantum dots and
metal nanoclusters as fluorescent donors, and use graphene
oxide (GO) and molybdenum disulfide (MoS2) as the
fluorescent acceptor.
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A.Mechanism
In fluorescence, the intensity is measured directly, without
comparison with a reference beam. Cationic polythiophenes
transduce oligonucleotide hybridization into a colorimetric
output based on conformational changes of the polymer upon
interaction with single-stranded DNAs or double-stranded
DNAs. Cationic materials serve as donors in fluorescence
energy-transfer assays, displaying signal amplification. Signal
transduction in aqueous media is controlled by specific
electrostatic interactions [18]. A novel fluorescent paper-based
DNA sensor that employs a highly specific pyrrolidinyl peptide
nucleic acid (acpcPNA) probe was developed for the sensitive
and selective detection. The monetization of fluorescent signal
responses of a fluorescent dye performs the DNA detection.
The dye binds to the single-strand DNA target selectively over
the PNA probe, which employs a custom-made portable
fluorescent camera gadget. Under the optimal conditions, the
limit of detection of 5 pM was obtained for short synthetic
oligonucleotides. Benefitting from the signal amplification
achieved, this system was successfully applied to detect the
HCV complementary DNA (cDNA) obtained from clinical
samples with satisfactory results [19]. The proposed fluorescent
paper-based sensor demonstrated a great potential to be used as
a low-cost, simple, label-free, sensitive, and selective DNA
sensor for point-of-care applications.
B.Applications
Hu et al. reported a multicolor fluorescent biosensor for
multiplexed detection of DNA [20]. This work showed for the
first time that cationic aggregated and quenched perylene can
act as a broad-spectrum, label-free quencher through violet
electrostatic interactions. When aggregated with
oligonucleotides, PDI could efficiently quench a wide range of
adjacent conjugated anionic fluorophores that emit in the
visible to near-infrared wavelength range. This broad-spectrum
quencher was subsequently employed to create a multicolor
biosensor for label-free multiplexed fluorescence detection of
DNA. Aggregated PDI has a very high quenching efficiency of
all the sensing system's ssDNA-labeled fluorophores. This can
include low background fluorescence and thus low detection
limits. The sensing system they proposed enables simultaneous
and multicolor analysis of several oligonucleotides in a
homogenous solution. This implies the sensing system has
potential application in the rapid screening of various bio
targets.
As shown in Figure 3, Kamaci et al. developed a highly
selective and sensitive fluorescent biosensor based on
poly(azomethine-urethane) and zeolite for the determination of
DNA molecules [21]. DNA molecules were detected by using a
novel fluorescent zeolite-based composite. A novel fluorescent
composite including poly(azomethine-urethane) (PAMU) and
zeolite was first created for this purpose. Zeolite was employed
to improve the interaction between polymer and DNA by
enhancing anionic or cationic functional groups in the polymer
matrix. The sensing property of zeolite-based composites was
further investigated using fluorescence measurements.
Shen et al. designed a novel and sensitive turn-on
fluorescent biosensor for DNA detection using Sm3+-modulated
glutathione-capped CdTe quantum dots [22]. The designed
biosensor was used to determine HsDNA in synthetic samples
and human fresh serum samples. It was an exceptional finding
to further study flawless analytical performance.
Figure 3. Schematic illustration of the developed biosensing method [21].
C.Drawbacks
Fluorescent as a fast and easy to operate method with high
stability was widely applied in the diagnoses of diseases.
However, there are two big problems which are the lack of
sensitivity when detecting low concentration samples and the
false-positive signal due to DNA amplification [23]. For the
next part, we are will talk about current methods which could
effectively solve the problems.
Figure 4. Schematic diagram illustrating the biosensing method using DNA-
functionalized Au nanoparticles [24].
The detection sensitivity of fluorescent biosensors was
lower than other detection methods. To achieve the goal of
high-sensitivity detection, people began to focus on the
research of signal amplification. After research, people enhance
the fluorescent signal through the target cycle and the cascade
amplification of the fluorescent signal. The methods mostly use
strand displacement reaction and enzyme to promote the target
cycle and signal amplification. In recent years, signal
amplification strategies have made great progress in improving
sensor sensitivity, such as rolling circle amplification [23] and
exonuclease-assisted cycle amplification [25].
Fluorescent biosensors are also limited by the false-positive
signals produced during the signal amplification. To avoid
DNA amplification with many drawbacks, the called DNA
functionalized Au nanoparticles fluorescent probes were
introduced [24]. As shown in Figure 4, DNA-functionalized Au
nanoparticles, which function as an indicator, are constructed
by connecting a 20 nm Au particle and a 60 nm Au particle to
dsDNA and ssDNA. As the ssDNA dissolves when exposed to
the CRISPR-Cas12a complex activated by the target DNA, the
nanoparticle is disintegrated, followed by an optical signal of
red-purple color generated from fluorescein isothiocyanate
(FITC). By detecting a distinct color change from purple to
red-purple, people can easily determine the presence of the
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target DNA. With the improved optical signal-enhancing
method, there will be no nucleic acid amplification anymore.
IV.ELECTROCHEMICAL BIOSENSORS
Electrochemical biosensors have gradually caught people's
attention with the development of nucleic acid electrochemistry.
The electrochemical biosensor uses the electrode as the
transducer, fixes the ssDNA probe to the surface of a gold
electrode, carbon paste electrode or glass electrode, and then
immerses it in a solution containing the target ssDNA molecule.
At this time, the ssDNA probe on the electrode is a
hybridization of target DNA single-stranded molecules with
complementary sequences in solution. The DNA sensor uses
DNA as a sensitive element and converts the biological signals
generated by the interaction between various molecules into
detectable physical signals such as light, electricity, and sound
waves through a transducer.
Because DNA molecules as probes have strong affinity
with biomacromolecule, electrochemical biosensors have the
characteristics of rapid and direct access to complex
information, low cost, high selectivity, and no damage to the
test system. In recent years, these biosensors have been widely
used in genetic diagnosis, environmental monitoring, drug
research and other fields.
A.Mechanism
The principle of electrochemical biosensor is the biological
reaction between bioreceptor and target which produce or
consume ions or electrons, changing the electric current,
potential, or other electrical properties of the detecting solution.
The biological signals will be converted into a detectable
electrical signal proportional to target concentration by
transducer, displaying on a computer as a recorder. The DNA
structural modifications and damage can be electrochemically
detected following the changes in the oxidation peaks of
guanosine and adenosine residues and the occurrence of the
free guanine residues electrochemical signal. The processes
include leading to the condensation and aggregation of the
DNA strands, producing rigid structures which favored-the
second step in which the guanine hydrogen atoms-the
participation of them in the C-G base pair and interacting with
the GEM ribose moiety fluorine atoms [26].
The functionalized gold electrodes with the single stranded
DNA capture probe are been used for the detection of DNA. A
redox molecule into the buffer such as fairy ferrocyanide works
along with the operation. A differential pulse voltammetry can
be used with electrochemical methodologies such as
electrochemical impedance spectroscopy. Differential pulse
voltammetry is a technique for the DNA detection where the
DNA signals and signal peak heights are related which every
time a new signal is received, a new peak height is been
changed accordingly as the concentration increases.
B.Methods
Electrochemical biosensors offer sensitivity, selectivity and
low cost for the detection of selected DNA sequences or
mutated genes associated with human disease. All of them take
advantage of the nanoscale interactions between the target
molecules in the solution which would be a recognition layer
with a solid electrode surface. Numerous approaches to
electrochemical detection have been developed.
Direct electrochemical detection is based on the reduction
and oxidation of DNA at a mercury electrode. The amount of
DNA reduced or oxidized could reflect the amount of DNA
captured. DNA oxidation has been carried out through
absorption stripping voltammetry. By inducing an electrostatic
buildup of analyte at the electrode surface before the detection
step, this technique archives its high sensitivity as a biosensor.
Methods to oxidize target DNA indirectly through the use
of electro-chemical mediators have also been explored.
Polypyridyl complexes of Ru(II) and Os(II) mediates the
electrochemical oxidation of guanine. In this strategy,
chemically modified bases are incorporated into PCR products,
and the resulting DNA is detected at an ITO electrode by
catalytic oxidation of the modified base. This method provides
high sensitivity without complex instrumentation through
redox-mediated DNA oxidation.
DNA-specific redox indicator detection is similar to
fluorescent methods discussed above. Target DNA sequences
are labeled with redox-active reporter molecules. Appearance
of the characteristic electrochemical response of the redox
reporter therefore signals the hybridization events. Using
physical separation methods to isolate the labeled sequences,
detection limits on the order of ∼1010 molecules have been
reported.
C.Applications
Tan et al. created a simple, fast, immobilization-free, and
ultrahigh selective electrochemical biosensor to identify target
DNA species [27]. It made use of the signal amplification of
nicking endonuclease-assisted target recycling as well as the
differential diffusivity of electroactive reporter-tagged long and
short DNA toward a negatively charged ITO electrode surface.
Furthermore, because of the high selectivity of nicking
endonuclease assisted target recycling, the suggested biosensor
can discriminate even against a single-base mismatch.
Moreover, DNA hybridization and recognition were all carried
out in a homogeneous solution, which has high efficiency. The
suggested biosensor can be used to quantify DNA and is
predicted to identify single nucleotide variations (SNPs). The
proposed method could be used to detect other DNA sequences
that contain the recognized sequence.
Liu et al. developed a homogeneous or immobilization-free
electrochemical biosensor [28]. It addressed issues that include
long assay time and high cost caused by relatively complex
interface operation and washing procedures and the inclusion
of extra exogenous reagents. Three dynamic DNA assembly
strategies, including DNA- fueled target recycling, CHA and
HCR were explicitly intended to generate proximate DNA
motifs for the autonomous execution of proximity-based
surface hybridization. The biosensor has enormous promise for
the development of sensitive biosensing platforms for
application in bioanalysis, illness diagnostics, and clinical
biomedicine.
As shown in Figure 5, Xiong et al. created a reusable,
selective, and simple E-DNA biosensor for the detection of
target DNA by integrating a triple-helix molecular switch with
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an electrochemical dual-signaling radiometric to detect target
DNA. Such electrochemical biosensor could be easily adapted
to detect arbitrary targets by just changing its DNA sequence.
This broad applicability has enormous potential in bioanalysis,
early clinical diagnosis, and scientific research.
Figure 5. Schematic diagram of the electrochemical iosensor for T-DNA
detection [29].
D.Drawbacks
To detect the small changes of the signal of samples, the
sensitivity of the biosensor is really important. Although the
electrochemical biosensor requires an easy operation, and
provides with relatively cheap, selective, and sensitive
detection of the target, while doing low concentration detection,
the electrochemical biosensors are not sensitive enough to do
precise detection due to the limited redox tags that could be
attached to the target, which can only provide relatively low
reaction signal compared to the noise [30-32].
To improve the sensitivity, amplification of signal should
be conducted, which could be done by an advanced signal
magnification method called coenzyme-mediated electro-
grafting with electro reversible addition-fragmentation chain-
transfer (eRAFT) polymerization [31]. The electro-grafting
method help recruiting more ferrocene tags to the surface of the
electrodes which significantly increased the voltammetric
signal. As the polymerization method of electro-grafting
eRAFT has already been proved to be an efficient method that
could be easily operated at room temperature where proteins
and biological materials can function normally. However, the
traditional initiating process of eRAFT requires radical form
outside, which could react with the radicals in charge of the
growth of the polymer chain stagnating polymerization, and
coenzyme is applied as an alternative to mediates RAFT agents
to get initiating radicals which is much easier and controllable.
With amplified signal and simplified operation process,
electrochemical biosensors will become increasingly popular in
the future.
V. CONCLUSIONS
The present paper mainly introduced mechanisms,
applications, some current challenges to three types of widely
used DNA biosensors, including solid-state nanopores,
fluorescent biosensors, and electrochemical biosensors. The
detection method using solid-state nanopore which is durably
and highly adjustable becomes more mature as the problem of
low temporal and low spatial resolutions were ameliorated,
with better fabrication techniques and method control of single
molecules developed, which made the solid-state nanopore a
promising technology for DNA sequencing in the future.
Owing to the application of better amplification of DNA
samples and optical signals, the fluorescent improved in its
sensitivity while reduced it false-positive rate. Due to the
sensitivity and low cost, the fluorescent biosensor could be
applied in drug discovery and diseases diagnosis.
With the application of nanomaterials, the challenges,
including a variety of interference factors and low sensitivity
which impeded the electrochemical biosensor from practical
applications, has been overcome. Hopefully, electrochemical
biosensor could be improved and applied in research of DNA
interaction and drug production.
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