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Fabrications, Applications and Challenges of Solid-State Nanopores: A Mini Review

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Fabrications, Applications and Challenges of Solid-State Nanopores: A Mini Review

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Nanopore sensors are expected to be one of the most promising next generation sequencing technologies, with label-free, amplification-free and high-throughput fea‐ tures, as well as rapid detections and low cost. Solid-state nanopores have been widely explored due to their diverse fabrication methods and CMOS compatibility. Here, we highlight the fabrication methods of solid-state nanopores, including the direct opening and the tuning methods. In addition, molecular translocation developments, DNA sequencing and protein detections are summarized. Finally, the latest progress relating to solid-state nanopores is discussed, which helps to offer a comprehensive under‐ standing of the current situation for solid-state nanopore sensors.
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ARTICLE
Nanomaterials and Nanotechnology
Fabrications, Applications and Challenges
of Solid-state Nanopores: A Mini Review
Review Article
Zifan Tang1, Daihua Zhang1, Weiwei Cui1, Hao Zhang1, Wei Pang1 and Xuexin Duan1*
1 State Key Laboratory of Precision Measuring Technology and Instruments, College of Precision Instrument and Opto-electronics Engineering,
Tianjin University, Tianjin, China
*Corresponding author(s) E-mail: xduan@tju.edu.cn
Received 19 October 2015; Accepted 29 April 2016
DOI: 10.5772/64015
© 2016 Author(s). Licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Abstract
Nanopore sensors are expected to be one of the most
promising next generation sequencing technologies, with
label-free, amplification-free and high-throughput fea‐
tures, as well as rapid detections and low cost. Solid-state
nanopores have been widely explored due to their diverse
fabrication methods and CMOS compatibility. Here, we
highlight the fabrication methods of solid-state nanopores,
including the direct opening and the tuning methods. In
addition, molecular translocation developments, DNA
sequencing and protein detections are summarized.
Finally, the latest progress relating to solid-state nanopores
is discussed, which helps to offer a comprehensive under‐
standing of the current situation for solid-state nanopore
sensors.
Keywords Nanopore, Fabrication, Molecular Transloca‐
tion, DNA Sequencing, Protein Detection
1. Introduction
In recent years, advances in the “Nano-Bio” research field
have prompted a great deal of interest in the scientific
world. Nanoscale tools serve as ideal interfaces to inter‐
rogate biological systems, since the sizes of many nano‐
structures are comparable to those of typical biomolecules.
Among them, nanopore sensors have been highlighted as
potential tools to detect individual biomolecules [1-10]. By
mimicking the functions of natural biological ion channels,
nanopore sensors can control access and selectively
identify for biomolecules at the single molecule level. The
principle of nanopore sensing is based on the Coulter
counter technique [11, 12]. As shown in Figure 1, an ultra-
thin membrane with a nanoscale pore separates two
reservoirs filled with electrolyte solutions. Ionic current
information is created by electrically driving the individual
biomolecule into a nanopore. Furthermore, by analysing
the ionic current signature, a molecule's conformation, as
well as structural and chemical properties of the biomole‐
cules, can be obtained.
Currently, there are three major types of nanopores:
biological nanopores, solid-state nanopores and hybrid
nanopores. The biological nanopores are mainly created
from natural protein molecules (e.g., channel proteins),
which present precisely controlled structures and interfa‐
cial chemistry [13, 14]. However, the biological nanopores
are limited by a short life time, intrinsic instability and the
strict requirement of a specific environment, which are not
favoured for a device’s long-term operations. Solid-state
nanopores are usually fabricated by top-down lithography,
which have the advantages of higher stability, precisely
tunable size, robust chemical and thermal characteristics,
1
Nanomater Nanotechnol, 2016, 6:35 | doi: 10.5772/64015
and CMOS compatibility [15-17]. The detection principles
of the nanopores are distinguishing the current fluctuations
induced by analytes passing through the nanopores. If
analytes are within identical spherical shapes, it is easy for
solid state nanopores to distinguish different sizes of the
analytes by the recording amplitude of the current fluctu‐
ations [18]. However, if the analytes show a little difference
in shape and size, the detection results of solid state
nanopores are usually unsatisfied [19]. This has been
improved by introducing specific interactions between
nanopores and analytes by assembling pore-forming
synthetic soft materials inside solid-sate nanopores; these
are referred to as hybrid nanopores. By combining specific
surface chemistry, the drawbacks relating to the solid
nanopores can be overcome and the detection limit of
nanopore sensors can be improved [20, 21].
This review focuses on solid-state nanopores. We will first
introduce the principle of nanopore sensors, and then
present fabrications and applications of solid-state nano‐
pores. Furthermore, recent advances, challenges and
opportunities of nanopore sensors are discussed as well.
2. Principle
Due to the small size of the sensors, nanopore sensors are
capable of detecting small objects (e.g., nanoparticles), even
at the individual molecule level [22]. The principles of the
detection process and the equivalent circuit are shown in
Figure 1. An insulating membrane containing a nanometre
pore is sandwiched between two reservoirs filled with
electrolytes [14, 23, 24]. Ions are driven through the
nanopore to generate an ionic current with the applied
voltage. The conductivity of the apparatus remains
stationary in a pure electrolyte solution and the current is
a constant value with only a few fluctuations, which
happens if there are no objects passing through. When
analytes are added to one side of the chamber, they can be
electrophoretically driven through the pore. A current
blockage is created when an object passes through the
nanopore. The measurable signal is determined mainly by
two factors: steric exclusion and ion polymer properties.
Steric exclusion can decrease the effective pore diameter
and decrease the current. An ion polymer contains two
parts: one is for co-ion repulsion, which will decrease the
current, and the other is for counter-ion attraction, which
will increase the current. Furthermore, these factors are all
affected by the target concentrations. By increasing the
concentration of the free analytes, the appearance frequen‐
cy of the blockage current will increase. It provides a direct
measurement of the frequency content, which contains the
characteristic timescales of the analyte-nanopore interac‐
tions. Therefore, we can analyse the abundant bimolecular
properties from the current information, such as their size,
charge, length and specificity.
3. Fabrications of Solid-State Nanopores
The solid-state nanopores have gained increasingly
attention because of their high stability and potential to be
produced on a large scale. A variety of materials have been
successfully utilized in fabricating nanopores, such as
silicon [25, 26], silicon nitride [27], silicon oxide [28-30],
polymers [31, 32], aluminium oxide [33, 34] and graphene
[35-41]. The general nanopore fabrication process can be
divided into the opening and the tuning methods. The
opening methods include focused ion beam (FIB) drilling
[42-47], electron beam (e-beam) drilling [16, 30, 36, 39, 41,
48, 49], anodized alumina oxide transferring [50-53] and the
wet etching method [25, 26, 54-57]. However, in most cases,
the pore, with the desired size and shape, cannot be
obtained directly. Extra tuning steps are normally required,
such as deposition and thermal treatment. By combining
all of these techniques, different sizes, shapes and proper‐
ties of nanopores can be fabricated. Table 1 summarizes the
features of these methods.
3.1 Direct opening methods
FIB involves a direct drilling method, which can create
nanopores in specific areas relating to different types of
membranes [47, 48, 58]. It was reported as the first techni‐
que for fabricating a single nanopore in 2001 by Li et al. [47].
The drilling process is shown in Figure 2(a). Li et al. used
an Ar+ ion beam to drill a nanohole in a free-standing
silicon nitride (Si3N4) membrane with a cavity on its
opposite surface. A feedback detector was attached below
the ion beam machine to indicate the stop point when the
ions penetrated the membrane. By controlling the exposure
time of the ion beam, the size of the nanopore can be well
controlled. In addition, some critical parameters during the
FIB process are also important in order to adjust the pore
size, which will be discussed in 3.2.
An intense e-beam is involved in another common method
to fabricate nanopores [16, 30, 36, 39, 48, 49]. The first
reported example using an e-beam to drill nanopores was
Storm et al. [59]. An e-beam can fabricate nanopores in the
range of 2-200 nm by manipulating the beam parameters,
such as current, intensity and dwell time. However, the
diameter of the nanopore is limited to the thickness of the
membrane. In order to prepare nanopores with high
precision in feature size, auxiliary gases are introduced.
analyte s olution
nanopore
membrane A
V
Circuit
board
(c) (d) (e)(b)
(a)
Figure 1. Nanopore principle scheme: (a) the profile of the device; (b-e)
different analytes passing through the pore, which will create characteristic
signals
2 Nanomater Nanotechnol, 2016, 6:35 | doi: 10.5772/64015
Yemini et al. first reported etching Si3N4 using XeF2, which
eventually resulted in 17–200 nm nanopores in the Si3N4
membrane [49]. The drilling process is shown in Figure
2(b). Furthermore, Kim et al. found that the intensity of e-
beam determines the formations of the nanopores: (a)
nanopore expansion is caused by atom sputtering at higher
intensities, while (b) surface-tension-driven nanopore
contraction occurs at lower intensities [60].
Anodized alumina oxide transferring can be used to
fabricate nanopores as well; see Figure 2(c). This method
utilizes plasma etching through a nanoporous template to
transfer the pore patterns onto the underneath substrates
[50-53]. A typical nano-alumina template can be created by
electrochemical anodization of aluminium film, which is
rather easy compared with FIB or e-beam fabrications,
while the templates can be used multiple times [61, 62].
Another advantage of this masked method is that the
nanopore array can be efficiently fabricated.
Besides directly nanodrilling, wet chemical etching, which
follows the standard micro-scale lithography process, has
been demonstrated to be an alternative nanopore fabrica‐
tion technique. The advantages of this method are simple
and cost-effective, as well as offering multifunctional
characters [25, 26, 54-57]. Figure 2(d) shows a typical wet
etching process. First, a standard micrometre pattern is
fabricated by the standard lithography process, then an
inverted pyramid structure with a sharp tip on the bottom
is created using anisotropic wet etching. Finally, nanopores
are formed by etching the back on the other side of the
substrate using alkaline solutions (e.g., KOH). Given the
different etching rates in each of the crystal faces, aniso‐
tropic wet etching can fabricate nanopores with conical or
pyramidal geometries, in contrast to the cylindrical inner
structures drilled by FIB or e-beam. Nanopore arrays can
be efficiently fabricated by wet etching as well [63, 64].
3.2 Tuning methods
In order to obtain the desired dimensions of the nano‐
pores, a tuning process to further enlarge or shrink the
nanopores is usually required following direct drilling. In
FIB tuning, temperature plays an important role in pore
opening and shrinking. According to the experiments of
Li et al. [47], when an Ar ion beam is sputtered on the edge
of the nanopore at room temperature, the pore prefers to
be closed, since a very thin (~5 nm) stressed viscous surface
layer is created by the ion beam energy. However, when
the temperature is reduced to 0 °C, the nanopore prefers
to be opened [59, 65, 66]. Besides the temperature, the type
of ions has an effect on the shrinkage of the pore. The
shrinkage happens when the diameter of the pore is
smaller than the thickness of the membrane [47, 48, 58].
Heavier ions (He, Ne, Ar, Kr and Xe) can shrink the pores
more efficiently than lighter ones [67, 68]. By fine tuning
these factors, nanopores with desired diameters can be
fabricated.
The e-beam can tune the nanopores as well. When the
membrane is exposed to a higher intensity of e-beam, the
size of nanopore tends to be expanded through atom
sputtering. On the other hand, a lower e-beam intensity
will lead to nanopore shrinkage [60]. In addition, similar
to the FIB, nanopore shrinkage also happens when the
diameter of the pore is smaller than half of its thickness
[49, 69].
Deposition of nanoscale thin films on nanopores is another
effective method to decrease the pore diameter. Atomic
layer deposition is one of the most popular deposition
methods. Deposition of thin polymer films through a layer-
by-layer (LBL) assembly approach has been reported to
shrink nanopores; this approach also has great advantages
in terms of low cost and the ability to tune the surface
chemistry of the nanopores [16, 27, 30, 31, 35, 70, 71].
Direct annealing can shrink the nanopore as well [72, 73].
In contrast to FIB and e-beam shrinkage, thermal treatment
can change the morphology of the nanopores. For a silicon
dioxide (SiO2) membrane, it was found that, at the appro‐
priate temperature (1,125 °C), the average shrinking rate of
the pore is ~22 nm per minute. Meanwhile, at a lower
temperature (<1,000 °C), the diameter of the pore shows
little or even no change. When the nanopore is exposed to
a higher temperature (>1,250 °C), the SiO2 membrane may
be broken, while the shrinkage rate is too fast to be con‐
trolled. Another advantage of thermal shrinkage is that it
will not increase the noise of the electrical signal of the
nanopore sensors, since no additional surface charge is
added.
4. Applications
Due to the simple operating principle of nanopore sensing
and the technology available for nanopore fabrications,
increasing developments regarding nanopore sensors have
occurred. Solid-state nanopore devices have been success‐
fully applied, from an initial method as a simple detector
to a powerful technique to study complex molecular
interactions, as well as mimicking the functions of natural
systems. In this section, we will discuss the applications of
nanopores as sensing platforms, including molecular
translocation, DNA sequencing and protein detections.
4.1 Molecular translocation
Biomolecular translocation is an important process in the
life sciences. In the biological system, migration of large
biomolecules through pores (1~10 nm) is a common
physical behaviour and usually plays key biological roles.
Typical examples include DNA transduction between cells,
phages causing viral infections, RNA translation and
protein secretion.
Kasianowicz et al. first reported their studies into DNA
translocation using nanopore devices [69]. As shown in
Figure 3(a), they were able to measure the length of the
polynucleotide according to the durations of the transient
3
Zifan Tang, Daihua Zhang, Weiwei Cui, Hao Zhang, Wei Pang and Xuexin Duan:
Fabrications, Applications and Challenges of Solid-state Nanopores: A Mini Review
current. After a large amount of experiments, for a given
polymer size, they found that the durations of the transient
current showed a linear relationship with the polymer
length. Since then, the measurement of the length of
different biopolymers using nanopore devices has been
carried out by many other groups [74-78]. However, it was
also found that the linear relationship between the mole‐
cule length and the durations of transient current cannot be
(a)
(b)
(c)
(d)
Figure 2. Schematic illustration of the nanopore fabrication process: (a) FIB, (b) e-beam, (c) anodized alumina transferring and (d) wet chemical etching methods
Method Material Description Feature Reference
Ion beam
(opening, tuning)
SiC, Si3N4, SiO21. FIB directly drills the surface to open a
pore
2. The ion acceleration sputters the
nanoscale pore for shrinkage
1. The pore prefers to be opened at 0°C and
closed at room temperature
2. Heavier ions shrink the pores more
efficiently than lighter ones
3. Shrinkage happens when the pore
diameter is less than the film thickness
[42-47]
e-beam
(opening, tuning)
Si3N4, Al2O3, graphene
SiO2
1. A focused e-beam directly drills film by
water vapours or XeF2 assisted
2. e-beam irradiates nanoscale pores for
shrinkage
1. The pore prefers to open under high e-
beam intensity and shrink under low
intensity
2. Shrinkage happens when the pore
diameter is less than the film thickness
[16, 30, 36, 39, 48, 49]
Wet etching
(opening)
SiC, Si 1. Conventional anisotropic wet etching
with proper length width ratio
1. Nanopore arrays
2. Larger pore diameter than other methods
[25, 26, 54-57]
Anodized alumina
transferring
(opening)
Al2O32. Plasma etching through a nanoporous
template occurs in order to transfer the pore
patterns
1. Nanopore arrays
2. Mask can be used multiple times
[50-53, 61, 62]
Deposition
(tuning)
SiC, Si, Si3N4, Al2O31. Chemical vapour or mental deposits on a
nanoscale pore enable tuning of the
diameter
1. LBL-dominated shrinking process
2. Fine-tuning the size and surface
properties
[16, 27, 30, 31, 35, 70,
71]
Thermal treatment
(tuning)
Si, SiO21. Direct heating due to a high temperature
(1,000-1,250 °C) causes shrinkage
1. Linear shrinkage rate
2. Unfavourable surface charge and
electrical noise will not be introduced
[72, 73]
Table 1. Nanopore fabrication methods
4 Nanomater Nanotechnol, 2016, 6:35 | doi: 10.5772/64015
applied to every case. It only works well when the scale of
nanopores is well matched to the polymer size. A possible
reason for this is that the length of the molecule not only
dominates polymer effective friction with the wall, the
shape of the pore and the state of the polymer also affect
the time taken by the polymer to pass through the pore.
Storm et al. reported their experiments on electrophoreti‐
cally deriving DNA molecules, ranging from 6,500 to 97,000
base pairs through a 10 nm pore [79]. They proposed that
both hydrodynamic dragging and electrically driving
contribute to the force on polymers. When the pore is much
larger than the polymer, the linear relationship between the
signals and polymer size is not correct. Instead, the
exponential relationship can be applied [80]. In this case,
the forces on the polynucleotide are complicated, which
may include the applied driving voltage, pore-polymer
interactions, viscous forces and the force from non-targeted
polymers. All of these factors will affect the durations of the
polymer translocations. Furthermore, it was found that the
directionality of polynucleotide molecules passing through
the nanopore is very important for translocation analysis
[81, 82]. Polynucleotides have global orientation, with one
end at 5' and the other end at 3'. Experiment showed that
the ionic blockade current is different when DNA passes
through the nanopore from different directions [83]. If it is
threaded from 5’, the bases of a five-threaded DNA
experience larger effective frictions, resulting in a higher
blockage current and better signal resolution [81, 82].
4.2 DNA sequencing
To date, the most attractive application for nanopore
sensing is DNA sequencing; indeed, it is expected to result
in the third generation of DNA sequencing technology.
Compared with previous methods, such as Sanger,
Illumina and Ion Torrent sequencing, nanopore devices
show great advantages in terms of label-free, amplification-
free, high-throughput DNA sequencing without the
requirement of cutting long DNA chains into segments.
The implementation of nanopore devices in DNA sequenc‐
ing should represent substantial progress, along with a
higher speed and a lower price.
Li et al. reported the first DNA sequencing experiment
using solid-state nanopores [85]. As shown in Figure 3(b),
a bias is applied between the two chambers and the
polynucleotides are pushed into the nanopore due to being
negatively charged. When DNA molecules pass through
the nanopore, the ionic conductance changes due to the
relatively smaller charge carried by DNA molecules.
Meanwhile, salt concentration influences the current as
well. Changes in the current depend on the conductance
difference between salt concentration and DNA molecules
[29, 86]. The base structures of DNA are different. Purine
bases (A and G) are larger than pyrimidine bases (C and T),
which will result in stronger interactions with the nanopore
surface. Thus, the purine bases show a stronger blockade
current than pyrimidine bases. Besides, each base has
different charges, interaction potentials and orientations
relating to the dipole moments against the nanopore
surface. Due to the different properties of these bases, each
base can be discriminated by analysing the spikes of the
ionic current (spike durations, blockade fractions or voltage
fluctuations in the longitudinal direction of the pore).
The sensing rate of DNA sequencing, when using nano‐
pores, is limited due to the fast translocation rate of DNA
molecules. This problem could be solved by controlling the
electrolyte temperature, salt concentration, solution
viscosity and the bias voltage across the nanopores.
Fologea et al. reduced the molecule translocation speed by
an order of magnitude, which largely facilitated the base
discrimination ability at such a low translocation speed
[87]. Meanwhile, numerous studies have focused on DNA
sequencing using nanopore arrays, which will largely
increase the throughput of sequencing [88-90].
(a)
(b)
(c)
Figure 3. Typical applications of nanopore sensors: a nanopore device for (a) polymer length measurement, (b) DNA sequencing tool and (c) single protein
detections [84]
5Zifan Tang, Daihua Zhang, Weiwei Cui, Hao Zhang, Wei Pang and Xuexin Duan:
Fabrications, Applications and Challenges of Solid-state Nanopores: A Mini Review
4.3 Protein detections
Proteins are significant to life. They transform into different
multidimensional structures to execute an amazing variety
of functions [91]. Using nanopores is also leading to rapid
strides in protein detections (Figure 3c). It offers a distinct
advantage when protein size, shape or charge state can be
identified at the scale of a single molecule. Besides, protein
folding or unfolding states can be analysed as well, which
is important in order to understand the stability and
conformation properties of proteins. Purnell [92] demon‐
strated that, by adding the chemical denaturing agent to the
protein solutions, the signal of the protein translocation
shows different blockades, which are responding to the
folded and unfolded states of the proteins, respectively.
Furthermore, the dynamic nature of the proteins can be
detected in real time by nanopores, which is crucial in order
to understand protein structures and functions [93]. It has
been reported that the conversion from normal proteins to
misfolded ones is the pathogenesis of many diseases, such
as prion proteins [94-96]. Nanopore-based protein detec‐
tions can distinguish the conformation difference from the
current properties [97]. Based on these results, a nanopore
detection system is a rather promising tool in the realm of
portable healthcare devices.
5. Recent Advances and Challenges
5.1 Recent advances
Nanopore sensors, which offer a fantastic technique for
detecting molecules at the single molecule level, have been
developed for more than 15 years. Many promising
applications have been explored in the process, including
genome sequencing and medical diagnostics. In recent
years, due to the development of two-dimensional (2D)
materials, many studies have used these new types of
materials to fabricate nanopore devices (figure 4a), such as
graphene [35-41], mica [98] and MoS2 [99]. Compared with
conventional solid materials, 2D materials are thinner and
more flexible, as well as demonstrating higher sensitivity
[100]. Meanwhile, the effects of the geometric nanopores on
an ionic current have been studied. The electric field inside
the pore will be different when the pore has a different
geometry [101-104].
The surface modifications of nanopore have been devel‐
oped to reduce the non-specific adsorptions, pore clogging
and electrical noises [106-111] (Figure 4(b-c)). Chemical [27,
70, 112, 113], physical [30] and biological modifications [81,
114] have been applied to realize diverse functions of solid-
state nanopores [115-117]. In previous report, the physical
modification of nanopores is usually neglected as a surface
modification technique. As mentioned in Section 2,
different ions caused shrinkage and thermal treatments on
nanopores showed a great improvement in device per‐
formance, indicating the ability to fine-tune the surface
properties with angstrom precisions. Besides, after the
physical modifications, the surface charge is neutralized,
which is preferable for DNA captures, and the 1/f noise can
be reduced. All of these modifications improve the DNA
sequencing resolutions [118]. The chemical surface modi‐
fications (such as through silane or thiol chemistry) are
applied to functionalize the nanopores to different chemi‐
cal reactive groups, which can be used to further attach
other biomolecule probes. Thus, the chemical selectivity of
nanopore sensors increases. The receptors’ modified
nanopores will reduce the translocation rate [119]. Lipid
coating has been applied to nanopore sensing to achieve
better controlled surface properties and fine-tune pore
diameters in subnanometre resolutions. When specific
ligands are incorporated into the lipid bilayer, the specific
molecule interactions will reduce the translocation rate of
the DNA sufficiently to time-resolve translocation events
of individual bases; in turn, all four of the ionic current
blockage levels can be easily distinguished from the current
[84, 120].
In addition to the development of the nanopore itself, there
has been significant progress in relation to detection
systems for nanopores in recent years. Traditional nano‐
pore detection is based on ionic current blockage [9,
121-123]. Alternative read-out methods, which are based
on force, optical detections and electronic transverse
current, have been explored to further promote nanopore
sensing [87, 124, 125]. Nanopore force spectroscopy, as a
new detection method, exerts the localized bond-rupture
force to the native electrical charge of biomolecules.
Furthermore, one can detect the biomolecules’ responses
and their mechanical properties [126]. Liu et al. used an
optofluidic chip with an integrated nanopore [127]. By
controlling the single nanoparticles in relation to an optical
excitation region, the results regarding the discrimination
of fluorescent-labelled influenza viruses within a mixture
of equally sized fluorescent nanoparticles showed 100%
(a)
(b)
(c)
Figure 4. Recent advances in nanopore devices: (a) graphene nanopore
device [105] and (b-c) surface modifications of nanopores
6 Nanomater Nanotechnol, 2016, 6:35 | doi: 10.5772/64015
fidelity. Lagerqvist et al., who first introduced electronic
transverse current detections, embedded electrodes in the
walls of a nanopore, which performed orders of magnitude
faster than conventional methods [87]. Until now, the
transverse current and optical signals are the most prom‐
ising read-out methods, while the identity of the nucleo‐
bases based on optoelectronic differences are more reliable.
5.2 Challenges
Many advantages have been offered by the nanopore
sensing method, including fast detection rate, label- and
amplification-free detections, less sample consumed and
low cost. However, there are still problems to be solved.
Solid-state nanopores present the properties of chemical
and thermal characteristics, which are precisely size-tuned
and reliable, as well as the possibility for them to be
integrated with electrical and optical systems. That said, the
sensitivity of solid-state nanopores needs to be improved
to discriminate molecules with similar sizes but different
biological characteristics. New types of nanopore materi‐
als, advanced processing techniques and better surface
modification schemes have been applied to overcome the
drawbacks of nanopores. More experiments are still
required, along with new concepts to realize higher specific
detections. For example, the electronic properties of probe-
DNA interactions still need to be optimized to control DNA
translocation, orientation and base contrast [111, 128].
Another challenge for nanopore detections is the translo‐
cation rate of analytes. Some experimental data indicate
that it is difficult to identify different bases if the DNA
translocation rate is too fast [111]. However, if we can
properly control the passing rate, high signal-to-noise
ratios (SNRs) and spatial resolution can be attained. Thus,
the sensitivity of the nanopore would be greatly improved.
Besides, not only for DNA and protein detections, counting
single molecules or nanoparticles, which are homogene‐
ously mixed in the solution, is still challenging. It is difficult
to control the analyte capture and detection efficiency,
predominantly due to the limited of the diffusions. It is
helpful if some extra electrokinetic forces are added, such
as electrophoresis and dielectrophoresis. The analytes can
be controlled in order to pass through the nanopore
without delaying or clogging [129-131]. However, the
applied electric field will induce heat in the solutions,
which will influence the SNR during the detections. The
solid-state nanopore itself reveals two dominant noise
sources. The capacitance of the silicon support chip causes
a high-frequency noise (dielectric noise), while 1/f α
characteristics cause a low-frequency current fluctuation
(flicker noise). Besides, the measurement system also
influences the SNR of nanopores. During the detections,
both the signal bandwidth and the noise of the current are
very important factors; however, if we want to obtain more
information content at a high signal bandwidth, the noise
of current recording also strongly increases. Further
optimization is still required to reduce the unwanted effects
[132, 133]. Novel device architecture and developing more
sophisticated read-out methods are desirable to increase
the SNR. Efforts to fabricate nanopore sensors, which
contain nanogap-based tunnelling detectors and electronic
transverse signals, and optical read-out methods are
currently underway [134].
6. Conclusion
Nanopore-based sensing is structured with an ionic
conductance of nanoscale pores when analytes are driven
through by an extra applied electric field. Solid-state
nanopores represent the most promising sensor devices for
single molecule detections, due to their relatively easy
fabrications and high stability, prompting a great deal of
interest in this scientific research field. Besides, nanopore
sequencing technology is believed to be one of the next
generation DNA sequencing techniques. It will provide a
huge reduction in sequencing costs and may well achieve
the USD 1,000 per mammalian genome. The principles,
fabrications, applications and challenges of solid-state
nanopore devices are reviewed here. However, most
applications are still at their initial proof of principle stage.
It can be expected that continuous research to improve the
performance of nanopore sensing technology will appear
in the near future.
7. Acknowledgements
The authors gratefully acknowledge the financial support
they have received, particularly from Tianjin Applied Basic
Research and Advanced Technology (14JCYBJC41500) and
the 111 Project (B07014).
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12 Nanomater Nanotechnol, 2016, 6:35 | doi: 10.5772/64015
... Two classes of engineered nanopores are applied as tools in biotechnology: (i) naturally occurring biological nanopores [19] and (ii) solid-state, artificial ones [21,22]. As biological pores are assembled with the atomic precision and tuned through genetic modifications, they are very small and sensitive to environmental changes, which may trigger problems with their structural stabilities [13]. ...
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Artificial membranes with conical pores and controllable thickness reveal ionic-transport capabilities that are superior compared with those offered by cylindrical pores. By simulating the translocation of an abstract chain-like body through a conical pore in a membrane with a variable thickness, we formulate a statistical model of the translocation time τ. Our rough model encodes the biochemical details of a given real chain-like molecule as evolving sequences of the allowed chain-like body’s conformations. In our simulation experiments, we focus primarily on pore geometry and kinetic aspects of the translocation process. We study the impact of the membrane thickness L, and both conical-pore diameters ϕcis,ϕtrans on the probability distribution of τ. We have found that for all considered simulation setups, the randomness of τ is accurately described by the family of Moyal distributions while its expected value τ is proportional to Lξ, with ξ being dependent on ϕcis,ϕtrans.
... Moreover, the mechanical robustness of the biological nanopores is poor, which limits their application range. Recently, solid-state nanopores have received more and more research interest due to their multiple fabrication methods, mechanical stability, low cost and adjustable pore size [14][15][16][17][18][19][20][21][22][23] . Among the family of solid-state nanopores, glass nanopore has been reported as a versatile platform that enable multiple single-molecule investigations [24][25][26][27][28][29][30] . ...
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The fabrication of nanopores with a matched pore size, and the existence of multiple interferents make the reproducible detection of small-sized molecules by means of solid-state nanopores still challenging. A useful method to solve these problems is based on the detection of large DNA nanostructures related to the existence of small-sized targets. In particular, a DNA tetrahedron with a well-defined 3D nanostructure is the ideal candidate for use as a signal transducer. Here, we demonstrate the detection of an L1-encoding gene of HPV18 as a test DNA target sequence in a reaction buffer solution, where long single-stranded DNA linking DNA tetrahedra onto the surface of the magnetic beads is cleaved by a target DNA-activated CRISPR-cas12 system. The DNA tetrahedra are subsequently released and can be detected by the current pulse in a glassy nanopore. This approach has several advantages: (1) one signal transducer can be used to detect different targets; (2) a glassy nanopore with a pore size much larger than the target DNA fragment can boost the tolerance of the contaminants and interferents which often degrade the performance of a nanopore sensor.
... Si3N4 and SiO2 nanopores are among the most broadly employed nanopores, and their manufacturing is in accord with the complementary metal oxide semiconductor industrial integrated circuit processes. Ion etching in free-standing Si3N4 and SiO2 films using argon is the method by which these nanopores are produced (Tang et al. 2016). Graphene holds unique chemical properties because of being electrically conductive and even much stronger than steel (Thompson and Milos 2011). ...
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The field of sequencing is a topic of significant interest since its emergence and has become increasingly important over time. Impressive achievements have been obtained in this field, especially in relations to DNA and RNA sequencing. Since the first achievements by Sanger and colleagues in the 1950s, many sequencing techniques have been developed, while others have disappeared. DNA sequencing has undergone three generations of major evolution. Each generation has its own specifications that are mentioned briefly. Among these generations, nanopore sequencing has its own exciting characteristics that have been given more attention here. Among pioneer technologies being used by the third-generation techniques, nanopores, either biological or solid-state, have been experimentally or theoretically extensively studied. All sequencing technologies have their own advantages and disadvantages, so nanopores are not free from this general rule. It is also generally pointed out what research has been done to overcome the obstacles. In this review, biological and solid-state nanopores are elaborated on, and applications of them are also discussed briefly.
... Such drawbacks can be improved by combining specific bioreceptors with nanopores. In these cases, the nanopores became working electrodes, going through a chemistry modification process and then immobilizing the recognized element [231]. In nanopore devices, the potential application causes a flow of molecules that directs the target to the entrance of the nanopore channels [232]. ...
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In January 2020, the World Health Organization (WHO) identified a new zoonotic virus, SARS-CoV-2, responsible for causing the COVID-19 (coronavirus disease 2019). Since then, there has been a collaborative trend between the scientific community and industry. Multidisciplinary research networks try to understand the whole SARS-CoV-2 pathophysiology and its relationship with the different grades of severity presented by COVID-19. The scientific community has gathered all the data in the quickly developed vaccines that offer a protective effect for all variants of the virus and promote new diagnostic alternatives able to have a high standard of efficiency, added to shorter response analysis time and portability. The industry enters in the context of accelerating the path taken by science until obtaining the final product. In this review, we show the principal diagnostic methods developed during the COVID-19 pandemic. However, when we observe the diagnostic tools section of an efficient infection outbreak containment report and the features required for such tools, we could observe a highlight of electrochemical biosensing platforms. Such devices present a high standard of analytical performance, are low-cost tools, easy to handle and interpret, and can be used in the most remote and low-resource regions. Therefore, probably, they are the ideal point-of-care diagnostic tools for pandemic scenarios.
... One of the effective ways to produce these nanochannels on a substrate is by swift heavy ion bombardment (Hoppe et al. 2008;Kaniukov et al. 2016;Nebogatikova et al. 2018;Rawat et al. 2010). Other techniques such as focused ion beam drilling, electron beam drilling and wet etching have also been used extensively in this regard (Tang et al. 2016). Fabrication of nanochannels via ion track etching techniques provide tuneable pore geometries such as conical, hour glass, funnel, cylindrical and dumbbell. ...
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The confinement of ionic liquid inside the nanochannels and its transportation through it under applied potential is being reported. The nanochannels in SiON/Si structure have been created by swift heavy ion bombardment of Au26+ ionś beam at a fluence of 108 ions/cm2 having 350 MeV energy. After chemical etching, these channels (~ 50 to 80 nm diameter) have been filled by ionic liquid (IL) to see their behaviour under applied electrical bias. Due to the high self-diffusion coefficient and low viscosity (compared to other ionic liquids), EMImTFSI has been chosen for the said purpose. The effect of temperature (35–50 °C) and concentration of ionic liquid (undiluted and 50%, 60% and 75% diluted) on IL-SiON/Si structures has been studied. Dissociation of the ionic liquid by the applied voltage and charge extraction/injection through ion channels results in diode-like current–voltage behaviour. Ion current rectification presented in this paper depends on ionś concentration and the temperature of the ionic liquid. It also depends on the applied voltage at a given temperature. It has been found that the ion current rectification ratio decreases with dilution of the ionic liquid. For the system with 75% diluted IL, SiON/Si system has the same behaviour as the one without IL. Since the temperature affects the mobility of ions hence, it also affects the current–voltage behaviour of the system.
... Moreover, the mechanical robustness of the biological nanopores is poor, which limits their application range. Recently, solid-state nanopores have received more and more research interest due to their multiple fabrication methods, mechanical stability, low cost and adjustable pore size (Alibakhshi et al., 2017;Chen and Liu, 2019;Fragasso et al., 2020;Garoli et al., 2019;Tang et al., 2019;Tang et al., 2016;Xie et al., 2019;Xue et al., 2020;Yuan et al., 2018;Zhu et al., 2019). Among the family of solid-state nanopores, glass nanopore has been reported as a versatile platform that enable multiple single-molecule investigations (Bafna and Soni, 2016;Chen et al., 2018b;Farajpour et al., 2021;Freedman et al., 2016a;Li et al., 2013;Ren et al., 2020;Wang et al., 2019a;Yu et al., 2019). ...
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The fabrication of nanopore with matched pore size, and the existence of multi interferents make the reproducible detection of small-sized molecules by means of solid-state nanopore still challenging. A useful method to solve these problems is based on the detection of large DNA nanostructure related to the existence of small-sized target. In particular, DNA tetrahedron with well-defined 3D nanostructure is the ideal candidate to be used as signal transducer. Here, we demonstrate the detection of L1-encoding gene of HPV18 as test DNA target sequence in a reaction buffering solution, where long single-stranded DNA linking DNA tetrahedrons onto the surface of magnetic beads are cleaved by target DNA-activated CRISPR-cas12 system. The DNA tetrahedrons are subsequently released and can be detected by the current pulse in a glassy nanopore. This approach has several advantages: (1) One signal transducer can be used to detect different targets; (2) Glassy nanopore with pore size much larger than the target DNA fragment can boost the tolerance of contaminants and interferents which often degrade the performance of nanopore sensor.
... Si 3 N 4 and SiO 2 nanopores are one of the most widely used nanopores and their fabrication is compatible with the complementary metal oxide semiconductor industrial integrated circuit processes [28]. These nanopores can be ion etched in free-standing Si 3 N 4 and SiO 2 films, using argon ion beam or electron beam [29]. ...
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In recent years, nanopore technology has become increasingly important in the field of life science and biomedical research. By embedding a nano-scale hole in a thin membrane and measuring the electrochemical signal, nanopore technology can be used to investigate the nucleic acids and other biomacromolecules. One of the most successful applications of nanopore technology, the Oxford Nanopore Technology, marks the beginning of the fourth generation of gene sequencing technology. In this review, the operational principle and the technology for signal processing of the nanopore gene sequencing are documented. Moreover, this review focuses on the applications using nanopore gene sequencing technology, including the diagnosis of cancer, detection of viruses and other microbes, and the assembly of genomes. These applications show that nanopore technology is promising in the field of biological and biomedical sensing.
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Solid-state nanopore has the ability to detect proteins at a single-molecule level with its high sensitivity, high-throughput, and low cost. Improvements in fabrication, functionalization, and characterization of solid-state nanopores keep evolving. Various analytical methods targeted towards diagnostic applications using nanopore-based devices are appearing. This review article provides an overview of recent progress in the field of solid-state and biological nanopores for protein detection in a complex analyte. The advantages and challenges involved in nanopore sensing have been discussed. Further, the review surpasses the steady-state resistive pulse techniques of sensing and incorporate transient variations in the nanopore conductance. Application of the power spectral density of these fluctuations toward sensing has been highlighted with importance on reducing the detection limit in a complex environment. Lastly, the current problems and future perspectives have been discussed with a perspective to increase nanopores performance towards diagnostic applications in complex medium.
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Single-molecule techniques are being developed with the exciting prospect of revolutionizing the healthcare industry by generating vast amounts of genetic and proteomic data. One exceptionally promising route is in the use of nanopore sensors. However, a well-known complexity is that detection and capture is predominantly diffusion limited. This problem is compounded when taking into account the capture volume of a nanopore, typically 10 8-10 10 times smaller than the sample volume. To rectify this disproportionate ratio, we demonstrate a simple, yet powerful, method based on coupling single-molecule dielectrophoretic trapping to nanopore sensing. We show that DNA can be captured from a controllable, but typically much larger, volume and concentrated at the tip of a metallic nanopore. This enables the detection of single molecules at concentrations as low as 5 fM, which is approximately a 10 3 reduction in the limit of detection compared with existing methods, while still maintaining efficient throughput.
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Graphene nanopore device, since its proposal, has witnessed tremendous progress toward the goal of single-molecule detection. However, one central challenge of preparing electrodes with nanometer precision on the graphene remains unsolved. Here we show theoretically the feasibility of graphene/hexagonal BN (h-BN)/graphene structure where top graphene layer acts as one electrical contact while the bottom layer as the other. Based on quantum chemistry/nonequilibrium Green's function investigation, we give clear physical pictures why ABC stacking of the above heterogeneous layers results in excellent insulating of the top and bottom graphene electrodes. On the other hand, when the target molecule is inside the nanopore the background conductance through the h-BN dielectric will not keep decreasing even though more layers of h-BN are inside the nanopore. The mechanism is illustrated as that the presence of the molecule will enhance the vertical transmission through the h-BN dielectric via quantum interference. We employ a single-level molecule model, and show quantitatively that the discussed effect can be utilized as a powerful signal amplifier for the molecule conductance, thus enhancing the measurability of single molecules by 3-4 orders.
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Next-generation sequencing methods based on nanopore technology have recently gained considerable attention, mainly because they promise affordable and fast genome sequencing by providing long read lengths (5 kbp) and do not require additional DNA amplification or enzymatic incorporation of modified nucleotides. This permits health care providers and research facilities to decode a genome within hours for less than $1000. This review summarizes past, present, and future DNA sequencing techniques, which are realized by nanopore approaches such as those pursued by Oxford Nanopore Technologies.
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Probably no other field of statistical physics at the borderline of soft matter and biological physics has caused such a flurry of papers as polymer translocation since the 1994 landmark paper by Bezrukov, Vodyanoy, and Parsegian and the study of Kasaniowicz in 1996. Experiments, simulations, and theoretical approaches are still contributing novel insights to date, while no universal consensus on the statistical understanding of polymer translocation has been reached. We here collect the published results, in particular, the famous-infamous debate on the scaling exponents governing the translocation process. We put these results into perspective and discuss where the field is going. In particular, we argue that the phenomenon of polymer translocation is non-universal and highly sensitive to the exact specifications of the models and experiments used towards its analysis.
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Inverted-pyramid silicon nanopore arrays are realized with a well-controlled, three-step, anisotropic wet etching process with different KOH bath temperatures. The influence of etchant concentration and temperature on the etching rate is investigated. Nanopore arrays with an average size of 100 nm and individual nanopores with feature sizes as small as 30 nm were successfully fabricated at low cost using this method. This study paves the way toward the controllable, large-scale production of arrays of inverted-pyramid nanopores with desired size.
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This review outlines the recent achievements in the field of nanopore research. Nanopores are typically used in single-molecule experiments and are believed to have a high potential to realize an ultra-fast and very cheap genome sequencer. Here, the various types of nanopore materials, ranging from biological to 2D nanopores are discussed together with their advantages and disadvantages. These nanopores can utilize different protocols to read out the DNA nucleobases. Although, the first nanopore devices have reached the market, many still have issues which do not allow a full realization of a nanopore sequencer able to sequence the human genome in about a day. Ways to control the DNA, its dynamics and speed as the biomolecule translocates the nanopore in order to increase the signal-to-noise ratio in the reading-out process are examined in this review. Finally, the advantages, as well as the drawbacks in distinguishing the DNA nucleotides, i.e., the genetic information, are presented in view of their importance in the field of nanopore sequencing.
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Protein nanopores can detect post-translational modifications in proteins.
Article
Nanopore-based DNA sequencing has led to fast and high resolution recognition and detection of DNA bases. Solid-state and biological nanopores have low signal to noise ratio (SNR) (<10) and are generally too thick (>5 nm) to be able to read at single base resolution. A nanopore in graphene, a 2-D material with sub-nanometer thickness, has a SNR of ~ 3 under DNA ionic current. In this report, using atomistic and quantum simulations, we find that a single-layer MoS2 is an extraordinary material (with a SNR > 15) for DNA sequencing by two competing technologies, i.e., nanopore and nano-channel. A MoS2 nanopore shows 4 distinct ionic current signals for single nucleobase detection with low noise. In addition, a single layer MoS2 shows a characteristic change/response in the total Density of States (DOS) for each base. The band gap of MoS2 is significantly changed compared to other nano-materials (e.g. graphene, h-BN, and silicon nanowire) when bases are placed on top of the pristine MoS2 and armchair MoS2 nanoribbon, thus making MoS2 a promising material for base detection via transverse current tunneling measurement. MoS2 nanopore benefits from a craftable pore architecture (combination of Mo, and S atoms at the edge) which can be engineered to obtain the optimum sequencing signals.
Article
The analysis of individual biological nanoparticles has significantly advanced our understanding of fundamental biological processes, but is also rapidly becoming relevant for molecular diagnostic applications in the emerging field of personalized medicine. Both optical and electrical methods for detection and analysis of single biomolecules have been developed, but they are generally not used in concert and in suitably integrated form to allow for multimodal analysis with high throughput. Here, we report on a dual-mode electrical and optical single nanoparticle sensing device with capabilities that would not be available with each technique individually. The new method is based on an optofluidic chip with an integrated nanopore that serves as a smart gate to control the delivery of individual nanoparticles to an optical excitation region for ensemble-free optical analysis in rapid succession. We demonstrate electro-opto-fluidic size discrimination of fluorescent nanobeads, electro-optical detection of single, fluorescently labeled influenza viruses, and the identification of single viruses within a mixture of equally-sized fluorescent nanoparticles with up to 100% fidelity.
Article
Graphene-based nanopore devices are promising candidates for next-generation DNA sequencing. Here we fabricated graphene nanoribbon-nanopore (GNR-NP) sensors for DNA detection. Nanopores with diameters in the range of 2-10 nm were formed at the edge or in the center of graphene nanoribbons (GNRs), with widths between 20 and 250 nm and a length of 600 nm, on 40 nm thick silicon nitride (SiNx) membranes. GNR conductance was monitored in situ during electron irradiation-induced nanopore formation inside a transmission electron microscope (TEM) operating at 200 kV. We show that GNR resistance increases linearly with electron dose and that GNR conductance and mobility decrease by a factor of ten or more when GNRs are imaged at relatively high magnification with a broad beam prior to making a nanopore. By operating the TEM in scanning TEM (STEM) mode, in which the position of the converged electron beam can be controlled with high spatial precision via automated feedback, we were able to prevent electron beam-induced damage and make nanopores in highly conducting GNR sensors. This method minimizes the exposure of the GNRs to the beam before and during nanopore formation. The resulting GNRs with unchanged resistances after nanopore formation can sustain microampere currents at low voltages (∼ 50 mV) in buffered electrolyte solution and exhibit high sensitivity, with a large relative change of resistance upon changes of gate voltage, similar to pristine GNRs without nanopores.