Pore-Based Sensing for Virus Particles Detection: Comparison
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Pore-based sensing is a highly sensitive sensing technology for the detection of extremely small particles such as molecules, proteins, and viruses (50–200 nm). Pore-based sensing is conducted by applying an electric field across nanopores, usually made of biomacromolecules, e.g., α-hemolysin or synthetic materials, e.g., graphene and semiconductor. When a particle passes through the pore, changes in the current waveform can be observed. The presence of specific waveform changes indicates the presence of target, and the number of this specific waveform can be used to determine the concentration. In this chapter, an overview of pore-based sensing technology is presented. Their applications in virus detection are discussed.

  • virus detection
  • pore-based assay
  • nanopore
  • particle detection

1. Introduction

In particle detection, the current reading of a charged pore changes when a particle suspended in an electrolyte were brought through it. This principle is known as Coulter principle.  Pore-based sensing technology has been established based on Coulter principle. Pore-based sensing is a promising candidate for the early detection of extremely small particles such as molecules, proteins, and viruses (50–200 nm). The system used in pore-based sensing usually consists of a nano- to micrometer-diameter pore formed within an electric-conducting substrate which acts as a barrier between two electrolyte-filled reservoirs. A pair of electrodes are placed on each side of a substrate, and voltage is applied across the pore, then the current flowing through the pore is measured (Figure 1). Particles are counted in real-time based on the modulation in an ion current derived from obstruction of pore in the translocation process. Since the magnitude of the ion current depends on the size of particles, pore-based sensing can be used to estimate the size of individual particles and the statistics can be collected by transmission electron microscopy[1]. Notably, pores at nanometer scale are called “nanopores” and are particularly suitable for measuring nanometer-sized viruses.
Figure 1. Schematic illustration of pore-based sensing. An electrolyte is divided by a pore membrane, and electrodes are placed on each side of the substrate (a). When voltage is applied to the electrodes, an ion current is generated and passes through the pore membrane. Small particles which are analytes (indicated as purple circles) in the solution pass through the pores by electrophoresis or electroosmotic force. Particles passing through the pore (a particle moves in ➀, ➁, ➂ order) block the ion current (b), and the corresponding current value change is measured as a pulse (c).
Nanopores are widely used in biochemical and single molecule detection, and could be made of biomacromolecule or synthetic materials. For example, molecular measurements using nanopores, in which α-hemolysin with cyclodextrins inside is embedded in lipid membranes, were reported[2][3]. Pore-based sensing is widely recognized as a feasible method for single molecule analysis. On the other hand, the limitation in the choice of naturally occurring pores has limited the size of measurable particles. Therefore, artificially fabricated pores have been developed for particle measurement to fulfill the need to measure a wide range of particles. Viral particle sensing using artificially fabricated pores will be discussed in this chapter.

2. Fabrication of Pores for Sensing

An important aspect of nanopore measurement is techniques for pores fabrication. There are many ways to penetrate thin membranes for the fabrication of pores such as ion beam drilling, electron beam lithography, electrochemical etching, etc.[4][5][6][7][8]. For example, it has been reported that the fabrication of pores in glass with sub-micrometer diameter uses a femtosecond-pulsed laser[5][9] to analyze Paramecium bursaria chlorella virus 1 with a diameter of 175–190 nm[10][11]. Other reports have also demonstrated the use of a single heavy ion to fabricate pores[4][12][13], while in another method, a needle is used to penetrate a membrane[14]. Pore prepared by needle penetration is available as commercial products, and is a necessary process for tunable resistive pulse sensing (TRPS) (The details of TRPS are discussed below).
Another advantage of particle analysis based on pore-based sensing is that not only the size of the particles, but also the shape of nanoparticles can be estimated based on the waveform of electric current. Therefore, the preparation of pores with precisely controlled geometry is also of great importance to obtain highly reproducible measurements. For example, uniform, low-aspect ratio pore precisely prepared by electron beam lithography and reactive ion etching can yield specific current waveform derived from the shape of measured particles[15][16][17]. Pore fabrication methods can be customized according to the parameters of the particles to be measured.

3. Quantification of Virus Using Pore-Based Sensing

Conventional virus-detecting techniques quantify the amount of virus either by infection titer, e.g., hemagglutination inhibition assay and plaque assay or concentration of virus-specific nucleic acid, e.g., polymerase chain reaction. However, these methods do not quantitatively measure the concentration of the virus itself, nor guarantee the integrity of the virus to maintain its infectivity, i.e., a virus with its membrane compromised (which has lost its infectivity), can still be detected with polymerase chain reaction. Therefore, conventional methods do not provide valuable information on virus infectivity. While it is difficult to directly evaluate the infectivity of a virus, pore-based sensing provides a quantitative solution for virion (a complete virus particle) detection based on specific characteristics of virus.
However, challenges remained for pore-based sensing. The main challenge of this technology is that the process of particle capture in a nanopore is dictated by stochastic process. The probability that a viral particle in the vicinity of a pore passes through the pore relies on the concurrent action of Brownian movement, advection, and electrical forces. The frequency of passing particles is determined by bulk concentration of particles, pore size, diffusion coefficient, density of electrolyte, effective potential, and size of particles. Generally, other parameters besides the bulk concentration are constant, therefore, the frequency of passing particles increases with bulk concentration of particles. Therefore, this concentration range is the dynamic range of the pore sensor. It is important to note that a passing efficacy does not only depend on a particle concentration but characteristics of particles. The main driving force for particles to pass through the pores is electrophoresis caused by the application of voltage. Accordingly, particles with higher or lower surface potential relative to their environment are more likely to pass through the pores, while particles with no charge rarely pass through the pores by electrophoresis. Electroosmotic flow also allows particles to pass through the pore[18], but the drive by electroosmotic flow is limited in scope. Therefore, the frequency of particles passing through is difficult to be directly treated as particle concentration.
The problem of pore-based sensing can be improved through the application of external forces. Pore sensors, in which a pore is fabricated in a stretchable membrane and the size of the pore is changed by stretching, are called tunable resistive pulse sensors[19][20][21]. In the case of TRPS, the particles are forced through the pore regardless of their surface charge by a pressure-driven mechanism. Quantitation of vesicular stomatitis virus with TPRS has been demonstrated[22]. The passing rate of viral particle is 1 particle per minute when 1.0 × 107 particles/mL viral suspension was applied, which is roughly viral concentration at the limit of detection by single pore-based sensing. Although this value requires more viruses than the PCR detection limit of 100 copies/mL, it should be considered that the viral particles are measured without further manipulation or pre-processing, such as gene extraction or gene amplification. The fact that PCR involves dozens of amplification operations which will result in sample loss also indicates that pore-based sensing is inherently capable of detecting very small amounts of viruses. Apart from this, the upper limit should also be considered. According to this report, the limit of linearity for the counting rate against concentration of virus is approximately 1.0 × 1010 particles/mL viruses[22]. This is because high concentration of the virus results in miscalculation derived from temporary clogging, and the virus concentration must be adjusted for quantitative evaluation.
Pore-based sensing is a useful technique to quantitatively evaluate the concentration of virus in suspension. The quantity of infectious virion is different from its titer and nucleic acid concentration. The nucleic acid concentration differs by subspecies and the measurement has poor interlaboratory reproducibility[23][24], probably due to the variation in the yield of nucleic acid. Given the difference among various parameters, these parameters should be matched from the viewpoint of infection risk. While it is challenging to quantify the risk of infection, virus evaluation by pore-based sensing might provide a useful solution to address this issue.

4. Advanced Techniques of Pore-Based Sensing for Virus Detection

To this point, the principles and properties of virus quantitation based on pore-based sensing technology have been discussed. However, samples are usually contaminated with impurities in real setting, which could interfere quantitation of virion. While pore-based sensing is an attractive method for evaluating each particle individually, the properties of the particles collected are limited to physical parameters such as size and charge density. Therefore, the performance of pore-based sensing technology must be improved such that it can be used to selectively measure biological particles, e.g., viruses. Clogging of the pore, which is one of the most troubling problems for pore-based sensing, should also be addressed, as the impurities contained in virus suspension could prevent the viruses from passing through the pore.
Hydrophilic plasma treatment is commonly used to prevent the clogging of pores. However, facilities for plasma irradiation are required to perform plasma treatment and the effect depletes over time. Surface functionalization of a pore is another effective technique to improve the performance of pore-based sensing. For example, it could help to prevent undesired adhesion. Surface functionalization is widely used in the field of biomaterials and biosensing, which is help to solve most of the issues occurred. For instance, it is known that polyethylene glycol can provide non-fouling characteristics to a surface by preventing impurities from approaching because of excluded volume effects derived from a hydrophilic chain in its chemical structure[25]. Zwitterion-based materials are also effective candidates for preventing pore clogging by altering the state of water condition around materials. An adhesion mechanism is strongly related to the state of water conditions around the materials, which is called bound water or non-freezing water[26], which promotes adhesion via the dehydration of bound water molecules. Zwitterionic surface minimizes bound water which prevents adhesion through this mechanism[27]. It has been demonstrated that surface modification by zwitterions and polyethylene glycol to the pore could inhibit pore clogging[28].
Some methods are developed for specific detection of target particles. One technique is to use a specially shaped pore for sensing. As above-mentioned, a low aspect ratio pore can obtain detail of particle shape based on the current waveform. For example, several kinds of viruses, such as vesicular stomatitis virus, tobacco mosaic virus[29], bafinivirus, and ronivirus, have distinctive shapes and can be easily distinguished based on their waveforms. Pores with high aspect ratios provide accurate volume information because the entire particle could enter the pore. While the shape of the particles can also be determined, the performance is not as well as with pores with low aspect ratios[30][31][32]. However, many kinds of virions are near-spherical shape, which makes it difficult to distinguish the virus species. Therefore, a further advanced technique is required.
An approach proposed to distinguish among spherical virions is through capturing of target virion via surface functionalization of pores. Conventional biosensors such as surface plasmon resonance (SPR) and quartz crystal microbalance (QCM) sensors have their surface modified with ligands for specific detection. Since ligands are provided on the surface of the pore or its proximity, measuring the time required for a particle to pass through the pores will reveal whether a particle is captured through molecular recognition (Figure 2). This approach of pore-based sensing has been reported not only for viruses but also for proteins[33][34][35][36][37][38][39]. On the other hand, capturing the target on the pore surface possess a risk of pore-clogging because molecular recognition keeps the targets on the pore surface, which results in congestion. Therefore, pore-based sensing by molecular recognition on the pore surface requires ingenuity in adjusting target concentration and binding strength.
Figure 2. Molecular recognition on the pore surface. When a target analyte passes through the pore, molecular recognition prolonged the passing time by capturing the analyte on the pore. This translocation process has been recorded as a pulse waveform that can be used to identify the target analyte.
Apart from this, the conjugation approach has also been suggested to identify viruses. For example, when the virus and antibody interact specifically, the volume of the virus increases because the virus is covered by the antibody via complex formation. Therefore, the presence of the virus can be determined by the change in size of the viral particle[9]. It has been reported that artificial nanomaterials are used because they undergo significant size changes upon compositing (Figure 3). In this case, human influenza virus-specific ligands are immobilized on 20 nm of gold nanoparticles, which can be used as virus-recognition nanoparticles[40]. Since the typical size of influenza viruses is 80–120 nm, the binding of nanoparticles results in the a statistically significant change of virus particle size.
Figure 3. Molecular recognition using nanomaterials. If target particles exist in a sample solution, the target particles are covered with molecular recognition particles that shows the particle size changes (simultaneously, the signals change from ‘Original’ to ‘After molecular recognition’ as shown in the right graph of the figure).
As a recent trend, artificial intelligence (AI) technologies for pore-based sensing have been explored[18][36][38][41][42]. In this approach, AI models were used to identify the virus species by learning the characteristics of the pulse shape measured from each virus[41]. It is reported that AI techniques can identify not only the virus species but also the virus subtype such as influenza A H1N1 and H3N2[18]. Although AI-based virus identification is a promising technology, it is important to note that this approach is not based on biological analysis such as traditional detection methods. It is difficult to explain on what basis the AI model identifies the type of virus, thus careful discussion is needed for its use as a diagnostic method. The combination of molecular recognition and AI is also investigated[36][38]. As mentioned above, if target particles bind strongly on the pore surface, serious pore clogging will occur easily. However, as the interaction is weakened, the difference in pulse shape becomes smaller, making simple identification more difficult. Therefore, AI technology capable of identifying subtle differences in pulse waveforms would be useful.
In this chapter, pore-based sensing technologies for virus detection have been discussed. This method is still an emerging technology and needs further development to become a general sensing technology. However, the method of detecting and analyzing viruses in their particle form is unprecedented and is expected to lead to rapid diagnosis. Since pore-based sensing only measures current values, it does not require optical devices, etc., and can be miniaturized. It is anticipated that pore-based sensing will be widely used as a particulate measurement method in the future.

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