key: cord-0966224-ce3opb6q
authors: Bukkitgar, Shikandar D.; Shetti, Nagaraj P.; Aminabhavi, Tejraj M.
title: Electrochemical investigations for COVID-19 detection-A comparison with other viral detection methods
date: 2020-11-02
journal: Chem Eng J
DOI: 10.1016/j.cej.2020.127575
sha: 479ef1b8ebe8b05ea01a40ac1b994b66c8e8192b
doc_id: 966224
cord_uid: ce3opb6q

Virus-induced infection such as SARS-CoV-2 is a serious threat to human health and the economic setback of the world. Continued advances in the development of technologies are required before the viruses undergo mutation. The low concentration of viruses in environmental samples makes the detection extremely challenging; simple, accurate and rapid detection methods are in urgent need. Of all the analytical techniques, electrochemical methods have the established capabilities to address the issues. Particularly, the integration of nanotechnology would allow miniature devices to be made available at the point-of-care. This review outlines the capabilities of electrochemical methods in conjunction with nanotechnology for the detection of SARS-CoV-2. Future directions and challenges of the electrochemical biosensors for pathogen detection are covered including wearable and conformal biosensors, detection of plant pathogens, multiplexed detection, and reusable biosensors for on-site monitoring, thereby providing low-cost and disposable biosensors.

Viruses are the simple structures consisting of genetic information that can replicate through the hosts [1] . These intercellular agents cannot replicate outside the host cell, but remain as a crystalline structure for longer period until they come in contact with a host [2] .

The genetic material, either DNA or RNA, is surrounded by a sheet of protein, called capsid.

Once the viral genome enters the host cell, the replication and protein synthesis machinery is hijacked to make more virus particles, called Virions [1] that have the ability to infect new cells after releasing from the host cell. Viruses get easily adapted to new conditions due to mutation, thereby increasing the genetic diversity. Since virus do not have any enzyme system, antibodies may not affect them. These viruses consist of only digestive enzyme helpful to dissolve the host cell membrane and viruses belong to a wide variety of families such as DNA virus and RNA virus. Typical examples are Adenoviridae, Parvoviridae, Herpesviridae, Retroviridae, Rhabdoviridae, etc [3] . rapid and accurate detection of virus is necessary. Several methods used for the detection of SARS-CoV-2 are the most commonly used ones that are either molecular tests or serological tests. The viral or molecular tests often indicate the active infection and these are designed to detect the genetic material of the virus. On the other hand, serological tests can detect the antibodies present in the blood and tissues produced during the fight against the virus, but these tests do not show about the current infected state.

Recent developments in molecular biotechnology have facilitated nucleic acid detection methods that are growing rapidly as the revolutionary technology, since polymerase chain reaction-based methods are advantageous to provide high sensitivity and rapid detection.

Further, non-PCR-based methods are developed for the detection of SARS-CoV-2 RNA, which involves nucleic acid sequence-based amplification and isothermal nucleic acid amplification.

PCR is a vital tool used in molecular biology to make millions to billions of DNA copies rapidly. It is very much advantageous to the medical fraternity that uses a small sample of DNA and amplifies it to significant amount for detailed investigations. This process involves initially separating a DNA strand containing the gene segment and a primer can be used to mark its location. Further, DNA polymerase accumulates a copy to each separated strand and then copies the copy continuously. The advantages and wide range of applications of PCRbased technique can be routinely and reliably used for detecting SARS-CoV-2 [25, 26] . Since SARS-CoV-2 consists of RNA as a genetic material, a reverse transcription is also carried before the PCR followed by product determination using appropriate detection methods or an instrumental analysis, which includes sequencing or gel visualization [27, 28] . Diagnosis in the early infection stage is more helpful and hence, real-time reverse transcriptase-PCR is predominantly used than the conventional PCR assay [29] .

Van Elden et al. [30] described some disadvantages of RT-PCR methods such as contamination, time consumption, sample handling and analysis of post PCR can be easily avoided using TaqMan-based real-time RT-PCR. The sensitivity of this method was further improved by Yip et al. [31] using two TaqMan probes as a replacement for one probe for the detection of SARS-CoV. However, massive efforts are needed to overcome the difficulties in clinical detection such as lack of safe and external positive controls (EPC). EPC is an important component, which when the problem was avoided by using the armoured RNA as EPC for the detection of SARS-CoV [32] having the low detection limit of 10 copies /µL. Further, significant consideration should be given to reduce the risk of false negative results due to the variation in genome sequence due to genetic diversion caused as a result of rapid mutation in corona viruses. In such cases, multiplex RT-PCR is favourable to detect via multi-targeting detection of the coronavirus. Distinguishing between the non-pathogenic and pathogenic strains by using the mismatch-tolerant molecular beacons [33] demonstrated the detection limit of 5 copies/reaction [33].

PCR-based techniques are widely used, but these techniques require the separation of DNA strands using a thermocycling, which limits its application in actual field applications.

Isothermal nucleic acid amplification-based (INAA) methods developed in the past two decades without using thermocycler machine are useful for the detection of nucleic acid target sequence.

Loop-Mediated Isothermal Amplification (LAMP) is one of the INAA method with higher efficiency commonly used for the amplification of DNAs and RNAs exhibiting higher sensitivity and specificity. This method involves the use of a DNA polymerase along with four sets of specially designed primers that identifies six distinct sequences on the targeted DNA [34] . Gel electrophoresis is another commonly used approach to analyse the amplified products after LAMP essay. Poon et al. [35] and Pyrc et al. [36] demonstrated a LAMP reaction for SARS-CoV with the detection rates similar to those of the conventional PCR-based methods and 1 copy of RNA template per reaction, respectively.

Step 2

Step 1

The problem of virus detection can be simplified by using the precipitation of magnesium pyrophosphate or fluorescence dyes monitoring turbidity [37] . Shirato et al. [38] demonstrated one such a procedure for the detection of MERS-CoV RNA with the capability of detecting 3.4 copies without cross reaction with other respiratory viruses. Further, Thai et al. [39] demonstrated photometric method of measuring turbidity in one-step single-tube accelerated real-time quantitative for SARS-CoV having the sensitivity of 100-folds more than that of the conventional RT-PCR with a detection limit of 0.01 plaque formation unit.

Step 3

Step 4

In the above mentioned methods, the problems aroused due to the fact that primer dimer or non-primer reactions cannot be excluded as these techniques rely on nonspecific signal transducers such as solution turbidity or fluorescence dye intercalation. In such situations, sequence-specific LAMP-based methods that can readily separate nonspecific noise with true signal may be advantageous. In this direction, Huang et al. [40] proposed a method using RT-LAMP-VF (RT-LAMP and a vertical flow visualization strip) for the detection of MERS-CoV with a detection limit of 10 copies/µL. However, the major contributions from Ellington's group improved in terms of specificity, reliability and LAMP detections. Replacement of dye in fluorescence detection with toehold-mediated strand exchange reaction for RT-LAMP-VF showed the detection of 0.02 to 0.2 PFU MERS-CoV without cross reaction with other respiratory viruses [41] . Du et al. [42] demonstrated a method combining strand exchange signal transduction, LAMP and a glucometer for the detection of MERS-CoV with a sensitivity of 20-100 copies/μl, equating to atto-molar.

Rolling circle amplification (RCA) is another technique that has attracted various scientific groups in nucleic acid determination. It is a unidirectional process of replicating nucleic acid producing numerous copies of circular molecules of DNA and RNA capable of 109 folds of amplification of each circle in 90 min under isothermal conditions. Further, the use of RCA has advantages such as requirement of minimum reagents and exclusion of falsepositive results, which are frequently observed in PCR-based methods. An efficient method for sensitive detection of SARS-CoV genome using RCA in both liquid and solid phases was proposed by Wang et al. [43] .

A typical microarray experiment involves the hybridization of an mRNA molecule to DNA template from which it is originated. Many DNA samples are used here to construct an array. The amount of mRNA bound to each site on the array indicates the expression level of various genes and this number may run in thousands. All the data are collected and a profile is generated for gene expression in the cell.

Shi et al. [44] designed 30 specific 60 mer oligonucleotide microarray based on TOR2 sequence in clinical samples that was successfully used for detecting SARS coronavirus. These designed microarrays represent the whole genome of SARS coronavirus, which was printed into an oligo microarray, and then applied to hybridizing with the samples of SARS patients treated and labelled by RD-PCR. This method offered results for seven samples hybridized on the microarray with no signals on blank and negative probe sites. Rapid mutation in SARS-CoV associated with 27 single nucleotide polymorphism mutations among the spike gene has lead to epidemicity. Considering such a mutation problem in SARS-CoV, Guo et al. [45] designed a microarray based on a single nucleotide polymorphism DNA, which would detect and genotype these single nucleotide polymorphisms and allow us to understand the pathogenicity and epidemicity of a given strain. Amplified products of cDNA from PCR technique of different strains of SARS-CoV were hybridized on the fabricated microarray. This method detected 24 single nucleotide polymorphism and the method was helpful to identify the strain with 100% accuracy for 19 samples in detecting and genotyping.

Electrochemical investigations favour significant advantages such as simplicity in design, higher sensitivity and selectivity, low cost equipment, lower power need and easy to integrate within the microfluidic devices compared to other proposed methods [48 -50] .

Electrochemical investigations have also demonstrated excellent applications in health care applications [51, 52] . Recently, the World has witnessed the outbreaks of diseases associated with viruses such as Ebola, MERS-CoV, SARS-CoV-1 and SARS-CoV-2 highlighting the need for rapid testing kit that can be used in the community to avoid further pandemic. A novel device with advanced instrumentation for cases such as COVID-19 is an upcoming challenge for the point-of-care diagnostic industries. However, it was observed that OECD countries have achieved a massive scaling in testing of the coronavirus that are predominately based on PCR-centralised laboratory testing than using the point-of-care devices. Moreover, reducing the sample-to-answer time is also crucial in contact tracing. Thus, reliable and high throughput testing devices continue to play the central role in containing the pandemic. Hence, in this section, we will discuss the advances made in electrochemical techniques for the detection of pathogen that can be reliable and powerful to fight against even for any future pandemics.

pathogens via the generated antibodies and pathogen epitopes, make these techniques a flexible approach to detect the pathogens. On other hand, if the availability of antigens is limited or antigen production in the organism is significantly lower even in the presence of pathogen causing infection, then DNA-based assays can be commonly employed though these techniques require the sample to contain pathogen at the time of analysis.

The well-known bio-analytical techniques usually detect one or more components in the sample using a molecular probe as a bio-recognition element combined with the analytical system such as PCR analyzer or a plate reader. However, the robustness and sensitivity of these techniques are advantageous, and these techniques have offered time-to-results due to extensive reagent utilization in sample and complex sample preparation steps. In addition, as discussed in the previous section, PCR-based bio-analytical methods may also be affected due to contextual species in the sample, resulting in a bias and uncertainty of the measurements Table 1 gives a summary of the utilization of some of the methods to detect different viruses, but in any case, as per literature the PCRbased analysis of viruses is the first choice.

Lowering the detection limit is the key for early detection of the infection and individuals are not infectious before they are normal. In such situations, electrochemical methods play a vital role. Further, this is easy to fabricate miniature devices to be useful at the point-to-care, offering immediate and reliable results. However, construction of electrochemically-based biosensors depends on the components such as transducer element, bio-recognition elements, and measurement formats.

In case of an electrochemical biosensor, transducer element is a cell consisting of three electrode system (potentiostat) or a two electrode system (conductometry and electrochemical impedance spectroscopy) in which much importance relies on the working electrode [58 -60].

The working electrode can be fabricated with semiconducting and conducting materials ranging from metals to non-metals such as carbon, and using the materials of various sizes from bulk materials to micro and nano-structures. The electrode properties and structures affecting the performance of the electrode in terms of selectivity and limit of detection are dependent on the materials used, fabrication methods employed and the design approach. 

Various metal-based electrodes consisting of gold and platinum are used as biosensors [107] [108] [109] . For instance, thick metal surface or a thin film metal electrode have been fabricated by cutting or traditional micro-fabrication using physical vapour deposition and screen printing techniques [110, 111] . In addition, ceramic electrode (consisting of polysilicon, TiO 2 , and indium tin oxide) and polymer electrodes (with advantageous properties of stability, biocompatibility and tuneable electric conductivity) have also been used in the fabrication of electrodes [112, 113] . However, the selection of materials for the fabrication of electrochemical sensors, especially while detecting pathogens requires expert skills. Since significant aspects of electrochemical sensor performance such as rate of heterogeneous electron transfer, double layer capacitance, nature of coupling chemistry required immobilising the bio-receptors may be affected. Furthermore, since Faradic current is dependent on the active electrode surface area, increasing the surface area improves the sensitivity as well as controls the background current.

A simple and effective mode to increase surface area is to use the nanomaterial and the composites. This would also facilitate easy immobilization of bio-receptors, thus increasing the sensitivity in a wider dynamic range, thereby allowing higher collision frequency between the antigens and the antibodies [114] .

Elevating the target and/or selective binding based on enzymes or antibodies are the principal needs for biomolecular recognition. Limited stability of these complex materials are often accompanied with multifaceted protocols and specific handling protocols. For virus detection receptors to be reused they can mimic antibodies recognition properties that are favourable, especially in health care systems. Hence, recent efforts on molecular imprinting strategies have evolved significantly allowing the fabricated sensor to mimic immunological interactions [115] .

In molecular imprinting, the first step involves the interaction between cross-linking agents and the monomers in a suitable solvent with the templates; then following the arrangement of formed molecular assemblies by PCR around the template molecules, and finally removing the templates leaving behind the analyte selective binding moieties. Recently, extensive studies based on molecularly imprinted polymers have detected a wide range of species targeting proteins, cells and viruses [116, 117] . These included different polymerization strategies such as surface imprinting (2D) and bulk imprinting (3D). To perform the bulk imprinting, the respective template was directly added to a monomer mixture and the hydrogels formed with 3D matrices could offer less restricted diffusion pathways [118, 119] .

Diverse examples of hydrogels used to imprint viruses are available in the literature [120 -122] . On other hand, surface imprinting can be achieved by attaching the template to the supporting material or by a thin polymer film decoration. These methods can be carried out using soft lithography, self-assembly or by core-shell particles via immobilized templates. On the other hand, the traditional imprinting techniques have focussed on materials that can favour small molecular templates. Key issues such as solubility, size, fragility, and compositional complexity are to be considered while imprinting the viruses. The fabrication of electrodes using carbon materials has advanced significantly and classical carbon-based sensors are mainly glassy carbon, carbon fibers and pyrrolytic graphite [123, 124] . Most of the carbon-based nanomaterials have many advantageous properties such as higher electro-catalytic, adsorption bio-compatibility and fast electron transfer rate [125] .

For sensor applications, carbon nanotubes and graphene have been investigated as these can be directly incorporated into a biological sensor following the simple drop casting, growing the material directly on the substrate, co-depositing with metal nanoparticles and then using them in field effect transistors [126] .

Wasik et al. [127] The single walled carbon nanotube network can be synthesised by self-assembly on gold electrode lithiographically where the primary amine linker, 1 -pyrenemerhylamine can be adsorbed on the single walled carbon nanotubes that are cross-linked with heparin carboxyl groups and used for detecting the dengue virus. Selectivity of the biosensor was evaluated [127] using influenza virus H1N1 as the negative control.

Navakul et al. [128] demonstrated electrochemical biosensor based on impedance spectroscopy using gold electrode deposited with graphene oxide to detect in the limit of 0. 

In recent years, outstanding achievements in nanotechnology have allowed novel materials to steadily intensify their new horizons across the globe [168 -176] . Shariati et al. [178] proposed label free detection of human papilloma virus based on gold nanotubes using the electrochemical impedimetric technique. In this study, external electric field applied allowed the preferred orientation of the negatively charged DNA oligonucleotide to increase the sensing response via controlled hybridization and immobilization of the sequence onto gold nanotubes surface. This biosensor has shown a lower detection limit of 1 fM in the linear range of 0.01 pM to 1 µM.

Lee et al. [179] developed an electrochemically based label-free avian influenza virus detection method using multi-functional DNA structure on a porous (p) AuNPs-modified electrode. The proposed DNA 3 way-junction/pAuNPs based detection method can be applied for multiple-target detections as a valuable biosensor for determining the pathogen subtype in one platform or one target detection using the dual detection method with high reliability. Nanomaterials based on graphene are advantageous due to their outstanding chemical, mechanical, thermal and electronic properties and these are quite predominant to design the biosensors for DNA detection due to their enhanced affinity towards single-stranded DNA by the hydrophobic interaction and π-π stacking [182] . Graphene can be used as a substrate to interface with different cells and biomolecules, which is beneficial to improve its biocompatibility, solubility and selectivity

Li et al. [183] proposed DNA-assisted magnetic reduced graphene oxide-copper In recent years, personalized medicine and digital health monitoring is becoming increasingly attractive and this tremendous potential has now become realistic due to the fabulous advances in skin interfaced wearable sensors. These sensors interface with the skin in a wide range of sizes from cellular level down to molecular level and these hold the capability for therapeutic and diagnostic functions with excellent precision, continuity and expediency.

In addition, the new opening of adding artificial intelligence and integrated cloud-based technologies would enhance the utilization of smarter healthcare systems. These devices compared to the traditional healthcare systems, can collect non-invasive data from the human body to provide an insight into both fitness monitoring and medical diagnostics along with keeping a track of molecular biomarkers of the human system. For such sensor devices, electrochemical detection would probably be one of the most fitting techniques due to its easiness in miniaturization, and low electric power consumption. This review will not dare to dwell into these details as it is beyond the scope of the subject though some recent publications address these issues [185 -193] .

WHO in such current pandemic situation has given a suggestion for the development of techniques, which are rapid in response, especially that are based on nucleic acid and protein test formats [194] . These developed techniques should offer advantages for use in short-term at the point-of-care. Effectiveness for tracking and surveillance can be enhanced using serological test for the detection of protein. Further, emphasis on cost effectiveness, lowering the burden on clinical and central laboratories by easing the operation must be performed [195] .

SHERLOCK method for the detection is one of the nucleic acid-based methods that has emerged and has all the potentials to be applied for the detection of SARS-CoV-2. Based on CSISPR method, a gene-editing tool used for RNA sensing using variants of Cas9, known as Cas13a ribonuclease. The process works by targeting the virus RNA followed by reverse transcription to DNA and isothermal amplification. Further DNA is transformed back to RNA where it interacts with Cas 13a. The targeted molecule activates Cas13a allowing the cleavage with fluorescent probe that yields the signal. Hou et al. [196] developed an isothermal, CRISPR-based method for the detection of SARS-CoV-2.

Detection of viral spike proteins and antibodies generated in the patients after the infection is another approach for the diagnosis of SARS-CoV-2. In detecting the coronavirus, antibodies studies have shown that S proteins from SARS-CoV-2 have greater reactivity. On other hand, an enzyme linked immuno-sorbent assay (ELISA) for detecting immuno-globins G and M in serum of the infected persons was demonstrated [197] . The studies used for nucleocapsid protein Rp3 from SARS-CoV-2 that has 90% similarity with SARS viruses. The results recorded on day 0 showed 50% positive for IgM and 80% for IgG, further increasing to 80% and 100% on day 5 [198] . The method has flexibility of sample such as blood, fecal and respiratory organs.

Considering the on-site testing that plays an important role in point-of-care that provides many advantage in which the key point is the on-spot detection avoiding the transport of samples to laboratories. One such a method proposed is the lateral flow assay, which is still under development for SARS-CoV-2. This method utilizes a paper strip coated with gold nanoparticles functionalized with antibodies. Simple colour change due to clustering through plasmon banding of gold nanoparticles are observed to derive the results. Such methods have been used for MERS-CoV, but challenges such as single usage and low sensitivity are yet to be addressed and further research is needed to be done on the amplification of readouts.

Another approach used is the designing of Microfluidic devices using a small chip consisting of micro-channels for the reaction. Such microfluidic device-based smart phone for detecting antibodies of sexually transmitted diseases has been demonstrated [199] . acids of these can be targeted in these tests. The advantage of this device is that the analysis of RNA takes place in less than 2 h on site avoiding the need for sample transportation to laboratories [200] .

Chemiluminesence immuno-assay is one such an approach that has been popularly used 

In recent years, serious public health issues and crises due to viral infectious diseases However, some drawbacks associated with this method are: (1) due to inherent off-target effects, improved specificity is a concern in CRISPR-based detection;

(2) addition of protospacer adjacent motif for CRISPR targeted recognition results in reduced range of sequences that can be detected due to sequence limitation; The electrochemical biosensors rely on proteins such as antigen/antibody or nucleic acid viz., RNA/DNA and the yield may not be 100% due to contamination of these bio-receptors. In such CRISPR techniques, specific techniques that can depend on aerosol mediated diagnosis may produce new advantages of response time, selectivity and sensitivity as well as lack of sampler perturbation. In the lab-scales, better and lower limit of detection can be achieved due to easy modification of the electrode surface.

Recently, health and safety related issues due to the pathogenic infections have raised concerns regarding its identification and prevention. In such consequences, detection of [55] S. Sang, Y. 

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Graphitic carbon nitride (g-C3N4)-based metal-free photocatalysts for water splitting: A review

Aminabhavi Polymeric graphitic carbon nitride (g-C3N4)-based semiconducting nanostructured materials: Synthesis methods, properties and photocatalytic applications

Photocatalytic recovery of H2 from H2S containing wastewater: Surface and interface control of photo-excitons in Cu2S@TiO2 core-shell nanostructures

Cyclodextrin-based siRNA delivery nanocarriers: a state-ofthe-art review

Quinoline-n-butylcyanoacrylate-based nanoparticles for brain targeting for the diagnosis of Alzheimer's disease

Nanomedicine: An effective tool in cancer therapy

The role of nanotechnology in the treatment of viral infections

An ultrasensitive label free human papilloma virus DNA biosensor using gold nanotubes based on nanoporous polycarbonate in electrical alignment

Fabrication of electrochemical biosensor consisted of multi-functional DNA structure/porous au nanoparticle for AIV (H5N1) in chicken serum

New electrochemical DNA sensor based on nanoflowers of Cu 3 (PO 4 ) 2 -BSA-GO for hepatitis B virus DNA detection

Electrochemical immunoassay for the detection of antibodies to tickborne encephalitis virus by using various types of bioconjugates based on silver nanoparticles

Kis, ssDNA Binding Reveals the Atomic Structure of Graphene

Sensitive electrochemical detection of hepatitis C virus subtype based on nucleotides assisted magnetic reduced graphene oxide-copper nano-composite

Electrochemical immunosensor with graphene quantum dots and apoferritin-encapsulated Cu nanoparticles double-assisted signal amplification for detection of avian leukosis virus subgroup J

Non-invasive wearable electrochemical sensors: a review

System Architectures in wearable electrochemical sensors

Wearable electrochemical alcohol biosensors

Wearable sweat sensors

Soft Wearable systems for colorimetric and electrochemical analysis of biofluids

Wearable electrochemical sensors for forensic and clinical applications

Wearable biosensors for healthcare monitoring

Wearable electrochemical sensors for noninvasive monitoring of healtha perspective

COVID-19) technical guidance: laboratory testing for 2019-nCoV in humans

Lateral flow assays towards pointof-care cancer detection: a review of current progress and future trends

Development and Evaluation of A CRISPR Based Diagnostic for 2019-novel Coronavirus, medRxiv

Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes

Application of a Portable Instrument for Rapid and Reliable Detection of SARSCoV-2

Infection in Any Environment

Microfluidic and Paper-Based Devices for Disease Detection and Diagnostic Research

Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice

Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing, medRxiv

A peptidebased magnetic chemiluminescence enzyme immunoassay for serological diagnosis of coronavirus disease 2019 (COVID-19)

Evaluation of two automated and three rapid lateral flow immunoassays for the detection of anti-SARS-CoV-2 antibodies

[111] W. Guo, K. Shim, Y-T. Kim 

 COVID-19 created a threat, leading to global economic crises due to massive lockdown to control the transmission.  A comparative discussion on COVID-19 using electrochemical techniques is summarised  Electrochemical detection of various viruses is discussed.  Role of nanotechnology for pathogen detection is discussed.  The major focus is given on tracing, testing and treatment.[205]