Plasmonic metamaterial based virus detection system: a review

Our atmosphere is constantly changing and new pathogens are erupting now and then and the existing pathogens are mutating continuously. Some of these pathogens, such as SARS-CoV-2, become so deadly that they put the whole technological advancement of healthcare under challenge. Within this very decade several other deadly virus outbreaks were witnessed by humans such as Zika virus, Ebola virus, MERS-coronavirus etc. Though conventional techniques have succeeded in detecting these viruses to some extent, these techniques are time-consuming, costly, and require trained human-resources. Plasmonic metamaterial-based biosensors might pave the way to low-cost rapid virus detection. So this review discusses in details the latest development in plasmonics and metamaterial-based biosensors for virus, viral particles and antigen detection and the future direction of research in this field. Emergence of quantum properties in biosensing, application of machine learning, artificial intelligence and novel materials in biosensing is also discussed in brief.


Introduction
In late 2019, a unprecedented case of pneumonia was diagnosed in China which later was proved to be caused by a novel severe acute respiratory syndrome -coronavirus (SARS-CoV-2) or novel coronavirusHuang et al. (2020) ;Lu et al. (2020). This novel coronavirus disease (COVID-19) spread throughout the world in a very short time and was declared a pandemic by the World Health Organization (WHO) Organization et al. (2020). It is to be noted that this is the third large scale outbreak of coronavirus associated disease within a very short period after Severe Acute Respiratory Syndrome (SARS) in 2003Zhong et al. (2003 and Middle East Respiratory Syndrome (MERS) in 2012Alhamlan et al. (2017). Apart from novel Coronavirus, a number of other virus related diseases also cause significant damage to the global population and it is needless to say that a rapid, reliable and accurate detection of viruses can contribute greatly to control the spread of the disease and prevent future pandemics like COVID-19.
Currently, several common methods are used for detecting infectious viruses. Serological testing Bastos et al. (2020), Immunofluorescence, Nucleic Acid Amplification Test (NAAT) are the most common genre of diagnosis Vemula et al. (2016). Hemagglutination inhibition assay (HI) and Enzyme Linked Immunosorbent Assay (ELISA) are the major serological testing Souf (2016). However, they have some major drawbacks which have hindered their ubiquitous usage for virus detection. For instance, preparation of antibody for ELISA is a costly technique and requires expert manpowerSakamoto et al. (2018). On the other hand, HI has low specificity under certain levels of agglutination and the sample may contain non-specific hemagglutinating factors Soares et al. (1999). Nucleic acid amplification based Reverse Transcription Polymer Chain Reaction (RT PCR) test is another technique to detect virus and till date it is the most widely used technique to detect novel CoronavirusCorman et al. (2020). RT-PCR technique is highly sensitive, specific and reliable diagnostic method. But this test typically takes longer than other detection methods and requires expert manpower and hence is expensive. Nucleic acid sequence-based amplification (NASBA), Loopmediated iso-thermal amplification (LAMP), RT-PCR and q-PCR are in the genre of Nucleic Acid Amplification Test (NAAT). Most of these testing schemes are costly and require a lot of time and highly trained manpower. Other methods to detect viruses such as CRISPR Qin et al. (2019) and culture methods have apparently also failed to be a rapid and reliable method for satisfactory diagnosis of different viruses as they are not widely used yet. In such circumstances, real time and label-free biosensors have recently emerged as auspicious diagnostic tools for different infectious diseases. These sensors overcome the need for fluorescence or radioactive tagging for virus detection, thus enabling compact, robust, cost-effective point-of-care diagnostics. Different bio-sensing platforms based on optical, electrical Luo and Davis (2013), and mechanical Savran et al. (2004) signal transduction have been rendered for applications ranging from laboratory investigation to clinical diagnostics and drug development to combating emerging infectious diseases. Among these different genre of biosensors, optical detection platforms have gained considerable interest in recent years. Optical biosensors allow remote diagnosis scheme of the bio-molecular binding signal from the sensing volume without any physical connection between the excitation source and the detection media. Unlike mechanical and electrical sensors, these optical sensors are also compatible with physiological solutions and are not sensitive to the changes in the ionic strengths of the solutions. Among different optical biosensors plasmonic and metamaterial based plasmonic biosensors are highly potential in this regard due to their exotic properties like miniaturized sensor chipYesilkoy et al. (2018), real-time sensing Guner et al. (2017), label-free sensing mechanism Maalouf et al. (2007).
The aim of this comprehensive review is to present the advances in plasmonic and metamaterial based plasmonic biosensors for virus or viral particles detection and highlight the scopes of future work in this field. There have been some recent review papers on plasmonic biosensors for virus detection Mauriz (2020), different methods of Coronavirus detection Samson et al. (2020); Yüce et al. (2020); Ji et al. (2020); Antiochia (2020) and recent progress in nanophotonic biosensors to combat the COVID-19 pandemic Soler et al. (2020). In this review, metamaterial based virus detection methods are discussed in details which is unprecedented and different plasmonic biosensors are classified in five broad fields on the basis of the detection technique and structure of the biosensors. Due to the ongoing COVID-19 pandemic, emphasis is given to the family of Coronavirus detection techniques and performance of different biosensors for different virus detection are also compared and summarized. Moreover, we have discussed the future trends in plasmonic and metamaterial based biosensing such as surface plasmon resonance imaging (SPRi), (a) Planar structure (c) Nano particle based  Figure 1: Schematic of different plasmonic and metamaterial based virus-sensing structures; (a)Planar structure : Surface plasmon is generated in between dielectric and metal; (b)Opto fluidic structure: nano aperture holding antibody increasing binding potential for flowing virus antigen; (c) Nano particle: localized surface plasmon around NPs enhances the sensitivity (d) Quantum dots attachment with NPs: Binding QD with NP enables enhanced fluorescent LSPR sensing; (e) Nano wire : Plasmons are generated around nano wires increasing the sensitivity; (f) 2D metamaterial: virus attachment in metamaterial changes capacitance which changes the resonant frequency; (g) 3D metamaterial: 3D shaped metamaterial can mend magnetic field of light more efficiently which has the potential to materialize ultra-sensitive biosensors; (f) Metasurface: Unusual patterns of metasurface performs as an efficient virus sensing platform.
incorporating quantum properties of materials in biosensing, novel materials based biosensors, artificial intelligence, and machine learning application in biosensing. As a non-destructive virus sensing platform, potential application of plasmonic and metamaterial based biosesnors for rapid, multiplexed, point-of-care detection of virus is also highlighted.

Evaluation of plasmonic biosensors
To evaluate the performance of biosensors several figures of merit are widely used. Among them detection limits or limit of detection (LOD), sensitivity, selectivity or specificity are the most popular. Selectivity or specificity (S) is defined as the ability of a sensor to detect a particular virus from a sample containing admixtures of similar or other materials. Sensitivity and detection limit are two significant metrics that can be used to compare biosensors of different platforms. Sensitivity in the case of virus detection expresses how a sensor interacts in the presence of virus. For virus detection generally sensitivity of plasmonic biosensor is defined as- Here Δ is the change in reflection/transmission wavelength of the plasmonic biosensor.
Another important FOM limit of detection (LOD) or detection limit (DL) is defined as the minimum virus concentration that can be detected by the sensor. In other words, LOD is the minimum number of virus necessary to cause a detectable change in the output signal of the sensor. For determination of LOD a formula commonly used is- Shrivastava et al. (2011);Suthanthiraraj and Sen (2019) Here is standard deviation of the control without virus which is basically the system noise floor and S is the slope of the linear fit for wavelength shift versus virus concentration plot which is basically the sensitivity of the sensor.

Plasmonic excitation in biosensing
In 1902 Wood observed an unusual distribution of light in diffraction grating. He introduced the idea of plasmonic excitation Wood (1902). Metal-dielectric contact has been one of the primary methods of generating excitation. Generally, it is a guided mode that propagates along metal/dielectric interfaces. Plasmonic excitations are characterized into two segments, namely Surface Plasmon (SP) and Localized Surface Plasmon (LSP). SP that propagates at the flat interface between a conductor and a dielectric are two-dimensional electromagnetic waves. It is the collective resonant oscillation of conduction electrons and incoming photons at the interface between metal and dielectric. On the other hand, LSPR is generated by a light wave trapped within conductive nanoparticles (NPs) smaller than the wavelength of light. The size of the NPs is typically in the region of Mie scattering. When an external electric field is applied to metallic NPs, the conduction electrons encounter combined harmonic oscillations causing strongly localized electromagnetic field which has very high intensity. Ever since the discovery of this unique characteristic, many exciting researches of biosensing has been conducted using this exotic property and it has been used in virus detection as well. Viruses like HIV, Coronavirus, Influenza, dengue, Adeno virus, Zika virus, hepatitis, Norovirus etc. have been reported to be successfully detected by employing various kinds of plasmonic biosensors.
To induce SPR in the boundary between metal and dielectric, the momentum of the incident photon must be matched with the momentum of the conduction band electrons. If the matching condition is met light can be coupled in the interface between metal and dielectric plane. For flat planar surfaces, this phase matching is fulfilled by the attenuated total reflection (ATR). This usually requires a media of higher refractive index (RI). The matching condition can be interpreted from the dispersion relation given below Raether (1988): where is the refractive index of the coupling prism, Θ is the incident angle of light, is the dielectric constant of metal, is the dielectric constant of dielectric, is the wave vector of surface plasmon.
As the refractive index of the analyte media changes, also changes, eventually altering the wave vector k. When and are equal and opposite of each other, the wave vector is maximum which results in resonance. Here depends on the wavelength of incident light and depends on the refractive index of the dielectric environment.
Diverse configurations are used to generate SPR or LSPR for bio-sensing. In this review, these plasmonic biosensors are broadly classified into five different groups based on their structure and sensing principle namely planar structure, opto-fluidic structure, nano particle based structure, quantum dot based structure and nano rod-based structure.

Emergence of metamaterials in biosensing
In recent years, to increase the sensitivity of plasmonic biosensors metamaterial based plasmonic biosensors have been employed. Advantages of using metamaterial based sensors are that a variety of geometric structures and different sensing principles can be utilized which were not feasible with conventional plasmonic biosensors.
In 1968, Russian physicist Victor Veselago first came up with the theoretical concept of left-handed materials Veselago (1968)

Bio sensing principle of plasmonic biosensors
Biosensor-based detection methods always utilize a specific bio-receptor surface to analyze either intact viruses or viral proteins. A common and widely explored bio-receptor is antibodies that originates in animal bodies against specific viral surface proteins or antigens. There are also diverse types of artificial capturing molecules that are de- at different analyte concentrations are integrated to derive the rate constants (association, ; dissociation, ; and equilibrium, ). Thus, by using the SPR signal, amount, and condition of analyte in the sample is diagnosed. SPR signal is usually measured in two ways for planar structures. Firstly, the change of incident angle with respect to generation of SPR. Secondly, change of wavelength about SPR occurrence. SPR sensors are also categorized in this regard as incident angle modulated SPR sensor Zhou et al. (2017) and wavelength modulated SPR sensor Liu et al. (2005) respectively.

Planar structure
Many recent studies with SPR based planar structured virus detectors are in the spotlight of research. Mosquito borne dengue virus is a life-threatening pathogen. In 2020 Dengue Virus Type (DENV) 2 E-Proteins with high sensitivity and accuracy was successfully detected Omar et al. (2020). A SPR sensor based on self-assembled monolayer/reduced graphene oxide-polyamidoamine dendrimer (SAM/ NH2rGO/ PAMAM) thin film was developed which detected the DENV-2 E-proteins with the lowest detection of 0.08 pM. This same research group also developed another sensor chip back in 2018 to detect dengue virus Omar et al. (2018). But in the later work they introduced a graphene-oxide(GO) layer in the sensor chip which significantly enhanced the overall performance of the sensor. In a similar work graphene-based material sensor chips were investigated for real time and quantitative detection of DENV protein. In this study the sensor chip was developed by accumulating cadmium sulfide quantum dots-reduced GO upon a thin gold plate. By changing the angle of incident light this graphene-based chip was able to detect DENV protein as low as 0.1 pM. Like dengue another deadly disease that causes hemorrhagic fever is ebola. Certainly, this virus has the full potential to create global pandemic. Recently a SPR chip was developed to diagnosis ebola virus with high specificity and sensitivity Sharma et al. (2020). To develop the sensor a gold SPR chip was modified with 4-mercaptobenzoic acid (4-MBA). Three different monoclonal antibodies (mAb1, mAb2 and mAb3) of Ebola virus were in the race. The interactions of antibodies were then investigated to determine the best mAb based on the affinity constant ( ). After the screening mAb3 showed the highest affinity which was also confirmed by ELISA. This study also suggested the interaction was spontaneous, endothermic, and driven by entropy.
In 2013 a new type of avian influenza H7N9 virus emerged in China, causing human infection with high mortality taking 612 lives. A quantitively and real time diagnosis was crucial for eradicating the outbreaks of this emerging disease. A straightforward strategy for rapidly and sensitively detecting the H7N9 virus using an intensity-modulated surface plasmon resonance (IM-SPR) biosensor integrated with a new generated monoclonal antibody was proposed Chang et al. (2018). In another study a similar structure was developed to detect different respiratory viruses. In this  work a SPR-based biosensor was developed for specific detection of nine common respiratory virus including influenza A and influenza B, H1N1, respiratory syncytial virus (RSV), parainfluenza virus 1-3 (PIV1, 2, 3), adenovirus, and severe acute respiratory syndrome coronavirus (SARS) Shi et al. (2015). A significant challenge in this work was amplifying viral bodies by PCR (Polymerase chain reaction). But an advantage was the same sensor chip could be used to diagnose multiple times after washing with NaOH solution.
In a recent study HIV virus was also successfully detected by commercially available simple planar SPR biosensor.
HIV-related DNA with hairpin type DNA aptamers was diagnosed. The proposed SPR biosensor could detect target DNA sensitively in a linear range from 1 pM to 150 nM with a detection limit of 48 fM. Diao et al. (2018). Lately a typical planar SPR biosensor for medical diagnostics of human hepatitis B virus (hHBV) has been developed Tam et al. (2017). A 7-fold higher limit of detection and 2-fold increase in coefficient of variance (CV) of the replicated results, were shown as compared to typical enzyme-linked immunosorbent assay (ELISA) testing.

Optofluidic systems
Another commonly used compact portable plasmonic bio sensing platform is optofluidic media. Itis the combi- biosensor. In a more advanced work, programmable control systems for microfluidic analytes flow were used to develop a more efficient and portable plasmonic biosensor. In this study the 9 kinds of samples with different reflective index and antigen/antibody systems were utilized for characterization. By using these programmable optofluidic arrays, the biomarker of the liver cancer was tested in situ and real time. Geng et al. (2014).

Nano particle enabled plasmonic structures
Nano particles (NP) are most used for development plasmonic sensor due to their easy fabrication process and cost-effectiveness. Gold (Au) and silver (Ag)   a crucial role in virus sensing as they make label free detection possible. As a result, no fluorescence or colorimetric biomarker is required. Different immobilizing antibodies are used on to capture the viral particles or proteins.
The first virus detection using nano particle based plasmonic sensor was reported by Fatih Inci et. al. in 2013Inci et al. (2013. They used Au nano particles with immobilized antibodies to detect and quantify different subtypes of HIV viruses from unprocessed whole blood. Their limit of detection was 98 ± 39 copies/mL for HIV subtype D. They . It is to be noted that this was non-specific detection of Adenovirus particles but based on numerical results they proposed specific detection models. They used rigorous couple wave analysis and transfer matrix method using effective medium theory for numerical analysis. Change in reflectivity was measured to detect adenovirus particles and the limit of detection was 109 viruses/mL.  (2019) used thermally annealed thin silver film deposited onto silicon substrate to detect NS1 antigen of dengue virus in whole blood. Refractive index sensitivity of the biosensor was 10 − 3. A polyethersufone membrane filter was used at the inlet of the sensor to separate blood cells from plasma and anti NS1 antibody was used to ensure specific binding of the NS1 antigen. Increase in absorption was found for antigen binding and for the highest 50 g/mL concentration 108nm redshift in peak absorption wavelength was found.
Sensitivity of this LSPR sensor was found to be 9nm/( g/mL) and limit of detection was .  They achieved maximum wavelength shift of 46nm for a virus concentration of 10 5 PFU/mL and they acieved LOD of 126 ± 3 PFU/mL. Very recently, Nasrin and her group Nasrin et al. (2020) employed CdZnSeS/ZnSeS QD-peptide and gold nano particle composites to enhance the LSPR signal to detect different concentrations of influenza virus from 10 − 14 to 10 − 9 g/mL. They varied fluorescence intensity by changing the distance between the QD and NP by using different peptide chain lengths to find the optimized condition to detect the virus and achieve a detection limit of 17.02 fg/mL.

Quantum dots in plasmonic structures
Previously, the same group detected norovirus Nasrin et al. (2018) using the same mechanism and their LOD was 95 copies/mL. However, this system could not detect the small change in norovirus concentration due to the smaller crosslinker between two NPs.

Nanowire and nanorod based plasmonic biosensor
Nanowires and nanorods are usually used to enhance the properties of existing biosensors due to their ability of confining electromagnetic fields in a superior way.
Das and his colleagues designed and simulated a plasmonic immunoassay, in 2020, which comprised of sandwich plasmonic biosensor whose sensitivity was enhanced by using gold nanorod. They have varied the prismatic configuration and found that the BK-7 glass based sensor has sensitivity of 111.11 deg/RIU Das et al. (2020). They also varied the distance of the gold NRs and their aspect ratio and recorded their observations. This sensor was desgined for SARS-COV-2 detection, the gold NRs and gold nanosheets are functionalised with SARS-COV-2 spike-protein antibody and shift is observed in the SPR angle. In 2010, A biosensor by functionalizing gold nanorods with monoclonal hepatitis B surface antibody (HBsAb) through physical adsorption was devised. The characteristic plasmon absorption spectra is then measured after placing these nanorods in the vial containing blood serum. The LOD of the sensor is 0.01 IU/ml Wang et al. (2010).
In 2006  The THz spectrum before and after placing the virus was used for the detection purpose Hong et al. (2018).

Bio sensing principle of metamaterial based plasmonic biosensors
Metamaterials are engineered materials; they possess properties which are not found in naturally occurring elements Kshetrimayum (2004). These exotic properties depend on the geometry of the material hence can be tuned as Figure 8: LC equivalent circuit for a metamaterial reproduced from Withayachumnankul et al. (2010) per requirement. Usually specific repeating patterns are created on the material and each pattern has size smaller than the wavelength they need to have an effect on.
Metamaterials enable the detection of biomeolecules in THz-GHz frequency regimes which is difficult otherwise, as microorganisms such as fungi, bacteria, and viruses have scattering cross-sections which are much smaller than THz/GHz wavelengths. Sensing biomolecules in the THz-GHz electromagnetic spectra has several advantages as it provides label-free, non-contact and non-destructive sensing.
Metamaterial was first used in biosensing by Lee et al. In 2008 Lee andYook (2008). They used gold split ring resonator (SRR) array to detect biotin and streptavidin to show the biosensing capability of the metamaterial. SRR worked as biosensor as it can be considered as a simple LC circuit with simple resonant frequency of . So, the resonant frequency of the system changes as the capacitance or inductance changes. As biotin and streptavidin binds to the system the capacitance of the SRR changes which is reflected in the resonant frequency thus it can be used as a biosensor. In 8 the equivalent LC representation of a specific metamaterial with rectangular geometry with a split is shown. In this way the metamaterials with nanogaps can be modeled and their sensing mechanism can be understood using 2.

Different metamaterial based biosensors for virus detection
In 2017, S.J. Park and his group created a metamaterial surface using gold rectangular structure on quartz. Metamaterial has certain capacitance and inductance equivalent parameters. Presence of virus particles within the capacitor gap changes the resonance frequency which can be explained by a simple LC circuit. Hence different viruses were detected by observing the THz transmission spectra. They detected bacteriophage viruses PRD1 (60 nm) and MS2 (30 nm). Sensitivity was 80 GHz/ particle Park et al. (2017). Ahmadivand and his colleagues designed a toroidal metamaterial based biosensor they sensed zikavirus envelope protein by measuring the spectral shifts of the toroidal resonance in 2018. They also added gold nanoparticles to see the effect in the sensitivity and observed enhancement in the performance of the sensitivity Ahmadivand et al. (2018). In 2018, A THz biosensing metamaterial absorber for A. B. C.
D. E. F. virus detection based on Spoof Surface Plasmon Polariton (SSPP) Jerusalem cross apertures metamaterial absorber was devised. They determined the shift in absorption and resonant frequency as the alpha beta parameters of the viruses were changed. Analyte thickness of H9N2 was also changed to see the variation in resonant frequency and absorption. From these they claimed that virus subtypes can be uniquely identified using this sensor. H5N2, H1N1, H9N2 viruses were detected Cheng et al. (2018). In 2017, Ahmadivand and his group used 2D micro-structures composed of iron (Fe) and titanium (Ti) for the magnetic and electric resonators (torus), respectively to design a set of asymmetric split resonators as meta-atoms to support ultra-strong and narrow magnetic toroidal moments in the THz spectrum.
Limit of detection of 24.2 pg/mL and sensitivity of 6.47 GHz/log(pg/mL) their system resulted in toroidal response lineshape extremely sharp, narrow and deep. They analyzed the sensitivity of the dip with Zika virus envelope protein attached to the system Ahmadivand et al. (2017). In 2017, Lee et. al. used a multi-resonance and single resonance nano antenna sensing chip which was fabricated using gold nano antennas printed on silicon wafer to sense different types of Avian Influenza viruses. H9N2 was sensed using a multi resonance sensor. By using a single resonance nano antenna they demonstrated that viruses can be classified in terms of resonance frequency and decreased transmission ratio Lee et al. (2017a). In 2019 Vafapour and his colleagues developed a biosensor using metamaterial comprising of H-shaped graphene resonator on a semiconductor film which they used to detect Avian Influenza Keshavarz and Vafapour (2019). Ahmed et al. developed a cost-effective metasurface based biosensor in 2020. They used a Digital Versatile Disc which already has built-in periodic grating where they deposited multilayers of gold, silver and titanium and showed that the device exhibits fano-resonance. When the HIV virus particles were captured they observed a shift in the fano resonance peak from which HIV can be detected Ahmed et al. (2020) In 2016, Aristov et al. devised a 3D metamaterial based biosensor composed of woodpile structure which has not yet been used in virus detection but showed sensitivity greater than 2600nm/RIU and phase sensitive response is more than 3 × 10 4 degrees/RIU for analytes which is very high. In the same year Sreekanth et al. designed a biosensor with grating coupled hyperbolic metamaterial which is a bulk 3D sub-wavelength structure that enhances angular senistivity of plasmonic biosensor.They detected cowpea virus with it and obtained a mximum sensitivity of 7000deg per RIU Sreekanth et al. (2016)

Plasmonic Biosensors for Coronavirus Detection
Currently, diagnosis of COVID-19 is primarily accomplished by three techniques-quantitative reverse-transcription polymerase chain reaction (RT-qPCR) Corman et al. (2020) and gene sequencing, a lateral flow immunoassay, which is a common point-of-care (POC) diagnostic approach that detects antibodies against SARS-CoV-2 in patient samples Böger et al. (2020); Bastos et al. (2020), and chest computed tomography (CT) Zhang et al. (2020). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) is widely used as the confirmatory test for COVID-19 detection and it is considered as the gold standard in this regard. However, RT-qPCR method requires long and difficult processing method. It also demands highly trained manpower and cost which hinder the large scale testing for COVID-19.
Although RT-qPCR test is highly sensitive, may give false negative reports especially if the specimen is collected from the upper respiratory tract after a certain period from the onset of symptoms Tahamtan and Ardebili (2020). Therefore, there is an ongoing demand for an alternative detection method for novel coronavirus.
Plasmonic biosensing is a promising field for the detection of Coronavirus, as it can enable rapid testing and also reduce the manpower needed for performing the diagnosis. There are already many ongoing and reported works on plasmonic detection of novel Coronavirus. The schemes that were developed for detecting other Cornaviruses can be useful for SARS-CoV-2 detection as well. Commercially available surface plasmon resonance (SPR) and localized surface plasmon resonance (LSPR) sensors are already being used for viral strains detection such as SARS, MERS and influenza Bhalla et al. (2020).

Future perspective
Researchers are always on the quest of finding new methods of pathogen detection which is faster, accurate and sensitive and also can be used as POC device because the population is increasing at a fast pace and epidemics are materialising more frequently than ever. Relatively newly discovered materials like graphene Cucci et al. (2019) Researchers are also using machine learning in sensing to get better results Moon et al. (2020). In addition to that, topological insulator has been used to enhance the sensitivity and detection limit of surface plasmon resonance based sesnor Zhu et al. (2019). These methods and many others are yet to be explored extensively in biosensing field.
Almost all plasmonic biosensors works on the basis of antigen-antibody binding. Though there has been much research on antigen antibody binding but there was very little focus on antibody adsorption with the sensor chip. Typically metallic plasmonic materials like Au, Ag are used on the top layer sensor chip. Therefore, capturing molecules like antibody is adsorbed onto the plasmonic materials. Systematic numerical model of adsorption might open up new possibilities in this regard Osborne (2018). Quantum enhanced plasmonic sensing is an state of the art idea which can be explored as well. Quantum properties can amplify the sensitivity of a sensor and thus has the potential to shake up the plasmonic sensing scheme through the development of quantum-enhanced sensors. Dowran et al. (2018). Machine learning and artificial intelligence assisted plasmonic biosensing can be also applied for virus sensing. Recently researchers has started to blend neural network algorithms with plasmonic diagnosis. Li et al. (2019). Surface plasmon resonance imaging (SPRi) is another emerging field that has been applied in detection and monitoring of biomolecular events Puiu and Bala (2016). There has been a study of apple stem pitting virus (ASPV) by imaging the aptamer binding with the coat protein using SPR Lautner et al. (2010). Recently, researchers have achieved sub-100nm resolution using this technique Ohannesian et al. (2020) which can be applied for virus detection as well.
Finally, sensitivity of plasmonic and metamaterial based biosensors have reached femtomolar detection limit but here limiting factor is the specificity of the biosensors which requires attention. Although employing aptamer and peptide based binding molecules specificity has improved significantly their application is still not suitable for all biosensors. Moreover, the biosensors may detect viruses successfully in laboratory environment, their performance need to be evaluated from clinical samples. Another problem for metamaterial based biosensors can be mass production for which the sensing platform needs to be compact. Multiplexing capability for detecting multiple viruses Sánchez-Purrà et al. (2017) using the same sensing platform using plasmonic and metamaterial based biosensors can be developed as well.

Conclusion
The world is currently fighting with the pandemic caused by SARS-CoV-2, there is no assurance when will this pandemic end let alone the next one. Disease diagnosis in the early stage is one of the main weapon in this ongoing fight against the pandemic. Though during last few years there has been significant improvement in disease diagnosis by optical biosensors, even COVID-19 has been successfully detected by LSPR based biosensors there is still room for development. Plasmonic and metamaterial based biosensors exist in many different forms and each form has one or more supremacy over conventional techniques, some are already being used in laboratories for drug and vaccine developments Myszka and Rich (2000). Some of the plasmonic biosensors like planar metal-dielectric interface based biosensors have simple fabrication techniques and give pretty good sensitivity and low LOD. Plasmonic biosensors like those based on metamaterial allow label-free, non-destructive sensing. Nanoparticle based plasmonic biosensors allow a broad-range of antibody binding. Addition of metamaterials in plasmonic biosensors have increased the sensitivity manifolds. Most importantly all the biosensors make rapid detection possible. However, plasmonic and metamaterial based biosensors need to be robust and reproducible to become mainstream virus caused disease diagnosis method.
Also biosensors need to be developed as a lab-on-a-chip system in order to make them ubiquitous. Many of the researchers are already working on lab-on-a-chip configuration of plasmonic biosensors. If these shortcomings can be overcome in near future then plasmonic and metamaterial based biosensors will enable faster and more accurate detection of pathogens which will greatly help to prevent outbreaks in future.