key: cord-327392-9psblokc
authors: Srivastava, A.K.; Dwivedi, Neeraj; Dhand, Chetna; Khan, Raju; Sathish, N.; Gupta, Manoj K.; Kumar, Rajeev; Kumar, Surender
title: Potential of Graphene-based Materials to Combat COVID-19: Properties, Perspectives and Prospects
date: 2020-10-21
journal: Mater Today Chem
DOI: 10.1016/j.mtchem.2020.100385
sha: 
doc_id: 327392
cord_uid: 9psblokc

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new virus in coronavirus family that causes coronavirus disease (COVID-19), emerges as a big threat to the human race. To date, there is no medicine and vaccine available for COVID-19 treatment. While the development of medicines and vaccines are essentially and urgently required, what is also extremely important is the repurposing of smart materials to design effective systems for combating COVID-19. Graphene and graphene-related materials (GRMs) exhibit extraordinary physicochemical, electrical, optical, antiviral, antimicrobial, and other fascinating properties that warrant them as potential candidates for designing and development of high-performance components and devices required for COVID-19 pandemic and other futuristic calamities. In this article, we discuss the potential of graphene and GRMs for healthcare applications and how they may contribute to fighting against COVID-19.

The recent outburst of coronavirus disease-19 is devastating for global health systems [1, 2] . COVID-19 is a fatal disease which is caused by a newly born severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1, 2] . Due to its severity and reach to most of the nations across the world, the world health organization (WHO) has declared it a pandemic [1, 2] . As of 11 th June 2020, there are more than 7 Over the past few years, graphene and graphene-related materials (GRMs) have attracted huge attention of the researchers owing to their wide spectrum properties such as high surface area, high electrical mobility and conductivity, excellent mechanical, electrochemical and piezoelectric properties, and efficacy against microbes and viruses [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] . Recently, few good reviews appeared in the literature revealing the authors views and projections on the possible contribution of graphene-based materials in the global fight against COVID-19 [15] [16] [17] . For example, Palmeri and Papi [15] have emphasized over the various modes of interactions among graphene materials and different virions that can helps in blocking or destroying the viruses. Authors also briefed over the plausible role of the graphene textiles and filters in controlling the epidemiological spread of COVID-19 and implications of graphene materials for development of environmental sensors. Udugama et al. [16] focused on discussing the emerging diagnosis technologies for COVID-19 detection.

These technologies include reverse transcription recombinase polymerase amplification (RT-RPA), loop mediated isothermal amplification method (LAMP), nucleic acid sequence based amplification (NASBA), rolling circle amplification, enzyme-linked immunosorbent assay J o u r n a l P r e -p r o o f (ELISA), magnetic biosensor, magnetic ELISA, DNA-assisted immunoassay, etc., which all mainly used nucleic acid and protein biomarkers for viral and bacterial diagnosis [16] .

Cordaro et al. [17] compiled the literature on contribution of graphene-based materials and stretegies in liquid biopsy and the diagnosis of viral diseases, and discussed on the potential of graphene in COVID-19 diagnosis. In general, most of the recent reports briefly reviewed the literature related to the implications of graphene related materials in virus diagnosis and their role in designing personal protective equipments with special reference to COVID-19.

In the present review, we have discussed in detail the various functional properties of 

Graphene is an atomically thin layer (single layer) of sp 2 bonded carbon atoms arranged in a hexagonal pattern (Figure 2a) . Single-layer graphene (SLG) displays outstanding properties.

In SLG the π and π* bands touch at the Dirac point that makes it a zero-band gap material, and at Dirac point, the SLG electrons behave-like massless fermions (Figure 2b ) [4] [5] [6] [7] . SLG displays high carrier mobility that can reach to about 10 5 -10 6 cm 2 V -1 s -1 , two to three orders of magnitude higher than silicon; high mechanical strength of about 130 GPa (130 GPa = 13256310768.713 Kg/m 2 ), several times higher than steel; electrical and thermal conductivities higher than copper and diamond, respectively; high transmission of about 97.7%; excellent lubricity; broad spectrum antimicrobial properties etc. [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] . Graphene and GRMs can be produced by various top down and bottom up approaches [4] [5] [6] [7] . Dry and liquid exfoliations are among the common methods for the synthesis of graphene. Geim and Novoselov used the mechanical exfoliation method to peel off the graphite through the scotch tape to produce graphene [4] . Thermal chemical vapour deposition (CVD) is one of the best methods for the synthesis of high-quality graphene with minimal defects [5] which could be used in the development of graphene field-effect transistor (FET), electrochemical, and piezoelectric biosensors. The CVD process of graphene production requires the thermal decomposition of carbon containing precursor gas, mainly methane, at high temperature about 1000 o C on specific substrate viz. copper [18] . Other materials such as Ni [19] , Pt [20] , Fe [21] and their alloys [22] have also been employed as the substrates for the deposition of the graphene layer. Preconditioning of the susbtrate is also required before the deposition of high quality graphene on copper [22] . Once the sysnthesis of graphene has been done on specific substrate, the transfer methods are employed to place the graphene on desired surfaces. Commonly, the the transfer of graphene from Cu foil to desired susbtrate requires following steps: (i) coating of poly(methyl methacrylate) (PMMA) on graphene on copper, J o u r n a l P r e -p r o o f where PMMA acts as a support layer for graphene, ii) etching of copper in FeCl 3 solution, iii) rinsing of PMMA/graphene film with ultrapure water, iv) lifting off PMMA/graphene film on a desired substrate, v) removal of PMMA, and cleaning and baking of the graphene to get good quality transferred graphene [23] . Likewise GRMs, such as bilayer graphene (BLG) and multilayer graphene (Figure 2c ) can be obtained by repeadtedly transfer of the SLG on top of one another. Unlike, SLG, the BLG has a greater feasibility to tune its band gap and hence in recent past this material has attracted considerable interst for optoelectronic applications in particular. The engineering of the band gap and other properties of BLG and MLG can be performed by the application of electric field, and chemical doping [4] [5] [6] [7] . Top down approach is the simple, scalable and fast method for the synthesis of GRMs such as graphene oxide ( Figure 2d ), which is an oxide sheet of graphene. Hummer's, Brodie, and Staudenmaier methods or modified versions of these methods are used for the synthesis of GO [24] Graphite is the starting material which is oxidized in acidic envriment, and then ultrasonication and purification steps are employed to reduc the number of layers of graphite oxide to a few layer GO, and evn single layer GO. Furthermore, GO possesses a band gap due to the presence of functional groups but it shows inferior electrical and thermal properties than graphene [4] [5] [6] [7] . It is essential for many applications, in particular for electronics and bioelectronics like biosensors, to enhance the conductivity of GO so as to develop highly sensitivive, selective and fast sensing devcies. Thus, the chemical reduction of GO is perfomed commonly using hydrazine, and the resultant reduced graphene oxide (rGO) demonstrates considerably improved electrical properties than GO [4] [5] [6] [7] . This is attributed to a reduced amount of oxygen-containing groups in rGO with respect to GO, but the electrical proeprties of rGO remain slightly inferior to pristine graphene [4] [5] [6] [7] . The detailed description of sysntehsis and properties of graphene and GRMs can be found in Ref. [5, 7, 24, 25] J o u r n a l P r e -p r o o f 

Unveiled in December 2019, a new fatal SAR-CoV-2 virus starts circulating among the humans [26] . Transmission through sub-micron size respiratory droplets is the common pathway for COVID-19 spread [27] . Moreover, a person can also catch this virus by coming in contact with the contaminated objects or surfaces and then touching their mouth, nose, or eyes. A recent study reported the variable stability of SAR-CoV-2 virus on different surfaces [28] . The SARS-CoV-2 is found to have higher survival time on plastic (72 h) and stainless steel (48 h) surfaces compared to copper (4 h) and cardboard (24 h) . Moreover, the virus is confirmed to be more stable on smooth surfaces compared to rough surfaces such as printing/tissue papers (3 h), wood (2 h) and cloths (2 h). Unfortunately, the detectable level of J o u r n a l P r e -p r o o f the virus is reported to be available on the external layer of the surgical masks even on day 7 [29] . Thus, contaminated high touch surfaces which offers high virus stability can enhance the chances of COVID-19 spread. In the present pandemic situation, where the COVID-19 cases are exponentially increasing each day globally, development of efficient anti-SARS-CoV-2 protective surfaces/coatings can play a significant role in controlling the viral spread through high touch components, products and systems.

Graphene-based materials have been explored extensively for their antimicrobial potentials [14, 30] . Reported studies provided evidence about the broad-spectrum inhibition activity of graphene oxide and its derivatives against bacteria [31] and fungi [32] . In 2014, Sametband et al. [33] reported the antiviral properties of GO and partially reduced sulfonated properties of GO are found to be enhanced under elevated temperature conditions (56 o C). In another report, GO sheets are reported to exhibit significant antiviral inhibition potentials towards enveloped feline coronavirus (FCoV), and incorporating silver particles into GO structure broadens its antiviral potential towards non-enveloped infectious bursal disease virus (IBDV) as well [36] . Yang et al. [37] have prepared multifunctional curcumin loaded β-CD functionalized sulfonated graphene composite (GSCC) and investigated its antiviral potential against negative sense respiratory syncytial virus (RSV) which like SARS-CoV-2 infect both lower and upper respiratory tract with children and elderly as their easy targets.

The results revealed that GSCC could inhibit RSV from infecting the host cells by inactivating the virus directly and prohibiting the attachment of the virus, and have prophylactic and therapeutic effects towards the virus. In a recent study, authors have attempted to investigate the antiviral effect of GO-Silver nanoparticles composite on the replication of porcine reproductive and respiratory syndrome virus (PRRSV) [38] . The results suggest that the exposure of virus with GO-AgNPs composite obstruct the virus to enter the host cell with 59.2% efficiency and also promotes the production of IFN-stimulating genes (ISGs) and interferon-α (IFN-α) which inhibits the virus proliferation. Table 1 

Early-stage, accurate and rapid detection of viruses is a prerequisite to control the infection spread. In particular, the commonly available diagnostic kits for the diagnosis of SARS-CoV-2 virus are based on polymerase chain reaction (PCR) such as RT-PCR [39] . While the RT-PCR-based technique is highly sensitive and shows significant specificity for SARS-CoV-2, it is a slow diagnostic method (3-4 hours), and has a high cost. Thus, the development of a rapid, economical viable, and reliable point-of-care (POC) test for detection of SARS-CoV-2 viral infection is the need of the hour. Biosensors are potential candidates for the detection of bio-molecules and viruses. The surface of the biosensor is important in the performance of the analytical device; it is where immobilization and transduction take place [40] .

Researchers have developed electrochemical-, colorimetric-, lateral flow-, SERS-based biosensors, etc. which have the advantages of high sensitivity and selectivity, costeffectiveness, portability, and easy to use. The gold and carbon electrodes have been used as as electrochemical transducers for fast and sensitive biosensors [41] . Refs [42, 43] show the development of an impedance-based boron-doped diamond biosensor for early detection of influenza M1 virus. Electrochemical biosensors in particular are considered as reliable and sensitive biosensors [44] [39] . Nanomaterials [45] are often used to amplify the signal and sensitivity of electrochemical biosensors. In electrochemical biosensors, any electrochemical change at the interface between electrodes and an electrolyte, based on a conformational change produced by biometric recognition between antibody and antigen, is measured.

Graphene has been explored to design highly efficient biosensors due to its stable electrochemical and optical behavior, high electrocatalytic activity, and excellent mechanical and thermal properties [46] . Graphene-based platforms have been used to immobilize biomolecules to create biosensors. Ref. [47] describes the method to immoblize the biomolecules onto graphene surface via surface chemical engineering. These strategies al. [50] reported highly sensitive electrochemical biosensor based on chitosan/Silver nanoparticle (AgNPs)-graphene composite materials. The developed biosensor shows efficacy in detecting the avian influenza virus H7 (AIV H7) with a detection limit as low as 1.6 pg/mL. Thus, the effectiveness of graphene-based electrochemical biosensors for the detection of biomolecules, in particular for the viruses, suggests that these biosensors have the potential to effectively detect the novel coronavirus SARS-CoV-2 as well [51] but a lot of high-end research needs to be performed to develop reliable diagnostic devices. We present a hypothetical mechanism in Figure 4 that shows how electrochemical biosensors based on graphene and GRMs could be used for the detection of SARS-CoV-2 virus. Table 2 

Graphene field-effect transistors (GFET) have huge potential for sensitive, fast, and early detection of viruses; many recent works indeed show its application for virus detection.

GFET employs an ultrathin graphene channel between the source and the drain. Chen et al. [52] demonstrated the application of GFET for the detection of Ebola virus antigen. The rGO was placed between the electrodes to form the sensitive and conducting channel and alumina was coated on the rGO for surface passivation [52] . The Ebola antibodies were conjugated with gold nanoparticles on rGO channel and acted as a sensing platform. The developed GFET displayed high sensitivity with a limit of detection down to 1 ng/mL for Ebola glycoprotein (EGP) [52] . Ono et al. [53] demonstrated the detection of influenza virus using GFET; the GFET device was prepared using the exfoliated graphene on Si/SiO 2 substrate having metal electrodes. Ref. [54] demonstrates the application of liquid coplanar gate GFET testing is the need of hour. While the initial results are promising, a significant amount of work is yet to be performed to fully understand the GFET for designing sensitive and fast biosensor devices for the accurate detection of SARS-CoV-2. Table 2 compiles the literature on graphene and GRMs-based FET biosensors for the detection of various viruses including SARS-CoV-2.

Piezoelectric biosensors have become a popular technology to detect viruses, hormones, bacteria, cells and to study a broad range of biomolecular interactions. Piezoelectric biosensor offers real-time and label-free transduction with high sensitivity, simplicity, and swiftness [58] [59] [60] [61] . Particularly, the piezoelectric immunosensor was first developed by Shons in 1972 to detect cow serum IgG antibody [58] . Among them, piezoelectric quartz crystal microbalance biosensor has become important to detect various coronaviruses that work on the principle of piezoelectricity, which measures the mass change and viscoelasticity variation of materials/virus by measuring the frequency and damping change of a piezoelectric quartz crystal resonator [61, 62] . Piezoelectric materials generate electric field /potential under external pressure, and this phenomenon is known as the direct piezoelectric The schematic of the device configuration is presented in Figure 5a . It was clearly shown that the frequency shifts have a linear dependency on antigen concentration in the range of J o u r n a l P r e -p r o o f 0.6-4 μg/mL [65] . The developed piezoelectric device exhibited good reproducibility and can be reused 100 times without a detectable loss of activity [60] . The schematic representation of the piezoelectric quartz microbalance biosensor along with the computer-controlled signal detector is shown in Figure 5b . The relation of frequency to mass for piezoelectric quartz crystal resonator is governed by the following equation

where Δf is the change in resonance frequency, F is the resonance frequency of the crystal, ρ is the density of the crystal, Δm is the mass change, n is the overtone number and A is the area. Moreover, such a piezoelectric biosensor was not able to only detect the coronavirus but also successfully used to detect the human immunodeficiency virus type 1 (HIV-1). Nicoletta increase the specificity and sensitivity of piezoelectric biosensors [67, 68] . Graphene can be used as a piezoelectric two dimensional (2D) materials to detect the SARS-CoV virus through piezoelectric crystal microbalance biosensor. CVD grown graphene exhibits a centrosymmetric crystal structure and has proven as an active nanosheet for electrode J o u r n a l P r e -p r o o f applications [69] . Recently, strong piezoelectricity in SLG deposited on SiO 2 grating substrates is demonstrated by Andrei Kholkin and his team [70] . Since the pristine graphene layer(s) do not possess any piezoelectric activity due to its intrinsically centrosymmetric crystal structure, piezoelectricity can be induced by breaking of the inversion symmetry. 

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease (Cas) proteins, guided by single standard RNA, is emerging potential tool for sequencespecific targeting and detection [80] . 

Besides the conventional approach for the component and system developments, 3D printing could also be used for the design and development of graphene/GRMs-based components to be used for COVID-19 [12, 67, 68] . 3D printing is a powerful and futuristic manufacturing process whereby the properties of the materials can be varied to match the properties of conventional metals and alloy and polymers. GRMs-metal or GRMs-polymer composites have been used to develop components using 3D printing for applications in aerospace structures, engines, electrical vehicles, heat exchanger, transformer core, etc. These would result in highly efficient engines, vehicles, and less fuel consumption and less carbon emission. 3D printing has also been used to develop medical components based on GRMscomposites [82] . For example, SS316L-and AlSi10Mg-GRMs composites, both are medical grade materials, were 3D printed, and by varying the amount of GRMs the properties were tuned to suit the need of various spares parts in less lead time [12, 83] . The chitosangraphene, poly(trimethylene carbonate)-graphene, poly(methacrylic acid)-graphene, polyethylene glycol-graphene composites-based scaffolds have been developed employing 3D printing [82] . with a size of less than 100 nm have been synthesized by researchers [90] . Nanoporous carbons with pore sizes in the range of 10−100 nm and extremely high surface areas have been prepared using silica nanoparticles as templates [90] . Similarly, Huang et al. [86] have developed nanoporous graphene foams with the controlled pore size ~ 100 nm using graphene oxide and silica spherical particles as a template. Presently, the N-95 face mask, a face mask that blocks about 95% of contaminant particles and contains a filter of pore size about 300 nm, is popular among the masks category to protect infection transmission [91] .

However, due to a pore size of about 300 nm, there is considerable loss in filtration efficacy of N-95 for sub-300 nm contaminant particles. It is important to note that the size of the SARS-CoV-2 is ~ 60-140 nm [92] . Sneezing may produce few thousands of droplets of diameter about 500-1200 nm [93] . Likewise, coughing produces droplets of size mainly below 1000 nm [93] . These droplets may contain significant and variable amounts of contaminant particles which could be germs and viruses. However, the liquid in droplets may evaporate and their size could be reduced while traveling in the air for quite sometime [94] .

Thus, present N-95 masks though effectively protect the transmission of sneezing or coughing droplets, lower sized (sub-300 nm) particles may not be completely blocked.

Moreover, it is proposed that SARS-CoV-2 virus may stay in the air for some time [16] .

Thus, designing of face mask with a pore size less than 300 nm could be an effective strategy to combat infection problems, in particular against COVID-19. Taking this on a serious note, recently, Al-Etab et al. [95] worked on developing an improved N-95 face mask with pore size lower than 300 nm. Indeed, they developed a polyimide membrane with pore sizes between 5 and 55 nm using plasma and lithography technologies, and the developed membrane could be used in improved N-95 face masks to effectively block SARS-CoV-2 whose size is higher than the size of nano pores created in polyimide membrane [96] .

Multilayer graphene nanofoams-based filters with pore size about 100 nm or lower may also 

Gold nanomaterials are commonly used as surface plasmon resonance (SPR) substrate for biomolecule detection and chemical sensing [97] . The signature of chemical moiety gets increased due to the interaction of electromagnetic waves with gold nanoparticles. The J o u r n a l P r e -p r o o f molecules, which are "hard-to-find", can be easily detected using the SPR effect of gold nanoparticles. The SPR effect has also been observed with a graphene sheet, a 2-dimensional sheet with nanoscale features, where the unpaired 2p electron on nano graphene sheet can enhance the signal of chemical or biomolecules by several folds. Thus, SPR characteristics of graphene-based materials can be exploited for the detection of viruses using a spectroscopic technique such as the Raman spectroscopy. Figure 9 shows the concept of SPR in graphenebased materials. When electromagnetic (EM) wave strikes the graphene surface the electron cloud of graphene sheets interacts with radiation, leading to enhancement of Raman signal.

The schematic for enhancement of signal (red curve) with respect to original signal (blue curve), as a consequence of SPR effect, is also shown in Figure 9 . Wu et al. reported the graphene decorated gold film for SPR applications [97] . Theoretically, the relationship between the number of graphene layers and the sensitivity of SPR was shown using Kretschmann excitation concept. Offeman methods [100] . Atomic force microscopy was deployed for the quality assessment of graphene oxide and its arrangement with gold nanoparticles. To observe the SPR effect of the gold-graphene oxide composite film, human IgG was taken in investigation as a target analyte. A wavelength modulation was used in SPR sensor to observe antibody-antigen binding interactions. The composite film was decorated with goat anti-human IgG as a capture antibody. The target solution having human IgG passed onto the composite film surface to find the detection limit of the system. The detection limit of the gold-graphene oxide film was four times higher than pure gold film alone. Hu et al. functionalized the graphene oxide sheets with polydopamine through oxidative polymerization in alkaline medium for the detection of biomarkers in serum [101] . An SPR chip was developed by depositing gold over the film to further enhance the sensitivity. The detection limit of 500 pg ml -1 was reported with a carcinoembryonic antigen in ten percent human serum. These findings reinforce that graphene-based SPR substrates could be used for designing and development of the sensitivity devices for the detection of SARS-CoV-2 and other viruses. In particular, due to synergistic effects, the hybrid graphene/GRMs-Au nanoparticles-based materials could be more promising for designing SPR-based diagnostic systems and devices.

J o u r n a l P r e -p r o o f scenerio many graphene-based protective equipments/components have been developed such as face mask, 3D printed components, biosensors, surface coatings etc., and some of these technologies are expected to convert into the commercial products in near future. Overall, while the path for graphene and GRMs to reach the product level seems to be long, however, recent progress on science and technology of these materials for medical applications may help to achieve the commercialization target soon .

Materials and Processes Research Institute, Bhopal, India. His research interest includes characterization of nanomaterials using electron microscopy, and exploration of nanomaterials, graphenebased materials, and metal oxides for wide-spectrum applications. 

Advanced healthcare materials

Materials Horizons

Proceedings of the National Academy of Sciences

76th Device Research Conference (DRC)

Zeitschrift für physik

Kinetics and evaporation of water drops in air

The authors declare no conflict of interest

Data is available upon request