key: cord-268468-036i1082 authors: Asif, Muhammad; Ajmal, Muhammad; Ashraf, Ghazala; Muhammad, Nadeem; Aziz, Ayesha; Iftikhar, Tayyaba; Wang, Junlei; Liu, Hongfang title: The role of biosensors in COVID-19 outbreak date: 2020-09-18 journal: Curr Opin Electrochem DOI: 10.1016/j.coelec.2020.08.011 sha: doc_id: 268468 cord_uid: 036i1082 Herein, we have summarized and argued about biomarkers and indicators used for the detection of SARS-CoV-2. Antibody detection methods are not considered suitable to screen individuals at early stages and asymptomatic cases. The diagnosis of COVID-19 using biomarkers and indicators at point of care level is much crucial. Therefore, it is urgently needed to develop rapid and sensitive detection methods which can target antigens. We have critically elaborated key role of biosensors to cope the outbreak situation. In this review, the importance of biosensors including electrochemical, surface enhanced Raman scattering, field-effect transistor and surface plasmon resonance biosensors in the detection of SARS-CoV-2 has been underscored. Finally, we have outlined pros and cons of diagnostic approaches as-well-as future directions. The coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared as pandemic on 13 March 2020. It has not only come to be the leading cause of mortalities around the globe but has also become the unexpected socioeconomic burden [1] . Since the COVID-19 outbreak reported in early December 2019 in Wuhan, millions of people have been infected, thousands of them died and even the economy of many countries has halted [2] . The transmission of virus may occur through breathing, aerosols particles and direct touching of abiotic surfaces. There are also evidences of virus transmission through fecal since the SARS-CoV-2 has been found in feces samples. The transfer of virus through asymptomatic patients has also been observed in many cases [3, 4] . In this regards; world health organization (WHO) has urged the scientific community to carry out huge amount of diagnostic tests to curb the spread of virus since testing is an important tool to understand the epidemiology of the outbreak. Furthermore, fast diagnostic testing is very crucial in making prompt decisions to treat and isolate the infected patients which can ultimately slow down the transmission of infectious disease. The testing platforms together with the risk management and the healthcare system are vital responses in all outbreaks. In this outbreak, three different types of diagnosis tests are being used including (i) chest CT scan along with clinical indications, (ii) RNA detection using RT-PCR assay and (iii) lateral flow assays, full automatic chemiluminescence method, enzyme-linked immunosorbent assay (ELISA) for the determination of antibodies [5] . Nevertheless, there are some drawbacks related to CT scan method such as the use of CT scan diagnosis is limited to big hospitals, rural hospitals do not have the facility of CT scan, well-trained radiologists are required to analyze the images of CT scan and CT scan method cannot distinguish whether the infection is caused by SARS-CoV-2 or any other virus. On contrary, RT-PCR is a time consuming assay that may take four hour to execute one test and possesses great possibility of false-negative results. The patients with initial false-negative test results can transmit the virus to healthy individuals while preventing the proper control of infection. In the meantime, antibody response appears at about 10 th day after the onset of symptoms so all the assays that can target antibodies cannot be reliable in case of early diagnosis and identification of asymptomatic individuals. The false-positive results are also most likely owing to the interference caused by other proteins that are present in serological samples. The more precise and targeted detection of the virus can be carried out using biosensor based approaches. The technology that exists behind the testing is biosensing platforms that apply the strategy of bio-recognition elements or binding target molecules in a particular way for the detection of biological analytes [6, 7] . This type of binding acts as transducers which create measurable signals either directly through impedance measurements, surface plasmon resonance, or labeling the molecules such as enzymes/optical compounds [8, 9] . In this review, we have summarized the biosensor based technologies which are able to detect SARS-CoV-2 effectively. There are several biomarkers and indicators that can be used for the detection of SARS-CoV-2. Single-stranded RNA is very crucial biomarker which is used to detect SARS-CoV-2. Generally, conserved or fully expressed genes are the desired targets for RT-PCR assays [5, 10] . There are some special primers that can specifically target these genes with high sensitivity in detecting SARS-CoV-2 while rule out the detection of other similar types of viruses including MERS, (OC43 and 229E) and influenza [11] . Three different kinds of novel RT-PCR assays were developed that targeted N and S genes of SARS-CoV-2 and also compared with each other [12] . The excellent sensitivity was achieved while using nasopharyngeal samples and no crossreactivity with other coronaviruses was observed. The diagnosis of COVID-19 may also be carried out by using the structural proteins such as S, M, E and N proteins ( Figure 1A ) as antigens. Expectedly, SARS-CoV-2 has 28 different types of proteins [13] . It has been reported in several studies that M and E proteins are very crucial in assembling the virus structure [14] . The S protein is of much importance that combines with host J o u r n a l P r e -p r o o f cells and receptor-binding domain of S protein interacts with ACE2 receptors. It is more likely that S and N proteins could be imperative antigen biomarkers which might be employed for the detection of SARS-CoV-2 because the same proteins have also been used previously in various methods for the detection of SARS-CoV [15, 16] . Recently, Jiang et al. fabricated the proteome microarray using 18 out of 28 proteins and employed to monitor antibody responses. The patients in recovering stage show full antibodies response to proteome particularly to protein N, S1 but not S2 [17] . Moreover, detection technique based on viral proteins has also been investigated using lateral-flow assays for the diagnosis of COVID-19. The diagnosis of COVID-19 can also be carried out by detecting specific antibodies to SARS- [20] . Till this end, the diagnosis of COVID-19 using antibodies detection assays is not reliable. The antibody detection can be helpful for the patients at recovering phase as well as much crucial for the design of vaccine since it exact level correlates with virus neutralization titre [18]. There are some other biomarkers as well that can be monitored for the diagnosis of COVID-19 including blood and urine samples, infection index, hemagglutination level, blood gas index, and cytokine levels. Table 1 A biosensor is defined as an analytical tool consisting of a transducer portion and a biological element. Besides the clinically employed approaches for the diagnostics purposes in hospitals, various biosensor based technologies are being developed and some have already been established for the diagnosis of COVID-19 pneumonia. Figure 1B shows the schematic illustration of currently used diagnostic techniques and possible biosensing platforms for COVID-19, (i) COVID-19 patient, (ii) sampling ways, iii) biomarkers and indicators, (iv) diagnostic methods, (v) promising biosensors. Biosensors being capable for continuous monitoring of biomarkers would be potential candidates for diagnosing COVID-19 patients with mild to critical conditions and evaluating the success rate of anti-inflammation therapies [22] . Though the nucleic acid testing and antibody detection using RT-PCR and ELISA respectively, have been well-developed but these approaches still suffer from some practical limitations. Therefore, biosensors are the ideal alternative tools which show rapid response, high accuracy, The surface plasmonic resonance (SPR) biosensors are now essential tools and have obtained the key role in characterizing and quantifying bio-analytical targets both in life science and pharmaceutical research. These biosensors are label-free, highly sensitive and can be applied to different types of clinically interested target analytes. The SPR biosensors have also been used for the detection of antibody of SARS-CoV using a protein which was created by genetically fusing gold binding polypeptides to a SARS coronaviral surface antigen [27] . Recently, Masson's research group has reported the use of human serum sample without dilution for the detection of nucleocapsid antibodies which are specific against the SARS-CoV-2 employing SPR biosensing technology [28] . The peptide monolayer was successfully coated on SPR biosensor and further functionalized with virus nucleocapsid protein which was finally able to detect SARS-CoV-2 antibodies at nanomolar level. The portable SPR instrument was used to carry out the bioassay. The working mechanism is that when the sensor is exposed to SARS-CoV-2, the immune system gives response by expressing antibodies at levels which can be Considering the availability of current diagnostic approaches, field-effect transistor (FET)-based biosensing platforms have many promising benefits such as capability to be very sensitive and to detect small volume of target analyte instantaneously. These biosensors have potential use in clinical analysis, point-of-care tests, and on-site diagnostics [30] . Graphene with the hexagonal carbon atoms exposed on its surface, being electronically conductive, having high charge mobility and specific surface area, has proved to be ultrasensitive in sensing systems owing to its capability to detect nearby variations on their surface and to provide an ideal sensing platform. Therefore, graphene-based FET biosensors are very important to carry out the immunological diagnosis with high sensitivity. In this regard, Seo and co-workers have successfully fabricated a device based on FET technology for the detection of SARS-CoV-2 in clinical specimens as shown in Figure 2B [31]. The graphene sheets of the FET were conjugated with specific antibodies against SARS-CoV-2 spike protein in order to construct the biosensor. The sensing aptitude of the biosensor was evaluated employing antigen protein, self-cultured virus, and nasopharyngeal swab samples taken from people infected with COVID-19 pneumonia. The FET biosensor was able to detect SARSCoV-2 spike protein 1 fg/mL in phosphate-buffersaline and 100 fg/mL clinical transport medium. Additionally, FET biosensor performed very well in detection of SARCoV-2 in self-cultured medium and nasopharyngeal swab samples with detection limits of 1.6 × 10 1 plaque-forming units/mL (pfu/mL) and 2.42 × 10 2 copies/mL. Interestingly, the fabricated biosensing device showed no any quantifiable cross-reactivity with MERS-CoV antigen. The [39] . The low possible concentration detected with this biosensor was 1×10 7 copies/mL for these three viruses. The SERS spectra enabled the discrimination of viruses. J o u r n a l P r e -p r o o f The previous treatment of SARS-CoV-1 and MERS patients with corticosteroids gave disparate results that is why WHO has discouraged the usage of corticosteroids for COVID-19 treatment. However some reports show good results if they are administered at cautious doses [47, 48] . Kinetic profile of cytokine like IL-6 can convey important data which further can guide the onset of corticosteroids therapy and regulate the doses to lower the inflammation while keeping side effects at minimum level [49] . The severe COVID-19 infected people have high level of lymphopenia and a proinflammatory cytokine storm compared with mild infection persons. Table 3 shows some other anti-inflammatory therapies that can take advantages from biosensorbased guide for administration of hydroxychloroquine, [50] immunoglobulins, azithromycin [51] and convalescent plasma treatments [52] . Other drugs such as tocilizumab [53] or anakinra [54] have also anti-inflammatory effects for COVID-19. The mechanism of these treatments is to halt the particular pro-inflammatory signaling pathways. These drugs can be administrated using some analogous techniques "companion diagnostics" which are used for cancer care. The exact monitoring of specific pro-inflammatory factors would guide how to administrate these drugs. For instance, the mechanism of tocilizumab is to bind with receptor IL-6 and hinder the interaction with membrane binding that consequently stops the stimulation of downstream Janus kinase accountable for signal cascading [55] . These blockers of IL6-mediated inflammatory response including tocilizumab and sarilumab must be directed by measuring IL-6 [56, 57] . It is well-documented that antibodies are crucial in the treatment of unwanted cytokine excrete conditions in immune anti-cancer treatments. Moreover, measuring serial IL-6 shows that after appropriately administrating tocilizumab there is small upsurge in IL-6 following the decrease in time [56] . The aforementioned studies show that the improvement of inflammatory infections can be monitored by executing kinetic measurements of biomarkers. pandemic. The wearable biosensors are able to monitor the patients continuously, a much-desired feature of biosensors. The authors declare no conflict of interest. Dear Editor, Professor Zbigniew Stojek, It gives us a lot of pleasure to submit the enclosed manuscript entitled "The role of biosensors in COVID-19 outbreak: A topical mini review" to Current Opinion in Electrochemistry. It is hereby made sure that the manuscript's approval and consent have been taken from all authors and no author claims any conflict of interest. It is also made sure that the research work we are going to submit is not under any review or publication process in any of the journals. Therefore, we are hopeful that this work can turn out as an effective contribution to COVID-19 diagnostics. We wish that it could be published in Current Opinion in Electrochemistry. Your efforts in reviewing the manuscript are greatly appreciated. Thanking you in anticipation. 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