Skip to main content Accessibility help
Hostname: page-component-564cf476b6-4htn5 Total loading time: 0.27 Render date: 2021-06-18T12:41:10.950Z Has data issue: false Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": true, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true }

Rapid and label-free detection of COVID-19 using coherent anti-Stokes Raman scattering microscopy

Published online by Cambridge University Press:  13 November 2020

Tanveer A. Tabish
UCL Cancer Institute, University College London, London, Bloomsbury WC1E 6DD, UK
Roger J. Narayan
Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Raleigh, NC 27599-7115, USA
Mohan Edirisinghe
Department of Mechanical Engineering, University College London, Torrington Place, London WC1E 7JE, UK
E-mail address:
Get access


From the 1918 influenza pandemic (H1N1) until the recent 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, no efficient diagnostic tools have been developed for sensitive identification of viral pathogens. Rigorous, early, and accurate detection of viral pathogens is not only linked to preventing transmission but also to timely treatment and monitoring of drug resistance. Reverse transcription-polymerase chain reaction (RT-PCR), the gold standard method for microbiology and virology testing, suffers from both false-negative and false-positive results arising from the detection limit, contamination of samples/templates, exponential DNA amplification, and variation of viral ribonucleic acid sequences within a single individual during the course of the infection. Rapid, sensitive, and label-free detection of SARS-CoV-2 can provide a first line of defense against the current pandemic. A promising technique is non-linear coherent anti-Stokes Raman scattering (CARS) microscopy, which has the ability to capture rich spatiotemporal structural and functional information at a high acquisition speed in a label-free manner from a biological system. Raman scattering is a process in which the distinctive spectral signatures associated with light-sample interaction provide information on the chemical composition of the sample. In this prospective, we briefly discuss the development and future prospects of CARS for real-time multiplexed label-free detection of SARS-CoV-2 pathogens.

Prospective Articles
Copyright © The Author(s), 2020, published on behalf of Materials Research Society by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below.


Ferretti, L., Wymant, C., Kendall, M., Zhao, L., Nurtay, A., Abeler-Dörner, L., and Fraser, C.: Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing. Science 368, 17 (2020).CrossRefGoogle ScholarPubMed
Wang, C., Horby, P., Hayden, F., and Gao, G.: A novel coronavirus outbreak of global health concern. Lancet 395, 470473 (2020).CrossRefGoogle ScholarPubMed
Astuti, I.: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): an overview of viral structure and host response. Diabetes Metab. Syndr. 14, 407412 (2020).CrossRefGoogle ScholarPubMed
Mehta, P., McAuley, D., Brown, M., Sanchez, E., Tattersall, R., and Manson, J.: Across speciality collaboration. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395, 1033 (2020).CrossRefGoogle ScholarPubMed
Van Doremalen, N., Bushmaker, T., Morris, D., Holbrook, M., Gamble, A., Williamson, B., and Lloyd-Smith, J.: Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N. Engl. J. Med. 382, 15641567 (2020).CrossRefGoogle ScholarPubMed
Wang, W., Xu, Y., Gao, R., Lu, R., Han, K., Wu, G., and Tan, W.: Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 323, 18431844 (2020).Google ScholarPubMed
Li, Y., Yao, L., Li, J., Chen, L., Song, Y., Cai, Z., and Yang, C.: Stability issues of RT-PCR testing of SARS-cov-2 for hospitalized patients clinically diagnosed with COVID-19. J. Med. Virol. 92, 903908 (2020).CrossRefGoogle ScholarPubMed
Emery, S., Erdman, D., Bowen, M., Newton, B., Winchell, J., Meyer, R., and Rota, P.: Real-time reverse transcription–polymerase chain reaction assay for SARS-associated coronavirus. Emerg. Infect. Dis. 10, 311 (2004).CrossRefGoogle ScholarPubMed
Xiao, A., Tong, Y., and Zhang, S.: False-negative of RT-PCR and prolonged nucleic acid conversion in COVID-19: rather than recurrence. J. Med. Virol. (2020). doi:10.1002/jmv.25855.CrossRefGoogle ScholarPubMed
Tahamtan, A. and Ardebili, A.: Real-time RT-PCR in COVID-19 detection: issues affecting the results. Expert Rev. Mol. Diagn. 20, 453454 (2020).CrossRefGoogle ScholarPubMed
Alvarez-Moreno, C. and Rodríguez-Morales, A.: Testing dilemmas: post negative, positive SARS-CoV-2 RT-PCR–is it a reinfection? Travel Med. Infect. Dis. (2020). doi:10.1016/j.tmaid.2020.101743.CrossRefGoogle Scholar
Udugama, B., Kadhiresan, P., Kozlowski, H., Malekjahani, A., Osborne, M., Li, V., and Chan, W.: Diagnosing COVID-19: the disease and tools for detection. ACS Nano 14, 38223835 (2020).CrossRefGoogle ScholarPubMed
Corman, V., Landt, O., Kaiser, M., Molenkamp, R., Meijer, A., Chu, D., Bleicker, T., Brünink, S., Schneider, J., and Schmidt, M.: Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro. Surveill. 25, 2000045 (2020).CrossRefGoogle ScholarPubMed
Kilic, T., Weissleder, R., and Lee, H.: Molecular and immunological diagnostic tests of COVID-19–current status and challenges. iScience 101406, 119 (2020).Google Scholar
Rabiee, N., Bagherzadeh, M., Ghasemi, A., Zare, H., Ahmadi, S., Fatahi, Y., and Varma, R.: Point-of-use rapid detection of sars-cov-2: nanotechnology-enabled solutions for the COVID-19 pandemic. Int. J. Mol. Sci. 21, 5126 (2020).CrossRefGoogle ScholarPubMed
To, K., Tsang, O., Yip, C., Chan, K., Wu, T., Chan, J., Leung, W., Chik, T., Choi, C., and Kandamby, D.: Consistent detection of 2019 novel coronavirus in Saliva. Clin. Infect. Dis. 71, 841843 (2020).CrossRefGoogle ScholarPubMed
Zhang, Y., Odiwuor, N., Xiong, J., Sun, L., Nyaruaba, R., Wei, H., and Tanner, N.: Rapid molecular detection of SARS-CoV2 (COVID-19) virus RNA using colorimetric LAMP. Medrxiv. Posted online February 29, 2020. doi:10.1101/2020.02.26.20028373.Google Scholar
Freeman, B., Lester, S., Mills, L., Rasheed, M., Moye, S., Abiona, O., Hutchinson, G., MoralesBetoulle, M., Krapinunaya, I., and Gibbons, A.: Validation of a SARS-CoV-2 spike protein ELISA for use in contact investigations and serosurveillance. Biorxiv. Posted online April 25, 2020. doi:10.1101/2020.04.24.057323.Google Scholar
Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., Wang, B., Xiang, H., Cheng, Z., and Xiong, Y.: Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 323, 10611069 (2020).CrossRefGoogle ScholarPubMed
Martinez Pancorbo, P., Thummavichai, K., Clark, L., Tabish, T., Mansfield, J., Gardner, B., and Zhu, Y.: Novel Au–SiO2–WO3 core–shell composite nanoparticles for surface-enhanced Raman spectroscopy with potential application in cancer cell imaging. Advan. Funct. Mat. 29, 1903549 (2019).CrossRefGoogle Scholar
Lui, H., Zhao, J., McLean, D., and Zeng, H.: Real-time Raman spectroscopy for in vivo skin cancer diagnosis. Cancer Res. 72, 24912500 (2012).CrossRefGoogle ScholarPubMed
Rafalsky, V., Zyubin, A., Moiseeva, E., and Samusev, I.: Prospects for Raman spectroscopy in cardiology. Cardiovas. Therap. Preven. 19, 7077 (2020).CrossRefGoogle Scholar
Willemse-Erix, D., Scholtes-Timmerman, M., Jachtenberg, J., van Leeuwen, W., Horst-Kreft, D., Schut, T., and Maquelin, K.: Optical fingerprinting in bacterial epidemiology: Raman spectroscopy as a real-time typing method. J. Clin. Microbiol. 47, 652659 (2009).CrossRefGoogle ScholarPubMed
Verwer, P., Van Leeuwen, W., Girard, V., Monnin, V., van Belkum, A., Staab, J., and van de Sande, W.: Discrimination of Aspergillus lentulus from Aspergillus fumigatus by Raman spectroscopy and MALDI-TOF MS. Eur. J. Clin. Microbiol. Infect. Dis. 33, 245251 (2014).CrossRefGoogle ScholarPubMed
Saleem, M., Bilal, M., Anwar, S., Rehman, A., and Ahmed, M.: Optical diagnosis of dengue virus infection in human blood serum using Raman spectroscopy. Laser Phys. Lett. 10, 035602 (2013).CrossRefGoogle Scholar
Cheng, J. and Xie, X.: Coherent anti-Stokes Raman scattering microscopy: instrumentation, theory, and applications. J. Phys. Chem B. 108, 827840 (2004).CrossRefGoogle Scholar
Matharu, R., Tabish, T., Trakoolwilaiwan, T., Mansfield, J., Moger, J., Wu, T., and Edirisinghe, M.: Microstructure and antibacterial efficacy of graphene oxide nanocomposite fibres. J. Colloid Interface Sci. 571, 239252 (2020).CrossRefGoogle ScholarPubMed
Tabish, T., Dey, P., Mosca, S., Salimi, M., Palombo, F., Matousek, P., and Stone, N.: Smart gold nanostructures for light mediated cancer theranostics: combining optical diagnostics with photothermal therapy. Adv. Sci., 7, 1903441 (2020).CrossRefGoogle ScholarPubMed
Camp, C. and Cicerone, M.: Chemically sensitive bioimaging with coherent Raman scattering. Nat. Photonics 9, 295305 (2015).CrossRefGoogle Scholar
Lombardini, A., Mytskaniuk, V., Sivankutty, S., Andresen, E., Chen, X., Wenger, J., and Rigneault, H.: High-resolution multimodal flexible coherent Raman endoscope. Light Sci. Appl. 7, 18 (2018).CrossRefGoogle ScholarPubMed
Jones, R., Hooper, D., Zhang, L., Wolverson, D., and Valev, V.: Raman techniques: fundamentals and frontiers. Nanoscale Res. Lett. 14, 134 (2019).CrossRefGoogle ScholarPubMed
Zumbusch, A., Holtom, G., and Xie, X.: Three-dimensional vibrational imaging by coherent anti-Stokes Raman scattering. Phys. Rev. Lett. 82, 4142 (1999).CrossRefGoogle Scholar
Mitra, R., Chao, O., Urasaki, Y., Goodman, O., and Le, T.: Detection of lipid-rich prostate circulating tumour cells with coherent anti-Stokes Raman scattering microscopy. BMC Cancer 12, 540 (2012).CrossRefGoogle ScholarPubMed
Le, V., Yoo, S., Yoon, Y., Wang, T., Kim, B., Lee, S., and Chung, E.: Brain tumor delineation enhanced by moxifloxacin-based two-photon/CARS combined microscopy. Biomed. Opt. Express 8, 21482161 (2017).CrossRefGoogle ScholarPubMed
Masihzadeh, O., Ammar, D., Kahook, M., and Lei, T.: Coherent anti-Stokes Raman scattering (CARS) microscopy: a novel technique for imaging the retina. Invest. Ophthalmol. Visual Sci. 54, 30943101 (2013).CrossRefGoogle ScholarPubMed
Ko, A., Mostaço-Guidolin, L., Ridsdale, A., Pegoraro, A., Smith, M., Slepkov, V., and Sowa, M.: Using multimodal femtosecond CARS imaging to determine plaque burden in luminal atherosclerosis. In Multiphoton Microscopy in the Biomedical Sciences XI, Proceedings of SPIE Vol. 7903 (International Society for Optics and Photonics, 2011) p. 790318.CrossRefGoogle Scholar
Schie, W., Krafft, C., and Popp, J.: Applications of coherent Raman scattering microscopies to clinical and biological studies. Analyst 140, 38973909 (2015).CrossRefGoogle ScholarPubMed
Bae, K., Zheng, W., Ma, Y., and Huang, Z.: Real-time monitoring of pharmacokinetics of antibiotics in biofilms with Raman-tagged hyperspectral stimulated Raman scattering microscopy. Theranostics 9, 1348 (2019).CrossRefGoogle ScholarPubMed
Heuke, S., Vogler, N., Meyer, T., Akimov, D., Kluschke, F., Röwert-Huber, J., and Popp, J.: Detection and discrimination of non-melanoma skin cancer by multimodal imaging. Healthcare 1, 6483 (2013).CrossRefGoogle ScholarPubMed
Heaton, N. and Randall, G.: Multifaceted roles for lipids in viral infection. Trends Microbiol. 19, 368375 (2011).CrossRefGoogle ScholarPubMed
Nan, X., Tonary, A., Stolow, A., Xie, X., and Pezacki, J.: Intracellular imaging of HCV RNA and cellular lipids by using simultaneous two-photon fluorescence and coherent anti-Stokes Raman scattering microscopies. ChemBioChem 7, 18951897 (2006).CrossRefGoogle ScholarPubMed
Lyn, R., Kennedy, D., Sagan, S., Blais, D., Rouleau, Y., Pegoraro, A., and Pezacki, J.: Direct imaging of the disruption of hepatitis C virus replication complexes by inhibitors of lipid metabolism. Virol. 394, 130142 (2009).CrossRefGoogle ScholarPubMed
Lyn, R., Kennedy, D., Stolow, A., Ridsdale, A., and Pezacki, J.: Dynamics of lipid droplets induced by the hepatitis C virus core protein. Biochem. Biophys. Res. Commun. 399, 518524 (2010).CrossRefGoogle ScholarPubMed
Rakic, B., Sagan, S., Noestheden, M., Bélanger, S., Nan, X., Evans, C., and Pezacki, J.: Peroxisome proliferator-activated receptor α antagonism inhibits hepatitis C virus replication. Chem. Biol. 13, 2330 (2006).CrossRefGoogle ScholarPubMed
Kennedy, D., Lyn, R., and Pezacki, P.: Cellular lipid metabolism is influenced by the coordination environment of copper. J. Am. Chem. Soc. 131, 24442445 (2009).CrossRefGoogle ScholarPubMed
Hellerer, T., Axäng, C., Brackmann, C., Hillertz, P., Pilon, M., and Enejder, A.: Monitoring of lipid storage in Caenorhabditis elegans using coherent anti-Stokes Raman scattering (CARS) microscopy. Proc. Natl. Acad. Sci. USA 104, 1465814663 (2007).CrossRefGoogle ScholarPubMed
Le, T., Duren, H., Slipchenko, M., Hu, C., and Cheng, X.: Label-free quantitative analysis of lipid metabolism in living Caenorhabditis elegans. J. Lipid Res. 51, 672677 (2010).CrossRefGoogle ScholarPubMed
Robinson, I., Ochsenkühn, M., Campbell, C., Giraud, G., Hossack, W., Arlt, J., and Crain, J.: Intracellular imaging of host-pathogen interactions using combined CARS and two-photon fluorescence microscopies. J. Biophotonics 3, 138146 (2010).CrossRefGoogle ScholarPubMed
Deckert, V., Deckert-Gaudig, T., Cialla, D., Popp, J., Zell, R., Sokolov, A., and Scully, M.: Laser spectroscopic technique for direct identification of a single virus I: FASTER CARS. PNAS 202013169, 15 (2020).Google ScholarPubMed
Abu-Farha, M., Thanaraj, T., Qaddoumi, M., Hashem, A., Abubaker, J., and Al-Mulla, F.: The role of lipid metabolism in COVID-19 virus infection and as a drug target. Int. J. Mol. Sci. 21, 3544 (2020).CrossRefGoogle ScholarPubMed
Müller, C., Hardt, M., Schwudke, D., Neuman, W., Pleschka, S., and Ziebuhr, J.: Inhibition of cytosolic phospholipase A2α impairs an early step of coronavirus replication in cell culture. J. Virol. 92, e01463-17 (2018).Google ScholarPubMed
Vijay, R., Hua, X., Meyerholz, D., Miki, Y., Yamamoto, K., Gelb, M., and Perlman, S.: Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome–CoV infection. J. Exp. Med. 212, 18511868 (2020).CrossRefGoogle Scholar
Zhang, J., Lan, Y., and Sanyal, S.: Modulation of lipid droplet metabolism – a potential target for therapeutic intervention in flaviviridae infections. Front. Microbiol. 8, 2286 (2017).CrossRefGoogle ScholarPubMed
Xu, X., Wu, X., Jiang, X., Xu, K., Ying, L., Ma, C., and Sheng, J.: Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. Br. Med. J. 368, m606 (2020).CrossRefGoogle Scholar
Wu, Q., Zhou, L., Sun, X., Yan, Z., Hu, C., Wu, J., and Li, K.: Altered lipid metabolism in recovered SARS patients twelve years after infection. Sci. Rep. 7, 112 (2017).Google ScholarPubMed
Tabish, T.A. and Hamblin, M.R.: Multivalent nanomedicines to treat COVID-19: a slow train coming. Nano Today 35, 100962 (2020).CrossRefGoogle ScholarPubMed
Mansouri, K., Rastegari-Pouyani, M., Ghanbri-Movahed, M., Safarzadeh, M., and Kiani Z, S.: Ghanbari-Movahed: Can a metabolism-targeted therapeutic intervention successfully subjugate coronavirus? A scientific rational. Biomed. Pharmacother 21, 110694 (2020).CrossRefGoogle Scholar

Send article to Kindle

To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Rapid and label-free detection of COVID-19 using coherent anti-Stokes Raman scattering microscopy
Available formats

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

Rapid and label-free detection of COVID-19 using coherent anti-Stokes Raman scattering microscopy
Available formats

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

Rapid and label-free detection of COVID-19 using coherent anti-Stokes Raman scattering microscopy
Available formats

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *