Now that COVID-19 is here with us for the foreseeable future, there is a need for virus detection methods that are quick, versatile, and accurate. Developing such a technique would allow us to effectively screen patients for infection, aid the safe reopening of the economy, and bring peace of mind to the general populace. One method that shows great promise for this purpose is SERS-based Raman spectroscopy.
Raman spectroscopy is a non-destructive spectroscopic technique based on the Raman scattering effect, a phenomenon discovered and first demonstrated by the physicist V. L. Raman in 1928. In this effect, a sample of interest is hit with a high intensity light source such as a laser beam which then scatters while interacting with vibrational modes in the molecules of the sample. The energy of the scattered light will be higher (called anti-Stokes shift) or lower (called Stokes shift) depending on what molecular bonds the light interacted with, and measuring the full spectrum of scattered light will give a detailed picture of the structure of the sample, allowing for accurate classification of materials. Because of this property, Raman spectroscopy has become commonly used for applications involving material identification, such as research and forensics.
Unfortunately, the level of light produced by the Raman scattering is very small (multiple orders of magnitude smaller than the excitation source), and for analytes of interest that are in low concentration like viruses, the signal will be swamped out by other effects like sample fluorescence. Because of this low light level, it took the invention of the laser to provide a light source powerful enough to make Raman spectroscopy commercially viable. However, more recently, the Raman signal can be amplified greatly using surface-enhanced Raman spectroscopy, or SERS. In SERS, the analyte is placed on or near a specially designed nanostructure, typically made of a metal like gold or silver, or in a colloidal solution of metallic particles. The excitation laser interacts with oscillations of plasmonic electrons in the nanostructure, causing the Raman signal from any analyte adsorbed to the surface to be amplified by up to 14 orders of magnitude. This means that SERS provides ultrasensitive detection limits and can even come close to single molecule sensitivity.
SERS media can come in many different forms, depending on the desired application. Metal nanoparticles can be suspended in colloidal solutions and will amplify the Raman signal of particles added to the solution. These solutions can have problems with reproducibility of measurements, as nanoparticles can bunch up, creating amplification hotspots where the optical field is heavily concentrated. The shape of the nanoparticles can also contribute to the creation of hotspots . To ameliorate this, the nanoparticles can also be introduced to substrates in a way that immobilizes them, such as embedding them in glass, or printing them onto paper substrates. The paper-based substrates (PSERS) are created by mixing nanoparticles in an alcohol solution and then printing them onto cellulose substrates using inkjet or thermal printing [1,2], making them much more inexpensive to produce. SERS substrates can also be made by depositing nanoparticles on solid substrates using nanolithography techniques to produce repeatable structures that can be tailored to the analyte of interest. In addition to solid structures, carbon nanotubes have also been used as a deposition medium for the metal nanoparticles, adding another layer of customization that allows for selection of particles by size .
Another benefit of SERS in relation to detection of viruses is that it is already a proven technology for this purpose. Research groups have used Raman spectroscopy and SERS to detect many viruses, including hepatitis B , influenza , and RSV . This opens the possibility that a SERS-based system designed to detect one virus could be successfully modified to detect other viruses as well, allowing such a system to be useful in the long term.
Until an effective vaccine is found, the need for a fast, effective, and affordable test for COVID-19 is essential to get society and the economy safely running again, and SERS has the potential to be that test. And even after COVID is gone, this test will be instrumental in reducing the impact of another pandemic or other existing diseases.
 P. A. Mosier-Boss, “Review of SERS Substrates for Chemical Sensing,” Nanomaterials, 7(30):142, 2017.
 R. Chimenti, J. Elliott, R.A. Bux, “Raman Spectroscopy Could Facilitate Deployment of Amantadine-Based Cancer Screening Technology— Enabling the Transition from Labs to Villages,” American Pharmaceutical Review, online, 2015.
 Y.-T. Yeha, K. Gulinob, Y.H. Zhanga, et al., “A rapid and label-free platform for virus capture and identification from clinical samples,” PNAS, 117(7):895, 2020.
 D. Tong, C. Chen, J.J. Zhang, et al., “Application of Raman spectroscopy in the detection of hepatitis B virus infection,” Photodiagnosis Photodyn Ther, 28(5): 248, 2019.
 J. Lim, J. Nam, S. Yang, “Identiﬁcation of Newly Emerging Inﬂuenza Viruses by Surface Enhanced Raman Spectroscopy,” Anal Chem, 87(8): 11652, 2015.
 S. Shanmukh, L. Jones, Y.-P. Zhao, et al., “Identification and classification of respiratory syncytial virus (RSV) strains by surface-enhanced Raman spectroscopy and multivariate statistical techniques,” Anal Bioanal Chem, 390(6):1551, 2008.