This minireview reports the recent advances in surface-enhanced Raman scattering (SERS)-based assay devices for the diagnosis of infectious diseases. SERS-based detection methods have shown promise in overcoming the low sensitivity and multiplex detection problems inherent to fluorescence detection. Therefore, it is interesting to investigate the current status, challenges, and applications associated with SERS-based microdevices for the point-of-care (POC) diagnosis of infectious diseases. The majority of this review highlights three different types of microdevices, namely microfluidic channels, lateral flow assay strips, and three-dimensional nanostructured substrates. Furthermore, the integration of portable Raman spectrophotometry with microdevices provides an ideal platform for the diagnosis of various infectious diseases in the field. Integrated SERS-based assay systems also enable measurements in minimal sample volumes and at low analyte concentrations of viral or bacterial samples. A significant number of studies using the SERS-based assay system have been performed recently to realize POC diagnostics, especially under resource-limited conditions. This portable SERS sensor is expected to be a next-generation POC assay system that could overcome the limitations of current fluorescence-based assay systems. This minireview summarizes recent advances in the development of SERS-based microdevices for the diagnosis of infectious diseases. Lastly, challenges to overcome and future perspectives are discussed.

Recent advances in surface-enhanced Raman scattering-based microdevices for point-of-care diagnosis of viruses and bacteria

In wavelength division multiplexing (WDM) schemes, splitters must be used to combine and separate different wavelengths. Conventional splitters are fairly large with footprints in hundreds to thousands of square microns, and experimentally-demonstrated MMI-based and inverse-designed ultra-compact splitters operate with only two channels and large channel spacing ($>$100 nm). Here we inverse design and experimentally demonstrate a three-channel wavelength demultiplexer with 40 nm spacing (1500 nm, 1540 nm, and 1580 nm) with a footprint of 24.75 $\mu\mathrm{m}^2$. The splitter has a simulated peak insertion loss of -1.55 dB with under -15 dB crosstalk and a measured peak insertion loss of -2.29 dB with under -10.7 dB crosstalk.

Inverse design and demonstration of a compact on-chip narrowband three-channel wavelength demultiplexer

This review reports the recent advances in surface-enhanced Raman scattering (SERS)-based lateral flow assay (LFA) platforms for the diagnosis of infectious diseases. As observed through the recent infection outbreaks of COVID-19 worldwide, a timely diagnosis of the disease is critical for preventing the spread of a disease and to ensure epidemic preparedness. In this regard, an innovative point-of-care diagnostic method is essential. Recently, SERS-based assay platforms have received increasing attention in medical communities owing to their high sensitivity and multiplex detection capability. In contrast, LFAs provide a user-friendly and easily accessible sensing platform. Thus, the combination of LFAs with a SERS detection system provides a new diagnostic modality for accurate and rapid diagnoses of infectious diseases. In this context, we briefly discuss the recent application of LFA platforms for the POC diagnosis of SARS-CoV-2. Thereafter, we focus on the recent advances in SERS-based LFA platforms for the early diagnosis of infectious diseases and their applicability for the rapid diagnosis of SARS-CoV-2. Finally, the key issues that need to be addressed to accelerate the clinical translation of SERS-based LFA platforms from the research laboratory to the bedside are discussed.

Recent advances in sensitive surface-enhanced Raman scattering-based lateral flow assay platforms for point-of-care diagnostics of infectious diseases

Surface-enhanced Raman spectroscopy (SERS) is a promising cellular identification and drug susceptibility testing platform, provided it can be performed in a controlled liquid environment that maintains cell viability. We investigate bacterial liquid-SERS, studying plasmonic and electrostatic interactions between gold nanorods and bacteria that enable uniformly enhanced SERS. We synthesize five nanorod sizes with longitudinal plasmon resonances ranging from 670 to 860 nm and characterize SERS signatures of Gram-negative Escherichia coli and Serratia marcescens and Gram-positive Staphylococcus aureus and Staphylococcus epidermidis bacteria in water. Varying the concentration of bacteria and nanorods, we achieve large-area SERS enhancement that is independent of nanorod resonance and bacteria type; however, bacteria with higher surface charge density exhibit significantly higher SERS signal. Using cryo-electron microscopy and zeta potential measurements, we show that the higher signal results from attraction between positively charged nanorods and negatively charged bacteria. Our robust liquid-SERS measurements provide a foundation for bacterial identification and drug testing in biological fluids.

Plasmonic and Electrostatic Interactions Enable Uniformly Enhanced Liquid Bacterial Surface-Enhanced Raman Scattering (SERS)

Challenges of SERS technology as a non-nucleic acid or -antigen detection method for SARS-CoV-2 virus and its variants.

In a pandemic era, rapid infectious disease diagnosis is essential. Surface-enhanced Raman spectroscopy (SERS) promises sensitive and specific diagnosis including rapid point-of-care detection and drug susceptibility testing. SERS utilizes inelastic light scattering arising from the interaction of incident photons with molecular vibrations, enhanced by orders of magnitude with resonant metallic or dielectric nanostructures. While SERS provides a spectral fingerprint of the sample, clinical translation is lagged due to challenges in consistency of spectral enhancement, complexity in spectral interpretation, insufficient specificity and sensitivity, and inefficient workflow from patient sample collection to spectral acquisition. Here, we highlight the recent, complementary advances that address these shortcomings, including (1) design of label-free SERS substrates and data processing algorithms that improve spectral signal and interpretability, essential for broad pathogen screening assays; (2) development of new capture and affinity agents, such as aptamers and polymers, critical for determining the presence or absence of particular pathogens; and (3) microfluidic and bioprinting platforms for efficient clinical sample processing. We also describe the development of low-cost, point-of-care, optical SERS hardware. Our paper focuses on SERS for viral and bacterial detection, in hopes of accelerating infectious disease diagnosis, monitoring, and vaccine development. With advances in SERS substrates, machine learning, and microfluidics and bioprinting, the specificity, sensitivity, and speed of SERS can be readily translated from laboratory bench to patient bedside, accelerating point-of-care diagnosis, personalized medicine, and precision health.

Ximena Hasbach

Papers

Toward rapid infectious disease diagnosis with advances in surface-enhanced Raman spectroscopy.