Infrared spectroscopy provides unique information on the composition and dynamics of biochemical systems by resolving the characteristic absorption fingerprints of their constituent molecules. Based on this inherent chemical specificity and the capability for label‐free, noninvasive, and real‐time detection, infrared spectroscopy approaches have unlocked a plethora of breakthrough applications for fields ranging from environmental monitoring and defense to chemical analysis and medical diagnostics. Nanophotonics has played a crucial role for pushing the sensitivity limits of traditional far‐field spectroscopy by using resonant nanostructures to focus the incident light into nanoscale hot‐spots of the electromagnetic field, greatly enhancing light–matter interaction. Metasurfaces composed of regular arrangements of such resonators further increase the design space for tailoring this nanoscale light control both spectrally and spatially, which has established them as an invaluable toolkit for surface‐enhanced spectroscopy. Starting from the fundamental concepts of metasurface‐enhanced infrared spectroscopy, a broad palette of resonator geometries, materials, and arrangements for realizing highly sensitive metadevices is showcased, with a special focus on emerging systems such as phononic and 2D van der Waals materials, and integration with waveguides for lab‐on‐a‐chip devices. Furthermore, advanced sensor functionalities of metasurface‐based infrared spectroscopy, including multiresonance, tunability, dielectrophoresis, live cell sensing, and machine‐learning‐aided analysis are highlighted.

Conventionally, metallic nanostructures are used for surface-enhanced Raman spectroscopy (SERS), but recently there has been increasing interest in the enhancement of Raman scattering from dielectric substrates due to their improved stability and biocompatibility compared with metallic substrates. Here, we report the observation of enhanced Raman scattering from rhodamine 6G molecules coated on silica microspheres. We excite the whispering gallery modes (WGMs) supported in the microspheres with a tapered fiber coupler for efficient WGM excitation, and the Raman enhancement can be attributed to the WGM mechanism. Strong resonance enhancement in pump laser intensity and modified Raman emission from the Purcell effect in the microsphere resonator are observed from the experiment and compared with theoretical results. A total Raman enhancement factor of $1.4\times {10}^4$ is observed, with contribution mostly from the enhancement in pump laser intensity. Our results show that, with an efficient pumping scheme, dielectric microspheres are a viable alternative to metallic SERS substrates.

Whispering gallery mode (WGM) resonators are compact and ultrasensitive devices, which enable label-free sensing at the single-molecule level. Despite their high sensitivity, WGM resonators have not been thoroughly investigated for use in dynamic biochemical processes including molecular diffusion and polymerization. In this work, the first report of using WGM sensors to continuously monitor a chemical reaction (i.e. gelation) in situ in a hydrogel is described. Specifically, we monitor and quantify the gelation dynamics of polyacrylamide hydrogels using WGM resonators and compare the results to an established measurement method based on rheology. Rheology measures changes in viscoelasticity, while WGM resonators measure changes in refractive index. Different gelation conditions were studied by varying the total monomer concentration and crosslinker concentration of the hydrogel precursor solution, and the resulting similarities and differences in the signal from the WGM resonator and rheology are elucidated. This work demonstrates that WGM alone or in combination with rheology can be used to investigate the gelation dynamics of hydrogels to provide insights into their gelation mechanisms.

A plasmonic metasurface is used for the enhanced infrared spectroscopy of live cells. Real-time cellular response to trypsinization and cholesterol depletion is monitored, and spectro-chemical imaging using the metasurface is demonstrated.

A mid-infrared plasmonic metasurface is integrated with a multiwell cell culture chamber to monitor dynamic cellular changes related to cell adhesion and cell receptor signaling activation through infrared spectroscopy.

Infrared spectroscopy has drawn considerable interest in biological applications, but the measurement of live cells is impeded by the attenuation of infrared light in water. Metasurface-enhanced infrared reflection spectroscopy (MEIRS) had been shown to mitigate the problem, enhance the cellular infrared signal through surface-enhanced infrared absorption, and encode the cellular vibrational signatures in the reflectance spectrum at the same time. In this study, we used MEIRS to study the dynamic response of live cancer cells to a newly developed chemotherapeutic metal complex with distinct modes of action (MoAs): tricarbonyl rhenium isonitrile polypyridyl (TRIP). MEIRS measurements demonstrated that administering TRIP resulted in long-term (several hours) reduction in protein, lipid, and overall refractive index signals, and in short-term (tens of minutes) increase in these signals, consistent with the induction of endoplasmic reticulum stress. The unique tricarbonyl IR signature of TRIP in the bioorthogonal spectral window was monitored in real time, and was used as an infrared tag to detect the precise drug delivery time that was shown to be closely correlated with the onset of the phenotypic response. These results demonstrate that MEIRS is an effective label-free real-time cellular assay capable of detecting and interpreting the early phenotypic responses of cells to IR-tagged chemotherapeutics.