This perspective gives an overview of recent developments in surface-enhanced Raman scattering (SERS) for biosensing. We focus this review on SERS papers published in the last 10 years and to specific applications of detecting biological analytes. Both intrinsic and extrinsic SERS biosensing schemes have been employed to detect and identify small molecules, nucleic acids, lipids, peptides, and proteins, as well as for in vivo and cellular sensing. Current SERS substrate technologies along with a series of advancements in surface chemistry, sample preparation, intrinsic/extrinsic signal transduction schemes, and tip-enhanced Raman spectroscopy are discussed. The progress covered herein shows great promise for widespread adoption of SERS biosensing.

A multitude of biological processes are enabled by complex interactions between lipid membranes and proteins. To understand such dynamic processes, it is crucial to differentiate the constituent biomolecular species and track their individual time evolution without invasive labels. Here, we present a label-free mid-infrared biosensor capable of distinguishing multiple analytes in heterogeneous biological samples with high sensitivity. Our technology leverages a multi-resonant metasurface to simultaneously enhance the different vibrational fingerprints of multiple biomolecules. By providing up to 1000-fold near-field intensity enhancement over both amide and methylene bands, our sensor resolves the interactions of lipid membranes with different polypeptides in real time. Significantly, we demonstrate that our label-free chemically specific sensor can analyze peptide-induced neurotransmitter cargo release from synaptic vesicle mimics. Our sensor opens up exciting possibilities for gaining new insights into biological processes such as signaling or transport in basic research as well as provides a valuable toolkit for bioanalytical and pharmaceutical applications.

Inexpensive, reproducible and high-throughput fabrication of nanometric apertures in metallic films can benefit many applications in plasmonics, sensing, spectroscopy, lithography and imaging. Here we use template stripping to pattern periodic nanohole arrays in optically thick, smooth Ag films with a silicon template made via nanoimprint lithography. Ag is a low-cost material with good optical properties, but it suffers from poor chemical stability and biocompatibility. However, a thin silica shell encapsulating our template-stripped Ag nanoholes facilitates biosensing applications by protecting the Ag from oxidation as well as providing a robust surface that can be readily modified with a variety of biomolecules using well-established silane chemistry. The thickness of the conformal silica shell can be precisely tuned by atomic layer deposition, and a 15-nm-thick silica shell can effectively prevent fluorophore quenching. The Ag nanohole arrays with silica shells can also be bonded to polydimethylsiloxane (PDMS) microfluidic channels for fluorescence imaging, formation of supported lipid bilayers, and real-time, label-free SPR sensing. Additionally, the smooth surfaces of the template-stripped Ag films enhance refractive index sensitivity compared with as-deposited, rough Ag films. Because nearly centimeter-sized nanohole arrays can be produced inexpensively without using any additional lithography, etching or lift-off, this method can facilitate widespread applications of metallic nanohole arrays for plasmonics and biosensing.

In this work, we present an infrared plasmonic biosensor for chemical-specific detection and monitoring of biomimetic lipid membranes in a label-free and real-time fashion. Lipid membranes constitute the primary biological interface mediating cell signaling and interaction with drugs and pathogens. By exploiting the plasmonic field enhancement in the vicinity of engineered and surface-modified nanoantennas, the proposed biosensor is able to capture the vibrational fingerprints of lipid molecules and monitor in real time the formation kinetics of planar biomimetic membranes in aqueous environments. Furthermore, we show that this plasmonic biosensor features high-field enhancement extending over tens of nanometers away from the surface, matching the size of typical bioassays while preserving high sensitivity.