Plasmonic nanostructures strongly localize electric fields on their surfaces via the collective oscillations of conducting electrons under stimulation by incident light at a certain wavelength. Molecules adsorbed onto the surfaces of plasmonic structures experience a strongly enhanced electric field due to the localized surface plasmon resonance (LSPR), which amplifies the Raman scattering signal obtained from these adsorbed molecules. This phenomenon is referred to as surface-enhanced Raman scattering (SERS). Because Raman spectra serve as molecular fingerprints, SERS has been intensively studied for its ability to facilely detect molecules and provide a chemical analysis of a solution. Further enhancements in the Raman intensity and therefore higher sensitivity in SERS-based molecular analysis have been achieved by designing plasmonic nanostructures with a controlled size, shape, composition, and arrangement. This review paper focuses on the current state of the art in the fabrication of SERS-active substrates and their use as chemical and biosensors. Starting with a brief description of the basic principles underlying LSPR and SERS, we discuss three distinct nanofabrication methods, including the bottom-up assembly of nanoparticles, top-down nanolithography, and lithography-free random nanoarray formation. Finally, typical applications of SERS-based sensors are discussed, along with their perspectives and challenges.

Colloidal assemblies have been used to make mechanochromic materials. As interparticle spacing of colloids in the elastomeric polymer matrix can be changed by mechanical strain, the structural colors are also dynamically tunable. In common, such mechanochromic colloidal structures have been prepared in a film format. Here, we design elastic colloidal structures with a microbead format to provide high reconfigurability over a macroscopic shape and optical property. As the assembly of microbeads can fit into any macroscopic templates, we can utilize them as building blocks for secondary assembly to produce mechanochromic materials with any formats. To produce the elastic photonic microbeads, we use microfluidic technology to prepare oil-in-water emulsion droplets, where the dispersion of silica particles in an elastomer-forming photopolymerizable resin with acrylate group is used as a dispersed phase. The silica particles spontaneously form a non-close-packed colloidal array in each droplet due to repulsive interparticle potential, which is stabilized by in situ photopolymerization. The resulting microbeads display structural color depending on the size of silica particles. The mechanochromic microbeads are further assembled to form 2D and 3D structures, where the interstitial voids of the microbeads are filled with another elastomeric silicone-based polymer with higher modulus than the microbeads. These macroscale assemblies show rotation-independent structural colors and low angle dependency. More importantly, the assemblies show the mechanochromic property as individual microbeads dynamically deform under macroscopic strain.

Surface-enhanced Raman scattering (SERS) provides a dramatic increase of Raman intensity for molecules adsorbed on nanogap-rich metal nanostructures, serving as a promising tool for molecular analysis. However, surface contamination caused by protein adsorption and low surface concentration of small target molecules reduce the sensitivity, which severely restricts the use of SERS in many applications. Here, charged microgels containing agglomerates of gold nanoparticles (Au NPs) are designed using droplet-based microfluidics to provide a reliable SERS substrate with molecular selectivity and high sensitivity. The limiting mesh size of hydrogel enables the autonomous exclusion of large proteins and the charged matrix concentrates oppositely charged small molecules through electrostatic attraction. As nanogaps among Au NPs in the agglomerates enhance Raman intensity, Raman spectrum of the adsorbed molecules is selectively measured with high sensitivity in the absence of interruption from adhesive proteins. Therefore, the SERS-active-charged microgels can be used for direct analysis of pristine biological samples without the pretreatment steps of separation and concentration, which are commonly a prerequisite for Raman analysis. For the purpose of demonstration, a direct detection of fipronil sulfone with partial negative charges, a metabolite of toxic insecticide, dissolved in eggs using the positively charged microgels without any pretreatment of the samples, is shown.

We report a microfluidic strategy for creating semipermeable microgels containing metal nanoparticles to directly detect small molecules included in the solution of large adhesive proteins using surface-enhanced Raman scattering. With a capillary microfluidic device, gold nanoparticle-laden microgels are prepared to have uniform size. The microgels allow diffusion of smaller molecules than mesh size of their gel network while excluding larger molecules. This enables the selective infusion of small analytes onto the surface of gold nanoparticles from the solutions of adhesive proteins, thereby providing high Raman intensity by metal-surface enhancement; otherwise, proteins adsorb the surface, which significantly reduces the intensity. Therefore, this microgel platform enables the direct detection of analytes from biological fluids and obviates complicated pre- or post-treatment of samples. In addition, the microgels are able to be injected into target volume such as vessels or living organisms, which are then either recovered for analysis or potentially analyzed in situ. This simple but pragmatic method will provide new opportunity in a wide range of molecular detection applications based on Raman spectrum.

The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10. 1002/smll.201905076. Surface-enhanced Raman scattering (SERS) is one of the most promising methods to detect small molecules for point-of-care analysis as it is rapid, nondestructive, label-free, and applicable for aqueous samples. Here, microgels containing highly concentrated yet evenly dispersed gold nanoparticles are designed to provide SERS substrates that simultaneously achieve contamination-free metal surfaces and high signal enhancement and reproducibility. With capillary microfluidic devices, water-in-oil-in-water (W/O/W) doubleemulsion drops are prepared to contain gold nanoparticles and hydrogel precursors in innermost drop. Under hypertonic condition, water is selectively pumped out from the innermost drops. Therefore, gold nanoparticles are gently concentrated without forming aggregates, which are then captured by hydrogel matrix. The resulting microgels have a concentration of gold nanoparticles ≈30 times higher and show Raman intensity two orders of magnitude higher than those with no enrichment. In addition, even distribution of gold nanoparticles results in uniform Raman intensity, providing high signal reproducibility. Moreover, as the matrix of the microgel serves as a molecular filter, large adhesive proteins are rejected, which enables the direct detection of small molecules dissolved in the protein solution. It is believed that this advanced SERS platform is useful for in situ detection of toxic molecules in complex mixtures such as biological fluids, foods, and cosmetics. www.advancedsciencenews.com

Droplet-guiding superhydrophobic SERS substrates are created by a combinatorial lithographic technique. Photolithography defines the pattern of a micropillar array with a radial density gradient, whereas colloidal lithography features a nanotip array on the top surface of each micropillar. The nanotip array renders the surface superhydrophobic, and the pattern of micropillars endows the radial gradient of the contact angle, enabling the spontaneous droplet migration toward the center of the pattern. Water droplets containing target molecules are guided to the center, and the molecules dissolved in the droplets are concentrated at the surface of the central micropillar during droplet evaporation. Therefore, the molecules can be analyzed at the predefined position by Raman spectra without scanning the entire substrate. At the same time, the SERS-active nanotip array provides high sensitivity of Raman measurement.

Molecular detection in complex mixtures is of great importance in biomedical diagnosis, food safety, and environmental monitoring. Although surfaceenhanced Raman scattering serves as one of the most promising detection methods, metal surfaces are prone to contamination, making the direct detection of small molecules in mixtures elusive. Metal nanoparticle-loaded hydrogels have been used for the exclusion of large adhesive molecules and direct detection of small molecules. Here, we design microgels containing highly concentrated gold nanoparticles through the simultaneous formation of hydrogel and gold nanoparticles in emulsion droplets. Monodisperse water-in-oil droplets are microfluidically prepared to contain a gold precursor, hydrogel precursor, and photoinitiator. Upon ultraviolet irradiation, a hydrogel is gradually formed in the drop by photocross-linking at which gold nanoparticles are synthesized and grown by photo and thermal reduction. The in situ synthesis provides the uniform distribution of gold nanoparticles at very high concentrations without aggregation, which is otherwise very difficult to achieve. Using the microgels, small molecules in albumin solutions can be detected by Raman measurement with high signal sensitivity and reproducibility in the absence of interruption from albumin. As a proof of concept, we demonstrate the direct detection of pyocyanin, a biomarker for Pseudomonas infection spiked in unpurified saliva.

Metal nanoparticles are frequently employed for the colorimetric detection of specific target molecules using an aggregation‐induced shift of the localized surface plasmon resonance. However, metal nanoparticles dispersed in bulk solutions are prone to be contaminated by adhesive molecules and the dispersions tend to be diluted by sample fluids, restricting direct application to unpurified pristine samples. Here, a versatile capsule sensor platform is proposed that can encompass a variety of different types of nanoparticle‐based sensors. The capsule sensors are microfluidically prepared to obtain close control over their dimensions and composition. Their aqueous cores that are loaded with sensing materials are surrounded by an ultrathin inner oil shell and an outer hydrogel shell. The hydrogel shell prevents the diffusion of large adhesive molecules into the core, thereby preventing contamination of the sensing materials. The oil shell is selectively permeable such that it further improves the sensor selectivity. Importantly, these shells confine the sensing materials and prevent them from being diluted, securing a consistent optical property. Moreover, the capsule‐based sensors display a higher sensitivity than bulk dispersions because a smaller amount of sensing materials is used. The power of nanoparticle‐loaded capsule sensors is demonstrated using lysine‐coated gold nanoparticles to detect mercury ions.