Nanofluidics have recently attracted significant attention with regard to the development of new functionalities and applications, and producing new functional devices utilizing nanofluidics will require the fabrication of nanochannels. Fused silica nanofluidic devices fabricated by top-down methods are a promising approach to realizing this goal. Our group previously demonstrated the analysis of a living single cell using such a device, incorporating nanochannels having different sizes (102–103 nm) and with branched and confluent structures and surface patterning. However, fabrication of geometrically-controlled nanochannels on the 101 nm size scale by top-down methods on a fused silica substrate, and the fabrication of micro-nano interfaces on a single substrate, remain challenging. In the present study, the smallest-ever square nanochannels (with a size of 50 nm) were fabricated on fused silica substrates by optimizing the electron beam exposure time, and the absence of channel breaks was confirmed by streaming current measurements. In addition, micro-nano interfaces between 103 nm nanochannels and 101 μm microchannels were fabricated on a single substrate by controlling the hydrophobicity of the nanochannel surfaces. A micro-nano interface for a single cell analysis device, in which a nanochannel was connected to a 101 μm single cell chamber, was also fabricated. These new fabrication procedures are expected to advance the basic technologies employed in the field of nanofluidics.

Integrating analytical systems in 101–103 nm spaces provides ultrasensitive analytical devices at the single cell and the single molecule levels due to the ultrasmall space, and fundamental technologies for nanofluidics are developed. A simple and ultrasensitive detection method is one of the essential technologies for nanofluidics; however, it is still challenging due to the ultrasmall volume at the attoliter to femtoliter scale. In this study, we report a new photothermal detection method of nonfluorescent molecules for a 102 nm space, photothermal optical diffraction (POD), which utilizes light absorption and heat generation by an analyte and optical diffraction by a nanochannel after heat diffusion. Concentration determination of nonfluorescent molecules in a 400 nm channel was successfully demonstrated, and a limit of detection (LOD) of 5.0 μM was achieved, corresponding to 500 molecules (0.84 zmol) in a detection volume of 230 aL. Also, detection in a 200 nm channel was successfully demonstrated without degradation of the LOD. Our method can be widely used for chemical and biological analyses in 102–103 nm nanofluidics.

Photothermal spectroscopy, a remarkable detection method that can analyze microscale objects in a noninvasive and nondestructive manner, has been successfully coupled with micro/nanofluidic devices. Specifically, methods that employ a thermal lens microscope (TLM), including a photothermal optical phase shift and photothermal optical diffraction, are a powerful tool for the sensitive detection of nonfluorescent or nonlabeled molecules in micro/nanofluidic channels. This review focuses on the family of TLMs in terms of their historical development. Their recent applications, ranging from separation, particle, biomedical, energy, and environmental analyses, are summarized, and future perspectives in nanoscale liquid science, system integration, and biological studies, such as single-cell analyses, are also discussed.

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Detection and characterization of individual nanoparticles less than 100 nm are important for semiconductor manufacturing, environmental monitoring, biomedical diagnostics, and drug delivery. Photothermal spectroscopy is a light absorptiometry and promising method for detection and characterization because of its high sensitivity and selectivity compared with light scattering or electrical detection methods. However, the characterization of individual nanoparticles in liquids is still challenging for conventional photothermal detection methods. Here, we report a method for the ultrasensitive detection and accurate characterization of individual nanoparticles in liquids by photothermal optical diffraction, which utilizes enhancement of optical diffraction by a nanochannel after light absorption and heat generation of individual nanoparticles in the channel. Our method realized individual 20 nm Au nanoparticle detection with almost 100% detection efficiency by utilizing nanochannels, leading to concentration determination without a calibration curve. Furthermore, we measured individual nanoparticle size and discriminated 20 and 40 nm Au nanoparticles from their photothermal signals. Our photothermal-based nanoparticle detection method in nanochannels has a potential for a wide range of applications such as on-site evaluation of synthesized plasmonic nanoparticles and drug delivery particles.