Advances in Label-Free Detections for Nanofluidic Analytical Devices

Abstract

Nanofluidics, a discipline of science and engineering of fluids confined to structures at the 1-1000 nm scale, has experienced significant growth over the past decade. Nanofluidics have offered fascinating platforms for chemical and biological analyses by exploiting the unique characteristics of liquids and molecules confined in nanospaces; however, the difficulty to detect molecules in extremely small spaces hampers the practical applications of nanofluidic devices. Laser-induced fluorescence microscopy with single-molecule sensitivity has been so far a major detection method in nanofluidics, but issues arising from labeling and photobleaching limit its application. Recently, numerous label-free detection methods have been developed to identify and determine the number of molecules, as well as provide chemical, conformational, and kinetic information of molecules. This review focuses on label-free detection techniques designed for nanofluidics; these techniques are divided into two groups: optical and electrical/electrochemical detection methods. In this review, we discuss on the developed nanofluidic device architectures, elucidate the mechanisms by which the utilization of nanofluidics in manipulating molecules and controlling light-matter interactions enhances the capabilities of biological and chemical analyses, and highlight new research directions in the field of detections in nanofluidics.

Keywords: lab-on-a-chip; label-free detection; microTAS; nanofluidic analytical device; nanofluidics.

Figure 1

Nanofluidic devices using photonic structures for RI sensing: (a) nanohole array with “flow-through” scheme (adapted with permission from [37]. Copyright 2009 Optical Society of America), (b) the response time of sensors using plasmonic nanohole arrays with “flow-through” (green markers) and “flow-over” (blue markers) schemes showing a significant improvement in the response time of sensors in “flow-through” devices (adapted with permission from [38]. Copyright 2009 American Chemical Society), and (c) nanohole arrays integrated in a Fabry–Pérot (FP) cavity (adapted with permission from [42]. Copyright 2011 American Institute of Physics).

Figure 2

Nanofluidic devices for SERS: (a) device exploiting the localization of nanoparticles and preconcentration of target molecules at micro/nanochannel junction (adapted with permission from [51]. Copyright 2011 American Chemical Society), (b) electrokinetic capture of a single molecule at a nanopore to increase its residual time (adapted with permission from [55]. Copyright 2019 Springer Nature), and (c) self-rolled nanotube integrated with Ag NPs supporting the coupling of whispering-gallery resonances and surface plasmon generated on Ag NPs that improves the enhancement factor in SERS. The scale bar in the right image is 3 μm (adapted with permission from [56]. Copyright 2015 Springer Nature).

Figure 3

(a) Plasmonics-nanofluidics hybrid device consisting of an Au mirror and an array of periodic Au nanostructures separated by a nanofluidic channel, (b) the numerical calculation result of electric field profile |E| indicating the accumulation of light energy inside the nanogap as hot-spots, (c) vibrational modes of target molecules detected as peaks in the reflectance dip of the original plasmon resonance (adapted with permission from [60]. Copyright 2017 American Chemical Society), (d) vibrational absorption of water confined in a 10 nm gap (adapted with permission from [61]. Copyright 2018 American Chemical Society), and (e) Out-of-plane refractive index $n_{\perp }$ of water confined in 10–100 nm gaps (adapted with permission from [62]. Copyright 2020 The Royal Society of Chemistry).

Figure 4

(a) Principle of photothermal optical phase shift (POPS). A probe beam (red) is separated by a differential interference contrast (DIC) prism and integrated by another DIC prism. An excitation beam (blue) is not separated and induces a photothermal effect (heat followed by a change in refractive index). The photothermal effect produces a phase shift for one of the probe beams and the phase shift is detected through an interference. (b) Detection of non-labeled bovine serum albumin by POPS. The limit of detection was 50 nM (30 molecules) (adapted with permission from [66]. Copyright 2020 The Royal Society of Chemistry).

Figure 5

Nanofluidic devices for electrical/electrochemical detection, (a) detection of conductivity on nanochannel surfaces during chemical reaction (adapted with permission from [90]. Copyright 2016 American Chemical Society), (b) detection of streaming current/potential induced by pressure-driven flow in a nanochannel (adapted with permission from [115]. Copyright 2015 American Chemical Society), and (c) detection of electrochemical reaction using electrodes integrated in a nanochannel. (adapted with permission from [120]. Copyright 2014 American Chemical Society).