Electro‐Optical Detection of Single Molecules Based on Solid‐State Nanopores

Abstract

Solid-state nanopore-based biosensors have received considerable attention in the past two decades and are promising for the next-generation single-molecule detection and sequencing platforms. Typically, the sensor is comprised of a thin inorganic membrane that separates two chambers containing an ion conductive solution. A nanoscale pore is drilled in the membrane as the only channel connecting the two chambers (cis chamber and trans chamber). The charged molecules are driven through the nanopore by an electric field applied across the membrane. At the same time, as the molecules block a fraction of the ionic current that flows through the pore, there will be a set of current pulses. The characteristics of the pulses, such as dwell time (duration of the pulses) and current blockages, give us a wealth of information about the passing analytes. Typically, excluded volumes, charges, capture rates, configurations, dynamics, and possible interactions of the analyte molecules can be concluded from electrical signals. Biological nanopores have been commercially used for DNA sequencing. [1] However, for solid-state nanopores, there are still challenges that need to be addressed for commercial use: specifically, spatial resolution, temporal resolution, and reproducibility. To achieve the identification of nucleotides during a stepwise displacement of DNA through the nanopores, our sensors must have a spatial resolution of 0.34 nm, considering the distance between adjacent base pairs of a double-stranded DNA chain. [2] Such a spatial resolution is a real challenge for nanofabrication of solid-state pores. Temporal resolution depends on the maximum bandwidth of the platforms and translocation speed of the analyte molecules. Limited temporal resolution leads to anomalously low event rates and distorted signals of proteins. [3] Signal reproducibility is another problem for solid-state nanopores compared with their biological counterparts. Biological nanopores, such as α-hemolysin [4] and mycobacterium smegmatis porin A, [5] serve as reliable sensors with excellent signal reproducibility because of the same genetically encoded structure. In comparison, due to the nonuniformity of the fabrication process or other unknown reasons, each solid-state nanopore is slightly different from one to another. In addition, there are other limitations for conventional solid-state nanopore sensors, such as low throughput, background noise, and lack of external handles to manipulate the analytes. Several strategies have been proposed to address these challenges, among which the combination of solid-state nanopores and optical detection has obvious advantages. Introducing a synchronized optical detection would help to improve the spatial resolution of solid-state nanopore platforms. Optical detection, in particular fluorescence [6] and surface-enhanced Raman spectroscopy (SERS), [7,8] has been widely used for

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