Molecular electronics sensors on a scalable semiconductor chip: A platform for single-molecule measurement of binding kinetics and enzyme activity

Abstract

For nearly 50 years, the vision of using single molecules in circuits has been seen as providing the ultimate miniaturization of electronic chips. An advanced example of such a molecular electronics chip is presented here, with the important distinction that the molecular circuit elements play the role of general-purpose single-molecule sensors. The device consists of a semiconductor chip with a scalable array architecture. Each array element contains a synthetic molecular wire assembled to span nanoelectrodes in a current monitoring circuit. A central conjugation site is used to attach a single probe molecule that defines the target of the sensor. The chip digitizes the resulting picoamp-scale current-versus-time readout from each sensor element of the array at a rate of 1,000 frames per second. This provides detailed electrical signatures of the single-molecule interactions between the probe and targets present in a solution-phase test sample. This platform is used to measure the interaction kinetics of single molecules, without the use of labels, in a massively parallel fashion. To demonstrate broad applicability, examples are shown for probe molecule binding, including DNA oligos, aptamers, antibodies, and antigens, and the activity of enzymes relevant to diagnostics and sequencing, including a CRISPR/Cas enzyme binding a target DNA, and a DNA polymerase enzyme incorporating nucleotides as it copies a DNA template. All of these applications are accomplished with high sensitivity and resolution, on a manufacturable, scalable, all-electronic semiconductor chip device, thereby bringing the power of modern chips to these diverse areas of biosensing.

An electro-optical bead-nanochip technology for the ultrasensitive and multi-dimensional detection of small extracellular vesicles and their markers

“…3B). Given the compatible fabrication of E-NEXOS with standard procedures in the semiconductor industry, the number of nanogap-based sensors can be increased to around 2,000,000 nanogapbased sensors per nanochip by integrating CMOS technology, as demonstrated by others [38][39][40].…”

Electron Transport through Nanoconfined Ferrocene Solution: Density Functional Theory─Nonequilibrium Green Function Approach

“…5 In this study, we focused on the electron transport characteristics through an aqueous solution phase aligned by molecular interactions in nanogap devices, where a ferrocene molecule was introduced as a redox signaling molecule. This approach is distinguished from other research [1][2][3][4]6 in that quantum-tunneling current can be enhanced by the redox molecule under external bias conditions even through an aqueous solution without conducting molecular chain wiring the electrodes.…”

“…Detection of a single molecule in the nanoscale has become an important technology for various applications such as diagnostic devices, biophysics, and DNA sequencing. − For the advancement of sensing technology, it is crucial to comprehend electrode–molecule interactions and their interfacial environment as devices for sensing applications have been manufactured at nanometer scales. Especially, the molecular interaction at the metal–water interface is known to effectuate the structural rearrangement of water molecules in the vicinity of the metal surface, inducing the variation in density and behavior of water molecules and, thereby, surface reactions .…”

Humidity sensors based on molecular rectifiers

“…6,8–10 The versatility in chemical structure offered by organic compounds allows for synthetic designs that target specific interactions with water, and hence they quickly became popular in the humidity sensing arena, alongside active components in chemical and biological sensors. 11–17 Single-molecule-based sensors are particularly attractive since they can be integrated into semiconductor array chips to provide the much-sought electronics miniaturization. Additionally, they are manufactured by low-cost, high-throughput techniques and hence can be easily mass-produced and deployed.…”