Stochastic single-entity Biosensing using CMOS-based Nanocapacitor arrays Mohammad Saghafi, Suryasnata Tripathy, Selvaraj Chinnathambi, Serge G. Lemay University of Twente, Netherlands All-electrical signal transduction in biosensors has the potential to revolutionize point-of-care diagnostics and real-time healthcare monitoring. However, several obstacles such as ionic screening, capacitive and 1/ f noise and slow background drift have hindered their commercialization. A proposed solution involves integrating individually addressable nanoelectrodes with readout circuitry onto a chip to create a parallel, real-time, and highly-sensitive sensory system based on stochastic detection of single analytes. Our primary prototype of this approach is CMOS-based nanocapacitor arrays, impedimetric biosensors consisting of 256×256 nanoelectrodes integrated with A2D units and registers on a small chip. These sensors can work up to 70 MHz, thus exceeding the inverse charging time even at submicron dimensions. This allows probing both the nanoelectrode surface as well as into the bulk beyond the electrical double layer by tuning the excitation frequency, even under physiological salt concentration. For low conductivity samples it is also possible to reach the dielectric cutoff frequency, beyond which the electrolyte essentially behaves as a dielectric. Finally, with ~65,000 parallel sensors extensive data is available for statistical analysis to understand the distribution and nature of the signals resulting from single-entity detection events. Our present interests include detecting DNA, monitoring supported lipid bilayer (SLB) formation, quantifying neurotransmitter concentrations using aptamers, and detecting virus particles with antibodies. The platform enables distinguishing rare events from background noise, making it possible to detect low amounts of DNA, study the electrostatic interaction of single vesicles with the electrode during SLB formation, and detect nanoparticles individually. The current version of CMOS-based nanocapacitor arrays is just the beginning, with electrode sizes decreasing to a few nanometers, the number of electrodes approaching millions, and the working frequency entering the GHz regime. Flexible electronics and custom fluidic systems are also available, moving closer to an olfactory-like sensory system. References 1. Saghafi, M., Chinnathambi, S., & Lemay, S. G. (2022). High-frequency phenomena and electrochemical impedance spectroscopy at nanoelectrodes. Current Opinion in Colloid and Interface Science, 63, 101654. https://doi.org/10.1016/j. cocis.2022.101654 2. Renault, C., Laborde, C., Cossettini, A., Selmi, L., Widdershoven, F., & Lemay, S. G. (2022). Electrochemical characterization of individual oil micro-droplets by high-frequency nanocapacitor array imaging. Faraday Discussions, 233, 175–189. https://doi.org/10.1039/d1fd00044f 3. Laborde, C., Pittino, F., Verhoeven, H. A., Lemay, S. G., Selmi, L., Jongsma, M. A., & Widdershoven, F. (2015). Real-time imaging of microparticles and living cells with CMOS nanocapacitor arrays. Nature Nanotechnology, 10(9), 791–795. https:// doi.org/10.1038/nnano.2015.163
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