Platforms that offer massively parallel, label-free biosensing can, in principle, be created by combining all-electrical detection with low-cost integrated circuits. Examples include field-effect transistor arrays, which are used for mapping neuronal signals and sequencing DNA. Despite these successes, however, bioelectronics has so far failed to deliver a broadly applicable biosensing platform. This is due, in part, to the fact that d.c. or low-frequency signals cannot be used to probe beyond the electrical double layer formed by screening salt ions, which means that under physiological conditions the sensing of a target analyte located even a short distance from the sensor (∼1 nm) is severely hampered. Here, we show that high-frequency impedance spectroscopy can be used to detect and image microparticles and living cells under physiological salt conditions. Our assay employs a large-scale, high-density array of nanoelectrodes integrated with CMOS electronics on a single chip and the sensor response depends on the electrical properties of the analyte, allowing impedance-based fingerprinting. With our platform, we image the dynamic attachment and micromotion of BEAS, THP1 and MCF7 cancer cell lines in real time at submicrometre resolution in growth medium, demonstrating the potential of the platform for label/tracer-free high-throughput screening of anti-tumour drug candidates.
A method to represent the effect of ionized impurity scattering in Monte Carlo calculations is presented. It is based on a model of B. K. Ridley [J. Phys. C 10, 1589 (1977)] and does not have the computational disadvantages of the Brooks–Herring and Conwell–Weisskopf models.
We describe the realization of a fully-electronic label-free temperature-controlled biosensing platform aimed to overcome the Debye screening limit over a wide range of electrolyte salt concentrations. It is based on an improved version of a 90 nm CMOS integrated circuit featuring a nanocapacitor array, readout and A/D conversion circuitry, and an FPGA-based interface board with NIOS II soft processor. We describe the chip's processing, the mounting, the microfluidics, the temperature control system, as well as the calibration and compensation procedures to reduce systematic errors, which altogether make up a complete quantitative sensor platform. Capacitance spectra recorded up to 50-70 MHz are shown and successfully compared to predictions by FEM numerical simulations in the Poisson-Drift-Diffusion formalism. They demonstrate the ability of the chip to reach high upper frequency of operation, thus overcoming the low-frequency Debye screening limit at nearly physiological salt concentrations in the electrolyte, and allowing for detection of events occurring beyond the extent of the electrical double layer. Furthermore, calibrated multi-frequency measurements enable quantitative recording of capacitance spectra, whose features can reveal new properties of the analytes. The scalability of the electrode dimensions, inter-electrode pitch and size of the array make this sensing approach of quite general applicability, even in a non-bio context (e.g. gas sensing).
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