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.
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).
We have developed a measurement platform for performing high-frequency AC detection at nanoelectrodes. The system consists of 65 536 electrodes (diameter 180 nm) arranged in a sub-micrometer rectangular array. The electrodes are actuated at frequencies up to 50 MHz, and the resulting AC current response at each separately addressable electrode is measured in real time. These capabilities are made possible by fabricating the electrodes on a complementary metal-oxide-semiconductor (CMOS) chip together with the associated control and readout electronics, thus minimizing parasitic capacitance and maximizing the signal-to-noise ratio. This combination of features offers several advantages for a broad range of experiments. First, in contrast to alternative CMOS-based electrical systems based on field-effect detection, high-frequency operation is sensitive beyond the electrical double layer and can probe entities at a range of micrometers in electrolytes with high ionic strength such as water at physiological salt concentrations. Far from being limited to single- or few-channel recordings like conventional electrochemical impedance spectroscopy, the massively parallel design of the array permits electrically imaging micrometer-scale entities with each electrode serving as a separate pixel. This allows observation of complex kinetics in heterogeneous environments, for example, the motion of living cells on the surface of the array. This imaging aspect is further strengthened by the ability to distinguish between analyte species based on the sign and magnitude of their AC response. Finally, we show here that sensitivity down to the attofarad level combined with the small electrode size permits detection of individual 28 nm diameter particles as they land on the sensor surface. Interestingly, using finite-element methods, it is also possible to calculate accurately the full three-dimensional electric field and current distributions during operation at the level of the Poisson-Nernst-Planck formalism. This makes it possible to validate the interpretation of measurements and to optimize the design of future experiments. Indeed, the complex frequency and spatial dependence of the data suggests that experiments to date have only scratched the surface of the method's capabilities. Future iterations of the hardware will take advantage of the higher frequencies, higher electrode packing densities and smaller electrode sizes made available by continuing advances in CMOS manufacturing. Combined with targeted immobilization of targets at the electrodes, we anticipate that it will soon be possible to realize complex biosensors based on spatial- and time-resolved nanoscale impedance detection.
We present new experimental evidence and extensive numerical simulations of a few distinct fingerprints generated by dielectric and conductive microparticles in electrolyte environment on the capacitance spectra of nanoelectrode array sensors. Finite element simulations in good agreement with measurements allow us to identify unambiguously the physical origin of these features, and to illustrate their dependence on the system's geometrical and physical properties. In particular, we show that conductive particles induce a response with complex space and frequency dependencies, caused by the formation of an AC electrical double layer at the particle surface, and its interaction with the working and counter electrodes in the array. Furthermore, we highlight features that could lead to false-negative detection events in sensing applications. The theoretical predictions are confirmed by experiments on a state of the art CMOS pixelated nanocapacitor biosensor platform.
CMOS-based nanocapacitor arrays allow local probing of the impedance of an electrolyte in real time and with sub-micron spatial resolution. We report on the physico-chemical characterization of individual microdroplets of oil in a continuous water phase.
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