Monolithic CMOS sensor platform featuring an array of 9'216 carbon-nanotube-sensor elements and low-noise, wide-bandwidth and wide-dynamic-range readout circuitry.

We present the design and characterization of a monolithic complementary metal-oxide-semiconductor (CMOS) biosensor platform comprising of a switch-matrix-based array of 9'216 carbon nanotube field-effect transistors (CNTFETs) and associated readout circuitry. The switch-matrix allows for flexible selection and simultaneous routing of 96 sensor elements to the corresponding readout channels. A low-noise, wide-bandwidth, wide-dynamic-range transimpedance continuous-time amplifier architecture has been implemented to facilitate resistance measurements in the range between 50 kΩ and 1 GΩ at a bandwidth of up to 1 MHz. The achieved accuracy of the resistance measurements over the whole range is 4%. The system has been successfully fabricated and tested and shows a noise performance equal to 2.14 pArms at a bandwidth of 1 kHz and 0.84 nArms at a bandwidth of 1 MHz. A batch integration of the CNTFETs has been achieved by using a dielectrophoresis (DEP)-based manipulation technique. The current-voltage curves of CNTFETs have been acquired, and the sensing capabilities of the system have been demonstrated by recording resistance changes of CNTFETs upon exposure to solutions with different pH values and different concentrations of NaCl. The smallest resolvable concentrations for the respective analytes were estimated to amount to 0.025 pH-units and 4 mM NaCl.

A Multi-Functional Microelectrode Array Featuring 59760 Electrodes, 2048 Electrophysiology Channels, Stimulation, Impedance Measurement and Neurotransmitter Detection Channels.

Biological cells are characterized by highly complex phenomena and processes that are, to a great extent, interdependent. To gain detailed insights, devices designed to study cellular phenomena need to enable tracking and manipulation of multiple cell parameters in parallel; they have to provide high signal quality and high spatiotemporal resolution. To this end, we have developed a CMOS-based microelectrode array system that integrates six measurement and stimulation functions, the largest number to date. Moreover, the system features the largest active electrode array area to date (4.48×2.43 mm2) to accommodate 59,760 electrodes, while its power consumption, noise characteristics, and spatial resolution (13.5 µm electrode pitch) are comparable to the best state-of-the-art devices. The system includes: 2,048 action-potential (AP, bandwidth: 300 Hz to 10 kHz) recording units, 32 local-field-potential (LFP, bandwidth: 1 Hz to 300 Hz) recording units, 32 current recording units, 32 impedance measurement units, and 28 neurotransmitter detection units, in addition to the 16 dual-mode voltage-only or current/voltage-controlled stimulation units. The electrode array architecture is based on a switch matrix, which allows for connecting any measurement/stimulation unit to any electrode in the array and for performing different measurement/stimulation functions in parallel.

Microarray-based MALDI-TOF mass spectrometry enables monitoring of monoclonal antibody production in batch and perfusion cell cultures.

Cell culture process monitoring in monoclonal antibody (mAb) production is essential for efficient process development and process optimization. Currently employed online, at line and offline methods for monitoring productivity as well as process reproducibility have their individual strengths and limitations. Here, we describe a matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)-based on a microarray for mass spectrometry (MAMS) technology to rapidly monitor a broad panel of analytes, including metabolites and proteins directly from the unpurified cell supernatant or from host cell culture lysates. The antibody titer is determined from the intact antibody mass spectra signal intensity relative to an internal protein standard spiked into the supernatant. The method allows a semi-quantitative determination of light and heavy chains. Intracellular mass profiles for metabolites and proteins can be used to track cellular growth and cell productivity.

22.8 Multi-Functional Microelectrode Array System Featuring 59,760 Electrodes, 2048 Electrophysiology Channels, Impedance and Neurotransmitter Measurement Units.

Various CMOS-based micro-electrode arrays (MEAs) have been developed in recent years for extracellular electrophysiological recording/stimulation of electrogenic cells [1-5]. Mostly two approaches have been used: (i) the activepixel approach (APS) [2-4], which features simultaneous readout of all electrodes, however, at the expense of a comparably high noise level, and (ii) the switchmatrix (SM) approach, which yields better noise performance, whereas only a subset of electrodes (e.g.,1024) is simultaneously read out [5]. All systems feature, at most, voltage recording and/or voltage/current stimulation functionalities.

Mitotic cells contract actomyosin cortex and generate pressure to round against or escape epithelial confinement.

Little is known about how mitotic cells round against epithelial confinement. Here, we engineer micropillar arrays that subject cells to lateral mechanical confinement similar to that experienced in epithelia. If generating sufficient force to deform the pillars, rounding epithelial (MDCK) cells can create space to divide. However, if mitotic cells cannot create sufficient space, their rounding force, which is generated by actomyosin contraction and hydrostatic pressure, pushes the cell out of confinement. After conducting mitosis in an unperturbed manner, both daughter cells return to the confinement of the pillars. Cells that cannot round against nor escape confinement cannot orient their mitotic spindles and more likely undergo apoptosis. The results highlight how spatially constrained epithelial cells prepare for mitosis: either they are strong enough to round up or they must escape. The ability to escape from confinement and reintegrate after mitosis appears to be a basic property of epithelial cells.

Monolithic integration of a silicon nanowire field-effect transistors array on a complementary metal-oxide semiconductor chip for biochemical sensor applications.

We present a monolithic complementary metal-oxide semiconductor (CMOS)-based sensor system comprising an array of silicon nanowire field-effect transistors (FETs) and the signal-conditioning circuitry on the same chip. The silicon nanowires were fabricated by chemical vapor deposition methods and then transferred to the CMOS chip, where Ti/Pd/Ti contacts had been patterned via e-beam lithography. The on-chip circuitry measures the current flowing through each nanowire FET upon applying a constant source-drain voltage. The analog signal is digitized on chip and then transmitted to a receiving unit. The system has been successfully fabricated and tested by acquiring I-V curves of the bare nanowire-based FETs. Furthermore, the sensing capabilities of the complete system have been demonstrated by recording current changes upon nanowire exposure to solutions of different pHs, as well as by detecting different concentrations of Troponin T biomarkers (cTnT) through antibody-functionalized nanowire FETs.

High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels.

Studies on information processing and learning properties of neuronal networks would benefit from simultaneous and parallel access to the activity of a large fraction of all neurons in such networks. Here, we present a CMOS-based device, capable of simultaneously recording the electrical activity of over a thousand cells in in vitro neuronal networks. The device provides sufficiently high spatiotemporal resolution to enable, at the same time, access to neuronal preparations on subcellular, cellular, and network level. The key feature is a rapidly reconfigurable array of 26 400 microelectrodes arranged at low pitch (17.5 µm) within a large overall sensing area (3.85 × 2.10 mm(2)). An arbitrary subset of the electrodes can be simultaneously connected to 1024 low-noise readout channels as well as 32 stimulation units. Each electrode or electrode subset can be used to electrically stimulate or record the signals of virtually any neuron on the array. We demonstrate the applicability and potential of this device for various different experimental paradigms: large-scale recordings from whole networks of neurons as well as investigations of axonal properties of individual neurons.

Fully integrated CMOS microsystem for electrochemical measurements on 32 × 32 working electrodes at 90 frames per second.

Microelectrode arrays offer the potential to electrochemically monitor concentrations of molecules at high spatial resolution. However, current systems are limited in the number of sensor sites, signal resolution, and throughput. Here, we present a fully integrated complementary metal oxide semiconductor (CMOS) system with an array of 32 × 32 working electrodes to perform electrochemical measurements like amperometry and voltammetry. The array consists of platinum electrodes with a center-to-center distance of 100 µm and electrode diameters of 5 to 50 µm. Currents in the range from 10 µA down to pA can be measured. The current is digitized by sigma-delta converters at a maximum resolution of 13.3 bits. The integrated noise is 220 fA for a bandwidth of 100 Hz, allowing for detection of pA currents. Currents can be continuously acquired at up to 1 kHz bandwidth, or the whole array can be read out rapidly at a frame rate of up to 90 Hz. The results of the electrical characterization meet the requirements of a wide range of electrochemical methods including cyclic voltammograms and amperometric images of high spatial and temporal resolution.

A 1024-Channel CMOS Microelectrode Array With 26,400 Electrodes for Recording and Stimulation of Electrogenic Cells In Vitro.

To advance our understanding of the functioning of neuronal ensembles, systems are needed to enable simultaneous recording from a large number of individual neurons at high spatiotemporal resolution and good signal-to-noise ratio. Moreover, stimulation capability is highly desirable for investigating, for example, plasticity and learning processes. Here, we present a microelectrode array (MEA) system on a single CMOS die for in vitro recording and stimulation. The system incorporates 26,400 platinum electrodes, fabricated by in-house post-processing, over a large sensing area (3.85 × 2.10 mm2) with sub-cellular spatial resolution (pitch of 17.5 µm). Owing to an area and power efficient implementation, we were able to integrate 1024 readout channels on chip to record extracellular signals from a user-specified selection of electrodes. These channels feature noise values of 2.4 µVrms in the action-potential band (300 Hz-10 kHz) and 5.4 µVrms in the local-field-potential band (1 Hz-300 Hz), and provide programmable gain (up to 78 dB) to accommodate various biological preparations. Amplified and filtered signals are digitized by 10 bit parallel single-slope ADCs at 20 kSamples/s. The system also includes 32 stimulation units, which can elicit neural spikes through either current or voltage pulses. The chip consumes only 75 mW in total, which obviates the need of active cooling even for sensitive cell cultures.