Alexander Stettler

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 mm ) 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 μV in the action-potential band (300 Hz-10 kHz) and 5.4 μV 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.

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.

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.

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 active-pixel approach (APS) [2-4], which features simultaneous readout of all electrodes, however, at the expense of a comparably high noise level, and (ii) the switch-matrix (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.

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.

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.

CMOS chip for electrochemical monitoring of the metabolic activity of biological cells

An integrated CMOS chip for performing electrochemical experiments, which can continuously monitor the metabolic activity of biological cells, is presented. The chip comprises an array of 1024 platinum working electrodes, 64 current readout channels, an integrated potentiostat with on-chip counter, as well as reference electrodes and a temperature sensor. Two different sigma-delta analog-to-digital converters are implemented to realize the current measurement. The first-order sigma-delta converter has a linearity and resolution of better than 11 bits, whereas the second-order sigma-delta converter achieves a resolution and linearity of better than 12 bits. The current range can be set from 2 μA down to 100 pA. The chip package comprises small wells for the cells and reservoirs for the culture media; moreover, it protects the electrical connections. Proof-of-concept measurements of glucose concentrations are shown.

Monolithic system featuring a gold nanowire array on a CMOS chip for biosensing applications

We present a monolithic CMOS-based biosensor system comprising an array of gold nanowires and the signal-conditioning circuitry on the same chip. Different numbers of parallel nanowires have been patterned on the chip via e-beam lithography and lift-off process after the CMOS fabrication. The on-chip circuitry monitors the resistance of the nanowires by applying a constant voltage and measuring the respective current. The analog signal is then digitized on chip and transmitted. The system has been successfully fabricated and tested. I-V curves of the bare nanowires as well as resistance changes for different gold nanowires after applying NaCl solution onto the chip are shown.