Joerg Rothe

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.

Multi-target electrochemical biosensing enabled by integrated CMOS electronics

An integrated electrochemical measurement system, based on CMOS technology, is presented, which allows the detection of several analytes in parallel (multi-analyte) and enables simultaneous monitoring at different locations (multi-site). The system comprises a 576-electrode CMOS sensor chip, an FPGA module for chip control and data processing, and the measurement laptop. The advantages of the highly versatile system are demonstrated by two applications. First, a label-free, hybridization-based DNA sensor is enabled by the possibility of large-scale integration in CMOS technology. Second, the detection of the neurotransmitter choline is presented by assembling the chip with biosensor microprobe arrays. The low noise level enables a limit of detection of, e.g., 0.3 µM choline. The fully integrated system is self-contained: it features cleaning, functionalization and measurement functions without the need for additional electrical equipment. With the power supplied by the laptop, the system is very suitable for on-site measurements.

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.

Differential impedance spectrometer and vision system for analysis of single cells

This paper reports on a differential impedance spectroscopy system for single-cell analysis, which also features an optical setup with machine-vision that simultaneously provides optical data for a direct comparison. Such a combined setup allows for benchmarking the differential impedance spectroscopy against the optical data in a quantitative way. Here we present simultaneously acquired optical and impedance-spectroscopic data of yeast cells and polystyrene beads. Signal simulations have been performed and fitted to the measured data to increase the quality of the results and to explain the recorded signal shapes.

Multisite monitoring of choline using biosensor microprobe arrays in combination with CMOS circuitry.

Abstract A miniature device enabling parallel in vivo detection of the neurotransmitter choline in multiple brain regions of freely behaving rodents is presented. This is achieved by combining a biosensor microprobe array with a custom-developed CMOS chip. Each silicon microprobe comprises multiple platinum electrodes that are coated with an enzymatic membrane and a permselective layer for selective detection of choline. The biosensors, based on the principle of amperometric detection, exhibit a sensitivity of 157±35 µA mM-1 cm-2, a limit of detection of below 1 µM, and a response time in the range of 1 s. With on-chip digitalization and multiplexing, parallel recordings can be performed at a high signal-to-noise ratio with minimal space requirements and with substantial reduction of external signal interference. The layout of the integrated circuitry allows for versatile configuration of the current range and can, therefore, also be used for functionalization of the electrodes before use. The result is a compact, highly integrated system, very convenient for on-site measurements.

Robust Functionalization of Large Microelectrode Arrays by Using Pulsed Potentiostatic Deposition

Surface modification of microelectrodes is a central step in the development of microsensors and microsensor arrays. Here, we present an electrodeposition scheme based on voltage pulses. Key features of this method are uniformity in the deposited electrode coatings, flexibility in the overall deposition area, i.e., the sizes and number of the electrodes to be coated, and precise control of the surface texture. Deposition and characterization of four different materials are demonstrated, including layers of high-surface-area platinum, gold, conducting polymer poly(ethylenedioxythiophene), also known as PEDOT, and the non-conducting polymer poly(phenylenediamine), also known as PPD. The depositions were conducted using a fully integrated complementary metal-oxide-semiconductor (CMOS) chip with an array of 1024 microelectrodes. The pulsed potentiostatic deposition scheme is particularly suitable for functionalization of individual electrodes or electrode subsets of large integrated microelectrode arrays: the required deposition waveforms are readily available in an integrated system, the same deposition parameters can be used to functionalize the surface of either single electrodes or large arrays of thousands of electrodes, and the deposition method proved to be robust and reproducible for all materials tested.

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.

Real-time multi-analyte online monitoring of 3d cell cultures by integrated enzyme-based biosensors in hanging drop networks

We present the integration of enzyme-based lactate and glucose biosensors into hanging-drop networks. Hangingdrop networks are an ideal microfluidic platform for formation, cultivation, and continuous and long-term observation of 3D microtissues. The implementation of biosensors enables in-situ online monitoring of the effects of different culturing conditions and compound dosages on the microtissues. A hybrid approach including glass sensor modules embedded into a microfluidic polydimethylsiloxane (PDMS)-based chip facilitates system integration. The biosensors enable real-time recording of lactate production and glucose consumption of human colon carcinoma spheroids.

Multi-site monitoring of choline and glutamate using biosensor microprobe arrays in combination with CMOS circuitry

Biosensor microprobe arrays for the simultaneous in vivo detection of the neurotransmitters choline and L-glutamate are presented. Combined with a custom-developed CMOS chip, comprising 24 potentiostatic circuits, recordings can be performed at high signal-to-noise ratio in multiple areas of a rats brain in parallel. The functionalization to create selective enzyme electrodes is based on electrochemical deposition methods and can be obtained by using functions of a versatile CMOS circuitry chip. The result is a compact all-in-one system convenient for on-site measurement. Biosensors show good selectivity, sensitivities larger than 100 µA mM−1 cm−2, detection limits of less than 0.3 µM, and response times below 1 second.