Microelectronic system for high-resolution mapping of extracellular electric fields applied to brain slices.

There is an enduring quest for technologies that provide - temporally and spatially - highly resolved information on electric neuronal or cardiac activity in functional tissues or cell cultures. Here, we present a planar high-density, low-noise microelectrode system realized in microelectronics technology that features 11,011 microelectrodes (3,150 electrodes per mm(2)), 126 of which can be arbitrarily selected and can, via a reconfigurable routing scheme, be connected to on-chip recording and stimulation circuits. This device enables long-term extracellular electrical-activity recordings at subcellular spatial resolution and microsecond temporal resolution to capture the entire dynamics of the cellular electrical signals. To illustrate the device performance, extracellular potentials of Purkinje cells (PCs) in acute slices of the cerebellum have been analyzed. A detailed and comprehensive picture of the distribution and dynamics of action potentials (APs) in the somatic and dendritic regions of a single cell was obtained from the recordings by applying spike sorting and spike-triggered averaging methods to the collected data. An analysis of the measured local current densities revealed a reproducible sink/source pattern within a single cell during an AP. The experimental data substantiated compartmental models and can be used to extend those models to better understand extracellular single-cell potential patterns and their contributions to the population activity. The presented devices can be conveniently applied to a broad variety of biological preparations, i.e., neural or cardiac tissues, slices, or cell cultures can be grown or placed directly atop of the chips for fundamental mechanistic or pharmacological studies.

Cell recordings with a CMOS high-density microelectrode array.

Recordings have been performed with a CMOS-based microelectrode array (MEA) featuring 11'016 metal electrodes and 126 channels, each of which comprises recording and stimulation electronics for extracellular, bidirectional communication with electrogenic cells. The important features of the device include (i) high spatial resolution at (sub) cellular level with 3'200 electrodes per mm(2) (diameter 7 microm, pitch 18 microm), (ii) a reconfigurable routing of the electrodes to the 126 channels, and (iii) low noise levels. Recordings from neonatal rat cardiomyocytes forming confluent layers and microtissues are shown. Moreover, signals from dissociated rat hippocampal neurons and from neurons in an acute cerebellar slice preparation are presented.

Using microelectronics technology to communicate with living cells.

A monolithic microsystem in CMOS (complementary metal oxide semiconductor) technology is presented that provides bidirectional communication (stimulation and recording) between standard microelectronics and cultured electrogenic cells. The 128-electrode chip can be directly used as a substrate for cell culturing. It features circuitry units for stimulation and immediate cell signal treatment near each electrode. In addition, it provides on-chip A/D conversion as well as a digital interface so that a fast interaction is possible at good signal quality. Spontaneous and stimulated electrical activity recordings with neuronal and cardiac cell cultures will be presented. The system can be used to, e.g., study the behavior and development of neural networks in vitro, to reveal the effects of neuronal plasticity and to study network activity in response to pharmacological treatments.

A CMOS-based microelectrode array for interaction with neuronal cultures.

We report on the system integration of a CMOS chip that is capable of bidirectionally communicating (stimulation and recording) with electrogenic cells such as neurons or cardiomyocytes and that is targeted at investigating electrical signal propagation within cellular networks in vitro. The overall system consists of three major subunits: first, the core component is a 6.5 mm x 6.5 mm CMOS chip, on top of which the cells are cultured. It features 128 bidirectional electrodes, each equipped with dedicated analog filters and amplification stages and a stimulation buffer. The electrodes are sampled at 20 kHz with 8-bit resolution. The measured input-referred circuitry noise is 5.9 microV root mean square (10 Hz to 100 kHz), which allows to reliably detect the cell signals ranging from 1 mVpp down to 40 microVpp. Additionally, temperature sensors, a digital-to-analog converter for stimulation, and a digital interface for data transmission are integrated. Second, there is a reconfigurable logic device, which provides chip control, event detection, data buffering and an USB interface, capable of processing the 2.56 million samples per second. The third element includes software that is running on a standard PC performing data capturing, processing, and visualization. Experiments involving the stimulation of neurons with two different spatio-temporal patterns and the recording of the triggered spiking activity have been carried out. The response patterns have been successfully classified (83% correct) with respect to the different stimulation patterns. The advantages over current microelectrode arrays, as has been demonstrated in the experiments, include the capability to stimulate (voltage stimulation, 8 bit, 60 kHz) spatio-temporal patterns on arbitrary sets of electrodes and the fast stimulation reset mechanism that allows to record neuronal signals on a stimulating electrode 5 ms after stimulation (instantaneously on all other electrodes). Other advantages of the overall system include the small number of needed electrical connections due to the digital interface and the short latency time that allows to initiate a stimulation less than 2 ms after the detection of an action potential in closed-loop configurations.

Single-chip microelectronic system to interface with living cells.

A high degree of connectivity and the coordinated electrical activity of neural cells or networks are believed to be the reason that the brain is capable of highly sophisticated information processing. Likewise, the effectiveness of an animal heart largely depends on such coordinated cell activity. To advance our understanding of these complex biological systems, high spatiotemporal-resolution techniques to monitor the cell electrical activity and an ideally seamless interaction between cells and recording devices are desired. Here we present a monolithic microsystem in complementary metal oxide semiconductor (CMOS) technology that provides bidirectional communication (stimulation and recording) between standard electronics technology and cultured electrogenic cells. The microchip can be directly used as a substrate for cell culturing, it features circuitry units per electrode for stimulation and immediate cell signal treatment, and it provides on-chip signal transformation as well as a digital interface so that a very fast, almost real-time interaction (2 ms loop time from event recognition to, e.g., a defined stimulation) is possible at remarkable signal quality. The corresponding spontaneous and stimulated electrical activity recordings with neuronal and cardiac cell cultures will be presented. The system can be used to, e.g., study the development of neural networks, reveal the effects of neuronal plasticity and study cellular or network activity in response to pharmacological treatments.