High-Density Electrical Recording and Impedance Imaging With a Multi-Modal CMOS Multi-Electrode Array Chip

Abstract

Multi-electrode arrays, both active or passive, emerged as ideal technologies to unveil intricated electrophysiological dynamics of cells and tissues. Active MEAs, designed using complementary metal oxide semiconductor technology (CMOS), stand over passive devices thanks to the possibility of achieving single-cell resolution, the reduced electrode size, the reduced crosstalk and the higher functionality and portability. Nevertheless, most of the reported CMOS MEA systems mainly rely on a single operational modality, which strongly hampers the applicability range of a single device. This can be a limiting factor considering that most biological and electrophysiological dynamics are often based on the synergy of multiple and complex mechanisms acting from different angles on the same phenomena. Here, we designed a CMOS MEA chip with 16,384 titanium nitride electrodes, 6 independent operational modalities and 1,024 parallel recording channels for neuro-electrophysiological studies. Sixteen independent active areas are patterned on the chip surface forming a 4 × 4 matrix, each one including 1,024 electrodes. Electrodes of four different sizes are present on the chip surface, ranging from 2.5 × 3.5 μm 2 up to 11 × 11.0 μm 2 , with 15 μm pitch. In this paper, we exploited the impedance monitoring and voltage recording modalities not only to monitor the growth and development of primary rat hippocampal neurons, but also to assess their electrophysiological activity over time showing a mean spike amplitude of 144.8 ± 84.6 μV. Fixed frequency (1 kHz) and high sampling rate (30 kHz) impedance measurements were used to evaluate the cellular adhesion and growth on the chip surface. Thanks to the high-density configuration of the electrodes, as well as their dimension and pitch, the chip can appreciate the evolutions of the cell culture morphology starting from the moment of the seeding up to mature culture conditions. The measurements were confirmed by fluorescent staining. The effect of the different electrode sizes on the spike amplitudes and noise were also discussed. The multi-modality of the presented CMOS MEA allows for the simultaneous assessment of different physiological properties of the cultured neurons. Therefore, it can pave the way both to answer complex fundamental neuroscience questions as well as to aid the current drug-development paradigm.

Comparison of Sneo-Based Neural Spike Detection Algorithms for Implantable Multi-Transistor Array Biosensors

“…The LFP characterizes the low frequency content of the background noise (≤300 Hz). Thermal noise, which takes into account the contribution due to the analog front-end and is very important for EOSFET MTAs [7], is simulated by adding a Gaussian noise with zero mean to the extracellular recording.…”

“…The biocompatibility is guaranteed by the manufacturing process, that combines a complementary metal-oxide-semiconductor (CMOS) standard technique with a biocompatible metal oxide for the gate [5,6]. The small size and pitch of the grid pixels (electrodes) of the EOSFET MTAs results in a very good spatial resolution; on the other hand, these sensors, being extracellular, provide a limited signal-to-noise ratio (3-6 dB) compared to the standard passive electrodes [7], due to the weak capacitive coupling between the nearby neurons and the sensor and the high noise power coming from the analog front-end. For this reason, very efficient spike detection algorithms are required for this kind of sensors to extract the relevant neural spikes from the background noise.…”

A Single-Neuron: Current Trends and Future Prospects

“…The monkeys experiments were conducted to perform three tasks out of which two were strategy tasks, and one was the control task, and the activity of isolated neurons was recorded [84]. Similarly, microelectrode arrays with 59,760 platinum microelectrodes [85], a complementary metal-oxide-semiconductor (CMOS) multielectrode array (MEA) chip with 16,384 titanium nitride electrodes [86], and 26,400 bidirectional platinum electrodes [87] also exist for in vitro electrophysiological recording with single-neuron resolution. The results depicted the activation of single-neuron arrays via intracellular stimulations.…”

Advanced real-time recordings of neuronal activity with tailored patch pipettes, diamond multi-electrode arrays and electrochromic voltage-sensitive dyes

“…MEAs also promise to have many more exciting features in the future as the growing production of new prototypal sensors shows. Besides conventional materials [58], such as metals [101], silicon [68], polymers [38] and glass [67], diamond-based substrates became an attractive alternative during the last decade since they offer unique advantages due to the outstanding properties of this material, in terms of thermal conductivity, wide optical transparency, mechanical robustness and chemical inertness [63]. Furthermore, for the applications presented here, other peculiar properties of the diamond must be highlighted, like the optimal biocompatibility which is essential for performing long-term cultures [72], the lower absorption of organic molecules minimizing electrodes fouling [34], the chemically and electrochemically stability [112] and, above all, the possibility to control the electrical properties by means of doping [27] or inducing graphitization [62,82], essential for the realization of conductive microelectrodes.…”