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

Abstract

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.

Keywords: extracellular recording and stimulation; high channel count; high-density microelectrode array (HD-MEA); impedance spectroscopy; low noise; low power; multi-functionality; neural interface; neurotransmitter detection; pre-charging; pseudo-resistor; switch matrix.

Fig. 1

Illustration of the multi-functional, switch-matrix-based HD-MEA system featuring action potential (AP) readout, local field potential (LFP) readout, current readout (CR), impedance measurement (IM), neurotransmitter detection (NTD) and stimulation (ST) channels.

Fig. 2

Block diagram of the multi-functional MEA system.

Fig. 3

Block diagram of an array pixel. Switch SW0 connects the electrode to either a horizontal (sigH) or a vertical (sigV) wire. SW1 connects two intersecting wires, SW2 connects a pair of parallel wires. m, n, p, q ∈ [0,15], r ∈ [0,11].

Fig. 4

AP recording channels. (a) Block diagram of the 2048 AP recording channels. (b) Open-loop amplifier (A₁) used in the first stage and its constant-g_m bias circuit. (c) Two types of pseudo resistors and their bias circuits. (d) MOSFET-only R-2R current DAC for tuning high-pass corner frequencies.

Fig. 5

The pre-charging technique. (a) Schematic of a portion of the SC third-stage amplifier, drawn as single-ended circuit for brevity. (b) A sketch of V_{o2_i} with/without using the pre-charging technique.

Fig. 6

Block diagram of the neurotransmitter detection channel and schematics of TIA_A, TIA_B, and the Gm cell.

Fig. 7

Schematic of the lock-in-amplifier-based impedance measurement channel.

Fig. 8

Schematic of the current/voltage-controlled stimulation buffer.

Fig. 9

(a) Chip micrograph. (b) Bio-compatible chip packaging and PCB. (c) SEM image of the chip surface, showing in-house post-processed Pt-electrodes and dissociated primary rat cortical neurons, cultured on top.

Fig. 10

(a) Noise power spectral density of the AP recording channel including the ADC. (b) Input-referred offset distribution of the 2048 AP channels. (c) Gain distribution of the 2048 AP channels. (d) The first- and second-stage HPF corner frequency (f_HPF) tuned by the current DAC. (e) Transfer function of 2048 AP channels and f_HPF distribution.

Fig. 11

(a) Noise power spectral density of TIA_A and TIA_B including multiplexer and ADC. b) Gain distribution across 3 chips. (c) Recorded FSCV results for concentrations of 200 μM, 300 μM, 400 μM and 500 μM dopamine in 0.1 M PBS. TIA_B connected to a single electrode has been used. Each of the curves is an average over 98 scans applied within 1 s.

Fig. 12

(a) Noise power spectral density of the TIA with R_f = 10 MΩ. (b) Magnitude and phase of the bright Pt and Pt-black electrode impedance in a frequency range between 1 Hz and 1 MHz, averaged over 6 and 8 electrodes for bright Pt and Pt-black, respectively.

Fig. 13

Voltage (black) and current (red) waveforms, generated by the stimulation buffer operated in current/voltage-controlled mode and connected to a 610 pF external load. The blue dashed line indicates the input waveform. (a) Low-current mode configuration, (b) High-current mode configuration.

Fig. 14

(a) Average negative peak amplitudes, recorded by an HD electrode configuration (45×45 pixels, 607.5×607.5 μm²) from dissociated primary rat cortical neurons. Each pixel in the image corresponds to an electrode. (b) AP waveforms, recorded in a sub-region of (a), averaged 20 times. (c) Mouse cerebellar slice electrical activity, recorded with a single sparse configuration of 2000 electrodes. The recording electrodes are displayed 9 times larger than their original size for visual clarity. (d) Overlap of (c) and a microscopy image of the slice (inset).

Fig. 15

Six frames showing 2.5 ms of evoked neuronal activity from a culture of dissociated rat cortical neurons. A biphasic voltage-controlled pulse (300 mV phase amplitude and 200 μs phase duration) was applied to a single electrode (white cross), while the other electrodes were scanned for recording from the entire array (4.48×2.43 mm²) at full spatial resolution (13.5 μm electrode pitch). 100 averages were computed for each electrode and temporally aligned with respect to the stimulation pulses.