A 16-Channel CMOS Reconfigurable Recording Unit for Simultaneous In-Vitro Microelectrode Array and Current-Clamp Measurements

Abstract

In-vitro cell culturing technique is widely used in many branches of science such as in neuroscience and cardiology to investigate the dynamics of large population of cells. Cultured cells can be studied by means of two fundamental recording techniques that are intracellular and extracellular recordings. Patch-clamp technique is the gold standard of high-fidelity action potentials (APs) and synaptic potentials of an individual cell. However, patch-clamp method suffers from very poor scalability. Approximately only 10 cells can be studied per day by experienced personnel working on a bulky and expensive setup. Microelectrode arrays (MEAs) have been proposed to perform multi-site and high-throughput extracellular recordings. Although MEA technology is utilized to understand network dynamics of large population of cells, MEA electrodes lack intracellular access to cell membrane which results in highly-attenuated potentials. Thus, MEA electrodes are only capable of recording action potentials (APs), and they are completely blind to synaptic events. Recent studies report that APs and synaptic potentials of an individual cell play a role in an increase in network activities as well as extracellular field potentials can induce a single-cell activity. Concurrent high throughput patch-clamp and MEA measurements are needed to gain insight into correlation between single-cell and network dynamics. The thesis project presents the design of 16-channel dual-mode recording unit for simultaneous measurements of intracellular and extracellular activities. The recording channel consists of capacitively-coupled instrumentation amplifier (CCIA) to reject DC offset of electrodes and unary-weighted current-steering DAC for stimulation of cells. The ratio of CCIA capacitors defines the gain of the amplifier, and the capacitors with MOS-based pseudo-resistors determine the low-frequency cut-off frequency. Single-stage single-ended 5T operational transconductance amplifier (OTA) is implemented in the core of CCIA. The unit current source of 4-bit thermometer-coded DAC copies 100 pA current from the reference and is localized in each channel. The injected current is increased by activating the adjacent unit current sources, and total current can reach to 1.6 nA. The reconfigurable recording channel has been designed in standard 0.18 $\mu$m CMOS technology. By post-layout simulations, the gain of the amplifier equals to 23.5 dB. The input-referred noise of the channel is 8.1 $\mu$V$_{rms}$ in the frequency band ranging from 1.05 Hz to 10 kHz with NEF of 6.2. The power consumption of each individual recording unit is 7.18 $\mu$W. Each reconfigurable channel occupies 0.021 mm$^{2}$ area on a die. This thesis projects integrates dual-mode functionality which opens a door to high-throughput multi-site intracellular and extracellular recordings for further understanding of correlation between single-cell activity and network dynamics of cells.