CMOS microelectrode array for the monitoring of electrogenic cells

Abstract

Signal degradation and an array size dictated by the number of available interconnects are the two main limitations inherent to standalone microelectrode arrays (MEAs). A new biochip consisting of an array of microelectrodes with fully-integrated analog and digital circuitry realized in an industrial CMOS process addresses these issues. The device is capable of on-chip signal filtering for improved signal-to-noise ratio (SNR), on-chip analog and digital conversion, and multiplexing, thereby facilitating simultaneous stimulation and recording of electrogenic cell activity. The designed electrode pitch of 250 m significantly limits the space available for circuitry: a repeated unit of circuitry associated with each electrode comprises a stimulation buffer and a bandpass filter for readout. The bandpass filter has corner frequencies of 100 Hz and 50 kHz, and a gain of 1000. Stimulation voltages are generated from an 8-bit digital signal and converted to an analog signal at a frequency of 120 kHz. Functionality of the read-out circuitry is demonstrated by the measurement of cardiomyocyte activity. The microelectrode is realized in a shifted design for flexibility and biocompatibility. Several microelectrode materials (platinum, platinum black and titanium nitride) have been electrically characterized. An equivalent circuit model, where each parameter represents a macroscopic physical quantity contributing to the interface impedance, has been successfully fitted to experimental results.

Label‐Free Impedance Biosensors: Opportunities and Challenges

“…Microscopic roughness can cause this effect [99,100], but a convincing review by Pajkossy [101] suggests that microscopic chemical inhomogeneities and ion adsorption play an even larger role (supported by data in [102][103][104]). Jorcin demonstrated that both surface effects and inhomogeneous current distribution contribute to CPE behavior [105].…”

Light induced stimulation and delay of cardiac activity

“…Multi-site analysis of tissue is one of the most common applications for MEAs in vitro. Application of MEAs to record heart tissue [8,9] as well as neuronal network 35 behavior [10,11] is commonly done in various types of in vitro and in vivo preparations. Advantages are the good spatial resolution in combination with a high temporal resolution.…”

Microfluidics/CMOS orthogonal capabilities for cell biology

“…Nutrient flow was set at 50 μL·min −1 and at 100 μL·min −1 for drug delivery experiment done with the upper hole and lower hole, respectively. Fluorescence intensities for both experiments cannot be directly compared owing to photobleaching as a consequence of intermediary observation with a fluorescence microscope In our first CMOS design, (Heer, et al, 2004) we used an array of 4 × 4 electrodes, where each electrode has an associated unit of circuitry which filters and amplifies the recorded electrical signal. Additionally, each electrode can be used to apply electrical stimuli to the cellular culture to elicit an action potential.…”

“…A reactive-ion etch (RIE) is then used to open the nitride stack defining the size and shape of the electrodes. Detailed information regarding the design of the electronic circuitry was published previously (Heer et al, 2004).…”