Single-cell recording and stimulation with a 16k micro-nail electrode array integrated on a 0.18 μm CMOS chip

Abstract

To cope with the growing needs in research towards the understanding of cellular function and network dynamics, advanced micro-electrode arrays (MEAs) based on integrated complementary metal oxide semiconductor (CMOS) circuits have been increasingly reported. Although such arrays contain a large number of sensors for recording and/or stimulation, the size of the electrodes on these chips are often larger than a typical mammalian cell. Therefore, true single-cell recording and stimulation remains challenging. Single-cell resolution can be obtained by decreasing the size of the electrodes, which inherently increases the characteristic impedance and noise. Here, we present an array of 16,384 active sensors monolithically integrated on chip, realized in 0.18 μm CMOS technology for recording and stimulation of individual cells. Successful recording of electrical activity of cardiac cells with the chip, validated with intracellular whole-cell patch clamp recordings are presented, illustrating single-cell readout capability. Further, by applying a single-electrode stimulation protocol, we could pace individual cardiac cells, demonstrating single-cell addressability. This novel electrode array could help pave the way towards solving complex interactions of mammalian cellular networks.

System-on-Chip Considerations for Heterogeneous Integration of CMOS and Fluidic Bio-Interfaces

“…There are also numerous examples of successful integrated systems designed for direct interaction with biology or fluids [7], such as neural amplifiers [8]- [10], magnetic sensors [11]- [13], optical sensors [14], [15] and electrochemical sensors [16]- [18]. The main reasons for combining CMOS with MEMS surface structures and fluidics are: weak signals, sensing that requires active circuits, extreme size constraints, applications for which wires are not possible, and desired additional functionality or increased density of sensing sites.…”

“…Another example of an industrial solution that was successfully adapted for fluidic integration was based on the commonly used low temperature co-fired ceramic (LTCC) package. CMOS chips were bump-bonded to ceramic carriers, and passivation material was applied to the bonds to isolate them from fluid, allowing cell culture on the surface of the IC [10]. LTCC packages themselves can be designed to incorporate microfluidic channels (in addition to the electrical traces) within the stacked layers that form the ceramic substrate [58].…”

Reflective lens-free imaging on high-density silicon microelectrode arrays for monitoring and evaluation of in vitro cardiac contractility

“…RCD was calculated in a region of 0.124 mm 2 around the electrodes of interest. In the first system, simultaneous intracellular action potential measurements were obtained by combining the RLFI setup with a CMOS-based microelectrode array with 16,384 individually addressable electrodes as previously described [7,39]. Briefly, intracellular access was achieved by electroporating the cell membrane locally through sub-cellular sized electrodes, achieving intracellular-like ('open-cell') recordings.…”

“…In the case of LFI, only biological samples grown on transparent substrates have been analyzed. Even though microfabricated silicon chips are used increasingly in biological applications to improve resolution, sensitivity and throughput in cell analysis [39][40][41], compatibility with silicon-based devices is not yet achieved. This problem can be circumvented by reflection lens-free imaging (RLFI), which uses off-axis holography based systems [42].…”

An Evaluation of Different Coating for TiN Microelectrode Chambers Used for Neonatal Cardiomyocytes

“…The number of substrate-integrated recording electrodes (channels) is in the range from units to thousands in recently presented applications [5][6][7]. The size, shape and electrode spacing might also vary from units to hundreds of micrometres.…”