A CMOS 21 952-Pixel Multi-Modal Cell-Based Biosensor With Four-Point Impedance Sensing for Holistic Cellular Characterization

A CMOS Multi-Electrode Array for Four-Electrode Bioimpedance Measurements

“…al. [16], electroless processes can lead to improper coverage of the underlying electrodes. For electrode stability during long-term cell-based measurements, the group instead deposited Au electrodes by E-beam evaporation.…”

“…This also improves both the sensitivity and the accuracy of the measurements [5]. The first implementation of a four-electrode system on a multi modal chip was recently successfully demonstrated by Jung et al [16]. In this impressive work with a chip encompassing 21952 pixels, the authors demonstrated holistic cellular characterization where four-electrode impedance measurements proved to be an important module.…”

“…Since there are many properties of an optimally designed four-electrode system that could vary from a multi-modal system, such as the important relative placement of the CC and PU electrode pairs, we believe it is essential to investigate how a system dedicated to fourelectrode measurements can be designed. This is important both for future dedicated four-electrode systems, as well as for multi-modal chips such as the one demonstrated by Jung et al [16].…”

A Multimodal and Multifunctional CMOS Cellular Interfacing Array for Digital Physiology and Pathology Featuring an Ultra Dense Pixel Array and Reconfigurable Sampling Rate

“…The monitoring of various parameters such as cellular potential, impedance, and optical responses in real time was achieved in each individually configured and controlled pixel, enabling a sensor array to monitor multiple cellular physiological properties at the single pixel level, radically extending our abilities to study digital physiology and pathology of cells and tissues. However, despite various previously reported multimodal CMOS biosensor arrays [8,9,14,16,17,[43][44][45][46][47][48][49][50][51][52] and considering their higher complexity compared to single-modal biosensors, there is still a great need to significantly advance multimodal CMOS biosensors arrays with higher pixel density, higher sampling rate, improved area efficiency, higher yield during post-CMOS processing, optimized electrodes for biological interfacing, and new reconfigurable sensing/actuation modalities. These desired features will enable next-generation digital physiology/pathology cellular characterization platforms to extract a vast assortment of different physiological information from various cells under various settings, including those with fast physiological characteristics, such as neuron/cardiac cells.…”

“…1, with 21,952 individually addressable multimodal pixels with a 13-µm center-to-center pixel pitch fully integrated into a 2.91 mm × 1.28 mm active sensing area, achieving both single-cell resolution and tissuelevel field-of-view (FoV). Each pixel supports four multifunctional modalities, including three multi-modal sensing modalities, (1) full array (FA) or fast scan (FS) voltage recording (VR) to investigate cellular electrical activity and ion concentration [17,42,43], (2) bright/dim optical detection (OD) to examine cell morphology and transparency [51,53], and (3) 2-/4-point impedance sensing (ZS) imaging to track cell adhesion and contractility [14,43,47,[54][55][56], as well as a cellular actuating modality in the form of single-cell/tissuelevel biphasic current stimulation (BCS) to achieve cell electrical stimulation, controlled charge delivery, and membrane electroporation [17,57]. Each modality can be reconfigured for different functionalities with adjustable scan rates versus FOV in VR to operate as FA, which analyzes the whole active area, or FS, which enables the recording of sharp electrophysiological changes, variable reset periods in OD to accommodate bright or dim lighting, programmable selection of pixels in ZS to permit 2-or 4-point ZS, and configurable stimulation area in BCS to excite selective single cells in a culture or collectively a tissue sample.…”