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

This article presents a fully integrated multi-modal CMOS cellular sensor/stimulator array chip with 21 952 pixels and 1568-pixel concurrent readouts, while each array pixel can be independently reconfigured to support three sensing and one stimulation modalities: cellular potential recording, optical-point impedance sensing, and bi-phasic current stimulation. The CMOS sensor/stimulator array chip provides 3.6 mm $\times $ 1.6 mm active field-of-view (FoV). Each pixel contains one 8 $\mu \text{m}\,\,\times $ 8 $\mu \text{m}$ gold deposited electrode, one 6 $\mu \text{m}\,\,\times $ 6 $\mu \text{m}$ photodiode, and in-pixel circuits within 8 $\mu \text{m}\,\,\times $ 11 $\mu \text{m}$ pixel area, while the pixel-to-pixel pitch is 16 $\mu \text{m}\,\,\times $ 16 $\mu \text{m}$ . As a proof of concept, the CMOS array is implemented in a standard 130-nm BiCMOS process. Comprehensive electrical testing (potential/optical/four-point impedance/stimulation) and biological measurements (potential/optical/four-point impedance) with on-chip rat cardiomyocytes demonstrate the functionalities and unique advantages of this multi-modality cellular array. With high throughput multi-modal cellular sensing supported at the pixel level, this array chip enables holistic characterization of on-chip cellular samples with single-cell resolution.