Real-time simultaneous visualization of lactate and proton dynamics using a 6-μm-pitch CMOS multichemical image sensor.

Multi-analyte detection and imaging of extracellular chemical signaling molecules are crucial for understanding brain function and molecular pathology. In this work, we present a 6-μm-pitch, CMOS-based multichemical image sensor that enables the simultaneous visualization and spatiotemporal multimodal analysis of the lactate and proton (H) dynamics without any labeling. Using semiconductor lithography, gold electrode patterns functioning as lactate-sensing regions were formed on a potentiometric sensor array. Lactate is detected potentiometrically because of redox reactions using lactate oxidase and horseradish peroxidase. The resulting multichemical image sensor exhibited a pH sensitivity of 65 mV and a superior detection limit of 1 μM for lactate with a reasonable selectivity. Furthermore, diffusion images of lactate and H distributions were obtained concurrently, allowing for simultaneous real-time imaging of the two chemicals with subcellular resolution. We believe that our novel imaging device can be successfully applied to extracellular microenvironments in tissue or cell samples as an effective bioimaging tool.