Building a defense against epidemic diseases and understanding of neural intercellular signaling are two important biomedical engineering missions in the next 50 years. With mass production marching to 10nm CMOS technology and beyond, we are fast approaching the information resolution of the biological systems such as DNA/RNA and cellular ion channels. Electronic sensing, amplification, stimulation and transmission can effectively realize a small proximity system with interface to the biomolecular and biological domains. On the one hand, we can approach the never-before accessible biological and biomedical information, but on the other hand, many aspects of fundamental understanding on solid-fluid interface with bio-molecules and cells on the nanoscale remain lacking.

In consideration of molecular redox and lysing at the bioelectronic interface, nonamperometric high-impedance electrodes such as in ISFET are more applicable in view of reliability and invasiveness. I will present the sensor operations of the chemoreceptive MOS (CMOS) for monitoring ions, biomarkers, pathogen DNA/mRNA, cellular action potentials and exocytosis. The steric and molecular correlation effects on the sensing surface will cause a stiff system (large range of various time constants) and thus require specific operational methods for reliable sensing and actuation. I will then present two successful enzyme-free and readout-label-free sensing implementations on (1) Fast DNA-segment recognition for epidemic disease diagnosis, and (2) intercellular signal monitoring of enteric neurons, each with the respective signal processing to mitigate the long-term drift issues and to enhance the tolerance to low signal-to-noise ratio. With the unparalleled resolution in space and time, high sensitivity and versatile integration, this CMOS biosensor platform is potential to enable many new biomedical applications as well as research tools.