A 65-nm CMOS Fluorescence Sensor for Dynamic Monitoring of Living Cells

Abstract

Abstract—Integrating silicon chips and live bacterial biosen- sors in a miniaturized “cell-silicon” system can enable a wide range of applications in smart medicine and environmental sensing. Such integrated systems need on-chip optical filtering in the wavelength range compatible with fluorescent proteins (FPs), which are the widely used signal reporters for bacterial biosen- sors. However, the operating range of the prior works falls short in detecting the FP signals. Here, we report a fully integrated fluorescence (FL) sensor in 65-nm standard CMOS comprising on-chip bandpass optical filters, photodiodes (PDs), and process- ing circuitry. The metal/dielectric layers in CMOS are employed to implement low-loss cavity-type optical filters achieving a band- pass response at 600- to 700-nm range suitable to work with FPs. The sensitivity of the sensor is further improved in the electrical domain by using a capacitive transimpedance (C-TIA) with variable switched-capacitor gain, a voltage-controlled current source (VCCS), and feedback-controlled low-leakage switches, resulting in a minimum measured current of 1.05 fA with SNR > 18 dB. The sensor can measure the dynamics of the FL signal as well as the growth of living E. coli bacterial cells. By employing a differential design and layout, the sensor can dis- tinguish two biochemical signals by measuring two FPs encoded in a single bacterial strain. Using optogenetic control, a proof of concept is demonstrated to establish bidirectional communication between living cells and the CMOS chip. This integrated system creates a promising platform for the development of future closed-loop therapeutics.