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

Integrating silicon chips and live bacterial biosensors 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 biosensors. 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 processing circuitry. The metal/dielectric layers in CMOS are employed to implement low-loss cavity-type optical filters achieving a bandpass 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 distinguish 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.