4.3 A programmable sub-nanosecond time-gated 4-tap lock-in pixel CMOS image sensor for real-time fluorescence lifetime imaging microscopy

Abstract

Fluorescence-based time-resolved (TR) analysis techniques are fundamental and effective methods in life science and medicine. Among others, fluorescence lifetime imaging microscopy (FLIM) is one of the representative measurement techniques for biomedical applications. Recently, advanced all-solid-state imaging devices for FLIM, e.g., a CCD with optional electron-multiplication (EM) readout, a single-photon avalanche diode (SPAD), and a TR CMOS image sensor (CIS), have been reported [1-3]. These devices can be implemented compactly in comparison with the typical FLIM systems such as a time-correlated single-photon counting (TCSPC) system [4]. However, imaging devices based on the CCD or SPAD still have some issues, including the need for specialized fabrication processes, use of higher voltages, and greater circuit complexity. The recent TR CIS with two taps in a pixel [3] shows us a way to realize real-time lifetime imaging, but the two-tap CIS has a limitation that a sample's lifetime cannot be measured in real time if the sample has multi-exponential decay components. This paper presents a sub-nanosecond time-gated four-tap lock-in pixel CIS using in-pixel pulse generator (PG) for fluorescence lifetime (FLT) imaging system. To realize a real-time FLT measurement system, good low-noise performance and the capability for fast data acquisition are essential. Thus, a lateral electric field charge modulator (LEFM) implemented with in-pixel PG block, 2-stage chargetransfer technique for true correlated double sampling (CDS) operation, and multi-tap design are used for the developed lock-in pixel. Additionally, a narrow time-window (TW) generated in pixel-level PG helps to attain the high signal-tonoise ratio (SNR) FLT measurement results.