A Time-Resolved Four-Tap Lock-In Pixel CMOS Image Sensor for Real-Time Fluorescence Lifetime Imaging Microscopy

Abstract

A programmable sub-nanosecond time-gated four-tap CMOS lock-in pixel (LIP) image sensor that uses an in-pixel pulse generator (PG) is developed for time-resolved (TR) biomedical imaging applications, such as a fluorescence lifetime imaging microscopy (FLIM). We demonstrate the system's effectiveness with simulations and measurements. Using pixel-level PG circuits, very narrow time windows (TWs) that are less than 0.8 ns can be used for charge modulation. This rapid gating allows very weak signals from living cells to be captured with a high signal-to-noise ratio (SNR). The prototype CMOS imaging system displays a fast intrinsic response of 170 ps at 472 nm and a very low temporal random noise of 0.85 e-rms at 45 frames/s under truly correlated-double-sampling operation using two-stage charge transfer. Four outputs from the LIPs allow real-time fluorescence lifetimes (FLTs) measurement, even from samples with multiple FLT components.