IDBR: CMOS cameras for high-frame-rate time-correlated single-photon counting

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IDBR: CMOS cameras for high-frame-rate time-correlated single-photon countingRecent advances in biological imaging techniques, particularly those exploring molecular dynamics, are outpacing technological innovation. Fluorescence lifetime holds great potential as a biomarker that can reveal changes in a fluorophore's local chemical and physical environment, as well as the binding dynamics of single proteins through excited state interactions and Förster resonance energy transfer (FRET). Many of the latest active dyes, molecular probes and even transgenic labeling strategies exploit FRET to enable real-time observation of cellular processes both in-vitro and in-vivo. While FRET can be detected using intensity-only measurements, quantitation can be dramatically impaired by experimental factors such as photobleaching, whereas lifetime-based FRET measurements are significantly more robust. Nevertheless, adoption and widespread use of fluorescence lifetime imaging microscopy (FLIM) for biological research has been hindered by two major factors: the speed with which FLIM images can be acquired and the cost and complexity of the instrumentation required for FLIM. In this multidisciplinary proposal, a novel two-dimensional high-frame-rate complementary metal-oxide-semiconductor (CMOS) fluorescent lifetime camera chip based on single-photon avalanche diodes (SPADs) will be developed. This chip will be applied to both wide-field and laser-scanning-based microscopy techniques to enable several important advances in FLIM imaging. In widefield imaging, this will result in acquisition of images at a incident-photon-limited frame rate as high as 1 kHz.Solid-state imagers are based primarily on two technologies, charged-coupled device (CCD) and CMOS. Both of these imaging technologies are based on converting photons to electrons and collecting many of these electrons to produce a measurable signal. These imagers are now employed in digital cameras of every type, from cell phone cameras to the high-end cameras employed in biological imaging. Since optical techniques are so pervasive in probing biological systems, cameras represent the fundamental interface between the biological world and the solid-state world. In this effort, an entirely new camera chip will be designed based on a device that, instead of collecting electrons produced by photons, counts them, one-by-one. This enables very high sensitivity for photon detection. At the same time it allows resolution of very short (and dim) optical events (on the order of 10's of ps). Such capabilities will enable new types of biological imaging applications. This project supports the multidisciplinary training of graduate and undergraduate students and a significant K-12 outreach effort.