A telescopic microscope equipped with a quanta image sensor for live-cell bioluminescence imaging

Bioluminescence is an attractive alternative to fluorescence for live-cell imaging; however, its low intensity has prevented widespread adoption. Specialized microscopes compensate by sacrificing spatial resolution, field of view and dynamic range-constraints imposed by the highest-sensitivity camera to date: the electron-multiplying charge-coupled device. Recently, quanta image sensor (QIS) technology has emerged for low-light imaging. Here, we show that a commercial QIS camera has exceptional sensitivity; however, its sensor dimensions necessitate a microscope designed to maximize its properties. We introduce a Keplerian-telescope-inspired microscope setup that, with the QIS, results in modestly improved signal-to-noise ratios at substantially higher spatial resolution, field of view and dynamic range, relative to the state of the art. The telescopic design also confers modularity, enabling multimodal imaging with epifluorescence. The 'QIScope' makes bioluminescence a viable tool for technically challenging live-cell experiments such as monitoring intracellular and extracellular vesicles simultaneously and the dynamics of low-abundance proteins.