Abstract
Fluorescence live-cell imaging allows for continuous interrogation of cellular behaviors, and the recent development of portable live-cell imaging platforms has rapidly transformed conventional schemes with high adaptability, cost-effective functionalities and easy accessibility to cell-based assays. However, broader applications remain restrictive due to compatibility with conventional cell culture workflow and biochemical sensors, accessibility to up-right physiological imaging, or parallelization of data acquisition. Here, we introduce miniaturized modular-array fluorescence microscopy (MAM) for compact live-cell imaging in flexible formats. We advance the current miniscopy technology to devise an up-right modular architecture, each combining a gradient-index (GRIN) objective and individually-addressed illumination and acquisition components. Parallelization of an array of such modular devices allows for multi-site data acquisition in situ using conventional off-the-shelf cell chambers. Compared with existing methods, the device offers a high fluorescence sensitivity and efficiency, exquisite spatiotemporal resolution (∼3 µm and up to 60 Hz), a configuration compatible with conventional cell culture assays and physiological imaging, and an effective parallelization of data acquisition. The system has been demonstrated using various calibration and biological samples and experimental conditions, representing a promising solution to time-lapse in situ single-cell imaging and analysis.
Highlights
Visualizing diverse anatomical and functional behaviors of single cells provides critical insights into the fundamentals of living organisms
We introduce miniaturized modular-array microscopy (MAM) for compact portable fluorescence live-cell imaging in flexible formats
Individual modular microscopes were threaded onto a 3D-printed mounting cover that environmentally encloses the cell culture chamber (e.g. a 12-well plate was utilized in this work as shown in Fig. 1(b)) and positions the microscopes in a user-defined array pattern according to the specimens of interest
Summary
Visualizing diverse anatomical and functional behaviors of single cells provides critical insights into the fundamentals of living organisms. The rapid development of time-lapse imaging techniques permits uninterrupted and noninvasive interrogation of cells with exquisite spatiotemporal contextual details [1–3]. These techniques have greatly enabled recent studies on various dynamic cellular mechanisms and behaviors such as cell proliferation [4], morphology evolution [5], cell-cell interaction [6], and cell interaction with microenvironment [7]. The methods can induce cell stress due to environmental alterations from native physiological conditions, detrimental to many sensitive cell types and impeding long-term observation [10] Many of these high-end instruments lack the flexibility to adapt to diverse project-specific requirements and become impractical for those chip-based biological systems incompatible with conventional microscopy [11–13]
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