Ultrastructural Study of Microphysiological Systems of the Tumor Microenvironment

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Abstract
The importance of studying the ultrastructure is underwritten by decades of research. Ultrastructural features help to understand pathological processes or inform disease diagnosis. However, ultrastructural studies in the promising cancer‐on‐a‐chip models are practically nonexistent because of the complexity of sample preparation for electron microscopy techniques, which is particularly aggravated with these miniaturized models. Our aim was to study ultrastructural features of microphysiological systems (MPS) of the tumor microenvironment consisting of 3D multicellular tumor structures that were grown in hydrogel‐based cancer‐on‐a‐chip models. To this end, we selected two different MPS from our lab as examples and devised a sample preparation technique for their observation under dual‐beam focused ion beam scanning electron microscopy (FIB‐SEM) and transmission electron microscopy (TEM). The proposed methodology allowed high‐resolution visualization of both external and internal organization of 3D multicellular tumor structures, including cell–matrix interactions, cell–cell junctions, spheroid–spheroid contacts, matrix deposition, and extracellular vesicle‐mediated intercellular communication. This study demonstrates the feasibility of using advanced electron microscopy techniques to observe ultrastructural features of miniaturized cancer models, thus revealing a new dimension in the use of these models to study tumor processes and find new therapeutic targets.

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