Integrated Array Tomography: Development and Applications of a Workflow for 3D Correlative Light and Electron Microscopy

Research output: ThesisDissertation (TU Delft)

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Multi-modal imaging techniques have become essential for better understanding fundamental questions in cell biology such as disease progression. While individual microscopy methods have rapidly advanced in recent years, the information content of any one imaging technique is limited to the type of contrast that particular technique is sensitive to. By tagging particular biomolecules with a fluorescent protein, fluorescence microscopy (FM), for example, can relay dynamic information about the distribution of these biomolecules in their cellular environment. It struggles, however, to convey information regarding the structure of the organelles that might contain these biomolecules or the surroundings of their cellular environment. Electron microscopy (EM), on the other hand, can provide detailed layouts of cellular structure by staining membranes with heavy metals. Thus, by correlating these modalities (correlative light and electron microscopy, CLEM), a more holistic understanding of the relationship between structure and function at the (sub-)cellular level can be achieved. Array tomography (AT) is a technique combining FM and EM for volumetric imaging, first introduced in 2007 for studying brain tissue. The technique has since expanded, but the approach has largely remained the same. Biological material is cut into a series of ultrathin (∼100 nm) sections (an array) and prepared for sequential FM and EM imaging by applying a series of immunofluorescence and heavy metal stains. Correlative images of the serial sections are then computationally aligned to reconstruct the 3D structure (tomography). Compared to other volumetric imaging techniques in the life sciences, AT offers the ability to correlate structure and function at high resolution across large fields of view. Moreover, it enables high axial resolutionfor both EM and FM as determined by the section thickness...
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Delft University of Technology
  • Hoogenboom, J.P., Supervisor
  • Carroll, E.C.M., Advisor
Thesis sponsors
Award date4 Oct 2022
Print ISBNs978-94-6366-603-9
Publication statusPublished - 6 Sep 2022


This project was financially supported by the Building Blocks of Life (BBoL) program of the Netherlands Organization for Scientific Research (NWO), with cash and in-kind contributions from Delmic B.V. and Genentech.


  • correlative light and electron microscopy
  • volume electron microscopy
  • array tomography


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