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Open research questions in Advanced Electron Microscopy Techniques and Applications

86 unresolved questions extracted from the limitations and future-work sections of 220 Advanced Electron Microscopy Techniques and Applications papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The study is based on simulations, - The analysis is limited to the influence of key instrumental parameters, - The study does not consider the effects of other instrumental parameters or sample properties

    On the Accuracy of Atomic-Resolution Electrostatic Measurements in 2D Materials · 2026 · DOI

  • Further research is needed to investigate the effects of other instrumental parameters on DPC-STEM measurements, - The development of more robust methodologies to ensure accurate analyses is necessary

    On the Accuracy of Atomic-Resolution Electrostatic Measurements in 2D Materials · 2026 · DOI

  • This delicate tradeoff relies on their interior diffusion pathways, which are difficult to fully characterize and remain poorly understood.

    Interior Morphology and Pore Structure in High Surface Area Carbon Catalyst Supports · 2025 · DOI

  • Despite being a crucial parameter directly affecting attainable resolution, optimal lamella thickness has not been systematically investigated nor the extent of structural damage caused by gallium ions used for FIB milling.

    Thinner is not always better: Optimizing cryo-lamellae for subtomogram averaging · 2024 · DOI

  • Advances in attosecond spectroscopy have enabled tracing and controlling the electron motion dynamics in matter, although they have yielded insufficient information about the electron dynamic in the space domain.

    Attosecond electron microscopy and diffraction · 2024 · DOI

  • The direct application of state-space models to anisotropic EM data has been limited. Existing methods have insufficient global modeling capabilities or local feature extraction capabilities. There is a need for a novel network that adapts state-space models to anisotropic 3D EM images.

    MambaSSM: efficient segmentation of brain structures in anisotropic 3D EM images via state-space models · 2026 · DOI

  • The need for high thermal and mechanical stability in cryogenic fluorescence microscopy. The challenge of introducing super-resolution fluorescence methods in the field of cryogenic fluorescence microscopy. The difficulty of performing cryo-SR-FM due to vibrations or other movements in the setup.

    On-lamella super-resolution cryo-CLEM for cryo-ET enabled by vacuum-free ultra-stable cryogenic fluorescence microscopy · 2026 · DOI

  • The need for pumps and other sources of variations in the cooling rate can introduce artefacts and lead to misinterpretation. Vibrations or other movements in the setup, especially those occurring on comparable timescales to the molecular dynamics, can introduce artefacts and lead to misinterpretation.

    On-lamella super-resolution cryo-CLEM for cryo-ET enabled by vacuum-free ultra-stable cryogenic fluorescence microscopy · 2026 · DOI

  • Improving cryoFIFA for small particles using image denoising and tight masks. Exploring the potential of cryoFIFA for future applications in Cryo-EM analysis. Developing new deep learning-based methods for Cryo-EM reconstruction.

    CryoFIFA: deep curriculum learning for cryo-EM fine and fast ab-initio reconstruction · 2026 · DOI

  • Traditional Cryo-EM reconstruction methods are based on maximum likelihood approaches, which can be time-consuming and limited in resolution. Deep learning-based methods have begun to emerge, but there is still a need for improved methods.

    CryoFIFA: deep curriculum learning for cryo-EM fine and fast ab-initio reconstruction · 2026 · DOI

  • Manual LN2 replenishment every 10-12 hours represents a logistical burden and safety risk. Temperature fluctuations and sample instability can occur during manual refilling. The need for a stable and uninterrupted cryogenic cooling system.

    Automated LN2 refill device for uninterrupted cryoFIB-SEM operations. · 2026 · DOI

  • The need for a constant supply of LN2 is a limitation for long-term cryoFIB-SEM operations. Commercially available systems can only provide ~4-5 days of continuous operations.

    Automated LN2 refill device for uninterrupted cryoFIB-SEM operations. · 2026 · DOI

  • Further development of the BPC method to improve its accuracy and robustness. Application of the BPC method to other types of electron detectors. Investigation of the BPC method's potential in improving crystallography metrics and structure solutions.

    Robust electron counting for direct electron detectors with the Back-propagation counting method · 2026 · DOI

  • The method may not perform well with very noisy or low-resolution cryo-EM density maps, - The method requires a significant amount of computational resources and expertise, - The method is limited to medium-resolution cryo-EM density maps, - Deep-learning methods may require larger labelled datasets and extensive tuning

    A Novel Machine-Learning Based Method for Resolving Secondary Structure Topology in Medium-Resolution Cryo-EM Density Maps · 2026 · DOI

  • Exploring the application of deep-learning methods for map segmentation, SSE annotation, and backbone tracing, - Investigating the use of other classification algorithms and feature spaces, - Developing methods to improve the accuracy of SSE correspondence in very noisy or low-resolution cryo-EM density maps

    A Novel Machine-Learning Based Method for Resolving Secondary Structure Topology in Medium-Resolution Cryo-EM Density Maps · 2026 · DOI

  • The existence of the quantum offset in velocity imaging-based electron spectrometry is unclear. The accuracy of velocity imaging-based electron spectrometry measurements is uncertain.

    Evaluation of quantum offset in velocity imaging-based electron spectrometry · 2026 · DOI

  • Low signal-to-noise ratio in scanning transmission electron microscopy. Image artifacts introduced by simple defocus. The need to optimize the signal-to-noise ratio in low-dose conditions.

    Enhancing Dose Efficiency of Optimum Bright‐Field Scanning Transmission Electron Microscopy Using a Phase‐Shifted Electron Probe · 2026 · DOI

  • The limitations of cryo-EM in battery research, such as the risk of frost contamination. The need for a review of the benefits and limitations of cryo-EM in battery research.

    Freeze it or leave it? Evaluating the role of cryo-electron microscopy in battery research · 2026 · DOI

  • Manual particle picking is inefficient and inadequate for the demands of reconstruction - Conventional denoising methods decrease noise but frequently overlook high-level semantic information

    CryoPromptSeg: Prompt-guided Segmentation with Integrated Denoising for Cryo-EM Particle Picking · 2026 · DOI

  • Future research will focus on expanding the high-quality and diverse cryo-EM annotated dataset to improve the model’s generalization capability. Future work will explore integrating a classifier into SAM to increase particle picking accuracy. However, the model’s performance is limited by the scale and diversity of the training data.

    CryoPromptSeg: Prompt-guided Segmentation with Integrated Denoising for Cryo-EM Particle Picking · 2026 · DOI

  • The risk of structural hallucination remains a critical concern for data-driven methods. The risk of overfitting to ideal secondary structures remains a concern.

    EMReady2: improvement of cryo-EM and cryo-ET maps by local quality-aware deep learning with Mamba · 2026 · DOI

  • To better leverage AreTomo3's comprehensive corrections for downstream tasks. To extend AreTomoLive to iteratively refine tomographic alignment. To define a common deformation model to bridge the gap between AreTomo3 and RELION-4/5 STA workflows.

    AreTomoLive: automated reconstruction of comprehensively corrected and denoised cryo-electron tomograms in real time and at high throughput · 2026 · DOI

  • The lack of integrated pipelines for cryo-electron tomography and subtomogram averaging. The need for high-throughput data processing to realize the full potential of cryo-electron tomography and subtomogram averaging.

    AreTomoLive: automated reconstruction of comprehensively corrected and denoised cryo-electron tomograms in real time and at high throughput · 2026 · DOI

  • The use of the cryo-EM-FIB-SIMS workflow for studying the uptake and storage of other chemical pollutants by environmental bacteria. The exploration of the use of the workflow for subcellular localization of molecules in eukaryotic cells.

    Subcellular chemical mapping using correlated cryogenic electron and mass spectrometry imaging · 2026 · DOI

  • The lack of a direct way to assign chemical identity to densities observed in electron micrographs. The need for a correlative workflow combining cryo-EM and MS for integrated spatiochemical analysis of biological samples.

    Subcellular chemical mapping using correlated cryogenic electron and mass spectrometry imaging · 2026 · DOI

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86 open questions have been extracted from the limitations and future-work passages of 220 Advanced Electron Microscopy Techniques and Applications papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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