ArticleNature communications2022
Waffle Method: A general and flexible approach for improving throughput in FIB-milling.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed.
- Structural plasticity of mouse intestinal microvilli revealed by tissue-level cryo-ET.Biophysics reports · 2026Article
- Article
- Beyond structure: spectroscopic imaging in cryogenic electron microscopy.Current opinion in structural biology · 2026Review
- Hypoxia rescues complex 1-associated disease caused by proteostatic defects.Nature metabolism · 2026Article
- Integrated fluorescence light microscopy-guided cryo-focused ion beam-milling for in situ montage cryo-ET.Nature protocols · 2026Review
- Subcellular chemical mapping using correlated cryogenic electron and mass spectrometry imaging.Nature methods · 2026Article
- Characterization Standard forbioRxiv : the preprint server for biology · 2026Article
- In situ structure of the human gap junction.Science advances · 2026Article
- Electron microscopy-based three-dimensional subcellular imaging of plant male gametophyte.Journal of integrative plant biology · 2026Review
- A robust workflow for 3D imaging of human mitochondria using cryo-electron tomography.bioRxiv : the preprint server for biology · 2026Article
- Cryo-FIB-enabled 3D imaging of biological specimens.Applied microscopy · 2026Review
- Radiation-dose effects in correlative X-ray/cryo-electron microscopy of frozen-hydrated biological samples.Acta crystallographica. Section D, Structural biology · 2026Article
- Cryogenic electron tomography by the numbers: Charting underexplored lineages in structural cell biology.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Eg5 activity and density-driven bundling organize the human metaphase mitotic spindle independently of spindle bipolarity.bioRxiv : the preprint server for biology · 2026Article
- Visualizing Postsynaptic Density in Excitatory Synapses with Electron Tomography.Advances in neurobiology · 2026Review
- Water freeze-drying for high-resolution SEM: an accessible strategy for capturing native microorganism morphology without dedicated rapid-freezing systems.Frontiers in microbiology · 2026Article
- Multiscale structure of chromatin condensates explains phase separation and material properties.Science (New York, N.Y.) · 2025Article
- Dimeric gold nanoparticles enable multiplexed labeling in cryoelectron tomography.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Strategies for studying discrete heterogeneity in situ using cryo-electron tomography.Current opinion in structural biology · 2025Review
- Demonstrating soft X-ray tomography in the lab for correlative cryogenic biological imaging using X-rays and light microscopy.Scientific reports · 2025Article
10 more citing papers are in PubMed but not listed here.
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11 authors.
Funding
Abstract
Cryo-FIB/SEM combined with cryo-ET has emerged from within the field of cryo-EM as the method for obtaining the highest resolution structural information of complex biological samples in-situ in native and non-native environments. However, challenges remain in conventional cryo-FIB/SEM workflows, including milling thick specimens with vitrification issues, specimens with preferred orientation, low-throughput when milling small and/or low concentration specimens, and specimens that distribute poorly across grid squares. Here we present a general approach called the 'Waffle Method' which leverages high-pressure freezing to address these challenges. We illustrate the mitigation of these challenges by applying the Waffle Method and cryo-ET to reveal the macrostructure of the polar tube in microsporidian spores in multiple complementary orientations, which was previously not possible due to preferred orientation. We demonstrate the broadness of the Waffle Method by applying it to three additional cellular samples and a single particle sample using a variety of cryo-FIB-milling hardware, with manual and automated approaches. We also present a unique and critical stress-relief gap designed specifically for waffled lamellae. We propose the Waffle Method as a way to achieve many advantages of cryo-liftout on the specimen grid while avoiding the long, challenging, and technically-demanding process required for cryo-liftout.
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