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  • Primer
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Holotomography

Nature Reviews Methods Primers volume 4, Article number: 51 (2024) Cite this article

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Abstract

Holotomography (HT) represents a 3D, label-free optical imaging methodology that leverages refractive index as an inherent quantitative contrast for imaging. This technique has recently seen notable advancements, creating novel opportunities for the comprehensive visualization and analysis of living cells and their subcellular organelles. It has manifested wide-ranging applications spanning cell biology, biophysics, microbiology and biotechnology, substantiating its vast potential. In this Primer, we elucidate the foundational physical principles underpinning HT, detailing its experimental implementations and providing case studies of representative research employing this methodology. We also venture into interdisciplinary territories, exploring how HT harmonizes with emergent technologies, such as regenerative medicine, 3D biology and organoid-based drug discovery and screening. Looking ahead, we engage in a prospective analysis of potential future trajectories for HT, discussing innovation-focused initiatives that may further elevate this field. We also propose possible future applications of HT, identifying opportunities for its integration into diverse realms of scientific research and technological development.

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Fig. 1: An overview of holotomography and diverse implementations.
Fig. 2: General landscape of contemporary holotomography applications.
Fig. 3: Optical measurement and numerical reconstruction in holotomography.
Fig. 4: Label-free 3D imaging of diverse live cells.
Fig. 5: Applications of holotomography in microbiology.
Fig. 6: Applications of holotomography in the study of organoids.
Fig. 7: Typical imaging artefacts in holotomography.
Fig. 8: Artificial-intelligence-assisted holotomography for investigating the organization of a 3D tissue.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (2015R1A3A2066550, 2022M3H4A1A02074314), Institute for Information and Communications Technology Planning and Evaluation (IITP; 2021-0-00745) grant funded by the Ministry of Science and ICT, Republic of Korea, the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (HI21C0977, HR22C1605), the Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korea government (the Ministry of Science and ICT and the Ministry of Health & Welfare) (21A0101L0), Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Republic of Korea (RS-2023-00241278).

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Authors and Affiliations

  1. Department of Physics, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

    Geon Kim, Herve Hugonnet, Chungha Lee & YongKeun Park

  2. KAIST Institute for Health Science and Technology, Daejeon, Republic of Korea

    Geon Kim, Herve Hugonnet, Chungha Lee & YongKeun Park

  3. Max Planck Institute for the Science of Light, Erlangen, Germany

    Kyoohyun Kim & Jochen Guck

  4. Max-Planck-Zentrum für Physik und Medizin, Erlangen, Germany

    Kyoohyun Kim & Jochen Guck

  5. Gwangju Centre, Korea Basic Science Institute, Gwangju, Republic of Korea

    Jae-Hyuk Lee & Seongsoo Lee

  6. Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland

    Sung Sik Lee

  7. Scientific Center for Optical and Electron Microscopy, ETH Zurich, Zurich, Switzerland

    Sung Sik Lee & Gabor Csucs

  8. Center for Genome Engineering, Institute for Basic Science, Daejeon, Republic of Korea

    Jeongmin Ha & Bon-Kyoung Koo

  9. Department of Biological Sciences, KAIST, Daejeon, Republic of Korea

    Hoewon Park & Ki-Jun Yoon

  10. Department of Mechanical Engineering, Seoul National University, Seoul, Republic of Korea

    Yongdae Shin

  11. Department of Biology, University of York, York, UK

    Ian Hitchcock, Luke Mackinder & Peter O’Toole

  12. Department of Obstetrics and Gynecology, Fertility Centre of CHA Bundang Medical Centre, CHA University School of Medicine, Seongnam, Republic of Korea

    Ji Hyang Kim

  13. Mayo Clinic Florida, Jacksonville, FL, USA

    Tae Hyun Hwang

  14. Department of Systems Biotechnology, Chung-Ang University, Anseong-si, Gyeonggi-do, Republic of Korea

    Seongsoo Lee

  15. Tomocube Inc., Daejeon, Republic of Korea

    YongKeun Park

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  1. Geon Kim
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Contributions

Introduction (Y.K.P. and G.K.); Experimentation (Y.K.P. and H.H.); Results (Y.K.P., G.K., H.H., K.K., J.-H.L., S.S.L., J.H., C.L., H.P., K.-J.Y., Y.S., G.C., I.H., L.M., J.H.K., T.H.H., S.L., P.O., B.-K.K. and J.G.); Applications (Y.K.P., G.K., K.K., J.-H.L., S.S.L., J.H., C.L., H.P., K.-J.Y., Y.S., G.C., I.H., L.M., J.H.K., T.H.H., S.L., P.O., B.-K.K. and J.G.); Reproducibility and data deposition (Y.K.P. and G.K.); Limitations and optimizations (Y.K.P. and H.H.); Outlook (Y.K.P. and G.K.); overview of the Primer (Y.K.P.).

Corresponding author

Correspondence to YongKeun Park.

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Competing interests

H.H., K.K. and Y.K.P. have financial interests in Tomocube Inc., a company that commercializes holotomography instruments. The other authors declare no competing interests.

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Nature Reviews Methods Primers thanks Kevin Tsia, Thomas Zangle and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Biomolecular condensates

Membrane-less assemblies of proteins and nucleic acids, characterized by inhomogeneous, non-stoichiometric molecular arrangements, encompassing structures such as nucleoli, nuclear speckles, heterochromatin, cytoplasmic stress granules, germ granules and others.

Coherent HT

A holotomography (HT) technique that uses a coherent light source such as a laser for angle-scanned illumination.

Coherent light illumination

Light with well-defined propagation angle that can be described by a plane wave.

Fourier diffraction theorem

A theorem that states that the Fourier transform of the aperture function of an object is proportional to the far-field diffraction pattern, linking the spatial domain with the frequency domain and enabling the reconstruction of 3D refractive index tomogram via the analysis inverse wave scattering and propagation.

Kramers–Kronig relations

A fundamental principle in physics that describes the relationship between the real and imaginary parts of a complex function, used in holotomography to retrieve phase information from intensity measurements.

Lipid droplets

Subcellular organelles primarily involved in the storage and regulation of lipids, serving as energy reservoirs and playing a role in cellular lipid metabolism and signalling pathways within cells.

Mach–Zehnder interferometric techniques

Optical techniques that split a laser beam into two distinct paths, which are then recombined to form interference patterns, providing an optical field with detailed amplitude and phase information.

Missing cone problem

The issue in tomographic imaging in which certain angles cannot be sampled owing to geometric or physical constraints, resulting in a loss of information and potentially leading to inaccuracies in the reconstructed images.

Non-negativity

In regularization algorithms addressing the missing cone problem, the non-negativity is a constraint applied during reconstruction that ensures all predicted values for the missing data are greater than or equal to zero.

Refractive index

A dimensionless number given by the ratio of speed of light in a medium to that in vacuum.

Spatially low-coherence HT

A holotomography (HT) technique that exploits spatially low-coherent light source for illumination and axially scans the sample.

Temporally low-coherence HT

A holotomography (HT) technique that exploits temporally low-coherent light sources such as light-emitting diode for angle-scanned illumination.

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Kim, G., Hugonnet, H., Kim, K. et al. Holotomography. Nat Rev Methods Primers 4, 51 (2024). https://doi.org/10.1038/s43586-024-00327-1

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  • DOI: https://doi.org/10.1038/s43586-024-00327-1

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