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  • Received: July. 18, 2018

    Accepted: Oct. 17, 2018

    Posted: Mar. 14, 2019

    Published Online: Feb. 18, 2019

    The Author Email: Fei Peng (, Hsiai Tzung K. (

    DOI: 10.1117/1.AP.1.1.016002

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    Peng Fei, Jun Nie, Juhyun Lee, Yichen Ding, Shuoran Li, Hao Zhang, Masaya Hagiwara, Tingting Yu, Tatiana Segura, Chih-Ming Ho, Dan Zhu, Tzung K. Hsiai. Subvoxel light-sheet microscopy for high-resolution high-throughput volumetric imaging of large biomedical specimens[J]. Advanced Photonics, 2019, 1(1):016002

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Advanced Photonics, Vol. 1, Issue 1, pp.016002 (2019)

Subvoxel light-sheet microscopy for high-resolution high-throughput volumetric imaging of large biomedical specimens

Peng Fei1,2,*, Jun Nie1, Juhyun Lee3,4, Yichen Ding3,5, Shuoran Li6, Hao Zhang1, Masaya Hagiwara7,8, Tingting Yu2, Tatiana Segura6, Chih-Ming Ho8, Dan Zhu2, and Tzung K. Hsiai3,5,*

Author Affiliations

  • 1Huazhong University of Science and Technology, School of Optical and Electronic Information, Wuhan, China
  • 2Huazhong University of Science and Technology, Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Wuhan, China
  • 3University of California, Los Angeles, Department of Bioengineering, Los Angeles, California, United States
  • 4University of Texas at Arlington, Joint Department of Bioengineering of UT Arlington/UT Southwestern, Arlington, Texas, United States
  • 5University of California, Los Angeles, School of Medicine, Los Angeles, California, United States
  • 6University of California, Los Angeles, Chemical and Biomolecular Engineering Department, Los Angeles, California, United States
  • 7Osaka Prefecture University, Nanoscience and Nanotechnology Research Center, Research Organization for the 21st Century, Osaka, Japan
  • 8University of California, Los Angeles, Mechanical and Aerospace Engineering Department, Los Angeles, California, United States


A key challenge when imaging whole biomedical specimens is how to quickly obtain massive cellular information over a large field of view (FOV). We report a subvoxel light-sheet microscopy (SLSM) method enabling high-throughput volumetric imaging of mesoscale specimens at cellular resolution. A nonaxial, continuous scanning strategy is developed to rapidly acquire a stack of large-FOV images with three-dimensional (3-D) nanoscale shifts encoded. Then, by adopting a subvoxel-resolving procedure, the SLSM method models these low-resolution, cross-correlated images in the spatial domain and can iteratively recover a 3-D image with improved resolution throughout the sample. This technique can surpass the optical limit of a conventional light-sheet microscope by more than three times, with high acquisition speeds of gigavoxels per minute. By fast reconstruction of 3-D cultured cells, intact organs, and live embryos, SLSM method presents a convenient way to circumvent the trade-off between mapping large-scale tissue (>100  mm3) and observing single cell (∼1-μm resolution). It also eliminates the need of complicated mechanical stitching or modulated illumination, using a simple light-sheet setup and fast graphics processing unit-based computation to achieve high-throughput, high-resolution 3-D microscopy, which could be tailored for a wide range of biomedical applications in pathology, histology, neuroscience, etc.