Award Abstract # 1902904
Compressed Sub-Aperture Super-Resolution Microscopy

NSF Org: CBET
Division of Chemical, Bioengineering, Environmental, and Transport Systems
Recipient: DUKE UNIVERSITY
Initial Amendment Date: March 26, 2019
Latest Amendment Date: March 26, 2019
Award Number: 1902904
Award Instrument: Standard Grant
Program Manager: Steve Zehnder
szehnder@nsf.gov
 (703)292-7014
CBET
 Division of Chemical, Bioengineering, Environmental, and Transport Systems
ENG
 Directorate for Engineering
Start Date: July 1, 2019
End Date: June 30, 2022 (Estimated)
Total Intended Award Amount: $485,352.00
Total Awarded Amount to Date: $485,352.00
Funds Obligated to Date: FY 2019 = $485,352.00
History of Investigator:
  • Joseph Izatt (Principal Investigator)
    jizatt@duke.edu
  • Sina Farsiu (Co-Principal Investigator)
Recipient Sponsored Research Office: Duke University
2200 W MAIN ST
DURHAM
NC  US  27705-4640
(919)684-3030
Sponsor Congressional District: 04
Primary Place of Performance: Duke University Biomedical Engineering
101 Science Drive
Durham
NC  US  27708-0281
Primary Place of Performance
Congressional District:
04
Unique Entity Identifier (UEI): TP7EK8DZV6N5
Parent UEI:
NSF Program(s): BioP-Biophotonics
Primary Program Source: 01001920DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 7236
Program Element Code(s): 723600
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.041

ABSTRACT

The investigators propose to take advantage of very recent developments in the field of optical microscopy and engineer a novel reflectance mode imaging instrument integrated with compressed sensing capability enabling the development of a system that can be used for super-resolved imaging of the eye and other biological targets. Scanning laser ophthalmoscopy (SLO) is a mainstay of diagnostic imaging of the retina. It is based on confocal laser scanning microscopy and has recently been combined with adaptive optics technology to provide sharper images of the retina.


The project will 1) Develop the concepts and technology necessary to use optical reassignment reflectance confocal microscopy. This will lead to scanning laser ophthalmoscope (ORSLO) for super-resolved retinal reflectance imaging. 2) Enhance ORSLO by developing a novel optical architecture based on digital micro-mirror technology. This will permit the visualization of retinal photoreceptor cells and vasculature. 3) Implement reflectance image scanning microscopy (ISM) with a compressed sensing technique into an adaptive optics scanning laser ophthalmoscope (AOSLO). This will enable super-resolved adaptive optical imaging.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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Qian, Ruobing and Zhou, Kevin_C and Zhang, Jingkai and Viehland, Christian and Dhalla, Al-Hafeez and Izatt, Joseph_A "Video-rate high-precision time-frequency multiplexed 3D coherent ranging" Nature Communications , v.13 , 2022 https://doi.org/10.1038/s41467-022-29177-9 Citation Details
Zhang, Jingkai and Qian, Ruobing and Zhou, Kevin C. and Viehland, Christian and Draelos, Mark and Dhalla, Al-Hafeez and Izatt, Joseph A. "Real-time wide-field spectral-scanning FMCW coherent 3D imaging and velocimetry" Optics Letters , v.47 , 2022 https://doi.org/10.1364/OL.463965 Citation Details
Zhou, Kevin_C and Dhalla, Al-Hafeez and McNabb, Ryan_P and Qian, Ruobing and Farsiu, Sina and Izatt, Joseph_A "High-speed multiview imaging approaching 4pi steradians using conic section mirrors: theoretical and practical considerations" Journal of the Optical Society of America A , v.38 , 2021 https://doi.org/10.1364/JOSAA.440592 Citation Details
Zhou, Kevin_C and McNabb, Ryan_P and Qian, Ruobing and Degan, Simone and Dhalla, Al-Hafeez and Farsiu, Sina and Izatt, Joseph_A "Computational 3D microscopy with optical coherence refraction tomography" Optica , v.9 , 2022 https://doi.org/10.1364/OPTICA.454860 Citation Details
Zhou, Kevin_C and Qian, Ruobing and Dhalla, Al-Hafeez and Farsiu, Sina and Izatt, Joseph_A "Unified k-space theory of optical coherence tomography" Advances in Optics and Photonics , v.13 , 2021 https://doi.org/10.1364/AOP.417102 Citation Details
Zhou, Kevin_C and Qian, Ruobing and Farsiu, Sina and Izatt, Joseph_A "Spectroscopic optical coherence refraction tomography" Optics Letters , v.45 , 2020 https://doi.org/10.1364/OL.389703 Citation Details

PROJECT OUTCOMES REPORT

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

The major goals of this project were to develop novel biophotonic technologies for robust, super-resolved compressed sub- and para-aperture confocal imaging for potential applications in the life sciences. Confocal microscopy is one of the original “super-resolution” microscopy techniques which has been a mainstay of biological imaging, both in benchtop applications such as cell biology and pathology as well as in clinical applications such as scanning laser ophthalmoscopy. However, most routine uses of confocal microscopy trade off nearly all of the potential resolution improvement to gain acceptable signal-to noise ratio. Image scanning microscopy is a recently introduced point-scanning super-resolution technology technique which allows for the full theoretical lateral resolution improvement of confocal microscopy without any loss of signal-to-noise ratio. The goals of this project were accomplished by introducing several novel technologies designed to extend the benefits of image scanning microscopy to high-speed reflectance imaging, with direct relevance to future applications in in vivo clinical and biological imaging.

The first objective of the project was to implement optical reassignment in a reflectance confocal microscope, implemented as a scanning laser ophthalmoscope. This required the development of new scanning systems with speeds approximately 10x greater than those used previously, and was achieved by utilizing a novel double-sided resonant scanner, thus rescanning the beam at a high rate. In the second objective, we developed a novel optical architecture based on digital micro-mirror technology to implement a fast, flexible, and user-configurable version of popular split detector and offset pinhole microscopy techniques, to enhance visualization of retinal photoreceptor cells and vasculature. In the third objective, we extended the split detector system to high-speed adaptive optic imaging using a novel compressive sensing approach. Accomplishment of the last objective will enable robust super-resolved adaptive-optic scanning laser ophthalmology images of photoreceptors and other living biological samples. Additionally, this objective comprised a high-speed modular super-resolution detection technology capable of integration with many confocal microscope designs.

Early accomplishment of the proposed objectives of the project allowed us to make significant unanticipated progress on other closely related biophotonic imaging technologies. Optical coherence refraction tomography (OCRT) is a technology we previously developed which overcomes the anisotropy inherent to traditional optical coherence tomography (OCT) by computationally reconstructing an image with isotropic resolution from multiple OCT images, each with superior axial to lateral resolution, taken from multiple angles. We extended OCRT to spectroscopic OCRT (SOCRT), in which we used SOCT images from multiple angles to reconstruct a spectroscopic image with isotropic spatial resolution limited by the OCT lateral resolution. Many forms of coherent imaging, including on- and off-axis confocal imaging as developed in this project, have their theoretical basis in the Fourier diffraction theorem, which relates the coherent interaction between a sample and plane wave to the Ewald sphere in the 3D k-space representation of the sample. We developed a unified 3D k-space formalism which allowed for an intuitive explanation of nearly every fundamental physical phenomenon or property of OCT, and also explicitly unified the concepts behind diffraction tomography, confocal microscopy, and OCT. Following our work extending the concept of optical coherence refraction tomography (OCRT) to spectroscopic imaging, we completed significant additional developments to extend OCRT to a fully 3D coherent microscopic imaging modality. This required development of very wide-field multi-view imaging with sufficient speed to eventually be capable of imaging living samples, which we accomplished using a novel arrangement of galvanometer scanners and a parabolic mirror. Finally, we developed a novel scheme for very high speed coherent LiDAR by extending concepts well known from confocal microscopy and OCT for time-frequency multiplexed 3D imaging.

The broader significance of the technical objectives is to extend modern super-resolution imaging techniques from their current focus on nanometer scale imaging of specially prepared and labelled samples to broader applications in biology and clinical laboratory diagnostics. The project also supported the education and scientific training of engineering students from Duke and elsewhere at multiple levels. The project comprised significant parts of the dissertation research of three Duke Biomedical Engineering Ph.D. students. The project also supported productive research experiences for two outstanding Duke undergraduates as independent study projects. Most of these research experiences resulting in inclusion of these students as authors on peer-reviewd publications and on presentations at national scientific conferences, and solidified their plans for continuing with STEM related careers.

 

 


Last Modified: 02/02/2023
Modified by: Joseph A Izatt

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