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Unrestricted super-resolution imaging deep in tissues through scattering immune spatial frequency modulated imaging

Award Number: R21EB025389
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Optical microscopes are routinely employed for imaging live cell dynamics. Until recently, conventional optical microscopes lacked the ability to resolve spatial features significantly smaller than the wavelength of light. This kept the structure and dynamics of a vast array of biological processes hidden. Although electron microscopes provide sub-nm spatial resolution images, they are incapable of monitoring live biological dynamics. Understanding the spatial organization and temporal dynamics of nanoscale molecular assemblies is critical to developing a comprehensive understanding of biology. In recent years, sub-diffraction limited microscopes, known as super-resolution (SR) microscopes, have enabled routine live cell imaging at spatial resolutions <50nm. These new tools produced discoveries that challenged multiple paradigms of intracellular processes. Because optical scattering severely distorts SR methods, the SR imaging revolution has failed to be translated deep into scattering tissue. Yet it is well known that the behavior of cells in tissues and tumors deviates strongly from the behavior of 2D cell cultures. Our long-term goal is to develop a new optical SR microscope capable of unlimited super-resolution imaging deep in live animal tissues. This transformational tool will enable discoveries of disease mechanisms that will facilitate the discovery of new treatment paradigms. The objective of this grant is to demonstrate the feasibility of a new approach to optical SR imaging with spatial frequency modulated imaging; this will open the ability for deep-tissue imaging with sub-diffraction limited resolution. The central hypothesis is that spatial frequency modulated SR imaging will exhibit robustness to imaging both for the spatial-temporally modulated illumination light and the collected light used for image formation. Our rationale is that a broad illumination bandwidth will homogenize speckle that would otherwise be accumulated by the spatially structured illumination light. This homogenization prevents the speckle from distorting the image formation process. Scattering of the fluorescent light emitted from the object does not impact the quality of the image. Our specific aims will test the following hypotheses: (Aim1) SR image formation with <50 nm spatial resolution with spatial frequency modulated illumination, and (Aim 2) the suppression of speckle in spatial frequency modulated image formation with broad bandwidth illumination in brain slices. Upon conclusion, we will understand the principles of spatial frequency modulated imaging for imaging deep inside of biological tissues. This contribution is significant since it will establish a new optical microscope technique that will bring the super-resolution imaging revolution deep inside live animal models, opening the path for new discoveries of disease mechanisms. Such discoveries will likely drive an improvement in our understanding of biology and disease, as well as drive the discovery of new diagnostic signatures and treatment targets. The proposed research is innovative because it explores new concepts for imaging with unprecedented spatial resolution at unprecedented depths in optical tissues.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = -$32 )
2022	2019	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	5/19/2022	NON-COMPETING CONTINUATION	-$32
														Subtotal = -$32

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	11/10/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $165,296 )
2019	2019	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	11/3/2018	NON-COMPETING CONTINUATION	$165,296
														Subtotal = $165,296

Issue Date FY: 2018 ( Subtotal = $196,353 )
2018	2018	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	11/23/2017	NEW	$196,353
														Subtotal = $196,353

Grand Total All Awards = $361,617

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Unrestricted super-resolution imaging deep in tissues through scattering immune spatial frequency modulated imaging

Award Number: R21EB025389

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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