Wednesday, August 20, 2025 8/20/2025

Unveiling Hidden Signatures in Life by Vibrational Photothermal Microscopy

Award Number: R35GM136223
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Unveiling Hidden Signatures in Life by Vibrational Photothermal Microscopy - Project Summary Optical microscopy is a fundamental tool for life science. Phase contrast microscope allows visualization of intracellular structures. Fluorescence microscope further allows real-time imaging of tagged molecules or organelles. Yet, the fluorescent tags such as fluorescent proteins are larger than many molecules inside a cell and their broad spectral profile prohibits highly multiplexed imaging. A central theme of the Cheng Research Group is to fill this gap in biomolecular imaging through invention and development of advanced bond-selective microscopy tools. Over the past 5 years, under the support of a MIRA grant R35GM136223, Cheng and co- workers have made substantial progress in development and applications of stimulated Raman scattering (SRS) microscopy and mid-infrared photothermal (MIP) microscopy, reported in 42 peer-reviewed articles and 16 patent applications. Despite these advances, there remains a need to develop highly sensitive vibrational imaging technologies and demonstrate killer applications to life science and/or medical research. While providing micromolar imaging sensitivity, the MIP technology is not sensitive to Raman-active bonds such as C-H or alkyne. Either SRS or MIP microscopy does not allow for high-resolution vibrational imaging of biomolecules in deep tissue environment. Thus far, most vibrational imaging applications are focused on high-concentration molecules such as lipid droplets or protein aggregates in cultured cells or thin tissue slices. Broader applications to address challenges not addressable by fluorescence imaging are needed to prove the value of vibrational imaging. This MIRA renewal is designed to address these needs in the next 5 years. First, Cheng and co-workers will develop stimulated Raman photothermal (SRP) microscopy to enable ultrasensitive Raman spectroscopic imaging. Based on a pilot demonstration (Science Advances, 2023), PI and co-workers will further build an OPA-based SRP microscope to reach micro-molar imaging sensitivity and apply this technique to image cholesterol-rich domains in live cells. PI and co-workers will also build a fiber-OPO based SRP microscope for broad use of this technology at ease of operation. Second, PI and co-workers will develop short-wave infrared photothermal (SWIP) microscopy to enable deep-tissue vibrational imaging with millimeter- scale penetration depth and sub-micron spatial resolution. Based on a pilot demonstration (Nature Photonics, 2024), PI and co-workers will further develop a SWIP-OCT system to enable high-speed volumetric bond- selective imaging of tumor spheroids, organoids, and deep tissues in their natural states. Finally, PI and coworkers will demonstrate a few paradigm-shifting applications of vibrational photothermal microscopy via collaboration with scientists in life science. Applications will include fingerprinting intracellular organelles through fluorescence-detected MIP microscopy, click-free imaging of transport and metabolism of small biomolecules, developing and imaging vibrational proteins to study protein machinery in live cells and in vivo, and MIP reporter (Nature Methods 2024) based super-multiplex spatial omics.


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: 2025 ( Subtotal = $2,811,668 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	002	6	8/4/2025	COMPETING CONTINUATION	$2,811,668
2025	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	5	11/6/2024	NON-COMPETING CONTINUATION	$0
2025	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	001	5	8/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,811,668

Issue Date FY: 2024 ( Subtotal = $577,500 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	5	7/9/2024	NON-COMPETING CONTINUATION	$577,500
														Subtotal = $577,500

Issue Date FY: 2023 ( Subtotal = $577,500 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	4	6/26/2023	NON-COMPETING CONTINUATION	$577,500
														Subtotal = $577,500

Issue Date FY: 2022 ( Subtotal = $577,500 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	3	7/6/2022	NON-COMPETING CONTINUATION	$577,500
														Subtotal = $577,500

Issue Date FY: 2021 ( Subtotal = $577,500 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	2	6/28/2021	NON-COMPETING CONTINUATION	$577,500
														Subtotal = $577,500

Issue Date FY: 2020 ( Subtotal = $535,971 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	1	6/30/2020	NEW	$535,971
														Subtotal = $535,971

Grand Total All Awards = $5,657,639

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Unveiling Hidden Signatures in Life by Vibrational Photothermal Microscopy

Award Number: R35GM136223

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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