The goal of this Bioengineering Research Grant (BRG) is to produce a novel multi-photon microendoscopy instrument that can rapidly vary focal depth and thus produce real-time vertical cross-sectional images from biological tissue in vivo, and to validate instrument performance in imaging of targeted peptide markers for colon cancer. Relative to prior miniature multi-photon instruments, the proposed instrument will feature much faster axial scanning for cross-sectional imaging without motion artifacts (frame rate 5-10 Hz) while maintaining a small diameter (3.4 mm) for compatibility with small animal imaging in the gastrointestinal tract. Instrument performance is expected to meet goals of sub-cellular resolution and deep tissue penetration with substantial field of view. Instrument development will be based on a multi-disciplinary collaboration of medical and engineering expertise in actuation, instrument design, optics, and cancer biology. Axial (into-tissue) scanning capabilities will be provided by high-speed, large- stroke thin-film PZT vertical translational actuators. A fiber-coupled, remote scanning architecture will permit modular insertion of optimized optics and actuators in a small handheld instrument. Instrument verification will be performed through benchmarking against of resolution, penetration depth, frame rate, and signal-to-noise ratio on standardized targets and/or phantom tissues. Full instrument validation will be performed in studies of in vivo imaging of genetically-engineered mouse models of cancer. Mice will be labeled with both targeted, dye-labeled peptides and general tissue dyes. Peptides will be optimized for bonding to specific targets exhibited in human disease and the mouse model. The optimized peptide will be characterized for binding affinity. In vivo imaging of the peptide with different fluorescent reporters will be used to identify optimal operating parameters for deep multi-photon imaging and characterize instrument performance.

Public Health Relevance

A miniature, endoscope-compatible multi-photon imaging instrument will be developed to perform real time, high-resolution, vertical cross-sectional imaging of living tissue. The instrument will be a novel tool for the study of biological processes related to cancer development, as through a validation study on imaging of targeted peptide markers for colon cancer applied to mouse models of cancer development. Successful instrument development should provide a new tool for the scientific study of normal and cancerous cell development in animal models of cancer, with a possibility of future clinical human diagnosis and monitoring of cancer and other diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB020644-02
Application #
9113414
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Shabestari, Behrouz
Project Start
2015-07-18
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Choi, Jongsoo; Wang, Thomas; Oldham, Kenn (2018) Dynamics of Thin-film Piezoelectric Microactuators with Large Vertical Stroke Subject to Multi-axis Coupling and Fabrication Asymmetries. J Micromech Microeng 28:
Choi, Jongsoo; Duan, Xiyu; Li, Haijun et al. (2017) Multi-photon vertical cross-sectional imaging with a dynamically-balanced thin-film PZT z-axis microactuator. J Microelectromech Syst 26:1018-1029
Li, Gaoming; Li, Haijun; Duan, Xiyu et al. (2017) Visualizing Epithelial Expression in Vertical and Horizontal Planes With Dual Axes Confocal Endomicroscope Using Compact Distal Scanner. IEEE Trans Med Imaging 36:1482-1490
Duan, Xiyu; Li, Haijun; Zhou, Juan et al. (2016) Visualizing epithelial expression of EGFR in vivo with distal scanning side-viewing confocal endomicroscope. Sci Rep 6:37315
Joshi, Bishnu P; Zhou, Juan; Pant, Asha et al. (2016) Design and Synthesis of Near-Infrared Peptide for in Vivo Molecular Imaging of HER2. Bioconjug Chem 27:481-94
Rabinsky, Emily F; Joshi, Bishnu P; Pant, Asha et al. (2016) Overexpressed Claudin-1 Can Be Visualized Endoscopically in Colonic Adenomas In Vivo. Cell Mol Gastroenterol Hepatol 2:222-237
Li, Haijun; Duan, Xiyu; Qiu, Zhen et al. (2016) Integrated monolithic 3D MEMS scanner for switchable real time vertical/horizontal cross-sectional imaging. Opt Express 24:2145-55
Zhou, Quan; Li, Zhao; Zhou, Juan et al. (2016) In vivo photoacoustic tomography of EGFR overexpressed in hepatocellular carcinoma mouse xenograft. Photoacoustics 4:43-54
Joshi, Bishnu P; Wang, Thomas D (2016) Gastrointestinal imaging in 2015: Emerging trends in endoscopic imaging. Nat Rev Gastroenterol Hepatol 13:72-3
Joshi, Bishnu P; Pant, Asha; Duan, Xiyu et al. (2016) Multimodal Video Colonoscope for Targeted Wide-Field Detection of Nonpolypoid Colorectal Neoplasia. Gastroenterology 150:1084-1086

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