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Multimodality Photoacoustic and Raman Imaging Open Access


Other title
realtime imaging
photoacoustic microscopy
optical-resolution photoacoustic microscopy
Type of item
Degree grantor
University of Alberta
Author or creator
Shi, Wei
Supervisor and department
Zemp, Roger (Electrical and Computer Engineering)
Examining committee member and department
Lewis, John (Department of Oncology)
Fedosejevs, Robert ( Electrical and Computer Engineering)
Wilson, Brian (Department of Medical Biophysics, University of Toronto/University Health Network)
DeCorby, Ray ( Electrical and Computer Engineering)
Department of Electrical and Computer Engineering
Biomedical Engineering
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Tumor metastasis is referred to the spread of cancer from one to another unadjacent part of the body, which results in more than 90% of tumor deaths, and however is still poorly understood. Circulating tumor cells (CTCs) have been proposed as an important biomarker of tumor metastasis. Many approaches have been developed for detection of CTCs, but each has its own advantages and disadvantages. With the aid of nanoparticles (NPs), photoacoustic detection along with efficient magnetic enrichment of CTCs demonstrated high sensitivity. However, differentiation of photoacoustic signals is non-trivial hence specificity can be poor. Surface-enhanced-Raman-scattering (SERS) NPs were used for detection of CTCs with high multiplexing capability. However, the lack of enrichment of CTCs limits its application for in vivo detection. High sensitivity and high specificity in vivo methods of detecting CTCs are in urgent need. A hallmark signature of metastasis is angiogenesis, the proliferation of vessel networks growing from pre-existing vasculature. Imaging angiogenesis is important for cancer research since angiogenesis is regarded as a necessity for tumor growth and tumor metastasis. Photoacoustic imaging (PAM) is a promising technique for imaging angiogenesis due to intrinsic high optical contrast between blood and tissues, and high spatial resolution at adequate penetration depth. Optical-resolution photoacoustic imaging (OR-PAM) pushed the lateral resolution limit of PAM to micron or submicron level, which enables imaging of single capillaries, the finest vasculature elements. However, the low imaging speed of OR-PAM may limit its application in the clinic, and for practical pre-clinical imaging of animal models. A single modality tool for studies on tumor metastasis is unlikely to be able to fullfill these needs. Therefore, the long term goal of this dissertation is to develop a multimodality imaging tool for imaging tumor metastasis and detecting of CTCs with high specificity and high sensitivity. Specially, we focused on the approach of combing PAM with a Raman imaging technology for this purpose. For the task of detecting CTCs, the photoacoustic subsystem could aid in placement of a magnet for trapping of such CTCs and gaging the flow rate for optimal optical and multiplexed detection with the Raman sub-system. The photoacoustic sub-system could also be used for detecting absorption signatures from nanoparticles on tumor cells. For detecting metastases, the Raman imaging subsystem could be used to detect multiple flavors of nanoparticles targeted to (non-circulating) tumor cells and the photoacoustic sub-system could be used to detect neoplasm angiogenesis. We aimed to push limits of OR-PAM imaging frame-rate, to develop a novel CTC detection technique with high sensitivity and high specificity, and to further build a multimodality photoacoustic-Raman imaging tool for high sensitivity and high specificity molecular imaging. Our work presented in this dissertation can be divided into three parts. First, we worked on developing realtime OR-PAM using various high pulse repetition rate lasers and combined with a fast optical scanning galvanometer mirror systems. We reported the first near realtime volumetric OR-PAM with 4 frames per second (fps) imaging speed and ~ 6 m lateral resolution by employing a fiber laser with up to 600 kHz pulse repetition rate. Further, we demonstrated in vivo near realtime sustained OR-PAM imaging of dynamic process and 30 fps realtime imaging of cardiac-induced mircrohemodynamics in murine microvasculature. In addition, we studied the scanning speed dependence of photoacoustic signals which may lead to a super-resolution technique in the future. Second, we demonstrated for the first time the magnetic enrichment and detection of CTCs in circulating PBS or rat blood with high specificity and high sensitivity by targeting tumor cells with both SERS NPs and magnetic NPs (MNPs). Third, we presented a multimodality imaging system consisting of PAM and SERS imaging which may advance the research of tumor metastasis in the future.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
W. Shi, S. Kerr, I. Utkin, J. C. Ranasinghesagara, L. Pan, Y. Godwal, R. J. Zemp, and R. Fedosejevs, “Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers,” J. Biomed. Opt. 15, 056017 (2010).W. Shi, P. Hajireza, P. Shao, A. Forbrich, and R. J. Zemp, “In vivo near-realtime volumetric optical-resolution photoacoustic microscopy using a high-repetition-rate nanosecond fiber-laser,” Opt. Express 19, 17143(2011).W. Shi, P. Shao, P. Hajireza, A. Forbrich, and R. J. Zemp, “In vivo dynamic process imaging using real-time optical-resolution photoacoustic microscopy ”, J. Biomed. Opt. 18, 026001 (2013).W. Shi, P. Shao, and R. J. Zemp, “Investigation of Photoacoustic Signal Strength as a Function of Scan-Speed and Laser-Repetition-Rate”, 2013 Joint UFFC, EFTF and PFM Symposium, 1534 (Prague, 2013).W. Shi, R. J. Paproski, R. Moore, and R. J. Zemp, “Detection of circulating tumor cells using targeted surface-enhanced Raman scattering nanoparticles and magnetic enrichment”, Journal of Biomedical Optics 19(5), 056014, (2014).W. Shi, P. Shao, R. J. Paproski, A. Forbrich, R. Moore, and R. J. Zemp, “Multimodality photoacoustic and Raman imaging of magnetically-trapped tumor cells”, Proc. SPIE 8943, 894367 ( SPIE Photonics West,San Francisco, 2014).

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