Abstract

In this study, micrometer-sized (< 5μm) microbubbles (MBs) were investigated as optical contrast agents. Exogenous contrast agents in optical imaging can enhance the detection of cancerous tissue, however they are limited by their potential side effects such as organ accumulation and toxicity with repeated administration. In ultrasound imaging, microbubbles are FDA approved and used clinically as contrast agents. Microbubbles can also produce a refractive index mismatch between the gas-filled core and surrounding water media, potentially modifying optical properties of tissue when injected intravenously into tissue. Cancer detection can potentially be achieved by imaging microvasculature functionality through the blood volume fraction measurements with diffuse optical imaging (DOI). In order to study the potential application of using MBs for DOI, the effect of MBs on the bulk optical properties of a skin tissue phantom solution at various volume fraction of human blood was assessed at various injection doses of Definity® microbubble. The absorption and reduced scattering coefficients were computed and compared in the absence and presence of microbubbles. The presence of microbubbles in the blood caused a statistically significant enhancement in the reduced scattering contrast (~1.3 times) at 660 nm wavelength which increases with the dose of Definity® MBs (166 μL/kg) at 6% blood volume fraction. However, the absorption contrast enhancement remained relatively constant as microbubble dose increased. The scattering contrast enhancement confirmed the feasibility of using MBs as DOI contrast agents to improve the detection of tissue with high blood concentration conditions. Microbubbles were also investigated as optical coherence tomography (OCT) contrast agents. OCT structural and speckle variance (sv) images, as well as the speckle decorrelation times, were evaluated under no-flow and flow conditions from a skin tissue phantom with two embedded microtubes. Faster decorrelation times and greater structural and svOCT image contrasts were detected with the presence of MBs. The effects of the presence of MBs on the image contrast were maximal (2 times) at no flow in the svOCT imaging mode and reduced with blood average flow velocity from zero to 12 mm/s. This result confirmed the feasibility of using MBs to enhance svOCT visualization of microvasculature morphology.

Highlights

  • 1.1 Optical imaging of tissue and cancer detectionThe motivation of the thesis was to determine if microbubble contrast agents can be used to enhance the detection of cancerous tissue with optical imaging techniques

  • The morphology of the microvasculature is important for cancer detection because cancerous tissue typically has new vessel formation with a higher vessel density than healthy surrounding tissue [4]

  • The microvasculature functionality is of great significance for cancer detection since blood flow [5], [6] and blood volume fraction [4], [7] are generally higher because of new vessel formation in cancerous tissue than surrounding healthy tissue

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Summary

Optical imaging of tissue and cancer detection

The motivation of the thesis was to determine if microbubble contrast agents can be used to enhance the detection of cancerous tissue with optical imaging techniques. The microvasculature functionality is of great significance for cancer detection since blood flow [5], [6] and blood volume fraction [4], [7] are generally higher because of new vessel formation in cancerous tissue than surrounding healthy tissue. Imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), x-ray and ultrasound (US) are unable to detect a cancerous tumor at an early stage or to visualize vessels smaller than 300 μm in routine clinical practice [8]. MBs are made from non-toxic gas such as perfluorocarbon, which introduce a refractive index mismatch that cause scattering to differentiate between blood and surrounding tissues Their use as potential optical contrast agents for DOI and OCT was investigated in this study. This is the first study of the effect of MBs on speckle variance (sv) OCT image contrast of blood flow in vessels

Diffuse optical imaging (DOI)
Optical properties of tissue
Calculating optical properties by inverse adding doubling (IAD)
Optical coherence tomography
OCT images of tissue
Optical contrast agents
Thesis hypothesis and specific aims
Overview of the Dissertation
Spectroscopy experiment
Inverse adding doubling and optical properties
Bulk tissue phantom solution (Intralipid, Human Blood, PBS)
Microbubbles
Optical stability of MBs solution
Ethic approval for use of human blood
Optimal wavelength selection
Statistical analysis method
Optical coherence tomography method
Structural OCT image
Autocorrelation
Skin tissue phantoms for OCT
Microbubbles in OCT experiments
Optical properties
The effect of microbubbles on μs′at wavelengths 660 nm and 1310nm
Reduced scattering contrast and reduced scattering contrast enhancement
Absorption coefficient (μa)
The effect of microbubbles on μa at wavelengths 660 nm and 1310 nm
Absorption contrast and absorption contrast enhancement
One dimension decorrelation analysis
Contrast enhancement of 2D structural images
Contrast enhancement of 2D speckle variance (sv OCT) images
Chapter 5 Summary and Conclusions
Calculating optical properties by Mie theory
Methods
Preliminary results
Findings
Potential in-vivo study
Full Text
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