Date of Award
Doctor of Philosophy (PhD)
Optical imaging offers advantages in distinguishing different tissue structures based on their chemical compositions. However, biological tissue is a highly scattering medium for visible light, which limits the penetration depth of the imaging modality.
Photoacoustic tomography (PAT) uses the photoacoustic effect to overcome the high scattering of electromagnetic waves in biological tissue, and can thus create multiscale, multicontrast images of living tissues. Here, we describe the advances PAT has made toward medical applications, including optical and ultrasound improvements, hardware and software design, signal processing, multi-view reconstruction methods, and statistical analysis techniques. This dissertation addresses the innovative medical application of state-of-the-art computer vision methods. The first part of this dissertation describes how using a contour map of biological tissue improved PAMs scanning speed. In scanning, signal processing includes segmentation of blood vessels, quantitative analysis of vessel density, and boundary detection of biological tissue. We utilized a tracking-based algorithm using a computer vision library that includes distance map transformation, skeleton morphological operations, and a support vector machine (SVM) algorithm. The linear SVM utilizes the clear linear boundary between the normal and abnormal region, to predict the tumor region.
The second part of this dissertation describes PAT applications in renal tumor modelling and pulse wave velocity measurement. For the tumor study, we investigated arteriovenous shunts and the metabolism rate of oxygen. Studying AV shunts in tumors is critical for understanding their development mechanism and metabolic basis. However, current imaging modalities cannot provide the high spatial resolution required to detect AV shunts, nor can they measure the hemoglobin landscape of AV shunts during tumor development. Here, using a high-resolution photoacoustic microscope, we report a new blood oxygenation (sO2)-based disease marker induced by the AV shunt effect in tumor angiogenesis. During our investigation, we discovered a striking biological phenomenon. Bloodstreams with two dramatically different sO2 values can flow side-by-side in a single vessel. By tracing abnormal sO2 values in the blood vessels, we can identify a tumor region at an early stage. We expect that this new discovery will find many clinical applications, such as tracing sO2-based biomarkers in internal organs and the brain in humans.
The metabolic rate of oxygen (MRO2) is a useful indicator of tumor oxygen metabolism. MRO2 is also an important indicator of cell functionality, associated with the product of blood flow flux and arteriovenous oxygenation difference. Although our understanding of tumor metabolism has advanced considerably, we lack a tool to noninvasively and longitudinally quantify MRO2 in tumors. Here, we present noninvasive, label-free, longitudinal optical-resolution photoacoustic microscopy (L-ORPAM) to quantify blood flow flux, oxygen saturation (sO2), and thereby MRO2 for a renal tumor model in the same mouse, over weeks to months. Experiments showed that the sO2 difference between an artery and vein within the tumor region decreased greatly due to the arteriovenous shunting effect during tumor growth.
Blood pulse wave velocity (PWV) is an important physiological parameter that characterizes vascular stiffness. We present electrocardiogram-synchronized photoacoustic microscopy for noninvasive quantification of the PWV in the peripheral vessels of living mice. Interestingly, blood pulse wave-induced fluctuations in blood flow speed were clearly observed in arteries and arterioles, but not in veins and venules. Simultaneously recorded electrocardiograms served as references to measure the travel time of the pulse wave between two cross sections of a chosen vessel, and vessel segmentation analysis enabled accurate quantification of the travel distance. PWVs were quantified in ten vessel segments from two mice. Statistical analysis showed a linear correlation between the PWV and the vessel diameter, which agrees with known physiology.
The third part of the dissertation describes PAT for whole-body small-animal study. The universal back-projection algorithm is implemented for multi-view reconstruction of a 3D object. We have enhanced photoacoustic computed tomography with a dry acoustic coupling that eliminates water immersion anxiety and wrinkling of the animal, and facilitates incorporating complementary modalities and procedures. The dry acoustic coupler is made of a tubular elastic membrane enclosed by a closed transparent water tank. The tubular membrane ensures water-free contact with the animal, and the closed water tank allows pressurization to stabilize the animal. The dry coupler was tested using a whole-body small-animal ring-shaped photoacoustic computed tomography system. In addition to its convenience and facilitation of complementary modalities, dry coupling was found to provide image quality comparable to that of conventional water coupling.
Lihong V. Wang
Jung-Tsung Shen, Lan Yang, Jin-Moo Lee, Mark Anastasio,
Available for download on Friday, May 15, 2116