Lau Shing-tat. / Chinese title: / Bibliography: leaves 129-130 / Thesis (M.Phil.)--Chinese University of Hong Kong, 1983

Thesis (Ph. D.)--University of Nevada, Reno, 2007. / "May, 2007." Includes bibliographical references. Online version available on the World Wide Web.

Thesis (M.S.)--Rutgers University, 2009. / "Graduate Program in Oceanography." Includes bibliographical references (p. 22-27).

Thesis (M.S.) University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on August 29, 2007) Vita. Includes bibliographical references.

Optoacoustic (OA) imaging is an emerging low-cost hybrid imaging investigation/technique currently in clinical feasibility studies for breast cancer diagnosis and staging. The technique applies pulsed light to the tissue of interest where molecules absorb the light photons and generate acoustic pressure waves. The resulting acoustic responses are detected using ultrasound transducers and converted into images. Image contrast within a pixel is dependent on the relative concentration and absorption characteristics (i.e. spectrum) of the chromophores within the illuminated tissue. Thus, tissue responses from illumination using multiple wavelengths, chosen to reflect the differential absorption of oxy-/deoxy- and total haemoglobin, can be measured. In turn, these signals can be regarded as surrogate measures of tissue hypoxia and neoangiogenesis, hallmarks of cancer associated with adverse outcomes. The aim of this PhD was to translate optoacoustic imaging into the breast clinic to try and fulfil some of the unmet clinical needs in breast cancer imaging using the imaging biomarker roadmap by O'Connor et al. Translation of this new technology to the clinical environment required extensive preparatory work, including the procurement and installation of a scanner prototype, liaison with UK regulatory bodies to secure ethical and MHRA approval, as well as several technical developments (performed during the course of the PhD) to make the technology suitable for breast cancer imaging. The first chapter of the thesis reviews the unmet needs of breast cancer imaging, being followed by a summary of recent techniques and technologies that may potentially fulfil gaps in knowledge and address some of the specific diagnostic challenges in breast cancer imaging. The capabilities of optoacoustic imaging are then discussed in the context of this evolving landscape of new imaging techniques and technologies with a particular focus on the tumour biology (neoangiogenesis and hypoxia) that can be measured in humans using multimodality and multi parametric imaging. Chapter 2 reviews of the current state of clinical translation of optoacoustic imaging, highlighting the particular areas in which clinical translation has advanced the most (breast cancer, melanoma and inflammatory bowel disease). Chapter 3 discusses the logistical, regulatory and technical challenges and solutions involved in translating optoacoustic imaging to the clinic and setting up a clinical service. Chapter 4 presents a series of validation experiments of oxygen saturation aimed at establishing the relationship between the optoacoustic signal and invasive pO2 measurements with an OxyLite probe in a porcine kidney model. This work was conducted in close collaboration with leading clinicians from the local transplant team. The following chapter describes the results of the first stage of our clinical work in the breast, namely the healthy volunteer study. This part had several aims: to perform qualitative assessment of the optoacoustic features of the normal breast under physiological conditions; to establish a robust scanning technique and identify technical and image interpretation pitfalls; and to perform qualitative evaluation of the hormonal changes that occur during the menstrual cycle and menopause, which, in turn, were used to validate surrogate measures of oxy-, deoxy and total haemoglobin. Chapter 6 then focuses on the qualitative assessment of benign and malignant breast lesions and their appearances on optoacoustic imaging. The patient study was divided into three phases. Phase 1 created a feature set to differentiate benign from malignant lesions, while Phase 2 was a transition between the prototype scanner and the installation of the first-generation clinical scanner. In Phase 3 the feature set created in Phase 1 was validated in a reader study. The sensitivity and specificity of optoacoustic imaging for lesion detection and differentiation of benign from malignant lesions was compared with mammography and ultrasound. Chapter 7 then deals with the quantitative analysis of the Phase 1 and Phase 3 data acquired in Chapter 6, assessing the relationships between the use of single wavelengths, spectral unmixing, vascularity versus receptor status, heterogeneity of signal intensity in relation to tumour stage and grade. This chapter also discusses the potential and limitations of quantifying the optoacoustic signal and leads to the final chapter, a discussion of future directions in optoacoustic imaging in breast cancer. At the end of this thesis, chapter 8 briefly discusses the potential future directions for the use of optoacoustic imaging as a clinical and scientific tool.

Understanding the complex information transfer process of our nervous system is one of the most urgent needs in the biomedical community. Neuromodulation is a technique that can artificially influence or modulate the activity of the target neurons. It's an inevitable tool in both the neuroscience study but also the clinical treatment of neurological diseases. The conventional method for neural modulation is the electrical stimulation using implantable electrodes. However, its intrinsic current leakage problem is an obstacle for further improving its performance in clinical scenarios because of the finite spatial resolution and recording artifacts. In general, an ideal method should be able to modulate neural activities with a high spatial, temporal and functionality specificity but without biocompatibility and reliability issues even in long term. Photoacoustic stimulation is an emerging light-mediated, non-genetic neural modulation method with high spatiotemporal resolution. Multiple devices have been designed in the past few years. But there are still several gaps to be filled to further expand its applications. One is the material mismatch, and another is that more function is needed, for example the capability of simultaneous recording. My research focused on the design and development of two new types of photoacoustic materials to expand the use of photoacoustic stimulation. A soft hydrogel film and a multifunctional fiber-based emitter for photoacoustic neuromodulation have been developed in my Ph.D. research. The study on these materials increased our knowledge to photoacoustic neurostimulation, also help us to investigate the effect of photoacoustic neuromodulation in the treatment of neurological and neurodegenerative diseases.

A photoacoustic spectrometer was developed and built for measuring absorption of light by collected particles. Major advantages of the photoacoustic method are that it measures absorption directly, it is insensitive to scattered light, and it is readily used at different wavelengths. To evaluate the performance of the spectrometer, comparisons were made between photoacoustic absorption spectra and spectra calculated with Mie thoery. Pure powders with varied optical properties were used in the comparison, including carbon, hematite, and others. Results were reasonable in both absolute magnitude and spectral shape. Aerosol particles were collected in different environments in southern Arizona under background conditions in the mid-troposphere, and in a moderately polluted city. Results for the two locations, and two size ranges, are compared and contrasted in this thesis. Absolute magnitudes of absorption coefficients, measured at green wavelengths, are used to summarize many important results. Absorption by fine urban aerosol was 6 ± 4 x 10⁻⁷ m⁻¹, and four times larger than absorption by coarse urban aerosol. Normalized photoacoustic absorption spectra for urban aerosol are uniform with wavelength; background aerosol spectra have a relative increase in absorption at near UV wavelengths compared to near IR wavelengths. Urban aerosol absorption can be attributed to carbon particles larger than approximately 0.1 micron. Absorption by hematite (alpha iron oxide) particles in more strongly wavelength dependent than absorption by carbon particles, of the same size. This wavelength dependence is still not great enough to be attributed to hematite alone--although submicron hematite particles may be the dominant absorber in coarse background aerosol. (Abstract shortened with permission of author.)

University of Macau / Faculty of Health Sciences

Poor oxygenation of solid tumours has been linked with resistance to chemo- and radio-therapy and poor patient outcomes. Measuring the functional status of the tumour vasculature, including blood flow fluctuations and changes in oxygenation is important in cancer staging and therapy monitoring. A robust method is needed for clinical non-invasive measurement of the oxygen supply and demand in tumours. Current clinically approved imaging modalities suffer high cost, long procedure times and limited spatio-temporal resolution. Optoacoustic tomography (OT) is an emerging clinical imaging modality that can provide static images of endogenous haemoglobin concentration and oxygenation. In this work, an integrated framework for quantitative analysis of functional imaging using OT is developed and applied in vivo with preclinical cancer models. Oxygen Enhanced (OE)-OT is established here to provide insight into tumour vascular function and oxygen availability in the tissue. Tracking oxygenation dynamics using OE-OT reveals significant differences between two prostate cancer models in nude mice with markedly different vascular function (PC3 & LNCaP), which appear identical in static OT. OE-OT metrics are shown to be highly repeatable and correlate directly on a per-tumour basis to tumour vascular maturity, hypoxia and necrosis, assessed ex vivo. Dynamic Contrast Enhanced (DCE) OT demonstrates the relationship between OE-OT response and tumour perfusion in vivo. Finally, the possibility of using OT data acquired at longer wavelengths to report on tumour water and lipid content is investigated, with a view to future providing intrinsically co-registered imaging of tumour oxygenation and cellular necrosis. These findings indicate that OE-OT holds potential for application in prostate cancer patients, to improve delineation of aggressive and indolent disease, while combined with DCE-OT, it may offer significant advantage for localised imaging of tumour response to vascular targeted therapies. Further work is needed to establish whether OT can provide a new method to detect tumour necrosis in vivo.

This research is primarily focused on laser-based non-invasive photoacoustic tomography of small animal brains. Photoacoustic tomography, a novel imaging modality, was applied to visualize the distribution of optical absorptions in small-animal brains through the skin and skull. This technique combines the high-contrast advantage of optical imaging with the high-resolution advantage of ultrasonic imaging. Based on the intrinsic optical contrast, this imaging system successfully visualized three-dimensional tissue structures in intact brains, including lesions and tumors in brain cerebral cortex. Physiological changes and functional activities in brains, including cerebral blood volume and blood oxygenation in addition to anatomical information, were also satisfactorily monitored. This technique successfully imaged the dynamic distributions of exogenous contrast agents in small-animal brains. Photoacoustic angiography in small-animal brains yielding high contrast and high spatial resolution was implemented noninvasively using intravenously injected absorbing dyes. In the appendix, the theory of Monte Carlo simulation of polarized light propagation in scattering media was briefly summarized.