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.

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.

Cancer mortality is progression-dependent thus its treatment relies on effective therapy and monitoring of responses. Nanoparticles have long been used to improve the therapeutic index of drugs by facilitating their transit to the target site at higher concentrations than free drugs, whilst protecting healthy tissues from an often potent and cytotoxic payload. Through the EPR (enhanced permeability and retention) effect, injected, PEGylated nanoparticles preferentially accumulate in tumour tissue deeming them eminently suitable for cancer intervention for delivery of both therapeutic and contrast agents The development of theranostic liposomal systems comprising both imaging and therapeutic capabilities exploits the facets of liposomes, and forms an elegant strategy to address major problems which hinder effective cancer therapy. Liposomes can be tailored to be thermosensitive in a low hyperthermic range of ~42°C, above physiological temperature but below that which can induce tissue damage. This allows the use of heating as an external triggering modality to induce targeted drug release. Throughout the course of this work, the photoacoustic contrast agent ICG was successfully incorporated into PEGylated doxorubicin-encapsulating liposomes, marrying two FDA approved entities. The project commenced with the development of the basic liposomal-DOX. Differing lipid compositions of varying fluidities were tested against those which have been previously established. These compositions carried a range of phase transition temperatures, above which the liposomes release the encapsulated DOX. This study concluded with the generation of a library of liposomes with differing release kinetics at 42°C in simulated physiological conditions. The second section of the project investigated the methodology behind the incorporation of ICG into the liposomal bilayers. The lipid composition used for the study was based on the DOXIL® formulation, due to its robust structure and establishment in the field of cancer therapy. The protocols used varied on the basis of chronology in regards to the liposome preparation protocol. The film insertion method incorporated the ICG in initial lipid film generation. The freeze fracture protocol introduced the ICG during lipid film hydration. The post insertion protocol introduced ICG in the final stages of DOX loading. The downsizing protocol was also varied between extrusion and sonication. Through varying of the protocols and downsizing methodology, it was possible to incorporate differing ICG concentrations and attain differing levels of structural stability. The most successful liposome was then tested for its imaging potential in vivo through a photoacoustic imaging modality namely multispectral optoacoustic tomography. This validated accumulation of the liposomes at the tumour site along with co-localisation of both drug and dye. The project culminated in the combination of the two studies, producing a thermosensitive theranostic ICG labelled liposomal doxorubicin system. The system showed improved blood stability than the current clinical systems, and demonstrated imaging potential through IVIS based fluorescence imaging. Through exploitation of the photothermal effects of ICG within a thermosensitive lipid vesicle, it was also possible to induce drug release through irradiation with a non-thermal near-infrared laser. This shows promise for future therapy, allowing simultaneous imaging, optimum release induction and monitoring response to therapy, in a cheap, effective and time-efficient manner.

In recent years, revolutionary "hybrid" or "multi-physics" methods of medical imaging have emerged. By combining two or three different types of waves these methods overcome limitations of classical tomography techniques and deliver otherwise unavailable, potentially life-saving diagnostic information. Thermoacoustic (and photoacoustic) tomography is the most developed multi-physics imaging modality. Thermo- and photo-acoustic tomography require reconstructing initial acoustic pressure in a body from time series of pressure measured on a surface surrounding the body. For the classical case of free space wave propagation, various reconstruction techniques are well known. However, some novel measurement schemes place the object of interest between reflecting walls that form a de facto resonant cavity. In this case, known methods cannot be used. In chapter 2 we present a fast iterative reconstruction algorithm for measurements made at the walls of a rectangular reverberant cavity with a constant speed of sound. We prove the convergence of the iterations under a certain sufficient condition, and demonstrate the effectiveness and efficiency of the algorithm in numerical simulations. In chapter 3 we consider the more general problem of an arbitrarily shaped resonant cavity with a non constant speed of sound and present the gradual time reversal method for computing solutions to the inverse source problem. It consists in solving back in time on the interval [0, T] the initial/boundary value problem for the wave equation, with the Dirichlet boundary data multiplied by a smooth cutoff function. If T is sufficiently large one obtains a good approximation to the initial pressure; in the limit of large T such an approximation converges (under certain conditions) to the exact solution.

To confirm the presence of prostate cancer which is the most incident visceral cancer in men, prostate biopsies are acquired using the magnetic resonance imaging fusion-guided prostate biopsy protocol. For this approach annotated magnetic resonance imaging is overlaid onto real-time ultrasound imaging to guide sampling of suspicious regions marked by uroradiologists. Additional biopsy samples are acquired via the previous clinical gold standard, i.e. the templated 12-core transrectal ultrasound-guided prostate biopsy protocol. While this approach improves the sensitivity of the prostate biopsy, a real-time, multiparametric imaging method of identifying biopsy targets could help overcome some of the inherent pitfalls of the magnetic resonance imaging fusion-guided prostate biopsy. Since ultrasound is used during the prostate biopsy, photoacoustic tomography, e.g. a hybrid imaging modality in which clinical ultrasound probes can be used to detect centimeters deep chemical alterations, has the potential to provide real-time targeting during biopsy. The translation of photoacoustic tomography to the clinic for prostate biopsy has been prevented by engineering challenges, which include identification of a biomarker for detecting suspicious regions of tissue and light delivery to the prostate for photoacoustic signal generation. Here, we present a vascular texture analysis method that identified 100% of primary and 67% of secondary tumors in the testing data set of ex vivo human prostate specimens. This method can be applied to future in vivo photoacoustic and ultrasound tomography of human prostates after further optimization of light delivery for photoacoustic tomography. To progress towards achieving this aim, we developed a transurethral light delivery device with angular light coupling method. By controlling the launch angle of the light into the fiber, the conversion of forward to side propagating energy can be improved from 27% to 98%, and the longitudinal emission profile can be controlled in order to illuminate the whole prostate simultaneously.<br>

We demonstrate a versatile phase-change sub-micron contrast agent providing three modes of contrast enhancement: 1) photoacoustic imaging contrast, 2) ultrasound contrast with optical activation, and 3) ultrasound contrast with acoustic activation. This agent, which we name 'Cy-droplet', has the following novel features. It comprises a highly volatile perfluorocarbon for easy versatile activation, and a near-infrared optically absorbing dye chosen to absorb light at a wavelength with good tissue penetration. It is manufactured via a 'microbubble condensation' method. The phase-transition of Cy-droplets can be optically triggered by pulsed-laser illumination, inducing photoacoustic signal and forming stable gas bubbles that are visible with echo-ultrasound in situ. Alternatively, Cy-droplets can be converted to microbubble contrast agents upon acoustic activation with clinical ultrasound. Potentially all modes offer extravascular contrast enhancement because of the sub-micron initial size. Such versatility of acoustic and optical 'triggerability' can potentially improve multi-modality imaging, molecularly targeted imaging and controlled drug release. (C) 2017 The Authors. Published by Elsevier GmbH.