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.

Thesis (doctoral)--Universität der Bundeswehr, München, 2000. / Includes bibliographical references (p. 165-172).

By integrating three complementary imaging techniques - ultrasound, elasticity and photoacoustic imaging, a hybrid imaging system utilizing an array transducer is proposed for various biomedical imaging applications including cancer detection, diagnosis and therapy monitoring. Simultaneous imaging of the anatomy (ultrasound imaging), changes in biomechanical properties (elasticity imaging) and cancer-induced angiogenesis (photoacoustic imaging) of tissue is based on many synergistic features of these modalities and may result in a unique and important imaging tool. In this study, numerical analysis and experimental studies are presented to demonstrate the feasibility, to evaluate the performance, and also to improve the quality of the combined array-based ultrasound, elasticity and photoacoustic imaging system. To estimate spatial resolution, a point source was imaged using ultrasound and photoacoustic imaging modes. Then, several tissue mimicking phantoms were examined using ultrasound, photoacoustic and elasticity imaging. In elasticity imaging, ultrasound frames were acquired during deformation of the tissue. To reduce the data acquisition time of the system, high frame rate imaging was used. High frame rate imaging is possible by transmitting a broader and less focused ultrasound beam but the image quality is sacrificed. Thus, we compared the quality of the high frame rate and conventional ultrasound images. In photoacoustic imaging, acoustic transients are generated simultaneously in the entire volume of the laser irradiated tissue. Hence, image formation (beamforming) algorithms were developed based on the characteristics of the photoacoustic signals. Then, adaptive beamforming method is suggested to improve the image quality of the photoacoustic imaging. The results of the numerical analyses and experimental studies clearly indicate that ultrasound, elasticity and photoacoustic imaging techniques complement each other and together provide critical information needed for the reliable detection and diagnosis of diseases. / text

Recent clinical studies have demonstrated that photoacoustic imaging (PAI) provides important diagnostic information for breast cancer staging. Despite these promising studies, PAI remains an unfeasible option for clinics due to the cost to implement, the required large modification in user conduct and the inflexibility of the hardware to accommodate other applications for the incremental enhancement in diagnostic information. The research described in this dissertation addresses these issues by designing attachments to clinical ultrasound probes and incorporating custom detectors into commercial ultrasound scanners. The ultimate benefit of these handheld devices is to expand the capability of current ultrasound systems and facilitate the translation of PAI to enhance cancer diagnostics and neurosurgical outcomes. Photoacoustic enabling devices (PEDs) were designed as attachments to two clinical ultrasound probes optimized for breast cancer diagnostics. PAI uses pulsed laser excitation to create transient heating (<1°C) and thermoelastic expansion that is detected as an ultrasonic emission. These ultrasonic emissions are remotely sensed to construct noninvasive images with optical contrast at depths much greater than other optical modalities. The PEDs are feasible in terms of cost, user familiarity and flexibility for various applications. Another possible application for PAI is in assisting neurosurgeons treating aneurysms. Aneurysms are often treated by placing a clip to prevent blood flow into the aneurysm. However, this procedure has risks associated with damaging nearby vessels. One of the developed PEDs demonstrated the feasibility to three-dimensionally image tiny microvasculature (<0.3mm) beyond large blood occlusions (>2.4mm) in a phantom model. The capability to use this during surgery would suggest decreasing the risks associated with these treatments. However, clinical ultrasound arrays are not clinically feasible for microsurgical applications due to their bulky size and linear scanning requirements for 3D. Therefore, capacitive micromachined ultrasound transducer (CMUT) two-dimensional arrays compatible with standard ultrasound scanners were used to generate real-time 3D photoacoustic images. Future probes, designed incorporating CMUT arrays, would be relatively simple to fabricate and a convenient upgrade to existing clinical ultrasound equipment. Eventually, a handheld tool with the ability to visualize, in real-time 3D, the desired microvasculature, would assist surgical procedures. The potential implications of PAI devices compatible with standard ultrasound equipment would be a streamlined cost efficient solution for translating photoacoustics into clinical practice. The practitioner could then explore the benefits of the enhanced contrast adjunctive to current ultrasound applications. Clinical availability of PAI could enhance breast cancer diagnostics and cerebrovascular surgical outcomes.

Thesis (Ph. D.)--University of Texas at Austin, 2008. / Vita. Includes bibliographical references.

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.

Research in biology and medicine depends heavily on what we can measure. Photoacoustic imaging techniques allow for imaging both structural and functional information simultaneously. Current photoacoustic imaging technology is limited by either the speed at which the images are formed or resolution of the images. By increasing the resonant frequency at which the transducers receive photoacoustic signals, the resolution of a photoacoustic tomography setup can be improved without compromising on imaging speed. Due to their size, the resulting transducers must be placed directly onto a complementary metal-oxide-semiconductor (CMOS) integrated circuit (IC). This thesis describes a fabrication flow and electronics design that opens the door to high speed, high resolution photoacoustic imaging. A microfabrication flow is developed to place high frequency polyvinylidene fluoride transducers onto an integrated circuit. A 1-D array of transducers are fabricated and characterized on a CMOS IC. The custom IC (TSMC 90 nm) is designed to amplify the signals coming from the small transducers using a proposed two-stage LNA. The circuit is electrically characterized before and after transducer fabrication showcasing the CMOS-compatible nature of the fabrication flow. The transducers and integrated circuit are characterized in a photoacoustic setup using two phantoms to verify the functionality of the system. Compared to similar systems, this system displays monolthically integrated transducers that receive broadband responses centered at 35 MHz with 140 bandwidth.

abstract: This thesis intends to cover the experimental investigation of the propagation of laser-generated optoacoustic waves in structural materials and how they can be utilized for damage detection. Firstly, a system for scanning a rectangular patch on the sample is designed. This is achieved with the help of xy stages which are connected to the laser head and allow it to move on a plane. Next, a parametric study was designed to determine the optimum testing parameters of the laser. The parameters so selected were then used in a series of tests which helped in discerning how the Ultrasound Waves behave when damage is induced in the sample (in the form of addition of masses). The first test was of increasing the mases in the sample. The second test was a scan of a rectangular area of the sample with and without damage to find the effect of the added masses. Finally, the data collected in such a manner is processed with the help of the Hilbert-Huang transform to determine the time of arrival. The major benefits from this study are the fact that this is a Non-Destructive imaging technique and thus can be used as a new method for detection of defects and is fairly cheap as well. / Dissertation/Thesis / Masters Thesis Mechanical Engineering 2019

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.

Optoacoustic spectroscopy is a relatively old technique first described by Alexander Graham Bell in 1881. However, over the intervening years, little use was made of the technique due to its low sensitivity. This was due to low source intensities of available infrared light sources which limited the optoacoustic signal strength. With the advent of laser infrared light sources in the 1960's, there has been a resurgence of interest in optoacoustics. No longer is low source intensity a major limitation to successful optoacoustic spectroscopy. Although adequate infrared light sources are available, the large window background signal observed in all optoacoustic systems has been the major limitation in extending trace gas detection limits to the ppb or sub-ppb level. Similarly, there has been little demonstration of the use of the optoacoustic technique in environments where mixtures of gases are present which have severe spectral overlap. This work will discuss a new windowless cell design that largely eliminates the signal background problem ubiquitous to all presently available optoacoustic cells. New methodologies will be discussed that allow analyses of mixtures to be performed even in cases where spectral overlap is severe. Limitations to both the windowless cell and the various multicomponent analysis strategies are discussed.