Phase-change contrast agents (PCCAs) are an innovative form of imaging agent with practical applications in both the research and clinical settings. PCCAs are derived from gaseous microbubbles, which are able to act as targeted-contrast agents through conjugation of a ligand that is selective for an overexpressed receptor or biomarker in a given disease. Gaseous microbubbles can be condensed to liquid phase nanodroplets, which should be sufficiently small to extravasate into cells and/or tissues given their size and stability. Once liquid nanodroplets have internalized within a given tissue, they can be "activated" back into gaseous microbubbles with ultrasound at clinically used frequencies and energy outputs. This is purposeful as microbubbles provide much greater ultrasound reflectivity than nanodroplets. In this study, PCCAs and/or microbubbles act as a targeting agent in multiple scenarios. The projects in this study include- examination of binding and internalization of targeted PCCAs with different gaseous cores within MDA-MB-231 breast cancer cells, vaporization of liquid phase nanodroplets through application of acoustic energy via focused ultrasound (FUS), and targeting vulnerable plaque in the heart with different types of targeted microbubbles under varying shear-stresses.

Humpback Chub Gila cypha are endangered cyprinids endemic to the Colorado River drainage and are adapted to live in fast currents of warm, turbid water. Although nine known aggregations of Humpback Chub currently exist in the main-stem Colorado River in the Grand Canyon, little is known about their reproduction. I hypothesized that Colorado River water temperatures below Glen Canyon Dam are too low due to hypolimnetic water releases from Lake Powell for female Humpback Chub to develop mature eggs for spawning. Ultrasonic imaging, also called ultrasound, is an effective, non-lethal method used to determine sex and maturity of a variety of freshwater, anadromous, and marine fishes. However, many previous studies have been performed in laboratory environments. I developed a standardized method for ultrasonically scanning endangered Humpback Chub Gila cypha in remote locations within Grand Canyon, Arizona, USA. This method minimized stress to individual fish and took less than 1 min to perform. I was able to identify female fish with eggs based on two jpeg images and one 10 s video clip collected in the field. I also used ImageJ®, a National Institute of Health image processing program, to develop a brightness index to evaluate the maturity of eggs in female fish. I collected ultrasonic scans of captive, ripe Humpback Chub held at the Southwestern Native Aquatic Resources and Recovery Center (SNARRC) to determine that female fish were potentially ripe when a subsample of their eggs exhibited a brightness value within the 32-44 range. Although I was able to estimate egg maturity, I was not able to estimate egg mass of female fish. I used ultrasound to evaluate reproductive condition of 751 Humpback Chub in Grand Canyon. I documented egg development in female fish from the main-stem Colorado River, Little Colorado River, Havasu Creek, and Shinumo Creek. Egg development in Humpback Chub varies by location and time of year. Potentially ripe (stage 3) female fish were found at all sample locations and dates except at Shinumo Creek in 2013 and 2014. Potentially ripe females were also detected in every main-stem aggregation except for Pumpkin Springs and in two locations outside of established aggregations. Fisheries managers can use ultrasound to collect vital information about the reproductive status of fishes that cannot be killed and that are found in remote or rugged field locations. My findings indicate that female Humpback Chub are able to produce eggs throughout the main-stem Colorado River and that internal egg development and egg production likely do not limit recruitment. However, female fish may never experience the environmental triggers they need to spawn or may not experience conditions that would allow eggs and larvae to survive.

Thesis (PhD)--University of Stellenbosch, 2011. / ENGLISH ABSTRACT: Although transthoracic ultrasonography is a well established modality, it is still underutilised by chest physicians. The aim of this research project was to investigate the feasibility, diagnostic yield and safety of ultrasound(US)-assisted transthoracic biopsies performed by clinicians in various settings relevant to daily practice of respiratory medicine. We conducted four clinical trials which are summarised below: 1. In a prospective study on the feasibility of US-assisted transthoracic fine needle aspiration (TTFNA) of drowned lung secondary to a proximal mass lesion, a novel indication for US-assisted TTFNA was described. TTFNA passes >20mm from the visceral pleura had a sensitivity of 74.2% and were also more likely to contain malignant cells than more superficial passes. The surprisingly high yield and the fact that no serious complications were observed validated this approach, which may be an alternative to bronchoscopy. 2. In the largest single-centre study on US-assisted TTFNA with rapid on-site evaluation (ROSE) and cutting needle biopsy (CNB) in the setting of superior vena cava (SVC) syndrome ever reported, we were able to accurately diagnose 96% of all patients who presented with an associated mass lesion that abutted or infiltrated the chest wall. No pneumothoraces or major haemorrhage was caused. We also validated the single-session approach, and were able to conclude that US-assisted TTFNA (with ROSE) is the initial investigation of choice in suspected bronchogenic carcinoma, whereas both TTFNA and CNB need to be performed in all other cases. 3. We continued to validate the novel single-session sequential approach in a study on anterosuperior mediastinal masses. US-assisted TTFNA with ROSE was performed on 45 consecutive patients, immediately followed by CNB where a provisional diagnosis of epithelial carcinoma or probable tuberculosis (TB) could not be established. An accurate cytological diagnosis was made in 73.3%, and was more likely to be diagnostic in epithelial carcinoma and TB than all other pathology (p<0.001). CNB yielded a diagnosis in 88.2%. Overall 93.3% of patients were diagnosed by the single-session approach. No pneumothorax or major haemorrhage was observed. 4. In a prospective study, we compared US-assisted Abrams and Tru-Cut needle biopsies with regard to their yield for pleural TB. Pleural biopsy specimens obtained with Abrams needles contained pleural tissue in 91.0% of cases and were diagnostic in 81.8%, whereas Tru-Cut needle biopsy specimens only contained pleural tissue in 78.7% (p=0.015) and were diagnostic in 65.2% (p=0.022). In conclusion, we investigated the feasibility of US-assisted biopsies performed by respiratory physicians in various settings, and consistently found acceptable to very high diagnostic yields with minimal complications. Furthermore, we were able to validate a novel indication for US-assisted TTFNA (US-assisted TTFNA of drowned lung), validate the use of a single-session sequential approach (USassisted TTFNA with ROSE followed by CNB where indicated) in at least two clinical settings (SVC syndrome and anterosuperior mediastinal masses) and we were able to show that US-assisted Abrams needle biopsy is superior to Tru-Cut needles biopsy when histological confirmation of TB pleuritis is required. / AFRIKAANSE OPSOMMING: Alhoewel transtorakale ultrasonografie ‘n gevestigde modaliteit is, word dit onderbenut deur pulmonoloë. Die doel van hierdie navorsingsprojek was om die praktiese uitvoerbaarheid, diagnostiese opbrengs en veiligheid van sonargerigte transtorakale biopsies uitgevoer deur klinici in verskeie situasies relevant tot die alledaagse praktyk te ontleed. Ons het vier kliniese proewe uitgevoer wat hieronder opgesom word: 1. In ‘n prospektiewe studie oor die praktiese uitvoerbaarheid van sonargerigte transtorakale fyn naald aspirasie (TTFNA) van areas van obstruktiewe pneumonitis sekondêr tot proksimale massa letsels, is ‘n nuwe indikasie vir sonargerigte TTFNA beskryf. TTFNA aspirasies wat >20mm van die visserale pleura geneem is, het ‘n sensitiwiteit van 74.2% gehad en was meer geneig om maligne selle op te lewer as meer oppervlakkige aspirasies. Die verbasende hoë diagnostiese sensitiwiteit en afwesigheid van ernstige komplikasies het die praktiese waarde van hierdie benadering bevestig. 2. In die grootste studie nog oor sonargerigte TTFNA met spoedige in-teater evalusies (SITE) en sny-naald biopsie (SNB) in die teenwoordigheid van superior vena cava (SVC) sindroom, kon ons 96% van pasiënte wat presenteer het met ‘n geassosieerde massa letsel wat die borskaswand betrek, akkuraat diagnoseer. Geen pneumotoraks of major bloeding is waargeneem nie. Ons kon ook die praktiese uitvoerbaarheid van ‘n enkelsessie benadering bevestig en kon tot die gevolgtrekking kom dat sonargerigte TTFNA (met SITE) die aanvanklike ondersoek van keuse is waar bronguskarsinoom vermoed word, maar dat beide TTFNA en SNB noodsaaklik is in ander gevalle. 3. Ons het voortgegaan om die waarde van die nuwe enkel-sessie benadering te bevestig in ‘n studie oor antero-superior mediastinale massas. Sonargerigte TTFNA met SITE is uitgevoer op 45 pasiënte en in gevalle waar ‘n voorlopige diagnose van epiteliale karsinoom of waarskynlike tuberkulose (TB) nie bevestig kon word nie, is dit onmiddelik gevolg deur SNB. ‘n Akkurate sitologiese diagnose is gemaak in 73.3% van gevalle en meer algemeen in epiteliale karsinoom en TB as ander patologie (p<001). SNB was diagnosties in 88.2%. In 93.3% kon ‘n diagnose verkry word met die enkel-sessie benadering. Geen pneumotoraks of major bloeding is waargeneem nie. 4. In ‘n prospektiewe studie is sonargerigte Abrams naald en Tru-Cut naald biopsies se opbrengs vir pleurale TB met mekaar vergelyk. Pleurale biopsie monsters wat met ‘n Abrams naalde geneem is, het pleurale weefsel in 91.0% gevalle getoon en was diagnosties in 81.8%, vergeleke met Tru-Cut naalde wat slegs in 87.7% pleurale weefsel opgelewer het (p=0.015) en wat net in in 65.2% diagnosties was (p=0.022). Opsommend het ons die praktiese uitvoerbaarheid van sonargerigte biopsies uitgevoer deur pulmonoloë in veskeie kliniese situasies nagevors, en het deurlopend aanvaarbare tot hoë diagnostiese opbrengste gevind met minimale komplikasies. Verder kon ons ‘n nuwe indikasie vir sonargerigte TTFNA beskryf en evalueer (sonargerigte TTFNA van obstruktiewe pneumonitis); ‘n enkel-sessie sekwensiële benadering se waarde bevestig (sonargerigte TTFNA met SITE, gevolg deur SNB waar aangedui) in ten minste twee kliniese situasies (SVC sindroom en anterosuperior mediastinale massas); en was dit moontlik om te bewys dat UK-geleide Abrams naald biopsies superior tot Tru-cut naald biopsies is in die histologiese bevestiging van TB pleuritis.

Surface mount devices (SMDs), such as flip chip packages and ball grid array (BGA) packages are gaining in popularity in microelectronics industry because they provide high density inputs/outputs, better electrical and thermal performance. However, these solder bump interconnections in SMDs are sandwiched between the silicon die and the substrate, which makes them challenging to be inspected. Current non-destructive solder bump inspection techniques like electrical testing, X-ray and acoustic microscopy have some application gaps. New solder bump inspection technique is urgently needed to fill these gaps. Previous work has shown the potential of using a non-contact, non-destructive laser ultrasonics and laser interferometer based inspection system for assessing solder bump qualities. The system uses a pulsed Nd:YAG laser to induce ultrasound in the chip packages and a laser interferometer to measure the transient out-of-plane displacement on the package surface. The quality of the solder bumps can be evaluated by analyzing the out-of-plane displacement. However, there are still some gaps that need to be addressed before the system is ready on the shelf. This dissertation focuses on addressing some of these existing issues. The research work consists of the following: 1) a control interface was developed to integrate all the different modules to achieve automation. 2) a new signal-processing method for analyzing the transient out-of-plane displacement signals without requiring a known-good reference chip was developed. 3) the application scope of the system was expanded to inspect the second level solder bumps in BGA packages. Two types of process-induced defects including poor-wetting and solder bump voids were investigated. Meanwhile, solder bump fatigue caused by cyclic mechanical bending and thermal cycle was also studied using this system. 4) a finite element analysis was performed to study the thermo-mechanical reliability of solder bumps in PBGA package under cyclic thermal loads. The successful completion of the research objectives has led to a laser ultrasound solder bump inspection system prototype with more user-friendliness, higher throughputs, better repeatability and more flexibility, which accelerate the commercialization the system.

The primary purpose of this work was to evaluate the capability of nanoparticles to transform electromagnetic energy at microwave frequencies into therapeutic heating. Targeted nanoparticles, in conjunction with microwave irradiation, can increase the temperatures of the targeted area over the peripheral region. Therefore, to become clinically viable, microwave absorbing nanoparticles must first be identified, and a system to monitor the treatment must be developed. In this study, ultrasound temperature imaging was used to monitor the temperature of deep lying structures. First, a material-dependent quantity to correlate the temperature induced changes in ultrasound images (i.e. apparent time shifts) to differential temperatures was gathered for a tissue-mimicking phantom, porcine longissimus dorsi muscle, and porcine fat. Then microwave nanoabsorbers were identified using an infrared radiometer. The determined nanoabsorbers were then injected into ex-vivo porcine longissimus dorsi muscle tissue. Ultrasound imaging frames were gathered during microwave treatment of the inoculated tissue. Finally, the ultrasound frames were analyzed using the correlation between temperature and apparent shifts in ultrasound for porcine muscle tissue. The outcome was depth-resolved temperature profiles of the ex-vivo porcine muscle during treatment. The results of this study show that magnetite is a microwave nanoabsorber that increases the targeted temperature of microwave hyperthermia treatments. Overall, there is clinical potential to use microwave nanoabsorbers to increase the efficiency of microwave hyperthermia treatments. / text

<p>The aim with this thesis was to assess the impact of prenatal ultrasound exposure on psychotic illness, childhood brain tumors (CBT) and school achievement, and to evaluate prenatal X-ray exposure and the risk of CBT.</p><p>In a cohort study, children born in Malmö 1973-1978, where prenatal ultrasound was used routinely, were considered exposed (n=13, 212) and children born at hospitals with no use of ultrasound, were considered unexposed (n=357,733). Exposed men had a tendency toward a higher risk of schizophrenia. For other psychoses there were no differences between groups. Other factors related to place of birth might have influenced the results. </p><p>In a case control study, children born 1975-1984 with a diagnosis of CBT (n=512), and randomly selected control children (n=524) were included. Exposure data on X-ray and ultrasound from antenatal records was completed with information from the Medical Birth Register. We found no overall increased risk for CBT after prenatal X-ray exposure. When stratifying by histological subgroups, primitive neuroectodermal tumors had the highest risk estimates. For ultrasound exposure, no increased risk for CBT was seen and numbers of examinations or gestational age at exposure had no substantial impact on the results. </p><p>In a follow-up of a randomized trial on prenatal ultrasound scanning 1985-87, we assessed the children’s school grades when graduating from primary school (15-16 years of age). We performed analyses according to randomization, ultrasound exposure in the second trimester and exposure at any time during pregnancy. There were no differences in school performance for boys or girls according to randomization or exposure in the second trimester. Boys exposed to ultrasound any time during fetal life had a reduced mean score in physical education and small, non-significant increased risk of poor school performance in general.</p>

Early detection of cancer is paramount for improved patient survival. This dissertation presents work developing imaging techniques to improve cancer diagnostics and detection utilizing light and microwave induced thermoacoustic imaging. In the second chapter, the well-established pre-clinical mouse window chamber model is interfaced with simultaneously acquired high-resolution pulse echo (PE) ultrasound and photoacoustic (PA) imaging. Co-registered PE and PA imaging, coupled with developed image segmentation algorithms, are used to quantitatively track and monitor the size, shape, heterogeneity, and neovasculature of the tumor microenvironment during a month long study. Average volumetric growth was 5.35 mm³/day, which correlated well with two dimensional results from fluorescent imaging (R = 0.97, p < 0.01). Spectroscopic PA imaging is also employed to probe the assumed oxygenation status of the tumor vasculature. The window chamber model combined with high-resolution PE and PA imaging could form a powerful testbed for characterizing cancers and evaluating new contrast and therapeutic agents. The third chapter utilizes a clinical ultrasound array to facilitate fast volumetric spectroscopic PA imaging to detect and discriminate endogenous absorbers (i.e. oxy/deoxygenated hemoglobin) as well as exogenous PA contrast agents (i.e. gold nanorods, fluorophores). In vivo spatiotemporal tracking of administered gold nanorods is presented, with the contrast agent augmenting the PA signal 18 dB. Furthermore, through the use of spectral unmixing algorithms, the relative concentrations of multiple endogenous and exogenous co-localized absorbers were reconstructed in tumor bearing mice. The concentration of Alexaflour647 was calculated to increase nearly 20 dB in the center of a prostate tumor after a tail-vein injection of the contrast agent. Additionally, after direct subcutaneous injections of two different gold nanorods into a breast tumor, the concentration of each nanoparticle was discriminated in vivo with a signal-to-noise ratio of greater than 25 dB. This technique has great potential for improved early cancer detection and individualized cancer treatment through advanced pharmacokinetic monitoring of therapeutic agents. Finally, the fourth chapter presents significant improvements made to enhance breast cancer detection with thermoacoustic (TA) imaging. In a breast cancer simulating phantom, the initial demonstration of TA spectroscopy (TAS) is used to detect and discriminate relative water / fat composition based solely on the sample's intrinsic spectral absorption. The slope of the TA signal was highly correlated with that of the absorption coefficient (R² = 0.98, p < 0.01), indicating TAS can distinguish materials based on their dielectric properties. Furthermore, the use of carbon nanotubes as a potential TA contrast agent is explored. These nanoparticles significantly enhance the magnitude of the TA signal (8 dB larger than water), and also demonstrate unique absorption spectra. Finally, short microwave pulses (Δt ≥ 10 ns) are achieved through novel microwave hardware, and used to generate high-frequency TA signals. In conclusion, this section presents advancements made to the sensitivity, contrast, and resolution of TA imaging. Overall, this dissertation presents enhancements made to the diagnostic capabilities of PA and TA imaging for improved detection and characterization of cancer.

Single frame ultrasound B-mode image quality is largely governed by the ability to focus the ultrasound beam over a range in depths both in transmission and reception. By developing a comprehensive understanding of acoustic wave propagation two signal processing methods were identified for solving the transmission problem. We made use of both the impulse response using the classical point spread function (PSF) and the spatial sensitivity function (SSF) which describes the spatial distribution at a particular time. Using the angular spectrum method, an accurate analytical model was developed for the field distribution arising from a finite geometry, apodized and focused, plane piston transducer. While there is a thorough understanding of the radiated field arising from uniformly excited plane piston transducers, the focused equivalent (i.e., one that allows a continuous change in phase over the plane piston surface) is incomplete and assumes the Fresnel approximation. Our model addresses the effects of diffraction and evanescent waves without the use of the Fresnel approximation and is applicable at all near- and far-field locations in a lossless medium. The model was analyzed to identify new insights into wave propagation and compared with the Fresnel approximation and the spherically-focused, concave transducer. The piston transducer model was then extended to an attenuating and dispersive medium. After analysing existing models of power-law frequency dependent attenuation, a causal, spherical wave Green’s function was derived from the Navier-Stokes equation for a classical viscous medium. Modifications to the angular spectrum method were presented and used to analyze the radiated field of a focused, planar piston transducer. Finally, after presenting our signal processing strategy for improving imaging spatial resolution through minimization of the SSF, two signal processing methods were derived and analysed in simulation: a deconvolution technique to remove the effects of the ultrasound excitation wave and suppress additive noise from the received ultrasound signal, and a retrospective transmit focusing method that changed the response from a predefined transmit focus to an arbitrary transmit focal depth. Proof-of-concept simulations were presented using a variable number of scatterers and compared with the traditional matched filtering and envelope detection technique.

<p>Implemented on an intracardiac echocardiography transducer, acoustic radiation force methods may provide a useful means of characterizing the heart's elastic properties. Elasticity imaging may be of benefit for diagnosis and characterization of infarction and heart failure, as well as for guidance of ablation therapy for the treatment of arrhythmias. This thesis tests the hypothesis that with appropriately designed imaging sequences, intracardiac acoustic radiation force impulse (ARFI) imaging and shear wave elasticity imaging (SWEI) are viable tools for quantification of myocardial elasticity, both temporally and spatially. Multiple track location SWEI (MTL-SWEI) is used to show that, in healthy in vivo porcine ventricles, shear wave speeds follow the elasticity changes with contraction and relaxation of the myocardium, varying between 0.9 and 2.2 m/s in diastole and 2.6 and 5.1 m/s in systole. Infarcted tissue is less contractile following infarction, though not unilaterally stiffer. Single-track-location SWEI (STL-SWEI) is proven to provide suppression of speckle noise and enable improved resolution of structures smaller than 2 mm in diameter compared to ARFI and MTL-SWEI. Contrast to noise ratio and lateral edge resolution are shown to vary with selection of time step for ARFI and arrival time regression filter size for STL-SWEI and MTL-SWEI. </p><p>In 1.5 mm targets, STL-SWEI achieves alternately the tightest resolution (0.3 mm at CNR = 3.5 for a 0.17 mm filter) and highest CNR (8.5 with edge width = 0.7 mm for a 0.66 mm filter) of the modalities, followed by ARFI and then MTL-SWEI.</p><p>In larger, 6 mm targets, the CNR-resolution tradeoff curves for ARFI and STL-SWEI overlap for ARFI time steps up to 0.5 ms and kernels $\leq$1 mm for STL-SWEI. STL-SWEI can operate either with a 25 dB improvement over MTL-SWEI in CNR at the same resolution, or with edge widths 5$\times$ as narrow at equivalent CNR values, depending on the selection of regression filter size. Ex vivo ablations are used to demonstrate that ARFI, STL-SWEI and MTL-SWEI each resolve ablation lesions between 0.5 and 1 cm in diameter and gaps between lesions smaller than 5 mm in 3-D scans. Differences in contrast, noise, and resolution between the modalities are discussed. All three modalities are also shown to resolve ``x''-shaped ablations up to 22 mm in depth with good visual fidelity and correspondence to surface photographs, with STL-SWEI providing the highest quality images. Series of each type of image, registered using 3-D data from an electroanatomical mapping system, are used to build volumes that show ablations in in vivo canine atria. In vivo images are shown to be subject to increased noise due to tissue and transducer motion, and the challenges facing the proposed system are discussed. Ultimately, intracardiac acoustic radiation force methods are demonstrated to be promising tools for characterizing dynamic myocardial elasticity and imaging radiofrequency ablation lesions.</p> / Dissertation

The goal of this thesis is to design, implement and evaluate an automated algorithm to detect cancerous tissues and segment the malignant tumour in ultrasound images of the prostate. To accomplish this goal, first, the important image features which would lead to the optimal segmentation are identified. This work focuses on the local texture feature and spatial features. Various approaches to extract the local texture feature are explored, including grey-level co-occurrence matrix (GLCM), recurrent random-pulsed neural networks (RNN), and a novel wavelet-based filter. The spatial features are represented using conventional one dimensional fuzzy membership functions and novel multi-dimensional fuzzy membership functions. The texture and spatial features are combined using the fuzzy inference system. Two of the techniques investigated in this thesis could potentially constitute the basis for key paradigm shifts in medical imaging research. One of these is the idea that medical images in general, and ultrasound images in particular, contain information which are hidden from medical professionals due to limitations in the human visual system. This thesis shows that this information could be extracted using a computerized approach by separating the deterministic components in the image from the indeterministic components, or noise. The other idea concerns the representation of multidimensional statistical distribution information with fuzzy membership functions with the corresponding dimensions. This thesis shows that increasing the number of dimensions with which to represent the statistical distributions results in a more accurate mapping of information that relates to human anatomy, which is essentially 3D in nature. In the thesis, the natures of the various techniques are explored by testing on synthesized images. Then, these approaches are adapted to the ultrasonic prostate cancer segmentation problem and are evaluated with trans-rectal ultrasound images (TRUS). The segmentation using only texture features yields results with high sensitivity. When the spatial features are incorporated using the fuzzy inference system, the specificity of the diagnosis improves dramatically and the overall classification accuracy is also increased. Clinically, this automated diagnostic system could be used as a decision support tool for radiologists when identifying suspicious regions in the prostate from which to draw biopsy samples. The proposed system improves the consistency of the cancer detection process and could provide savings in both time and cost in the prevention and treatment of prostate cancer.