Histotripsy is a non-invasive, non-thermal, and non-ionizing therapy that utilizes converging high-pressure ultrasound waves at a focal point to produce cavitation and induce mechanical tissue destruction. Currently, rapid prototyped histotripsy transducers consist of multiple elements and are made using 3D printing methods. Multi-element transducers introduce size constraints and 3D printing has limitations in material choice, cost, and time for larger scale manufacturing. This thesis investigates the development of rapid prototyped single element histotripsy transducers and the use of injection molding for transducer fabrication, utilizing an in-house metal CNC mill for mold manufacturing and a desktop injection molding machine. Nylon 101 and 30% glass-filled nylon were chosen as the plastics to inject as these were found to have the most similar acoustic properties to WaterShed, an ABS-like plastic currently used. Six single-element transducers were constructed with a 2 MHz curved Pz26 piezoceramic disc: two with SLA 3D printed housing, two with SLS 3D printed housing, and two with injection molded housing. Electrical impedance, beam dimensions, focal pressure output, and cavitation were characterized for each element. The results show that rapid prototyped single element transducers can generate enough pressure to perform histotripsy. This marks the development of the first rapid prototyped single element histotripsy transducer and further confirms that injection molding can produce transducers comparable, if not identical or potentially superior, to 3D printed counterparts. Future work aims to further characterize these transducers, explore more material options, and apply injection molding to various transducer designs while optimizing both CNC and injection molding parameters. / Master of Science / Histotripsy is a form of cancer therapy that can non-invasively treat tumors using focused ultrasound waves. Focused ultrasound transducers are used to achieve this and are currently prototyped using 3D printing. However, these methods are limiting in material options and upscale manufacturing. Many of these devices currently used tend to be larger in size, comparable to the size of a mixing bowl, which limits its applications. This thesis investigates the development of single element histotripsy transducers and the use of injection molding for transducer fabrication, using an in-house metal CNC mill for mold manufacturing and desktop injection molding machine. Nylon 101 and 30% glass-filled nylon were chosen as the plastics to inject due to their ideal acoustic properties. Six single-element transducers were constructed: two with SLA 3D printing, two with SLS 3D printing, and two with injection molding. All transducers were tested and compared against each other. The results show that 3D printed single element transducers can perform histotripsy and that injection molding can produce comparable results. Future work should continue to test and characterize these transducers, explore more material options for injection molding, apply injection molding to other transducer designs, and optimize CNC and injection molding parameters.

Ultrasonic humidifiers use sound vibrations at frequencies higher than can be heard by humans (> 20,000 Hz) to generate aerosolized water also have potential for inducing sonochemical reactions for chemicals present in water. This research focuses on examining oxidants formed within ultrasonic humidifiers, as well as the oxidants effects of contaminants in water used in the systems. Hydroxyl radicals were found using DMPO as a spin trap. Caffeine and 17β-estradiol, as pharmaceutical contaminants of drinking water, were both emitted from the humidifier when present in the water reservoir and would enter breathing air. Emitted 17β-estradiol was found at 60% of the initial concentration filled in the ultrasonic humidifier after 480 minutes. Caffeine exhibited less degradation than 17β-estradiol. Degradation of both pharmaceuticals was attributed to ultrasonic processes, most likely oxidation with hydroxyl radicals produced. Bromide as a contaminant of the fill water was found to remain constant over time. / MS / Ultrasonic humidifiers carry health benefits from humidified air, but also have potential for chemical reactions within the systems that can impact human health. This research focuses on examining oxidants formed in ultrasonic humidifiers, as well as the degradation of contaminants in water used in the ultrasonic humidifiers. Hydroxyl radicals were found to be generated within the humidifier system. Caffeine and 17β-estradiol, a common estrogen, are possible contaminants in drinking water, which may be used to fill a humidifier. Both were introduced and emitted from the ultrasonic humidifier. Emitted 17β-estradiol was found at 60% of the initial concentration filled in the ultrasonic humidifier at the start of 8 hours. Degradation of both pharmaceuticals was attributed to ultrasonic processes, most likely oxidation with hydroxyl radicals produced.

A reticulonodular splenic pattern is commonly associated with neoplastic or infectious etiologies. However, this has been described as an age-related variant in both humans and dogs, likely representing lymphoid follicles. The purpose of this study was to determine whether the ultrasonographic appearance of the spleens of growing kittens mimics the canine presentation. This was a prospective, descriptive study design. Healthy kittens up to 18 months old were scanned using a high frequency linear transducer. A reticulonodular pattern was present in (89%) of spleens. After 4 months of age, there was an overall negative correlation with age and the grade of the imaged spleen, which persisted even amongst the kittens that were enrolled serially. The findings of this study suggest that a reticulonodular pattern in young cats and kittens may be a normal finding within this population.

Although the drug-eluting stent (DES) has dramatically reduced the rate of coronary restenosis, it still occurs in up to 20% of patients with a DES. Monitoring drug delivery could be one way to decrease restenosis rates. We demonstrate real-time photoacoustic imaging and spectroscopy (PAIS) using a wavelength-tunable visible laser and clinical ultrasound scanner to track cardiac drug delivery. The photoacoustic signal was initially calibrated using porcine myocardial samples soaked with a known concentration of a drug surrogate (Dil). Next, an in situ coronary artery was perfused with DiI for 20 min and imaged to monitor dye transport in the tissue. Finally, a partially DiI-coated stent was inserted into the porcine brachiocephalic trunk for imaging. The photoacoustic signal was proportional to the DiI concentration between 2.4 and 120 mu g/ml, and the dye was detected over 1.5 mm from the targeted coronary vessel. Photoacoustic imaging was also able to differentiate the DiI-coated portion of the stent from the uncoated region. These results suggest that PAIS can track drug delivery to cardiac tissue and detect drugs loaded onto a stent with sub-mm precision. Future work using PAIS may help improve DES design and reduce the probability of restenosis. (C) 2017 Society of Photo-Optical Instrumentation Engineers (SPIE)

A caracterização de tecido ósseo por ultra-som para o diagnóstico de osteoporose tem sido investigada como uma alternativa a densitometria óssea baseada em radiação ionizante. A interação do ultra-som com o tecido ósseo é fundamentalmente diferente da que ocorre com a energia ionizante. O potencial da técnica ultra-sônica baseia-se nos efeitos sobre a propagação do campo acústico causados pela estrutura, composição e massa do tecido que está sendo investigado. Quatro estudos in-vitro e um estudo clínico estão descritos neste trabalho. O primeiro estudo in-vitro compara a correlação entre medidas ultra-sônicas e de densidade mineral óssea (em g/cm3) em tecido trabecular humano e bovino. A velocidade e atenuação ultra-sônicas em amostras ósseas foram determinadas pela técnica de inserção convencional (modo de transmissão) e a medida de densidade mineral óssea foi realizada por absortometria de um fóton (SPA). O mecanismo de interação do ultra-som com osso trabecular é pouco conhecido. O segundo estudo in-vitro investigou como a presença da medula óssea afeta as medidas de velocidade e atenuação. As correlações entre medidas ultrasônicas e de densidade mineral óssea (em g/cm3) por SPA, com e sem a presença da medula óssea, são também determinadas. A medida ultra-sônica de inserção convencional é comparada a medida de inserção por contato. O terceiro estudo in-vitro investigou em amostras de calcâneo as correlações entre medidas ultra-sônicas e de densidade mineral óssea (em g/cm3 e em g/cm2) por SPA. A determinação da densidade mineral Óssea em g/cm2 (BMD) a partir de medidas ultra-sônicas nas amostras foi pela primeira vez investigada, utilizando-se uma técnica de regressão linear univariável e multivariável e uma técnica multivariável não-linear baseada em redes neurais. Um novo parâmetro, baseado na média da frequência instantânea (MIF) do sinal da amostra e de referência, foi proposto para caracterizar o tecido ósseo devido a sua alta correlação com a atenuação. O efeito das corticais ósseas do calcâneo nas medidas ultra-sônicas é pouco conhecido. O quarto estudo in-vitro determinou a correlação entre medidas ultrasônicas e de densidade mineral óssea (em g/cm3) por SPA, com e sem a presença das corticais ósseas. Finalmente, no estudo clínico foram determinadas as correlações entre medidas ultra-sônicas no calcanhar e de densidade mineral óssea por DEXA (em g/cm2) no cólo femoral. A determinação da densidade óssea a partir de medidas ultra-sônicas no calcanhar foi pela primeira vez investigada, utilizando-se uma técnica de regressão linear univariável e multivariável e uma técnica multivariável não-linear baseada em redes neurais. / Ultrasonic assessment of bone for managing osteoporosis has been investigated as an alternative to radition-based bone densitometry technology. In contrast with the ionizing electromagnetic radiation of such clinical bone densitometric technique, ultrasound is a mechanical wave and thus interacts with bone in a fundamentally distinct manner. Ultrasound is viewed as having great potential for assessing bone since its propagation is affected by the structure, composition, and mass of the bone tissue being interrogated. Four in-vitro and one clinical study are reported in this work. In the first in-vitro study a comparison is reported on the ultrasonic assessment of human trabecular and bovine trabecular bone samples. Both ultrasonic velocity and attenuation were evaluated through a standard transmission insertion technique and correlated with bone mineral density (in g/cm3 ) as determined with single photon absorptiometry (SPA). There is a relatively limited understanding of how ultrasound interacts with cancellous bone. One potentially model leads analytically to the demonstration that ultrasound propagation through bone is dependent on several factors, including the properties of the fluid, which saturates the pores of the cancellous bone tissue. The second in-vitro study was carried out to assess how the presence of marrow affects the velocity and attenuation measurements. The correlation between ultrasonic and densitometric measurements (in g/cm3) by SPA, with and without the bone marrow, are also determined. A second part of this study compared the measurements of ultrasonic attenuation and velocity on bovine cancellous bone samples using a standard insertion technique with those obtained using a contac method. The thrid in-vitro study with the calcis trabecular samples investigated the correlations between ultrasonic measurements and bone mineral density (in g/cm3 e em g/cm2) as measured by SPA. A nonlinear multivariate estimation technique based on neural network was the first time investigated to determine the ability of ultrasonic measurements to estimate bone mineral density in g/cm2 (BMD). A linear univariate and multivariate estimation of BMD was compared with the neural network approach. A new parameter to characterize the trabecular bone is been proposed, which is based on the mean instantaneous frequency (MIF) of the sample and reference signals after transmission through the os calcis. It was founded a high correlation between MIF and the attenuation (BUA). Little is known about the effect of the os calcis cortical shell on ultrasonic measurements. The fourth in-vitro study with os calcis samples determined the correlation between ultrasonic and densitometric measurements (in g/cm3) by SPA with and without the cortical shell. Finally, a nonlinear multivariate estimation technique based on neural network was the first time investigated to determine the ability of clinical ultrasonic measurements in the heel to estimate bone mineral density (BMD) in the femoral neck. A linear univariate and multivariate estimation to predict BMD in patients is also compared with the neural network approach.

A level set-based segmentation procedure has been implemented to identify target object boundaries from 3D medical ultrasound images. Several test images (simulated, scanned phantoms, clinical) were subjected to various preprocessing methods and segmented. Two metrics of segmentation accuracy were used to compare the segmentation results to ground truth models and determine which preprocessing methods resulted in the best segmentations. It was found that by using an anisotropic diffusion filtering method to reduce speckle type noise with a 3D active contour segmentation routine using the level set method resulted in semi-automated segmentation on par with medical doctors hand-outlining the same images.

<p>In this work, I examine the problem of rapid imaging of stroke and present ultrasound-based approaches for addressing it. Specifically, this dissertation discusses aberration and attenuation due to the skull as sources of image degradation and presents a prototype system for simultaneous 3D bilateral imaging via both temporal acoustic windows. This system uses custom sparse array transducers built on flexible multilayer circuits that can be positioned for simultaneous imaging via both temporal acoustic windows, allowing for registration and fusion of multiple real-time 3D scans of cerebral vasculature. I examine hardware considerations for new matrix arrays--transducer design and interconnects--in this application. Specifically, it is proposed that signal-to-noise ratio (SNR) may be increased by reducing the length of probe cables. This claim is evaluated as part of the presented system through simulation, experimental data, and in vivo imaging. Ultimately, gains in SNR of 7 dB are realized by replacing a standard probe cable with a much shorter flex interconnect; higher gains may be possible using ribbon-based probe cables. In vivo images are presented depicting cerebral arteries with and without the use of microbubble contrast agent that have been registered and fused using a search algorithm which maximizes normalized cross-correlation. </p><p>The scanning geometry of a brain helmet-type system is also utilized to allow each matrix array to serve as a correction source for the opposing array. Aberration is estimated using cross-correlation of RF channel signals followed by least mean squares solution of the resulting overdetermined system. Delay maps are updated and real-time 3D scanning resumes. A first attempt is made at using multiple arrival time maps to correct multiple unique aberrators within a single transcranial imaging volume, i.e. several isoplanatic patches. This adaptive imaging technique, which uses steered unfocused waves transmitted by the opposing or "beacon" array, updates the transmit and receive delays of 5 isoplanatic patches within a 64°×64° volume. In phantom experiments, color flow voxels above a common threshold have increased by an average of 92% while color flow variance decreased by an average of 10%. This approach has been applied to both temporal acoustic windows of two human subjects, yielding increases in echo brightness in 5 isoplanatic patches with a mean value of 24.3 ± 9.1%, suggesting such a technique may be beneficial in the future for improving image quality in non-invasive 3D color flow imaging of cerebrovascular disease including stroke.</p><p>Acoustic window failure and the possibility of overcoming it using a low frequency, large aperture array are also examined. In performing transcranial ultrasound examinations, 8-29% of patients in a general population may present with window failure, in which it is not possible to acquire clinically useful sonographic information through the temporal acoustic window. The incidence of window failure is higher in the elderly and in populations of African descent, making window failure an important concern for stroke imaging through the intact skull. To this end, I describe the technical considerations, design, and fabrication of low-frequency (1.2 MHz), large aperture (25.3 mm) sparse matrix array transducers for 3D imaging in the event of window failure. These transducers are integrated into the existing system for real-time 3D bilateral transcranial imaging and color flow imaging capabilities at 1.2 MHz are directly compared with arrays operating at 1.8 MHz in a flow phantom with approximately 47 dB/cm0.8/MHz0.8 attenuators. In vivo contrast-enhanced imaging allowed visualization of the arteries of the Circle of Willis in 5 of 5 subjects and 8 of 10 sides of the head despite probe placement outside of the acoustic window. Results suggest that the decrease from approximately 2 to 1 MHz for 3D transcranial ultrasound may be sufficient to allow acquisition of useful images either in individuals with poor windows or outside of the temporal acoustic window by untrained operators in the field.</p> / Dissertation

<p>Ultrasound can be used for a variety of therapeutic purposes. High-intensity focused ultrasound (HIFU) has progressed over the past decade to become a viable therapeutic method and is valuable as a non-invasive alternative to many surgical procedures. Ultrasonic thermal therapies can also be used to release thermally sensitive liposomes encapsulating chemotherapeutic drugs. In the brain, the permeability of the blood-brain barrier to drugs, antibodies, and gene transfer can be increased with a mechanical mechanism using ultrasound and contrast agent.</p><p>The work presented in this dissertation tests the hypothesis that a diagnostic system can be used for combined imaging and therapeutic applications. In order to evaluate the effectiveness of a diagnostic system for use in therapeutic applications, a set of non-destructive tests is developed that can predict the potential for high acoustic output. A rigorous, nondestructive testing regimen for standard, diagnostic transducers to evaluate their potential for therapeutic use is formulated. Based on this work, transducer heating is identified as the largest challenge. The design and evaluation of several custom diagnostic transducers with various modifications to reduce internal heating are described. These transducers are compared with diagnostic controls using image contrast, face heating, hydrophone, and ARFI displacement measurements. From these results, we conclude that the most promising design is a passively and actively cooled, PZT-4 multilayer composite transducer, while the acoustically lossless lens and capactive micro-machined transducers evaluated herein are determined to be ineffective.</p><p>Three therapeutic applications are evaluated for the combined system. Image-guided spot ablations, such as in the treatment of early stage liver cancers, could not be successfully performed; however, the additional acoustic output requirements are determined to be on the order of 2.4 times those that can be currently produced without transducer damage in a clinically relevant amount of time (10-20 seconds per spot). The potential of a diagnostic system for a hyperthermia application is shown by producing temperatures for the duration necessary to release chemotherapeutic agents from thermally-activated liposomes without damage to the transducer. Finally, a mechanically-based therapeutic method for opening the BBB with ultrasonic contrast agent and specialized sonication regimes under ultrasonic B-mode guidance is demonstrated.</p><p>These studies indicate that a diagnostic system is capable of both moderate thermal and mechanical therapeutic applications under co-registered image-guidance.</p> / Dissertation

Current technology used to diagnose hearing disorders is limited. This is mostly due to the fact that the auditory structures are very small and not easily accessible with existing imaging technologies. The objective of this dissertation was to investigate the potential of high-frequency ultrasound as a tool for exploring the anatomy of the auditory system. Three studies were conducted in order to demonstrate the feasibility of high-frequency ultrasound as a diagnostic technology for hearing disorders. In the first study, an in-house developed 50 MHz annular array-based ultrasound system was used to provide ex-vivo images of auditory structures in cadaveric temporal bones. It was shown that the spatial resolution was sufficient to visualize a high level of detail of the ossicular bones of the middle ear as well as intra-cochlear structures of the inner ear. In the second study, a 50 MHz 1.26? pitch phased array ultrasound transducer was designed for imaging intra-cochlear structures through the round window membrane. As this element pitch results in large grating lobe artifacts, novel transmit beamforming techniques were developed to suppress grating lobes resulting from this large-pitch array. Theoretical techniques using the impulse-response simulation method and experimental verification using high-frequency linear array ultrasound system (Vevo 2100, VisualSonics, Canada) showed that these techniques were able to suppress grating lobe levels up to 40 dB. In the third study, a needle mounted 45 MHz single-element ultrasound probe was fabricated in order to measure the vibrations of intra-cochlear structures on human cadavers. Basilar membrane velocimetry measurements were successfully performed using pulsed-wave Doppler ultrasound in the frequency range between 100 Hz-2 KHz. The measured velocity of the basilar membrane and the round window membrane showed that the middle ear resonance frequency near 1 KHz was present over multiple temporal bones. This is the first work that has explored the human auditory system with high resolution ultrasonic visualization and Doppler velocimetry.

Nonlinear ultrasonic waves have demonstrated high sensitivities to various microstructural changes in metal including coherent precipitates; these precipitates introduce a strain field in the lattice structure. The thermal aging of certain alloy steels leads to the formation of coherent precipitates, which pin dislocations and contribute to the generation of a higher harmonics in an initially monochromatic wave. The objective of this research is to develop a robust technique to perform nonlinear Rayleigh wave measurements in metals using a non-contact receiving transducer. In addition a discussion about the data processing based on the two-dimensional diffraction and attenuation model is provided in order to calculate the relative nonlinearity parameter. A precipitate hardenable material, 17-4 PH stainless steel, is used to obtain different precipitation stages by thermal treatment and the influence of precipitates on the ultrasonic nonlinearity is assessed. Conclusions about the microstrucutural changes in the material are drawn based on the nonlinear Rayleigh surface wave measurement and complementary measurements of thermo-electric power, mircohardness and ultrasonic velocity. The results show that the nonlinearity parameter is sensitive to coherent precipitates in the material and moreover that precipitation characteristics can be characterized based on the obtained experimental data.