Yes / Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs. Methods: Using a microfluidic microbubble production platform, we generated thMBs comprising VEGFR2-targeted microbubbles with attached liposomal payloads for localised ultrasound-triggered delivery of irinotecan and SN38 in mouse models of colorectal cancer. Intravenous injection into tumor-bearing mice was used to examine targeting efficiency and tumor pharmacodynamics. High-frequency ultrasound and bioluminescent imaging were used to visualise microbubbles in real-time. Tandem mass spectrometry (LC-MS/MS) was used to quantitate intratumoral drug delivery and tissue biodistribution. Finally, 89Zr PET radiotracing was used to compare biodistribution and tumor accumulation of ultrasound-triggered SN38 thMBs with VEGFR2 targeted SN38 liposomes alone. Results: ThMBs specifically bound VEGFR2 in vitro and significantly improved tumor responses to low dose irinotecan and SN38 in human colorectal cancer xenografts. An ultrasound trigger was essential to achieve the selective effects of thMBs as without it, thMBs failed to extend intratumoral drug delivery or demonstrate enhanced tumor responses. Sensitive LC-MS/MS quantification of drugs and their metabolites demonstrated that thMBs extended drug exposure in tumors but limited exposure in healthy tissues, not exposed to ultrasound, by persistent encapsulation of drug prior to elimination. 89Zr PET radiotracing showed that the percentage injected dose in tumors achieved with thMBs was twice that of VEGFR2-targeted SN38 liposomes alone. Conclusions: thMBs provide a generic platform for the targeted, ultrasound-triggered delivery of cytotoxic drugs by enhancing tumor responses to low dose drug delivery via combined effects on circulation, tumor drug accumulation and exposure and altered metabolism in normal tissues. / EPSRC funding (EP/I000623/1, EP/K023845/1 and EP/P023266/1) and the MRC for a Confidence in Concept award and MR/L01629X. L.E. McVeigh was funded by an EPSRC PhD Studentship (EP/L504993/1).

Yes / A green approach has been used for co-crystallization of non-congruent co-crystal pair of caffeine – maleic acid using water. Ultrasound is known to affect crystallization hence the effect of high power ultrasound on the ternary phase diagram has been investigated in detail using a slurry co-crystallization approach. A systematic investigation was performed to understand how the accelerated conditions during ultrasound assisted co-crystallization will affect different regions of the ternary phase diagram. Application of ultrasound showed considerable effect on the ternary phase diagram; principally on caffeine/maleic acid 2:1 (disappeared) and 1:1 co-crystal (narrowed) regions. Also, the stability regions for pure caffeine and maleic acid in water were narrowed in the presence of ultrasound, expanding the solution region. The observed effect of ultrasound on the phase diagram was correlated with solubility of caffeine and maleic acid and stability of co-crystal forms in water.

Over the past two decades, molecular detection platforms have seen rapid advancement, reshaping the way we monitor the safety and security of our environment and human health. One of the key drivers of this transformation has been the development of simpler, faster, and more accessible nucleic acid amplification tests (NAATs) that have enabled point-of-contact (POC) DNA testing, delivering real-time results in resource-limited settings. Despite these advancements, the DNA sample preparation process is laborious, resource-intensive, and often requires hazardous chemicals, preventing the performance of DNA extraction at the POC and severely limiting the potential of POC NAATs. Thus, DNA sample preparation methods have been the primary bottleneck restricting the widespread use and applicability of POC NAATs. To overcome this bottleneck, focused ultrasound extraction (FUSE) was recently introduced as a novel DNA extraction method capable of rapidly releasing DNA from complex tissue matrices without labor-intensive techniques or strong chemicals. This technology utilizes high-pressure focused ultrasound pulses that disintegrate tissue and release DNA through the control of acoustic cavitation. An initial feasibility study demonstrated the potential of FUSE for simple biological tissues, but the use of FUSE for preparing complex tissues has not been explored previously. Understanding the potential of the FUSE technology with diverse sample types is essential for developing versatile DNA preparation methods that can effectively protect both the environment and human health. This dissertation investigates the performance of FUSE in complex tissue matrices and evaluates the utility of a miniaturized FUSE system for streamlined DNA sample preparation. Specifically, this work addresses (1) the feasibility of FUSE in robust sample types with physical and chemical complexities that hinder DNA release, (2) the optimization of FUSE pulsing parameters to enhance the time efficiency of FUSE processing and improve the quality of released DNA, and (3) the development of a compact, accessible device for the performance of FUSE DNA sample preparation in resource-limited settings. The completion of this work will introduce a novel DNA sample preparation method to enable the use of POC NAATs. / Doctor of Philosophy / Over the past two decades, DNA testing platforms have seen rapid advancement, reshaping the way we monitor the safety and security of our environment and human health. One of the key drivers of this transformation has been the development of simpler, faster, and more accessible genetic technologies that have enabled point-of-contact (POC) DNA testing, delivering real-time results in resource-limited settings. Despite these advancements, the DNA sample preparation process is laborious, resource-intensive, can take hours or days to complete, and often requires hazardous chemicals, preventing the performance of DNA extraction at the POC and severely limiting the potential of POC DNA testing platforms. Thus, DNA sample preparation methods have been the primary bottleneck limiting the full potential of POC DNA testing platforms. To overcome this bottleneck, focused ultrasound extraction (FUSE) was recently introduced as a novel DNA extraction method capable of rapidly releasing DNA from complex tissues without labor-intensive techniques or strong chemicals. This technology uses sound waves to generate a cloud of microbubbles capable of breaking down tissue and releasing DNA. An initial feasibility study demonstrated the potential of FUSE for simple biological tissues, but the use of FUSE for preparing complex tissues has not been explored previously. Understanding the potential of the FUSE technology with diverse sample types is essential for developing versatile DNA preparation methods that can effectively protect both the environment and human health. This dissertation investigates the performance of FUSE in complex tissue matrices and evaluates the utility of a miniaturized FUSE system for streamlined DNA sample preparation. Specifically, this work addresses (1) the feasibility of FUSE in robust sample types with physical and chemical complexities that hinder DNA release, (2) the optimization of FUSE pulsing parameters to enhance the time efficiency of FUSE processing and improve the quality of released DNA, and (3) the development of a compact, accessible device for the performance of FUSE DNA sample preparation in resource-limited settings. The completion of this work will introduce a novel DNA sample preparation method to enable the molecular detection of complex samples at the POC.

Background: Goal-directed ultrasound protocols have been developed to facilitate efficiency, throughput, and patient care. Hands-on instruction and training workshops have been shown to positively impact ultrasound training. Objectives: We describe a novel undifferentiated chest pain goal-directed ultrasound algorithm-focused education workshop for the purpose of enhancing emergency medicine resident training in ultrasound milestones competencies. Methods: This was a cross-sectional study performed at an academic medical center. A novel goal-directed ultrasound algorithm was developed and implemented as a model for teaching and learning the sonographic approach to a patient with undifferentiated chest pain. This algorithm was incorporated into all components of the 1-day workshop: asynchronous learning, didactic lecture, case-based learning, and hands-on stations. Performance comparisons were made between postgraduate year (PGY) levels. Results: A total of 38 of the 40 (95%) residents who attended the event participated in the chest pain objective standardized clinical exam, and 26 of the 40 (65%) completed the entire questionnaire. The average number of ultrasounds performed by resident class year at the time of our study was as follows: 19 (standard deviation [SD]=19) PGY-1, 238 (SD=37) PGY-2, and 289 (SD=73) PGY-3. Performance on the knowledge-based questions improved between PGY-1 and PGY-3. The application of the novel algorithm was noted to be more prevalent among the PGY-1 class. Conclusion: The 1-day algorithm-based ultrasound educational workshop was an engaging learning technique at our institution.

In the context of location, large amounts of information are available on the Internet to be accessed by people via different devices. However, at times people have to manually search and access it. If the space where location-based services are available can be identified by hand-held devices, people can be prompted with services available around them. This thesis explores the use of ultrasound as a communication medium to tag such spaces and access location-based services with the related information; and demonstrates the indoor implementation of the prototype of a location-based services enabling system for hand-held devices. This system allows users to search and access the available services in their surroundings through their hand-held devices. A beacon generator placed in the service location broadcasts a service code mappable to the services particular to that location encoded in an ultrasound signal. The hand-held device can identify this signal and prompt the user with available services. System design and architecture is demonstrated and the viability of the system is tested through a variety of environments and scenarios showing that potentially this has both a wide range of applications and can enhance the way people access location-based services. / Thesis (Master, Computing) -- Queen's University, 2013-01-30 17:50:20.285

Atherosclerosis is often diagnosed using an ultrasound (US) examination in the carotid and femoral arteries and the abdominal aorta. A decision to operate requires two measures of disease severity: the degree of stenosis measured using B-mode US; and the blood flow patterns in the artery measured using spectral Doppler US. However other biomechanical factors such as wall shear stress (WSS) and areas of flow recirculation are also important in disease development and rupture. These are estimated using an image-guided modelling approach, where a three-dimensional computational mesh of the artery is simulated. To generate a patient-specific arterial 3D computational mesh, a 3D ultrasound (3DUS) system was developed. This system uses a standard clinical US scanner with an optical position sensor to measure the position of the transducer; a video capture card to record video images from the scanner; and a PC running Stradwin software to reconstruct 3DUS data. The system was characterised using an industry-standard set of calibration phantoms, giving a reconstruction accuracy of ± 0.17 mm with a 12MHz linear array transducer. Artery movements from pulsatile flow were reduced using a retrospective gating technique. The effect of pressure applied to the transducer moving and deforming the artery was reduced using an image-based rigid registration technique. The artery lumen found on each 3DUS image was segmented using a semi-automatic segmentation technique known as ShIRT (the Sheffield Image Registration Toolkit). Arterial scans from healthy volunteers and patients with diagnosed arterial disease were segmented using the technique. The accuracy of the semi-automatic technique was assessed by comparing it to manual segmentation of each artery using a set of segmentation metrics. The mean accuracy of the semi-automatic technique ranged from 85% to 99% and depended on the quality of the images and the complexity of the shape of the lumen. Patient-specific 3D computational artery meshes were created using ShIRT. An idealised mesh was created using key features of the segmented 3DUS scan. This was registered and deformed to the rest of the segmented dataset, producing a mesh that represents the shape of the artery. Meshes created using ShIRT were compared to meshes created using the Rhino solid modelling package. ShIRT produced smoother meshes; Rhino reproduced the shape of arterial disease more accurately. The use of 3DUS with image-guided modelling has the potential to be an effective tool in the diagnosis of atherosclerosis. Simulations using these data reflect in vivo studies of wall shear stress and recirculation in diseased arteries and are comparable with results in the literature created using MRI and other 3DUS systems.

Sabe-se que o aumento na temperatura do tecido tumoral pode aumentar a eficiência de técnicas convencionais de combate ao câncer (radioterapia e quimioterapia). Além disso, a variação de temperatura em tumores pode ser uma forma de tratamento alternativo à cirurgia, feito por meio do fornecimento de calor direcionado às células cancerosas e preservando o tecido sadio. Para maior eficácia e segurança no emprego de técnicas que utilizam fornecimento de calor ao tecido biológico, é necessário o monitoramento da temperatura tecidual para garantir que a morte celular por ablação térmica seja limitada ao tecido alvo, minimizando os danos aos tecidos adjacentes. A imagem fotoacústica é uma técnica baseada no efeito fotoacústico, o qual consiste na absorção de radiação eletromagnética pelo tecido e, devido à expansão termoelástica, na geração de ondas acústicas. A amplitude da onda de pressão gerada pelo efeito fotoacústico possui dependência com a temperatura do meio pelo parâmetro de Grueneisen, que depende das propriedades mecânicas do material. Portanto, mudanças na amplitude do sinal fotoacústico carregam informações a respeito da variação na temperatura do material. Neste trabalho, a dependência da amplitude do sinal fotoacústico com a temperatura foi estudada em um material simulador de tecido biológico (phantom) em condições similares a de tratamentos por hipertermia Nesse caso, imagens fotoacústicas foram adquiridas para cada grau de temperatura em uma faixa de 36 até 41 ºC durante o procedimento de aquecimento por banho térmico. Mudanças na amplitude e fase do sinal fotoacústico foram avaliadas através da aplicação de algoritmos de speckle tracking. Para estimar a variação na amplitude do sinal também foram utilizados e avaliados diferentes métodos de comparação. Os resultados são apresentados por imagens fotoacústicas termais produzidas pela aplicação de um fator de calibração aos mapas de variação relativa da amplitude do sinal em função da temperatura do meio. Finalmente, avaliamos um experimento de hipertemia por ultrassom focalizado de alta intensidade (High Intensity Therapeutic Ultrasound - HITU) em uma amostra de músculo suíno. Nesse caso foram geradas imagens termais fotoacústicas e imagens termais produzidas pela mudança de fase do sinal pulso-eco de ultrassom. Os resultados sugerem uma maneira não invasiva de calcular a distribuição da variação de temperatura do meio que pode ser aplicada para monitoramento durante tratamentos que utilizam o fornecimento de calor ao tecido biológico. / Several studies have shown that elevating the temperature of tumoral tissue improves standard cancer treatments success rate (radiotherapy and chemotherapy). This procedure can also be a therapy to cancer by delivering heat and killing cancer cells while healthy tissues are preserved. For improved efficiency and security in heat applications, it is important to monitor tissue temperature during treatments. Photoacoustic (PA) pressure wave amplitude has a temperature dependence given by the sample mechanical properties (Gruenesein parameter). These changes in photoacoustic signal amplitude carry information about temperature variation in tissue. Therefore, PA has been proposed as an imaging technique to monitor temperature during hyperthermia. In this study, PA images were acquired for temperatures ranging from 36ºC to 41ºC using a tissue-mimicking phantom immersed in a temperature controlled thermal bath. Relative amplitude variation was calculated using speckle tracking algorithms using four different methods to estimate these variations in PA signal amplitude. The results are presented as PA-based thermal images, generated using a calibration factor to the percentage variations in the amplitude maps. Finally, PA-based and ultrasound-based thermal images were acquired during heating by high intensity focused ultrasound (High Intensity Therapeutic Ultrasound - HITU) in a porcine muscle. The results suggest a non-invasive way to monitor temperature during hyperthermia procedures.

Este trabalho apresenta uma análise sobre um novo método de formação de imagem, utilizando aparelhos de ultra-som a elastografia. Esta técnica baseia-se no fato de que quando um meio elástico, como o tecido, é deformado por uma tensão constante e uniaxial, todos os pontos no meio possuem um nível de deformação longitudinal cujo componente principal está ao longo do eixo de deformação. Se elementos do tecido possuem um módulo elástico diferente dos demais, a deformação nestes elementos será relativamente maior ou menor. Elementos mais rígidos geralmente deformam-se menos. Desta forma, pode-se mapear e identificar estruturas com diferentes níveis de dureza. A comparação entre os mapas de RF de pré e pós-deformação foi realizada pela técnica de block matching. Esta técnica consiste em comparar regiões, ou kernels, no mapa de pré-deformação com regiões de mesmo tamanho no mapa de pós-deformação. Esta comparação é feita pela minimização de uma função custo. Nesta técnica, o tamanho do kernel, é um dos principais parâmetros para melhorar a precisão das medidas de deslocamento. O principal objetivo neste trabalho é aperfeiçoar o algoritmo de block matching visando melhorar a precisão da determinação de deslocamento em técnicas de deformação dinâmica e estática, mantendo o custo computacional baixo. Para isto, foram utilizados phantoms com e sem inclusões mais duras que o meio. Os phantoms foram submetidos a deformações estáticas e dinâmicas. Foi possível determinar o comportamento destes phantoms sob estas formas de deformação, e as faixas de kernel e funções custo que forneceram os melhores resultados. Também foram gerados elastogramas do phantom com inclusão. Estas imagens permitiram avaliar a influência dos diferentes kernels sobre a resolução dos elastogramas e a capacidade em diferenciar a lesão do tecido circundante. Comparando os elastogramas obtidos sobre deformação dinâmica, utilizando os kernels que apresentaram o melhor desempenho, com as respectivas imagens em modo B, pôde-se observar que a inclusão estava clara e bem delimitada. / This work provides an analysis about a new method for image formation using ultrasound devices elastography. This technique is based on the fact that when an elastic medium, as the tissue, is deformed under a constant and directional stress, all the points in the medium have a deformation level whose main component is along the deformation axis. If tissues elements have different elastic modules, the deformation in these elements will be higher or lower. Normally harder elements have lower deformations. In this way, one can detect and identify structures with different elastic levels. The comparisons between the pre and post-deformation RF maps were done by the block matching technique. This technique is based on the comparison of regions, or kernels, in the pre-deformation maps with regions of the same size in the post-deformation map. This is done by the minimization of a cost function. In this technique, the kernel size is one of the most important parameters to obtain better resolution and precision in the displacement measurements. The goal of this work is to optimize the block matching algorithm to improve the displacement estimates precision in both dynamic and static deformations, while keeping a low computational cost. To obtain this, we used phantoms with and without inclusions harder than the medium. These phantoms were submitted to both static and dynamic deformations. It was possible to estimate the behavior of these phantoms under these deformations, and the kernel range and cost functions that provided the best results. Also, we generated the elastograms of the phantom with the inclusion. These images allowed us to evaluate the influence of the different kernel sizes under the elastograms resolution and their capability in differentiate the lesion from the embedding tissue. Comparing the elastograms obtained under dynamic deformation that had the best performance, with the B mode images, we could conclude that the inclusion was well delimited and clear.

Innovations and process understanding is the current focus in pharmaceutical industry. The objective of this research was to explore application of high power ultrasound in the slurry crystallisation and application of low power ultrasound (3.5 MHz) as process analytical technology (PAT) tool to understand pharmaceutical processing such as hot melt extrusion. The effect of high power ultrasound (20 kHz) on slurry co-crystallisation of caffeine / maleic acid and carbamazepine / saccharin was investigated. To validate low power ultrasound monitoring technique, it was compared with the other techniques (PAT tools) such as in-line rheology and in-line NIR spectroscopy. In-line rheological measurements were used to understand melt flow behaviour of theophylline / Kollidon VA 64 system in the slit die attached to the hot melt extruder. In-line NIR spectroscopic measurements were carried out for monitoring any molecular interactions occurring during extrusion. Physical mixtures and the processed samples obtained from all experiments were characterised using powder X-ray diffraction, thermogravimetry analysis, differential scanning calorimetry, scanning Electron Microscopy, dielectric spectroscopy and high performance liquid chromatography, rotational rheology, fourier transform infrared spectroscopy and near infrared spectroscopy. The application of high power ultrasound in slurry co-crystallisation of caffeine / maleic acid helped in reducing equilibrium time required for co-crystal formation. During carbamazepine / saccharin co-crystallisation high power ultrasound induced degradation of carbamazepine was negligible. Low power ultrasound can be used as a PAT tool as it was found to be highly sensitive to the changes in processing temperatures and drug concentration.

A magneto-acustografia ou, em uma nova terminologia mais abrangente, vibromagneto-acustografia (VMA) é uma técnica que combina técnicas magnéticas e acústicas, a fim de observar o comportamento visco-elástico de um meio material marcado com partículas magnéticas (alvo). A força magnética oscilatória de frequência () provoca, dentro do alvo, movimento das partículas e do meio material com frequência (2). O feixe acústico pulso-eco utilizado para detectar o movimento das estruturas, tem uma frequência de repetição de pulso (PRF), no mínimo, cinco vezes maior que a frequência do movimento do alvo. Assim, a proposta deste projeto foi desenvolver um protocolo de aquisição, processamento e análise da técnica VMA, por meio da implementação de uma plataforma automatizada de aquisição, que forneça dados estruturados para posteriormente através de uma plataforma de processamento analisar diferentes aplicações da técnica VMA em fantomas e in vivo. A primeira etapa foi desenvolver a plataforma de aquisição utilizando um equipamento de ultrassom diagnóstico por imagem. Nesta etapa foi desenvolvido um software, com interface gráfica de usuário, escrito em C++ e Qt com a função de automatizar a excitação magnética e a aquisição acústica de alta resolução temporal, foram definidos os protocolos padrão dos modos de excitação magnética e de aquisição acústica em termos da taxa de aquisição dos frames ultrassônicos para gerar movimentos oscilatórios ou ondas de cisalhamento. Em seguida, os dados provenientes das aquisições foram estruturados por meio de um cabeçalho para transferência para outros computadores através do protocolo TCP/IP. Depois foi desenvolvida um software, com interface gráfica de usuário, para a fase de processamento e análise. O processamento dos frames adquiridos em modo radiofrequência (RF) consistiu em obter mapas de deslocamentos ou velocidades das estruturas internas do meio material utilizado como alvo. Nesta etapa adaptamos o algoritmo de correlação cruzada normalizada com correção de pico de máxima correlação x e obtivemos mapas otimizados para a técnica VMA. A avaliação da otimização destes mapas foi baseada na avaliação entre a resolução espacial e tempo computacional. A partir do uso destes softwares em experimentos com fantomas e in vivo foram desenvolvidos métodos de análise da frequência dos deslocamentos e segmentação/caracterização de ondas de cisalhamento em termos da sua velocidade e atenuação. Por fim, foi implementado um sistema VMA automatizado composto, por uma plataforma de aquisição embarcada em equipamento de diagnóstico por ultrassom para aquisição de mapas de RF e, que posteriormente eram transferidos para um computador com hardware superior para geração de mapas de deslocamento do meio material. Os mapas foram analisados para determinação de parâmetros visco-elásticos. Além disso, através da implementação da técnica VMA, viabilizou-se estudos clínicos de maneira rápida e eficiente, por exemplo, análises gástricas após a digestão de alimentos marcados com partículas magnéticas e produção de ondas de cisalhamento para caracterização viscoelástica. / The magneto motive ultrasound (MMUs) is a novel technique, which combines magnetism and acoustics, in order to observe viscoelastic behavior of medium labeled with inserted magnetic particles. The magnetic force with modulation frequency () creates a mechanical disturbance in the object of study with twice the modulation frequency (2). Was applied a pulse-echo ultrasonic beamforming with pulse repetition frequency (PRF) at least five times greater than frequency of internal structure movement. The aim of this study was to develop an acquisition, processing and analysis protocol for MMUs through implementation of an automated platform for acquisition, which provides structured datasets for further processing and analysis of different applications (tissue mimicking phantoms or in vivo) of MMUs. First step was to develop the acquisition platform using an ultrasound research interface (URI). At this stage was developed a software with graphical user interface (GUI) written using C++ and Qt. This software automates magnetic excitation and acoustic acquisition, which has high frame rate. In addition, were defined default presets to provide oscillatory movement or shear waves. Then was created datasets acquired were structured and a header and transferred to an external personal computer through TCP/IP network. Second, the processing software with graphical user interface for processing and analyzing was developed. The frames acquired in radiofrequency (RF) mode were processed into displacement or velocity maps of medium internal structures. In this stage, we adapted a cross correlation algorithm to optimize for MMUs datasets. The evaluation of these maps was based on tradeoff between spatial resolution and computation time. Protocols for analysis of motion frequency and segmentation/characterization of shear waves, extracting velocity and attenuation for experiments performed with phantoms or in vivo were developed . In this work, it was implemented an automated MMUs system integrated with a software framework running on an ultrasound research interface (URI), which is used for acquisition of RF maps, further transferred for a PC with robust hardware to process into displacement maps. These maps were analyzed to obtain viscoelastic parameters of the medium. Moreover, this implementation of MMUs enables clinical fast and efficient trials for gastric evaluation of meals with magnetic particles and shear wave production for viscoelastic characterization.