As opposed to current Intraoperative Ultrasound (IOUS) systems and their relatively large probes and limited superficial high frequency imaging, the use of a biopsy needle with an integrated transducer that is capable of minimally invasive and high-resolution ultrasound imaging is proposed. Such a design would overcome the compromise between resolution and penetration depth which is associated with the use of a probe on the skins surface. It is proposed that during interventional procedures, a transducer array positioned at the tip of a biopsy needle could provide real-time image guidance to the clinician with regards to the needle position within the tissue, and aid in the safe navigation of needles towards a particular target such as a tumour in tissues such as the breast, brain or liver, at which point decisions surrounding diagnosis or treatment via in vivo tissue characterisation could be made. With this objective, challenges exist in the manufacturing these miniature scale devices and theirincorporation into needle packages. The reliable realisation of miniature ultrasound transducer arrays on fine-scale piezoelectric composites, and establishing interconnects to these devices which also fit into suitably sized biopsy needles are two such hurdles. In this thesis, the fabrication of miniature 15 MHz ultrasound transducers is presented. The first stage of development involved the production of single element transducers in needles ~2 mm inner diameter, using various piezoelectric materials as the active material. These devices were tested andcharacterised, and the expertise developed during their fabrication was used as the foundation upon which to design a wafer-scale fabrication process for the production of multiple 15 MHz transducer arrays. This process resulted in a 16 element 15 MHz array connected to a flexible printed circuit board and integrated into a breast biopsy needle. Characterisation tests demonstrated functionality of each of the 16 elements, both individually and combined as an array. To explore potential applications for these devices, the single element transducers were tested in fresh and Thiel embalmed cadaveric brain tissue. Plasticine targets were embedded in these brain models and the needle transducers were tested as navigational real-time imaging tools to detect these targets within the brain tissue. The results demonstrated feasibility of such devices to determine the location of the target as the needle devices were advanced or withdrawn from the tissue, showing promise for future devices enabling neurosurgical guidance of interventional tools in the brain. The application of breast imaging was also considered. Firstly, Thiel embalmed cadaveric breasts were assessed as viable breast models for ultrasound imaging. Following this, anatomical features, with diagnostic significance in relation to breast cancer i.e. axillary lymph nodes and milk ducts, were imaged using a range of ultrasound frequencies (6 – 40 MHz). This was carried out to determinepotential design parameters (i.e. operational frequency) of an interventional transducer in a biopsy needle probe which would best visualise these features and aid current breast imaging and diagnosis procedures.

Targeted imaging with microbubbles may resolve the molecular expression within the abnormal blood vessels of tumours. Optimal imaging requires understanding the interaction between targeted microbubbles and high-frequency ultrasound. Therefore, the subharmonic signal, and backscattering cross-section of individual bound microbubbles were examined with coaligned 30 MHz pulses and optical images. The peak subharmonic signal was generated for 1.6 µm diameter microbubbles for 20% and 11% bandwidth pulses and 1.8 µm for 45% bandwidth pulses at 200 kPa, consistent with estimations of the resonant size of microbubble's at 15 MHz. In order to measure the scattering cross-section, a new method was proposed to measure the receive transfer function of a transducer. Measurements of the backscattering cross-section scaled with the square of the radius, with signi cant size-independent variability. The results of this thesis will help optimise the parameters for targeted imaging, as well as further our understanding of the behaviour of microbubbles.

Ultrasound-based tissue characterization has been an active eld of cancer detection in the past decades. The main concept behind various techniques is that the returning ultrasound echoes carry tissue-dependent information that can be used to distinguish tissue types. Recently, a new paradigm for tissue typing has been proposed which uses ultrasound Radio Frequency (RF) echoes, recorded continuously from a xed location of the tissue, to extract tissue-dependent information. This is hereafter referred to as RF time series. The source of tissue typing information in RF time series is not a well known concept in the literature. However, there are two main hypotheses that describe the informativeness of variations in RF time series. Such information could be partly due to heat induction as a result of consistent eradiation of tissue with ultrasound beams which results in a virtual displacement in RF echoes, and partly due to the acoustic radiation force of ultrasound beams resulting in micro-vibration inside tissue. In this thesis, we further investigate RF time series signals, collected at high frequencies, by analyzing the properties of the RF displacements. It will be shown that such displacements exhibit oscillatory behavior, emphasizing on the possible micro-vibrations inside tissue, as well as linear incremental trend, indicating the e ect of heat absorbtion of tissue. i The main focus of this thesis is to study the oscillatory behavior of RF displace- ments in order to extract tissue-dependent features based on which tissue classi ca- tion is performed. Using various linear and nonlinear tools, we study the properties of such displacements in both frequency and time domain. Nonlinear analysis, based on the theory of dynamical systems, is used to study the dynamical and geometrical properties of RF displacements in the time domain. Using Support Vector Machine (SVM), di erent tissue typing experiments are performed to investigate the capability of the proposed features in tissue classi ca- tion. It will be shown that the combination of such features can distinguish between di erent tissue types almost perfectly. In addition, a feature reduction algorithm, based on principle component analysis (PCA), is performed to reduce the number of features required for a successful tissue classi cation. / Thesis (Master, Electrical & Computer Engineering) -- Queen's University, 2012-03-29 13:52:10.874

Targeted imaging with microbubbles may resolve the molecular expression within the abnormal blood vessels of tumours. Optimal imaging requires understanding the interaction between targeted microbubbles and high-frequency ultrasound. Therefore, the subharmonic signal, and backscattering cross-section of individual bound microbubbles were examined with coaligned 30 MHz pulses and optical images. The peak subharmonic signal was generated for 1.6 µm diameter microbubbles for 20% and 11% bandwidth pulses and 1.8 µm for 45% bandwidth pulses at 200 kPa, consistent with estimations of the resonant size of microbubble's at 15 MHz. In order to measure the scattering cross-section, a new method was proposed to measure the receive transfer function of a transducer. Measurements of the backscattering cross-section scaled with the square of the radius, with signi cant size-independent variability. The results of this thesis will help optimise the parameters for targeted imaging, as well as further our understanding of the behaviour of microbubbles.

The second most common cause of cancer deaths in the developed world is bowel cancer. Improving the ability to detect and classify lesions as early as possible, allows treatment earlier. The work presented in this thesis is structured around the following detailed aims:Development of high frequency, broadband µUS (micro-ultrasound) imaging transducers through optimization of ultra-thinning processes for lithium niobate (LNO) and fabrication of novel ‘mass-spring’ matching layers using carefully controlled vacuum deposition is demonstrated. The effectiveness of this technique was quantified by applying multiple matching layers to 3 mm diameter 45 MHz LNO µUS transducers using carefully controlled vacuum deposition. The bandwidth of single mass-spring layer µUS transducer was measured to be 46% with an insertion loss of 21 dB. The bandwidth and insertion loss of a multiple matching layer µUS transducer was measured to be 59% and 18 dB respectively. The values were compared with an unmatched transducer which had a bandwidth and insertion loss of 28% and 34 dB respectively. All the experimentally measured values were in agreement with unidimensional acoustic model predictions. µUS tools that can detect and measure microscopic changes in precancerous tissue using a mouse small bowel model with an oncogenic mutation was developed. µUS transducer was used to test the hypothesis that the intestinal tissue morphology of WT (wild type) and ApcMin/+ (adenomatous polyposis coli) diverges with progressing age intervals (60, 90 and 120 days) of mice. A high frequency ultrasound scanning system was designed and the experiments were performed ex vivo using a focused 45 MHz, f-# = 2.85, µUS transducer. The data collected by scanning was used to compute the backscatter coefficients (BSC) and acoustic impedance (Z) of WT and ApcMin/+ mice. The 2D and 3D ultrasound images showed that µUS detects polyps < 500 µm in the scan plane. The measured values of BSC and Z showed differences between normal and precancerous tissue. The differences detected in precancerous murine intestine and human tissue using µUS were correlated with high resolution 3D optical imaging. This novel approach may provide a powerful adjunct to screening endoscopy for improved identification and monitoring, allowing earlier treatment of otherwise undetectable lesions.

Ultrasound is a valuable tool to monitor wound healing. In this report, ultrasound is used to determine the features in the B-scans that correspond to a bruise. High frequency ultrasound scans show clear and distinct features that correspond to a laceration or a late stage pressure ulcer. This is because of the extensive damage and the rupture of the epidermis in both the cases. This study assumes significance because it is an effort to find such artifacts in the ultrasound scans of bruises caused by blunt forces where the epidermis remains intact. In this study, the structure of the skin was visualized using a 20 MHz ultrasound scanner. Skin thickness and echogenicity changes may result due to blood extravasations or edema. The thickness and the echogenicity values are plotted against time to determine the trend in the variation of these parameters. We see an intraday and a daily fluctuation of skin thickness and echogenicity albeit with no distinct trend on a day to day basis or between subjects. The results also give us a good estimation of the variation observable in these parameters in the event of an injury. A snapshot analysis is also performed, which describes qualitatively the structural changes in the B-scan of the bruise site compared to the control site. There are six different types of qualitative changes which can appear in the B-scan of a bruised site compared to the control. In the event of an injury, usually, more than one of these changes is manifested in the scan of a bruise. Skin thickness and echogenicity vary considerably due to a number of physiological factors which can seldom be controlled. Therefore, these parameters can give conclusive evidence of a bruise only if the change between a bruised region and a control region is much greater than the daily, normal variations. Snapshot analysis can help detect a bruise or a deep tissue injury. Further work involves the application of pattern recognition or face recognition algorithms to automate the detection.

No description available.

This thesis aims to investigate the acoustic properties of ultrasound contrast agents (UCAs) at high ultrasound frequencies. In recent years, there has been increasing development in the use of high frequency ultrasound in the fields of preclinical, intravascular, ophthalmology and superficial tissue imaging. Although research studying the acoustic response of UCAs at low diagnostic ultrasonic frequencies has been well documented, quantitative information on the acoustical properties of UCAs at high ultrasonic frequencies is limited. In this thesis, acoustical characterisation of three UCAs was performed using a preclinical ultrasound scanner (Vevo 770, VisualSonics Inc., Canada). Initially the acoustical characterisation of five high frequency transducers was measured using a membrane hydrophone with an active element of 0.2 mm in diameter to quantify the transmitting frequencies, pressures and spatial beam profiles of each of the transducers. Using these transducers and development of appropriate software, high frequency acoustical characterisation (speed and attenuation) of an agar-based tissue mimicking material (TMM) was performed using a broadband substitution technique. The results from this study showed that the acoustical attenuation of TMM varied nonlinearly with frequency and the speed of sound was approximately constant 1548m·s-1 in the frequency range 12-47MHz. The acoustical properties of three commercially available lipid encapsulated UCAs including two clinical UCAs Definity (Lantheus Medical Imaging, USA) and SonoVue (Bracco, Italy) and one preclinical UCAs MicroMarker (untargeted) (VisualSonics, Canada) were studied using the software and techniques developed for TMM characterisation. Attenuation, contrast-to-tissue ratio (CTR) and subharmonic to fundamental ratio were measured at low acoustic pressures. The results showed that large off-resonance and resonant MBs predominantly contributed to the fundamental response and MBs which resonated at half of the driven frequency predominantly contributed to subharmonic response. The effect of needle gauge, temperature and injection rate on the size distribution and acoustic properties of Definity and SonoVue was measured and was found to have significant impacts. Acoustic characterisations of both TMM and UCAs in this thesis extend our understanding from low frequency to high frequency ultrasound and will enable the further development of ultrasound imaging techniques and UCAs design specifically for high frequency ultrasound applications.

Actuellement, l'étude exploratoire de la fonction hémostatique en routine se fonde essentiellement sur les tests du bilan standard d'hémostase, c'est à dire la détermination du temps caractéristique de formation d'un gel de fibrine dans des conditions standardisées. Cependant, la dernière décennie a vu la naissance de nouveaux tests se focalisant sur les transformations mécaniques du sang lors de sa coagulation. Portés par les récentes avancées dans la connaissance des phénomènes biochimiques et biophysiques menant à ces transformations mécaniques, ces tests, basés sur une étude dynamique des propriétés viscoélastiques de la coagulation du sang total, sont aujourd'hui de plus en plus adoptés par les hématologues et sont au centre d'un nombre grandissant d'études cliniques. C'est dans ce contexte que, s'appuyant sur les récents développements des techniques ultrasonores haute-fréquence, un dispositif de monitoring ultrasonore haute-fréquence de la coagulation sanguine sur sang total a été développé au sein de notre équipe. Grâce à une analyse simultanée de plusieurs paramètres acoustiques, ce dispositif à montré ses capacités à suivre les transformations mécaniques du sang coagulant. Le travail de cette thèse a consisté à poursuivre le développement de ce dispositif en s'attachant notamment à discriminer le rôle respectif des différents phénomènes ayant lieu lors de la coagulation sur les cinétiques acoustiques mesurées. En analysant les effets de traitements anticoagulant et anti-agrégant plaquettaires sur notre monitoring ultrasonore dans le cadre d'une étude clinique pilote, un premier potentiel diagnostic du dispositif a été établi. Les résultats de cette étude ont ensuite mené à la mise en place de mesures spécifiques centrées sur deux phénomènes : la formation de la fibrine et la contraction plaquettaire. Une visualisation originale de la formation du réseau de fibrine a pu être mise en place et a mené à la détermination d'un nouveau paramètre capable de déterminer à la fois le temps de gélification et le temps de rétraction. La gélification du milieu s'est avéré être primordiale dans l'évolution de l'atténuation dans le milieu, tout comme la rétraction du caillot est essentiellement responsable de l'augmentation de la vitesse. / Today, routine blood coagulation tests rely principally on the measurement of the time for a blood sample to gel under standardized conditions. However, in the last decade, new tests focused on monitoring mechanical changes during blood coagulation have been developped. Thanks to a new understanding of the biochemical and biophysical phenomena leading to those mechanical changes, these tests, dynamically studying the viscoelastic properties of coagulating whole blood, tend to be more and more adopted by haematologists and are the focus of a tremendous amount of clinical studies. Within this context and due to the recent development of high-frequency ultrasound techniques, a high-frequency ultrasound apparatus allowing the monitoring of whole blood coagulaion has been developped by our team. Simultaneously analysing the kinetics of four acoustical parameters, it has shown its potential in monitoring the mechanical changes appearing in whole blood coagulation. In this PhD thesis, new developments of this technique have been carried out and allowed to discriminate the respective role of the different phenomena appearing during coagulation on our acoustical parameters. Analysing the effect of anticoagulant and antiplatelet therapy within a pilot clincal study, the diagnostic potential of our test has been established. Following the results of this study, specific measurements have been set up and have shown the importance of two phenomena : fibrin formation and platelet contraction. A new way to visualize the fibrin network formation has been devised and has led to the computation of a new parameter capable of defining gel time and retraction time. Gelation of the medium was shown to be linked to the changes in attenuation in the medium and retraction of the clot was found to be critical in the rise of longitudinal velocity.

Pre-eclampsia is associated with increased risk of cardiovascular disease (CVD) later in life. The ‘gold standard’ for estimating cardiovascular risk - ultrasound assessment of the common carotid artery intima-media thickness (CCA-IMT) - does not convincingly demonstrate this increased risk. The aim of this thesis was to examine whether high-frequency (22 MHz) ultrasound assessment of the individual CCA intima and media layers and calculation of the intima/media (I/M) ratio - can indicate the increased cardiovascular risk after pre-eclampsia. After validation of the method in premenopausal women with systemic lupus erythematosus (SLE) who have a recognized increased risk of CVD, women during and after normal and preeclamptic pregnancies were investigated. Assessment of the individual artery wall layers reliably demonstrated the increased cardiovascular risk in premenopausal women with SLE, while CCA-IMT did not. The artery wall layer dimensions in women with SLE were comparable to those of postmenopausal women without SLE and were 30 years older. Among the women with normal pregnancies negative changes to the artery wall later on in the pregnancy were seen in those with lower serum estradiol, older age, higher body mass index or higher blood pressure early in the pregnancy. About one year postpartum, both the mean intima thickness and the I/M ratio had improved, compared to values during pregnancy. These findings support the theory that normal pregnancy is a stress on the vascular system. Women who developed pre-eclampsia (mean age 31 years) had thicker intima layers, thinner media layers and higher I/M ratios, both at diagnosis and one year postpartum, than women with normal pregnancies, indicating increased cardiovascular risk. Women with a history of severe pre-eclampsia (mean age 44 years; mean 11 years since the last delivery) had thicker intima layers and higher I/M ratios than women with a history of normal pregnancies, indicating long-standing negative vascular effects. Assessment of individual CCA wall layers, but not of CCA-IMT, provided clear evidence of the well-known increased cardiovascular risk in women with SLE or pre-eclampsia. The method has the potential to become an important tool in reducing cardiovascular morbidity and mortality in these women through early diagnosis and intervention.