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.

O câncer de pele é uma doença com grande incidência mundial. O tratamento tópico do câncer de pele é uma estratégia desejada uma vez que pode diminuir os efeitos adversos graves causados pelo tratamento cirúrgico e quimioterapia sistêmica. No entanto, os tratamentos tópicos atuais são limitados pela baixa efetividade das formulações em carrear o fármaco até as camadas mais profundas da pele. Desta forma, o ultrassom de baixa frequência (LFU) apresenta-se como um método atrativo, mas ainda pouco estudado, para aumentar a permeabilidade da pele. Portanto, o objetivo desse trabalho foi estudar modificações na composição dos meios de acoplamento do LFU visando aumentar as regiões de transporte localizadas (LTRs) da pele e a permeabilidade do quimioterápico doxorrubicina (DOX) para o tratamento tópico do câncer de pele. Para isso, um hidrogel de Poloxamer (nanogel) enriquecido com nanopartículas lipídicas sólidas (NLS) contendo DOX foi preparado e caracterizado; diferentes meios de acoplamento, dentre eles os tradicionais, contendo tensoativo, e os inovadores, contendo as NLS ou hidrogéis com diferentes potenciais zeta e viscosidades semelhantes, foram avaliados associados ao LFU para verificar sua influência na formação das LTRs e penetração cutânea de dois fármacos, calceína e DOX; a penetração cutânea da DOX livre e encapsulada em NLS foi quantificada nas diferentes camadas da pele pré-tratada com LFU; e, finalmente, o pré-tratamento mais promissor, LFU associado ao nanogel, seguido da aplicação passiva da DOX incorporada no nanogel foi avaliada in vivo em tumores cutâneos induzidos em camundongos imunossuprimidos. As NLS apresentaram tamanho e PdI de aproximadamente 200 nm e 0,3 respectivamente, com alto potencial zeta catiônico e pH de 3. A incorporação das NLS no nanogel não alterou o tamanho e PdI, no entanto, diminuiu o potencial zeta da formulação e elevou o pH para 5,5. Verificou-se por difração de raios X a baixo ângulo que as NLS continham fases cristalinas lamelares, enquanto o nanogel, fases cristalinas cúbicas, que foram mantidas quando as formulações foram associadas. O uso das NLS e dos hidrogéis, incluindo o nanogel, como meio de acoplamento do LFU modificou consideravelmente a distribuição e número de LTRs na pele em relação aos meios tradicionais. Tanto o número de LTRs quanto a sua distribuição parecem estar relacionados à tensão interfacial e a viscosidade do meio hidrofílico, sendo que a maior viscosidade dos géis gerou maior área de LTRs. O uso do nanogel originou LTRs em 50% da área da pele tratada, área esta 24 vezes maior do que a área de LTRs formada quando o meio de acoplamento convencional, com lauril sulfato de sódio, foi utilizado. Observou-se que a influência das LTRs na penetração de fármacos aniônicos (calceína) e catiônicos (DOX) depende do potencial zeta do hidrogel usado como meio de acoplamento e da dissociação do fármaco. Desta forma, a permeação cutânea da calceína foi menor quando gel aniônico foi utilizado como meio de acoplamento e o inverso ocorreu para a DOX. A penetração da DOX através do estrato córneo da pele pré-tratada com LFU/nanogel aumentou mais de 4 vezes, mas a encapsulação da DOX nas NLS dificultou a passagem da DOX para as camadas mais profundas da pele após o pré-tratamento da mesma com LFU, sugerindo um recuperação da pele desestruturada pelas partículas lipídicas administradas após o pré-tratamento. Nos estudos in vivo, o pré-tratamento da pele com LFU/nanogel seguido da aplicação diárias do nanogel contendo DOX resultou em diminuição de 6 vezes do volume do tumor após 21 dias de tratamento e apenas 5 aplicações do LFU/nanogel. No entanto, a diminuição do volume do tumor só ocorreu quando a sonda do LFU foi posicionada a 10 mm da superfície do tumor. O posicionamento da sonda a uma distância mais próxima do tumor (5 mm) não diminuiu o tamanho do tumor. Conclui-se que a aplicação de LFU com hidrogéis como meio de acoplamento é uma alternativa simples e efetiva para aumentar a penetração de fármacos na pele. Esta penetração pode ser modulada em função do potencial zeta do meio de acoplamento e da posição da sonda do ultrassom em relação à superfície do tumor. Desta forma, o tratamento tópico do câncer de pele usando LFU/nanogel como pré-tratamento é uma estratégia promissora para o tratamento tópico do câncer de pele. / Skin cancer is a disease with high worldwide incidence. Topical treatment of skin cancer is a desired strategy since it can reduce the serious adverse effects caused by surgery and systemic chemotherapy. However, current topical treatments are limited by low effectiveness of the formulations delivery drug to the deeper layers of the skin. Thus, the low frequency ultrasound (LFU) presents itself as an attractive method, but still little studied, to increase skin permeability. Therefore, the objective of this work was to study changes in the LFU coupling medium composition to increase the transport localized region (LTRs) in the skin and the permeability of chemotherapeutic doxorubicin (DOX) for the topical skin cancer treatment. For this, a Poloxamer hydrogel (nanogel) supplemented with solid lipid nanoparticles (SLN) containing DOX was prepared and characterized; different coupling medium, including traditional, containing surfactant, and innovative, containing the NLS or hydrogels with different viscosities and zeta potential similar, were evaluated associated with the LFU to verify its influence in LTRs formation and skin penetration of two drugs, calcein and DOX; skin penetration of free and encapsulated DOX was quantified in the different layers of the LFU pretreated skin; and finally, the most promising pretreatment, LFU associated with nanogel, followed by the passive application of DOX incorporated into the nanogel was evaluated in vivo, in skin tumors induced in immunosuppressed mice. The NLS showed size and PDI of approximately 200 nm and 0.3, respectively, with high cationic zeta potential and pH 3 value. The incorporation of the NLS into the nanogel did not change the size and PDI, however, decreased the zeta potential of the formulation and increased pH value to 5.5. It was found by low angle X-ray diffraction that NLS-containing lamellar crystalline phase while the nanogel, cubic crystalline phases, which were maintained when the formulations were associated. The use of NLS and hydrogels, including nanogel, as coupling medium of LFU substantially modify the distribution and number of the LTRs in the skin compared to traditional medium. Both, LTRs number and distribution may be related to the interfacial tension and viscosity of the hydrophilic medium, hydrogel with higher viscosity produced greater LTRs area. The use of nanogel as coupling medium resulted in LTRs formation in 50% of treated skin area, this area is 24 times larger than the LTR area LTRs formed when conventional coupling medium sodium lauryl sulfate was used. It was observed that the influence of the LTRs in the penetration of anionic drugs (calcein) and cationic (DOX) depends on the zeta potential of the hydrogel used as coupling medium and drug. Thus, the permeation of calcein was lower when anionic gel was used as the coupling medium and the opposite occurred for DOX. DOX penetration through the stratum corneum of the skin pretreated with LFU / nanogel increased more than 4 times but the encapsulation of DOX in the NLS difficult the passage of DOX to the deeper layers of the skin after pre-treatment with LFU, suggesting the recovery of the skin by lipid particles administered after pretreatment. In the in vivo study, pretreatment of the skin with LFU / nanogel followed by the daily application of nanogel containing DOX resulted in a 6-fold decrease in tumor volume after 21 days of treatment with only 5 applications LFU / nanogel. However, the reduction of tumor volume occurred only when the LFU probe was positioned 10 mm from the tumor surface. The positioning of the probe at distance closer tumor (5 mm) has not decreased tumor size. It is concluded that the application of coupling medium hydrogels with LFU is a simple and effective alternative to enhance drug penetration into the skin. This penetration can be adjusted depending on the zeta potential of the coupling means and ultrasound probe position on the tumor surface. Therefore, topical treatment of skin cancer using LFU / nanogel as pre-treatment is a promising strategy for the topical treatment of skin cancer.

O câncer de pele é uma doença com grande incidência mundial. O tratamento tópico do câncer de pele é uma estratégia desejada uma vez que pode diminuir os efeitos adversos graves causados pelo tratamento cirúrgico e quimioterapia sistêmica. No entanto, os tratamentos tópicos atuais são limitados pela baixa efetividade das formulações em carrear o fármaco até as camadas mais profundas da pele. Desta forma, o ultrassom de baixa frequência (LFU) apresenta-se como um método atrativo, mas ainda pouco estudado, para aumentar a permeabilidade da pele. Portanto, o objetivo desse trabalho foi estudar modificações na composição dos meios de acoplamento do LFU visando aumentar as regiões de transporte localizadas (LTRs) da pele e a permeabilidade do quimioterápico doxorrubicina (DOX) para o tratamento tópico do câncer de pele. Para isso, um hidrogel de Poloxamer (nanogel) enriquecido com nanopartículas lipídicas sólidas (NLS) contendo DOX foi preparado e caracterizado; diferentes meios de acoplamento, dentre eles os tradicionais, contendo tensoativo, e os inovadores, contendo as NLS ou hidrogéis com diferentes potenciais zeta e viscosidades semelhantes, foram avaliados associados ao LFU para verificar sua influência na formação das LTRs e penetração cutânea de dois fármacos, calceína e DOX; a penetração cutânea da DOX livre e encapsulada em NLS foi quantificada nas diferentes camadas da pele pré-tratada com LFU; e, finalmente, o pré-tratamento mais promissor, LFU associado ao nanogel, seguido da aplicação passiva da DOX incorporada no nanogel foi avaliada in vivo em tumores cutâneos induzidos em camundongos imunossuprimidos. As NLS apresentaram tamanho e PdI de aproximadamente 200 nm e 0,3 respectivamente, com alto potencial zeta catiônico e pH de 3. A incorporação das NLS no nanogel não alterou o tamanho e PdI, no entanto, diminuiu o potencial zeta da formulação e elevou o pH para 5,5. Verificou-se por difração de raios X a baixo ângulo que as NLS continham fases cristalinas lamelares, enquanto o nanogel, fases cristalinas cúbicas, que foram mantidas quando as formulações foram associadas. O uso das NLS e dos hidrogéis, incluindo o nanogel, como meio de acoplamento do LFU modificou consideravelmente a distribuição e número de LTRs na pele em relação aos meios tradicionais. Tanto o número de LTRs quanto a sua distribuição parecem estar relacionados à tensão interfacial e a viscosidade do meio hidrofílico, sendo que a maior viscosidade dos géis gerou maior área de LTRs. O uso do nanogel originou LTRs em 50% da área da pele tratada, área esta 24 vezes maior do que a área de LTRs formada quando o meio de acoplamento convencional, com lauril sulfato de sódio, foi utilizado. Observou-se que a influência das LTRs na penetração de fármacos aniônicos (calceína) e catiônicos (DOX) depende do potencial zeta do hidrogel usado como meio de acoplamento e da dissociação do fármaco. Desta forma, a permeação cutânea da calceína foi menor quando gel aniônico foi utilizado como meio de acoplamento e o inverso ocorreu para a DOX. A penetração da DOX através do estrato córneo da pele pré-tratada com LFU/nanogel aumentou mais de 4 vezes, mas a encapsulação da DOX nas NLS dificultou a passagem da DOX para as camadas mais profundas da pele após o pré-tratamento da mesma com LFU, sugerindo um recuperação da pele desestruturada pelas partículas lipídicas administradas após o pré-tratamento. Nos estudos in vivo, o pré-tratamento da pele com LFU/nanogel seguido da aplicação diárias do nanogel contendo DOX resultou em diminuição de 6 vezes do volume do tumor após 21 dias de tratamento e apenas 5 aplicações do LFU/nanogel. No entanto, a diminuição do volume do tumor só ocorreu quando a sonda do LFU foi posicionada a 10 mm da superfície do tumor. O posicionamento da sonda a uma distância mais próxima do tumor (5 mm) não diminuiu o tamanho do tumor. Conclui-se que a aplicação de LFU com hidrogéis como meio de acoplamento é uma alternativa simples e efetiva para aumentar a penetração de fármacos na pele. Esta penetração pode ser modulada em função do potencial zeta do meio de acoplamento e da posição da sonda do ultrassom em relação à superfície do tumor. Desta forma, o tratamento tópico do câncer de pele usando LFU/nanogel como pré-tratamento é uma estratégia promissora para o tratamento tópico do câncer de pele. / Skin cancer is a disease with high worldwide incidence. Topical treatment of skin cancer is a desired strategy since it can reduce the serious adverse effects caused by surgery and systemic chemotherapy. However, current topical treatments are limited by low effectiveness of the formulations delivery drug to the deeper layers of the skin. Thus, the low frequency ultrasound (LFU) presents itself as an attractive method, but still little studied, to increase skin permeability. Therefore, the objective of this work was to study changes in the LFU coupling medium composition to increase the transport localized region (LTRs) in the skin and the permeability of chemotherapeutic doxorubicin (DOX) for the topical skin cancer treatment. For this, a Poloxamer hydrogel (nanogel) supplemented with solid lipid nanoparticles (SLN) containing DOX was prepared and characterized; different coupling medium, including traditional, containing surfactant, and innovative, containing the NLS or hydrogels with different viscosities and zeta potential similar, were evaluated associated with the LFU to verify its influence in LTRs formation and skin penetration of two drugs, calcein and DOX; skin penetration of free and encapsulated DOX was quantified in the different layers of the LFU pretreated skin; and finally, the most promising pretreatment, LFU associated with nanogel, followed by the passive application of DOX incorporated into the nanogel was evaluated in vivo, in skin tumors induced in immunosuppressed mice. The NLS showed size and PDI of approximately 200 nm and 0.3, respectively, with high cationic zeta potential and pH 3 value. The incorporation of the NLS into the nanogel did not change the size and PDI, however, decreased the zeta potential of the formulation and increased pH value to 5.5. It was found by low angle X-ray diffraction that NLS-containing lamellar crystalline phase while the nanogel, cubic crystalline phases, which were maintained when the formulations were associated. The use of NLS and hydrogels, including nanogel, as coupling medium of LFU substantially modify the distribution and number of the LTRs in the skin compared to traditional medium. Both, LTRs number and distribution may be related to the interfacial tension and viscosity of the hydrophilic medium, hydrogel with higher viscosity produced greater LTRs area. The use of nanogel as coupling medium resulted in LTRs formation in 50% of treated skin area, this area is 24 times larger than the LTR area LTRs formed when conventional coupling medium sodium lauryl sulfate was used. It was observed that the influence of the LTRs in the penetration of anionic drugs (calcein) and cationic (DOX) depends on the zeta potential of the hydrogel used as coupling medium and drug. Thus, the permeation of calcein was lower when anionic gel was used as the coupling medium and the opposite occurred for DOX. DOX penetration through the stratum corneum of the skin pretreated with LFU / nanogel increased more than 4 times but the encapsulation of DOX in the NLS difficult the passage of DOX to the deeper layers of the skin after pre-treatment with LFU, suggesting the recovery of the skin by lipid particles administered after pretreatment. In the in vivo study, pretreatment of the skin with LFU / nanogel followed by the daily application of nanogel containing DOX resulted in a 6-fold decrease in tumor volume after 21 days of treatment with only 5 applications LFU / nanogel. However, the reduction of tumor volume occurred only when the LFU probe was positioned 10 mm from the tumor surface. The positioning of the probe at distance closer tumor (5 mm) has not decreased tumor size. It is concluded that the application of coupling medium hydrogels with LFU is a simple and effective alternative to enhance drug penetration into the skin. This penetration can be adjusted depending on the zeta potential of the coupling means and ultrasound probe position on the tumor surface. Therefore, topical treatment of skin cancer using LFU / nanogel as pre-treatment is a promising strategy for the topical treatment of skin cancer.

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.