There is a need for cancer imaging to provide “real-time” information about the cellular responses of tumours in contrast to standard evaluations of tumour size. Quantitative ultrasound techniques have recently been demonstrated to be a potential method of assessing tumour response at the cellular level through the analysis of radiofrequency backscatter data. In this thesis, prostate cancer xenografts were evaluated in vivo using high-frequency ultrasound analysis techniques to assess tumour response. The anti-cancer treatments consisted of radiotherapy and also a novel anti-vascular therapy utilizing encapsulated microbubble agents in the presence of ultrasound. Quantitative ultrasound results demonstrated a statistically significant change in backscatter parameters in tumours treated with high doses of radiotherapy or a high concentration of microbubbles during treatments. Histopathological assessment demonstrated that tumour cell death due to apoptosis and necrosis correlated with increases in ultrasound parameters.

Gas microbubbles have a high compressibility, which make them very efficient sound scatterers. As another consequence of their high compressibility, microbubbles can be compressed by the pressure of the fluid around them, which affects their scattering properties. Due to recent progress in shelled ultrasound contrast agents and the development of almost monodispersed microbubbles, we believe it could now be possible to measure blood pressure using microbubbles as non-invasive manometers, an idea first suggested more than 30 years ago. In this thesis, both simulations and in vitro experiments will be used to investigate the changes related to the resonance of bubbles and how the concept of bubble size population affects the accuracy of this technique. In particular, it will be shown how shell dynamics dominates the response of microbubbles to blood pressure.

There is a need for cancer imaging to provide “real-time” information about the cellular responses of tumours in contrast to standard evaluations of tumour size. Quantitative ultrasound techniques have recently been demonstrated to be a potential method of assessing tumour response at the cellular level through the analysis of radiofrequency backscatter data. In this thesis, prostate cancer xenografts were evaluated in vivo using high-frequency ultrasound analysis techniques to assess tumour response. The anti-cancer treatments consisted of radiotherapy and also a novel anti-vascular therapy utilizing encapsulated microbubble agents in the presence of ultrasound. Quantitative ultrasound results demonstrated a statistically significant change in backscatter parameters in tumours treated with high doses of radiotherapy or a high concentration of microbubbles during treatments. Histopathological assessment demonstrated that tumour cell death due to apoptosis and necrosis correlated with increases in ultrasound parameters.

Gas microbubbles have a high compressibility, which make them very efficient sound scatterers. As another consequence of their high compressibility, microbubbles can be compressed by the pressure of the fluid around them, which affects their scattering properties. Due to recent progress in shelled ultrasound contrast agents and the development of almost monodispersed microbubbles, we believe it could now be possible to measure blood pressure using microbubbles as non-invasive manometers, an idea first suggested more than 30 years ago. In this thesis, both simulations and in vitro experiments will be used to investigate the changes related to the resonance of bubbles and how the concept of bubble size population affects the accuracy of this technique. In particular, it will be shown how shell dynamics dominates the response of microbubbles to blood pressure.

A pose estimation method is proposed for measuring the position and orientation of a biopsy needle. The technique is to be used as a touchless needle guide system for guidance of percutaneous procedures with 4D ultrasound. A pair of uncalibrated, light-weight USB cameras are used as inputs. A database is prepared offline, using both the needle line estimated from camera-captured images and the true needle line recorded from an independent tracking device. A nonparametric learning algorithm determines the best fit model from the database. This model can then be used in real-time to estimate the true position of the needle with inputs from only the camera images. Simulation results confirm the feasibility of the method and show how a small, accurately made database can provide satisfactory results. In a series of tests with cameras, we achieved an average error of 2.4mm in position and 2.61° in orientation. The system is also extended to real ultrasound imaging, as the two miniature cameras capture images of the needle in air and the ultrasound system captures a volume as the needle moves through the workspace. A new database is created with the estimated 3D position of the needle from the ultrasound volume and the 2D position and orientation of the needle calculated from the camera images. This study achieved an average error of 0.94 mm in position and 3.93° in orientation.

The utility of microbubble agents in a variety of diagnostic and therapeutic ultrasound techniques has been widely demonstrated, most notably in Contrast Enhanced Ultrasound (CEUS) imaging. Unfortunately, the underlying mechanisms of their response to ultrasound excitation are poorly understood, restricting the development of promising techniques, such as quantitative perfusion imaging. A significant reason for this is that current microbubble characterisation techniques suffer from one or more of the following limitations: i) large experimental uncertainties, ii) physical restrictions on microbubble response and iii) failure to provide large data sets suitable for statistical analysis. This thesis presents a new technique to overcome these limitations. A co-axial microfluidic device is used to hydrodynamically confine microbubbles through the focal region of a laser and ultrasound field. The magnitude of light scattered by isolated microbubbles during ultrasound excitation is converted to radius using Mie Scattering theory. This technique is capable of obtaining large samples (>10³/min) of microbubbles to be efficiently characterised. The response of a commercial contrast agent, SonoVue®, is first investigated for a range of ultrasound exposure parameters; frequency (2 MHz - 4.5 MHz), peak negative pressure (6 kPa - 400 kPa) and pulse length (3 cycles - 8 cycles). Second the device is used to investigate the effect of composition and fabrication on microbubble response to similar ultrasound conditions. The results demonstrate a very large variability in microbubble response independent of initial size, indicating a significant lack of uniformity of coating properties. This is further supported by quantitative fluorescence imaging and quasi-static pressure chamber measurements. The implications of the findings for CEUS imaging and the development of microbubble contrast agents are discussed, as well as the limitations and suggested improvements of the characterisation technique.

Drug delivery plays a crucial role in the chemotherapeutic treatment of cancerous solid tumours. A drug, no matter how potent, is only truly effective when it can be delivered to all targeted cells. In recent years it has been recognised that the poor response of tumours to chemotherapy is in part due to inadequate drug delivery. Numerous strategies have been developed to overcome this issue. Of particular interest to the present work is the application of ultrasound and cavitation, which has been shown to be capable of enhancing drug delivery in solid tumours. These enhancements are attributed to the acoustic cavitation of microbubbles and the effects cavitation induces in the surrounding tissue. To better understand how ultrasound and cavitation can enhance drug delivery, an instrument was developed that is capable of monitoring in real-time and in-situ the effect of ultrasound and cavitation on drugs and drug analogues within flow channel models. The developed instrument was used to investigate the effect of ultrasound and cavitation on drug-eluting beads used for chemoembolisation, the effects of drug loading on microbubble dynamics, the effects produced by different cavitation agents, and the performance of passive acoustic mapping as a means of cavitation monitoring. The findings of the above investigations include: more physiologically relevant characterisations of drug-eluting beads pharmacokinetics, the possibility of significant changes in microbubble dynamics due to drug loading, a lack of general correlation between detected cavitation activity and induced effects, and the potential of passive acoustic mapping for monitoring cavitation and ultrasound induced effects. These and other findings also demonstrate the utility of the developed instrument for studying the many facets and applications of ultrasound and cavitation mediated drug delivery.

No description available.

Ultrasound is now a widely used technique in medicine. The precise mechanisms by which ultrasound interacts with tissues are still not fully understood, however, and it is possible that ultrasound presents a small hazard to those who receive it. An understanding of the possible mechanisms by which ultrasound may be hazardous is necessary if reliable safety levels are to be set. One possible damage mechanism is transient cavitation, which is the creation, expansion and collapse of small bubbles in tissues in response to the variations in pressure produced by the ultrasound wave. During the collapse stage, very high temperatures can be produced within the bubble and it is likely that free radicals are formed. Sonoluminescence is the name given to the light emissions that accompany transient cavitation, and is an indication that cavitation has occurred. In this thesis the phenomenon of sonoluminescence, and various factors that influence it, are investigated under similar conditions to those obtaining in clinical practice. When the effect of physiotherapeutic ultrasound on a tank of water was investigated and light output was detected using either a photomultiplier or an image intensifier, sonoluminescence was found to increase with increasing ultrasonic intensity above a well defined threshold. Sonoluminescence also increased with increasing temperature and was found to depend on duty cycle and standing wave ratio. Subsequently sonoluminescence was also recorded from water after insonation with quite short pulses of ultrasound, but thresholds, were much higher than with long pulses. The effect of ultrasound on monolayers of cells growing in culture was found to depend on the position of the monolayer in the standing wave field. Finally a direct attempt to measure sonoluminescence from the human cheek was made, but none was observed.

In this research, Acoustography Nondestructive Evaluation method was investigated for inspecting “tight radii” in carbon fiber reinforced polymer (CFRP) components. Ultrasonic inspection of tight radii is challenging because of refraction and/or mode conversion of ultrasound waves at the entry and exiting surfaces of the tight radii. Snell’s law was used to first study the refraction and/or mode conversion behavior of the ultrasound beam at the entry and exiting surfaces of a CFRP panel; to help establish the angular range over which ultrasound is transmitted through CFRP material. Snell’s law data was then used as a guide for setting up the Acoustography system and part orientation to optimize inspection of several real-world CFRP components containing tight radii. CFRP tight-radii specimens were prepared by strategically placing markers around the tight radius of each specimen to ensure full coverage of the tight radius region. Acoustography inspection was first performed with a straight beam to establish limitation of the straight beam in detecting markers in the tight-radii region, as predicted by Snell’s law. Acoustography inspection was then performed using a multi-angle beam (+/- 12.5o) to improve detection of markers in the tight-radii region. Results confirmed that straight beam (flat transducer) could not penetrate the sample at the start of the tight radius because of refraction or mode conversion effects. However, the use of multi-angle beam (multi-angle transducer) greatly improved the penetration through the tight radius because some of beam angles were within the ultrasound transmission range for the tight radii. Experiments were also performed by changing orientation of the CFRP sample under the multi-angle or straight beam. Sample orientation was changed at five-degree increments so that optimum conditions for the tight-radii inspection could be determined. This research provides a basis on which further improvements can be made to advance the Acoustography NDE method for the inspection of tight radii in CFRP components.