Acoustic investigation of microbubble response to medical imaging ultrasound pulses

Abstract

Ultrasound contrast agents have the ability to provide locally increased echogenicity, improving the sensitivity and specificity of images. Due to the unique interaction of microbubbles with the imaging ultrasound field, contrast ultrasonography offers both improved diagnostic techniques, and the potential therapeutic uses of gene and drug delivery through the use of targeted agents. By enhancing the contrast at the tissue-blood interface, an improved image of the structure of organs can be achieved, which is useful in many areas of medical ultrasound imaging. Monitoring the flow of contrast agent in the blood stream also offers information on the degree of blood perfusion into an organ or microvasculature. Present knowledge of the interaction of microbubbles with ultrasound is far from complete. The full potential of contrast agents in improving diagnostic and therapeutic techniques has therefore not yet been achieved. The nonlinear and dynamic properties of microbubble response offer potentially large improvements in contrast to tissue ratio, through intelligent pulse sequence design and/or improved signal processing. Due to various drawbacks of populations studies, only by studying the response from single microbubbles can the interaction be fully understood. The variations of microbubble size and shell parameters within a typical sample of contrast agent dictate that a large number of single scatterer data are necessary to obtain information on the variability of microbubble response, which is not possible with current optical systems. This thesis aims to be a contribution to the understanding of contrast behaviour in response to medical imaging ultrasound pulses. A fully characterized microacoustic system, employing a wide-band piezoelectric transducer from a commercial ultrasound imaging system, is introduced, which enables the measurement of single scattering events. Single microbubble signals from two commercially available contrast agents, Definity R and biSphereTM, have been measured experimentally in response to a range of clinically relevant imaging parameters. The data has been analyzed, together with the results from appropriate theoretical models, in order to gain physical insight into the evolution and dynamics of microbubble signals. A theoretical model for the lipid shelled agent Definity has been developed, and the predicted response from a real sample of single microbubbles investigated. Various characteristics of resonant scatter have been identified, and used to distinguish resonant scatter in experimental acoustic single bubble data for the first time. A clear distinction between the populations of resonant and off-resonant scatter has been observed for a range of incident frequencies and acoustic pressures. Results from consecutive imaging pulses have been used to gain understanding of how initial size, shell material and encapsulated gas may effect the lifetime of a microbubble signal. The response to a basic pulse sequence is also investigated, and an alternative processing method which takes advantage of observed behaviour is presented. Improved understanding of the contrast-ultrasound interaction will provide the basis for improved signal processing tools for contrast enhanced imaging, with potential benefits to both diagnostic techniques and microbubble manufacture.