Ternary piezocrystals is the name given to a new group of single crystal piezoelectric materials that have a much higher mechanical Q and much higher energy densities than the binary compositions. Ternary piezocrystals have properties that are now sufficient for enabling their incorporation in high power ultrasonic devices. Their doped counterparts are a very recent development offering previously unavailable properties. Most importantly for high power ultrasonic transducers, they have increased the mechanical Q from around 100 to nearly 1000. However, completely new ultrasonic transducer configurations are needed to exploit fully this increased performance. Through characterisation and incorporation of doped ternary piezocrystal materials, and by capitalising on their significant potential for transducer enhancements, we will be able to create next generation high performance, high power ultrasonic devices for surgery. We will particularly investigate their integration in novel orthopaedic devices, aiming at the extremely challenging and potentially disruptive technology of ultrasonically-assisted needles. For minimally invasive, highly accurate, interventional surgery via direct penetration through bone, we will deliver devices offering the clinician entirely new and potentially transformational capabilities in a range of clinical applications including oncology, neurosurgery, orthopaedics, bone biopsy, regional anaesthesia and rheumatology. In meeting this challenge, we will develop new techniques for characterisation of the materials and create designs for novel transducers, based on the measured characteristics, for actuation of power ultrasonic surgical tools. We will research a new class of devices in the form of bone-penetrating ultrasonic needles that can be realised with doped ternary piezocrystals to permit the highly challenging surgical tasks of (i) direct delivery of therapeutic drugs to targets within or obscured by bone, (ii) gaining access within medullary canals and inside cranial sinuses/cavities for surgical procedures, and (iii) obtaining biopsies from the inside of the bone for diagnosis. Binary compositions of the new materials are already replacing conventional piezoceramics in biomedical imaging applications and adoption of these and the newer ternary compositions for other high value applications will increase as on-going efforts to scale up crystal growth techniques mature. This project will thus position the UK in the forefront of research, while simultaneously offering transformative research in ultrasonic devices for surgery.

Colorectal Cancer (CRC) is the third most common cancer in the UK, with approximately 32,300 new cases diagnosed and 14,000 deaths in England and Wales each year. Occurrence of colorectal cancer is strongly related to age, with 83% of cases arising in people older than 60 years. It is anticipated that as our elderly population increases, CRC will increase in prevalence (National Institute for Clinical Excellence, www.nice.org.uk). This raises important questions relating to treatment in elderly patients balanced with quality-of-life and health economics considerations. The challenge to nanotechnology and engineering is to deliver cost-effective, less invasive treatments with fewer side-effects and potential benefits for quality of life in patients. This is particularly important in CRC at the present time as the NHS bowel-screening programme is rolled out for all individuals aged 60 to 69. This raises important issues for rapid, accurate, and acceptable, safe and cost-effective investigation and treatment of older symptomatic patients. Ultrasound has a clear and growing role in modern medicine and there is increasing demand for the introduction of ultrasound contrast agents such as microbubbles (MBs). These MBs are typically less than one hundredth of a millimetre in size, so that they can pass through the vasculature, and lead to imaging enhancements by scattering of the ultrasound signal. So-called third generation MBs will not only perform functional imaging with greatly enhanced sensitivity and specificity but will also carry therapeutic payloads for treatment or gene therapy. These will most likely be released by destroying the bubbles at the targeted site and their effect enhanced further by sonoporation (sound induced rupture of the cell walls to allow drugs in). Although the focus of our proposal is therapeutic delivery for cancer treatment, the basic technologies for MB development and ultrasound technology are equally applicable to other conditions e.g. cardiovascular and musculoskeletal disease where there is an unmet clinical need, particularly in ageing populations. As such this is a generic technology development relevant to different diseases.Our programme of research addresses several key issues central for the successful development of these 3rd Generation MBs. Firstly, we propose to develop a machine, based on microfluidics, for the creation of MBs of uniform size (necessary for human application). This instrument will also allow us to put suitable coatings on the MBs to target them specifically at cancerous cells. Secondly, we will develop novel coatings to allow control over the way bubbles respond to ultrasound signals. We will then add payloads of the required drug to be delivered onto the micro-bubble surface. At the same time we will develop novel methods of generating ultrasound signals which can be used to selectively destroy the MBs and simultaneously create holes in the cells to which the drugs should be delivered. A necessary part of such a programme of research is the full testing and evaluation of the MBs developed for targeted therapy of CRC using a combination models. Firstly, against cancer cells grown in test tubes and secondly, against mice infected with the relevant cancer. At the conclusion of our research project we will have enhanced our understanding of how MB and ultrasound technologies can be combined to yield new routes for therapeutic delivery/gene therapy. This will provide a platform to launch the next stage of research, required before such an approach could be used clinically.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

We have carefully planned this research programme to pioneer a wholly new capability in ultrasonic particle manipulation to allow electronic sonotweezers to take their place alongside optical tweezers, dielectrophoresis and other techniques in the present and future particle manipulation toolkit.Following end-user demand, particle manipulation is a rapidly growing field, notably applied to the life sciences, with emerging applications in analysis and sorting, measurement of cell forces and tissue engineering. Existing devices have valuable capabilities but also limits in terms of forces that can be produced and measured, particle sizes that can be handled, their range of compatible buffer characteristics and sensitivity to heating, and suitability for integration with sensors in low cost devices. Key to our programme is the concept of dynamic potential energy landscapes and the established ability of ultrasound to create such landscapes, potentially to generate forces under electronic / computer control. Our principal technical aim is to exploit this in integrated sonotweezers to apply and measure larger forces over longer length scales, extend micromanipulation to larger particles, and demonstrate this in pathfinder applications in life sciences.To achieve our aims, we have already carried out successful feasibility studies and brought together an outstanding multidisciplinary team of investigators including internationally established members, some of the UK's most exciting young scientists and engineers, and appropriate overseas collaborators. Such a team is a prerequisite for what we recognise as a challenging, highly complex, densely interlinked programme. Over its four years, with strong management and built-in research flexibility, we will explore key areas of science, technology and applications to create and demonstrate electronic sonotweezers. Throughout the work, there will be parallel activity in understanding of physical principles, modelling and design, state-of-the-art fabrication, sensor integration, and applications testing.