The aim of this project is to develop and evaluate a prototype laser based ultrasound imaging instrument for industrial and medical applications in collaboration with a UK SME, Precision Acoustics Ltd. The technology is based upon a novel patent-protected optical sensing technology that was invented at UCL and its feasibility subsequently demonstrated under a major 3m EPSRC funded research programme. Having demonstrated proof-of-concept, the technology is now ripe for commercial exploitation. The Collaboration Fund will be used to achieve this by constructing a prototype instrument for a targeted application, namely, imaging the output of therapeutic medical ultrasound devices such as those used to fragment kidney stones or destroy cancerous tumours in order to ensure compliance with regulatory standards. Although effort will be focused on this specific application, the concept is regarded as a technology platform which, in the longer term, will form the basis of a range of instruments each targeted at a specific application within the significantly larger industrial non destructive testing (NDT) and medical imaging markets. For example, with additional development, the same technology could ultimately be used to visualise faults in engineering materials or as a medical imaging system for the detection, diagnosis and treatment monitoring of cancer and cardiovascular disease.

The research has produced a sensor system for identifying the optimum positioning of extracorporeal shockwave lithotripsy (ESWL) equipment and for identifying the degree of fragmentation of the stone as the treatment proceeds. ESWL is a treatment used for patients suffering renal, ureteric, salivary duct and gall stone disease. An acoustic shockwave - generated outside the body - is used to fragment the stones to a small size so that they can more easily pass through the body or be dissolved using drugs. The intention of this invention is to allow the clinical operator of the lithotripter machine to determine more accurately when the treatment should be ended using a passive sensing technique. It consists of a passive acoustic pressure sensor that can be placed against the patient during treatment. The sensor picks up the acoustic signals generated by (and scattered from) the stone as the shockwave lithotripsy is progressed as well as signals resulting from an effect known as acoustic cavitation that occurs close to the stone. By monitoring characteristics of these signals it is possible to monitor whether the incident lithotripter shock is on-target and the degree to which stone cavitation has occurred.

High amplitude ultrasound waves propagating through tissue have been recently reported to induce a range of potentially beneficial phenomena, such as rapid tissue heating, increased permeability of cells to large drug molecules (sonoporation) or enhanced activity of drugs. These bioeffects are heavily correlated with the ultrasound-induced nucleation and subsequent excitation of micron-sized bubbles, yielding two types of acoustic cavitation activity: (1) inertial cavitation, which dramatically increases the energy transfer to tissue and can cause rapid heating and mechanical damage, and (2) stable cavitation, whereby bubbles act as micropumps that dramatically enhance the local mixing and transport length scales of drug molecules. In cancer treatment, local heating combined with chemotherpay will render cancer cells more sensitive to treatment, whilst local micropumping of the drug can help overcome delivery problems arising from the highly complex tumour structure. In the context of breaking down blood clots for stroke therapy, cavitation-enhanced mixing will promote delivery of the drug to a site of low blood flow and greatly increase the diffusion of the thombolyic drug across the clot surface.However, the nucleation of cavitating microbubbles and subsequent interaction with cells in biologically relevant media remain poorly understood. The objectives of the proposed research therefore are (i) to investigate the potential of cell- and site-specific cavitation nucleation using commercially available targeted nanoparticles currently being developed for molecular imaging; (ii) to understand and optimize the mechanism by which ultrasound and cavitation can enhance local drug delivery and drug activity across inaccessible interfaces such as tumours or blood clots; (iii) to develop clinically relevant means of monitoring cavitation activity and exploit them for real-time monitoring of drug delivery and (iv) to test the optimized drug delivery and treatment monitoring protocols in a clinically relevant organ model.It is hoped that the proposed resarch will pave the road for widespread clinical uptake of cavitaiton-enhanced targeted drug delivery by ultrasound. Particular advantages of this technique will include the ability to locally enhance drug activity, thus reducing the necessary drug dosages and their side effects, and to monitor therapy in real time. The outcomes of the proposed research are expected to be directly transferable to many other novel therapeutic ultrasound applications, such as non-invasive tissue ablation by High-Intensity Focussed Ultrasound (HIFU), acoustic haemostasis and ultrasound-induced opening of the blood-brain barrier for transcranial drug delivery.

The purpose of this research is to develop a promising new biomedical imaging technique called photoacoustic (PA) imaging. This involves firing very short (nanosecond) pulses of laser light into tissue. The light is absorbed by structures such as blood vessels producing a small heating effect. This leads to rapid thermoelastic expansion which generates high frequency (~tens of MHz) acoustic waves which travel though the tissue back to the surface. By measuring the time of arrival of these acoustic waves at a number of detectors positioned over the tissue surface, and with knowledge of the speed of sound, the acoustic signals can be backprojected to produce a 3D image of the internal absorbing structures within the tissue. The key advantage of the technique is that it combines the strong contrast of optical methods with the high spatial resolution available to ultrasound. This may make the technique a powerful diagnostic tool for identifying abnormalities such as certain types of cancer tumours that would be difficult to see using conventional medical imaging techniques such as X-ray or ultrasound imaging. This technique has many potential clinical applications, including detecting tumours in the breast, assessing skin abnormalities such as malignant melanomas or soft tissue damage such as burns or wounds. It can also be used to image small animals such as mice which are used extensively to model a wide range of human diseases. One of the most exciting features of photoacoustic imaging is its potential to characterise specific molecular processes, so called molecular imaging. This is achieved using probe molecules that strongly absorb certain wavelengths of light and have a high affinity for a specific cellular or molecular receptor that is characteristic of a particular disease such as cancer. In order to advance the technique to practical application, a substantial research program will be undertaken. A novel high resolution instrument, designed for non invasive imaging to depths of several mm, will be developed both for clinical use, for example to study skin pathologies and for the pre-clinical study of disease processes in small animal models. Endoscopic probes that are capable of being inserted into the body and guided deep within to image, for example, the inside of coronary arteries to assess the plaques that can build up and cause heart attacks will be developed. In addition, a dedicated instrument will be designed for the early detection and diagnosis of breast cancers and monitoring their treatment. Novel methods for recovering physiological information such as blood oxygenation and flow will also be explored and clinically tested. A programme of in vivo imaging both in humans and small animals to apply and validate these methods is planned, with specific emphasis on demonstrating the utility of the technique for the diagnosis and treatment of cancer, cardiovascular disease and neurological conditions. Overall this research offers the prospect of developing a powerful new diagnostic imaging tool that can be used to advance our understanding of disease mechanisms at an anatomical, physiological and molecular level and improving the clinical diagnosis and treatment of cancer and other major diseases.