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.

Over 120,000 people in the USA and over 6000 people in the UK are waiting for organ transplants, and many more are suffering from organ failure. Many donor organs are not transplanted (approximately 60% of donor hearts and 20% of kidneys are not used), often because they can only be kept for a short time. Long term preservation would mean better matching with recipients over larger geographical areas, reducing the chances of rejection and increasing the number of organs that could be used. One potentially transformative method of preserving organs for a longer time is cryopreservation. This involves freezing the organs at very low temperatures and then defrosting them when needed. However, this is currently limited to small volumes (<3 ml), largely due to the difficulty in rewarming the tissues without damage after freezing. To avoid damage on rewarming, tissues must be heated quickly and uniformly. This is not possible with existing water bath methods so the development of new methods for volumetric rewarming of large tissue volumes is critical. The aim of this fellowship is to develop a novel method of tissue rewarming using ultrasound. As ultrasound passes through frozen tissue, it loses energy which is deposited as heat. By controlling the pattern of the ultrasound waves entering the tissue, heat can be deposited as needed to raise the temperature of the tissue quickly and uniformly. First, the ultrasound parameters will be optimised for maximum cell viability and optimal heating rate using small volumes of cells. An ultrasound array based on these parameters will then be developed with methods of steering and shaping the acoustic field to uniformly and rapidly heat larger volumes of cells. This will be extended to warming tissues with inhomogeneous acoustic and thermal properties and larger volumes, using real time feedback to control the heating distribution, with the ultimate vision of creating a fully flexible tool that can be used to rewarm whole organs. Ultrasonic volumetric warming has the potential to enable long-term storage of tissues and organs which would transform the availability of organs for transplant. It would also have many other applications such as increasing access to therapies involving implanting cells and tissues in the body for diseases such as type 1 diabetes or for restoration of fertility after cancer therapy.

Multi-phase, trans/supercritical and non-Newtonian fluid flows with heat and mass transfer are critical in enhancing the performance of energy production, propulsion and biomedical systems. Examples include: hydraulic turbomachines, ship propellers, CO2-neutral e-fuels and e-motor cooling systems, particleladen flows in inhalers and focused ultrasounds for drug delivery. What all these cases have in common is the high level of complexity which makes Direct Numerical Simulations impossible. State-of-the-art LES simulations rely on simplified assumptions but do not have yet the desired accuracy, while often require enormously expensive CPU resources. The aim of project (acronym 'SCALE') is to develop simulation methods and reduced-order models using physics-informed and data-driven Machine Learning and optimisation methods for such flow processes. These will be trained against 'ground-truth' databases that will be generated for the first time using both DNS and experimentally validated, industry-relevant LES and multi-fidelity RANS simulations. The new simulation tools will be applied for the first time to industrial problems and their ability to accelerate design times and improve accuracy will be jointly pursued and evaluated with the non-academic partners of SCALE. These are international corporations and market leaders in the aforementioned areas. Holistic training by experts from science and industry includes broad reviews on relevant scientific topics, modern high performance computing architectures suitable for performing such simulations, big data analytics as well as extensive support for mastering scientific tasks and transferring the knowledge acquired to industrial practice. SCALE will also deliver transferable soft skills training from a well-connected cohort of leaders with the ability to communicate across disciplines and within the general public. This coupling of research with industry makes SCALE a truly outstanding network for doctoral candidates to start their careers.

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.