Imaging the stars from within: Super-resolution contrast ultrasound imaging

Using adaptive optics, first applied in astronomy and then (under STFC funding) successfully adapted for use in optical microscopy, we aim to to produce micrometric resolution ultrasound imaging. Specifically, the goal is to track microbubble contrast agents in circulation thus generating detailed images of the vascular network. This is to meet the unmet clinical need for microvascular assessment in common diseases associated with abnormal microvascular networks such as cancer, ischaemia, inflammatory disease, transplant rejection and tissue regeneration. An example is the ongoing need for rapid and low-risk biomarkers of treatment outcome and its prediction in cancer. The current response evaluation criteria for solid tumours (RECIST) utilises Computerised Tomography (CT) to assess tumour volume changes which typically is done three (3) months after the treatment. Such indirect assessment significantly limits early personalisation based on treatment response and may contribute to suboptimal morbidity and mortality rates.

Every year, over 250,000 people in England are diagnosed with cancer, and around 130,000 do not survived as a result of the disease. The annual NHS related costs are in the order of £4.5 billion, and the cost to society as a whole about £18.3 billion. Although these statistics are improving the UK Department of Health aims to achieve the average cancer survival rate on par with the rest of the European Union in an attempt to save an extra 5,000 lives every year.
Our proposed product will be used to provide additional benefits to the care of each patient that can be used for:
-Early diagnosis with the potential of becoming a screening test,
-Early and fast disease monitoring that enables early patient stratification. Ultrasound provides real time images at low cost and low risk to patients, which is very attractive for repeated imaging of tissues.

As recommended by the Department of Health we will assess our technique in the measurement of an established biomarker such as microvascular density (which is an established biomarker for many cancers), and consider the generation of new biomarkers such as capillary blood velocity, vessel structure and tortuosity that may provide a robust differentiation of vascular related disease. This is a significant improvement to all current imaging modalities that are macroscopic.
There is a real opportunity to establish CEUS as the leading modality for perfusion assessment by translating existing technology that provides super-resolution images of point sources in optics (microscopy, astronomy), mm-wave and radar. This proposal will deploy the scatter from single microbubbles as a priori knowledge for implementing an available maximum sharpness likelihood technique similar to that used in optical microscopy. We will implement existing algorithms in an ultrasound field simulation environment to define the experiments that will be used to test these algorithms in vitro and finalize the design of the beamforming method. By utilizing existing image analysis algorithms used for particle tracking we will generate the visualization of in vitro microvascular phantoms. A prototype tool that can be implemented in existing ultrasound imaging product provided by BK Medical, our industrial partner, will be delivered. Finally, we will use existing commercial equipment to collect cancer patient data in order to identify a patient group with promising image data (in comparison with a gold standard). This will provide a focal point in a follow up project for the commercialization of the enhanced imaging capability of our prototype.

This is a highly interdisciplinary project in a very important research area that will benefit:

1. Public Health and the management of major diseases in the NHS due to:
The development of early diagnostic or prognostic biomarkers is considered key to reducing mortality rates and NHS costs by early patient stratification. The NHS spends £4.5 billion a year in total in cancer care, which amounts to 5% of total NHS expenditure. Currently, there is an expected £5.9 billion shortfall anticipated by 2021.
The STFC CLASP Healthcare launch (20th May 2014) speaker Dr Linda Mahon-Daly Macmillan identified ultrasound as the single most cost-effective hazard-free imaging modality for diagnosis and treatment monitoring. It was specifically raised that the development of ultrasound imaging will provide significant reductions to NHS costs as well as improved quality of care to patients.
The micrometric detail of our new imaging technology will enable the accurate assessment of microvascular density, which is an established biomarker for angiogenic cancers. Therefore, our proposed technology may be used in the future to upgrade current therapy monitoring protocols that allow a prognosis in a few days post-treatment instead of the current 3 months (RECIST). It may also be introduced as a screening method of the UK population for the early detection of disease (such breast or prostate cancer). (see also 2. Timeliness under alignment with to the call section).

2. Life science research: Our work may stimulate other biomarker research. Measurements of capillary blood velocity, vessel structure and tortuosity may become possible through our new technology and these may provide a robust vascular differentiation of several vascular related diseases.
In addition, improved understanding of key disease processes is generated by relevant preclinical models. However, current preclinical investigations use post-mortem techniques (eg. Immunohistochemistry) for the evaluation of biomarkers. The proposed technology may replace (partially or fully) such laborious methodologies offering improved statistical power by means of an accurate longitudinal imaging assessment. The additional benefit here is the reduction of the number of animals required and the reduction of associated research costs.

3. The related ultrasound imaging, image analysis and microbubble manufacturing industry as new technologies may be generated and immediately exploited. (see also High likelihood of commercialization under Alignment to the call section).

4. The Science and Technologies Facilities Council (STFC):
The current proposal deals with an area that is not traditionally supported by the STFC but is directly reliant on technologies that are successfully developed with STFC funding. This is a case of demonstration of the wider impact of STFC funded research.

5. Inter-dsicplinary knowledge exchange and exploitation: The Edinburgh super-resolution imaging consortium (ESRIC), based in the Institute of Biological Chemistry, Biophysics and Bioengineering (IB3) and funded by the MRC, BBSRC and EPSRC is the leading super-resolution imaging consortium in the UK and the only one of its kind in Scotland. ESRIC cover the full range of commercial super-resolution microscopy methodologies, IB3 is also a partner of the Edinburgh Centre for In vivo Imaging Science (CIVIS). It is this environment that fostered the ideas and pilot work that inspired this application and importantly it is this environment that allows us to exploit any future developments across imaging disciplines. We have made the case here that super-resolution imaging can grow further with added benefits to the wider scientific area of active sensing and related industry including radar, sonar and astronomy, and indeed, due to the unprecendented expertise on hand within IB3 and ESRIC, feed directly back into super-resolution microscopy community.