Novel ultrasound methods for the detection and deflection of emboli in the bloodstream

Stroke affects approximately 150,000 people each year at a rate of one person every five minutes, and is the leading cause of adult disability, and third leading cause of death, in the UK (Stroke Association, UK). The majority of strokes are caused by pieces of plaque debris and blood-clots (emboli) that detach from the insides of diseased vessels and travel through the bloodstream to become lodged in the brain. Other sources of emboli include air bubbles entering the bloodstream during cardiovascular surgery, or formation of bubbles during sudden decompression (e.g. in Divers or Astronauts).

Since emboli are carried rapidly through the bloodstream at speeds of up to 1 m/s, conventional ultrasound machines, that build up an image line-by-line, are too slow to capture their motion. Emboli are therefore not usually visible on ultrasound images. Currently, emboli are detected using the same 'Doppler principle' as used to detect speeding cars, which is great for detecting emboli speeding through arteries, but is unable to provide information on embolus size or composition. As large pieces of plaque and blood clots are much more hazardous than small bubbles, it is vitally important that clinicians can distinguish between them. Unfortunately, this is not possible using existing Doppler-based techniques. Therefore, we are keen to develop mew methods of determining embolus size and composition. This research utilises recent advances in ultrafast ultrasound imaging technology to capture the ultrasonic appearance and motion of emboli at high speed. Since large particles and tiny bubbles are expected to respond differently to the presence of an acoustic radiation force, this could potentially provide a method for distinguishing between them. If a sufficiently large acoustic radiation force can be directed toward the embolus this also has potential for altering the trajectories of emboli at arterial bifurcations to divert emboli away from the brain. Diversion of bubbles and debris may help to reduce the risk of brain injuries during surgical procedures and is not thought to be harmful to other organs. New methods for embolus detection and characterisation could also be useful for monitoring the sizes and compositions of emboli in patients. At present, many operations involving the heart and arteries carry a high risk of brain injury, which could potentially be avoided using embolus deflection devices. In addition to deflection of emboli away from vital organs, potential applications of our research include 'steering' of ultrasound microbubble contrast agents, or drugs, towards targets of interest.

1. The first part of our study investigates the potential for detecting solid particles and bubbles by relating the Doppler ultrasound scattering properties of emboli to their appearance in the ultrafast ultrasound image. Particular attention will be paid to examining the properties of solid and gas emboli that generate equivalent Doppler signals.

2. The second part of the study directs a focused ultrasound beam toward the moving embolus to slightly alter it's trajectory. As bubbles feel the 'push' of the ultrasound beam more strongly than solid particles, we expect that bubbles, thrombus, and plaque will generate differing responses to application of an acoustic radiation force, which will enable us to distinguish between them.

3. Finally, we investigate whether it would be feasible to direct a stronger acoustic radiation force to divert solid and gaseous emboli along one artery rather than another. This will be tested using physiologically realistic laboratory models. The ability to safely direct emboli away from the cerebral arteries, or toward targets of interest, has potential to reduce the number of emboli reaching the brain use during heart surgery, and improve the neurological safety of medical procedures involving the heart and arteries.

Embolisation of plaque debris and thrombus is a major cause of stroke and a leading global cause of adult death and disability. Over a 5-10 year timescale, our research has potential to lead to changes in clinical practice by contributing to the neurological safety of cardiovascular interventions and enhancing our understanding of health problems relating to cerebral embolism. The current proposal is driven by a strong clinical impetus to confidently distinguish between thrombus, plaque and gaseous emboli to aid diagnosis of the source of embolisation and prevent future embolic brain injuries. Although emboli can be detected in a variety of clinical settings (e.g. surgery, decompression sickness, and acute stroke), our short-term impact plan focuses principally on monitoring of emboli during cardiac interventions, where brain injuries are common and potentially avoidable. Our existing collaborations with Cardiothoracic Surgeons (Prof Gavin Murphy, Prof Tom Spyt, Mr Mark Hickey, Mr Jacek Szostek) and Cardiologists (Prof Andre Ng and Dr David Adlam), Stroke Physicians (Prof Tom Robinson) and Vascular Surgeons (Prof Ross Naylor) at Leicester Glenfield Hospital and Leicester Royal Infirmary will facilitate future validation and translation of our techniques to monitoring patients within a clinical environment.

Technical skills and electronic and mechanical workshop facilities provided by the University Hospitals of Leicester Medical Physics Department will enable clinical prototype systems to be developed 'in house' and safety tested for future clinical trials and Medical Devices approval. Protection of Intellectual Property associated with the results of our study will be supported by the University of Leicester Enterprise and Business Development Office. Further funds to facilitate public and patient involvement and clinical trials in humans would be sought in collaboration with academic clinical colleagues within the University of Leicester Department of Cardiovascular Sciences and University Hospitals of Leicester NHS Trust to develop future proposals for clinical translation.

The clinical benefits of improved embolus detection techniques during cardiac interventions provide a direct pathway to clinical implementation of our findings. More specifically, this research project will form part of a wider programme of activities conducted by our group as part of the Leicester Cardiovascular Biomedical Research Unit (funded by the NIHR) for translation of novel technologies for the prevention and treatment of Cardiovascular Disease. The development of non-invasive ultrasound techniques for diagnostic decision-making and therapy has a high probability of making a valuable contribution to society through improved quality of life of patients. More specifically, the technology described in this proposal has potential to assist in guiding clinicians in reducing embolisation and improving the safety of cardiovascular procedures.

In addition to significant potential for clinical impact, these first grant funds come at a crucial moment in Dr Chung's research career, and will provide vital infrastructure to enable her to widen her research activities. The requested equipment has been carefully selected to provide a versatile experimental station to be utilised for a wide range of future ultrasound projects including biological interactions of ultrasound with tissue, ultrasound safety, beam characteristics, shear-wave elastography, ultrasound scattering theory, contrast agents, haemodynamics studies, and phantom research. This dedicated ultrasound facility will be used and adapted for many years to come and has potential to facilitate numerous projects and discoveries far beyond the lifetime and immediate impact of the grant.