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

Lead Research Organisation: University of Leicester
Department Name: Cardiovascular Sciences

Abstract

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.

Planned Impact

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.

Publications

10 25 50
 
Description We noticed during our initial ultrasound experiments that it was possible to use our ultrasound equipment to detect very small displacements of objects in the beam. This led our team to develop a software algorithm for estimation of displacement and we are now in the process of developing and testing a novel medical device for measuring tissue motion non-invasively through the skull. Potential applications include diagnosis of brain injury in patients with stroke or head injury,
Exploitation Route We performed a proof of concept study in ~20 patients and are developing a prototype medical device in collaboration with industry.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Please see outreach impacts. The study also helped with training staff within our team and fostering clinical collaborations. Too early to identify clinical impact for healthcare, but we hope to improve the diagnosis of brain injury in the future.
First Year Of Impact 2015
Sector Healthcare
Impact Types Societal

 
Description IPEM Innovation Award
Amount £9,800 (GBP)
Organisation Institute of Physics and Engineering in Medicine (IPEM) 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2016 
End 11/2017
 
Description Industry Exchange award to visit Nihon Kohden, Japan
Amount £3,000 (GBP)
Organisation University of Leicester 
Sector Academic/University
Country United Kingdom
Start 12/2018 
End 07/2019
 
Description Industry funding
Amount £50,000 (GBP)
Organisation Nihon Kohden (Japan) 
Sector Private
Country Japan
Start 01/2015 
End 01/2017
 
Description IoP carer's fund - travel award
Amount £300 (GBP)
Organisation Institute of Physics (IOP) 
Sector Learned Society
Country United Kingdom
Start 06/2016 
End 07/2016
 
Description LD3 - Brain TV Confidence in Concept study in moderate/severe stroke
Amount £30,000 (GBP)
Organisation University of Leicester 
Sector Academic/University
Country United Kingdom
Start 08/2018 
End 07/2019
 
Description MRC IMPACT DTP: Brain Tissue Pulsations: modelling and machine learning methods for the detection of raised intracranial pressure in adult intensive care.
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2020 
End 09/2023
 
Description STFC PoC
Amount £8,300 (GBP)
Organisation Science and Technologies Facilities Council (STFC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 07/2017
 
Title Doppler-ultrasound displacement estimation software 
Description This software uses Doppler measurements from a commercially available transcranial Doppler ultrasound machine and analyses these in a novel way to provide a highly sensitive estimate of displacement. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact We are testing the software and validating our measurements. We are hopeful they might have some potential for clinical impact through development of a medical device. 
 
Title Prototype for brain tissue motion measurement 
Description New ultrasound method for measuring motion of the brain. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2017 
Provided To Others? No  
Impact Can be used to detect abnormal brain tissue pulsations (e.g. in stroke or head injury research) 
 
Title Normative data for brain tissue motion measurements in healthy volunteers 
Description Brain tissue pulsation measurements obtained in healthy volunteers can be used to inform statistical models to detect abnormal pulsations in stroke or head injury patients. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact Data still being analyses and used for model building. 
 
Description 3D printed Medical Phantom development 
Organisation NPL Ltd
Country United Kingdom 
Sector Private 
PI Contribution Work towards characterisation of 3D printed phantoms and materials for medical ultrasound applications.
Collaborator Contribution Calibration and measurements expertise.
Impact Grant proposal in preparation
Start Year 2017
 
Description Industry collaboration with Nihon Kohden (Japan) 
Organisation Nihon Kohden (Japan)
Country Japan 
Sector Private 
PI Contribution We are collaborating with an industry partner (Nihon Kohden) to develop a novel wearable ultrasound device for diagnosis of brain injury. Our role in the collaboration is to develop and test algorithms and software for the analysis of Doppler ultrasound signals in relation to the device.
Collaborator Contribution Nihon Kohden is developing a research prototype for future clinical testing. The company paid £50k to enable us to collect pilot data in patients and have provided an 'in kind' contribution of ~£50k in equipment.
Impact As a result of this collaboration we performed a feasibility study in volunteers and a small number of stroke and head trauma patients with brain injury. We have developed software in MATLAB for analysis of Doppler ultrasound data and data interpretation. Nihon Kohden have developed a prototype for further testing.
Start Year 2015
 
Description Partnership with Nottingham University Hospitals Neurosurgeons and Adult Intensive Care Unit 
Organisation Nottingham University Hospitals NHS Trust
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribution of £2.5k to fund a feasibility trial in patients.
Collaborator Contribution Recruitment of a small number of patients.
Impact We obtained data from 5 patients.
Start Year 2016
 
Description Partnership with UHL NHS Trust Clinical Engineering, and Clinicians within the Stroke Unit and Emergency Medicine 
Organisation University Hospitals of Leicester NHS Trust
Country United Kingdom 
Sector Academic/University 
PI Contribution We have been working in partnership with the UHL NHS Trust Medical Physics (Clinical Engineering Group) in testing our device and seeking advice regarding next steps and MHRA approvals. As part of this study we provided funding for NHS Clinical Engineering support, and contributions to the Trust for recruitment of patients within the LRI stroke unit and A&E.
Collaborator Contribution The Trust has been supporting us in gaining ethical approval and understanding regulatory requirements for development and testing of medical devices within the NHS. An NHS STP trainee has also been supporting our study by performing measurements as part of her MSc. NHS clinical engineers were also instrumental in setting up the EPSRC plotting tank developed as part of this project, including software development and integration. We also work with clinicians within the Trust who provide advice on the clinical aspects of our research and access to patients.
Impact Multidisciplinary collaboration crossing physics, engineering and medicine: A fully functioning ultrasound beam plotting tank Loan of a programmable pump Support for ultrasound phantom development Loan of ultrasound equipment Advice on NHS and MHRA regulations Advice on the clinical aspects of our research and access to patients
Start Year 2015
 
Title Development of a medical device prototype to monitor brain motion 
Description We have been working with a manufacturer of medical equipment (Nihon Kohden) to develop a clinical prototype for MHRA approval and further clinical testing. The prototype should be arriving in April. We obtained proof of concept data in 20 patients and are actively seeking funding to facilitate larger clinical trials. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Actively seeking support
Impact New industry contacts. It's too early to say whether there will be any clinical impact. 
 
Description Assisting with the making of a BBC4 documentary 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I provided scientific advice and images for a BBC4 Documentary 'The Wonderful World of Blood with Michael Mosely'. This was broadcast in March 2015 and has been repeated at regular intervals on BBC iplayer.
Year(s) Of Engagement Activity 2015
 
Description Brain Awareness Day Outreach 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Outreach activity demonstrating our equipment for recruitment of healthy volunteer study participants.
Year(s) Of Engagement Activity 2017
 
Description Doppler Day at the Great Central Railway 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We held two events during National Science week. During the day, children from 3 Leicestershire schools (~70 children) came to the Great central railway to enact a classic science experiment to confirm the Doppler effect. This involved the schoolchildren using their mobile devices (and ears) to record the change in pitch of horn players on a steam train. We also has a speed camera demonstration, demonstration of laser vibrometry, and short talk from the Institute of Physics.

In the evening myself and a colleague from Physics and Astrophysics gave a free public open lecture at the National Space Centre planetarium on use of the Doppler effect to look inside the body using ultrasound, and into space to investigate the motion of stars in the Milky Way. The events received an excellent response.
Year(s) Of Engagement Activity 2015
 
Description IPEM outreach at Create-a-con 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Activities focusing on children aged 3 to 10, including a 'guess the fruit and veg from its MRI' quiz, hands-on ultrasound scanning (using a phantom), and making a paper 'Brain hat'. These activities are alway popular, and result in invites to conduct further STEM activities in local schools.
Year(s) Of Engagement Activity 2019
URL http://interactdigitalarts.uk/diary/2019/03/interact-at-create-a-con
 
Description Invited talk at the British Medical Ultrasound Society Annual Scientific Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk about our EPSRC project at a national ultrasound conference.
Year(s) Of Engagement Activity 2016
 
Description NIHR Brain Injury HTC Think Tank - technology showcase 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I showcased our emerging technology at an NIHR Brain Injury Health Technology co-operative Think Tank in Westminster and received a lot of interest from Clinicians and potential Industrial partner.
Year(s) Of Engagement Activity 2016
URL https://brainhtc.org/wp-content/uploads/2016/10/PROGRAMME-Brain-Injury-Technologies-Think-BITT-tank-...
 
Description The pulsing brain - an interactive exhibit for Brain Awareness Week and British Science Week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interactive, family friendly, exhibit held at the Leicester Creative Business (LCB) Depot as part of 'Creat_A_Con' to celebrate British Science week. The pulsing brain exhibit included an activity involving a waerable 'paper brain hat' for children to make, a demonstration of measurment of brain blood flow using Doppler ultrasound, 'hands-on' ultrasound scanning, and a pulsing brain phantom.
Year(s) Of Engagement Activity 2018