Contrast agent microbubble-cavitation for therapy

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Contrast agent microbubble (MB)-cavitation mediated tissue disruption underpins the next generation of (non-thermal) focused ultrasound (FUS) therapy. A flagship application for the technique has emerged as non-invasive and transient disruption of the blood-brain barrier for drug delivery, with at least 10 clinical trials for the technique currently underway around the world (ClinicalTrials.gov; NCT03551249, NCT03608553 for example), and phase-1 safety recently reported, (Lipsman et al. Nat. Comms 2018). Transcranial FUS, however, demands sub-MHz driving for sufficient transmission across the skull and MB-cavitation activity under such sub-resonant driving, remains (very) poorly understood. This projects seeks to build on recent insights gained by the host laboratory (Song et al. Ultrasound in Med. Biol. 2019, Cleve et al. Ultrasound in Med. Biol. 2019), with clinical translation projected via several exploratory in-vivo routes. A successful project will have significant academic and clinical impact, placing MB-cavitation mediated tissue disruption on a firm mechanistic and parametric foundation.Aims and objectives:The project seeks to identify MB-cavitation based mechanisms of tissue disruption, assess drug delivery effects, post-exposure tissue response and healing. On fully characterising MB-cavitation in-vitro, clinical translation will be sought via several novel in-vivo models. Ultrahigh-speed imaging, parallel acoustic detection and advanced microscopy techniques will be employed to realise the following experimental objectives include:Characterise in-vivo MB-cavitation activity in response to clinically relevant FUS, via high-speed imaging and acoustic emission signal collection.Determine cavitation-tissue interactions/deformations.Gauge extravasation from the vasculature.Inspection of post-exposure cellular/tissue-damage. Evaluate inflammatory response and resolution via immune-cell tracking and NF-KB regulation.Novelty of the research methodology:The project will be primarily conducted under the auspices of the Cavitation Research Laboratory (CavLab), at the newly established Centre for Medical and Industrial Ultrasonics (C-MIU), University of Glasgow. CavLab hosts two state-of-the-art high speed cameras, capable of imaging at up to 10 million frames per second, and a wide range of commercial and bespoke calibrated acoustic detectors and ultrasonic arrays. This infrastructure will be fully exploited to meet the Aims and Objectives described above, in collaboration with several strategic partners.Alignment to Research Council's strategies and research areas:The project aligns to the Healthcare Technologies theme and is complementary to existing EPSRC-funded research, including (but not limited to) the ThUNDDAR network+ (EP/N026942/1), Oxford Centre for Drug Delivery Devices (EP/L024012/1), and the microbubble fabrication project at the University of Leeds (EP/P023266/1). The project also supports an upcoming EPSRC proposal from the host laboratory, and fits to recently funded Centre for Doctoral Training; FUSE (Future of Ultrasonic Engineering, EP/S023879/1).Any companies or collaborators involved:Since the project was allocated we have secured industrial collaborations with the leading MB-manufacturers in the US and Europe: Lantheus Medical Imaging Inc. and Bracco Imaging S.p.A Corp. Both companies have agreed in-kind support of circa $30k (market value), via provision of 300 vials of their MB contrast agents (Definity and SonoVue, respectively) for CavLab experimentation. These are the MBs of choice for every clinical trial currently underway. As the project progresses we will actively seek further strategic industrial and clinical collaborative support.