Contrast agent microbubble-cavitation for therapy

造影剂微泡（MB）空化介导的组织破坏是下一代（非热）聚焦超声（FUS）治疗的基础。该技术的一个旗舰应用已经出现，即非侵入性和短暂的血脑屏障中断药物输送，目前全球至少有10项临床试验正在进行中（ClinicalTrials.gov；例如NCT03551249， NCT03608553），并且最近报告了1期安全性。Nat. Comms 2018)。然而，经颅FUS需要低于mhz的驱动才能在颅骨上充分传输，并且在这种次共振驱动下的mb空化活动仍然（非常）知之甚少。该项目旨在建立在宿主实验室最近获得的见解基础上（Song等人）。超声在医学。生物。2019，Cleve等。超声医学，生物，2019)，通过几种探索性体内途径预测临床转化。一个成功的项目将产生重大的学术和临床影响，为mb空化介导的组织破坏奠定坚实的机制和参数基础。目的和目标：该项目旨在确定基于mb空化的组织破坏机制，评估药物输送效果，暴露后组织反应和愈合。在充分表征mb空化体外，临床翻译将寻求通过几个新的体内模型。超高速成像、平行声检测和先进的显微镜技术将用于实现以下实验目标：通过高速成像和声发射信号收集，表征临床相关FUS的体内mb空化活动。确定空化-组织相互作用/变形。测量血管外渗。暴露后细胞/组织损伤检查。通过免疫细胞跟踪和NF-KB调节评估炎症反应和解决方案。研究方法的新颖性：该项目将主要在格拉斯哥大学新成立的医学和工业超声中心（C-MIU）的空化研究实验室（CavLab）主持下进行。CavLab拥有两台最先进的高速摄像机，能够以每秒1000万帧的速度成像，以及各种商业和定制校准的声学探测器和超声波阵列。将与几个战略伙伴合作，充分利用这一基础设施来实现上述宗旨和目标。与研究委员会的战略和研究领域保持一致：该项目与医疗保健技术主题保持一致，并补充了现有的epsrc资助的研究，包括（但不限于）ThUNDDAR网络+ (EP/N026942/1)、牛津药物输送设备中心（EP/L024012/1）和利兹大学的微泡制造项目（EP/P023266/1）。该项目还支持即将由主办实验室提出的EPSRC提案，并适合最近资助的博士培训中心；超声波工程的未来，EP/S023879/1)。任何参与的公司或合作者：自项目分配以来，我们已与美国和欧洲领先的MB制造商达成工业合作：Lantheus Medical Imaging Inc.和Bracco Imaging S.p.A Corp.。两家公司已同意提供约3万美元（市值）的现金支持，通过提供300瓶MB造影剂（分别为Definity和SonoVue）用于CavLab实验。这些是目前正在进行的每个临床试验的首选MBs。随着项目的进展，我们将积极寻求进一步的战略工业和临床合作支持。

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.