Fast 3D Super-Resolution Ultrasound Imaging Through Acoustic Activation and Deactivation of Nanodroplets

微血管系统在全身健康组织的功能中起着至关重要的作用。肿瘤和许多其他疾病，例如糖尿病和冠心病，会导致微血管的分布和/或其中的血流发生变化。因此，检测这些血管的细微结构和功能变化将有可能实现癌症和其他疾病的早期检测，并增加成功治疗的机会和生存率。此外，通过检测这些疾病治疗期间微脉管系统的变化，医生也许能够在早期阶段确定患者特定的治疗策略，同时监测对不同药物的反应（或缺乏反应）。目前的临床成像方式无法充分分辨组织内几毫米深度之外的这些微小血管。因此，临床迫切需要一种能够在相关组织深度提供高空间和时间分辨率的新成像方法。光学超分辨率通过组合多个帧的信息以实现单个超分辨率图像，彻底改变了光学荧光显微镜领域，并成为 2014 年诺贝尔化学奖的主题。然而，这种光学技术的穿透深度有限（<1毫米），因此不适合在临床上对人体进行成像。我们开发了使用造影剂（微泡）的超声超分辨率成像，其分辨率比现有的临床超声成像好几倍（在几厘米的深度下分辨率可降至数十微米）。然而，这种方法目前需要较长的超声数据采集时间（分钟），因为必须留出时间让稀疏分布的流动剂穿过整个视场。使用这种方法对脉管系统进行 3D 成像也具有挑战性，因为生成的数据量巨大（每秒高达 TB），这给传输和处理此类数据带来了巨大的硬件挑战。这些缺点极大地限制了超分辨率超声的临床转化。在这个项目中，我们提出了一种新技术，能够以比目前快两个数量级的成像速率实现超分辨率，从而使其适合临床使用。为了实现这一目标，我们将用新型“纳米液滴”试剂取代传统的微泡造影剂，其体内成像信号可以以受控方式通过声学方式打开和关闭，从而无需使用低浓度并等待它们流过整个感兴趣区域。其次，我们将使用一种新的传感器技术，将超过一万个元件以特定方式连接起来进行 3D 成像，从而实现快速数据捕获。我们还将开发优化且快速的信号处理算法和代码，以实现准确的超分辨率成像和适合实际使用的实时反馈。我们的目标是成为第一个在体内展示这种快速 3D 超分辨率技术的人。所提出的技术有望对深层组织中的脉管系统进行非侵入性、安全和快速的显微评估，这对于多种疾病的诊断、预测和干预非常有价值。

The microvasculature plays a crucial role in the functioning of healthy tissue throughout the body. Tumours and many other diseases, such as diabetes and coronary heart disease, cause changes in the distribution of microvessels and/or the flow within them. Detection of subtle structural and functional changes in these vessels would thus potentially enable early detection of cancer and other diseases and increase the chances of successful treatment and survival rates. Furthermore, by detecting changes in the microvasculature during treatment of these diseases, doctors may be able to identify at an early stage patient-specific treatment strategies while monitoring responses (or the lack of response) to different drugs. Current clinical imaging modalities cannot adequately resolve these tiny vessels beyond depths of a few millimetres inside the tissue. Hence there is an urgent clinical need for a new imaging method that can provide high spatial and temporal resolution at relevant tissue depths.Optical super-resolution has revolutionised the field of optical florescence microscopy by combining information from multiple frames to achieve a single super-resolved image and was the subject of the 2014 Nobel Prize in Chemistry. However, such optical techniques only have a limited penetration depth (<1 mm) and are therefore not suitable for imaging humans in the clinic. We have developed ultrasound super-resolution imaging with contrast agents (microbubbles) with a resolution of several times better than existing clinical ultrasound imaging (down to tens of micrometres resolution at depths of several centimetres). However this approach currently requires long ultrasound data acquisition times (minutes) as time must be allowed for sparsely distributed flowing agents to traverse the full field of view. It is also challenging to image the vasculature in 3D using this approach due to the huge amount of data generated (up to TBs per second) that poses significant hardware challenges in transferring and processing such data. These shortcomings significantly limit the clinical translation of super-resolution ultrasound.In this project, we are proposing a new technology to enable super-resolution at imaging rates up to two orders of magnitude faster than is currently possible, thereby making it becomes suitable for clinical use. To achieve this, we will replace conventional microbubble contrast agents with new "nanodroplet" agents whose in vivo imaging signal can be switched on and off acoustically in a controlled way, removing the need to use low concentrations and wait for them to flow through the entire region of interest. Second, we will use a new transducer technology with more than ten thousand elements linked in a specific way for 3D imaging that will enable rapid data capture. We will also develop optimised and fast signal processing algorithms and codes that will enable accurate super-resolution imaging and live feedback suitable for practical use. We aim to be the first to demonstrate this fast 3D super-resolution technology in vivo.The proposed technique promises non-invasive, safe and fast microscopic assessment of vasculature in deep tissue, which could prove highly valuable to diagnosis, prediction, and intervention in a wide range of diseases.