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

微血管系统在整个身体的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，如糖尿病和冠心病，会导致微血管分布和/或其中的流动发生变化。因此，检测这些血管中的细微结构和功能变化可能有助于早期检测癌症和其他疾病，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血管系统的变化，医生可以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）。目前的临床成像模式不能充分解决这些微小的血管超过深度的几毫米内的组织。因此，临床上迫切需要一种新的成像方法，可以在相关组织深度提供高的空间和时间分辨率。光学超分辨率通过结合多帧信息来实现单个超分辨率图像，从而彻底改变了光学荧光显微镜领域，并且是2014年诺贝尔化学奖的主题。然而，这样的光学技术仅具有有限的穿透深度（<1 mm），因此不适合于临床中的人体成像。我们已经开发出了超声超分辨率成像与造影剂（微泡）的分辨率比现有的临床超声成像（在几厘米的深度下，分辨率低至几十微米）好几倍。然而，这种方法目前需要长的超声数据采集时间（分钟），因为必须允许稀疏分布的流动剂穿过整个视场的时间。使用这种方法对脉管系统进行3D成像也是具有挑战性的，这是由于所生成的大量数据（高达每秒TB）在传输和处理此类数据时带来了显著的硬件挑战。这些缺点极大地限制了超分辨率超声的临床应用。在本项目中，我们提出了一种新技术，使超分辨率成像速度比目前可能的速度快两个数量级，从而使其适合临床使用。为了实现这一目标，我们将用新的“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的方式声学地打开和关闭，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，该技术将一万多个元件以特定的方式连接在一起，用于3D成像，从而实现快速数据捕获。我们还将开发优化和快速的信号处理算法和代码，以实现适用于实际应用的精确超分辨率成像和实时反馈。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。该技术有望实现对深部组织血管的无创、安全和快速的显微评估，这可能对诊断、预测和干预多种疾病具有重要价值。

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.