3D Dynamic Ultrasound Localization Microscopy

微血管是人体内最小的血管(100微米)。它们在组织内分布血液，从而分配氧气和营养物质，它们的功能障碍是我们许多最紧迫的医疗挑战的核心，从心力衰竭到糖尿病和神经退行性疾病。可用于对这些血管的解剖和体内功能进行成像的工具一直在迅速改进，但在实验室和临床环境中仍然有限，这阻碍了我们设计新的诊断技术和治疗方法的能力。使用超声的2D血管成像在过去的10年中经历了多项突破性的创新。最近，一项名为超声定位显微镜(ULM)的新技术受到超分辨率荧光显微镜的启发，通过以每秒数千帧的速度检测注入血流中的数百万个单独的微泡(获准用于人类)，将体内血管系统的空间分辨率从数百微米提高到几微米，从而能够使用任何可以探测大深度的成像方式生成前所未有的分辨率的血管地图。然而，ULM目前仍仅限于2D成像平面上的静态血管造影图像，其厚度可达1 mm，尽管平面内分辨率为5微米。我们最近为ULM引入了两项创新：1)以各向同性分辨率在体内执行三维图像的能力；2)动态图像的能力。总之，我们相信，这些创新将改变这一领域的游戏规则：实现真正的各向同性超分辨率，即5x5x5um3，而不是目前最先进的ULM获得的5x5x1000um3，并提供毫秒的时间分辨率，使现有医疗机构目前看不到的生物标记物的生成成为可能。我们的长期愿景是开发、验证和展示基于3D-DULM的新仪器和方法的可行性，以加强对与微血管异常相关的疾病的诊断和治疗监测。我们的短期目标旨在从根本上量化成像参数和图像质量之间的权衡，以便提取新的生物标志物，提出新的器械设计，并实现3D-DULM的临床前和临床转换。我们的总体方法包括在物理学领域进行创新，并通过与生物学家和临床医生合作，迅速传播到临床前和临床应用。我们的技术是基于超声波的，因此本质上是便携、非侵入性的、相对低成本和可转换的，因为我们的设备的大部分部件可以从小动物到人类使用。因此，它们可以迅速整合到现有的协议中，并立即产生影响。

Microvessels are the smallest blood vessels (<100 microns) in the body. They distribute blood, and thus oxygen and nutrients, within tissues, and their dysfunction is central to many of our most pressing healthcare challenges, from heart failure to diabetes and neurodegenerative diseases. The tools available to image the anatomy and the in vivo function of these vessels have been improving rapidly but remain limited in both the laboratory and clinical settings, which hampers our ability to devise novel diagnostic techniques and therapeutic approaches. 2D blood vessel imaging using ultrasound has undergone multiple breakthrough innovations over the past 10 years. Most recently, a novel technique inspired by super-resolved fluorescence microscopy called ultrasound localization microscopy (ULM) improved spatial resolution of the vasculature from hundreds to a few microns in vivo via the detection at thousands of frames per second of millions of individual microbubbles (approved for human use) injected in the blood stream, enabling the generation of vascular maps of unprecedented resolution with any imaging modality that can probe at large depth. ULM remains however currently limited to static angiographic images in 2D imaging planes, of which the thickness can reach up to 1 mm, despite a 5-um in-plane resolution. We have recently introduced two innovations to ULM: the capability of performing images in vivo in 1) three dimensions with isotropic resolution and 2) dynamically. Together, these innovations, we believe, will be game changers in the field: achieving true isotropic superresolution, i.e., 5X5X5 um3 instead of 5X5X1000 um3 as currently obtained by state-of the-art ULM, and providing a millisecond temporal resolution, enable the generation of biomarkers currently invisible to existing modalities. Our long-term vision is to develop, validate and demonstrate feasibility of novel instruments and methodologies based on 3D-DULM for enhanced diagnosis and treatment monitoring of diseases associated with microvascular abnormalities. Our short-term objectives aim to fundamentally quantify the trade-offs between imaging parameters and image quality in order to extract new biomarkers, propose novel instrumentation designs, and enable the pre-clinical and clinical translation of 3D-DULM. Our general approach consists in innovating in the field of physics and to disseminate rapidly to preclinical and clinical applications by implementing collaborations with biologists and clinicians. Our technologies are based on ultrasound and as such are intrinsically portable, non-invasive, relatively low-cost and translational, as most parts of our devices can be used from small animals to humans. As such, they can rapidly be integrated into existing protocols and lead to immediate impact.