3D Dynamic Ultrasound Localization Microscopy

微血管是人体内最小的血管（<100微米）。它们在组织内分配血液，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保健挑战的核心，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结构和体内功能进行成像的工具一直在快速改进，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。在过去的10年里，使用超声的2D血管成像经历了多次突破性创新。最近，一种受超分辨荧光显微镜启发的称为超声定位显微镜（乌尔姆）的新技术通过以每秒数千帧的速度检测数百万个单独的微泡，将体内脉管系统的空间分辨率从数百微米提高到几微米（批准用于人类）注射到血流中，使得能够利用能够在大深度处探测的任何成像模态生成前所未有的分辨率的血管图。然而，乌尔姆目前仍限于2D成像平面中的静态血管造影图像，尽管平面内分辨率为5 μ m，但其厚度可达1 mm。我们最近对乌尔姆引入了两项创新：1）以各向同性分辨率和2）动态方式在体内执行图像的能力。总之，我们相信，这些创新将改变该领域的游戏规则：实现真正的各向同性超分辨率，即，5 × 5 × 5 μ m3而不是目前通过最新技术水平的乌尔姆获得的5 × 5 × 1000 μ m3，并且提供毫秒级的时间分辨率，使得能够产生目前对现有模式不可见的生物标志物。我们的长期愿景是开发，验证和证明基于3D-DULM的新型仪器和方法的可行性，以增强微血管异常相关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，以提取新的生物标志物，提出新的仪器设计，并实现3D-DULM的临床前和临床翻译。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。我们的技术基于超声波，因此本质上是便携式，非侵入性，相对低成本和平移的，因为我们设备的大部分部件可以从小动物到人类使用。因此，它们可以迅速纳入现有的协议，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.