PiV Ultra 12 - 24 Ultra High Speed Camera for Ultrasound Microbubble Research

描述（由申请人提供）：造影剂微泡在医学成像中具有独特的多功能性。第一代药物被用作血流示踪剂，允许评估灌注缺陷。最近，研究集中在能够检测疾病分子特征的分子靶向剂上。最后，使用造影剂微泡作为以高度聚焦的方式（可能在实时超声成像引导下）沉淀药物和基因递送的手段提供了一种涵盖分子成像、功能成像和治疗的技术。在这些技术中的每一种中，理解微泡响应于高强度入射超声脉冲的行为是至关重要的。现有的气泡模型假设球对称，随着时间的推移，预计这些模型将被非对称振动模式的模型所取代。这些模型是可信的，如果支持的实验验证，建议的相机将提供。该相机还将能够分析微泡对辐射力效应的响应，合作者先前已经确定这对基于微泡的分子成像和药物递送的功效至关重要。该相机还将有助于了解“下一代”多层气泡的行为，这些气泡在外壳中包含药物有效载荷。额外的研究将调查血管和细胞的透化过程，这被认为是重要的成功的药物和基因传递，这是几乎不可能可视化，除非通过组合的高速摄像机和倒置的研究显微镜，这是考虑在本提案。目前设计用于微泡成像的超高速视频显微镜系统包括鹿特丹伊拉斯谟大学的Brandaris和密歇根大学和加州大学戴维斯分校的Imacon 468系统。虽然这些较旧的技术系统已经实现了大量的初步研究，但它们的时间和空间分辨率、动态范围和光灵敏度的物理约束限制了这些系统对于对高频或高振幅气泡成像感兴趣的微气泡研究人员有用的能力，或者限制了气泡非对称振荡或在低光环境（例如体内）中振荡的情况。12位动态范围，增强器增益高达2000，将产生比现有系统多4位的动态范围和比Imacon 468系统高4倍的灵敏度。这些实质性的改进将允许在降低的光照条件下（即体内）成像，并在比以前可能的更高的光学放大率下以最大帧率成像。3 ps的条纹时间分辨率将允许记录气泡事件比以前快1000倍以上。公共卫生相关性：所提出的高速摄像机与显微镜将使基础研究的复杂行为的超声造影剂具有良好的空间分辨率和约5纳秒的时间分辨率。利用所获得的知识，我们计划改进用于疾病检测和疾病治疗的超声造影剂的设计。涉及超声造影的长期目标是能够使用疾病的分子特征的早期检测来检测和治疗疾病，而不是等待检测对疾病的晚期解剖学反应，此时治疗可能涉及更高的风险、更多的副作用、更高的患者和社会成本以及更大的患者不适。

DESCRIPTION (provided by applicant): Contrast microbubbles offer unique versatility in medical imaging. First generation agents were used as tracers of blood flow permitting assessment of perfusion defects. More recently, research has focused on molecular targeted agents that enable the detection of the molecular signature of disease. Finally, the use of contrast microbubbles as a means of precipitating drug and gene delivery in a highly focal manner - potentially under real-time ultrasound imaging guidance - provides a technology that encompasses molecular imaging, functional imaging and therapy. In each of these technologies, it is critical to understand the behavior of the microbubble in response to high intensity incident ultrasound pulses. Existing bubble models assume spherical symmetry and over time it is anticipated that these models will be replaced by models accounting for asymmetric modes of vibration. These models are only credible if supported by the experimental validation that the proposed camera will provide. The camera will also enable analysis of the response of microbubbles to radiation force effects that the collaborators have previously established as being vital to the efficacy of microbubble-based molecular imaging and drug delivery. The camera will also facilitate understanding of the behavior of "next generation" multilayered bubbles that include a drug payload in the shell. Additional research will investigate the vessel, and cell, permeabilization process that is believed to be important to successful drug and gene delivery, which is practically impossible to visualize except by means of the combined high speed camera and inverted research microscope that is contemplated in this proposal. Current ultra-high-speed video microscopy systems designed for microbubble imaging include the Brandaris at Erasmus University in Rotterdam and the Imacon 468 systems at the University of Michigan and UC Davis. While these older technology systems have enabled a substantial body of preliminary research, physical constraints in their time and spatial resolution, dynamic range, and light sensitivity have limited the ability of these systems to be useful to microbubble researchers interested in high-frequency or high amplitude bubble imaging, or situations where bubbles oscillate non-symmetrically or in low-light environments such as in-vivo. The 12 bit dynamic range, with an intensifier gain of up to 2000 will yield 4 bits more dynamic range than prior systems and a factor of 4 fold more sensitivity than the Imacon 468 system. These substantial improvements will allow imaging in reduced light conditions (i.e. in-vivo) and imaging with maximum frame rate at higher optical magnification than previously possible. The 3 ps streak time resolution will allow recording of bubble events much over 1000 times faster than previously possible. PUBLIC HEALTH RELEVANCE: The proposed high speed camera with microscope will enable fundamental research into the complex behavior of ultrasound contrast agents with fine spatial resolution and approximately five nanosecond temporal resolution. Using the knowledge gained, we plan to improve the design of ultrasound contrast agents used in both disease detection and in disease treatment. A long term goal involving ultrasound contrast is to enable detection and treatment of disease using early detection of molecular signatures of disease rather than waiting to detect late stage anatomic responses to disease - at which point treatment may involve higher risk, more side effects, higher patient and societal cost and greater patient discomfort.