Acoustic Contrast Agents for Use with High-frequency Ultrasound

用于高频超声的声学造影剂

• 批准号: 7917415
• 负责人: Jeffrey Ketterling
• 金额: $ 31.83万
• 依托单位: RIVERSIDE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-22 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917415
• 关键词: Acoustics; Affect; Animal Experiments; Animal Model; Animals; Attention; Behavior; Blindness; Cardiovascular system; Ciliary Body; Clinical; Clinical Research; Code; Contrast Media; Custom; Definity; Development; Diagnosis; Drug Delivery Systems; Drug Formulations; Embryo; Eye; Focused Ultrasound Therapy; Frequencies; Future; Gene Delivery; Gene Targeting; Genes; Genetic Materials; Glaucoma; Goals; Housing; Image; Image Enhancement; Imaging Techniques; Individual; Knowledge; Lateral; Lead; Lipids; Macular degeneration; Measures; Mechanics; Microcirculation; Modeling; Mus; Nature; New Agents; Optic Nerve; Optison; Organ; Oryctolagus cuniculus; Penetration; Polymers; Property; Proteins; Radial; Research; Resolution; Scheme; Site; Speed; System; Techniques; Testing; Theoretical model; Thermal Ablation Therapy; Transfection; Ultrasonography; Uvea; Work; attenuation; base; clinical application; computerized data processing; design; disease diagnosis; human disease; improved; in vivo; insight; interest; pressure; public health relevance; research study; response; simulation; sonoporation; sound; thrombolysis; time use; tumor

DESCRIPTION (provided by applicant): The goal of this study is to utilize acoustic contrast agents with high-frequency ultrasound (HFU, > 10 MHz) in order to image microcirculation and initiate gene transfection via sonoporation. Current contrast agents were not designed for these high frequencies. The study will assess two important applications: 1) imaging of slow-flow microvasculature in rabbit eyes and mouse embryos; and 2) the initiation of sonoporation in mouse embryos to assess the potential for gene transfection. Unlike with conventional imaging frequencies (< 10 MHz), HFU provides the means to achieve fine-scale lateral resolution for microcirculation imaging and highly localized pressure exposure for sonoporation. Specifically, we propose undertaking comprehensive theoretical and experimental studies related to HFU excitation of acoustic contrast agents. Currently available protein-, lipid-, and polymer-shelled agents along with our own custom-made, polymer-shelled agents will be characterized experimentally to quantify backscatter (scattering cross section, nonlinear response, etc.), attenuation, speed of sound, and destruction threshold. Theoretical models that extend well-founded earlier models will be developed and simulations of radial response and agent destruction will be compared to experimental results. The models will be utilized to better understand the optimal material properties of contrast agents for HFU applications and to gain insight into the physical mechanisms that lead to the destruction of contrast agents. The theoretical and experimental results will then be used to formulate imaging and signal processing strategies to better visualize microcirculation. Knowledge gained from the initial experimental and theoretical work will also be applied to optimizing acoustic exposure conditions for in vivo animal experiments. The contrast agents will be used to image microcirculation in rabbit eyes and mouse embryos as well as to initiate gene transfection via sonoporation in mouse embryos. The animal experiments, particularly those involving the rabbit eye, will have direct relevance for imaging human diseases including glaucoma (2-3 million in U.S.), macular degeneration (200,000 new cases each year in U.S.), and primary intraocular tumors (3,000 new cases each year in U.S.). For instance, HFU with contrast agents may help diagnose glaucoma, the leading cause of blindness in the U.S., by permitting the assessment of microcirculation in the optic nerve and ciliary body. PUBLIC HEALTH RELEVANCE The ultimate goal of this research is to extend the use of acoustic contrast agents to higher frequencies in order to permit the imaging of microcirculation and the initiation of gene transfection via sonoporation. The knowledge we generate will assist in the design of new agents, optimizing acoustic exposure conditions, and, ultimately, will lead to new clinical applications such as ocular disease diagnosis and targeted gene transfection.

描述（由申请人提供）：这项研究的目的是利用具有高频超声（HFU，> 10 MHz）的声学对比剂，以通过Sonoporation对微循环进行成像并启动基因转染。当前的对比剂不是针对这些高频设计的。该研究将评估两个重要的应用：1）在兔眼和小鼠胚胎中慢流微脉管系统的成像； 2）在小鼠胚胎中启动Sonoporation以评估基因转染的潜力。与常规成像频率（<10 MHz）不同，HFU提供了实现微循环成像和高度局部压力暴露的精细横向分辨率的手段。具体而言，我们提出了与声学造影剂的HFU激发有关的全面理论和实验研究。当前可用的蛋白质，脂质和聚合物壳剂以及我们自己的定制，聚合物壳的剂将在实验中进行表征，以量化反向散射（散射横截面，非线性响应等），衰减，声音速度，声音速度和破坏性阈值。将开发出良好的早期模型的理论模型，并将径向响应和试剂破坏的模拟与实验结果进行比较。这些模型将被用来更好地理解HFU应用中对比剂的最佳材料特性，并深入了解导致破坏对比剂的物理机制。然后，理论和实验结果将用于制定成像和信号处理策略，以更好地可视化微循环。从最初的实验和理论工作中获得的知识也将用于优化体内动物实验的声学暴露条件。对比剂将用于对兔眼和小鼠胚胎中的微循环进行图像，并通过小鼠胚胎中的超声层启动基因转染。动物实验，尤其是涉及兔子眼的动物实验，将与包括青光眼（美国2-300万），黄斑变性（每年在美国为200,000例新病例）和眼内肿瘤（美国每年3,000例新病例）在内的人类疾病具有直接相关性。例如，具有造影剂的HFU可以通过允许评估视神经和睫状体的微循环来帮助诊断青光眼，这是美国失明的主要原因。公共卫生相关性这项研究的最终目标是将声学对比剂的使用扩展到更高的频率，以允许微循环成像和通过Sonoporation的基因转染的启动。我们产生的知识将有助于设计新药物，优化声学暴露条件，并最终导致新的临床应用，例如眼部疾病诊断和靶向基因转染。