Modeling and Characterization of Microbubble Contrast Agents for Medical Imaging and Drug Delivery

国家科学基金会-化学和运输系统颗粒和多阶段处理计划(1415)提案编号：0651912主要研究人员：Sarkar，Kausik附属公司：特拉华大学提案标题：用于医学成像和药物输送的微泡造影剂的建模和表征智能价值将微泡注入患者体内，以增强超声图像的对比度。它们还被设计成将药物输送到靶向组织。这项建议的目的是利用实验和分析来建立数学模型，并对这些微泡造影剂进行表征，以期改进它们的设计。这项工作的重点是模拟由蛋白质和脂质组成的对比微泡的保护性包裹，以及在声激励下微泡的破裂。新的界面模型将被开发用于具有本征表面流变性的包覆，这些特性将通过体外声学(衰减和散射)实验来确定几种对比微泡的这些特性。此外，还将开发模拟超声激励下微气泡大幅振荡的计算程序。尽管已有尝试，但目前还没有可靠的胶囊造影剂微气泡模型，该模型已被系统地验证与实验观测结果。将使用一种新的声学方法来确定界面流变性。同样的声学装置也将被用来研究微泡对超声激励的响应。微泡的流变性将通过超声脉冲通过微泡乳状液的衰减来确定。流变模型的有效性，以及它是否延伸到衰减数据之外，将通过比较模型预测和微泡的分散响应来确定。该方案的具体目的是：1.建立造影剂的动力学模型。将气泡包覆模拟为具有特征表面流变参数的界面。得到了非线性气泡动力学方程。使用它们来预测超声在造影剂乳剂中的衰减和散射。测量对比微泡的流变性并研究模型行为。通过实验确定超声在造影剂微泡乳剂中的衰减和散射。使用结果验证模型。将性能与现有型号进行比较。修改和实施附加功能以改进模型。对不同的浓度和激励参数(幅度、频率和脉冲重复频率)进行实验和仿真。研究气泡的振荡、稳定性和破坏。开发了一个基于边界元方法(BEM)的计算程序来研究造影剂微泡的大变形。建立了气泡通过胶囊化渗透时气泡生长和收缩的解析模型。更广泛的影响虽然超声仍然是最安全和最受欢迎的成像手段(世界上每三个成像中就有一个)，但由于对比度较差，其用途受到限制-2000年在美国进行的1700万例超声心动图中有20%是次优的。良好的造影剂将使异常血流的可靠成像能够早期诊断疾病。目前设计和使用造影剂的方法都是经验性的。我们的研究将有助于开发一种严格的方法，为特定的任务和应用定制造影剂设计。该提案将有助于在生物和力学的非传统跨学科界面上培训ME本科生和研究生。PI已经与摩根州立大学(HBCU)的一位合作者建立了联系，以确定有才华的本科生研究实习机会，并为UD的研究生学习培养他们。

National Science Foundation - Division of Chemical &Transport Systems Particulate & Multiphase Processes Program (1415)Proposal Number: 0651912Principal Investigators: Sarkar, KausikAffiliation: University of DelawareProposal Title: Modeling and Characterization of Microbubble Contrast Agents for Medical Imaging and Drug DeliveryIntellectual MeritMicrobubbles are injected into a patient's body to enhance the contrast of an ultrasound image. They are also designed to deliver drugs to target tissues. The goal of this proposal is to use experiments and analysis to develop mathematical models, and to characterize these microbubble contrast agents with a view to improving their design. The focus of the effort is on modeling the protective encapsulation of a contrast microbubble made of proteins and lipids, and microbubble breakup under acoustic excitation. New interface models will be developed for the encapsulation with intrinsic surface rheological properties, and these properties will be determined for several contrast microbubbles by in vitro acoustic (attenuation and scattering) experiments. A computational code to simulate large oscillation of a microbubble under ultrasonic excitation will also be developed.Despite previous attempts, currently there is no reliable model of encapsulated contrast microbubbles which has been systematically validated against experimental observations. A novel acoustic method will be used to determine the interfacial rheology. The same acoustic setup will also be used to investigate the microbubbles' response to ultrasound excitation. The rheological properties of a microbubble will be determined using the attenuation of an ultrasound pulse passing through a microbubble emulsion. The validity of the rheological model, and whether it extends beyond the attenuation data, will be determined by comparing model predictions with the microbubbles' scattered response. The specific aims of this proposal are:1. Develop dynamical models of contrast agents. Model a bubble encapsulation as an interface with characteristic surface rheological parameters. Obtain nonlinear bubble dynamics equations. Use them to predict attenuation and scattering of ultrasound in an emulsion of contrast agent.2. Measure rheological properties of contrast microbubbles and investigate model behaviors. Experimentally determine attenuation and scattering of ultrasound through an emulsion of contrast microbubbles. Use results to validate models. Compare performance with existing models. Modify and implement additional features to improve models. Perform experiments and simulations for varying concentration and excitation parameters (amplitude, frequency and pulse-repetition frequency).3. Investigate bubble oscillation, stability and destruction. Develop a Boundary Element Method (BEM) based computational code to investigate large deformation of contrast microbubbles. Develop an analytical model of bubble growth and shrinkage due to gas permeation through encapsulation. Broader ImpactAlthough the ultrasound remains the safest and the most popular (one in every three imaging in the world) means of imaging, its utility is limited due to poor contrast - 20% of the 17 million echocardiographies performed in the United States in 2000 were suboptimal. A good contrast agent will enable reliable imaging of abnormal blood flows leading to early diagnosis of disease. Current methods of contrast agent design and use are empirical. Our research will help develop a rigorous methodology to customize contrast agent design for specific tasks and applications. The proposal will help train ME undergraduate and graduate students in the non-traditional cross-disciplinary interface of biology and mechanics. The PI has established a link with a collaborator in Morgan State University (an HBCU) to identify talented undergraduate research internships and to groom them for graduate study at UD.