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

美国国家科学基金会-化学运输系统分部颗粒多相过程计划（1415）提案编号：0651912主要研究者：Sarkar，Kausik所属机构： 特拉华大学提案题目：用于医学成像和药物输送的微泡造影剂的建模和表征智力优势微泡被注射到患者体内以增强超声图像的对比度。它们还被设计用于将药物递送到靶组织。该提案的目标是使用实验和分析来开发数学模型，并表征这些微泡造影剂，以期改进其设计。工作的重点是对由蛋白质和脂质制成的对比微泡的保护性封装以及声激励下的微泡破裂进行建模。将开发新的界面模型与内在的表面流变性能的封装，这些属性将被确定为几个对比度微泡在体外声学（衰减和散射）实验。一个计算代码，以模拟大振荡的微泡在超声excitation.Despite以前的尝试，目前还没有可靠的模型，已被系统地验证了对实验观察的封装造影剂微泡。一种新的声学方法将被用来确定界面流变性。同样的声学设置也将用于研究微泡对超声激发的响应。微泡的流变学性质将使用通过微泡乳液的超声脉冲的衰减来确定。流变学模型的有效性，以及它是否超出衰减数据，将通过比较模型预测与微泡的散射响应来确定。该提案的具体目标是：1.建立造影剂的动力学模型。用特征表面流变参数模拟气泡封装界面。得到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特性并研究模型行为。通过对比微泡乳剂实验确定超声的衰减和散射。使用结果验证模型。将性能与现有型号进行比较。修改并实施附加功能以改进模型。进行实验和模拟不同的浓度和激励参数（振幅，频率和脉冲重复频率）。3.调查气泡振荡、稳定性和破坏。开发基于边界元法（BEM）的计算程序，研究造影剂微泡的大变形。开发一个分析模型的气泡生长和收缩，由于气体渗透通过封装。更广泛的影响虽然超声仍然是最安全和最流行的成像手段（世界上每三次成像中就有一次），但由于对比度差，其实用性有限-2000年在美国进行的1700万次超声心动图中有20%是次优的。良好的造影剂将能够对异常血流进行可靠的成像，从而导致疾病的早期诊断。目前的造影剂设计和使用方法是经验性的。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。该提案将有助于培养我的本科生和研究生在生物学和力学的非传统的跨学科接口。PI已与摩根州立大学（HBCU）的合作者建立了联系，以确定有才华的本科生研究实习，并培养他们在UD的研究生学习。

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.