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

美国国家科学基金会-化学与运输系统部门-颗粒与多相过程项目（1415）提案编号：0651912主要研究者：Sarkar， kausik隶属关系：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力水平微泡被注射到患者体内以增强超声图像的对比度。它们也被设计用于将药物输送到目标组织。本提案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，以期改进其设计。研究的重点是建立由蛋白质和脂质组成的对比微泡的保护性封装模型，以及微泡在声激励下的破裂过程。将为具有固有表面流变特性的封装开发新的界面模型，并通过体外声学（衰减和散射）实验确定几种对比微泡的这些特性。本文还将开发一个模拟超声激励下微气泡大振荡的计算程序。尽管以前有过尝试，但目前还没有可靠的胶囊化造影剂微泡模型，该模型已根据实验观察进行了系统验证。一种新的声学方法将被用于确定界面流变。同样的声学装置也将用于研究微泡对超声激励的响应。微泡的流变特性将通过超声脉冲通过微泡乳液的衰减来确定。流变模型的有效性，以及它是否超出了衰减数据，将通过将模型预测与微泡的散射响应进行比较来确定。本建议的具体目的是：1。建立造影剂的动力学模型。将气泡封装建模为具有特征表面流变参数的界面。获得非线性气泡动力学方程。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。实验确定衰减和散射超声通过对比微泡乳剂。使用结果来验证模型。将性能与现有模型进行比较。修改和实现附加功能以改进模型。对不同浓度和激励参数（振幅、频率和脉冲重复频率）进行实验和模拟。研究气泡的振荡、稳定性和破坏。开发基于边界元法（BEM）的计算程序来研究对比微泡的大变形。开发一个由于气体通过封装渗透而导致的气泡增长和收缩的分析模型。更广泛的影响尽管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），但由于对比度差，它的效用受到限制——2000年在美国进行的1700万次超声心动图检查中有20%是次优的。一种好的造影剂可以对异常血流进行可靠的成像，从而有助于疾病的早期诊断。目前造影剂的设计和使用方法都是经验性的。我们的研究将有助于开发一种严格的方法来定制造影剂设计的具体任务和应用。该方案将有助于培养生物学和力学非传统跨学科界面的ME本科生和研究生。该项目与摩根州立大学（Morgan State University）的合作伙伴建立了联系，以确定有才华的本科生研究实习机会，并为特拉华大学的研究生学习提供培训。

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.