Collaborative Research: Engineering monodisperse lipid-coated microbubbles with distinct scattering spectra for ultrasound molecular imaging applications

将产生直径小于7µm且尺寸分布窄的气泡，通过超声成像可以帮助诊断几种疾病。它们将用脂质外壳进行化学工程，使它们1)具有单一尺寸，2)能够附着在与特定疾病相关的分子上，3)具有基于尺寸和外壳材料特性的独特声学特征。针对病变细胞表达的不同分子的不同气泡，可以开发出准确且经济有效的超声诊断系统。智力价值：这项工作的主要创新之一在于能够控制这些气泡的大小。这将允许对它们的声学特性进行准确的调查，特别是它们的共振频率。在那里它们最有效地反映诊断超声&amp；#61630；作为半径、声压和脂质壳组成的函数。另一个创新是基于物理的气泡行为精确建模。能够准确地将包裹脂质外壳的分子组成与气泡联系起来的机制模型？S的声学特征将被开发。利用实验和理论方法来评估壳体的非线性粘弹性特性（即应力与变形之间的流变关系）与超声激励之间的关系。模型开发的显著特征是双重实验方法，其中两组独立的实验将用于确定模型参数和独立的模型验证。在模型开发和实验之间将有一个密切的联系，其中每个努力将不断地由另一个努力指导和校准。实验测量和理论预测的结果将用于形成一套具有不同散射光谱的脂质包被微泡。最后，将进行测试，以评估检测小浓度的单分散脂质包被微泡的能力，并区分不同人群的回声特征。从这项研究中获得的知识将导致新的成像方案的发展，以专门检测针对多种生物标志物的脂质包被微泡。更广泛的影响：分子成像的新前沿是通过单一的诊断成像模式同时检测多种疾病的生物标志物。如果针对不同生物标记物的特定形态的造影剂可以在图像中彼此区分，这是可能的。超声可以用于这种分子成像应用，前提是可以设计具有独特频率相关散射特性（即辐射压力信号）的靶向脂质包被微泡。由于散射特性取决于微泡半径和壳材料性质，因此需要严格控制微泡尺寸分布和脂质壳的粘弹性。教育：每所大学将有一名研究生参与该项目，以完成他们的博士论文。这两所学院都致力于向少数族裔学生推广工程学。PI-Porter担任BU学生管理的少数民族工程师协会的指导教师，并将在学年期间为其成员提供研究机会。PI-Sarkar已经与摩根州立大学（HBCU）的一位教授建立了联系（提供支持信），以招募少数民族学生在他的实验室暑期实习。PI-Porter每年夏季将至少招收两名由BU本科生研究机会计划（支持信）资助的本科生，研究目标脂质包被微泡的生产和表征。PI-Sarkar在他的对比微泡研究中有涉及本科生的历史，结果由一名本科生共同撰写了一篇出版物。两名本科生将在他的实验室从事这个项目。他还将研究实验室与非常成功的？工程酷东西？该项目由特拉华大学工程推广中心运营。

1134420/1134121Porter/SarkarBubbles with diameters less than 7 µm with a narrow size distribution will be created that can help in diagnosis of several diseases through ultrasound imaging. They will be chemically engineered with a lipid shell such that they are 1) of a single size, 2) able to attach to molecules associated with a specific disease, and 3) have a unique acoustic signature based upon size and shell material properties. Targeting different bubbles to different molecules expressed by diseased cells, one can develop an accurate and cost effective ultrasound-based diagnostic system. Intellectual Merit: One of the main innovations of this effort lies in the ability to control the size of these bubbles. It will allow an accurate investigation of their acoustic properties, specifically their resonance frequencywhere they are most efficient to reflect diagnostic ultrasoundas a function of radius, acoustic pressure, and lipid shell composition. The other innovation is physics-based accurate modeling of bubble behavior. Mechanistic models that can accurately relate the molecular composition of the encapsulating lipid shell to a bubble?s acoustic signature will be developed. Experimental and theoretical methods will be utilized to evaluate the relationship between the nonlinear viscoelastic properties (i.e. the rheological relations between the stress and the deformation) of the shell and the ultrasound excitation. The distinctive feature of the model development is the dual experimental approach, where two separate sets of experiments will be used for the determination of model parameters and the independent model validation. There will be a close connection between the model development and the experiments where each effort will be constantly guided by and calibrated against the other. The results from the experimental measurements and theoretical predictions will be used to formulate a suite of lipid-coated microbubbles with distinct scattering spectra. Finally, tests will be performed to assess the ability to detect small concentrations of monodisperse lipid-coated microbubbles and distinguish echogenic signatures from distinct populations. The knowledge gained from this study will lead to the development of novel imaging schemes to specifically detect lipid-coated microbubbles targeted to multiple biomarkers. Broader Impact: The new frontier for molecular imaging is the simultaneous detection of multiple biomarkers of disease with a single diagnostic imaging modality. This is possible provided contrast agents for a specific modality targeting different biomarkers can be distinguished from each other within an image. Ultrasound may be used for this molecular imaging application provided targeted lipid-coated microbubbles with unique frequency-dependent scattering characteristics (i.e. radiated pressure signal) can be engineered. Because the scattering characteristics depend upon microbubble radius and shell material properties, tight control over the microbubble size distribution and the viscoelastic properties of the lipid shell are required to achieve this goal.Education: One graduate student in each university will be involved in this project working towards their doctoral dissertation. Both PIs are committed to spread engineering to minority students. PI-Porter serves as the faculty advisor the student-governed Minority Engineers' Society at BU, and will provide research opportunities for its members during the academic year. PI-Sarkar has already established a contact with a Professor (letter of support) in Morgan State University (HBCU) to recruit minority student intern in his lab for the summer. PI-Porter will host at least two undergraduate students each summer research student funded by the BU Undergraduate Research Opportunity Program (letter of support) to work on the production and characterization of targeted lipid-coated microbubbles. PI-Sarkar has a history of involving undergraduates in his contrast microbubble research, resulting in a publication coauthored by an undergraduate. Two undergraduate students will be working in his lab on this project. He will also connect the research lab to the very successful ?Engineering Cool Stuff? program run by the UD Engineering Outreach.