Noninvasive Ultrasonic Pressure Estimation using subharmonic response of Contrast Microbubbles

封装的微泡用作诊断超声的造影剂。该建议基于使用来自这些微泡的次谐波信号（频率低于激励超声脉冲的频率的信号）来非侵入性地量化和监测器官中的环境血压。局部环境血压提供了关于许多器官的功能完整性的重要信息，并且其可用于诊断和监测许多疾病，诸如缺陷心脏瓣膜、恶性肿瘤和门静脉高压症。我们建议使用在体外实验，建模，微扰分析和数值模拟，以了解和优化这样的应用程序，以调查对比微泡的动力学：即使对比微泡已被广泛研究的临床医生，其中两个（Deadly和Optison）是目前批准的超声心动图由FDA，我们缺乏一个基本的了解他们的行为。具体而言，在设计优化的非线性成像模式之前，需要了解它们在较高声压下的非线性振荡，从而导致在次谐波和超谐波频率中的显著发射。我们在托马斯杰斐逊的合作者提出了一种次谐波辅助压力估计（SHAPE）技术，该技术依赖于次谐波信号对环境压力的敏感依赖性。然而，目前有相互矛盾的实验观察，是否分谐波响应增加或减少与环境压力。有必要了解非线性动力学为什么我们看到次谐波，它们是如何受到封装的影响，它们是否随着不同的参数增加或减少，为什么？我们建议回答这些问题。我们将与托马斯杰斐逊医学院和医院的Flemming Forsberg教授合作，在临床上实现压力估计。我们的实验研究将涉及商业造影剂，以及由德雷克塞尔大学的Margaret惠特利教授制备的实验剂。用非线性界面流变学模型表征微泡的包封：开发用于造影剂微泡包封的非线性流变学模型，并使用声学实验来确定商业和实验造影剂微泡的特征参数.研究造影剂微泡的非线性响应。开发一个实验装置来测量不同超压下微气泡的散射响应。测量不同微泡的散射响应，改变操作参数（稀释度、振幅、频率、脉冲重复频率和过压）。将实验与模型进行比较。研究形状振荡对散射信号的影响。发展了微泡的次谐波响应理论.最佳操作：与托马斯杰斐逊临床合作，确定造影剂微泡的最佳材料特性和次谐波压力估计的最佳激励。更广泛的影响：尽管超声仍然是最安全的成像手段，但其实用性受到对比度差的限制。在美国，每年进行的2000万次超声心动图检查中有20%不能提供冠心病的明确诊断。良好的造影剂可以显著改善超声成像。了解造影剂微泡的非线性响应对于精确的非线性造影成像模式至关重要。在教育方面，拟议的研究将培养我的学生在力学，生物学和医学的跨学科接口。PI致力于研究生和本科教育。该提案将支持两名博士生（Katiyar和Paul：见PI？s Bio）。PI是否积极参与UD？他每年两次向到访大学的公众人士讲解他的实验室。他定期在实验室雇佣本科生（最近有三名女性）实习生。PI与摩根州立大学（HBCU）的合作者建立了联系，每年进行研究报告，以招募本科研究实习生，他们将接受培训，随后在UD攻读研究生课程。

Encapsulated microbubbles are used as a contrast enhancing agent for diagnostic ultrasound. This proposal is predicated on the use of subharmonic signal (signal at frequency lower than that of the exciting ultrasound pulse) from these microbubbles to noninvasively quantify and monitor the ambient blood pressure in an organ. Local ambient blood pressure provides important information regarding the functional integrity of many organs, and it can be used to diagnose and monitor many diseases such as defective heart valves, malignant tumors and portal hypertension. We propose to use in vitro experiments, modeling, perturbative analysis and numerical simulation to investigate the dynamics of contrast microbubbles with a view to understand and optimize such applications.Intellectual Merit: Even though contrast microbubbles have been widely studied by clinicians, and two of them (Definity and Optison) are currently approved for echocardiography by FDA, we lack a fundamental understanding of their behavior. Specifically, their nonlinear oscillations at higher acoustic pressures resulting in significant emissions in sub and super harmonic frequencies need to be understood before optimized nonlinear imaging modalities can be designed. Our collaborators at Thomas Jefferson have proposed a Subharmonic Aided Pressure Estimation (SHAPE) technique which relies on sensitive dependence of subharmonic signals on ambient pressure. However, currently there are conflicting experimental observations as to whether subharmonic response increases or decreases with ambient pressure. There is a need to understand the nonlinear dynamics why we see subharmonics, how they are affected by the encapsulation, do they increase or decrease with different parameters and why? We propose to answer these questions. We will collaborate with Professor Flemming Forsberg of Thomas Jefferson Medical College and Hospital for the clinical realization of the pressure estimation. Our experimental investigation will involve commercial contrast agents, as well as experimental agents prepared by Professor Margaret Wheatley at Drexel University.The specific aims of this proposal are:1. Characterize encapsulation with nonlinear interfacial rheological model: Develop nonlinear rheological models for the encapsulation of contrast microbubbles, and use acoustic experiments to determine characteristic parameters for commercial and experimental contrast microbubbles.2. Investigate nonlinear response from contrast microbubbles. Develop an experimental setup to measure scattered response from microbubbles under varying overpressure. Measure scattered response from different microbubbles varying operating parameters (dilution, amplitude, frequency, pulse repetition frequency and over pressure). Compare experiments with models. Investigate effects of shape oscillation on scattered signal. Develop a theory of subharmonic response of encapsulated microbubbles.3. Optimum operation: Determine optimum material properties of contrast microbubbles and optimum excitation for subharmonic estimation of pressure, in clinical collaboration with Thomas Jefferson.Broader Impact: Although ultrasound remains the safest means of imaging, its utility is limited by poor contrast 20% of the 20 million echocardiographies performed each year in the United States do not provide definitive diagnosis for coronary heart disease. A good contrast agent can measurably improve ultrasound imaging. Understanding nonlinear response of a contrast microbubble is crucial to accurate nonlinear contrast imaging modalities. Educationally, the proposed research will train ME students at the cross-disciplinary interface of mechanics, biology and medicine. The PI is committed to graduate and undergraduate education. This proposal will support two PhD students (Katiyar and Paul: see PI?s Bio). PI is actively involved in UD?s outreach activities giving twice a year lecture demonstration of his lab to the general public visiting the university. He regularly employs undergraduate (recently three female) interns in his lab. PI has established a link with a collaborator in Morgan State University (an HBCU) to give yearly research presentation to recruit undergraduate research interns who will be trained to subsequently pursue graduate study at UD.