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.
The aim of the proposed research was to investigate the ultrasound signal (subharmonic response) from contrast microbubbles for noninvasive estimation of organ level pressure for diagnosis of diseases such as portal hypertension. We found several new and interesting properties of the subharmonic response that are critical for developing this technology. Contrary to what was supposed before--the subharmonic response decreases with increasing ambient pressure--we showed that it can either increase or decrease depending on other parameters. We also conclusively proved the physical reason behind this phenomenon. The subharmonic response from bubbles is only generated above a threshold excitation pressure. Classical perturbation analysis has shown that the minimum threshold appears at twice the resonance frequency. However, we showed that for contrast agents the minimum threshold occurs closer to resonance rather than twice its value. This result is shown to result from the enhanced damping due to the contrast agent encapsulation. Two graduate students—Amit Katiyar and Shirshendu Paul--obtained PhD working on contrast agent dynamics including its subharmonic response. Amit Katiyar got Colburn prize for best dissertation in Physical Sciences and Engineering at University of Delaware. Two undergraduate students—Daniel Russakaw and Tyler Rodgers—also worked as research interns coauthoring journal publications. Two other PhDs—Swarnajay Mukherjee and Rajesh Singh—and an MS—Priyesh Srivastava--were also supported partially in their research. Ten journal papers coauthored with these students resulted from this funded research. PI gave multiple invited talks on this research in international conferences and universities.
