Session R1: Mini-Symposium - Multiphase Flows in Biomedicine II

The Subharmonic Behavior and Thresholds of High Frequency Ultrasound Contrast Agents

Ultrasound contrast agents are encapsulated micro-bubbles used for diagnostic and therapeutic biomedical ultrasound. The agents oscillate nonlinearly about their equilibrium radii upon sufficient acoustic forcing and produce unique acoustic signatures that allow them to be distinguished from scattering from the surrounding tissue. The subharmonic response occurs below the fundamental and is associated with an acoustic pressure threshold. Subharmonic imaging using ultrasound contrast agents has been established for clinical applications at standard diagnostic frequencies typically below 20 MHz. However, for emerging applications of high frequency applications (above 20 MHz) subharmonic imaging is an area of on-going research. The effects of attenuation from tissue are more significant and the characterization of agents is not as well understood. Due to specificity and control production, polymer agents are useful for high frequency applications. In this study, we highlight novel measurement techniques to measure and characterize the mechanical properties of the shell of polymer contrast agents. The definition of the subharmonic threshold is investigated with respect to mono-frequency and chirp forcing waveforms which have been used to achieve optimal subharmonic content in the backscattered signal. Time frequency analysis using the Empirical Mode Decomposition (EMD) and the Hilbert-Huang transform facilitates a more sensitive and robust methodology for characterization of subharmonic content with respect to non-stationary forcing. A new definition of the subharmonic threshold is proposed with respect to the energy content of the associated adaptive basis decomposition. Additional studies with respect to targeted agent behavior and cardiovascular disease are discussed.   

Dynamics of encapsulated microbubbles for contrast ultrasound imaging and drug delivery: from pressure dependent subharmonic to collapsing jet and acoustic streaming

Intravenously injected microbubbles used as ultrasound contrast enhancing agents are encapsulated by a nanometer-thick layer of lipids, proteins or polymers to stabilize them against premature dissolution. Over the years, we have developed interfacial rheological models for the encapsulation and used them to characterize several contrast agents by acoustic means. We will present an overview of our research emphasizing recent efforts in two directions. The first is on using subharmonic signals from the contrast microbubbles for non-invasive pressure estimation. Experimental measurement and modeling show that the subharmonic signal can both increase or decrease with pressure depending on frequency. Secondly, we will discuss boundary element (BEM) simulation of the collapse of an encapsulated microbubbles forming a jet near a blood vessel wall. Different rheology models of the encapsulation have been rigorously implemented in the BEM formulation. We will discuss the resulting stresses and the acoustic streaming near the wall leading to sonoporation and other bioeffects.   

Nonspherical dynamics and shape mode stability of ultrasound contrast agent microbubbles

Ultrasound contrast agents (UCAs) are shell encapsulated microbubbles developed originally for ultrasound imaging enhancement. UCAs are more recently being exploited for therapeutic applications, such as for drug delivery, gene therapy, and tissue ablation. Ultrasound transducer pulses can induce spherical (radial) UCA oscillations, translation, and nonspherical shape oscillations, the dynamics of which are highly coupled. If driven sufficiently strongly, the ultrasound can induce breakup of UCAs, which can facilitate drug or gene delivery but should be minimized for imaging purposes to increase residence time and maximize diagnostic effect. Therefore, an understanding of the interplay between the acoustic driving and nonspherical shape mode stability of UCAs is essential for both diagnostic and therapeutic applications. In this work, we use both analytical and numerical methods to analyze shape mode stability for cases of small and large nonspherical oscillations, respectively. To analyze shape mode stability in the limit of small nonspherical perturbations, we couple a radial model of a lipid-coated microbubble with a model for bubble translation and nonspherical shape oscillation. This hybrid model is used to predict shape mode stability for ultrasound driving frequencies and pressure amplitudes of clinical interest. In addition, calculations of the stability of individual shape modes, residence time, maximum radius, and translation are provided with respect to acoustic driving parameters and compared to an unshelled bubble. The effects of shell elasticity, shell viscosity, and initial radius on stability are investigated. Furthermore, the well-established boundary element method (BEM) is used to investigate the dynamics and shape stability of large amplitude nonspherical oscillations of an ultrasonically-forced, polymer-coated microbubble near a rigid boundary. Different instability modes are identified based on the degree of jetting and proximity to the boundary. This insight is used to develop diagrams that delineate regions of stability from instability based on the breakup mechanism, in parameter ranges of ultrasound frequency and amplitude relevant to medical applications.