Nonlinear resonance behavior and linear shell estimates for Definity™ and MicroMarker™ assessed with acoustic microbubble spectroscopy.

There is a growing interest in microbubble based ultrasound contrast imaging applications in the 5-15 MHz range. In this study, individual microbubbles were insonified at low pressures (≤ 25 kPa) using an "acoustic spectroscopy" approach which entailed transmitting a sequence of tone bursts with center frequencies ranging from 4 to 13.5 MHz. The fundamental (transmit) frequency radial excursion amplitude was calculated from the scattered signals to produce a resonance curve for each bubble. For diameters between 2.5 to 4 μm, 69% of Target-Ready MicroMarker™ (Bracco, Geneva; Visualsonics, Canada) exhibited asymmetric resonance, characterized by a skewing of the resonance curve and indicative of nonlinear behavior. For Definity™ (Lantheus Medical Imaging, N. Billerica, MA), these responses were observed for 8% of diameters between 1.7 to 3.1 μm. For the subset of bubbles exhibiting linear, symmetric resonance curves, resonant frequencies, shell elasticity, and viscosity values were estimated. Between 10 to 12 MHz, for example, Target-Ready MicroMarker between 2.7 to 3.3 μm in diameter was resonant, where Definity was resonant between 1.7 to 2.6 μm. From 4 to 13.5 MHz, Target-Ready MicroMarker is characterized by a stiffer shell (3 < χ(0) < 5) N/m than Definity (0.5 < χ(0) < 2.5) N/m, and distinct strain-softening and shear-thinning rheological behavior. For Definity, no clear strain or shear-rate dependence of the shell properties is evident.