Assessment of ultrasound-induced fracture of polymer-shelled ultrasound contrast agents using superharmonic technique

Ultrasound imaging techniques can be greatly improved by the use of ultrasound contrast agents. Knowledge of the peak negative pressure at which contrast agents fracture is paramount for the imaging application as well as for local drug delivery. Gasholdning microbubbles encapsulated into biocompatible poly vinyl alcohol shells are of particular interest for their enhanced shelf life and demonstratedchemical versatility. A gas core allows microbubbles to efficiently scatter ultrasound waves. In vitro ultrasound tests showed a sufficient enhancement of the backscattered power (25±1 dB), comparable to the soft tissue attenuation coefficients (0.8±0.04 dB/cm MHz) and phase velocities (1519±2 m/s). At temperature values between 24 and 37 °C the monotonic increase of the attenuation and phase velocity with frequency indicates that thick-shelled microbubbles do not resonate in a typical medical ultrasound frequency range of 1-15 MHz. In fact, they work as an amplifier of the incident acoustic wave. The novel approach based on detection of superharmonics (3f and 4f) is proposed for assessment of the fracture pressure threshold, Pthr. In vitro tests suggests that fatigue, i.e. accumulation of damage within the shell, is the major physical mechanism responsible for the fracturing process. It has been observed that there is a decrease of Pthr from 1.15±0.09 MPa to 0.9±0.05 MPa when the number of cycles in the pulse, N, increases from 6 to 12. It is worth noting that the reported pressure values are within clinically approved safety limits. The main conclusion to be drawn from our study is that superharmonic approach appears to be more sensitive in Pthr assessment than traditional second harmonic imaging. This claim is supported also by images acquired with a commercially available system, where contrast pulse sequencing technique, specific to third harmonic, is required for visualization of thick-shelled microbubbles