High Frequency Array-Based Nanobubble Nonlinear Imaging in a Phantom and In Vivo.

There has been growing interest in nanobubbles for vascular and extravascular ultrasound contrast imaging and therapeutic applications. Studies to date have generally utilized low frequencies ( 109 mL-1), and uncalibrated B-mode or contrast-mode on commercial systems without reporting investigations on nanobubble signatures upon which the imaging protocols should be based. We recently demonstrated that low concentrations (106 mL-1) of porphyrin-lipid encapsulated nanobubbles scatter nonlinearly at low (2.5, 8 MHz) and high (12.5, 25, 30 MHz) frequencies in a pressure threshold-dependent manner that is advantageous for amplitude modulation imaging. Here we implement pressure-calibrated amplitude modulation at high frequency on a commercial preclinical array system to enhance sensitivity to nonlinear scattering of three phospholipid-based nanobubble formulations. With this approach, improvements in contrast to tissue ratio relative to B-mode between 12.4 and 22.8 dB are demonstrated in a tissue-mimicking phantom, and between 6.7 and 14.8 dB in vivo.