High frequency ultrasound nonlinear scattering from porphyrin nanobubbles

Emerging contrast imaging studies have highlighted the potential of nanobubbles for both intravascular and extravascular applications. Reports to date on nanobubbles have generally utilized low frequencies (<12 MHz), high concentrations (>10⁹ mL^-1), and B-mode or contrast-mode on preclinical and clinical systems. However, none of these studies directly examined nanobubble acoustic signatures systematically to implement nonlinear imaging schemes in a methodical manner based on nanobubble behaviour. Here, nanobubble nonlinear behaviour is investigated at high frequencies (12.5, 25, 30 MHz) and low concentration (10⁶ mL^-1) in a channel phantom, with different pulse types in single- and multi-pulse sequences to examine behaviour under conditions relevant to high frequency imaging. Porphyrin nanobubbles are demonstrated to initiate nonlinear scattering at high frequencies in a pressure-threshold dependent manner, as previously observed at low frequencies. This threshold behaviour was then utilized to demonstrate enhanced nanobubble imaging with pulse inversion, amplitude modulation, and a combination of the two, progressing towards the improved sensitivity and expanded utility of these ultrasound contrast agents.