Influence of Microbubble Properties and Carrier Frequency on Ultrasound Cavitation-Induced Flow Augmentation

Cavitation of microbubble (MB) contrast agents produces shear-mediated vasodilation and an increase in tissue perfusion. These effects are mediated through endothelial and erythrocyte shear-sensitive pathways. Our aim was to determine whether augmentation of tissue perfusion produced by cavitation is influenced by the deformability of MBs, MB charge-mediated interaction with vascular cells, or ultrasound (US) frequency, which affects MB resonance.

In mice, highly deformable lipid-stabilized decafluorobutane MBs with neutral or cationic charge, as well as less-deformable MBs (Sonazoid), were administered intravenously during proximal hind limb US (1.3 MHz, mechanical index = 1.3) for 10 minutes. In separate experiments, high-frequency US (7.0 MHz) was compared to low-frequency US. Conditional variables were compared using quantitative contrast-enhanced US perfusion imaging, and bioluminescence assays of shear-mediated adenosine triphosphate release. Beam spatial characteristics and passive cavitation detection response for each MB agent were assessed by calibrated hydrophone.

Passive cavitation detection confirmed intended differences in MB deformability. Cavitation at 1.3 MHz increased perfusion in the US-exposed limb by 6- to 8-fold for highly deformable MBs. There were no differences according to MB charge despite evidence for interaction with vascular endothelial cells on intravital microscopy. Cavitation-mediated flow augmentation was lower (4-fold) for less-deformable MBs (P < .05 vs other agents). Flow augmentation was attributable to increases in microvascular flux rate (β-value). Despite producing less flow augmentation, cavitation with the less-deformable MBs produced equivalent endothelial adenosine triphosphate release. Using high-frequency US for cavitation resulted in a 60% to 70% loss of flow augmentation response.

Factors that affect MB resonance such as US frequency and MB deformability influence the degree of flow augmentation achieved by MB cavitation. Alteration of MB charge that enhances interaction with the endothelial cells does not influence cavitation-mediated flow augmentation.