INFLUENCE OF MICROBUBBLE PROPERTIES AND CARRIER FREQUENCY ON ULTRASOUND CAVITATION-INDUCED FLOW AUGMENTATION.

Background: 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 frequency which affects MB resonance.

Methods: 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 hindlimb ultrasound (1.3 MHz, mechanical index 1.3) for ten minutes. In separate experiments, high-frequency US (7.0 MHz) was compared to low frequency US. Conditional variables were compared using quantitative contrast-enhanced ultrasound perfusion imaging, as well as bioluminescence assays of shear-mediated ATP release. Beam spatial characteristics and passive cavitation detection (PCD) response for each MB agent were assessed by calibrated hydrophone.

Results: PCD confirmed intended differences in MB deformability. Cavitation at 1.3 MHz increased perfusion in the ultrasound-exposed limb by 6-8-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<0.05 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 ATP release. Using high-frequency US for cavitation resulted in a 60-70% loss of flow augmentation response.

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