Correlating microvessel permeability directly with ultrasound-activated microbubble dynamics.

Ultrasonically activated microbubbles are promising candidates for targeted therapeutic applications such as drug and gene delivery. Understanding vascular permeability is thus important. In this study, ultra high-speed microphotography was used to directly visualize the dynamics of microbubbles in microvessels, under the excitation of ultrasound pulses with a duration time of about 2 μs, a center frequency of 1 MHz, and peak negative pressures (PNPs) between 0.8 and 7.2 MPa. Correlated vascular permeability was examined by imaging extravasation of bubbles from the vessels and by looking at the treated region histologically and under transmission electron microscopy. Local vessel distention and invagination caused by microbubble oscillations and liquid jet impinging on the vessel wall all appear to contribute to enhanced permeability for microvessels with diameters < 20 μm and insonation PNP > 4 MPa. Vascular permeation was also observed in larger vessels. However, in these cases vessel invagination was greater than distention in more than 80% of the cases and liquid jets always directed away from the vessel wall. We thus hypothesize that the dominant mechanisms for microbubble-induced permeation of smaller microvessels are different from larger microvessels. [Work supported by NIH EB000350 and AR053652.]