Direct observations of ultrasound microbubble contrast agent interaction with the microvessel wall

Abstract

Many thousands of contrast ultrasound studies have been conducted in clinics around the world. In addition, the microbubbles employed in these examinations are being widely investigated to deliver drugs and genes. Here, for the first time, the oscillation of these microbubbles in small vessels is directly observed and shown to be substantially different than that predicted by previous models and imaged within large fluid volumes. Using pulsed ultrasound with a center frequency of 1 MHz and peak rarefactional pressure of 0.8 or 2.0 MPa, microbubble expansion was significantly reduced when microbubbles were constrained within small vessels in the rat cecum (p<0.05). A model for microbubble oscillation within compliant vessels is presented that accurately predicts oscillation and vessel displacement within small vessels. As a result of the decreased oscillation in small vessels, a large resting microbubble diameter resulting from agent fusion or a high mechanical index was required to bring the agent shell into contact with the endothelium. Also, contact with the endothelium was observed during asymmetrical collapse, not during expansion. These results will be used to improve the design of drug delivery techniques using microbubbles.

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

“…At high PRPs, the bubble can expand to several times its equilibrium radius and then collapse due to the inertia of the surrounding medium. Both stable and inertial cavitation have been observed to both mechanically agitate the microvascular wall (8) and cause extravasation of vascular agents (7,21). Previous reports using longer PLs of 10 or 20 ms have analyzed the acoustic emissions radiating from the acoustically driven microbubbles and have indicated that BBB disruption may occur with stable cavitation or nonviolent inertial cavitation (22)(23).…”

“…Large radial bubble expansions may induce inertial cavitation activity, which may lead to bubble collapse due to the inertia of the surrounding media and affect the vascular physiology (8). Each type and magnitude of cavitation activity results in distinct vascular bioeffects and are dictated by the ultrasonic pulse shape and sequence, the microbubble composition and distribution (9), and the in vivo environment the microbubbles circulate (8,10). Selection of the exposure parameters is critical for effective drug delivery while minimizing side effects (11).…”

“…This activity has been associated with a range of bioeffects including displacement of the vessel wall through dilation and contractions (7,8). Large radial bubble expansions may induce inertial cavitation activity, which may lead to bubble collapse due to the inertia of the surrounding media and affect the vascular physiology (8). Each type and magnitude of cavitation activity results in distinct vascular bioeffects and are dictated by the ultrasonic pulse shape and sequence, the microbubble composition and distribution (9), and the in vivo environment the microbubbles circulate (8,10).…”

“…In stable cavitation, the microbubbles expand and contract with the acoustic pressure rarefaction and compression over several cycles (6). This activity has been associated with a range of bioeffects including displacement of the vessel wall through dilation and contractions (7,8). Large radial bubble expansions may induce inertial cavitation activity, which may lead to bubble collapse due to the inertia of the surrounding media and affect the vascular physiology (8).…”

Driving delivery vehicles with ultrasound

“…With a sufficiently high microbubble concentration, ultrasonic pressure on the order of 0.75 MPa at a center frequency of 1 MHz can produce capillary rupture in the intact rat muscle microcirculation; and the pressure required increases with increasing ultrasound frequency [11,12]. Direct visualization of microbubble-vessel interaction has been reported [13], where the expansion of the microbubble within small vessels was decreased, the lifetime of the microbubble increased, and larger microbubbles were shown to directly contact the wall.…”