Mechanisms of contrast agent destruction

Various applications of contrast-assisted ultrasound, including blood vesse l detection, perfusion estimation, and drug delivery, require controlled de struction of contrast agent microbubbles. The lifetime of a bubble depends on properties of the bubble shell, the gas core, and the acoustic waveform impinging on the bubble Three mechanisms of microbubble destruction are con sidered: fragmentation, acoustically driven diffusion, and static diffusion . Fragmentation is responsible for rapid destruction of contrast agents on a time scale of microseconds. The primary characteristics of fragmentation ar e a very large expansion and subsequent contraction, resulting in instabili ty of the bubble. Optical studies using a novel pulsed-laser optical system show the expansion and contraction of ultrasound contrast agent microbubbl es with the ratio of maximum diameter to minimum diameter greater than 10. Fragmentation is dependent on the transmission pressure, occurring in over 55% of bubbles insonified with a peak negative transmission pressure of 2.4 MPa and in less than 10% of bubbles insonified with a peak negative transm ission pressure of 0.8 MPa. The echo received from a bubble decorrelates si gnificantly within two pulses when the bubble is fragmented, creating an op portunity for rapier detection of bubbles via a decorrelation-based analysi s. Preliminary findings with a mouse tumor model verify the occurrence of f ragmentation in vivo. A much slower mechanism of bubble destruction is diffusion, which is driven by both a concentration gradient between the concentration of gas in the b ubble compared with the concentration of gas in the liquid, as well as conv ective effects of motion of the gas-liquid interface. The rate of diffusion increases during insonation, because of acoustically driven diffusion, pro ducing changes in diameter on the time scale of the acoustic pulse length, thus, on the order of microseconds. Gas bubbles diffuse while they are not being insonified, termed static diffusion. An air bubble with initial diame ter of 2 mum in water at 37 degreesC is predicted to fully dissolve within 25 ms. Clinical ultrasound contrast agents are often designed with a high m olecular weight core in an attempt to decrease the diffusion rate. C3F8 and C4F10 gas bubbles of the same size are predicted to fully dissolve within 400 ms and 4000 ms, respectively. Optical experiments involving gas diffusi on of a contrast agent support the theoretical predictions; however, shelle d agents diffuse at a much slower rate without insonation, on the order of minutes to hours. Shell properties play a significant role in the rate of s tatic diffusion by blocking the gas-liquid interface and decreasing the tra nsport of gas into the surrounding liquid. Static diffusion decreases the d iameter of albumin-shelled agents to a greater extent than lipid-shelled ag ents after insonation.