Dynamics of ultrasound contrast agents and microvessels with MHz-frequency ultrasound

Experimental studies of the dynamics of ultrasound contrast agents (UCAs) both in vitro and in vivo indicate that UCA oscillation can enhance vascular permeability and increase extravasation of drugs and genes at a target site. For improving local drug and gene delivery efficiency and minimizing any permanent damage to small blood vessels, it is essential to examine the mechanism whereby vascular permeability is enhanced and vascular injuries in small blood vessels are produced. In this work, we proposed a theoretical model to study the dynamics of the oscillation of UCAs and microvessels with MHz-frequency ultrasound (US) with emphasis on the potential application of drug and gene delivery. Numerical results demonstrate that the presence of UCAs with ultrasound can substantially increase the transmural pressure through the blood vessel and thus enhance the vascular permeability. For a microbubble within an 8 to 40-micron vessel with a low peak negative pressure such as 0.1 MPa and a center frequency of 1 MHz, small changes in the microbubble oscillation frequency and maximum diameter are observed. Strong nonlinear oscillation occurs and the induced circumferential stress in the vessel increases as the ultrasound pressure increases. For the compliable vessels considered in this work, 0.2 MPa PNP at 1 MHz is predicted to be sufficient for microbubble fragmentation. However, for a rigid vessel 0.5 MPa PNP at 1 MHz may not be sufficient to fragment the bubbles. For a center frequency of I MHz, a peak negative pressure of 0.5 MPa is predicted to be sufficient to induce the stress in the vessel which exceeds the vascular rupture limit in a small (diameter less than 15 gm) compliant vessel. As vasculature becomes more rigid, the UCA oscillation and vessel dilation decrease, however the circumferential stress is predicted to increase. The circumferential stress in the vessel increases as the vessel size decreases or the center frequency increases. For the two frequencies considered in this work, the circumferential stress does not scale as the inverse of the square root of the acoustic frequency v(a) in the Mechanical Index, but rather has a stronger frequency dependence, 1/v(a).