Abstract
Microbubble contrast agents are widely used in ultrasound imaging and therapy, typically with transmission center frequencies in the MHz range. Currently, an ultrasound center frequency near 250 kHz is proposed for clinical trials in which ultrasound combined with microbubble contrast agents is applied to open the blood brain barrier, since at this low frequency focusing through the human skull to a predetermined location can be performed with reduced distortion and attenuation compared to higher frequencies. However, the microbubble vibrational response has not yet been carefully evaluated at this low frequency (an order of magnitude below the resonance frequency of these contrast agents). In the past, it was assumed that encapsulated microbubble expansion is maximized near the resonance frequency and monotonically decreases with decreasing frequency. Our results indicated that microbubble expansion was enhanced for 250 kHz transmission as compared with the 1 MHz center frequency. Following 250 kHz insonation, microbubble expansion increased nonlinearly with increasing ultrasonic pressure, and was accurately predicted by either the modified Rayleigh–Plesset equation for a clean bubble or the Marmottant model of a lipid-shelled microbubble. The expansion ratio reached 30-fold with 250 kHz at a peak negative pressure of 400 kPa, as compared to a measured expansion ratio of 1.6 fold for 1 MHz transmission at a similar peak negative pressure. Further, the range of peak negative pressure yielding stable cavitation in vitro was narrow (~100 kPa) for the 250 kHz transmission frequency. Blood brain barrier opening using in vivo transcranial ultrasound in mice followed the same trend as the in vitro experiments, and the pressure range for safe and effective treatment was 75–150 kPa. For pressures above 150 kPa, inertial cavitation and hemorrhage occurred. Therefore, we conclude that (1) at this low frequency, and for the large oscillations, lipid-shelled microbubbles can be approximately modeled as clean gas microbubbles and (2) the development of safe and successful protocols for therapeutic delivery to the brain utilizing 250 kHz or a similar center frequency requires consideration of the narrow pressure window between stable and inertial cavitation.
Highlights
Microbubbles (MBs) composed of a gas core with a stabilizing shell serve as contrast agents for ultrasound imaging
The mechanical index[33] (PNP divided by the square root of the center frequency) and the cavitation index[34] (PNP divided by the center frequency) are parameters that were derived to gauge the likelihood of adverse bioeffects from inertial cavitation and monitor the MB activity during stable cavitation
We focused on finding the peak negative pressure (PNP) range that yields expansion ratios between 1.1 and 3.5 as approximate limits of stable and inertial cavitation, as previous literature has reported an upper limit of inertial cavitation between 2.3 and 3.513,49
Summary
Microbubbles (MBs) composed of a gas core with a stabilizing shell serve as contrast agents for ultrasound imaging. In vivo BBB opening studies with a center frequency of ~250 kHz in rabbits[7,41] and macaques[42], suggest that the window in which increased BBB permeability can be safely achieved is narrow, and report tissue damage above a relatively low PNP of 300 kPa. in order to use this low frequency safely, there is a need to characterize the oscillation of shelled MBs following transmission of an ultrasound pulse with a center frequency near 250 kHz. Here, characterization of MB dynamics was performed through theoretical predictions, ultra high-speed optical imaging and passive cavitation detection of single oscillating MBs. MB resting radii of ~0.75 and ~1.5 μm, were selected and investigated to approximate the radii of Definity and Optison (each commercially available) MBs. in vivo blood brain barrier opening was studied with transcranial ultrasound in mice
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