The use of focused ultrasound (FUS) with microbubbles has been proven to induce transient blood–brain barrier opening (BBB-opening). However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1–4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz) can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg) by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.

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Recently, blood-brain barrier disruption (BBBD) has been performed by focused ultrasound (FUS) combining with microbubbles (MBs). The outcome of BBBD enhances local drug or gene delivery for improving the treatment efficiency of brain diseases. However, over-excitation of FUS may cause brain damage such as shutdown blood flow, intracerebral hemorrhage and brain edema. Therefore, it is essential to develop a an imaging system to assess dynamic perfusion changes during FUS-induced BBBD process. Here, we used the high-frequency destruction/reperfusion contrast-enhanced imaging technique to observe the cerebral perfusion under the cases of with/without hemorrhage in BBBD procedure. The BBB was disrupted by a 2.25 MHz FUS combining with MBs at 0.5-0.7 MPa (pulse repetition frequency: 1 Hz, pulse length: 1 ms, sonication time: 60 s). The results showed that the velocity of blood flow decreased after BBBD induced by FUS sonication. Particularly, the plateau of time-intensity curve was higher than prior to MBs destruction at 20 s after sonication and the blood flow would be obstructed due to the blood coagulates at 60s after sonication. The pattern of hemorrhagic damage caused by FUS can be monitored by the TIC. In addition, the location of blood flow velocity decrease was consistent with the areas of BBBD and the variation of blood flow depends on the applied acoustic pressure. In conclusion, the blood flow velocity changes have potential as an in vivo tool for quantifying the extent of the FUS-induced BBBD and detecting intracerebral hemorrhage occurrence.

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