Abstract
Focused ultrasound combined with bubble-based agents serves as a non-invasive way to open the blood-brain barrier (BBB). Passive acoustic detection was well studied recently to monitor the acoustic emissions induced by the bubbles under ultrasound energy, but the ability to perform reliable BBB opening with a real-time feedback control algorithm has not been fully evaluated. This study focuses on characterizing the acoustic emissions of different types of bubbles: Optison, Definity, and a custom-made nanobubble. Their performance on reliable BBB opening under real-time feedback control based on acoustic detection was evaluated both in-vitro and in-vivo. The experiments were conducted using a 0.5 MHz focused ultrasound transducer with in-vivo focal pressure ranges from 0.1–0.7 MPa. Successful feedback control was achieved with all three agents when combining with infusion injection. Localized opening was confirmed with Evans blue dye leakage. Microscopic images were acquired to review the opening effects. Under similar total gas volume, nanobubble showed a more reliable opening effect compared to Optison and Definity (p < 0.05). The conclusions obtained from this study confirm the possibilities of performing stable opening using a feedback control algorithm combined with infusion injection. It also opens another potential research area of BBB opening using sub-micron bubbles.
Highlights
The blood-brain barrier (BBB) serves as a physiological barrier that separates the brain tissue and the circulation system
The conventional method to guide and confirm BBB opening is using magnetic resonance imaging (MRI)-guided focused ultrasound targeting followed by the acquisition of T1-weighted contrast enhanced images after treatment to detect leakage of contrast agent into the brain parenchyma[1,3,25,26]
Fundamental studies about cavitation detection were primarily conducted to investigate various cavitation types and their influence on BBB opening effect. It is believed the BBB opening induced by focused ultrasound (FUS) is mainly related to stable cavitation[27,31] and inertial cavitation could serve as an indicator of tissue damage[35]
Summary
The blood-brain barrier (BBB) serves as a physiological barrier that separates the brain tissue and the circulation system. Low pressure burst mode focused ultrasound (FUS) combined with microbubbles-based contrast agents has been shown to transiently open the BBB1–4. Fundamental studies about cavitation detection were primarily conducted to investigate various cavitation types and their influence on BBB opening effect It is believed the BBB opening induced by FUS is mainly related to stable cavitation[27,31] and inertial cavitation could serve as an indicator of tissue damage[35]. There are several commercially-available microbubbles: Optison (GE Healthcare, Milwaukee, WI, USA), Definity (Lantheus Medical Imaging, North Billerica, MA, USA) and SonoVue (Bracco, Milan, Italy) These agents are approved by FDA for clinical diagnostic use and have been confirmed to be effective in achieving BBB opening with FUS7,27,31,39. Real-time monitoring of the acoustic emission and more stabilized bubble administration is highly desired
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