Blood–brain barrier opening in a large animal model using closed-loop microbubble cavitation-based feedback control of focused ultrasound sonication

Focused ultrasound (FUS) in combination with microbubbles has been established as a promising technique for noninvasive and localized Blood–brain barrier (BBB) opening. Real-time passive cavitation detection (PCD)-based feedback control of the FUS sonication is critical to ensure effective BBB opening without causing hemorrhage. This study evaluated the performance of a closed-loop feedback controller in a porcine model. Calibration of the baseline cavitation level was performed for each targeted brain location by a FUS sonication in the presence of intravenously injected microbubbles at a low acoustic pressure without inducing BBB opening. The target cavitation level (TCL) was defined for each target based on the baseline cavitation level. FUS treatment was then performed under real-time PCD-based feedback controller to maintain the cavitation level at the TCL. After FUS treatment, contrast-enhanced MRI and ex vivo histological staining were performed to evaluate the BBB permeability and safety. Safe and effective BBB opening was achieved with the BBB opening volume increased from 3.8 ± 0.7 to 53.6 ± 23.3 mm(3) as the TCL was increased from 0.25 to 1 dB. This study validated that effective and safe FUS-induced BBB opening in a large animal model can be achieved with closed-loop feedback control of the FUS sonication.