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

Abstract

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 mm3 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.

Small volume blood-brain barrier opening in macaques with a 1 MHz ultrasound phased array

“…By demonstrating that smaller volume opening is possible in macaques we have improved the spatial selectivity of FUS BBB opening to smaller targets. Our system produced larger openings than a recent system tested in a porcine model which produced opening volumes from 3.8 to 53.6 mm 3 with a 500 kHz, 0.8 f-number transducer (Chien, Xu, et al 2022).…”

“…The geometric arrangement and frequency response of the cavitation monitor are known to be factors in sensitivity and could be improved upon to yield greater monitoring. A recent study in a porcine model achieved effective cavitation monitoring by tracking cavitation at the fourth harmonic of a 500 kHz transducer (2 MHz) (Chien, Xu, et al 2022). This approach used "dummy" signal captures following microbubble injection transmitted at 0.3 MPa to establish a baseline signal level at the fourth harmonic and tuned therapy pressures to increase the same signal metric relative to the baseline (Chien, Yang, et al 2022).…”

First-in-human prospective trial of sonobiopsy in glioblastoma patients using neuronavigation-guided focused ultrasound

“…Third, the integration of the FUS device with cavitation detection enables the development of quality assurance for the FUS device and real-time monitoring for the treatment. Future work can integrate cavitation feedback control algorithms to regulate the FUS acoustic pressure in real-time 39, 40 , which would ensure precise and consistent delivery of the ultrasound energy.…”

Transcranial focused ultrasound-induced blood‒brain barrier opening in mice without shaving hairs

“…In vivo contrast-enhanced T 1 -weighted MRI scan (TR/TE: 20/5; slice thickness: 0.13 mm; in-plane resolution: 0.13 mm; matrix size: 120 × 240; ip angle: 20°) was performed to evaluate the outcome of FUS-BBBO based on the extravasation of the MRI contrast agent gadobenate dimeglumin (Gd-BOPTA; MultiHance, Bracco Diagnostics Inc., Monrow Township, NJ) from the blood circulation into brain tissue. BBBO volume was calculated by comparing the contrast-enhanced volume in the T 1 -weighted images on the FUS + side and FUS-side using a custom MATLAB script reported in our previous publications 10, [19][20][21] .…”