Systems and methods for selective, targeted opening of the blood-brain barrier
Inventors
Levy, Yoav • Zadicario, Eyal • Grinfeld, Javier • De Picciotto, Rafi
Assignees
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Publication Number
US-11918832-B2
Publication Date
2024-03-05
Expiration Date
Abstract
Systems and methods for applying ultrasound sonication to temporarily disrupt a patient's blood-brain barrier (BBB) include storing threshold values of an acoustic response level, an acoustic response dose and a tissue response dose associated with a target BBB region and its surrounding regions based on anatomical characteristics thereof; causing the ultrasound transducer to transmit one or more pulses/waves; measuring the acoustic response level, the acoustic response dose, and/or the tissue response dose associated with the target BBB region and/or its surrounding regions; comparing the measurement with a corresponding stored threshold value; and operating the transducer based at least in part on the comparison.
Core Innovation
The invention provides a system for temporarily disrupting a patient's blood-brain barrier (BBB) using an ultrasound transducer and a controller. The controller stores a threshold value of a cumulative acoustic response dose associated with at least one target BBB region or its surrounding regions, where the threshold value corresponds to a maximum clinically tolerable cumulative amount of microbubble cavitation.
The controller causes the transducer to transmit at least one ultrasound pulse, acquires the cumulative acoustic response dose, and compares the acquired cumulative acoustic response dose with the stored threshold value. When the acquired cumulative acoustic response dose exceeds the stored threshold value, the controller suspends ultrasound sonication. The system further supports region- or tissue-specific control by determining threshold values based on anatomical characteristics associated with the at least one target BBB region or its surrounding regions.
The invention also includes embodiments that store an additional threshold value of an acoustic response value associated with the at least one target BBB region or its surrounding regions, corresponding to a maximum clinically tolerable magnitude of microbubble cavitation. During a sonication cycle, the controller transmits a plurality of ultrasound pulses, acquires acoustic response values for each ultrasound pulse and compares each to the second threshold value, and also acquires cumulative acoustic response dose across the sonication cycle to compare with the first threshold value.
Claims Coverage
The patent contains two independent claims. Both cover closed-loop control for temporarily disrupting a patient's BBB by monitoring microbubble cavitation-related acoustic response and suspending ultrasound sonication when clinically tolerable thresholds are exceeded.
Cumulative-dose threshold for target BBB regions
Store a threshold value of a cumulative acoustic response dose associated with at least one of a target BBB region or its surrounding regions, where the threshold value corresponds to a maximum clinically tolerable cumulative amount of microbubble cavitation.
Closed-loop accumulation and suspension
Acquire the cumulative acoustic response dose associated with the at least one of the target BBB region or its surrounding regions, compare the acquired cumulative acoustic response dose with the stored threshold value, and suspend ultrasound sonication when the cumulative acoustic response dose exceeds the stored threshold value.
Per-pulse acoustic magnitude and cumulative dose safety thresholds
Store a first threshold value of a cumulative acoustic response dose associated with at least one of a target BBB region or its surrounding regions and store a second threshold value of an acoustic response value associated with the at least one of the target BBB region or its surrounding regions, where the first and second threshold values correspond to maximum clinically tolerable cumulative amount of microbubble cavitation and maximum clinically tolerable magnitude of microbubble cavitation, respectively.
Dual-threshold control within a sonication cycle
During a sonication cycle transmit a plurality of ultrasound pulses; for each ultrasound pulse acquire the acoustic response value and compare it with the second threshold value; during the sonication cycle acquire the cumulative acoustic response dose and compare it with the first threshold value; suspend ultrasound sonication when the cumulative acoustic response dose exceeds the first threshold value or when the acoustic response value exceeds the second threshold value.
Across the independent claims, the core claim coverage is closed-loop BBB disruption with controller-stored clinically tolerable thresholds for microbubble cavitation-based acoustic response. One claim suspends sonication based on a cumulative acoustic response dose threshold, while the other uses both cumulative dose and per-pulse acoustic response magnitude thresholds within a sonication cycle.
Stated Advantages
Enables suspension of ultrasound sonication when a cumulative acoustic response dose exceeds a stored maximum clinically tolerable threshold associated with a target BBB region or its surrounding regions.
Provides safety control using both a cumulative acoustic response dose threshold and a per-pulse acoustic response value threshold corresponding to maximum clinically tolerable microbubble cavitation.
Documented Applications
Delivery of a therapeutic agent for brain tumors using the controlled BBB opening.
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