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Closed-loop cavitation control for focused ultrasound-mediated blood-brain-barrier opening by long-circulating microbubbles


Cavusoglu, Mustafa; Zhang, Jia; Ielacqua, Giovanna Diletta; Pellegrini, Giovanni; Signorell, Rea Deborah; Papachristodoulou, Alexandros; Brambilla, Davide; Roth, Patrick; Weller, Michael; Rudin, Markus; Martin, Ernst; Leroux, Jean Christophe; Werner, Beat (2019). Closed-loop cavitation control for focused ultrasound-mediated blood-brain-barrier opening by long-circulating microbubbles. Physics in Medicine and Biology, 64(4):045012.

Abstract

Focused ultrasound (FUS) exposure in the presence of microbubbles (MBs) has been successfully used in the delivery of various sizes of therapeutic molecules across the blood-brain barrier (BBB). While acoustic pressure is correlated with the BBB opening size, real-time control of BBB opening to avoid vascular and neural damage is still a challenge. This arises mainly from the variability of FUS-MB interactions due to the variations of animal-specific metabolic environment and specific experimental setup. In this study, we demonstrate a closed-loop cavitation control framework to induce BBB opening for delivering large therapeutic molecules without causing macro tissue damages. To this end, we performed in mice long-term (5 min) cavitation monitoring facilitated by using long-circulating MBs. Monitoring the long-term temporal kinetics of the MBs under varying level of FUS pressure allowed to identify in-situ, animal specific activity regimes forming a pressure-dependent activity bands. This enables to determine the boundaries of each activity band (i.e. steady oscillation, transition, inertial cavitation) independent from the physical and physiological dynamics of the experiment. However, such a calibration approach is time consuming and to speed up characterization of the in-situ, animal specific FUS-MB dynamics, we tested a novel method called "pre-calibration" that closely reproduces the results of long-term monitoring but with a much shorter duration. Once the activity bands are determined from the pre-calibration method, an operation band can be selected around the desired cavitation dose. To drive cavitation in the selected operation band, we developed an adaptive, closed-loop controller that updates the acoustic pressure between each sonication based on measured cavitation dose. Finally, we quantitatively assessed the safety of different activity bands and validated the proposed methods and controller framework. The proposed framework serves to optimize the FUS pressure instantly to maintain the targeted

Abstract

Focused ultrasound (FUS) exposure in the presence of microbubbles (MBs) has been successfully used in the delivery of various sizes of therapeutic molecules across the blood-brain barrier (BBB). While acoustic pressure is correlated with the BBB opening size, real-time control of BBB opening to avoid vascular and neural damage is still a challenge. This arises mainly from the variability of FUS-MB interactions due to the variations of animal-specific metabolic environment and specific experimental setup. In this study, we demonstrate a closed-loop cavitation control framework to induce BBB opening for delivering large therapeutic molecules without causing macro tissue damages. To this end, we performed in mice long-term (5 min) cavitation monitoring facilitated by using long-circulating MBs. Monitoring the long-term temporal kinetics of the MBs under varying level of FUS pressure allowed to identify in-situ, animal specific activity regimes forming a pressure-dependent activity bands. This enables to determine the boundaries of each activity band (i.e. steady oscillation, transition, inertial cavitation) independent from the physical and physiological dynamics of the experiment. However, such a calibration approach is time consuming and to speed up characterization of the in-situ, animal specific FUS-MB dynamics, we tested a novel method called "pre-calibration" that closely reproduces the results of long-term monitoring but with a much shorter duration. Once the activity bands are determined from the pre-calibration method, an operation band can be selected around the desired cavitation dose. To drive cavitation in the selected operation band, we developed an adaptive, closed-loop controller that updates the acoustic pressure between each sonication based on measured cavitation dose. Finally, we quantitatively assessed the safety of different activity bands and validated the proposed methods and controller framework. The proposed framework serves to optimize the FUS pressure instantly to maintain the targeted

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
05 Vetsuisse Faculty > Institute of Veterinary Pathology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Radiological and Ultrasound Technology
Health Sciences > Radiology, Nuclear Medicine and Imaging
Uncontrolled Keywords:Radiological and Ultrasound Technology, Radiology Nuclear Medicine and imaging
Language:English
Date:11 February 2019
Deposited On:25 Jan 2019 08:04
Last Modified:29 Jul 2020 08:58
Publisher:IOP Publishing
ISSN:0031-9155
OA Status:Green
Publisher DOI:https://doi.org/10.1088/1361-6560/aafaa5
PubMed ID:30577029
Project Information:
  • : FunderSNSF
  • : Grant IDCRSII3_147651
  • : Project TitleFocused Ultrasound-Mediated Delivery of Encapsulated MGMT Antagonists for the Treatment of Temozolomide-Resistant Glioblastoma

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