Abstract
BackgroundFocused ultrasound combined with microbubble injection is capable of locally and transiently enhancing the permeability of the blood-brain barrier (BBB). Magnetic resonance imaging (MRI) guidance enables to plan, monitor, and characterize the BBB disruption. Being able to precisely and remotely control the permeabilization location is of great interest to perform reproducible drug delivery protocols.MethodsIn this study, we developed an MR-guided motorized focused ultrasound (FUS) system allowing the transducer displacement within preclinical MRI scanners, coupled with real-time transfer and reconstruction of MRI images, to help ultrasound guidance. Capabilities of this new device to deliver large molecules to the brain on either single locations or along arbitrary trajectories were characterized in vivo on healthy rats and mice using 1.5 MHz ultrasound sonications combined with microbubble injection. The efficacy of BBB permeabilization was assessed by injecting a gadolinium-based MR contrast agent that does not cross the intact BBB.ResultsThe compact motorized FUS system developed in this work fits into the 9-cm inner diameter of the gradient insert installed on our 7-T preclinical MRI scanners. MR images acquired after contrast agent injection confirmed that this device can be used to enhance BBB permeability along remotely controlled spatial trajectories of the FUS beam in both rats and mice. The two-axis motor stage enables reaching any region of interest in the rodent brain. The positioning error when targeting the same anatomical location on different animals was estimated to be smaller than 0.5 mm. Finally, this device was demonstrated to be useful for testing BBB opening at various acoustic pressures (0.2, 0.4, 0.7, and 0.9 MPa) in the same animal and during one single ultrasound session.ConclusionsOur system offers the unique possibility to move the transducer within a high magnetic field preclinical MRI scanner, thus enabling the delivery of large molecules to virtually any rodent brain area in a non-invasive manner. It results in time-saving and reproducibility and could be used to either deliver drugs over large parts of the brain or test different acoustic conditions on the same animal during the same session, therefore reducing physiological variability.
Highlights
Focused ultrasound combined with microbubble injection is capable of locally and transiently enhancing the permeability of the blood-brain barrier (BBB)
Preclinical studies demonstrated that burst sonications combined with intravenous injection of microbubbles were able to disrupt the blood-brain barrier (BBB) locally, transiently, and without damages, allowing the delivery to brain tissues of large molecules which cannot normally access the central nervous system (CNS) because of their size [12, 13]
A growing number of studies have been exploring the optimal parameters for BBB disruption such as the influence of ultrasound parameters [23,24,25,26] and microbubble properties [27, 28], or the physiologic state of the animals [29] and the maximum gap size obtained in the vascular walls and the closure dynamics [30]
Summary
Focused ultrasound combined with microbubble injection is capable of locally and transiently enhancing the permeability of the blood-brain barrier (BBB). Preclinical studies demonstrated that burst sonications combined with intravenous injection of microbubbles were able to disrupt the blood-brain barrier (BBB) locally, transiently, and without damages, allowing the delivery to brain tissues of large molecules which cannot normally access the central nervous system (CNS) because of their size [12, 13]. Many feasibility studies have investigated the capability of FUS-induced BBB disruption to massively enhance the delivery of a wide variety of therapeutic agents such as anticancer drugs [14,15,16], antiamyloid antibodies [17,18,19], siRNA, or nanoparticles [20]. The variety of brain disease models available on rodents makes them good candidates for these studies
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