Safe long-term repeated disruption of the blood-brain barrier using an implantable ultrasound device: a multiparametric study in a primate model.
OBJECTIVE The main limitation to the efficacy of chemotherapy for brain tumors is the restricted access to the brain because of the limited permeability of the blood-brain barrier (BBB). Previous animal studies have shown that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue. Although many previous studies have been performed with external focused US transducers, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness. This method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring. The purpose of the present study was to determine if the BBB can be safely and repeatedly disrupted using such an implantable unfocused US device in a primate model. METHODS An 11.5-mm-diameter, 1-MHz, planar US device was implanted via a bur hole into the skull of 3 primates (2 Papio anubis [olive] baboons and 1 Macaca fascicularis [macaque]) for 4 months. Pulsed US sonications were applied together with the simultaneous intravenous injection of sulfur hexafluoride microbubbles (SonoVue) every 2 weeks to temporarily disrupt the BBB. In each primate, a total of 7 sonications were performed with a 23.2-msec burst length (25,000 cycles) and a 1-Hz pulse repetition frequency at acoustic pressure levels of 0.6-0.8 MPa. Potential toxicity induced by repeated BBB opening was analyzed using MRI, PET, electroencephalography (EEG), somatosensory evoked potential (SSEP) monitoring, behavioral scales, and histopathological analysis. RESULTS The T1-weighted contrast-enhanced MR images acquired after each sonication exhibited a zone of hypersignal underneath the transducer that persisted for more than 4 hours, indicating a broad region of BBB opening in the acoustic field of the implant. Positron emission tomography images with fluorine-18-labeled fluorodeoxyglucose (FDG) did not indicate any changes in the cerebral metabolism of glucose. Neither epileptic signs nor pathological central nerve conduction was observed on EEG and SSEP recordings, respectively. Behavior in all animals remained normal. Histological analysis showed no hemorrhagic processes, no petechia, and extravasation of only a few erythrocytes. CONCLUSIONS The studies performed confirm that an implantable, 1-MHz US device can be used to repeatedly open the BBB broadly in a large-animal model without inducing any acute, subacute, or chronic lesions.
CarThera Research Team, Brain and Spine Institute, Paris;|Departments of 2 Neurosurgery and.
Catherine
C
Horodyckid
CarThera Research Team, Brain and Spine Institute, Paris;
Michael
M
Canney
CarThera Research Team, Brain and Spine Institute, Paris;
Alexandre
A
Vignot
CEA, SHFJ, Orsay.
Raphael
R
Boisgard
Réseau d'Imagerie Parisien, Paris.
Aurélie
A
Drier
Paris VI Sorbonne University, School of Medicine, Paris.|INSERM U1129 "Infantile Epilepsies and Brain Plasticity," Paris.|Paris Descartes University, PRES Sorbonne Paris Cité.|CEA, Gif sur Yvette.
Gilles
G
Huberfeld
Sorbonne Universités, UPMC Univ Paris 06, UMRS 1127, ICM, F-75013 Paris.
Chantal
C
François
Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris.
Annick
A
Prigent
Centre de NeuroImagerie de Recherche-CENIR, Paris.|Institut du Cerveau et de la Moelle épinière - ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, Paris.
Mathieu D
MD
Santin
Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Pathology Department, Le Kremlin-Bicêtre, Paris; and.
Clovis
C
Adam
Physiologie, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris.|Paris VI Sorbonne University, School of Medicine, Paris.
Jean-Claude
JC
Willer
INSERM U1032, LabTau, University of Lyon, France.
Cyril
C
Lafon
INSERM U1032, LabTau, University of Lyon, France.
Jean-Yves
JY
Chapelon
Departments of 2 Neurosurgery and.|Paris VI Sorbonne University, School of Medicine, Paris.
Alexandre
A
Carpentier
D061605:Administration, Intravenous; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D002491:Central Nervous System Agents; D004569:Electroencephalography; D004867:Equipment Design; D005073:Evoked Potentials, Somatosensory; D005260:Female; D019788:Fluorodeoxyglucose F18; D008137:Longitudinal Studies; D008252:Macaca fascicularis; D008279:Magnetic Resonance Imaging; D008297:Male; D045423:Microbubbles; D023421:Models, Animal; D048530:Papio anubis; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D013459:Sulfur Hexafluoride; D014464:Ultrasonic Therapy / Q000295:instrumentation*
D002491:Central Nervous System Agents; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D013459:Sulfur Hexafluoride
AUC = area under the standard uptake value time activity curve; BBB = blood-brain barrier; EEG = electroencephalography; FDG = fluorine-18–labeled fluorodeoxyglucose; Gd = gadolinium; ROI = region of interest; SSEP = somatosensory evoked potential; SUV = standard uptake value; US = ultrasound; blood-brain barrier; brain tumor; drug delivery system; magnetic resonance imaging; primate; ultrasound; ultrasound contrast agent