Safe long-term repeated disruption of the blood-brain barrier using an implantable ultrasound device: a multiparametric study in a primate model

Abstract

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.

Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome

“…Studies have thus far provided information relating to the routes of leakage from the circulation into the brain3421 and have demonstrated examples of behavioural12222324, cellular111225, and protein expression42627 changes which may be related to the observed increases in BBB permeability. However, detailed information regarding the mechanisms driving increased permeability and the restoration of BBB function following FUS, as well as a full characterization of its safety profile, are lacking.…”

Nanotherapy for Early Dementia: Targeting Senile Dementia

“…Lastly, a completely separate and additional advantage of such LCM/ND lipid nanoemulsion(s), as a component of this combination therapeutic, stems from the characteristic lipid-coated microbubble subpopulation (D'Arrigo 2011) existing in this nanoemulsion type. Specifically, such preformed (lipidstabilized) microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment Alonso et al 2010;Alonso et al 2011;Aslund et al 2017;Bing et al 2014;D'Arrigo 2015;Delalande et al 2013;Goliaei et al 2015;Kotopoulis et al 2013;Kotopoulis et al 2014;Lammers et al 2015;Marquet et al 2011;Meairs 2015;Meng et al 2017;Miller and O'Callaghan 2017), or sonoporation (Aubry et al 2016;Bouakaz et al 2016;Burgess and Hynynen 2016;Castle and Feinstein 2016;Delalande et al 2015;Horodyckid et al 2016;O'Reilly et al 2017;Paefgen et al 2015;Qin et al 2016;Sennoga et al 2016), if additionally desired for the Alzheimer's patient.…”

Focused Ultrasound for Neuromodulation

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