Ultrasounds induce blood–brain barrier opening across a sonolucent polyolefin plate in an in vitro isolated brain preparation

Abstract

The blood–brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system. The combined use of low-intensity pulsed ultrasound waves and intravascular microbubbles (MB) represents a promising solution to this issue, allowing reversible disruption of the barrier. In this study, we evaluate the feasibility of BBB opening through a biocompatible, polyolefin-based plate in an in vitro whole brain model. Twelve in vitro guinea pig brains were employed; brains were insonated using a planar transducer with or without interposing the polyolefin plate during arterial infusion of MB. Circulating MBs were visualized with an ultrasonographic device with a linear probe. BBB permeabilization was assessed by quantifying at confocal microscopy the extravasation of FITC-albumin perfused after each treatment. US-treated brains displayed BBB permeabilization exclusively in the volume under the US beam; no significant differences were observed between brains insonated with or without the polyolefin plate. Control brains not perfused with MB did not show signs of FITC-albumin extravasation. Our preclinical study suggests that polyolefin cranial plate could be implanted as a skull replacement to maintain craniotomic windows and perform post-surgical repeated BBB opening with ultrasound guidance to deliver therapeutic agents to the central nervous system.

Engineered EVs designed to target diseases of the CNS

“…3b ). Another effort to non-invasively deliver drugs across the BBB is the use of intravascular microbubbles combined with focused ultrasound which disrupts the vasculature [ 141 , 142 ] ( Fig. 3c ), which could potentially be applied to EV administration.…”

“…(b) Intravascular microbubbles combined with focused ultrasound could potentially be applied to delivery of EVs into the CNS [ 140 ]. (c) EVs from various sources, including plants, milk and bacteria conjugated with microRNA molecules and administered orally were detected in mouse brain [ 141 , 142 ]. (d) Intravenous injection of EVs has the potential to deliver EVs to the brain but is limited due to limited biodistribution time and high clearance in peripheral organs [ 143 ] (e) Intraperitoneal injection showed high cell uptake of EVs at the local injection site [ 143 ] (f) Subcutaneous injection resulted in the lowest uptake of EVs by brain cells [ 129 ].…”

Letter: The Role of Sonolucent Implants in Global Neurosurgery

“…10,11 To address this, various ultrasound devices and solutions have been developed, including MR-guided US, implantable US transducers, and NaviFUS (NaviFUS Corp). 12 Despite the said advancements, these approaches are still limited in therapeutic application and acoustic feedback.…”

Ultrasound-Guided Mechanical High-Intensity Focused Ultrasound (Histotripsy) Through an Acoustically Permeable Polyolefin-Based Cranioplasty Device

“…bone for all transducers tested [9]. More recently, the cranioplasty device has been investigated pre-clinically for ultrasonic blood brain barrier (BBB) opening [10] and clinically for long-term ultrasound imaging surveillance in a patient with multi-recurrent oligodendroglioma [11]. The feasibility of applying high-intensity focused ultrasound (HIFU) therapies, such as histotripsy and thermal HIFU, across the prosthesis has not yet been investigated.…”