Opening of the blood-brain barrier with an unfocused ultrasound device in rabbits

Abstract

Object The blood-brain barrier (BBB) is a major impediment to the intracerebral diffusion of drugs used in the treatment of gliomas. Previous studies have demonstrated that pulsed focused ultrasound (US) in conjunction with a microbubble contrast agent can be used to open the BBB. To apply the US-induced opening of the BBB in clinical practice, the authors designed an innovative unfocused US device that can be implanted in the skull and used to transiently and repeatedly open the BBB during a standard chemotherapy protocol. The goal of this preliminary work was to study the opening of the BBB induced by the authors' small unfocused US transducer and to evaluate the effects of the sonications on brain parenchyma. Methods Craniectomy was performed in 16 healthy New Zealand White rabbits; epidural application of a single-element planar ultrasonic transducer operating at 1 MHz was then used with a pulse-repetition frequency of 1 Hz, pulse lengths of 10–35 msec, in situ acoustic pressure levels of 0.3–0.8 MPa, and sonication for 60–120 seconds. SonoVue was intravenously injected during the US applications, and opening of the BBB was determined by detecting extravasation of Evans blue dye (EBD) in brain tissues, quantitative measurement of EBD with UV-visible spectrophotometry, and contrast enhancement after Gd injection in 4.7-T MRI. A histological study was performed to determine adverse effects. Results An opening of the BBB was observed over a large extent of the US beam in the brain corresponding to in situ pressures of greater than 0.2 MPa. The BBB opening observed was highly significant for both EBD (p < 0.01) and MRI Gd enhancement (p < 0.0001). The BBB opening was associated with minor adverse effects that included perivascular red blood cell extravasations that were less than 150 μm in size and not visible on MR images. Moderate edema was visible on FLAIR sequences and limited to the extent of the sonication field. Conclusions The results demonstrate that the BBB can be opened in large areas of the brain in rabbits with lowpower, pulsed, and unfocused US with limited damage to healthy tissue.

Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits

“…While the few number of cases studied in this work may partially explain such a result, this observation is also in accordance with previously published studies in which opening of the BBB was more intense in the gray matter than in the white matter. 2,20 It has been hypothesized that this difference is due to a more dense vasculature network in the cortex (gray matter) than in the deep brain parenchyma (mix of white and gray matter), 7 causing the surface of exchange between blood circulation and brain parenchyma to be higher in the gray matter. This will need to be taken into consideration in future clinical applications.…”

“…This corresponded to volumes of almost 2 cm 3 (2.5-cm high cylinder with a radius of 0.5 cm) with a transducer of 1 cm in diameter. 2 In contrast, focused ultrasound systems have a small focal volume (3 × 6 mm) and therefore must be electronically steered or mechanically scanned to disrupt the BBB in larger volumes. For example, McDannold et al used a focused transcranial ultrasound system and performed sonications over 9 treatment points with a spacing of 2 mm to disrupt the BBB in a volume of tissue of 1 cm 3 .…”

“…These parameters correspond to safe parameters for BBB opening that were determined in a previous study. 2 For each session of BBB opening, a bolus injection of microbubbles (Sonovue, 0.1 ml/kg, Bracco Imaging) was injected through a peripheral vein followed by a 2-ml flush of saline. Sonovue is a UCA made of sulfur hexafluoride gas enveloped in a phospholipid shell with a mean diameter of 2.5 µm.…”

“…In a recent publication by our team, this concept was demonstrated, and a planar 1 MHz unfocused ultrasound transducer was used to open the BBB in a large but targeted volume in healthy rabbit brain. 2 The BBB disruption was visualized using Evans blue dye and confirmed using 4.7-T MRI after intravenous injection of Gd. The opening was limited to the extent of the ultrasound beam, and at acoustic pressure levels below 0.8 MPa, side effects were limited to a few perivascular red blood cell extravasations.…”

Therapeutic strategies to improve drug delivery across the blood-brain barrier

“…A study in rabbits sought to measure BBB disruption by applying FUS directly to the brain surface through a device implanted in a skull bur hole. 11 Further study is necessary to gauge the feasibility of this approach in humans.…”