While extracranial ultrasound can achieve such BBB opening, ultrasound energy is highly attenuated by the skull bone. The skull also defocuses and laterally shifts the ultrasound beam, resulting in an uncertain focal point. To overcome this hurdle, researchers at French start-up company CarThéra are developing an implantable ultrasound device, called SonoCloud, which enables transient and repeated opening of the BBB.

At the recent AAPM annual meeting in Indianapolis, IN, Cyril Lafon from INSERM's Laboratory of Therapeutic Applications of Ultrasound (LabTAU) updated delegates on progress to date. Lafon, one of CarThéra's co-founders, explained that brain tumours are commonly treated using surgical excision followed by chemotherapy. The SonoCloud device is designed to be implanted into the skull bone (via a burr hole) during the initial surgery. It can then be employed at all subsequent chemotherapy sessions to open the BBB and optimize intra-cerebral drug concentration.

Initial testing

SonoCloud is a 10 mm diameter, 1 MHz ultrasound transducer. It has no internal energy source, making it compatible for use in MRI scanners, and is instead powered by an external generator via a transdermal needle connection that's plugged in only during treatment sessions. The technique was originally proposed by Alexandre Carpentier, neurosurgeon at Pitie-Salpetriere Paris Sorbonne University hospital.

Lafon first described some of the pre-clinical research performed to assess the short term safety of the device. In one recently published study, Lafon and colleagues used the transducer, along with intravenous injection of SonoVue contrast agent, to perform BBB opening in 16 rabbits. Opening was confirmed by detecting extravasation of blue dye into the brain tissues.

A toxicity assessment performed seven days after BBB opening revealed limited damage to healthy tissue, with minor adverse effects and moderate oedema limited to the extent of the sonication field. A similar study on dogs revealed no adverse effects (using either MRI or histology) and no signs of behaviour modification. MR images recorded at day seven revealed a normal BBB.

The researchers also performed studies to evaluate uptake in the rabbit brain of two chemotherapy drugs: temozolomide - a small drug used to treat glioma which can traverse the BBB, and an alternative drug, irinotecan. Five minutes after chemotherapy administration, they used the ultrasound device to open the BBB. A 20% increase in uptake of temozolomide was seen in the ultrasonicated brain hemisphere, compared with the contralateral control hemisphere. The results for irinotecan were more pronounced, with an increased uptake of 206% following ultrasound exposure.

Long-term safety

Lafon went on to describe the current work being performed to evaluate the long term safety and potential toxicity of SonoCloud. For this study, the researchers implanted the ultrasound device in the skulls of three primates, using a typical neurosurgeon's burr hole. BBB opening was achieved by applying 1 MHz ultrasound pulses with 25 ms pulse length and a pressure of 0.6-0.8 MPa for 120 s, along with administration of SonoVue contrast agent.

The team performed BBB openings in the primary motor cortex every two weeks over a three month period (a total of seven openings). Contrast-enhanced MRI revealed BBB opening immediately after each sonication. Seven days later, PET scans with the radiotracer DPA-714 revealed no sign of inflammation.

The animals were followed up for four months, and all exhibited normal behaviour during this period. Electrophysiology follow-up revealed no signs of epilepsy, cognitive decline or medicinal encephalopathy. FDG PET scans showed no significant changes in cerebral glucose metabolism, while histology showed no signs of haemorrhagic processes or ischaemia, and no change in the vessel wall integrity.

Lafon concluded that SonoCloud is a promising and safe ultrasound device for repeated BBB opening in patients undergoing chemotherapy following surgical excision of brain tumours.