title: Opening of the blood-brain barrier with an unfocused ultrasound device in rabbits.
abstract: OBJECTIVE
  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 low-power, pulsed, and unfocused US with limited damage to healthy tissue.
authors.affiliation: CarThera Research Team, Brain and Spine Institute, Paris;
authors.forename: Kevin
authors.initials: K
authors.lastname: Beccaria
authors.forename: Michael
authors.initials: M
authors.lastname: Canney
authors.forename: Lauriane
authors.initials: L
authors.lastname: Goldwirt
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
authors.forename: Clovis
authors.initials: C
authors.lastname: Adam
authors.forename: Julie
authors.initials: J
authors.lastname: Piquet
authors.forename: Gwennhael
authors.initials: G
authors.lastname: Autret
authors.forename: Olivier
authors.initials: O
authors.lastname: Clément
authors.forename: Cyril
authors.initials: C
authors.lastname: Lafon
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Chapelon
authors.forename: Alexandre
authors.initials: A
authors.lastname: Carpentier
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D003287:Contrast Media; D016503:Drug Delivery Systems / Q000379:methods*; D008279:Magnetic Resonance Imaging; D045423:Microbubbles; D011817:Rabbits; D014465:Ultrasonics / Q000379:methods*
chemical_list: D003287:Contrast Media