title: Opening the Blood-Brain Barrier with MR Imaging-guided Focused Ultrasound: Preclinical Testing on a Trans-Human Skull Porcine Model.
abstract: Purpose To develop and test a protocol in preparation for a clinical trial on opening the blood-brain barrier (BBB) with magnetic resonance (MR) imaging-guided focused ultrasound for the delivery of chemotherapy drugs to brain tumors. Materials and Methods The procedures were approved by the institutional animal care committee. A trans-human skull porcine model was designed for the preclinical testing. Wide craniotomies were applied in 11 pigs (weight, approximately 15 kg). A partial human skull was positioned over the animal's brain. A modified clinical MR imaging-guided focused ultrasound brain system was used with a 3.0-T MR unit. The ultrasound beam was steered during sonications over a 3 × 3 grid at 3-mm spacing. Acoustic power levels of 3-20 W were tested. Bolus injections of microbubbles at 4 μL/kg were tested for each sonication. Levels of BBB opening, hemorrhage, and cavitation signal were measured with MR imaging, histologic examination, and cavitation receivers, respectively. A cavitation safety algorithm was developed on the basis of logistic regression of the measurements and tested to minimize the risk of hemorrhage. Results BBB openings of approximately 1 cm3in volume were visualized with gadolinium-enhanced MR imaging after sonication at an acoustic power of approximately 5 W. Gross examination of histologic specimens helped confirm Evans blue (bound to macromolecule albumin) extravasation, and hematoxylin-eosin staining helped detect only scattered extravasation of red blood cells. In cases where cavitation signals were higher than thresholds, sonications were terminated immediately without causing hemorrhage. Conclusion With a trans-human skull porcine model, this study demonstrated BBB opening with a 230-kHz system in preparation for a clinical trial.©RSNA, 2016 Online supplemental material is available for this article.
authors.affiliation: From the Department of Physical Sciences, Sunnybrook Research Institute, 2075 Bayview Ave, C713, Toronto, ON, Canada M4N 3M5 (Y.H., R.A., K.H.); Department of Medical Biophysics, University of Toronto, Toronto, Ont, Canada (R.A., K.H.); and Division of Neurosurgery, Sunnybrook Health Sciences Centre, Toronto, Ont, Canada (M.L.S.).
authors.forename: Yuexi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: From the Department of Physical Sciences, Sunnybrook Research Institute, 2075 Bayview Ave, C713, Toronto, ON, Canada M4N 3M5 (Y.H., R.A., K.H.); Department of Medical Biophysics, University of Toronto, Toronto, Ont, Canada (R.A., K.H.); and Division of Neurosurgery, Sunnybrook Health Sciences Centre, Toronto, Ont, Canada (M.L.S.).
authors.forename: Ryan
authors.initials: R
authors.lastname: Alkins
authors.affiliation: From the Department of Physical Sciences, Sunnybrook Research Institute, 2075 Bayview Ave, C713, Toronto, ON, Canada M4N 3M5 (Y.H., R.A., K.H.); Department of Medical Biophysics, University of Toronto, Toronto, Ont, Canada (R.A., K.H.); and Division of Neurosurgery, Sunnybrook Health Sciences Centre, Toronto, Ont, Canada (M.L.S.).
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schwartz
authors.affiliation: From the Department of Physical Sciences, Sunnybrook Research Institute, 2075 Bayview Ave, C713, Toronto, ON, Canada M4N 3M5 (Y.H., R.A., K.H.); Department of Medical Biophysics, University of Toronto, Toronto, Ont, Canada (R.A., K.H.); and Division of Neurosurgery, Sunnybrook Health Sciences Centre, Toronto, Ont, Canada (M.L.S.).
authors.forename: Kullervo
authors.initials: K
authors.lastname: Hynynen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000378:metabolism*; D003287:Contrast Media; D003399:Craniotomy; D016503:Drug Delivery Systems; D005466:Fluorocarbons; D006801:Humans; D053783:Magnetic Resonance Imaging, Interventional / Q000379:methods*; D045423:Microbubbles; D010539:Permeability; D012886:Skull / Q000000981:diagnostic imaging*; D013010:Sonication / Q000379:methods*; D013552:Swine
chemical_list: D003287:Contrast Media; D005466:Fluorocarbons; C042852:perflutren