title: 7.0-T magnetic resonance imaging characterization of acute blood-brain-barrier disruption achieved with intracranial irreversible electroporation.
abstract: The blood-brain-barrier (BBB) presents a significant obstacle to the delivery of systemically administered chemotherapeutics for the treatment of brain cancer. Irreversible electroporation (IRE) is an emerging technology that uses pulsed electric fields for the non-thermal ablation of tumors. We hypothesized that there is a minimal electric field at which BBB disruption occurs surrounding an IRE-induced zone of ablation and that this transient response can be measured using gadolinium (Gd) uptake as a surrogate marker for BBB disruption. The study was performed in a Good Laboratory Practices (GLP) compliant facility and had Institutional Animal Care and Use Committee (IACUC) approval. IRE ablations were performed in vivo in normal rat brain (n = 21) with 1-mm electrodes (0.45 mm diameter) separated by an edge-to-edge distance of 4 mm. We used an ECM830 pulse generator to deliver ninety 50-μs pulse treatments (0, 200, 400, 600, 800, and 1000 V/cm) at 1 Hz. The effects of applied electric fields and timing of Gd administration (-5, +5, +15, and +30 min) was assessed by systematically characterizing IRE-induced regions of cell death and BBB disruption with 7.0-T magnetic resonance imaging (MRI) and histopathologic evaluations. Statistical analysis on the effect of applied electric field and Gd timing was conducted via Fit of Least Squares with α = 0.05 and linear regression analysis. The focal nature of IRE treatment was confirmed with 3D MRI reconstructions with linear correlations between volume of ablation and electric field. Our results also demonstrated that IRE is an ablation technique that kills brain tissue in a focal manner depicted by MRI (n = 16) and transiently disrupts the BBB adjacent to the ablated area in a voltage-dependent manner as seen with Evan's Blue (n = 5) and Gd administration.
authors.affiliation: Bioelectromechanical Systems Lab, School of Biomedical Engineering and Sciences, Virginia Tech-Wake Forest University, Blacksburg, Virginia, United States of America. pgarcia@vt.edu
authors.forename: Paulo A
authors.initials: PA
authors.lastname: Garcia
authors.forename: John H
authors.initials: JH
authors.lastname: Rossmeisl
authors.forename: John L
authors.initials: JL
authors.lastname: Robertson
authors.forename: John D
authors.initials: JD
authors.lastname: Olson
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Ellis
authors.forename: Rafael V
authors.initials: RV
authors.lastname: Davalos
mesh_terms: D055011:Ablation Techniques; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004198:Disease Susceptibility; D018274:Electroporation / Q000379:methods*; D005682:Gadolinium / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000628:therapy; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012886:Skull
chemical_list: D005682:Gadolinium