Bioelectromechanical Systems Lab, School of Biomedical Engineering and Sciences, Virginia Tech-Wake Forest University, Blacksburg, Virginia, United States of America.
PLoS One. 2012;7(11):e50482. doi: 10.1371/journal.pone.0050482. Epub 2012 Nov 30.
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.
血脑屏障（BBB）对全身给予化学疗法治疗脑癌的药物传递构成了重大障碍。不可逆电穿孔（IRE）是一种新兴技术，它使用脉冲电场进行非热肿瘤消融。我们假设，在IRE 诱导的消融区域周围存在一个最小电场，该电场会导致 BBB 破坏，并且可以使用钆（Gd）摄取作为 BBB 破坏的替代标志物来测量这种瞬态反应。该研究是在符合良好实验室规范（GLP）的设施中进行的，并获得了机构动物护理和使用委员会（IACUC）的批准。IRE 消融是在正常大鼠脑中进行的（n=21），使用 1-mm 电极（直径 0.45 毫米），边缘到边缘的距离为 4 毫米。我们使用 ECM830 脉冲发生器以 1 Hz 的频率递送九十次 50-μs 脉冲处理（0、200、400、600、800 和 1000 V/cm）。通过系统地描述 7.0-T 磁共振成像（MRI）和组织病理学评估，评估了应用电场和 Gd 给药时间（-5、+5、+15 和+30 分钟）的影响。通过最小二乘拟合进行应用电场和 Gd 时间的统计学分析，α=0.05 和线性回归分析。通过 3D MRI 重建确认了 IRE 治疗的聚焦性质，消融体积与电场之间存在线性相关性。我们的结果还表明，IRE 是一种消融技术，可通过 MRI（n=16）以局灶方式杀死脑组织，并以电压依赖性方式暂时破坏邻近消融区域的 BBB（n=5）和 Gd 给药。
