Department of Biomedical Engineering, Columbia University, New York, NY, USA.
Phys Med Biol. 2010 Oct 21;55(20):6141-55. doi: 10.1088/0031-9155/55/20/007. Epub 2010 Sep 29.
The in vivo cavitation response associated with blood-brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity® microbubbles (mean diameter range: 1.1-3.3 µm, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 µm in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity® microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected without craniotomy in mice and IC may not be required for BBB opening at relatively low pressures.
为了更好地识别其无创应用中的潜在机制，研究了与血脑屏障（BBB）开放相关的体内空化反应，该反应是由经颅聚焦超声（FUS）与微泡联合诱导产生的。一个与 FUS 换能器共焦的圆柱形聚焦水听器被用作被动空化探测器（PCD），以确定存在 Definity®微泡（平均直径范围：1.1-3.3 µm，Lantheus Medical Imaging，MA，USA）时惯性空化（IC）的阈值。首先使用血管模型在体内使用之前确定 PCD 的可靠性。通过在聚丙烯酰胺凝胶内部生成直径为 610 µm 的圆柱形通道并使其体积充满微泡来模拟脑血管。通过切除的小鼠颅骨对微泡进行超声处理。其次，在体内非侵入性（即经皮和经颅）BBB 开放期间，使用相同的 PCD 设置进行空化检测。静脉内给予 Definity®微泡后，通过完整的头皮和颅骨向 26 只（n = 26）小鼠的右侧海马施加脉冲 FUS（频率：1.525 或 1.5 MHz，峰值稀疏压力：0.15-0.60 MPa，占空比：20%，PRF：10 Hz，持续时间：1 分钟，间隔 30 秒）。使用 T1 和 T2 加权 MR 图像验证 BBB 开放。为了检测 IC 起始和持续时间，在每个压力下生成声谱图。发现体内 BBB 开放的阈值为 0.30 MPa 峰值稀疏压力。在体模和体内研究中都表明，IC 压力阈值的峰值稀疏幅度为 0.45 MPa。这表明 BBB 开放可能不需要在阈值或附近产生 IC。组织学分析表明，在 0.30 和 0.45 MPa 时，可以在不造成任何细胞损伤的情况下诱导 BBB 开放。总之，在没有开颅术的情况下，可以在小鼠中检测到空化反应，并且在相对较低的压力下，BBB 开放可能不需要 IC。
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