Department of Biomedical Engineering, Columbia University, New York, NY, USA.
Ultrasound Med Biol. 2010 Sep;36(9):1445-59. doi: 10.1016/j.ultrasmedbio.2010.06.005.
As a potentially viable method of brain drug delivery, the safety profile of blood-brain barrier (BBB) opening using focused ultrasound (FUS) and ultrasound contrast agents (UCA) needs to be established. In this study, we provide a short-term (30-min or 5-h survival) histological assessment of murine brains undergoing FUS-induced BBB opening. Forty-nine mice were intravenously injected with Definity microbubbles (0.05 microL/kg) and sonicated under the following parameters: frequency of 1.525 MHz, pulse length of 20 ms, pulse repetition frequency of 10 Hz, peak rarefactional acoustic pressures of 0.15-0.98 MPa and two 30-s sonication intervals with an intermittent 30-s delay. The BBB opening threshold was found to be 0.15-0.3 MPa based on fluorescence and magnetic resonance imaging of systemically injected tracers. Analysis of three histological measures in hematoxylin and eosin-stained sections revealed the safest acoustic pressure to be within the range of 0.3-0.46 MPa in all examined time periods post sonication. Across different pressure amplitudes, only the samples 30 min post opening showed significant difference (p < 0.05) in the average number of distinct damaged sites, microvacuolated sites, dark neurons and sites with extravasated erythrocytes. Enhanced fluorescence around severed microvessels was also noted and found to be associated with the largest tissue effects, whereas mildly diffuse BBB opening with uniform fluorescence in the parenchyma was associated with no or mild tissue injury. Region-specific areas of the sonicated brain (thalamus, hippocampal fissure, dentate gyrus and CA3 area of hippocampus) exhibited variation in fluorescence intensity based on the position, orientation and size of affected vessels. The results of this short-term histological analysis demonstrated the feasibility of a safe FUS-UCA-induced BBB opening under a specific set of sonication parameters and provided new insights on the mechanism of BBB opening.
作为一种潜在可行的脑内药物递送方法，需要确定使用聚焦超声（FUS）和超声对比剂（UCA）打开血脑屏障（BBB）的安全性概况。在这项研究中，我们对接受 FUS 诱导的 BBB 开放的小鼠脑进行了短期（30 分钟或 5 小时存活）组织学评估。49 只小鼠静脉注射 Definity 微泡（0.05 μL/kg），并在以下参数下进行超声处理：频率为 1.525 MHz，脉冲长度为 20 ms，脉冲重复频率为 10 Hz，峰值稀疏声压为 0.15-0.98 MPa，两个 30 s 超声间隔，间歇 30 s 延迟。基于系统内注射示踪剂的荧光和磁共振成像，发现 BBB 开放阈值为 0.15-0.3 MPa。苏木精和伊红染色切片的三种组织学测量分析表明，在所有超声后检查时间段内，最安全的声压范围为 0.3-0.46 MPa。在不同的压力幅度下，只有在打开后 30 分钟的样本中，明显受损部位、微空泡部位、暗神经元和红细胞外渗部位的平均数量才有显著差异（p < 0.05）。还注意到围绕切断的微血管的增强荧光，并且发现其与最大的组织效应相关，而在实质中具有均匀荧光的轻度弥漫性 BBB 开放与无或轻度组织损伤相关。受影响血管的位置、方向和大小决定了超声脑的特定区域（丘脑、海马裂、齿状回和海马 CA3 区）的荧光强度存在差异。这项短期组织学分析的结果表明，在特定的超声参数下，安全的 FUS-UCA 诱导 BBB 开放是可行的，并为 BBB 开放的机制提供了新的见解。
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