Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
J Neurosurg. 2012 Dec;117(6):1128-40. doi: 10.3171/2012.7.JNS11144. Epub 2012 Sep 21.
In convection-enhanced delivery (CED), drugs are infused locally into tissue through a cannula inserted into the brain parenchyma to enhance drug penetration over diffusion strategies. The purpose of this study was to demonstrate the feasibility of ultrasound-assisted CED (UCED) in the rodent brain in vivo using a novel, low-profile transducer cannula assembly (TCA) and portable, pocket-sized ultrasound system.
Forty Sprague-Dawley rats (350-450 g) were divided into 2 equal groups (Groups 1 and 2). Each group was divided again into 4 subgroups (n = 5 in each). The caudate of each rodent brain was infused with 0.25 wt% Evans blue dye (EBD) in phosphate-buffered saline at 2 different infusion rates of 0.25 μl/minute (Group 1), and 0.5 μl/minute (Group 2). The infusion rates were increased slowly over 10 minutes from 0.05 to 0.25 μl/minute (Group 1) and from 0.1 to 0.5 μl/minute (Group 2). The final flow rate was maintained for 20 minutes. Rodents in the 4 control subgroups were infused using the TCA without ultrasound and without and with microbubbles added to the infusate (CED and CED + MB, respectively). Rodents in the 4 UCED subgroups were infused without and with microbubbles added to the infusate (UCED and UCED + MB) using the TCA with continuous-wave 1.34-MHz low-intensity ultrasound at a total acoustic power of 0.11 ± 0.005 W and peak spatial intensity at the cannula tip of 49.7 mW/cm(2). An additional 4 Sprague-Dawley rats (350-450 g) received UCED at 4 different and higher ultrasound intensities at the cannula tip ranging from 62.0 to 155.0 mW/cm(2) for 30 minutes. The 3D infusion distribution was reconstructed using MATLAB analysis. Tissue damage and morphological changes to the brain were assessed using H & E.
The application of ultrasound during infusion (UCED and UCED + MB) improved the volumetric distribution of EBD in the brain by a factor of 2.24 to 3.25 when there were no microbubbles in the infusate and by a factor of 1.16 to 1.70 when microbubbles were added to the infusate (p < 0.001). On gross and histological examination, no damage to the brain tissue was found for any acoustic exposure applied to the brain.
The TCA and ultrasound device show promise to improve the distribution of infused compounds during CED. The results suggest further studies are required to optimize infusion and acoustic parameters for small compounds and for larger molecular weight compounds that are representative of promising antitumor agents. In addition, safe levels of ultrasound exposure in chronic experiments must be determined for practical clinical evaluation of UCED. Extension of these experiments to larger animal models is warranted to demonstrate efficacy of this technique.
在对流增强递送（CED）中，通过插入脑实质的套管将药物局部输注到组织中，以增强药物穿透扩散策略的能力。本研究的目的是使用新型低轮廓换能器套管组件（TCA）和便携式袖珍超声系统，在体内证明超声辅助 CED（UCED）在啮齿动物大脑中的可行性。
将 40 只 Sprague-Dawley 大鼠（350-450g）分为 2 组（每组 20 只）。每组再次分为 4 个亚组（每组 5 只）。在磷酸盐缓冲液中，每组的尾状核以 2 种不同的输注速率（0.25μl/min 组 1 和 0.5μl/min 组 2）输注 0.25wt% Evans 蓝染料（EBD）。输注率从 0.05 缓慢增加到 0.25μl/min（组 1）和从 0.1 增加到 0.5μl/min（组 2），历时 10 分钟。最终流速保持 20 分钟。4 个对照组的啮齿动物在没有超声的情况下使用 TCA 进行输注，并且在输注物中添加或不添加微泡（分别为 CED 和 CED+MB）。4 个 UCED 亚组的啮齿动物在没有和添加微泡的情况下使用 TCA 进行输注（UCED 和 UCED+MB），并使用连续波 1.34MHz 低强度超声，总声功率为 0.11±0.005W，在套管尖端的峰值空间强度为 49.7mW/cm²。另外 4 只 Sprague-Dawley 大鼠（350-450g）在套管尖端以 62.0 至 155.0mW/cm²的不同和更高的超声强度接受 UCED 30 分钟。使用 MATLAB 分析重建 3D 输注分布。使用 H&E 评估脑损伤和形态学变化。
在输注过程中应用超声（UCED 和 UCED+MB）可将无微泡时 EBD 的体积分布提高 2.24 至 3.25 倍，而添加微泡时可提高 1.16 至 1.70 倍（p<0.001）。在大体和组织学检查中，没有发现任何一种应用于大脑的声暴露对脑组织造成损伤。
TCA 和超声设备有望改善 CED 期间输注化合物的分布。结果表明，需要进一步研究以优化用于小化合物和代表有前途的抗肿瘤药物的更大分子量化合物的输注和声学参数。此外，必须确定慢性实验中安全的超声暴露水平，以便对 UCED 进行实际的临床评估。将这些实验扩展到更大的动物模型是有必要的，以证明该技术的疗效。
