Hersh David S, Nguyen Ben A, Dancy Jimena G, Adapa Arjun R, Winkles Jeffrey A, Woodworth Graeme F, Kim Anthony J, Frenkel Victor
Department of Neurosurgery, University of Maryland School of Medicine, 22 S Greene St Suite 12D, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, 22 S Greene St, Baltimore, MD 21201, USA.
Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, 419 W Redwood St Suite 110, Baltimore, MD 21201, USA.
Brain Res. 2016 Sep 1;1646:543-550. doi: 10.1016/j.brainres.2016.06.040. Epub 2016 Jun 28.
Diffusion within the extracellular and perivascular spaces of the brain plays an important role in biological processes, therapeutic delivery, and clearance mechanisms within the central nervous system. Recently, ultrasound has been used to enhance the dispersion of locally administered molecules and particles within the brain, but ultrasound-mediated effects on the brain parenchyma remain poorly understood. We combined an electron microscopy-based ultrastructural analysis with high-resolution tracking of non-adhesive nanoparticles in order to probe changes in the extracellular and perivascular spaces of the brain following a non-destructive pulsed ultrasound regimen known to alter diffusivity in other tissues. Freshly obtained rat brain neocortical slices underwent sham treatment or pulsed, low intensity ultrasound for 5min at 1MHz. Transmission electron microscopy revealed intact cells and blood vessels and evidence of enlarged spaces, particularly adjacent to blood vessels, in ultrasound-treated brain slices. Additionally, ultrasound significantly increased the diffusion rate of 100nm, 200nm, and 500nm nanoparticles that were injected into the brain slices, while 2000nm particles were unaffected. In ultrasound-treated slices, 91.6% of the 100nm particles, 20.7% of the 200nm particles, 13.8% of the 500nm particles, and 0% of the 2000nm particles exhibited diffusive motion. Thus, pulsed ultrasound can have meaningful structural effects on the brain extracellular and perivascular spaces without evidence of tissue disruption.
在大脑的细胞外间隙和血管周围间隙中的扩散在生物过程、治疗药物递送以及中枢神经系统的清除机制中发挥着重要作用。最近，超声已被用于增强局部给药的分子和颗粒在脑内的分散，但超声对脑实质的影响仍知之甚少。我们将基于电子显微镜的超微结构分析与对非粘附性纳米颗粒的高分辨率追踪相结合，以探究在一种已知能改变其他组织扩散率的非破坏性脉冲超声治疗方案后，大脑细胞外和血管周围间隙的变化。刚获取的大鼠脑新皮质切片接受假处理或在1MHz频率下进行5分钟的脉冲低强度超声处理。透射电子显微镜显示细胞和血管完整，并且在超声处理的脑切片中存在间隙增大的迹象，尤其是在血管附近。此外，超声显著提高了注入脑切片中的100nm、200nm和500nm纳米颗粒的扩散速率，而2000nm颗粒则不受影响。在超声处理的切片中，91.6%的100nm颗粒、20.7%的200nm颗粒、13.8%的500nm颗粒以及0%的2000nm颗粒呈现出扩散运动。因此，脉冲超声可对脑细胞外和血管周围间隙产生有意义的结构影响，且无组织破坏的迹象。
