1 Division of MR Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
2 Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Stem Cells Dev. 2019 Apr 15;28(8):515-527. doi: 10.1089/scd.2018.0172. Epub 2019 Mar 28.
White matter damage persists in hypoxic-ischemic newborns even when treated with hypothermia. We have previously shown that intraventricular delivery of human glial progenitors (GPs) at the neonatal stage is capable of replacing abnormal host glia and rescuing the lifespan of dysmyelinated mice. However, such transplantation in the human brain poses significant challenges as related to high-volume ventricles and long cell migration distances. These challenges can only be studied in large animal model systems. In this study, we developed a three dimensional (3D)-printed model of the ventricular system sized to a newborn pig to investigate the parameters that can maximize a global biodistribution of injected GPs within the ventricular system, while minimizing outflow to the subarachnoid space. Bioluminescent imaging and magnetic resonance imaging were used to image the biodistribution of luciferase-transduced GPs in simple fluid containers and a custom-designed, 3D-printed model of the piglet ventricular system. Seven independent variables were investigated. The results demonstrated that a low volume (0.1 mL) of cell suspension is essential to keep cells within the ventricular system. If higher volumes (1 mL) are needed, a very slow infusion speed (0.01 mL/min) is necessary. Real-time magnetic resonance imaging demonstrated that superparamagnetic iron oxide (SPIO) labeling significantly alters the rheological properties of the GP suspension, such that, even at high speeds and high volumes, the outflow to the subarachnoid space is reduced. Several other factors, including GP species (human vs. mouse), type of catheter tip (end hole vs. side hole), catheter length (0.3 vs. 7.62 m), and cell concentration, had less effect on the overall distribution of GPs. We conclude that the use of a 3D-printed phantom model represents a robust, reproducible, and cost-saving alternative to in vivo large animal studies for determining optimal injection parameters.
即使在接受低温治疗的情况下，缺氧缺血性新生儿的白质损伤仍然存在。我们之前已经表明，在新生儿阶段向脑室中输送人神经胶质祖细胞 (GPs) 能够替代异常的宿主神经胶质并挽救脱髓鞘小鼠的寿命。然而，由于脑室体积大且细胞迁移距离长，这种移植在人类大脑中存在重大挑战。这些挑战只能在大型动物模型系统中进行研究。在这项研究中，我们开发了一种针对新生猪的脑室系统的 3D 打印模型，以研究可以使注入的 GPs 在脑室系统中实现最大全局分布的参数，同时将流出到蛛网膜下腔的量降到最低。生物发光成像和磁共振成像用于在简单的流体容器和定制设计的、猪脑室系统的 3D 打印模型中对转染了荧光素酶的 GPs 的生物分布进行成像。研究了七个独立变量。结果表明，低体积（0.1mL）的细胞悬浮液对于使细胞保持在脑室系统内至关重要。如果需要更高的体积（1mL），则需要非常缓慢的输注速度（0.01mL/min）。实时磁共振成像表明，超顺磁性氧化铁 (SPIO) 标记显著改变了 GP 悬浮液的流变特性，使得即使在高速和高体积下，流出到蛛网膜下腔的量也会减少。其他几个因素，包括 GP 种类（人 vs. 鼠）、导管尖端类型（端孔 vs. 侧孔）、导管长度（0.3 vs. 7.62m）和细胞浓度，对 GPs 的总体分布影响较小。我们得出结论，使用 3D 打印模型代表了一种稳健、可重复且节省成本的替代体内大型动物研究的方法，用于确定最佳注射参数。
