Computational Transport Models for Convection-Enhanced CNS Delivery

描述（由申请人提供）：局部药物递送方法，如对流增强递送（CED），正用于绕过血脑屏障，并将血脑屏障不可渗透的治疗剂分布在CNS内的大的选定体积上。在这项研究中，我们的目标是提供基本的了解CED运输的化合物进入海马治疗颞叶癫痫（TLE）。我们将使用耦合建模和实验CED方法选择性地针对海马体的大体积。研究将集中在正常和病理条件下的细胞外流量和大分子示踪剂分布的定量。将对不同的输注部位、输注速率和对照条件进行试验。对于计算，组织将被建模为多孔介质，并将使用高分辨率和扩散张量磁共振成像技术来解释现实的解剖边界、流体-组织相互作用和各向异性传输。将使用压力传感器系统和微压痕测试来测量细胞外运输特性。相应的体内磁共振成像研究将量化啮齿动物和灵长类动物大脑中CED后的空间浓度（灵长类动物研究将与NIH的研究人员合作进行）。这样一个全面的研究，量化CED运输TLE海马系统内，以前没有进行。本研究还将提供基本的工具和技术，以量化生物运输和测量在体内运输的CED。该研究将阐明细胞外流动、组织各向异性、病理变化、组织肿胀和回流的作用。基于MR的生物运输工具为患者特异性治疗提供了重要的一步，因为它们解释了疾病的解剖和结构变化。公共卫生相关性：在这项研究中，我们的目标是提供一个基本的了解对流增强递送（CED）的化合物进入海马治疗颞叶癫痫。体内高分辨率磁共振和扩散张量成像测量将指导三维计算模型的开发，该模型将用于确定解剖边界、流体-组织相互作用和组织结构对细胞外CED转运的影响。

DESCRIPTION (provided by applicant): Local drug delivery methods, such as convection-enhanced delivery (CED), are being used to circumvent the blood-brain-barrier and to distribute blood-brain-barrier-impermeable therapeutic agents over large selected volumes within the CNS. In this study, our goal is to provide fundamental understanding of CED transport of compounds into the hippocampus for the treatment of temporal lobe epilepsy (TLE). We will use a coupled modeling-and-experimental CED approach to selectively target a large volume of the hippocampus. Studies will concentrate on quantifying extracellular flows and macromolecular tracer distributions under both normal and pathological conditions. Varying delivery sites, infusion rates, and control conditions will be tested. For computations, tissues will be modeled as porous media and will account for realistic anatomical boundaries, fluid-tissue interactions, and anisotropic transport using high resolution and diffusion tensor magnetic resonance imaging technologies. Extracellular transport properties will be measured using pressure sensor systems and microindentation testing. Corresponding in vivo magnetic resonance imaging studies will quantify spatial concentrations following CED in rodent and primate brains (primate studies will be done in collaboration with researchers at the NIH). Such a comprehensive study, to quantify CED transport within the TLE hippocampal system, has not been previously conducted. This study will also provide fundamental tools and techniques to quantify bio- transport and measure in vivo transport by CED. The study will clarify the roles of extracellular flow, tissue anisotropy, pathological changes, tissue swelling, and backflow. MR-based bio-transport tools provide an important step towards patient-specific treatment since they account for anatomical and structural changes with disease. PUBLIC HEALTH RELEVANCE: In this study, our goal is to provide a fundamental understanding of convection enhanced delivery (CED) of compounds into the hippocampus for the treatment of temporal lobe epilepsy. High-resolution magnetic resonance and diffusion tensor imaging measurements in vivo will guide the development of a three- dimensional computational model that will be used to determine the effects of anatomical boundaries, fluid- tissue interactions, and tissue structure on extracellular CED transport.