Computational Transport Models for Convection-Enhanced CNS Delivery

描述（由申请人提供）：局部给药方法，如对流增强给药（CED），被用于绕过血脑屏障，并在中枢神经系统内选择大容量分布血脑屏障不可渗透的治疗剂。在这项研究中，我们的目标是提供化合物的CED转运到海马体治疗颞叶癫痫（TLE）的基本认识。我们将使用耦合建模和实验CED方法来选择性地靶向大体积的海马体。研究将集中于在正常和病理条件下定量细胞外流动和大分子示踪剂分布。将测试不同的递送地点、输注速率和控制条件。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考虑现实的解剖边界、流体-组织相互作用和各向异性输运。细胞外运输特性将使用压力传感器系统和微压痕测试进行测量。相应的体内磁共振成像研究将量化CED在啮齿动物和灵长类动物大脑中的空间浓度（灵长类动物研究将与美国国立卫生研究院的研究人员合作完成）。这样一个全面的研究，量化CED在颞叶海马系统内的运输，以前没有进行过。本研究也将提供基本的工具和技术，以量化生物转运和测量体内转运的CED。本研究将阐明细胞外流动、组织各向异性、病理改变、组织肿胀和回流的作用。基于核磁共振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，我们的目标是提供对对流增强输送（CED）化合物进入海马体治疗颞叶癫痫的基本理解。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发展，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运输的影响。

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.