Development of patient-specific mathematical models for the transport of solute molecules in the cerebrospinal fluid (CSF) along the spinal canal

开发患者特异性溶质分子转运的数学模型 沿着椎管的脑脊液（CSF） 项目总结/摘要 脑脊液（CSF）主要从血浆中分泌，并持续地沐浴和分泌。 在大脑和脊髓的外表面循环。它维持着体内的电解质平衡， 中枢神经系统（CNS），并作为向神经元和神经胶质细胞供应营养的介质， 清除细胞新陈代谢的废物。它还运输激素，神经递质和其他 神经肽在整个中枢神经系统。CSF循环的失调可能会损害这些物质的运输， 溶质和中枢神经系统的正常生理功能，有助于一些认知和 神经系统疾病CSF还提供了一个用于将强效镇痛剂和化疗药物递送至患者的管道。 CNS，一种通常称为鞘内或脊柱内药物递送（ITDD）的药物递送程序。迄今为止， 没有综合的方法能够预测患者特异性的、长期的CSF运动， 溶质分子沿着脊柱管的运输。因此，本提案的主要目标是制定一项 全面的建模方法，能够预测溶质分子的长期运输沿着 根据每个患者的具体椎管解剖结构和生理条件。建模方法结合了 利用双时间尺度渐近分析法对离体条件下椎管内脑脊液的欧拉速度场进行了研究。 实验和详细的体内验证与患者特异性放射测量。拟议 该方法对于宽范围的分子扩散率是有效的，并且考虑了CSF的对流效应， 包括“剪切增强扩散”、“稳态流”和“斯托克斯漂移”，以确定长时间拉格朗日量 溶质在椎管蛛网膜下腔（SAS）中的运输。拟议工作组的预期成果 研究是双重的：1）它将提供一个详细的了解机制，调节运输的所有 重要的分子关键的中枢神经系统的功能和2）它也将提供必要的方法， 优化ITDD协议。

Development of patient-specific mathematical models for the transport of solute molecules in the cerebrospinal fluid (CSF) along the spinal canal PROJECT SUMMARY / ABSTRACT The cerebrospinal fluid (CSF) is predominantly secreted from the blood plasma and continuously bathes and circulates around the external surfaces of the brain and spinal cord. It maintains the electrolytic balance of the central nervous system (CNS), and serves as a medium for the supply of nutrients to neuronal and glial cells and the removal of waste products of cellular metabolism. It also transports hormones, neurotransmitters, and other neuropeptides throughout the CNS. The deregulation of the CSF circulation may compromise the transport of these solutes and the normal physiologic functions of the CNS contributing to the development of some cognitive and neurological diseases. CSF also provides a conduit for the delivery of potent analgesics and chemotherapy to the CNS, a drug delivery procedure often referred to as intrathecal or intraspinal drug delivery (ITDD). To date, there is no comprehensive methodology capable of predicting the patient-specific, long-term, motion of the CSF and the transport of solute molecules along the spinal canal. Thus, the main objective of this proposal is to develop a comprehensive modeling methodology capable of predicting the long-term transport of solute molecules along the spinal canal in each patient-specific anatomy and physiological conditions. The modeling approach combines the use of two time-scales asymptotic analysis of the Eulerian velocity field of the CSF in the spinal canal with in-vitro experimentation and detailed in-vivo validation with patient-specific radiological measurements. The proposed methodology is valid for a wide range of molecular diffusivities and accounts for convective effects of the CSF, including “shear-enhanced diffusion”, “steady-streaming”, and “Stokes drift”, to determine the long-time Lagrangian transport of the solute in the subarachnoid space (SAS) of the spinal canal. The expected outcomes of the proposed research are twofold: 1) it will provide a detailed understanding of the mechanisms regulating the transport of all important molecules key to the functioning of the CNS and 2) it will also provide the methodology necessary to optimize ITDD protocols.