Development of Patient-Specific Mathematical Models for the Transport of Solute Molecules in the Cerebrospinal Fluid (CSF) Along the Spinal Canal

开发针对脑脊液 (CSF) 中溶质分子沿椎管运输的患者特定数学模型

• 批准号: 10470825
• 负责人: Antonio Luis Sanchez
• 金额: $ 46.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470825
• 关键词: Acid-Base Equilibrium; Affect; Analgesics; Anatomy; Bathing; Blood Circulation; Brain; Cerebrospinal Fluid; Characteristics; Clinical; Cognition Disorders; Convection; Development; Diffuse; Diffusion; Drug Delivery Systems; Drug Kinetics; Drug Transport; Electrolyte Balance; Excision; Formulation; Heart; Hormones; In Vitro; Injections; Intracranial Pressure; Investigation; Light; Liquid substance; Location; Lymphatic System; Malignant neoplasm of central nervous system; Measurement; Metabolism; Methodology; Modeling; Molecular; Motion; Neuraxis; Neuroglia; Neurons; Neuropeptides; Neurotransmitters; Nutrient; Outcome; Pathology; Patients; Pharmaceutical Preparations; Physiological; Plasma; Positioning Attribute; Posture; Procedures; Protocol Compliance; Protocols documentation; Radiology Specialty; Research; Rotation; Spinal; Spinal Canal; Spinal Cord; Stream; Subarachnoid Space; Surface; Time; Validation; Variant; Waste Products; bulk motion; cerebrospinal fluid flow; chemotherapy; chronic pain; density; experience; in vivo; mathematical model; multidisciplinary; nervous system disorder; neurotransmitter release; novel; particle; patient response; release factor; respiratory; solute; Acid-Base Equilibrium; Affect; Analgesics; Anatomy; Bathing; Blood Circulation; Brain; Cerebrospinal Fluid; Characteristics; Clinical; Cognition Disorders; Convection; Development; Diffuse; Diffusion; Drug Delivery Systems; Drug Kinetics; Drug Transport; Electrolyte Balance; Excision; Formulation; Heart; Hormones; In Vitro; Injections; Intracranial Pressure; Investigation; Light; Liquid substance; Location; Lymphatic System; Malignant neoplasm of central nervous system; Measurement; Metabolism; Methodology; Modeling; Molecular; Motion; Neuraxis; Neuroglia; Neurons; Neuropeptides; Neurotransmitters; Nutrient; Outcome; Pathology; Patients; Pharmaceutical Preparations; Physiological; Plasma; Positioning Attribute; Posture; Procedures; Protocol Compliance; Protocols documentation; Radiology Specialty; Research; Rotation; Spinal; Spinal Canal; Spinal Cord; Stream; Subarachnoid Space; Surface; Time; Validation; Variant; Waste Products; bulk motion; cerebrospinal fluid flow; chemotherapy; chronic pain; density; experience; in vivo; mathematical model; multidisciplinary; nervous system disorder; neurotransmitter release; novel; particle; patient response; release factor; respiratory; solute

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.

开发患者特异性的数学模型，用于在固体分子中运输 脑脊液（CSF）沿脊柱管 项目摘要 /摘要 脑脊液（CSF）主要从血浆中分泌，并连续沐浴 围绕大脑和脊髓的外表面循环。它保持 中枢神经系统（CNS），作为向神经元和神经胶质细胞供应营养的培养基，以及 去除细胞代谢的废物。它还运输激素，神经递质和其他 整个中枢神经系统的神经肽。 CSF循环的放松管制可能会损害这些运输 中枢神经系统的溶质和正常的生理功能有助于某些认知和 神经疾病。 CSF还提供了向潜在镇痛药和化学疗法提供的管道 中枢神经系统是一种药物输送程序，通常称为鞘内或次级药物递送（ITDD）。迄今为止，有 没有能够预测CSF和CSF的患者特异性，长期运动的全面方法 固体分子沿脊柱运河的运输。这是该提议的主要目的是开发 综合建模方法，能够预测固体分子沿着的长期运输 每个患者特异性解剖结构和身体状况中的脊柱管。建模方法结合了 使用VITRO的脊柱管中CSF的Eulerian速度场的两个时间尺度不对称分析 通过患者特异性放射学测量值进行的实验和详细的体内验证。提议 方法论对于广泛的分子扩散率有效，并解释了CSF的对流效应， 包括“剪切增强的扩散”，“稳定流”和“ Stokes Drift”，以确定长期的Lagrangian 脊柱管的亚蛛网膜下空间（SAS）中可溶性的运输。提议的预期结果 研究是双重的：1）它将对调查所有人运输的机制提供详细的理解 重要的分子是CNS功能的关键，2）它还将提供必要的方法 优化ITDD协议。