Convective Drug Transport in the Spinal Cord

描述（由申请人提供）：随着慢性疼痛、脊髓损伤和其他神经退行性疾病的治疗药物的发展，局部给药方法越来越被认为是克服大分子、缓慢扩散药物遇到的运输障碍的一种解决方案。局部治疗的智能设计将需要新的工具来评估特定于神经组织生理学的药物运输问题。最近，PI提出了一种预测脊髓注射大分子局部组织分布的方法。基于医学图像的计算模型被创建来确定间质（细胞外）流体流动以及白质和灰质区域的对流和扩散运输。进一步的研究需要将这种方法用于神经内输注和神经进入脊髓的对流运输。PI计划实施扩散加权成像（DWI）技术的新应用，该技术将使用有效的水扩散张量来预测沿白质束的优先间质输运方向。计算流体动力学（CFD）模型将DWI数据与多孔介质传输分析相结合，创建直接神经输注到脊髓组织的3D模型，作为替代的、侵入性较小的输送部位。同时，将开发一种压力传感器系统来测量间隙流体压力梯度并表征水力导电性。通过将预测分布拟合到大鼠脊髓研究中获得的大分子示踪剂数据中，将验证并进一步改善转运特性与输注力学之间的关系。成功的基于生理的药物传递模型可用于可行性研究和改进药物方案。最终，基于图像的药物转运模型为计算机辅助化学手术和患者特异性治疗提供了第一步。这将使患者能够根据年龄、性别和/或疾病进展的生理差异进行定制化医疗护理。

DESCRIPTION (provided by applicant): With the development of promising therapeutic agents for chronic pain, spinal injury, and other neurodegenerative diseases, local drug delivery methods are increasingly being considered as a solution to overcoming transport barriers encountered by macromolecular, slow-diffusing drugs. Intelligent design of regional therapy will require new tools to evaluate drug transport issues specific to nervous tissue physiology. Recently, the PI has presented a method for predicting the local tissue distribution of an injected macromolecule in the spinal cord. Medical image-based computational models are created to determine interstitial (extracellular) fluid flow and convective and diffusive transport in white and gray matter regions. Further research is warranted to develop this approach for intraneural infusion and convective transport at nerve entry into the spinal cord. The PI plans to implement a novel application of diffusion weighted imaging (DWI) technology which will use the effective water diffusion tensor to predict preferential interstitial transport directions along white matter tracts. Computational fluid dynamic (CFD) models will integrate DWI data with porous media transport analysis to create 3D models of direct nerve infusion into spinal cord tissue targeted as an alternative, less invasive delivery site. Concurrently, a pressure sensor system will be developed to measure interstitial fluid pressure gradients and characterize hydraulic conductivity. The relationship between transport properties and infusion mechanics will be validated and further improved by fitting predicted distributions to macromolecular tracer data obtained in rat spinal cord studies. Successful physiologically-based drug delivery models can be used for feasibility studies and improved drug protocols. Ultimately, image-based drug transport modeling provides the first step toward computer-aided chemical surgery and patient-specific therapeutic treatment. This will enable customized medical care for patients that inherently factors in physiological differences due to age, gender, and/or disease progression.