Computational and theoretical fluid mechanics modeling for transport in dense tumors

致密肿瘤中运输的计算和理论流体力学模型

• 批准号: 10816198
• 负责人: Saikat Basu
• 金额: $ 4.29万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10816198
• 关键词: Computational; theoretical; fluid; mechanics; modeling

Intratumoral perfusion has long been recognized as a critical issue in both clinical diagnosis and therapy of dense solid cancerous tumors. In such context, a first-principles mechanics-based model that can quantify perfusion in the intratumoral extracellular spaces as a function of the tumor vasculature shapes and the fiber packing fraction in the stroma – can launch new avenues in cancer diagnosis and care. With that vision, the proposed project will integrate computational fluid dynamics (CFD) tracking with theoretical fluid mechanics analysis to generate an in silico tumor uptake modeling framework, that can operate over a wide parametric space. The test geometries will be based off computed tomography (CT) scans of human pancreatic tumors implanted in mice. The project will also design supplementary physical experiments in microfluidic setups and artificial tumor spheroids to benchmark and validate the proposed in silico approach. With use of mean continuum-level transport frameworks such as Darcy's Law and Starling model still a go-to resort for basic fluids modeling of intratumoral uptake quantification, the proposed CFD-informed advanced theoretical fluid mechanics approach to parameterize tumor perfusion based on tumor geometry and intratumoral stress will constitute this project's key contribution to the literature. The long-term objective of the project is as follows: in a clinical setting, the packing fraction of the fiber bundles inside the stroma can be readily assessed from image-processing the CT-slices from a tumor, it being logarithmically proportional to the intratumoral stress. The proposed numerical-theoretical model will be designed such as to project the tumoral uptake as a function of the packing fraction. This can trigger new diagnostic/therapeutic solutions with the fluidic transport trends inside a solid tumor predictable solely from the medical scans through assessment of the packing fraction. Our central hypothesis is: an integration of numerical computations with theoretical modeling can cover a diverse range of tumor microenvironments, rendering greater usability for the fluid mechanics tools. The resulting in silico framework will generate percolation data over a wide parameter space of tumor geometry features, e.g., the packing fraction inside the stroma and the local curvatures of blood vessels in the tumor vasculature. The work is structured around the following specific aims: (a) Aim 1 will numerically simulate multiphase transport inside the tumor vasculature, considering realistic blood vessel shapes and electrohydrodynamic effects on the mean transport, (b) Aim 2 will import from Aim 1 the plasma dynamics information at the endothelial openings and use the data as initial conditions to develop an integrative numerical-theoretical model for intratumoral transport through the extracellular matrix. The theoretical setup will invoke a convection-diffusion approach, where the boundary conditions on the local concentrations at the tumor inlet and near the necrotic core (deep into the tumor) will be fed from the numerical simulations. Finally, the in silico perfusion predictions will be compared against physical experiments performed in simplified bio-inspired microfluidic systems and with cell culture-derived realistic tumor spheroids embedded in a fluidic environment.

肿瘤内灌注一直被认为是高密度实体癌临床诊断和治疗的关键问题。在这种情况下，基于第一原理力学的模型可以量化肿瘤内细胞外空间中的灌注，作为肿瘤脉管系统形状和基质中纤维填充分数的函数，可以在癌症诊断和护理中开辟新的途径。有了这个愿景，拟议的项目将整合计算流体动力学（CFD）跟踪与理论流体力学分析，以生成一个计算机肿瘤摄取建模框架，可以在广泛的参数空间。试验几何形状将基于植入小鼠体内的人胰腺肿瘤的计算机断层扫描（CT）。该项目还将在微流体设置和人工肿瘤球体中设计补充物理实验，以基准测试和验证所提出的计算机方法。使用平均连续水平的运输框架，如达西定律和Starling模型仍然是一个去诉诸基本流体建模的肿瘤内摄取定量，提出CFD通知先进的理论流体力学方法，以参数化肿瘤灌注的基础上，肿瘤的几何形状和肿瘤内的应力将构成该项目的主要贡献的文献。该项目的长期目标如下：在临床环境中，可以通过对肿瘤CT切片进行图像处理来容易地评估基质内纤维束的填充分数，其与肿瘤内应力成比例。所提出的数值-理论模型将被设计为例如将肿瘤摄取作为填充分数的函数进行投影。这可以触发新的诊断/治疗解决方案，其中实体肿瘤内的流体输送趋势仅通过评估填充分数从医学扫描可预测。我们的中心假设是：数值计算与理论建模的集成可以覆盖多种肿瘤微环境，从而为流体力学工具提供更大的可用性。所得到的计算机模拟框架将在肿瘤几何特征的宽参数空间上生成逾渗数据，例如，间质内的填充分数和肿瘤脉管系统中血管的局部曲率。这项工作围绕以下具体目标展开：（a）目标1将数值模拟肿瘤脉管系统内的多相运输，考虑到真实的血管形状和对平均运输的电流体动力学效应，（B）目标2将从目标1导入内皮开口处的血浆动力学信息，并使用该数据作为初始条件来开发综合数值模型。肿瘤内通过细胞外基质转运的理论模型。理论设置将调用对流扩散方法，其中将从数值模拟中提供肿瘤入口处和坏死核心附近（深入肿瘤）的局部浓度的边界条件。最后，在计算机灌注预测将进行比较，对物理实验进行简化的生物启发的微流体系统和细胞培养衍生的现实肿瘤球体嵌入在流体环境中。