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首页> 外文学位 >Multiphysics models of fluid and solute transport in the microvasculature of normal and malignant breast tissues with application to the detection and treatment of breast cancer.
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Multiphysics models of fluid and solute transport in the microvasculature of normal and malignant breast tissues with application to the detection and treatment of breast cancer.

机译：正常和恶性乳腺组织微血管中流体和溶质运移的多物理场模型，用于乳腺癌的检测和治疗。

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摘要

The limitations of the current diagnostic and therapeutic options available for breast cancer elucidate the need for improvements to the existing methods or the introduction of novel techniques. Many of the most promising novel options for both the diagnosis and treatment of cancer involve nanoparticles. Nanoparticles have unique imaging and therapeutic possibilities arising from their small size, surface tailorability, and binding capability. If properly designed nanoparticle may exploit the disordered architecture, increased vessel density, large pores, hyperpermeability, and other abnormalities characteristic of the vasculature in tumors, and achieve increased accumulation in cancerous tissue. The efficacy of nanoparticles may be further enhanced by active targeting through chemical or biological means, e.g., using ligands that bind specifically to receptors found on cancerous cells, or physical means, e.g., application of a magnetic field to the tumor after injection of magnetic nanoparticles. In order to optimize the diagnostic and therapeutic methods, it is necessary to understand the transport processes occurring in the breast and the changes that take place with the disease. Mathematical modeling is a valuable tool which provides a conceptual framework to understand these processes. The mathematical transport models found in the literature lacked of a consistent set of governing equations suggesting limited understanding. The transport parameters reported in the literature were similarly disparate, spanning several orders of magnitude in some cases.;The primary purpose of this research was to develop, calibrate, and validate a comprehensive mathematical model using mixture theory along with experimental data and parameter values available in the literature. The mixture theory formulation allowed for the application of external body forces, uptake of solutes by cells, aggregation of the solutes, and solid tissue deformation. The resulting model included a number of components not accounted for in the traditional transport equations. The dependence of the hydraulic permeability coefficient of the capillary wall on the concentration of solutes present was the most notable novel feature.;A simplified version of the mixture theory model was first utilized to describe steady state blood flow in an axisymmetric microvascular geometry for the case of no solutes or solid tissue deformation. Four influential parameters were calibrated using red blood cell velocity data from the literature. The computed velocities and calibrated parameters were in good agreement with experimental data. The mixture theory model was then utilized to examine the time dependent transport of fluid and a single macromolecular solute with no active targeting. In normal tissue, the radius of the unit cell, the pressure drop along the vessel, the osmotic pressure gradient, the hydraulic permeability coefficient, the reflection coefficient of the capillary wall, and the retardation factor substantially influenced the extravascular solute transport. These parameters, as well as the extravascular pressure, were important in cancerous tissue and were calibrated using a response surface methodology and experimental data from the literature for dextrans. The calibrated parameters were within the expected ranges. The validated results showed good agreement with the experimental data for both the mean extravascular concentration as a function of time and the penetration depth of the dextrans as a function of time across a wide range of molecular weights, 3.3 to 2000 kg mol -1. For the largest solutes, the results from the mixture theory model were markedly improved compared to those of the traditional models. Subsequent to exploring influence of passive targeting, both receptor mediated and magnetic active targeting were added to the mixture theory model. Both means of active targeting increased the extravascular accumulation. The efficacy of the targeting was dependent upon a number of factors, including the solute size. The mixture theory model will be a valuable tool for further exploration of these influences.
机译：当前可用于乳腺癌的诊断和治疗选择的局限性表明需要改进现有方法或引入新技术。用于诊断和治疗癌症的许多最有前途的新颖选择都涉及纳米粒子。纳米粒子具有尺寸小，表面可适应性强和结合能力强的特点，因此具有独特的成像和治疗可能性。如果适当设计的纳米颗粒可以利用无序的结构，增加的血管密度，大的孔，通透性高以及肿瘤中脉管系统的其他异常特征，并在癌组织中实现增加的积累。纳米颗粒的功效可通过化学或生物学手段主动靶向，例如使用与癌细胞上发现的受体特异性结合的配体，或物理手段（例如在注入磁性纳米颗粒后向肿瘤施加磁场）来进一步增强。为了优化诊断和治疗方法，有必要了解在乳房中发生的运输过程以及随着疾病发生的变化。数学建模是一种有价值的工具，它提供了一个概念框架来理解这些过程。文献中发现的数学输运模型缺乏一致的控制方程集，这表明了解有限。文献中报道的输运参数完全不同，在某些情况下跨越几个数量级。这项研究的主要目的是使用混合理论以及可用的实验数据和参数值来开发，校准和验证综合数学模型。在文学中。混合理论公式允许施加外力，细胞吸收溶质，溶质聚集和实体组织变形。生成的模型包括许多传统运输方程式未考虑的组件。最显着的新特点是毛细管壁的水力渗透系数与所存在的溶质浓度的关系。；首先，使用简化的混合理论模型来描述轴对称微血管几何结构中的稳态血流没有溶质或实体组织变形。使用来自文献的红细胞速度数据校准了四个有影响力的参数。计算出的速度和标定参数与实验数据吻合良好。然后，利用混合理论模型来检查流体和单个没有主动靶向的大分子溶质的时间依赖性传输。在正常组织中，单位细胞的半径，沿血管的压降，渗透压梯度，水力渗透系数，毛细血管壁的反射系数和阻滞因子会严重影响血管外溶质的转运。这些参数以及血管外压力在癌组织中很重要，并使用响应面方法和来自右旋糖酐文献的实验数据进行了校准。校准参数在预期范围内。验证的结果表明，在3.3至2000 kg mol -1的各种分子量范围内，平均血管外浓度与时间的关系以及右旋糖酐的渗透深度与时间的关系均与实验数据良好吻合。对于最大的溶质，与传统模型相比，混合理论模型的结果得到了显着改善。在探索了被动靶向的影响之后，将受体介导的和磁性主动靶向都添加到了混合理论模型中。主动靶向的两种方法均增加了血管外积聚。靶向的功效取决于许多因素，包括溶质的大小。混合理论模型将是进一步探索这些影响的有价值的工具。

著录项

  • 作者

    Schuff, Mary Maria.;

  • 作者单位

    Purdue University.;

  • 授予单位 Purdue University.;
  • 学科 Engineering Biomedical.;Biophysics Biomechanics.;Engineering Mechanical.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 422 p.
  • 总页数 422
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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