Transport of cells and drug delivery particles in blood flow

[132579 . pi]迈克尔·d·格雷厄姆血细胞在循环中的行为是复杂的，尽管已经观察到许多重要的现象，但人们对这些现象背后和联系在一起的原理仍然知之甚少。鉴于最近对药物输送颗粒合成的研究，了解流动血液中的运输具有额外的意义。合成方法的进步引起了最近对药物传递颗粒行为的物理方面的关注，如大小、形状和机械性能。合理设计血源性给药颗粒的前提是了解这些颗粒在血液中的实际行为，但目前还没有预测药物传递颗粒在血液循环中的分布情况。例如，靶向冠状动脉壁的颗粒的生物活性将在很大程度上取决于该颗粒在流动中是否倾向于留在血管壁附近，还是留在血管中心，在那里它不与血管壁相互作用。合成留在血管壁附近的粒子（例如，白细胞倾向于这样做）的设计原理尚不清楚。本工作的总体目标是通过实现以下目标来建立这些原理：(1)利用粒子水平的模拟和分析来预测红细胞流动悬浮液中药物载体颗粒的动力学，特别是横流迁移和剪切诱导扩散对颗粒大小、形状和可变形性的依赖；(2)将这些结果与传输建模框架相结合，从而能够系统地预测流动血液中颗粒的分布；(3)将预测结果与实验观测结果进行比较。这些目标将通过协调一致的努力来实现，将大规模、详细的模拟与理解和预测迁移和边缘化现象的基本理论框架结合起来。该奖项所开展的工作将导致复杂流体和药物输送方面的协同进展。它将为多相复杂流体的研究开辟新天地，特别是微循环中的血流动力学。它解决了血液中药物传递颗粒的物理动力学，因此将为该领域未来的转化研究奠定基础，这些研究必须开始考虑超出该领域大多数研究重点的特定化学和生物相互作用的问题。这项工作的高度跨学科性质，以及与一个专注于生物医学问题的实验小组的合作，将有助于为PI的研究小组成员提供出色的教育。这项工作还将为本科生和K-12学生提供教育机会。本科生将参与这项研究，PI和他的团队将与化学教育研究所和麦迪逊男孩女孩俱乐部合作，为K-12学生开发主题为：游泳微生物力学的教育材料。这些材料将包括教师的示范，以及孩子们可以建立自己的功能游泳工具包。

1132579PI: Michael D. GrahamThe behavior of blood cells in the circulation is complex, and although many important phenomena have been observed, the principles that underlie and couple these phenomena remain poorly understood. Understanding transport in flowing blood takes on additional significance in light of recent research into synthesis of particles for drug delivery. Advances in synthesis methods have led to recent attention to physical aspects such as size, shape and mechanical properties for drug delivery particle behavior. Rational design of blood-borne drug delivery particles can only occur with an understanding of how these particles will actually behave in the blood, but there is at present no predictive understanding of how drug delivery particles are distributed in the circulation. For example, the biological activity of a particle targeting the coronary artery walls will depend strongly on whether that particle tends to remain near blood vessel walls in flow or remains in the center of blood vessels where it does not interact with the blood vessel walls. The design principles for synthesizing a particle that remains near vessel walls (as, for example, a white blood cell tends to do) are not known. The overall goal of this work is to establish these principles, by accomplishing the following aims: (1) Use particle level simulations and analysis to predict the dynamics of drug carrier particles in flowing suspensions of red blood cells, and in particular the dependence of cross-stream migration and shear-induced diffusion on the size, shape and deformability of the particles; (2) Integrate these results with a transport modeling framework that enables systematic predictions of the distribution of particles in flowing blood; (3) Make comparisons between predicted results and experimental observations. These aims will be fulfilled by a concerted effort that integrates large scale, detailed simulations with a fundamental theoretical framework for understanding and predicting migration and margination phenomena. The work performed with this award will lead to concerted advances in complex fluids and drug delivery. It will break new ground in the study of multiphase complex fluids in general and the dynamics of blood flow in the microcirculation in particular. It addresses the physical dynamics of drug delivery particles in the blood and thus will be foundational for future translational research in the field, which necessarily must begin to consider issues beyond the specific chemical and biological interactions that have been the focus of most research in this area. The highly interdisciplinary nature of the work and collaboration with an experimental group focused on biomedical problems will contribute to an outstanding education for the members of the PI's research group. This work will also lead to educational opportunities for undergraduate and K-12 students. Undergraduate students will be involved in the research, and the the PI and his group will work with the Institute for Chemical Education and the Madison Boys and Girls Club to develop educational materials for K-12 students under the theme: Mechanics of swimming microorganisms. These materials will include demonstrations for teachers as well as kits with which children can build their own functioning swimmers.