Transport of cells and drug delivery particles in blood flow

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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.