CAREER: Convective and Diffusive Transport of Drug Delivery Vehicles in Blood Flow in Microcirculation

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。高性能计算的进步使科学界能够朝着全血的直接数值模拟发展，至少在微循环方面。尽管问题很复杂，但许多研究小组已经成功地模拟了半稠密悬浮液中多个可变形血细胞的运动。利用这一进展，这项研究解决了在数百至数千个可变形血细胞存在下药物载体在全血中的分散问题。 靶向药物递送方法依赖于载体，如大分子和亚微米颗粒，以将新型治疗剂精确地携带到疾病部位。例如，它们在癌症诊断和治疗方面显示出巨大的前景。一旦被递送，这些载体通过对流和扩散运输在血流中移动，然后通过粘附分子与患病细胞结合。本研究将量化的作用，红细胞动力学（翻滚/坦克踩踏）在不同的血液流变学条件下的亚微米颗粒的分散，比较结果与经典的泰勒-阿里斯分散理论，并确定载体的大小和血液流变学条件下的最佳分散。将对全血中的药物载体分散进行直接数值模拟（DNS），该全血表示为在微血管中流动的多达1000个可变形血细胞的半致密悬浮液。 个体血细胞的变形和非稳态动力学将通过适当的介观流变模型以高保真度解决。流体/结构耦合将通过浸没边界方法进行。同时平流，扩散和生物物理学的结合的聚合物上的细胞，和微球上的血管壁的作用将得到解决。DNS技术将与亚微米颗粒的拉格朗日跟踪、聚合物拉伸动力学的珠-弹簧链模型和结合过程中分子相互作用的粗粒模型相结合。 多学科研究将影响复杂流体流动，多相流动和流体-固体相互作用，以及生物学和疾病（以及潜在的医学）的预测。这里计划的计算和流体动力学研究将为设计具有改善传输性能的正常和病理血液的下一代药物载体提供理论基础。一项综合教育计划包括鼓励、招募和指导PI研究中的K11-K12女学生，方法是将罗格斯大学的两个独立项目（道格拉斯妇女暑期研究所和州长学校有抱负的工程师项目）结合起来。它还包括本科生的研究经验，介绍了跨学科课程，并通过组织一个小型研讨会的药物运输流体力学的结果传播。

Bagchi0846293 This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). Advances in high-performance computing have enabled the scientific community to progress toward the Direct Numerical Simulation of whole blood, at least in microcirculation. Despite the complexity of the problem, many research groups have succeeded in simulating the motion of multiple deformable blood cells in semi-dense suspension. Leveraging on this progress, this research addresses dispersion of drug-carriers in whole blood in presence of hundreds to thousands of deformable blood cells. Targeted drug delivery methods rely on carriers such as macromolecules and submicron particles to carry novel therapeutic agents precisely to disease location. They have shown great promise, for example, in cancer diagnosis and treatment. Once delivered, these carriers move through the bloodstream via convective and diffusive transport, and then bind to the diseased cells via adhesion molecules. This study will quantify the role of red blood cell dynamics (tumbling/tank-treading) in the dispersion of submicron particles under varying hemorheological conditions, compare the results with the classical Taylor-Aris theory of dispersion, and identify carrier size and hemorheological conditions for optimal dispersion. Direct Numerical Simulation (DNS) will be conducted on drug-carrier dispersion in whole blood represented as a semi-dense suspension of up to 1000 deformable blood cells flowing in a microvessel. Deformation and unsteady dynamics of individual blood cell will be resolved with high fidelity by appropriate mesocopic rheological models. The fluid/structure coupling will be done by an immersed boundary method. The simultaneous role of advection, diffusion, and biophysics of binding of a polymer on to a cell, and of a microsphere on to the vascular wall will be addressed. The DNS technique will be coupled with Lagrangian tracking of submicron particles, the bead-spring chain model for polymer stretching dynamics, and a coarse-grain model for molecular interaction during binding. The multidisciplinary research will impact prediction of complex fluid flows, multi-phase flows and fluid--solid interaction, and biology and disease (and potentially medicine). The computational and fluid dynamic research planned here will provide a theoretical basis for design of next-generation drug-carriers for normal and pathological blood with improved transport properties. An integrated educational plan includes encouraging, recruiting, and mentoring women students from K11-K12 in PI's research by coupling two till-date independent programs at Rutgers (Douglass Summer Institute for women, and Governor's School program for aspiring engineers). It also includes research experience for undergraduates, introduction of a cross-disciplinary course, and dissemination of results by organizing a mini-symposium on fluid mechanics of drug transport.