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

职业：微循环血流中药物输送载体的对流和扩散运输

• 批准号: 0846293
• 负责人: Prosenjit Bagchi
• 金额: $ 47.96万
• 依托单位: Rutgers University New Brunswick
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0846293&HistoricalAwards=false
• 关键词: CAREER; Convective; Diffusive; Transport; Drug

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.

Bagchi0846293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对全血进行直接数值模拟，至少在微循环方面是这样。尽管问题很复杂，但许多研究小组已经成功地模拟了多个可变形血细胞在半致密悬浮液中的运动。利用这一进展，这项研究解决了药物载体在存在数百至数千个可变形血细胞的全血中的分散问题。靶向给药方法依赖于大分子和亚微米颗粒等载体，将新型治疗药物精确地携带到疾病部位。例如，它们在癌症诊断和治疗方面表现出了巨大的希望。一旦交付，这些载体通过对流和扩散运输通过血流，然后通过黏附分子与患病细胞结合。本研究将量化红细胞动力学(翻滚/坦克踩踏)在不同血液流变学条件下亚微米粒子分散中的作用，将结果与经典的Taylor-Aris分散理论进行比较，并确定最佳分散的载体尺寸和血液流变学条件。将对药物载体在全血中的分散进行直接数值模拟(DNS)，将其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。通过适当的介观流变学模型，可以高保真地解决单个血细胞的变形和非稳定动力学问题。流固耦合采用浸没边界法。将讨论聚合物与细胞的结合以及微球与维管壁的结合的平流、扩散和生物物理的同时作用。DNS技术将与亚微米粒子的拉格朗日跟踪、聚合物拉伸动力学的珠弹力链模型以及结合过程中分子相互作用的粗粒模型相结合。这项多学科研究将影响复杂流体流动、多相流和流固相互作用的预测，以及生物学和疾病(可能还有医学)的预测。计划中的计算和流体动力学研究将为设计具有更好的传输性能的下一代正常和病理血液药物载体提供理论基础。综合教育计划包括通过结合罗格斯大学两个迄今的独立项目(道格拉斯女性暑期学院和州长为有抱负的工程师而设的学校项目)，鼓励、招聘和指导PI研究领域的K11-K12女学生。它还包括本科生的研究经验，介绍一个跨学科的课程，并通过组织一个关于药物运输流体力学的小型研讨会来传播结果。