CAREER: Defining the interplay between hemodynamics and shape/size in particle localization to the vascular wall - an integrated in vitro and in vivo study

职业：定义血管壁颗粒定位中的血流动力学和形状/大小之间的相互作用 - 一项体外和体内综合研究

• 批准号: 1054352
• 负责人: Omolola Eniola-Adefeso
• 金额: $ 40万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1054352&HistoricalAwards=false
• 关键词: CAREER; Defining; interplay; between; hemodynamics

This CAREER award will lead research in which a combination of in vitro and in vivo assays will used to systematically explore how shape and size dictates particle margination (localization and adhesion) dynamics in complex blood flow typical of medium and large blood vessels (M/LBVs). To date, limited attention has been given to how the interplay between particle shape/size and hemodynamics that prescribe the margination of vascular-targeted carriers to the vascular wall. While its effect may be minimal in capillaries, hemodynamics must be an important consideration in the design of drug carriers for application in M/LBVs involved in several human diseases. For example, atherosclerosis, the leading cause of death among adults in the US, is a multistage disease of M/LBVs (arteries). Improvements to the current treatments for atherosclerosis, statins therapy or bypass surgery, are necessary since, for instance, acute coronary events can still occur in 50-70% of patients on statins. Targeting drugs to the vascular wall via inflammation associated with atherosclerosis could provide a more viable approach for treating this disease. Yet, nanospheres typically proposed as vascular-targeted carriers have recently been shown to not be effective in localizing to the wall in M/LBVs. Larger microspheres that have a hemodynamic advantage for binding, however, can cause occlusion in capillaries. One approach to addressing this issue is a paradigm shift away from the spherical shape. The PI hypothesizes that spheroids would better marginate to the valscular wall in M/LBVs due to their complex hemodynamic interactions. Thus, the PI will characterize the in vitro margination spheroids in complex blood flow, and determine their in vivo efficacy. Since the PI?s research activities are driven by core chemical engineering (ChE) principles, it allows for the integration of her research into ChE education at all levels. Thus, this CAREER proposal will link the PI?s research activities to her educational program by (i) using her research to show ChE sophomores in the material and energy balance course how the knowledge of core ChE principles can be pieced together to solve important health problems and (ii) exposing graduate students to new knowledge created from this CAREER award in her ?Drug Delivery and Targeting? graduate course, and (iii) providing mentored research opportunities to underrepresented minority (URM) women in engineering. The PI is also developing a novel ?each-one-teach-one? multi-year on-campus K-12 outreach program focused on boosting the undergraduate enrollment of students of all backgrounds in engineering, where a cohort of students from a local school district are exposed to ChE concepts via undergraduate class projects.

该职业奖将引导研究，结合体外和体内试验，系统地探索形状和大小如何决定中、大血管（M/LBVs）典型复杂血流中的颗粒边缘（定位和粘附）动力学。迄今为止，很少有人关注颗粒形状/大小与血流动力学之间的相互作用，这些相互作用决定了血管靶向载体向血管壁的边界。虽然它在毛细血管中的作用可能很小，但在设计用于几种人类疾病的M/ lbv的药物载体时，血液动力学必须是一个重要的考虑因素。例如，动脉粥样硬化是美国成年人死亡的主要原因，是一种多阶段的M/LBVs（动脉）疾病。对目前动脉粥样硬化的治疗方法进行改进，他汀类药物治疗或搭桥手术是必要的，因为，例如，50-70%的他汀类药物患者仍可能发生急性冠状动脉事件。通过与动脉粥样硬化相关的炎症将药物靶向血管壁可能为治疗这种疾病提供更可行的方法。然而，纳米球通常被认为是血管靶向载体，最近被证明不能有效地定位到M/ lbv的壁上。然而，较大的微球具有结合的血流动力学优势，可能导致毛细血管闭塞。解决这个问题的一种方法是从球形转变为范式。PI假设椭球体由于其复杂的血流动力学相互作用而更好地边缘到M/LBVs的瓣膜壁。因此，PI将表征复杂血流中的体外边缘球体，并确定其体内功效。自从PI之后？她的研究活动以化学工程（ChE）的核心原则为驱动，这使得她的研究能够融入到各级化学工程教育中。因此，此CAREER提案将连接PI？她的研究活动与她的教育计划相结合，通过(i)利用她的研究向材料和能量平衡课程的ChE大二学生展示如何将核心原理的知识整合在一起来解决重要的健康问题，以及（ii）向研究生展示她的职业生涯奖所创造的新知识。药物递送和靶向？研究生课程，以及（iii）为工程领域未被充分代表的少数族裔（URM）女性提供指导研究机会。PI还在开发一本名为“一对一教学”的小说。多年的校园K-12外展计划侧重于提高所有工程背景学生的本科入学率，来自当地学区的一群学生通过本科课程项目接触到ChE概念。