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

这项职业奖将领导一项研究，该研究将结合体外和体内分析，系统地探索形状和大小如何决定中型和大型血管(M/LBV)典型的复杂血流中颗粒边际(定位和粘连)动力学。到目前为止，对颗粒形状/大小和血流动力学之间的相互作用如何规定血管靶向载体到血管壁的边缘的关注有限。虽然它对毛细血管的影响可能很小，但在设计药物载体时，血流动力学必须是一个重要的考虑因素，以应用于涉及多种人类疾病的M/LBVS。例如，动脉粥样硬化是美国成年人死亡的主要原因，它是一种多阶段的M/LBVS(动脉)疾病。改善目前的动脉粥样硬化治疗方法、他汀类药物治疗或搭桥手术是必要的，因为，例如，服用他汀类药物的患者中仍有50%-70%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一种更可行的方法。然而，通常被认为是血管靶向载体的纳米球最近被证明在定位到M/LBV的壁上并不有效。然而，更大的微球具有结合血流动力学的优势，可能会导致毛细血管闭塞。解决这个问题的一种方法是从球形转变为范式。PI假说M/LBVS中，由于其复杂的血流动力学相互作用，球体将更好地贴近瓣膜壁。因此，PI将表征复杂血流中的体外边集球体，并确定其在体内的疗效。由于皮？S的研究活动是由核心化学工程(CHE)原则驱动的，因此可以将她的研究整合到各级CHE教育中。因此，这份职业建议书将通过以下方式将皮？S的研究活动与她的教育计划联系起来：(I)利用她的研究向物质与能量平衡课程的CHE大二学生展示如何将核心CHE原理的知识拼凑在一起，以解决重要的健康问题；(Ii)让研究生在她的职业生涯奖中接触到从这个职业奖项中创造的新知识？药物输送和靶向？提供研究生课程，以及(Iii)为工程学中代表性不足的少数群体(URM)妇女提供指导研究机会。少年派还在开发一部小说？一本教一本？多年期校园K-12推广计划的重点是增加工程专业所有背景的学生的本科生入学人数，来自当地学区的一批学生通过本科生课程项目接触到CHE概念。

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.