NSF/FDA SIR: Focused ultrasound and microbubbles for transport of therapeutics across blood brain barrier: A cellular model

神经系统疾病是第二大死亡原因，占美国死亡人数的17%。对这些疾病进行医学干预的主要限制因素是治疗剂通过血脑屏障（BBB）的运输。在动物和临床试验中，经颅聚焦超声（FUS）和微泡通过破坏紧密连接蛋白，已显示BBB短暂开放。这为神经系统疾病的治疗干预提供了一条有前途的途径。因此，这个为期一年的NSF/FDA奖学金计划的目标是使用一系列BBB的细胞，微流体和体外（基于实验室）模型在细胞水平上研究FUS和微泡对BBB的影响。 从对FUS和微泡治疗的细胞机制的详细研究中获得的基本理解可以帮助科学家和临床医生为患者开发更有效和安全的神经系统疾病和障碍治疗方案。体外血脑屏障模型可能成为另一种监管工具，用于测试新的FDA申报文件中概述的标准，以确定拟议程序的安全性和有效性，并可用作快速评估的高通量模型。 该项目还将在FDA和研究者实验室之间建立强有力的合作，并为博士后学者提供独特的培训经验，后者将利用在FDA获得的经验指导高中，该项目的重点是开发有效的模型，以了解聚焦超声（FUS）和微泡对血脑屏障（BBB）的基本细胞效应。 尽管已知在微泡存在下的经颅FUS可逆地打开BBB并促进具有空间和时间控制的治疗化合物的递送，但尚未研究BBB打开的详细物理和细胞机制，因此，监管机构难以理解安全性相关问题。 该研究计划旨在缩小这一差距，其目标是提供对潜在生物效应的基本理解，并创建由诱导声应力的物理计算模型支持的高通量体外BBB模型。这些目标将通过在多个体外设置中研究细胞现象来实现，每个设置都比之前的设置更复杂，并提供新的信息。具有嵌入式神经元的微流体设置将允许在生物相关流中进行生物效应调查。3D水凝胶支架也将用于真实地再现大脑形态。最后，流体动力学模型和计算将被用来与FUS和微气泡动力学的剪切应力和微流造成的bioeffects.This奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

Neurological diseases are the second leading cause of death accounting for 17% of deaths in the US. A major limiting factor for medical interventions with these disorders is the transport of therapeutics past the blood brain barrier (BBB). The BBB has been shown to open transiently in presence of transcranial focused ultrasound (FUS) and microbubbles by disrupting the tight-junction proteins in animal and clinical trials. This offers a promising pathway for therapeutic interventions for neurological disorders. Thus, the goal of this one year NSF/FDA Scholar-in-Residence program is to investigate the effects of FUS and microbubbles on the BBB on a cellular level using a series of cell, microfluidic, and in vitro (lab based) models of the BBB. The fundamental understanding that is gained from the detailed study of the cellular mechanisms in response to FUS and microbubble treatments can help scientists and clinicians develop more effective and safe treatment options of neurological diseases and disorders for patients. The in vitro BBB model can potentially become another regulatory tool to test criteria outlined in new FDA submissions for the safety and efficacy of the proposed procedures and can be used as a high-throughput model for fast evaluation. The project will also establish a robust collaboration between the FDA and the Investigator’s lab and provide a unique training experience for a postdoctoral scholar who will in turn use experiences gained at the FDA to mentor high school, undergraduate and graduate students.This project is focused on developing validated models to understand the fundamental cellular effects of focused ultrasound (FUS) and microbubbles on the blood brain barrier (BBB). Though transcranial FUS in the presence of microbubbles is known to reversibly open the BBB and facilitate the delivery of therapeutic compounds with spatial and temporal control, the detailed physical and cellular mechanism of the BBB opening has not been studied, and as a result, it is difficult for regulatory agencies to understand safety-related issues. The research plan is aimed at closing this gap, with goals of providing a fundamental understanding of the underlying bioeffects and creating a high-throughput in vitro BBB model backed by a physical computational model of induced acoustic stresses. These goals will be achieved by investigating the cellular phenomena in multiple in vitro setups, each more complex than the one before and offering new information. A microfluidic setup with embedded neurons will allow bioeffects investigation in biologically relevant flows. A 3D hydrogel scaffold will also be used to realistically recapitulate the brain morphology. Finally, fluid dynamics models and computation will be used to relate the FUS and microbubble dynamics to the shear stresses and microstreaming flows causing the bioeffects.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.