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因，占美国死亡人数的17%。对这些疾病进行医学干预的一个主要限制因素是治疗药物通过血脑屏障(BBB)的运输。在动物和临床试验中，BBB已被证明在经颅聚焦超声(FUS)和微泡的存在下通过破坏紧密连接蛋白而瞬时开放。这为神经疾病的治疗干预提供了一条很有希望的途径。因此，这项为期一年的NSF/FDA学者驻留计划的目标是利用一系列细胞、微流体和体外(基于实验室)的血脑屏障模型，在细胞水平上研究FUS和微泡对血脑屏障的影响。从对FUS和微泡治疗反应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的治疗方案。体外血脑屏障模型可能成为FDA新提交的关于拟议程序的安全性和有效性的测试标准的另一种监管工具，并可用作快速评估的高通量模型。该项目还将在FDA和调查人员的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获得的经验来指导高中生、本科生和研究生。该项目专注于开发经过验证的模型，以了解聚焦超声(FUS)和微泡对血脑屏障(BBB)的基本细胞效应。虽然已知存在微泡的经颅FUS可以可逆地打开血脑屏障，并通过空间和时间控制促进治疗化合物的输送，但血脑屏障开放的详细物理和细胞机制尚未被研究，因此，监管机构很难理解与安全相关的问题。该研究计划旨在缩小这一差距，目标是提供对潜在生物效应的基本了解，并创建以诱导声应力的物理计算模型为支持的高通量体外BBB模型。这些目标将通过在多个体外装置中研究细胞现象来实现，每个装置都比以前更复杂，并提供新的信息。嵌入神经元的微流控装置将允许在生物相关的流动中进行生物效应研究。3D水凝胶支架也将被用来逼真地再现大脑的形态。最后，流体动力学模型和计算将被用来将FUS和微气泡动力学与引起生物效应的剪应力和微流流动联系起来。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.