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

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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.