Computational Fluid Dynamic Model Prediction of Focused Ultrasound-Enhanced Glymphatic Clearance

Focused Ultrasound (FUS) is the concentration of acoustic energy into a small region to produce therapeutic bioeffects via thermal or mechanical energy delivery. This technology has demonstrated ameliorative potential for a myriad of pathologies, including metastatic cancers, neurological motor disorders, and neurodegenerative diseases. FUS-induced blood-brain barrier opening (BBBO) has been shown to enhance glymphatic drainage, the brain-specific waste clearance pathway, and therefore represents a promising strategy for addressing the accumulation of neurotoxic solutes that is characteristic of many neurodegenerative diseases like Alzheimer's. It may also represent a compelling strategy to accelerate brain tumor antigen draining to meninges, which could trigger T cell priming, activation, and immunological tumor control. Here, we set out to define the biotransport mechanisms by which FUS produces a therapeutic effect on glymphatic drainage by engineering a 3D finite element COMSOL model of a single penetrating arteriole-venule vascular unit in the brain. This computational model, which takes in vivo literature values as inputs and produces flux and flow profiles as outputs, has produced insights into glymphatic waste clearance and FUS BBBO-mediated effects in the brain. Specifically, FUS BBBO causes spatially diverse changes that enhance the glymphatic system by increasing both convective and diffusive flux. This model can be used to optimize FUS parameterization and can increase clinician confidence in this emerging therapeutic.