Gladwell Ryan A, Fisher Delaney G, Wythe Joshua D, Highley Christopher B, Lukens John R, Price Richard J
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, USA.
Department of Cell Biology, University of Virginia, Charlottesville, VA, 22908, USA.
Adv Sci (Weinh). 2025 Sep 4:e10684. doi: 10.1002/advs.202510684.
Focused Ultrasound (FUS) is the concentration of acoustic energy into a small region to produce therapeutic bioeffects. FUS-induced blood-brain barrier opening (BBBO), a strategy to deliver drugs and genes to the brain, also enhances glymphatic drainage, the brain-specific waste clearance system. Thus, FUS BBBO is a promising strategy for addressing the accumulation of neurotoxic solutes that are characteristic of many neurodegenerative diseases. However, the biotransport mechanisms by which FUS augments glymphatic drainage are not well understood. To address this knowledge gap, a 3D finite element COMSOL model of a single penetrating arteriole-venule vascular unit in the brain is engineered. The model predicts that i) FUS greatly improves waste clearance by increasing both diffusion and convection, ii) the convection-mediated movement of cerebrospinal fluid (CSF) and solute from the arteriole to the venule is largely dependent on the diffusion-mediated interactions between the solute, the medium through which it is moving, and CSF and iii) solutes more centralized to the CSF flow profile and that have a higher diffusion coefficient tend to clear more rapidly due to increased convection and enhanced diffusive mixing. The computational model can both inform therapeutic strategies and elucidate mechanisms of secondary responses to FUS BBBO.
