Articles techniques et présentations

The brain is a heterogeneous porous medium with regions of anisotropy. Measurements of tortuosity (λ) showed that diffusion in gray matter (e.g. striatum) is isotropic (λ = 1.65), whereas it is anisotropic in white matter (e.g. corpus callosum) (λparallel = 1.38, λperpendicular = 1.80)[1-2]. Pressure-driven convection-enhanced delivery (CED) of macromolecules (e.g. drugs) was first described in the mid-90s to introduce high concentration of macromolecules into cat brain[3]. It was successful in delivering significantly higher volume of molecules to the brain than by diffusion alone. However, it was limited by several factors, including backflow of infusate of implanted tracts, edema, and lack of directional control[4-5]. Fluid and infused molecules have a tendency to travel to regions of higher permeability, e.g. along the axonal projections of corpus callosum rather than perpendicular through them. This makes any pressure infusions into low permeability regions, e.g. dorsal-ventral delivery across the corpus callosum, a difficult task. We developed an electrokinetic convection-enhanced delivery (Ek-CED) method in order to address some of these limitations. The main difference between the two methods is the driving force: Ek-CED uses an external electric field to drive fluid flow rather than pressure. As there are various complex processes taking place during this infusion process, a mathematical model is required for experimentalists to understand and implement the technique without performing costly experiments. Thus, we developed a brain model that includes that anisotropic nature of the corpus callosum by using a curvilinear coordinate system. The model uses the Electric Currents, Free and Porous Media Flow, and Transport of Diluted Species in Porous Media interfaces in COMSOL Multiphysics® software. Infusion of anionic fluorophore over 5 hours was simulated from a source capillary located in the cortex to a collection capillary in the striatum, passing perpendicular through the corpus callosum. We used calculations as a guide to determine optimal currents for infusion, the minimum time required for samples to reach the collection capillary, and whether or not directionality can be controlled. Calculations, along with experiments, show that while there is still some delivery along the axonal tract, there is a significant improvement in direction-controlled delivery to the striatum.