Anisotropic Diffusion of Flexible Random-Coil Polymers Measured in Brain Extracellular Space by Integrative Optical Imaging

1. Introduction In brain regions containing numerous parallel fibers, extracellular diffusion is anisotropic, i.e. faster along the fibers than across them, implying a preferential pathway for the transport of molecules in the extracellular space (ECS) [1,2]. To date, anisotropic diffusion in the ECS was measured with real-time iontophoretic method employing the small ion, tetramethylammonium (MW 74) [1,3,4] or with a FRAP-based technique using fluorophore-labeled dextran (MW 70,000) [5]. However, the ECS accommodates the diffusion of many endogenous macromolecules, and it is the exclusive route for interstitial transport of polymer-based drug carriers, therapeutic proteins, and virus-enclosed genes. To study how polymers of different sizes behave in an anisotropic ECS, we used integrative optical imaging (IOI) [6] to measure the diffusion of flexible random-coil dextran polymers (MW 3,000-cerebellum (Fig. 1).