Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 36, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2105328118
Keywords
brain tissue; hydraulic permeability; computational fluid dynamics; convection-enhanced delivery; imaging
Categories
Funding
- Engineering and Physical Sciences Research Council Established Career Fellowship [EP/N025954/1]
- European Union [688279]
- EPSRC [EP/N025954/1] Funding Source: UKRI
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The study analyzes the hydraulic permeability of two white matter areas and finds significant anisotropic behavior and permeability differences, indicating the importance of considering white matter heterogeneity in brain drug transport modeling. These findings not only contribute to drug delivery modeling but also shed light on interstitial transport mechanisms in the brain's extracellular space.
Brain microstructure plays a key role in driving the transport of drug molecules directly administered to the brain tissue, as in Convection-Enhanced Delivery procedures. The proposed research analyzes the hydraulic permeability of two white matter (WM) areas (corpus callosum and fornix) whose three-dimensional microstructure was reconstructed starting from the acquisition of electron microscopy images. We cut the two volumes with 20 equally spaced planes distributed along two perpendicular directions, and, on each plane, we computed the corresponding permeability vector. Then, we considered that the WM structure is mainly composed of elongated and parallel axons, and, using a principal component analysis, we defined two principal directions, parallel and perpendicular, with respect to the axons' main direction. The latter were used to define a reference frame onto which the permeability vectors were projected to finally obtain the permeability along the parallel and perpendicular directions. The results show a statistically significant difference between parallel and perpendicular permeability, with a ratio of about two in both the WM structures analyzed, thus demonstrating their anisotropic behavior. Moreover, we find a significant difference between permeability in corpus callosum and fornix, which suggests that the WM heterogeneity should also be considered when modeling drug transport in the brain. Our findings, which demonstrate and quantify the anisotropic and heterogeneous character of the WM, represent a fundamental contribution not only for drug-delivery modeling, but also for shedding light on the interstitial transport mechanisms in the extracellular space.
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