On the microstructural origin of brain white matter hydraulic permeability

Abstract

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.

On the microstructurally driven heterogeneous response of brain white matter to drug infusion pressure

“…Furthermore, the geometry of axon was also simplified. The mathematical model in this paper can be combined with realistic brain microstructure reconstructed from microscopic images (Bernardini et al 2021;Vidotto et al 2021) to further improve the model accuracy.…”

Insights into Infusion-Based Targeted Drug Delivery in the Brain: Perspectives, Challenges and Opportunities

“…Biomechanically, it can be broadly characterised by the stiff directional axons wrapped in insulating lipid-rich layers (myelin) that are supported by a soft matrix composed of glial cells and a network of biopolymers, the extracellular matrix (ECM). The directional axons can be a mechanical obstacle to drug diffusion and spatial distribution in the CNS tissue [ 18 , 19 ]. The presence of elongated axons can compel the drug particles to diffuse around fibre-like obstructions, hence the increased tortuosity and reduced effective diffusion.…”

“…Only a recent study on fixed tissue of sheep brain has revealed localised microstructural differences such as axon volume fractions and geometry in specific regions, i.e., the corpus callosum, corona radiata and fornix of CNS [ 58 ]. Appreciating this fact, Vidotto et al [ 19 ] used a computational approach and found a significant difference between hydraulic permeability in the corpus callosum and fornix. Using 3D reconstructed microstructure from electron microscopy images, they computed the corresponding permeability considering the tissue structure is mainly composed of directional axons.…”

“…Furthermore, the existing trend in the literature can also be attributed to the absence of evidence that heterogeneities in the micromechanical environment affect flow behaviour. However, this has been recently provided by our experimental [ 18 ] and computational studies [ 19 ]. The emerging evidence of the microstructurally driven heterogeneous response of brain white matter to infusion pressure due to the deformability of axons and ECM strengthens the idea of modifying the traditional Darcy’s law and adopting a multiscale approach [ 75 ].…”

“…While assuming localised homogeneity and isotropy agrees well with geology experiments [ 148 ], the same hypothesis may not applicable for brain tissues [ 18 ]. To achieve more accurate outcomes, it is worth moving to a microscopic scale in order to analyse the interaction between the hydraulic pressure and microstructures, which also raise the need for a reconstruction method with higher resolution imaging techniques [ 19 , 58 ]. It is also worth mentioning the mathematical models for backflow simulation here.…”