Linking fluid-axons interactions to the macroscopic fluid transport properties of the brain.

Many brain disorders, including Alzheimer's Disease and Parkinson's Disease, and drug delivery procedures are linked to fluid transport in the brain; yet, while neurons are extremely soft and can be easily deformed, how the microscale channel flow interacts with the neuronal structures (especially axons) deformation and how these interactions affect the macroscale tissue function and transport properties is poorly understood. Misrepresenting these relationships may lead to the erroneous prediction of e.g. disease spread, drug delivery, and nerve injury in the brain. However, understanding fluid-neuron interactions is an outstanding challenge because the behaviours of both phases are not only dynamic but also occur at an extremely small length scale (the width of the flow channel is ∼100 nm), which cannot be captured by state-of-the-art experimental techniques. Here, by explicitly simulating the dynamics of the flow and axons at the microstructural level, we, for the first time, establish the link between micromechanical tissue response to the physical laws governing the macroscopic transport property of the brain white matter. We found that interactions between axons and the interstitial flow are very strong, thus playing an essential role in the brain fluid/mass transport. Furthermore, we proposed the first anisotropic pressure-dependent permeability tensor informed by microstructural dynamics for more accurate brain modelling at the macroscale, and analysed the effect of the variation of the microstructural parameters that influence such tensor. These findings will shed light on some unsolved issues linked to brain functions and medical treatments relying on intracerebral transport, and the mathematical model provides a framework to more realistically model the brain and design brain-tissue-like biomaterials. STATEMENT OF SIGNIFICANCE: This study reveals how neurons interact with the fluid flowing around them and how these microscale interactions affect macroscale transport behaviour of the brain tissue. The findings provide unprecedented insights into some unsolved issues linked to brain functions and medical treatments relying on intracerebral fluid transport. Furthermore, we, for the first time, established a microstructure-informed permeability tensor as a function of local hydraulic pressure and pressure gradient for the brain tissue, which inherently captures the dynamic transport property of the brain. This study is a cornerstone to advance the predicting accuracy of brain tissue transport property and neural tissue engineering.