Diffuse axon injury is a common trauma that affects the axons in the brain's white matter. Computational models of axons, both in isolation and within the matrix, have been developed to study this injury at cellular and tissue levels. However, axonal behaviour depends strongly on the mechanical properties of the surrounding matrix. Accurate material properties of axons and the matrix are essential for realistic modelling of their behaviour. This study characterises the hyper-viscoelastic properties of axons and their matrix for human brain tissue in two different white matter regions. First, previous experimental data on isolated axons under tension were used to determine their mechanical properties. Then, employing finite element analysis, neural networks, and optimisation methods, matrix properties were inferred using experimental data on human brain tissue behaviour under three shear modes at large deformations and varying strain rates. The results indicate that axons are approximately 10–13 times stiffer than the surrounding matrix, depending on the region. The material properties defined in this study provide an accurate representation of axonal and matrix behaviour under injurious conditions, as they are based on large-strain and high-strain-rate data. The constitutive model can be used for a more precise assessment of the injury threshold and the mechanisms of diffuse axon injury at the cellular level.

Diffuse axonal injury (DAI), characterized by widespread damage to axons throughout the brain, represents one of the most devastating and difficult-to-treat forms of traumatic brain injury. Different theories exist about the mechanism of DAI, among which one hypothesis states that membrane poration of the axons initiates DAI. To investigate the hypothesis, molecular models of axonal membranes, incorporating 25 different lipids distributed asymmetrically in the leaflets, were developed using a coarse-grain description and simulated using molecular dynamics techniques. Different protein concentrations were embedded inside the lipid bilayer to describe the different sub-cellular parts in myelinated and unmyelinated axons. The models were investigated in equilibration and under deformation to characterize the structural and mechanical properties of the membranes, and comparisons were made with other subcellular parts, particularly myelin. Employing a bottom-top approach, the results were coupled with a finite element model representing the axon at the cell level. The results indicate that pore formation in the node-of-Ranvier occurs at a lower rupture strain compared to other axolemma parts, whereas myelin poration exhibits the highest rupture strains among the investigated models. The observed rupture strain for the node-of-Ranvier aligns with experimental studies, indicating a threshold for injury at axonal strains exceeding 10–13 % depending on the strain rate. The results indicate that the hypothesis suggesting mechanoporation triggers axonal injury cannot be dismissed, as this phenomenon occurs within the threshold of axonal injury.