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Infusion Mechanisms in Brain White Matter and its Dependence of Microstructure: An Experimental Study of Hydraulic Permeability

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Infusion-based drug delivery therapies use advective transport to rapidly deliver drugs to target sites, and can enhance efficiency of drug delivery several fold. The characteristics of the flow around the injection site are highly dependent on the local hydraulic permeability of the tissue. Previous characterisations of white matter (WM) hydraulic permeability typically rely on theoretical models or unconfined compression, and have yielded results that vary by up to three orders of magnitude.

Here we present the first experimental study to directly measure the hydraulic permeability of WM of infused fresh ovine brain. We constrain brain samples within a cylindrical holder and directly infuse fluid using the iPerfusion system, which provides high precision flow and pressure data that can be used to calculate permeability. We investigate the dependence of the permeability on i) infusion pressure, ii) the alignment between the flow direction and the orientation of the axonal fibres and iii) the effect of post-mortem time.

Our results indicate a significant anisotropy in the hydraulic permeability, with average values almost three times smaller when the flow direction was perpendicular to the axonal fibres, compared to parallel. The data also indicate a significant dependence of hydraulic permeability on pressure, a factor that has not typically been considered. Although there was no correlation between hydraulic permeability and post-mortem time, tissue degradation significantly affected our ability to measure hydraulic permeability beyond 11h post-mortem.

These directly measured experimental data provide a reference frame for theoretical models of WM permeability and can act as inputs for numerical models of drug transport. These results contribute to the development of realistic mechanical models of brain and can be used to optimise the infusion-based technologies for treatment of lethal tumours in brain, such as convection-enhanced delivery, and other infusion-based drug delivery techniques.

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