(489i) Convection Enhanced Drug Infusion into the Soft Brain Tissue

Many diseases of the Central Nervous System (CNS) require treatment by novel drugs and special techniques (e.g. viral vector). However, the efficiency of the treatment may be hampered by the lack of methods to administer the drug in regions of the brain in therapeutically effective concentration range. The difficulty to deliver drugs in the brain is due to Brain Blood Barrier (BBB) that prohibits large molecules to pass through the capillary bed into the brain. Invasive drug delivery techniques aim at overcoming the BBB by directly injecting large molecules into the brain parenchyma by a catheter. Recently there is interest for treating diseases of CNS with such invasive techniques.

Delivery of drugs by diffusion only does not provide an effective penetration depth. Convection enhanced drug delivery on the other hand has been proven effective to substantially increase the penetration depth creating a core of high concentration sufficient for many drug therapies [1]. However, there is still a need of engineering such therapies due to the lack of understanding the drug transport processes into the brain with diffusion and convection. Currently there is a lack in understanding of the micro-transport properties and the force interactions between the fluid field and the brain tissue. The diffusion coefficient and tortuosity of the extracellular space are unknown parameters that have to be considered.

In an effort to systematically design catheters and invasive drug therapies we propose to quantify the interaction of the drug and its transport in the parenchyma using a first principles model. This study describes the flow of the drug in the porous medium using consolidation theory that accounts for the interaction of the cell matrix as a solid skeleton and the dissolved drug in a bulk medium. We propose to overcome the complex geometry of the human brain by integrating imaging techniques with computational fluid mechanics methods. As a result, we are able to resolve very accurately the brain geometry and render physiologically consistent the distribution of the complex brain inner organization. We distinguish between gray and white matter and assign transport properties of relevance according to the data obtained by MR images. This approach is capable to resolve the anisotropic brain tissue properties such as permeability and the directionality along the strands of the oriented axons in the white matter. It will be shown that the treatment of the brain with physiologically consistent transport coefficients (diffusivity and porosity) is necessary to render an accurate picture of the drugs concentration field. However, the improvement of the drug therapeutic volume by convective field is limited by the stresses and strains sustainable by the brain tissue. Therefore, very large convective fields may injure the tissue and must be avoided.

Current approaches predict the actual stress-strain of the brain tissue under the assumption of a porous cell matrix. The proposed model is capable of predicting the deformation of the cell matrix under the fluid traction consistent with clinical observations. We would like to quantify the adverse effect of the drug seeping upwards the catheter tip (leak-back) [2]. With the proposed approach we are able to predict deformations of the cell matrix and the drug concentration in the presence of these fluid-structure interactions in the human brain.

[1] Morrison, P.F., Laske, D.W., Bobo, H., Oldfield, E.H., Dedrick, L.R., ?High-flow microinfusion: tissue penetration and pharmacodynamics?, American Journal of Physiology, 266, R292-R305, 1994.

[2] Chen, M. Y, Lonser, R. R, Morrison, P. F, Governale, L. S, Oldfield, E. H, ?Variables affecting convection-enchanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time?, Journal of Neurosurgery, 90, 315-320, 1999.