Motivation: The development of systematic drug delivery for brain disorders is a formidable challenge, and there is hardly any successful treatment protocol for the majority of neurodegenerative diseases. Data published by National Institutes of Health suggest that neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's disease affect millions of people worldwide. Targeted delivery of large macromolecules to specific locations in the brain is a challenging task in the treatment of neurodegenerative diseases of the Central Nervous System (CNS) owing to the presence of blood-brain barrier (BBB). In addition, the restriction offered by fibers of the white matter hampers the transport and metabolism of drugs at target areas and pose difficulty to catheter design and placement.

Methodology: In this presentation, we propose three innovations embedded into a hierarchical design procedure. The systematic approach to designing drug targeting faces three challenges and we aim to address them in this presentation: 1. Accurate three-dimensional reconstruction of the patient-specific brain geometry 2. Prediction of drug distribution in anisotropic heterogeneous brain tissue calibrated from in-vivo patient-specific diffusion tensor data 3. Quantification of infusate backflow in high flow micro-infusion regime The primary task is to accurately reconstruct the physiologically consistent three-dimensional patient-specific brain geometry. State of the art geometric image reconstruction tools are used to render and construct computational grids diffusion tensor magnetic resonance imaging data (DT-MRI). The second task is to predict distribution of therapeutic agents by accounting for anatomically consistent drug and tissue properties. With sophisticated calibration techniques, the anisotropic and heterogeneous effective diffusion and hydraulic perfusion tensors are calibrated and used in the first principles model. In addition, different catheter design such as single and multiple hole catheters are investigated based on volume of drug distribution. The computational model uses clinically relevant catheter designs and accounts for the fluid dynamics inside the catheter lumen. Proper boundary conditions are used to predict the distribution of high molecular weight trophic factor, glial derived neurotrophic factor (GDNF) infused into the putamen.

In high flow micro-infusion, backflow is a frequently occurring physical phenomenon and depends on the catheter design and infusion parameters. The first principles model accounts for the backflow mechanics and tissue deformation for a given choice of infusion and catheter design parameters in addition to considering anatomically consistent brain properties. Development of such a three dimensional holistic model applicable to a human brain will complement clinical trials.

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