Annals of Biomedical Engineering, Vol. 34, No. 8, August 2006 ( C  2006) pp. 1304–1321 DOI: 10.1007/s10439-006-9135-3 Computational Model of Interstitial Transport in the Spinal Cord using Diffusion Tensor Imaging MALISA SARNTINORANONT, 1 XIAOMING CHEN, 1 JIANBING ZHAO, 1 and THOMAS H. MARECI 2 1 Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL 32611, and 2 Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32611 (Received 26 October 2005; accepted 12 May 2006; published online: 11 July 2006) Abstract—Local drug delivery methods, including convection- enhanced delivery (CED), are being used to increase distribution in selected regions of nervous tissue. There is a need for 3D models that predict spatial drug distribution within these tissues. A methodology was developed to process magnetic resonance microscopy (MRM) and diffusion tensor imaging (DTI) scans, segment gray and white matter regions, assign tissue transport properties, and model the interstitial transport of macromolecules. Fiber tract orientation was derived from DTI data and used to assign directional dependence of hydraulic conductivity, K, and tracer diffusivity, D t , transport tensors. Porous media solutions for interstitial fluid pressure, velocity, and albumin distribution were solved using a finite volume method. To test this DTI-based methodology, a rat spinal cord transport model was developed to simulate CED into the dorsal white matter column. Predicted distribution results correspond well with small volume ( ∼ 1 µl) trends found experimentally, although albumin loss was greater at larger infusion volumes (>2 µl). Simulations were similar to those using fixed transport properties due to the bulk alignment of white matter fibers along the cord axis. These findings help to validate the DTI-based methodology which can be applied to modeling regions where fiber tract organization is more complex, e.g., the brain. Keywords—Diffusion-weighted imaging, DT-MRI, Mathemati- cal model, Convection-diffusion, Direct infusion, Interstitial flow. Abbreviations CED convection-enhanced delivery MRM magnetic resonance microscopy DTI diffusion tensor imaging FEM finite element method PBS phosphate buffered saline DWI diffusion-weighted imaging NURBS non-uniform rational B-spline surfaces CSF cerebrospinal fluid Address correspondence to Malisa Sarntinoranont, Department of Mechanical and Aerospace Engineering, University of Florida, 212 MAE-A, PO Box 116250, Gainesville, FL 32611-6250. Electronic mail: sarntm@ufl.edu INTRODUCTION With the development of promising therapeutic agents for chronic pain, spinal injury, and other neurodegener- ative diseases, local drug delivery methods 12 , 28, 30, 46, 49 are increasingly being considered as a solution to over- coming transport barriers encountered by macromolec- ular, slow-diffusing drugs (e.g., nerve growth factor with an apparent diffusion coefficient in brain tissue of ∼ 2.8 × 10 −7 cm 2 /s 53 ). One such local drug delivery method is convection enhanced delivery (CED), an in- vestigational surgical technique designed to bypass the blood-brain and blood-spinal cord barrier. 12, 30 , 31 , 46 By this method, a small diameter cannula is inserted directly in the tissue and the drug infusate is pumped out of the tip of the cannula and transported through the surrounding in- terstitial (extracellular) space by convection and diffusion. Previous infusion studies have shown CED into specific regions of the brain, spinal cord, and peripheral nerves to be reproducible and clinically safe. 12 , 14 , 29 –32, 59 Macro- molecular distributions were shown to be homogeneous and over larger volumes than could be attained by diffusion alone. Rational design of such regional therapy will require new tools to evaluate drug transport issues specific to ner- vous tissue physiology. In addition to anatomical boundary concerns, macromolecular tracer distribution can be sig- nificantly influenced by the site of delivery and flow of extracellular fluid along white matter tracts. 1, 12, 31 Previous models of local interstitial transport have been developed for nervous tissue using porous media assumptions. Morrison et al. successfully modeled high- flow microinfusion of 180 kDa macromolecules at rates of 0.5–6.0 µl/min in homogenous brain tissue, e.g., gray matter. 40 Kalyanasundaram et al. simulated the controlled release of drug from an implant in rabbit brain. 24 Diffusion, convection (due to vasogenic edema), and metabolism and clearance of interleukin-2 were modeled using a two-dimensional finite element method (FEM) model formulated using a single image slice of the brain. While capturing characteristics of controlled release, the model 0090-6964/06/0800-1304/0 C  2006 Biomedical Engineering Society 1304