Motivation for Improved Drug Delivery Treatment of a wide variety of neurological diseases.

1. Visualization Grid Generator Numerical Solver Governing Equations for flow through Porous Brain Parenchyma Continuity X-Momentum for Porous medium flow Y-Momentum for Porous medium flow Species (Drug) Conservation INPUTS CONVECTION ENHANCED DRUG DELIVERY INTO THE HUMAN BRAINMahadevaBharath R. Somayaji, Michalis Xenos, Srinivasa Kondapalli, Richard Penn* and Andreas A. LinningerLaboratory for Product and Process Design Department of Chemical Engineering, University of Illinois at Chicago(* in collaboration with University of Chicago) Motivation Blood Brain Barrier Schematic of a Brain Tumor Blood Brain Barrier (BBB) • Motivation for Improved Drug Delivery • Treatment of a wide variety of neurological diseases. • Neurological diseases range from brain tumors, epilepsy to Parkinson’s and Alzheimer’s disease. • More than 80 million people are affected with these diseases (NIH Data). • Large Proteins with therapeutic efficacy cannot be delivered to targeted areas as they do not pass the BBB. • In order to circumvent the BBB, the drugs are directly injected into the brain using catheters using Convection enhanced delivery. • CFD techniques give insight into the best infusion policy and drug distribution for a therapeutic drug specific to a localized target without clinical trails. • Brain Tumors • Brain Tumors are hard to treat due to the presence of BBB. • Recent attempts employed to circumvent the BBB include direct injection techniques. • However, the transport mechanism is not well understood. • The types of brain tumors include benign and malignant tumors. • Types of Drug Administration Techniques • Invasive Techniques: Drug administration using catheters (by direct injection) (E.g. Intracerebroventricular infusion and Intracerebral Implants) • Non-Invasive Techniques: Drug Administration using Carrier-Mediated Transport (E.g. Lipidization, Peptide Technology and Protein Cationization methods) • BBB is formed by a network of thin capillaries that protects • the brain from harmful substances. • The BBB is thus impermeable to certain antibiotics • and high molecular weight drugs (inulin, sucrose, • catecholamine). • The main interest lies in developing invasive strategies • to overcome BBB and deliver drugs to CNS for • treatment of diseases. Model Details Mathematical Model MRI-Computational Interface Steps Involved • Transport of the drug in the porous brain parenchyma is by diffusion and convection • The drug chosen in the simulation is a phantom mimicking real drug properties • Steady State simulations are presented • Finite Volume Discretization is used • Patient-Specific approach for rendering accurate brain geometry adopted (novel approach) • Single and multiple hole catheters are used to treat targeted cells. We propose to deploy CED using multiple hole catheters to achieve greater treatment volumes • The effect of white matter anisotropy is important in studying the drug distribution • Trade off in using Bulk Flow • Leak back of infusate near the catheter tip • Cavity or edema formation near the injection area • Toxicity formation as a result of cavity formation • The limit of convective flow is dictated by the porous material properties (porosity and permeability) and the molecular weight of the drug itself. Contours of Velocity Magnitude Additional Pressure drop term Contours of Species Concentration Additional Pressure drop term Image Reconstruction of the cortex Drug diffusion in 3D in the cortex Boundary Conditions Catheter (Direct Injection) GM- Gray Matter Catheter holes WM- White Matter 2D Idealized Brain Geometry Multiple Hole Catheters in 3D Brain Geometry B- Ventricular Interface Case Study: Effect of Bulk Flow on Penetration Depth Effect of White Matter Anisotropy Effect of Infusate Volume Effect of Drug Concentration Penetration Depth - Computed Drug and Porous Media Properties • The White matter consists of axons. • The axonal fibers are oriented that induces • directionality to bulk flow and diffusion. The • white matter is highly anisotropic • Drug Concentration directly influences the penetration depth. However, the toxicity levels have to taken care off. • At higher infusate flow rates, the penetration depth • increases. • Large treatment volumes of the brain could be achieved. • For injection in gray matter, for very high infusate flow rates • specified at the catheter tip, infusate- leak back or cavity formation • or edema could happen that is undesirable. Contours of Species Concentration Contours of Velocity Magnitude Version 1 Version 2 Effect of Drug Diffusivity OUTPUTS Effect of Catheter Angle on Drug Delivery • Drug diffusivity has nosignificant effect on Penetration depth • as convection dominates diffusion Contours of Species Concentration Contours of Species Concentration Run #1: 2.0 * 10-8 Kg/Sec Run #3: 6.0 * 10-8 Kg/Sec Run #2: 4.0 * 10-8 Kg/Sec In case A, the amount of the drug in each run was kept constant and Drug diffusivity of 2.88*10-5 m2/s In case B, the rate of infusion in each run was 6.0 * 10-8 Kg/s and Drug diffusivity of 2.88*10-5 m2/s In case C, the rate of infusion in each run was 6.0 * 10-8 Kg/s and C0 =0.4 Run #1 : C0 = 0.13 Run #2 : C0 = 0.3 Run #3 : C0 = 0.4 GM- Gray Matter WM- White Matter Low to High Angle = (90+30)° Angle = (90+10)° Low to High Conclusions References • Kalyanasundaram, S., Calhoun, D.V., Leong, W.K, A finite element model for predicting the distribution of drugs delivered intracranially to the brain, American Physiological Society, R1810-R1821, 1997. • 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. • Reisfeld, B., Kalyanasundaram, S., Leong, K., A mathematical model of polymeric controlled drug release and transport in the brain, Journal of Controlled Release, 36, 199-207, 1995. • Materialise, Inc., (Mimics), http://www.materialise.be/mimics/main_ENG.html, • The Fluent, Inc, (Gambit/Fluent/FIDAP), http://fluent.com/software/ • Convection enhanced drug delivery aims at circumventing the BBB for delivering large molecular weight macromolecules. • The variables that affect CED have been put forth and the effect of convection on penetration depth was quantified rigorously. • Quantitative levels of toxin formation with increase in drug concentration need to be addressed. • Tissue displacement at the vicinity of injection point needs to be studied using Consolidation Theory.