Experimental Setup

1. Cannula Backlight Gel Chamber Convection Enhanced Delivery Motivation • Circulating substances with molecular weight greater than 400 Da have difficulty in permeating the blood brain barrier. Holding frame Convection enhanced delivery is a bulk flow mechanism created by a pressure gradient which drives the distribution of the compound in the targeted site. • Most of drug molecules used to treat neurodegenerative diseases fall under this category cannot be systemically administered through blood. • Invasive techniques are used to delivery these large molecular weight drugs. Pure diffusive transport Drug Infusion Convective transport DrugDistribution • Advantages of CED technique over the conventional delivery methods • circumventing the blood brain barrier. • deliver both large and small molecular weight substances. • controlling the area of drug distribution to limit potential systemic toxicity. • targeted delivery by manipulating catheter placement and configuration Target Site BBB are tight junctions of the epithelium that lines capillaries in the brain. Human Brain MRI Image Coronal Slice (Level 1520)* Experimental Setup Brain Surrogate Mathematical Background Marker dye Bulk mass balance : (A) Catheter inlet • 0.6% agarose gel most accurately displays properties of the brain • Agarose gel is an effective brain surrogate in infusion experiments Bulk momentum balance : (B) Catheter wall (C) Permeable boundary (D) Gel-Catheter interface Species Transport Equation : Agarose gel (E) Gel boundary Digital Camera Syringe pump Computer Results Experimental Simulation 27 Gauge Cannula 23 Gauge Cannula 23 Gauge Cannula; Flow rate 0.5 μl/min Flow rate 0.5 μl/min Simulation Flow rate 0.5 μl/min Flow rate 1.0 μl/min t = 30 min t = 45 min t = 60 min t = 15 min Experimental Flow rate 1.0 μl/min t = 15 min t = 30 min t = 45 min t = 60 min Experimental results of reflux free trials are with in 10% error of the simulated results Ratio of volume of distribution to the volume of dye infused for different flow rates Comparison of penetration depth over experimental time for different cannula sizes and flow rates References Future Work Conclusions • Understanding the physics of phenomenon of backflow. • Simulate models to accommodate for reflux of infusate. • Conducting infusion experiments in animal brain and validating the results by simulations. • Volume of distribution increases with increasing flow rate. • Reflux of the infusate produces pear shaped distribution as opposed to expected spherical pattern. • Smaller diameter cannula display reflux of infusate, may be due to greater infusion pressure. • Reflux decreases the achievable penetration depth of the dye • The simulation model well predicts results of the experiments without reflux. [1] Raghavan R, Brady ML, Rodríguez-Ponce MI, et al: Convection-enhanced delivery of therapeutics for brain disease, and its optimization; Neurosurg Focus, Vol.20 (3):E12, 2006.[2] Z.J. Chen, G.T. Gillies, W.C. Broaddus, S.S. Prabhu, H. Fillmore, R.M. Mitchell, F.D. Corwin, P.P. Fatouros, “A realistic brain tissue phantom for intraparenchymal infusion studies”, Journal of Neurosurgery, Vol. 101, pp. 314-322, 2004. [3] Chen MY, Lonser RR, Morrison PF, et al: Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time. J Neurosurg 90:315-320, 1999. [4] Morrison PF, Chen MY, Chadwick RS, et al: Focal delivery during direct infusion to brain: role of flow rate, catheter diameter, and tissue mechanics. Am J Physiol 277:R1218-R1229, 1999. Acknowledgements • Dr. Richard Penn, University of Chicago • Fluent Inc. 2007, www.fluent.com • NSF REU Students, 2006 & 2007, LPPD Convection Enhancement of Drug Delivery to the BrainMadhu Smitha Harihara Iyer, Sukhraaj Basati, Brian Sweetman and Andreas A. LinningerLaboratory for Product and Process Design, Department of Bioengineering University of Illinois at ChicagoStudent Poster Session, Midwest Biomedical Engineering Conference, Chicago, 4th April, 2008