Ying Hsu Sep 16th, 2010 Collaborators: Dr Penn MD., Dr Madhawa, Brian Sweetman

1. Investigating Intrathecal Drug Delivery with a Computational Model Ying Hsu Sep 16th, 2010 Collaborators: Dr Penn MD., Dr Madhawa, Brian Sweetman Advisor: Dr A. A. Linninger Laboratory for Product and Process Design (LPPD) University of Illinois at Chicago

2. How would you dose this patient? • Medication target: • 1 cm deep into the cortex http://www.ispub.com/journal/the_internet_journal_of_radiology/volume_4_number_1_46/article_printable/neurological_damage_in_heat_stroke_in_a_child_ct_mri_and_spect_appearances.html LPPD

3. The Blood Brain Barrier • The blood brain barrier prevents biochemical macromolecules in the blood stream to reach the brain tissue • Drugs that can delivered intrathecally: • Chemotherapeutic agents • Anagelsics • siRNAs Blood Brain Barrier (BBB) is formed by the tight junctions of the endothelial cells inside the CNS Bridging the Blood-Brain Barrier: New Methods Improve the Odds of Getting Drugs to the Brain Cells That Need Them Ferber D PLoS Biology Vol. 5, No. 6, e169 doi:10.1371/journal.pbio.0050169 LPPD

4. What is intrathecal drug delivery? Administering medication directly to the spine’s subarachnoid space Bypassing the blood brain barrier Potential apllications: Gene therapy with viral vectors, proteins and nanoparticles

5. How Intrathecal Drug Delivery Bypasses BBB http://www.burtonreport.com/images/SASpaceDraw.jpg http://www.emory.edu/ANATOMY/AnatomyManual/fig14.jpg LPPD

6. Challenges in Predicting Drug Concentration in Intrathecal Delivery • A bolus injection reaches the high cervical region in 4 hours or less. • Much faster than pure diffusion • What causes the fast transport? by Dr Penn M.D Hypothesis: The pulsatile CSF motion without net flow accelerates drug transport. LPPD

7. Why Does the CSF Pulsates in the Spinal Canal • The cranial volume is fixed. • Increase in brain vasculature volume per cardiac cycle 0.9 c.c. of pulsating cerebrospinal fluid • zero net flow  How does the CSF pulsations affect drug transport in the spinal canal? Can it be responsible for the fast transport rate? LPPD

8. Main Goal Using computational fluid mechanics to quantify the effect of pulsations(convection) on drug transport • Aim 1: Accurately define the cerebrospinal fluid space with patient specific data • Aim 2: flow field simulations (Navier Stokes) • Aim 3: pulsatile drug transport simulations with Species Transport Equation LPPD

9. From Medical Images to Flow Field Simulations Image Reconstruction Software Aim 1 Equations for Fluid Mechanics Aim 2 http://www.imaginis.com/files/media/transfer/img/mri-scan/mri-spine.jpg MRI Images Cerebrospinal Fluid Flow Field Computational Mesh Generation LPPD

10. Aim 1Image Reconstruction of the CSF Space CSF flows in gyrations between brain tissue (sulci) CSF space of the central nervous system (31 pairs of nerves) LPPD

11. Aim 1Image Reconstrcution of the CSF Space CSF filled ventricles Coronal view of the complex geometry LPPD

12. Aim 2 Flow Field Simulations showing Velocity Direction Reversal over 1 Cardiac Cycle 0.25 second 0.5 second LPPD

13. Aim 2 Flow Field Simulation showing Velocity Direction Reversal over 1 Cardiac Cycle 0.75 second 1 second LPPD

14. Baclofen Concentration in Stagnant Flow Field over Time Minutes after injection T = 0 T = 5 T = 15 T = 25 LPPD

15. Baclofen Concentration in Pulsatile Flow Field over Time Minutes after injection T = 0 T = 5 T = 15 T = 25 LPPD

16. Conclusions • Therapeutic drugs don’t reach the brain • Intrathecal drug administration can delivery drugs bypassing blood brain barrier • Pulsations of the CSF have strong effects on the apparent transport speed of drugs administered intrathecally • Advanced computational fluid mechanics integrated with medical imaging enables rational design of IT treatment LPPD