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Wednesday, December 06, 2006

Drug Delivery into the Human Brain. Wednesday, December 06, 2006. Mahadevabharath R. Somayaji, Michalis Xenos, Libin Zhang, and Andreas A. Linninger Laboratory for Product and Process Design , Departments of Chemical and Bio-Engineering, University of Illinois, Chicago, IL, 60607, U.S.A.

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Wednesday, December 06, 2006

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  1. Drug Delivery into the Human Brain Wednesday, December 06, 2006 Mahadevabharath R. Somayaji, Michalis Xenos, Libin Zhang, and Andreas A. Linninger Laboratory for Product and Process Design, Departments of Chemical and Bio-Engineering, University of Illinois, Chicago, IL, 60607, U.S.A.

  2. Deploy first principles transport equations to predict drug transport mechanism in the human brain using a two and three-dimensional Patient-Specific computational model . Motivation Challenges • Neurodegenerative diseases of the Central Nervous System (CNS) affect millions of people worldwide • The targeted delivery of large molecular weight therapeutic drugs is hampered by • The Blood Brain Barrier (BBB) • Differences in brain tissue properties: Anisotropy and Inhomogeneity • Differences in patient-specific brain geometry: dimensions and shape • Localized prediction of drug distribution: achievable Penetration depths and Treatment volumes in the Human Brain

  3. CNS Disorders Requiring LARGE Molecules Drug Therapy CNS Disorders Treatable With small Drug Molecules • Alzheimer’s Disease • Parkinson’s Disease • Huntington’s Disease • Autism • Multiple Sclerosis • Brain Cancer • Stroke • Brain Trauma • Lyosomal Storage Disorders • Inherited Ataxias • Depression • Schizophrenia • Chronic Pain • Epilepsy The Blood Brain Barrier (BBB) BBB is formed by a network of microcapillaries that are in turn composed of endothelial cells. BBB is impermeable to large molecular weight chemotherapeutic agents Brain Capillaries Ref: Pardridge, 1996

  4. Structure of the Human Brain: Coronal Section Source: Michigan State University Ref: Lazar, M et al., “White Matter Tractography using Diffusion Tensor Deflection”, Human Brain Mapping, vol 18, pp 306-321, 2003.

  5. Tissue/Drug Properties • from • Heuristics • Literature Patient Specific Computer Assisted Brain Analysis

  6. Mathematical Description ofm Drug Transport in the brain Drug Convection – Diffusion in porous brain parenchyma Prediction of Bulk Diffusivity of Drug Effective Diffusivity in Porous Tissue Bulk Continuity Momentum Additional pressure drop – porous structure ρis the density of the fluid and μ is the viscosity k is the permeability and βis the inertial resistance factor. Deff is the effective drug diffusivity

  7. Prediction of Drug Distribution – Dynamic Simulation Thalamus Injection Caudate Nucleus (Target) Source White Matter Anisotropy Total Time: 4 weeks

  8. Three dimensional reconstruction of brain sub-structures

  9. Normal Brain Subarachnoid Space Ventricles Parenchyma Detailed substructure Gray matter Corpus Callosum White matter-left lobe Three dimensional reconstruction of sub-structures Ref: Ongoing work at LPPD Mauli Modi, Rajitha Mullapudi, MahadevaBharath R. Somayaji, Michalis Xenos, Andreas A. Linninger, David C. Zhu and Richard Penn, “Mimics – An Indispensable Tool for Patient-Specific Image Analysis”, Mimics Innovation Awards, Materialise, Belgium, June 2006

  10. Outflow boundary condition (porous medium) Inflow boundary conditions Symmetry boundary conditions The Human Brain in Three Dimensions Three-dimensional Computational Grid of Midbrain substructures Exact reconstruction of Cerebrospinal fluid pathways in the brain

  11. Patient Specific Approach Sets a scientific basis from ENGINEERING knowledge Synergism: experimental data and First principles. Innovation Improvement of the Existing Methodologies: Impact to the medical community Summary and Broader Impact Summary Broader Impact

  12. Acknowledgments List of Awards (Internal and External) • UIC Provost Award for Excellence in Doctoral Research, Fall 2005. • UIC Travel Award for participating in 2005 AICHE National Meeting, Spring 2006. • Sigma-Xi Award (GIAR) for Excellence in Doctoral Research, Spring 2006. • Mimics Innovation Awards, Runner-up, 2005. • Mimics Innovation Awards, Best Paper Award, 2006. LPPD Group, UIC • Brian Sweetman,M.S student, Laboratory for Product and Process Design, UIC. • Jeonghwa Moon, PhD student, Laboratory for Product and Process Design, UIC. Department of Neurosurgery, University of Chicago • Dr. Richard Penn, M.D, Department of Neurosurgery, University of Chicago. • Dr. David Zhu, Assistant Professor, Michigan State University. • Dr. Xiodong Guo, PhD, University of Chicago. • Michael Castelle, University of Chicago. • The Fluent Inc, NH. • Materialise Inc, Belgium.

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