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Transport and Biomechanics of Convection Enhanced Drug Delivery

Transport and Biomechanics of Convection Enhanced Drug Delivery. Master’s Thesis Defense Dec 7 th, 2010 219 SEO. Nikhil Sindhwani Bioengineering, UIC. Thesis Committee : Prof. Andreas Linninger Advisor Prof. Richard Magin Richard Penn, M.D. Laboratory for Product and Process Design

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Transport and Biomechanics of Convection Enhanced Drug Delivery

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  1. Transport and Biomechanics of Convection Enhanced Drug Delivery Master’s Thesis Defense Dec 7th, 2010 219 SEO Nikhil Sindhwani Bioengineering, UIC Thesis Committee: Prof. Andreas Linninger Advisor Prof. Richard Magin Richard Penn, M.D. Laboratory for Product and Process Design Department of Bioengineering University of Illinois at Chicago NS, LPPD, MS Thesis Defense, 2010

  2. Neurologic disorders and current treatment options NS, LPPD, MS Thesis Defense, 2010

  3. Parkinson’s disease: • Affected population: 1.5 million[1] • Symptoms: • Tremors • Dementia • Cause: Gradual loss of dopamine producing nerve cells, mostly in Substantia niagra region. • Current treatment options: • Levodopa: precursor to dopamine. • Surgery that would destroy areas of brain that trigger tremors. • Deep brain stimulation. • Inject viral vector containing GAD gene[2]. [3] [1] WebMD: http://www.webmd.com/parkinsons-disease/guide/parkinsons-disease-treatment-overview [2] Nytimes: http://www.nytimes.com/2003/08/19/science/19GENE.html [3] MedlinePlus: http://www.nlm.nih.gov/medlineplus/ency/imagepages/19515.htm NS, LPPD, MS Thesis Defense, 2010

  4. Huntington’s Disease: • Affected population: 5-10/100,000 persons [1]. • Symptoms: • Dementia, abnormal movements (chorea), irritability, hallucinations[2] . • Cause: • Genetic defect in chromosme #4 producing mutated Huntingtin protein (mHtt). • Loss of striatal small neurons[3]. • Current treatment options[2]: • No cure for HD. • Dopamine blockers like tetrabenzine. • co-enzyme Q10. [4] [1] Driver-Dunckley E, Caviness JN. (2007). "Huntington's disease". In Schapira AHV. Neurology and Clinical Neuroscience. Mosby Elsevier. pp. 879–885.. [2] https://health.google.com/health/ref/Huntington's+disease [3] Huot, P., M. Lévesque, et al. (2007). "The fate of striatal dopaminergic neurons in Parkinson's disease and Huntington's chorea." Brain 130(1): 222-232. [4] http://brainmind.com/BasalGanglia.html NS, LPPD, MS Thesis Defense, 2010

  5. Brain Tumors: • Statistics[1]: • About 22,020 new cases of malignant brain tumors in 2010. • 90% of all brain tumors are gliomas in people above 45 yrs of age. • Survival rate: Roughly 40% • Symptoms[1]: • Differs depending on the region affected, headaches, spasms etc. • Cause: • Mostly genetic • Current treatment options[1]: • Surgery: Craniotomy followed by placement of Gliadel (carmutsine) wafers. • Radiation therapy • Chemotherapy: IV or oral delivery, only a fraction reaches the tumor site. [2] [3] [1] www.cancer.org [2] http://www.mayfieldclinic.com/PE-Glioma.htm [3] www.imagingconsult.com NS, LPPD, MS Thesis Defense, 2010

  6. Blood Brain Barrier Allows only molecules smaller than 400-500 Da to enter. NS, LPPD, MS Thesis Defense, 2010

  7. CNS Disorders Requiring LARGE Molecules Drug Therapy • Alzheimer’s Disease • Parkinson’s Disease • Huntington’s Disease • Autism • Multiple Sclerosis • Brain Cancer • Stroke • Brain Trauma • Lyosomal Storage Disorders • Inherited Ataxias CNS Disorders Treatable With small Drug Molecules • Depression • Schizophrenia • Chronic Pain • Epilepsy NS, LPPD, MS Thesis Defense, 2010

  8. There is a need for a better drug delivery mechanism that can • Deliver to specific target area, • Reduce side effects, and • Bypass the Blood Brain Barrier. Pardridge, 1996 NS, LPPD, MS Thesis Defense, 2010

  9. Convection Enhanced Delivery (CED) • Pressure driven direct intra-parenchymal infusion of drugs using a catheter. • Flow rate can be controlled, providing good control over infusion volume. • Bypasses BBB, so large molecular drugs can be deliveryed. NS, LPPD, MS Thesis Defense, 2010

  10. Convection Enhanced Delivery delivers drugs to a large volume Pressure Driven delivery Interstitial concentration Diffusion Driven delivery [1] Distance [1] Raghavan, R., M. L. Brady, et al. (2006). "Convection-enhanced delivery of therapeutics for brain disease, and its optimization." Neurosurgical FOCUS 20(4): E12. NS, LPPD, MS Thesis Defense, 2010

  11. CED in Clinical Trials: [1] Clinical trials failed because therapeutic levels of drug could not reached target area [1] Bidros, D. S., J. K. Liu, et al. (2010) "Future of convection-enhanced delivery in the treatment of brain tumors." Future Oncology 6(1): 117-125. NS, LPPD, MS Thesis Defense, 2010

  12. Problems addressed in this thesis: NS, LPPD, MS Thesis Defense, 2010

  13. Brain tissue anisotropy and heterogeneity Lateral Ventricles • Complicated geometry, with many internal structures • White matter tracts Caudate nucleus Putamen Corpus Callosum Globus Pallidus Third Ventricle Cortex Hippocampus NS, LPPD, MS Thesis Defense, 2010

  14. Backflow Avoided by using very low flow rates: leading to low drug concentrations Uncontrolled leakage of infusate along the catheter shaft at high flow rates NS, LPPD, MS Thesis Defense, 2010

  15. GOAL To use principles of TRANSPORT and MECHANICS to Explain, Analyze and Improve existing CED protocols NS, LPPD, MS Thesis Defense, 2010

  16. M.S. Thesis Outline NS, LPPD, MS Thesis Defense, 2010

  17. Measurement of concentrations using digital images N. Sindhwani, et al.Methods for determining agent concentration profiles in agarose gel during Convection Enhanced Drug Delivery, IEEE Transactions on Biomedical EngineeringJournal of Biomechanical engineering, Accepted Nov 2010. NS, LPPD, MS Thesis Defense, 2010

  18. Experimental setup NS, LPPD, MS Thesis Defense, 2010

  19. Geometry effect Single port catheter Single port catheter NS, LPPD, MS Thesis Defense, 2010

  20. Geometry effect Porous membrane catheter NS, LPPD, MS Thesis Defense, 2010

  21. Intensity-concentration relation • a. Through a sample of constant concentration • b. Through a sample of varying concentration NS, LPPD, MS Thesis Defense, 2010

  22. Attenuation from a 3D spread NS, LPPD, MS Thesis Defense, 2010

  23. Camera Capture effect and calibration Camera has a non-linear recording range. Calibration to find the attenuation coefficient. (Arbitrary units) NS, LPPD, MS Thesis Defense, 2010

  24. Comparison of theoretical predictions and experimental values Results: Single port catheter experiments R2 = 0.98 R2 = 0.98, 0.97 NS, LPPD, MS Thesis Defense, 2010

  25. Comparison of theoretical predictions and experimental values R2 = 0.98 R2 = 0.99, 0.97 NS, LPPD, MS Thesis Defense, 2010

  26. Conclusions • Quantitative concentration measurement, instead of qualitative. • Less than 10% maximum measurement error. • Useful for verification of theoretical models that can be used for advanced computer simulations. • Can be applied for determining effective molecular diffusivity. NS, LPPD, MS Thesis Defense, 2010

  27. M.S. Thesis Outline NS, LPPD, MS Thesis Defense, 2010

  28. Motivation Morrison et al, 1999 NS, LPPD, MS Thesis Defense, 2010

  29. Overview O. Ivanchenko, N. Sindhwani and A. Linninger, Experimental techniques for studying poroelasticity in brain phantom gels under high flow micro-infusion, Journal of Biomechanical engineering, May 2010. NS, LPPD, MS Thesis Defense, 2010

  30. Stress Visualization NS, LPPD, MS Thesis Defense, 2010

  31. Photoelasticity NS, LPPD, MS Thesis Defense, 2010

  32. Stress visualization during infusion Isoclinic fringes Infusion late stages No infusion Infusion initial stages NS, LPPD, MS Thesis Defense, 2010

  33. Displacement measurement NS, LPPD, MS Thesis Defense, 2010

  34. Experimental setup NS, LPPD, MS Thesis Defense, 2010

  35. Displacement field calculation. NS, LPPD, MS Thesis Defense, 2010

  36. Displacement field and strains Porosity change NS, LPPD, MS Thesis Defense, 2010

  37. Theoretical predictions Based on first principle conservation of mass and momentum Simulated strains (X, Y, volumetric), porosity changes, and hydroconductivity changes. NS, LPPD, MS Thesis Defense, 2010

  38. Quantitative comparison of mathematical models and experimental results The profiles follow a similar trend, but agree poorly in terms of actual values. NS, LPPD, MS Thesis Defense, 2010

  39. Conclusions • Stresses develop at the tip of infusion catheter • There is significant displacement of agarose gels. • Displacement magnitude decreases with distance from the catheter tip. • Displacement causes 50% increase in porosity. • These methods can be used for testing novel backflow free catheter designs. NS, LPPD, MS Thesis Defense, 2010

  40. M.S. Thesis Outline NS, LPPD, MS Thesis Defense, 2010

  41. Overview NS, LPPD, MS Thesis Defense, 2010

  42. Computational models are based on First Principles of Mass and Momentum conservation Species transport: Clearance/ Binding Convection Reaction Diffusion Momentum: Extended Darcy’s Law Hydraulic Perfusion NS, LPPD, MS Thesis Defense, 2010

  43. The Finite Volume Method NS, LPPD, MS Thesis Defense, 2010

  44. Computational Results Brain Geometry Reconstruction Geometry Computer Algorithms Grid Generation Drug Distribution Prediction Extract geometry information MRI Data Computational Grid Model generation MR Imaging and geometry reconstruction using ImageJ NS, LPPD, MS Thesis Defense, 2010

  45. Computer models of Nerve Growth Factor (NGF) delivery using CED: Isotropic domain NS, LPPD, MS Thesis Defense, 2010

  46. Infusion in the caudate region of the brain, Axial slice simulation NS, LPPD, MS Thesis Defense, 2010

  47. Infusion in the corpus callosum, Coronal slice simulation NS, LPPD, MS Thesis Defense, 2010

  48. Infusion in the cingulum bundle, Sagittal slice simulation Ventricle NS, LPPD, MS Thesis Defense, 2010

  49. Computer models of Nerve Growth Factor (NGF) delivery using CED: Anisotropic and heterogeneous domain NS, LPPD, MS Thesis Defense, 2010

  50. Fibers of the Corpus Callosum Brain tissue is anisotropic and heterogeneous Lateral Ventricles • Internal structures • White matter fibers Caudate nucleus Putamen Corpus Callosum Globus Pallidus Third Ventricle Cortex Hippocampus NS, LPPD, MS Thesis Defense, 2010

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