A 3D Computational Model Of Cerebrospinal Fluid Dynamics For Predictive Biosimulation
Andreas Kuttler, Thomas Dimke, Steven Kern, Gabriel Helmlinger, Luca A. Finelli
Modeling & Simulation, Novartis Pharma AG, Basel, Switzerland
Objectives: With approximately 130,000 new cases per year globally, spinal cord injury (SCI) is a global epidemic [1] involving males between the age of 16-30 in 82% of case. While there is no cure for SCI, several new therapies targeting the spinal cord are in development. Drugs targeting spinal cord function, most notably local anesthetics and opioids, are typically administered into the cerebrospinal fluid (CSF) in the spinal canal by lumbar intrathecal injection or infusion. To optimize drug administration and distribution at a target site of pharmacologic action, a precise understanding of the anatomy and physiology relevant to intrathecal drug delivery is needed.
Methods: We developed a 3D computational fluid dynamics model of the spinal canal, based on actual geometry reconstructed from MRI data and dynamics controlled by transient Navier-Stokes equations. The driving forces for fluid transport (pulsating blood flow in the cranium and breathing) are modeled based on literature data [2,3]. These numerical investigations provided detailed quantitative data on CSF flow in the canal, allowing prediction of local differences in fluid dynamics (e.g., distribution of velocity profiles and flow direction over time). The simulated velocities are in good agreement with the velocities measured by phase contrast magnetic resonance imaging at five additional cross-sections [4].
Results: The pulsating nature of the fluid flow together with the specific geometry of the spinal canal results in convective transport of injected drug molecules. Because of these effects, even large molecules like monoclonal antibodies with a low molecular diffusion rate get distributed though not in a spatially homogenous manner. Virtual marker fluid analysis show reduced transport in some of the transition zones (e.g., T9/T10). We simulated the biodistribution of compounds in the CSF as a function of time and space, intrathecal injection site, and infusion modes, volumes and rates. The determined local transport velocities are in the same range as those measured by CSF radionuclide scintiphotography using radiolabeled human serum albumin [5,6].
Conclusions: Using modeling tools based on first principles of biophysics, transport phenomena as they occur in the spinal canal may be analysed in detail. By providing a framework for appropriate integration of population clinical data into a dynamic system physiology platform, this technology allows for the simulation of different clinical scenarios to support decision making, turning model based-drug development to reality.
References:
[1] www.campaignforcure.org
[2] Alperin, N.; Sivaramakrishnan, A.; Lichtor, T.: Magnetic resonance imaging-based measurements of cerebrospinal fluid and blood flow as indicators of intracranial compliance in patients with Chiari malformation, Neurosurg 103 46-52, 2005
[3] Lee, R.R.; Abraham, R.A.; Quinn, C.B.: Dynamic physiologic changes in lumbar CSF volume quantitatively measured by three-dimensional fast spin-echo MRI, Spine 2001;26:1172-1178
[4] Yallapragada, N.; Alperin, N. : Noninvasive mapping of the spinal canal hydrodynamic complaince using bond graph technique and magnatic resonance imaging , Bioengineering Conference, June 2003, Florida
[5] Ashburn, W.L.; Harbert, J.C.; Briner, W.H.; Di Chiro, G.: Cerebrospinal Fluid Rhinorrhea Studied With Gamma Scintillation Camera, Journal Of Nuclear Medicine, vol.9, no.7
[6] Di Chiro, G.; Hammock, M.K.; Bleyer, W.A.: Spinal Descent Of Cerebrospinal Fluid In Man, Neurology 26: 1-8, January 1976