Abstract
Cerebrospinal fluid (CSF) plays a vital role in the immunological support, structural protection and metabolic homeostasis of the central nervous system (CNS). The CSF is a promising route with many potentially important roles for CNS therapeutics such as: a) direct delivery of large drug molecules to the CNS tissue that is not possible via blood injection due to the blood brain barrier and b) CSF filtration, termed Neurapheresis therapy, to remove unwanted solutes in CNS diseases such as alzheimer’s disease, meningitis, subarachnoid hemorrhage and leptomeningeal metastasis. While many studies have shown increasing importance of the role of CSF in CNS system homeostasis, there is a need to understand the impact of realistic geometry on CSF flow patterns. An anatomically accurate and validated CFD model will allow testing and optimization of CNS biomedical technologies such as CSF filtration devices. Such a simulator could reduce cost of non-human primate studies and lead to more rapid application of these technologies for clinical use. In this dissertation, CSF dynamics in monkeys and humans was investigated in four stages as following:
First, a magnetic resonance imaging (MRI) protocol was developed and applied to quantify subject-specific CSF space geometry and flow and define the CFD domain and boundary conditions in non-human primates. An algorithm was implemented to reproduce the axial distribution of unsteady CSF flow by non-uniform deformation of the dura surface. Results showed that maximum difference between the MRI measurements and CFD simulation of CSF flow rates was <3.6%. CSF flow along the entire spine was laminar with a peak Reynold’s number of ~150 and average Womersley number of ~5.4. Maximum CSF flow rate was present at the C4-C5 vertebral level. Deformation of the dura ranged up to a maximum of 134 μm. Geometric analysis indicated that total spinal CSF space volume was ~8.7 ml. Average hydraulic diameter, wetted perimeter and SAS area was 2.9 mm, 37.3 mm and 27.24 mm2, respectively. CSF pulse wave velocity along the spine was quantified to be 1.2 m/s.
Second, a geometric and hydrodynamic characterization of CSF in eight cynomolgus monkeys (Macaca fascicularis) was presented at baseline and two-week follow-up. Results showed that CSF flow along the entire spine was laminar with a Reynolds number ranging up to 80 and average Womersley number ranging from 4.1-7.7. Maximum CSF flow rate occurred ~25 mm caudal to the foramen magnum. Peak CSF flow rate ranged from 0.3-0.6 ml/s at the C3-C4 level. Geometric analysis indicated that average intrathecal CSF volume below the foramen magnum was 7.4 ml. The average surface area of the spinal cord and dura was 44.7 and 66.7 cm2 respectively. Subarachnoid space cross-sectional area and hydraulic diameter ranged from 7-75 mm2 and 2-3.7 mm, respectively. Stroke volume had the greatest value of 0.14 ml at an axial location corresponding to C3-C4.
The third objective of this dissertation was to investigate the impact of spinal cord nerve roots (NR) on CSF dynamics. A subject-specific computational fluid dynamics (CFD) model of the complete spinal subarachnoid space (SSS) with and without anatomically realistic NR and non-uniform moving dura wall deformation was constructed. This CFD model allowed detailed investigation of the impact of NR on CSF velocities that is not possible in vivo using MRI or other non-invasive imaging methods. Results showed that NR altered CSF dynamics in terms of velocity field, steady-streaming and vortical structures. Vortices occurred in the cervical spine around NR during CSF flow reversal. The magnitude of steady-streaming CSF flow increased with NR, in particular within the cervical spine. This increase was located axially upstream and downstream of NR due to the interface of adjacent vortices that formed around NR. Average value for steady streaming velocity was 0.11 ± 0.12 and 0.05 ± 0.04 mm/s (mean ± stdev) for the model with versus without NR (120% greater with NR). The region of greatest difference in steady streaming velocity values was the cervical spine that had up to 5X larger value of steady streaming velocity with NR compared to without.
In fourth step, we formulated a subject-specific computational fluid dynamics (CFD) model to parametrically investigate the impact of a novel dual-lumen catheter-based CSF filtration system, the Neurapheresis therapy system (Minnetronix Neuro, Inc., St. Paul, MN), on intrathecal CSF dynamics. The operating principle of this system is to remove CSF from one location along the spine (aspiration port), externally filter the CSF routing the retentate to a waste bag, and return permeate (uncontaminated CSF) to another location along the spine (return port). The CFD model allowed parametric simulation of how the Neurapheresis system impacts intrathecal CSF velocities and steady-steady streaming under various Neurapheresis flow settings ranging from 0.5 to 2.0 ml/min and with a constant retentate removal rate of 0.2 ml/min. simulation of the Neurapheresis system were compared to a lumbar drain simulation with a typical CSF removal rate setting of 0.2 ml/min. Results showed that the Neurapheresis system at a maximum flow of 2.0 ml/min increased average steady-streaming CSF velocity 2X in comparison to lumbar drain (0.190 ± 0.133 versus 0.093 ± 0.107 mm/s, respectively). This affect was localized to the region within the Neurapheresis flow-loop. The mean velocities introduced by the flow-loop were relatively small in comparison to normal cardiac-induced CSF velocities.
Finally, a subject-specific multiphase CFD model was constructed based on high-resolution anatomic MRI. The dual-lumen Neurapheresis catheter geometry was added to the model within the posterior spinal subarachnoid space (SAS). Neurapheresis flow aspiration and return rate was 2.0 and 1.8 (mL/min), versus 0.2 (mL/min) drainage for lumbar drain. An in vitro CSF model was constructed with an identical fluid domain geometry. A detailed comparison of numerical and in vitro results was performed by the Bland-Altman correlation analysis. Neurapheresis therapy was found to have a larger impact on steady streaming in comparison to lumbar drain. Steady-streaming in the cranial SAS was ~50X smaller than in the spinal SAS for both cases. Results showed that 85% of the spinal SAS was cleared within one hour with the Neurapheresis flow loop in comparison to 50% clearance after 24-hour with lumbar drain. Clearance was maximized between the aspiration and the return ports with the Neurapheresis therapy. However, intracranial clearance for the Neurapheresis therapy was similar to lumbar drain (66% clearance). Quantitative comparison of Neurapheresis therapy results showed that the speed of clearance match with less than 4% error after 24-hour (50% CFD vs 46% in vitro).