Intrathecal catheter implantation decreases cerebrospinal fluid dynamics in cynomolgus monkeys.

A detailed understanding of the CSF dynamics is needed for design and optimization of intrathecal drug delivery devices, drugs, and protocols. Preclinical research using large-animal models is important to help define drug pharmacokinetics-pharmacodynamics and safety. In this study, we investigated the impact of catheter implantation in the sub-dural space on CSF flow dynamics in Cynomolgus monkeys. Magnetic resonance imaging (MRI) was performed before and after catheter implantation to quantify the differences based on catheter placement location in the cervical compared to the lumbar spine. Several geometric and hydrodynamic parameters were calculated based on the 3D segmentation and flow analysis. Hagen-Poiseuille equation was used to investigate the impact of catheter implantation on flow reduction and hydraulic resistance. A linear mixed-effects model was used in this study to investigate if there was a statistically significant difference between cervical and lumbar implantation, or between two MRI time points. Results showed that geometric parameters did not change statistically across MRI measurement time points and did not depend on catheter location. However, catheter insertion did have a significant impact on the hydrodynamic parameters and the effect was greater with cervical implantation compared to lumbar implantation. CSF flow rate decreased up to 55% with the catheter located in the cervical region. The maximum flow rate reduction in the lumbar implantation group was 21%. Overall, lumbar catheter implantation disrupted CSF dynamics to a lesser degree than cervical catheter implantation and this effect remained up to two weeks post-catheter implantation in Cynomolgus monkeys.

Characterization of intrathecal cerebrospinal fluid geometry and dynamics in cynomolgus monkeys (macaca fascicularis) by magnetic resonance imaging.

Recent advancements have been made toward understanding the diagnostic and therapeutic potential of cerebrospinal fluid (CSF) and related hydrodynamics. Increased understanding of CSF dynamics may lead to improved detection of central nervous system (CNS) diseases and optimized delivery of CSF based CNS therapeutics, with many proposed therapeutics hoping to successfully treat or cure debilitating neurological conditions. Before significant strides can be made toward the research and development of interventions designed for human use, additional research must be carried out with representative subjects such as non-human primates (NHP). This study presents a geometric and hydrodynamic characterization of CSF in eight cynomolgus monkeys (Macaca fascicularis) 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.

Nonuniform Moving Boundary Method for Computational Fluid Dynamics Simulation of Intrathecal Cerebrospinal Flow Distribution in a Cynomolgus Monkey.

A detailed quantification and understanding of cerebrospinal fluid (CSF) dynamics may improve detection and treatment of central nervous system (CNS) diseases and help optimize CSF system-based delivery of CNS therapeutics. This study presents a computational fluid dynamics (CFD) model that utilizes a nonuniform moving boundary approach to accurately reproduce the nonuniform distribution of CSF flow along the spinal subarachnoid space (SAS) of a single cynomolgus monkey. 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. An algorithm was implemented to reproduce the axial distribution of unsteady CSF flow by nonuniform 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 Reynolds 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 were 2.9 mm, 37.3 mm and 27.24 mm2, respectively. CSF pulse wave velocity (PWV) along the spine was quantified to be 1.2 m/s.