(98ba) Simulations of CSF Flow Dynamics in a Global CNS Model With Magnetically Targeted Intrathecal Drug Delivery

Introduction: Therapeutic
intervention for central nervous system diseases has limited effectiveness due
to drug transport restriction across the blood brain barrier. Intrathecal (IT)
drug delivery aims to circumvent this obstruction, however interpatient
variability impacts treatment outcomes. Drug distribution is affected by
patient anatomy, cerebrospinal fluid (CSF) properties (volume, pressure, and
density), heart rate, and drug infusion properties. A secondary problem with IT
drug delivery is localization of the compound to a region of interest. External
non-invasive magnetic fields have been shown to direct and concentrate magnetic
nanoparticles for treatment of several diseases such as tumors. We propose to understand
and explore the efficacy of treating CNS diseases with IT administration of
magnetic nanocarriers functionalized with therapeutic molecules. Multi-phase
simulations of a complete patient specific model of the CSF filled spaces can predict
dispersion patterns of nanoparticle-therapeutic complexes both in a native
state and under magnetic field influence. An in vitro bench top human
spinal canal model with magnetic field guidance is used to corroborate
computational simulation results.

Computational CSF Fluid Flow Methods:
Phase
contrast magnetic resonance imaging (PC-MRI) in combination with computational
fluid mechanics is beginning to provide a complete picture of patient specific
CSF flow fields. Patient specific MRI data allows for generation of an
anatomically consistent mesh for computer modeling giving accurate predictions
of drug dispersion patterns in the CNS.Modeling of spinal CSF flow is focusing
on the role of the micro-anatomy including nerve roots and trabeculae. Using
simulations, our lab showed that CSF pulsatility and nerve roots play a
significant role in the bio-distribution of drug molecules during intrathecal
drug delivery. Our work also illustrates the formation of complex micro-mixing
patterns which are attributable to nerve roots and trabeculae.

We constructed a patient-specific model
of the fluid filled spaces inside the CNS based on PC-MRI data. Pulsatile
motion of the CSF for the full model is generated by explicitly moving the
choroid plexus and parenchyma according to a Fourier series that captures the
velocity wave of the basilar artery. The model includes regions of production
and absorption at the choroid plexus and arachnoid villi respectively. Nerve
roots were reconstructed from the image data and incorporated into the full SAS
model. We added micro-anatomical detail below the image resolution threshold of
MRI to quantify the effect of trabeculae (6 micron diameter) on CSF flow. We
compared complex flow profiles to simulations in structures lacking the
anatomical detail. The effect on spinal flow resistance and their impact on
complex flow profiles as a function of varying trabeculae density. The full
spinal SAS model visualizes flow profiles at 31 nerve pairs over a complete
cardiac cycle predicting the effect of successive nerve roots.The computational
fluid dynamic solver ANSYS Fluent 14.0 is used for multi-phase fluid flow
simulations to predict dispersion of magnetic nanoparticle based drug infusate
within the spinal canal. Magnetic fields of varying strength were also applied
to the complete CNS model simulations to understand the effect on magnetic
nanocarrier transport and accumulation in a global model.

Bench top Testing Methods of
Magnetic Nanoparticle Guidance: Most intrathecally injected drugs are
required only at certain locations within the spinal canal where it is
essential for these drugs to diffuse into the spinal cord to produce a
therapeutic effect. Currently, in order to reach the crucial drug concentration
at the target site and aid diffusion into the spinal cord, high drug doses are
used. With no method to deliver the large drug doses locally, current
intrathecal drug delivery treatments are hindered with wide drug distributions
throughout the CNS which cause harmful side effects. Our lab proposed a
magnetic nanoparticle based drug delivery technique within the CNS by IT
administration. An externally applied magnetic field localizes the magnetic
drug coated nanoparticles at desired locations. Detailed simulations in COMSOL
Multi-physics optimized the placement and strength of the external magnet. A
physiologically consistent bench top model of the human spinal canal was constructed
to determine the effect of magnetic fields on magnetic nanoparticle
distribution, shown in Figure 1.

A co-precipitation technique using
ferrous and ferric salts was used to form the 8-10 nm diameter
superparamagnetic magnetite nanoparticle cores, which were then coated with a
highly functionalizable gold layer of thickness between 8-15 nm. The
nanoparticles were characterized by TEM, EDS, x-ray diffraction spectroscopy
and SQUID magnetometry. The in vitro spinal canal model was
physiologically consistent, and constructed out of a plastic tube (mimicking
the spinal canal wall), hard wood cylinder (representing the spinal cord), and
rubber projections (serving as spinal nerve roots). The proximal end of the
model was connected to a peristaltic pump which produced pulsatile fluid
motion. The model was filled with artificial cerebrospinal fluid, and a distensible
rubber balloon was fixed at the distal end to serve as the filumterminale. A
programmable syringe pump was used to inject the nanoparticles into the lumbar
region, and NdFeB magnets of different size and field strength were placed
below the targeting region. A strong 1.05 T magnet was used in the
cervical/barrier region to prevent any remaining particles from leaving the
system. Nanoparticle collection in different regions was achieved using ball
valves to separate the model into three zones (infusion, targeting, and barrier
zones) from which the particles were eluted, dried, and weighed. The in vitro
experiments were also simulated in Comsol 4.2a to help analyze model parameters
and to determine optimum magnetic field strength and orientation.

Global CSF Fluid Flow Simulation
Results and Discussion: CSF flow is driven by a pulsatile waveform and
Womersley (W_o) number is calculated to characterize the flow profile
as in phase (<1) or lagging behind the pressure wave (>1). The Womersley
number at the C4 region of the spinal SAS is W_o=4.63, T6 region W_o=4.38,
and L4 region W_o=5.38. Flow at all spinal regions of interest has a
phase lag behind the pressure wave. Velocity streamlines, shown in Figure 2,
are

generated which visualizes recirculating
flow patterns in the spinal SAS at multiple regions adjacent to nerve roots.
Reynolds number is calculated at multiple regions of the spinal canal to
determine if fluid is turbulent or laminar. Simulation results predict all regions
of the spine to have laminar flow; C4 Re<81, T6 had Re<37, and L4 has
Re<17. The presence of CSF recirculation patterns indicates micro-anatomy
influence the fluid flow profiles. The pressure drop increased as the density
of manually added trabeculae increased. Micro-anatomy has a significant role in
the dispersion of fluid flow which will impact the distribution of drug
nanoparticle complexes. Magnetic two-phasic flow predicts nanoparticle
localization at regions of interest under increasing external magnetic field
strength and gradient.It is plausible that the CSF pulsations and micro-anatomy
are both important for preventing the formation of dead zones in the spinal SAS
in which cell debris or metabolites might otherwise stagnate and even
accumulate.

In vitro Model Results and
Discussion: Multiple
magentic field strengths were tested using COMSOL Multi-physics as shown in
Figure 3. In the bench top model, collection efficiency at regions of interest,
using a magnetic field of 0.528 T, increased with time and reached a steady
collection level of 71% after 15 minutes (p-value = 0.341). No change in the
magnetic retention value was observed beyond 60 minutes. The nanoparticle
recovery at the region of interest increased with the rising field strength of
the magnet. Percentage retentions of 48%, 61%, and 71% were observed for the
surface field strengths of 0.396 T, 0.507 T, and 0.528 T respectively.
Experiments utilizing the same 0.528 T magnet placed at one of the three
regions of interest (C4, T6, or L4) for 15 minutes showed that location of
the applied magnetic field always corresponded to the site of maximum particle
retention around 76‑81%.

Therapeutic interventions for diseases
of the CNS can benefit from a patient specific understanding of the effect that
micro-anatomy has on the transport phenomena in the CNS leading to improved
applications of novel drug delivery techniques such as usingmagnetically
targeted nanocarriers.