A numerical investigation of intrathecal isobaric drug dispersion within the cervical subarachnoid space

Abstract

Intrathecal drug and gene vector delivery is a procedure to release a solute within the cerebrospinal fluid. This procedure is currently used in clinical practice and shows promise for treatment of several central nervous system pathologies. However, intrathecal delivery protocols and systems are not yet optimized. The aim of this study was to investigate the effects of injection parameters on solute distribution within the cervical subarachnoid space using a numerical platform. We developed a numerical model based on a patient-specific three dimensional geometry of the cervical subarachnoid space with idealized dorsal and ventral nerve roots and denticulate ligament anatomy. We considered the drug as massless particles within the flow field and with similar properties as the CSF, and we analyzed the effects of anatomy, catheter position, angle and injection flow rate on solute distribution within the cerebrospinal fluid by performing a series of numerical simulations. Results were compared quantitatively in terms of drug peak concentration, spread, accumulation rate and appearance instant over 15 seconds following the injection. Results indicated that solute distribution within the cervical spine was altered by all parameters investigated within the time range analyzed following the injection. The presence of spinal cord nerve roots and denticulate ligaments increased drug spread by 60% compared to simulations without these anatomical features. Catheter position and angle were both found to alter spread rate up to 86%, and catheter flow rate altered drug peak concentration up to 78%. The presented numerical platform fills a first gap towards the realization of a tool to parametrically assess and optimize intrathecal drug and gene vector delivery protocols and systems. Further investigation is needed to analyze drug spread over a longer clinically relevant time frame.

Fig 1. Geometry of the anatomical domain.

(a) 3D geometry of the cervical SAS with NRDL also showing relevant anatomical cross sections; (b) Injection positions; (c) Spherical system to define catheter angle; (d) Illustrative sections of the cervical SAS: sagittal (x = 1.7 cm), transverse (y = 6 cm) and coronal (z = 0.85 cm).

Fig 2. CSF flow streamlines at t/T = 4.5.

The reported streamlines are obtained from test cases (a) ${\text{PS}}_1^{\star }$ (without NRDL) and (b) PS₁ (with NRDL).

Fig 3. Normalized drug concentration profiles as a function of the distance Δy from the injection point P₁.

The reported profiles result from (a) ${\text{S}}_1^{\star }$ and (b) S₁.

Fig 4. Time evolution of the normalized drug concentration and relative linear fitting.

The blue lines represent the time evolution of the normalized drug concentration at different cross sections from the injection point for (a) ${\text{S}}_1^{\star }$ and (b) S₁. The red line indicates the relative linear fitting ($\overline{c}$).

Fig 5. Normalized drug concentration profiles as a function of the distance Δy from the injection point for different injection positions.

The profiles are obtained with test cases S₁-S₆.

Fig 6. Normalized drug concentration profiles as a function of the distance Δy from the injection point for different catheter angles.

The profiles are obtained with a dorsal injection located at P₂ (for test cases S₂, S₇, S₈) and with a lateral injection located at P₆ (for test cases S₆, S₉, S₁₀).

Fig 7. Normalized drug concentration profiles as a function of the distance Δy from the injection point P₂ for different injection speeds.

The profiles are obtained with test cases S₂, S₁₁, S₁₂.

Fig 8. Cross-sectional views of the CSF velocity magnitude and dimensional drug concentration.

(left) Magnitude of the CSF velocity at t = 20 T and (right) corresponding dimensional drug concentration (number of particles per volume) at Δy = 0 cm (C5-level) for test cases S₄, S₅ and S₆.