Study on Cerebrospinal Fluid Flow Dynamics and Its Application in Drug Delivery

Background Introduction

Cerebrospinal fluid (CSF) plays a crucial role in the human spinal canal, responsible for transporting dissolved nutrients and waste products. Due to its pulsatile nature, CSF flow is influenced by cardiac and respiratory cycles. In recent years, with the increasing demand for treating central nervous system (CNS) diseases, optimizing intrathecal (IT) drug delivery has become a research hotspot. Intrathecal injection leverages the fluid dynamics of CSF to deliver therapeutic molecules directly to the CNS, thereby improving treatment efficacy.

However, most existing computational fluid dynamics (CFD) models are based on individuals or small groups. Due to significant variability in spinal canal geometry, these findings may not be generalizable to a broader population. Therefore, this study aims to establish a universal principle for optimizing intrathecal injection protocols by evaluating the geometry of an individual’s spinal subarachnoid space (SAS), thereby enhancing the efficiency and effectiveness of drug delivery.

Source of the Paper

This paper was co-authored by Ziyu Wang, Mohammad Majidi, Chenji Li, and Arezoo Ardekani, all from the School of Mechanical Engineering at Purdue University. The paper was published in 2024 in the journal Fluids and Barriers of the CNS, titled “Numerical study of the effects of minor structures and mean velocity fields in the cerebrospinal fluid flow.”

Research Process

1. Research Objectives and Methods

The primary objective of this study is to identify a universal principle to guide the personalized design of intrathecal injection protocols for individual patients. To achieve this, the researchers numerically simulated pulsatile CSF flow fields and Lagrangian velocity fields in canonical spinal SAS geometries. The study also analyzed the impact of minor anatomical structures (such as nerve roots, denticulate ligaments, and the wavy arachnoid membrane) on drug delivery and separately examined the contributions of major mechanisms—steady streaming (SS) and Stokes drift (SD)—to mass transport.

2. Geometric Model Construction

The researchers constructed two canonical spinal SAS geometric models for CFD simulations. The first model is an eccentric annular pipe with an outer diameter of 1.8 cm, an inner diameter of 9 mm, and an eccentricity of 0.5. The second model adds simplified minor structures, such as nerve roots, denticulate ligaments, and a wavy arachnoid membrane, to the first model. Each geometric model spans three vertebrae, with each vertebra having a height of 2 cm.

3. CFD Simulations

The researchers used the pimpleFoam solver in OpenFOAM to handle unsteady, incompressible flow. The finite volume method was employed for numerical simulations, with a time step of 0.004 seconds and a maximum grid size of 0.2 mm to ensure the capture of complex flow and geometric details. The simulations assumed that CSF pulsation is solely driven by the heartbeat, and the inlet boundary condition used an adjusted CSF flow rate time profile to ensure the flow field in the region of interest is representative.

4. Data Analysis

By calculating the cycle-averaged Eulerian velocity field, Stokes drift velocity field, and Lagrangian velocity field, the researchers quantified upward and downward flows in different regions. Additionally, the Strouhal number was computed to characterize the number of pulsations required for drug particles to travel from the base to the top of a vertebra.

Key Findings

1. Impact of Minor Structures

The study found that minor structures (such as nerve roots, denticulate ligaments, and the wavy arachnoid membrane) play a critical role in modulating flow and transport dynamics within the spinal SAS. These structures can enhance fluid transport, particularly near the nerve roots, where steady streaming and Stokes drift velocities significantly increase.

2. Cycle-Averaged Velocity Fields

In the simplified geometric model, the cycle-averaged Eulerian and Lagrangian velocity fields were nearly identical, with Stokes drift velocities being relatively small. However, in the geometric model incorporating minor structures, the cycle-averaged velocity fields became complex, with Stokes drift velocities comparable to steady streaming velocities but in the opposite direction, resulting in overall lower magnitudes of the Lagrangian velocity field.

3. Optimization of Drug Delivery

The results indicate that injecting drugs into the wider region of the spinal canal can significantly improve upward drug delivery efficiency. This finding provides important insights for optimizing intrathecal injection protocols by leveraging the natural flow dynamics within the spinal canal.

Conclusions and Significance

This study highlights the critical role of minor structures in modulating flow and transport dynamics within the spinal SAS and emphasizes the necessity of using particle tracking in computational mass transport studies. The research also elucidates the complex relationship between spinal canal geometry and transport dynamics, offering new perspectives for optimizing intrathecal injection protocols. By designing injection protocols that direct drugs into the wider region, the efficiency and effectiveness of drug delivery can be significantly enhanced.

Research Highlights

1. Impact of Minor Structures: The study systematically analyzed the effects of nerve roots, denticulate ligaments, and the wavy arachnoid membrane on CSF flow and drug transport for the first time, revealing their key role in enhancing fluid transport.
2. Application of Particle Tracking: The study underscores the importance of using particle tracking in computational mass transport research, revealing significant discrepancies between Eulerian and Lagrangian velocity fields.
3. Proposal of a Universal Principle: The study proposes a universal principle based on individual spinal canal geometry for optimizing intrathecal injection protocols, offering significant clinical value.

Additional Valuable Information

The study also suggests that future research should further validate the proposed principle in patient-specific geometries and consider the effects of spinal curvature, tissue deformation, and gravity on CSF flow and drug transport. Additionally, the influence of respiration and sleep on CSF flow patterns should be incorporated into future studies.

Through this research, we have deepened our understanding of fluid dynamics within the spinal canal and provided new approaches and methods for treating CNS diseases.