経鼻吸入医薬品エアロゾルのパッシブとアクティブコントロールを使用した嗅覚ドラッグデリバリーのモデリングとシミュレーション

The overall goal of this methodology is to develop different protocols to deliver medications to the olfactory region in image based nasal airway models. This method can help answer key questions in attacking neurological drug delivery such as:Whether it is feasible to deliver adequate dosage to the olfactory region. How to control particle motions in the nose.

What is the best practice for olfactory targeting? The main advantage of this technique is that a significantly enhanced olfactory dosage can be achieved. This is a critical step for nose to brain drug delivery.

The implication of this technique extend towards therapy of brain tumors. Since drug particles deposited in the olfactory region can directly enter the brain. Begin by acquiring magnetic resonance, or MR images, of a healthy, nonsmoking 53 year old male, that consist of 72 coronal cross sections spaced 1.5 millimeters apart spanning the nostrils to the nasopharynx.

Open the imaging software and import the MR images by clicking File, Import Images. Select the MR images and click OK.To construct the 3D model click Segmentation, then Threshold. To set the grayscale range between negative 1024 and negative 419.

Click Segmentation and Calculate 3D. Next, click Segmentation and Calculate Polylines. Select the 3D body and click OK to generate the polylines that define the solid geometry.

Export the polylines as an IGES file. Now, open the model development software, and click File, Import, and IGES to import the IGES file into the program. Then, click the Edge Command button on the right panel, click Create Edge, and select NURBS to reconstruct smooth contours.

Click Face Command button, then, Form Face. Select Wire Frame to build a surface from edges. Continue to build all surfaces that cover the whole airway.

Retain the nasal anatomical details such as the uvula, epiglottal fold, and laryngeal sinus. Click File, Export, IGES to export the nasal airway model. Next, open the meshing software.

Click File, Import Geometry, Legacy, and STEPIES to import the nasal airway model. Click Create Parts to divide the airway surfaces into five different regions:The nasal vestibule, nasal valve, turbinate region, olfactory, and nasopharynx. Generate a computational mesh inside the airway by clicking Mesh, and Global Mesh Setup.

Specify the maximum mesh size as 0.1 millimeters and click Apply. Finally, add a body fitted mesh in the near wall region by clicking Compute Mesh, Prism Mesh. Specify the number of layers as five, and the expanding ratio as 1.25 and click Apply.

Begin by opening the model development software to develop the nasal model with front vestibular intubation. Click Volume, then Move Copy to change the location of the nebulizer catheter five millimeters into the vestibule from the nostril tip. Click Injection to release 150 nanometers of particles into the nostril.

Then, open the fluid simulation software to compute particle deposition rates inside the nose. To compute the airflow field inside the airway, select the laminar flow model by clicking Define, Models, Viscous, and then choose Laminar under Viscous Model. To track particle motions select the Discrete Phase Model.

Check Saffman Lift Force under Discrete Phase Model, click Report, and then choose Sample Trajectories. To find the number of particles deposited in the predefined olfactory region select Nasal under Boundaries and click Compute. Calculate the deposition rate as the ratio of the amount of deposited particles to the amount of particles entering the nostrils.

Next, develop the nasal model with back vestibular intubation. Conduct the same procedure as done with the front. Click Volume, then Move Copy to change the location of the nebulizer catheter five millimeters into the vestibule from the rear nostril.

Click Injection to release 150 nanometers of particles into the nostril. Proceed with deep intubation by inserting the nebulizer catheter right beneath the olfactory region. Release 150 nanometers of particles from the nebulizer.

Use fluid and simulation software to compute particle deposition rates inside the nose on both total and local bases by following similar procedures as done for the vestibular intubation. Finally, repeat deep intubation while exercising breath holding and exhalation respectively. Click Define, then Boundary Conditions to open the Boundary Condition panel.

Specify zero velocity at the two nostrils for breath holding. Specify vacuum pressure of 200 pascals at the nostrils, and zero pressure at the outlet for exhalation. Begin by opening magnetic particle tracking software.

Click Geometry, and Rectangle to build the two plate channel. Click Rectangle to build the magnets around the two plate channel. Compute the particle trajectories and deposition rate by clicking Model 1, Laminar Flow, and Inlet 1.

Then, specify the inlet velocity as 0.5 meters per second. Click Model 1, Magnetic Fields, and Magnetic Flux Conservation and specify the strength of the three magnets. Click Model 1, Particle Tracking for Fluid Flow, and Particle Properties.

Specify the particle diameter and density, then click Inlet to release 3, 000 particles and to specify particle relative permeability, click Magnetophoretic Force and Compute. To find how many particles are depositing in the selected area, click Results, 1D Plot Group, and Plot. Calculate the deposition rate as the ratio of the amount of particles deposited in a certain area to the amount of particles entering the geometry.

Next, to adjust the magnet's strength, click Model 1, then Magnetic Fields. Choose Magnetic Flux Conservation and change the magnet strength under Magnetization. Increase the magnet strength by an increment of one times ten to the fourth amps per meter and click Compute.

Begin by applying the recently obtained magnetic strengths into a 2D nose model by putting three magnets one millimeter above the nose. Click Model 1, Geometry 1, to specify the size and position of the magnet. Then, click Model 1, Particle Tracking for Fluid Flow, and Inlet to release 3, 000 particles into the left nostril.

Click Particle Properties to specify the particle size as 15 micrometers. Simulate the particle trajectories and subsequent olfactory delivery efficiencies by clicking Model 1, Laminar Flow, and Inlet 1. Specify the inlet velocity as 0.5 meters per second.

Click Model 1, Magnetic Fields, and Magnetic Flux Conservation and specify the strength of the three magnets. Lastly, adjust the magnet layout and strength to improve olfactory delivery efficiency. To adjust the magnet's size and position click Model 1, then Geometry 1, then choose the magnet of interest and change the values of width, depth, height or X, Y and Z.Adjust magnet strength by clicking Model 1, then Magnetic Fields.

Choose Magnetic Flux Conservation and change the magnet strength under Magnetization. Increase the magnet strength by an increment of one times ten to the fourth amps per meter, and click Compute. After completing testing in the 2D model, import the 3D nasal airway model into magnetic particle tracking software.

Just as done for the 2D nose model, put four magnets one millimeter above the nose, and release 3, 000 particles of 15 micrometer diameter from one selected point. Use magnetic particle tracking software to track particle trajectories and compute olfactory delivery efficiencies by following similar procedures previously mentioned. Following the same procedure as before, adjust the magnet layout and strength in the 3D model to improve the target delivery to the olfactory region.

Finally, test particle size ranging from one to 30 micrometers to find the right particle size for optimal magnetophoretic guidance to the olfactory region. Conventional nasal devices often deliver very low doses of drugs to the olfactory region due to the complicated structure of the nose. For vestibular intubation, there is a strong jedifact of particle release immediately downstream of the nasal.

As expected, more drug particles are delivered to the olfactory region with front intubation than back, for both 150 nanometer and one micrometer particles. To assess performance of magnetophoretic guidance, a two plate channel was used to find the working magnet strength, followed by an idealized 2D nose model to find a baseline magnet layout, and then an image based 3D nose model to test the performance. The optimal olfactory dosage comes from aerosols in the range of 13 to 17 micrometers.

Once mastered, this technique can be done well in two days, if conducted properly. While attempting this procedure, it's important to remember that procedures can be more time consuming for complex geometries. Following this procedure, other methods like electro guidance of charged particles can also be tested in order to answer whether charged particles can be used for effective olfactory drug delivery.

After this development, this technique paved the way for researchers in the field of targeted drug delivery to explore the usage of magnetic field in the lungs or other organs. After watching this video, you should have a good understanding of how to improve drug delivery and conduct simulations with Fluent and Comsol.