This study was funded by Central Michigan University Innovative Research Grant P421071 and Early Career Grant P622911.

The MRI images were provided by the Hamner Institutes for Health Sciences and the usage of these images was approved by the Virginia Commonwealth University institutional review board.
1. Image-Based Nasal Airway Preparation
<ol>
	<li>Acquire magnetic resonance (MR) images of a healthy non-smoking 53-year-old male (weight 73 kg and height 173 cm) that consist of 72 coronal cross-sections spaced 1.5 mm apart spanning the nostrils to the nasopharynx4.</li>
	<li>Open Imaging ...

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A coupled image-CFD method was presented in this study that incorporated the image-based model development, quality meshing, airflow simulation, and magnetic particle tracking. Multiple software modules were implemented to this aim, which included functions of segmentation of medical images, reconstruction/meshing of anatomically accurate airway models, and flow-particle simulations. Using this numerical method, performances of three intranasal delivery protocols were tested and compared. Compared to in vitro ex...

Drugs delivered to the olfactory region can bypass the blood-brain-barrier and directly enter the brain, leading to an efficient uptake and quick action onset of the drugs1,2. However, conventional nasal devices such as nasal pumps and sprays deliver extremely low doses to the olfactory region (&#60; 1%) via the nasal route3,4. It is primarily due to the complicated structure of the human nose which is composed of narrow, convoluted passageways (Figure 1). The olfactory region locates above the superior meatus, where only a very small fraction of inhaled air can reach5,6. Furthermore, conventional inhalation devices depend on aerodynamic forces to transport therapeutic agents to the target area7. There is no further control over the motions of particles after their release. Therefore, the transport and deposition of these particles predominately depend on their initial speeds and release positions. Due to the convoluted nasal passage as well as the lack of particle control, the majority of drug particles are trapped in the anterior nose and cannot reach the olfactory region8.
While there are many choices of nasal devices, those designed specifically for targeted olfactory delivery have rarely been reported7,9. One exception is Hoekman and Ho10 who developed an olfactory-preferential delivery device and demonstrated higher cortex-to-blood drug levels in rats as opposed to using a nose drop. However, scaling the deposition results in rats to humans is not straightforward, considering the vast anatomical and physiological differences between these two species11. Many limitations exist when using adapted versions of standard nasal devices for olfactory deliveries. One primary setback is that only a very small portion of medications can be delivered to the olfactory mucosa, through which the medications may enter the brain. Numerical modeling predicted that less than 0.5% of intranasally administered nanoparticles can deposit in the olfactory region3,5. The deposition rate is even lower (0.007%) for micrometer particles12. In order to make the nose-to-brain delivery clinically feasible, the olfactory deposition rate has to be significantly improved.
There exist several possible approaches to improve the olfactory delivery. One approach is the smart inhaler idea proposed by Kleinstreuer et al.13 As particles depositing in one region are mainly from one specific area at the inlet, it is possible to deliver particles to the target site by releasing them only from certain areas at the inlet. The smart delivery technique has been shown to generate a much more efficient lung delivery than conventional methods.13,14 It is hypothesized that this smart delivery idea can also be applied in intranasal drug delivery to improve dosages to the olfactory mucosa. By releasing particles into different positions at the nostril opening and from different depths within the nasal cavity, improved olfactory delivery efficiencies and reduced drug waste in the anterior nose are possible.
Another possible method is to actively control the particle motion within the nasal cavity using a variety of field forces, such as electric or magnetic force. Electric control of charged particles has been suggested for targeted drug delivery to the human nose and lungs15-17. Xi et al.18 numerically tested the performance of electric guidance of charged particles and predicted significantly improved olfactory doses. Similarly, guidance of ferromagnetic drug particles with an appropriate magnetic field also has the potential to target particles to the olfactory mucosa. Behaviors of inhaled agents, if ferromagnetic, can be altered by imposing appropriate magnetic forces19. Dames et al.20 demonstrated that it is practical to target ferromagnetic particles to specific areas in mouse lungs. By packaging therapeutic agents with superparamagnetic iron oxide nanoparticles, the deposition in one lung of a mouse under the influence of a strong magnetic field was significantly increased compared to the other lung20.
Particles were assumed to be spherical and ranged from 150 nm to 30 &#181;m in diameter. The governing equation is21: 
(1)<img alt="Equation 1" src="/files/ftp_upload/53902/53902eq1.jpg" />
The above equation describes the motion of a particle governed by drag force, gravitational force, Saffman lift force 22, Brownian force for nanoparticles, and magnetophoretic force if placed in a magnetic field. Here, vi is the particle velocity, ui is the flow velocity, &#964;p is the particle response time, Cc is the Cunningham correction factor, and &#945; is the air/particle density ratio. To effectively guide the intranasally administered drugs to the olfactory region, it is necessary for the applied magnetophoretic forces to overcome both the particle inertia and gravitational force. In this study, a composite of 20% maghemite (&#947;-Fe2O3, 4.9 g/cm3) and 80% active agent was assumed, which give a density of approximate 1.78 g/cm3 and a relative permeability of 50. The selection of &#947;-Fe2O3 was due to its low cytotoxic. Iron (3+) ions are widely found in human body and a slightly higher ion concentration will not cause significant side-effects23.

<table border="0" cellpadding="0" cellspacing="0" width="659">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:152px;">MIMICS 13</td>
			<td style="width:199px;">Materialise Inc, Ann Arbor, MI</td>
			<td style="width:188px;">MR image segmentation</td>
			<td style="width:120px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:152px;">Gambit</td>
			<td style="width:199px;">ANSYS Inc, Canonsburg, PA&#160;</td>
			<td style="width:188px;">Model development</td>
			<td style="width:120px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:152px;">ANSYS ICEMCFD</td>
			<td style="width:199px;">ANSYS Inc, Canonsburg, PA&#160;</td>
			<td style="width:188px;">Meshing</td>
			<td style="width:120px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:152px;">ANSYS Fluent</td>
			<td style="width:199px;">ANSYS Inc, Canonsburg, PA&#160;</td>
			<td style="width:188px;">Fluid and particle simulation</td>
			<td style="width:120px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:152px;">COMSOL Multiphsics</td>
			<td style="width:199px;">COMSOL Inc, Burlington, MA</td>
			<td style="width:188px;">Magnetic particle tracing</td>
			<td style="width:120px;"></td>
		</tr>
	</tbody>
</table>

modeling and simulations of olfactory drug delivery with passive and active controls of nasally inhaled pharmaceutical aerosols

There are many advantages of direct nose-to-brain drug delivery in the treatment of neurological disorders. However, its application is limited by the extremely low delivery efficiency (&#60; 1%) to the olfactory mucosa that directly connects the brain. It is crucial to develop novel techniques to deliver neurological medications more effectively to the olfactory region. The objective of this study is to develop a numerical platform to simulate and improve intranasal olfactory drug delivery. A coupled image-CFD method was presented that synthetized the image-based model development, quality meshing, fluid simulation, and magnetic particle tracking. With this method, performances of three intranasal delivery protocols were numerically assessed and compared. Influences of breathing maneuvers, magnet layout, magnetic field strength, drug release position, and particle size on the olfactory dosage were also numerically studied.
From the simulations, we found that clinically significant olfactory dosage (up to 45%) were feasible using the combination of magnet layout and selective drug release. A 64 -fold higher delivery of dosage was predicted in the case with magnetophoretic guidance compared to the case without it. However, precise guidance of nasally inhaled aerosols to the olfactory region remains challenging due to the unstable nature of magnetophoresis, as well as the high sensitivity of olfactory dosage to patient-, device-, and particle-related factors.

Control Case: 
Figure 3 displays the airflow field and particle deposition in the nasal airway with standard nasal devices. It clearly shows that airflow from the front nostril is ventilated to the upper passage and airflow from the back nostril is directed towards the nasal floor (Figure 3A). Aerosol particles are observed to move faster in the median passages and slower near the walls, forming an aerosol front in the mean flow dire...

Watch this Scientific Journal Video about Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols at JoVE.com

Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols

This manuscript reviews the modeling and simulations of different protocols to deliver medications to the olfactory region in image-based nasal airway models. Multiple software modules are used to develop the anatomically accurate nose model, generate computational mesh, simulate nasal airflows, and predict particle deposition at the olfactory region.

There are many advantages of direct nose-to-brain drug delivery in the treatment of neurological disorders. However, its application is limited by the ...

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.

modeling-simulations-olfactory-drug-delivery-with-passive-active

Research

JoVE Journal

Medicine

10.8K Views.  California Baptist University. 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 olfact...