**3.3. Multiphysics (COMOL) simulations of olfactory dosing delivery of charged particles**

## *3.3.1. Electric‐guided olfactory delivery diagram*

The olfactory doses between the vestibular and deep intubation protocols, as well as the conventional delivery method, were compared on the basis of deposition fraction per area

) (**Figure 4b**). The surface area of the olfactory mucosa in this study (**Figure 1c**) is 6.8

. Overall speaking, both intubation protocols significantly enhanced the olfactory targeting while the deep intubation outperformed the vestibular intubation. However, it is noted that even using the deep intubation method, very low fractions of administered dose (0.16%/cm2 or 1.09% in the olfactory region) were delivered to target, while nearly 99% was lost in other regions, causing tremendous waste and potentially significant unwanted side effects. Therefore, further efforts are needed to explore strategies that can precisely target drug particles to

Sar-Gel visualization of the local deposition inside the nasal replica is displayed in **Figure 5** for two common nasal spray products (Astelin and Nasonex). The angle of the spray plume

droplets were trapped by the narrow flow-limiting nasal valve. It is noted that the drug distribution is largely dictated by the physical properties of spray droplets. The high filtration by the slit-shaped nasal valve can be attributed to the high inertia of spray droplets that have large sizes (70–90 μm) and exit from the spray pumps with relatively high speeds. Dripping was absent in Astelin that had a wide spray plume angle, while dripping was observed in Nasonex that had a narrow plume and was prone to cause local droplet accumulation (**Figure 5a** vs. **5b**). Deposition of Astelin appeared to be more dispersed than Nasonex.

**Figure 5.** Deposition pattern in the nose with two nasal spray products: (a) Astelin and (b) Nasonex. The majority of

A commercially available jet nebulizer (Philips Respironics InnoSpire) was utilized to evaluate particle deposition in the nose. Nebulized aerosols were released into the nostril at an orien-

deposited in the anterior nose (vestibule and valve regions). Aerosol deposition in the middle

from the vertical direction. As shown in **Figure 6**, most administered droplets

spray droplets deposit in the nasal vestibule and valve region and cannot reach the olfactory region.

for Nasonex. The majority of spray

for Astelin and 20o ± 0.5o

the olfactory region while minimizing drug loss to other tissues.

**3.2. Sar‐Gel visualization of nasal deposition distributions**

± 0.8o

(%/cm2

was approximately 35o

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tation 15o

cm2

The principle of olfactory drug delivery under electric guidance is illustrated in **Figure 7**. There are four essential functions in this device: (1) generation, (2) charging, (3) focusing, and (4) navigation of the pharmaceutical aerosols (**Figure 7a**). A head brace can be added to fix the device relative to the patient's head. Commercially available nebulizers (droplets) and dry powder inhalers can be used to generate aerosolized particles [49]. Particle charging was achieved by letting particles going through a charging chamber, and the acquired charge number can be controlled by varying the voltage supply to the charging chamber [50]. The focusing chamber is composed of several slits [51], with the first slit having a positive voltage and the last one having zero voltage. When the positively charged dry powders travel through these slits, a repulsive force from the slit pushes the dry powders inward to form a focused beam; simultaneously, the forward component of the repulsion accelerates the aerosol beam to a certain exiting velocity. The benefit of knowing the initial speed of particles is that the deposition pattern can be estimated beforehand so that the optimal delivery protocol can be selected. Another benefit is that drug delivery will be more independent of the breathing condition if the initial particle velocities are much higher than the respiratory airflow velocities. This feature is very desirable for inhalation therapy for seniors or people with breathing problems or low compliance capability. After particles were administered into the nose, they will experience an external electric force and divert from their original course. For optimal drug delivery to the olfactory region, particles should move along the middle passage of the nose to minimize wall losses (**Figure 7b**). In this chapter, we will evaluate whether it is feasible to enhance the olfactory doing through electric guidance of charged particles with charge levels and electric potentials that are safe to humans.

**Figure 7.** Diagram of electric-guided olfactory drug delivery. (a) Charged particles will be attracted toward the olfactory region by an applied electric field. (b) For optimal olfactory drug delivery, particles should travel along the middle plane of the nasal passage.

## *3.3.2. Idealized 2‐D nose model*

The proposed delivery protocol was first evaluated in an idealized 2-D nose configuration. The inhaled airflow field in the nose is shown in **Figure 8a**. There are three streams due to the obstruction of the inferior and middle turbinate. The upper flow stream is further divided by the superior turbinate. Only a small fraction of inhaled airflow was ventilated into the uppermost olfactory region. Due to poor olfactory ventilations, inhaled particles are unlikely to be conveyed to the olfactory region by convection or inertia. It is also observed in **Figure 8a** that stream traces initiating from the posterior naris move toward the nasal floor, while those from the anterior naris move toward the upper passage (superior meatus). It is hypothesized that pharmaceutical agents released into the at the naris tip have a larger chance to deposit into the olfactory mucosa.

To generate a desirable external electric field, four electrodes were put on top of the nose. The electrode voltages were specified to be −3, −8, −12, and 0 V, respectively (**Figure 8a**). The small electric potential (3 V) above the nasal vestibule was intended to impart particles an upward attraction. The electric potential above the middle nose was increased to −8 V to attract particles further toward the olfactory mucosa. The electric potential close to the olfactory region was around −12 V in order to catch the charged aerosols. **Figure 8b** shows the numerically predicted electric field (E-field), which changes from nearly 0 V at the nostrils to about −12 V at the olfactory region.

From **Figure 8c**, electric guidance of charged particles significantly increased the olfactory dosing, which was two orders of magnitude higher in comparison with that when an electric field was absent. **Figure 8d** displays particle transport in the nose 1 second after administration. The majority of particles (∼95%) deposit in the olfactory mucosa. As a comparison, only 0.77% deposit in the olfactory region without an electric field.

Numerical Simulation and Experimental Testing to Improve Olfactory Drug Delivery with Electric Field Guidance of... http://dx.doi.org/ 10.5772/65858 101

**Figure 8.** Computational modeling of electric-guided delivery in a 2-D nose model. (a) Airflow field, (b) electric field, (c) comparison of the olfactory deposition rates with and without electric guidance for conventional and point-release delivery techniques, and (d) particle trajectories with and without electric force for the point-release technique. Electric-guided delivery of charged particles can enhance the olfactory doses by two orders of magnitude relative to the case without an electric field.

#### *3.3.3. Realistic 3‐D nose model*

nose to minimize wall losses (**Figure 7b**). In this chapter, we will evaluate whether it is feasible to enhance the olfactory doing through electric guidance of charged particles with charge levels

**Figure 7.** Diagram of electric-guided olfactory drug delivery. (a) Charged particles will be attracted toward the olfactory region by an applied electric field. (b) For optimal olfactory drug delivery, particles should travel along the middle

The proposed delivery protocol was first evaluated in an idealized 2-D nose configuration. The inhaled airflow field in the nose is shown in **Figure 8a**. There are three streams due to the obstruction of the inferior and middle turbinate. The upper flow stream is further divided by the superior turbinate. Only a small fraction of inhaled airflow was ventilated into the uppermost olfactory region. Due to poor olfactory ventilations, inhaled particles are unlikely to be conveyed to the olfactory region by convection or inertia. It is also observed in **Figure 8a** that stream traces initiating from the posterior naris move toward the nasal floor, while those from the anterior naris move toward the upper passage (superior meatus). It is hypothesized that pharmaceutical agents released into the at the naris tip have a larger chance to deposit

To generate a desirable external electric field, four electrodes were put on top of the nose. The electrode voltages were specified to be −3, −8, −12, and 0 V, respectively (**Figure 8a**). The small electric potential (3 V) above the nasal vestibule was intended to impart particles an upward attraction. The electric potential above the middle nose was increased to −8 V to attract particles further toward the olfactory mucosa. The electric potential close to the olfactory region was around −12 V in order to catch the charged aerosols. **Figure 8b** shows the numerically predicted electric field (E-field), which changes from nearly 0 V at the nostrils to about −12 V at the

From **Figure 8c**, electric guidance of charged particles significantly increased the olfactory dosing, which was two orders of magnitude higher in comparison with that when an electric field was absent. **Figure 8d** displays particle transport in the nose 1 second after administration. The majority of particles (∼95%) deposit in the olfactory mucosa. As a comparison, only 0.77%

deposit in the olfactory region without an electric field.

and electric potentials that are safe to humans.

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plane of the nasal passage.

*3.3.2. Idealized 2‐D nose model*

into the olfactory mucosa.

olfactory region.

A comparison of deposition patterns in the image-based 3-D nose model with and without electric guidance is shown in **Figure 9a**. The charge number of the particles is 5000, and the particle size is 0.5 μm. With an appropriate electric field, 3.7% of inhaled particles reached the olfactory mucosa (**Figure 9a**). However, only 0.06% of administered aerosols delivered to the olfactory mucosa without electric guidance.

**Figure 9.** Computational modeling of electric-guided delivery in an anatomically accurate 3-D nose model. Particle deposition patterns were compared with and without electric forces for (a) the entire nostril release method (conventional delivery) and (b) the point-release method. (c) Significantly improved olfactory doses were achieved with electric guidance for both the conventional and point-release techniques. Electric-guided delivery increased the olfactory doses by approximately two orders of magnitude than without an electric field.

To further improve drug delivery to the olfactory mucosa, particles are released into a small point in the anterior nostril to minimize the filtration by the nasal valve and turbinate. With appropriate electric field strength, a majority (92%) of administered particles were dispensed to the olfactory region (red ellipse) that would have otherwise landed in the upper posterior nose in the absence of an electric field (**Figure 9b**, right vs. left). A careful study of the deposition distribution in the upper nose (green square, **Figure 9b**) shows that more aerosols are deposited on the turbinate wall (outer side) than on the septum (inner side). To minimize deposition in the turbinate, a lateral force is required to keep the aerosols from depositing onto the turbinate.

## **3.4.** *In vitro* **experiments of electric‐guided olfactory delivery**

## *3.4.1. Normal inhalation delivery*

Particle deposition of charge particles was assessed in the realistic nose replicas. In order to generate a desirable electric field, two positive electrodes (25 and 100 V) were placed above the nose, and one electrode was placed below the nose as the ground. **Figure 10** compares deposition patterns of particles without and with electrostatic charges. For neutral particles, most inhaled particles deposited in the anterior nose while a small amount of particles reached the olfactory mucosa, which resembles the droplet deposition pattern visualized by Sar-Gel images (**Figure 5**). By contrast, significantly improved olfactory dosing was measured for charged particles under an external electric field (blue-dashed ellipse, **Figure 10b**). Meanwhile, filtration by the nasal vestibule and valve region was perceivably lower.

**Figure 10.** Particle deposition patterns in the 3-D nasal cast (a) without electric guidance versus (b) with electric guidance. Electric guidance of charged particles led to decreased deposition in the nasal valve region and noticeably enhanced deposition in the olfactory region.

#### *3.4.2. Bi‐directional delivery*

The distribution of particle deposition using the bi-directional method is shown in **Figure 11**. High particle accumulations were observed in the upper nose of the right nasal passage, indicating there is an effective electric field guidance of charged particles to the olfactory region. It was also noted that particle deposition in the two passages was apparently different (right panel, **Figure 11**). In the right passage, particle deposition was more uniformly distributed, and a large portion of particles appeared to be pulled toward the electrodes. By contrast, the majority of particles in the left passage deposited in the inferior nose while much fewer particles reached the upper nose, presumably due to the gravitational effect.

To further improve drug delivery to the olfactory mucosa, particles are released into a small point in the anterior nostril to minimize the filtration by the nasal valve and turbinate. With appropriate electric field strength, a majority (92%) of administered particles were dispensed to the olfactory region (red ellipse) that would have otherwise landed in the upper posterior nose in the absence of an electric field (**Figure 9b**, right vs. left). A careful study of the deposition distribution in the upper nose (green square, **Figure 9b**) shows that more aerosols are deposited on the turbinate wall (outer side) than on the septum (inner side). To minimize deposition in the turbinate, a lateral force is required to keep the aerosols from depositing onto the turbinate.

Particle deposition of charge particles was assessed in the realistic nose replicas. In order to generate a desirable electric field, two positive electrodes (25 and 100 V) were placed above the nose, and one electrode was placed below the nose as the ground. **Figure 10** compares deposition patterns of particles without and with electrostatic charges. For neutral particles, most inhaled particles deposited in the anterior nose while a small amount of particles reached the olfactory mucosa, which resembles the droplet deposition pattern visualized by Sar-Gel images (**Figure 5**). By contrast, significantly improved olfactory dosing was measured for charged particles under an external electric field (blue-dashed ellipse, **Figure 10b**). Meanwhile,

**Figure 10.** Particle deposition patterns in the 3-D nasal cast (a) without electric guidance versus (b) with electric guidance. Electric guidance of charged particles led to decreased deposition in the nasal valve region and noticeably en-

The distribution of particle deposition using the bi-directional method is shown in **Figure 11**. High particle accumulations were observed in the upper nose of the right nasal passage, indicating there is an effective electric field guidance of charged particles to the olfactory region. It was also noted that particle deposition in the two passages was apparently different

**3.4.** *In vitro* **experiments of electric‐guided olfactory delivery**

filtration by the nasal vestibule and valve region was perceivably lower.

*3.4.1. Normal inhalation delivery*

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hanced deposition in the olfactory region.

*3.4.2. Bi‐directional delivery*

**Figure 11.** Deposition pattern in the right nasal passage and nasopharynx with the bi-directional delivery method. Appreciable deposition of particles was observed in the olfactory region. Because particles travel through the right and left passages in sequence, more particles were observed in the right passage than in the left passage.

**Figure 12.** Comparison of the olfactory-to-nasal dosage ratio with and without electric guidance for the normal and bidirectional delivery strategies. \**p*-value < 0.05.

**Figure 12** shows the comparison of the olfactory-to-nasal dosage ratio between the cases with and without the electric field guidance. The particle releasing time is 20 seconds, and the results are presented as the mean ± SD from five trials. With electric field guidance, significantly improved olfactory depositions were obtained for both delivery strategies, i.e., by a factor of 5 for the normal delivery and by a factor of 3 for the bi-directional delivery. The effect of the delivery method was also examined in the absence of an electric field; the olfactory dose using the bi-directional method was 2.8 times that under the normal method. However, with electric field guidance, the bi-directional olfactory dose was only 1.6 times the normal dose.
