**4. Discussion and conclusion**

In this chapter, we presented a series of efforts in our lab aiming to improve the olfactory targeting of neurological medications. Both numerical and experimental tests were conducted to this aim by exploring various delivery strategies. Results of this study show that it is feasible to achieve clinically relevant olfactory doses using electric guidance of charged particles. All three protocols were demonstrated to give improved olfactory doses even though the improvement differs among the three. Compared to standard nasal devices, the point-release methods (vestibular and deep intubations) delivered approximately two order of magnitude higher doses to the olfactory region for both 150 nm and 1 μm particles. But even using the optimal delivery protocol (deep intubation), the olfactory dosage (1%) is still not adequate (∼1%) to be clinically practical for the purpose of direct nose-to-brain drug delivery. In contrast, active control of drug particles using an externally applied electric field has been demonstrated to deliver much higher doses to target than the case without an electric field. An olfactory deposition fraction of 16% was measured with electric guidance under bi-directional breathing conditions.

The ability to dispense medications to the olfactory epithelium has tremendous superiority over convention inhalation devices in treating neurological diseases. A significantly enhanced olfactory dosing remits or eases the prevailing problem of too low olfactory doses. Second, reduced particle deposition in regions other than the olfactory region can minimize adverse side effects in those regions. Third, charged particles under the control of an external electric force will be are less dependent on respirations, making it suitable for seniors or subjects with comprised breathing capacities [52, 53]. The feature of robust delivery with electric guidance is especially appealing when the administration of medications requires long durations.

The electric delivery device is envisioned to have two major parts: a head-mounted nasal mask and a particle charging system. The nasal mask holds the electrodes and fixes the electrode relative to the patient head (**Figure 13a**). One example of the particle charging system is

**Figure 13.** Electric-guidance olfactory delivery diagram and conceptual device designs. (a) A delivery system consists of two parts: a nose-mounted apparatus to generate desired electric field and a device to generate, charge, and pointrelease particles. (b) The conceptual delivery device uses a jet nebulizer and has an upright position.

illustrated in **Figure 13b** that contains a nebulizer, a charging ring, and a point-release nozzle. A prototype of this conceptual design was built using an Object30 Pro 3D printer (**Figure 13b**). An ideal design will generate small sized aerosols (<4 μm) at a slow speed and with high levels of electrostatic charges. Our preliminary test of this device, however, failed to produce such aerosols. Further testing and refinement are warranted to optimize the performance of this device.

Limitations of *in vitro* tests in this study include large particle size (30 μm), high exiting velocities of charge dry powders, large point-release area, and limited number of nasal models. Dry powders of 30 μm were selected because of the limited availability of dry powders satisfying both geometric and electrostatic requirements herein. Smaller aerosol particles are more sensitive to the guidance of electric forces and thus will lead to better doses in the olfactory region. A slow-moving particle will have longer residence time to respond to electric controls and is more likely to reach the target. In this study, the point-release catheter has a diameter of 4 mm and needs to be decreased to produce more site-specific doses. The nasal airway model was reconstructed from MRI images of one subject only and could not account intersubject variability. Future *in vitro* experiments and numerical simulations with more realistic scenarios are necessary to optimize the performance of electric-guidance delivery systems.

In conclusion, drug delivery of charged particles to the olfactory mucosa was assessed using both experiments and computations. Specific findings are as follows:

