Parameter characteristics in intranasal drug delivery: A key to targeting medications to the olfactory airspace.

BACKGROUND: The nose is a viable pathway for topical drug delivery to the olfactory cleft for treatment of obstructive smell loss and nose-to-brain drug delivery. This study investigates how variations in nasal vestibule morphology influence intranasal spray drug transport to the olfactory cleft and olfactory roof/bulb regions. METHODS: The unilateral nasal vestibule morphology in three healthy subjects with healthy normal nasal anatomy was classified as Elongated (Subject DN001), Notched (Subject DN002), and Standard (Subject DN003). Computational fluid and particle dynamics modelling were used to simulate nasal airflow and drug particle transport to the olfactory cleft and olfactory roof/bulb regions in each subject-specific nasal cavity. To evaluate highest drug depositions in these regions, the particle transport simulations involved extensive parameter combination analyses: 6 inspiratory flow rates mimicking resting to sniffing (10-50 L/min); 5 spray release locations (Top, Bottom, Central, Lateral, and Medial); 5 head positions (Upright, Tilted Forward, Tilted Back, Supine, and Mygind); 3 particle velocities (1, 5, and 10 m/s); 350,000 µm-particles (1-100 µm) and 346,500 nanoparticles (10-990 nm). FINDINGS: Particle size groups with highest depositions in olfactory cleft: DN001 left = 28.4% at 11-20 µm, right = 75.3% at 6-10 µm; DN002 left = 16.8% at 1-5 µm, right = 45.3% at 30-40 nm; DN003 left = 29.1% at 21-30 µm, right = 15.9% at 6-10 µm. Highest depositions in olfactory roof/bulb: DN001 left = 6.5% at 11-20 µm, right = 26.4% at 11-20 µm; DN002 left = 3.6% at 1-5 µm, right = 2.6% at 1-5 µm; DN003 left = 2.8% at 21-30 µm, right = 1.7% at 31-40 µm. INTERPRETATION: DN001 (Elongated nasal vestibule) had the most deposition in the olfactory regions. Micron-particles size groups generally had better deposition in the olfactory regions.

Olfactory drug delivery with intranasal sprays after nasal midvault reconstruction.

Conductive olfaction and nose to brain drug delivery are important processes that remain limited by inadequate odorant or drug delivery to the olfactory airspace. Primary challenges include anatomic barriers and poor targeting to the olfactory region. This study uses computational fluid dynamics to investigate the effects of nasal midvault surgery on olfactory drug delivery with intranasal sprays. Soft tissue elevation, spreader flaps, and spreader grafts were performed on two fresh cadaveric specimens, using computed tomography for airway reconstruction. Nasal airflow and drug particle transport simulations were performed under these conditions: inhalation rate (15, 30 L/min), spray velocity (1, 5, 10 m/s), spray location (top, bottom, center, medial, lateral), head position (upright, supine, forward, backward), and particle size (1-100 µm). Simulation results were used to calculate drug particle deposition to the olfactory airspaces and bulbs. Total olfactory deposition was < 5% but attained a maximum of 36.33% when sorted by particle size. There was no association between nasal midvault surgery and olfactory deposition. No single parameter or technique demonstrated superior olfactory deposition, but smaller particle size, slower spray velocity, and higher inhalation rate tended to optimize olfactory deposition, providing important implications for future intranasal spray and drug design to target the olfactory airspace.

A computational analysis on the impact of multilevel laryngotracheal stenosis on airflow and drug particle dynamics in the upper airway.

Laryngotracheal stenosis (LTS) is a type of airway narrowing that is frequently caused by intubation-related trauma. LTS can occur at one or multiple locations in the larynx and/or trachea. This study characterizes airflow dynamics and drug delivery in patients with multilevel stenosis. Two subjects with multilevel stenosis (S1 = glottis + trachea, S2 = glottis + subglottis) and one normal subject were retrospectively selected. Computed tomography scans were used to create subject-specific upper airway models. Computational fluid dynamics modeling was used to simulate airflow at inhalation pressures of 10, 25, and 40 Pa, and orally inhaled drug transport with particle velocities of 1, 5, and 10 m/s, and particle size range of 100 nm-40 µm. Subjects had increased airflow velocity and resistance at stenosis with decreased cross-sectional area (CSA): S1 had the smallest CSA at trachea (0.23 cm2) and resistance = 0.3 Pa·s/mL; S2 had the smallest CSA at glottis (0.44 cm2), and resistance = 0.16 Pa·s/mL. S1 maximal stenotic deposition was 4.15% at trachea; S2 maximal deposition was 2.28% at glottis. Particles of 11-20 µm had the greatest deposition, 13.25% (S1-trachea) and 7.81% (S2-subglottis). Results showed differences in airway resistance and drug delivery between subjects with LTS. Less than 4.2% of orally inhaled particles deposited at stenosis. Particle sizes with most stenotic deposition were 11-20 µm and may not represent typical particle sizes emitted by current-use inhalers.

Comparison of Inhaled Drug Delivery in Patients With One- and Two-level Laryngotracheal Stenosis.

OBJECTIVES/HYPOTHESIS: Laryngotracheal stenosis (LTS) is a functionally devastating condition with high respiratory morbidity and mortality. This preliminary study investigates airflow dynamics and stenotic drug delivery in patients with one- and two-level LTS. STUDY DESIGN: A Computational Modeling Restropective Cohort Study. METHODS: Computed tomography scans from seven LTS patients, five with one-level (three subglottic, two tracheal), and two with two-level (glottis + trachea, glottis + subglottis) were used to reconstruct patient-specific three-dimensional upper airway models. Airflow and orally inhaled drug particle transport were simulated using computational fluid dynamics modeling. Drug particle transport was simulated for 1-20 µm particles released into the mouth at velocities of 0 m/s, 1 m/s, 3 m/s, and 10 m/s for metered dose inhaler (MDI) and 0 m/s for dry powder inhaler (DPI) simulations. Airflow resistance and stenotic drug deposition in the patients' airway models were compared. RESULTS: Overall, there was increased airflow resistance at stenotic sites in subjects with two-level versus one-level stenosis (0.136 Pa s/ml vs. 0.069 Pa s/ml averages). Subjects with two-level stenosis had greater particle deposition at sites of stenosis compared to subjects with one-level stenosis (average deposition 2.31% vs. 0.96%). One-level stenosis subjects, as well as one two-level stenosis subject, had the greatest deposition using MDI with a spacer (0 m/s): 2.59% and 4.34%, respectively. The second two-level stenosis subject had the greatest deposition using DPI (3.45%). Maximum deposition across all stenotic subtypes except one-level tracheal stenosis was achieved with particle sizes of 6-10 µm. CONCLUSIONS: Our results suggest that patients with two-level LTS may experience a more constricted laryngotracheal airflow profile compared to patients with one-level LTS, which may enhance overall stenotic drug deposition. LEVEL OF EVIDENCE: NA Laryngoscope, 133:366-374, 2023.

Analyses on the influence of normal nasal morphological variations on odorant transport to the olfactory cleft.

OBJECTIVE: Olfaction requires a combination of sensorineural components and conductive components, but conductive mechanisms have not typically received much attention. This study investigates the role of normal nasal vestibule morphological variations in ten healthy subjects on odorant flux in the olfactory cleft. MATERIALS AND METHODS: Computed tomography images were used to create subject-specific nasal models. Each subject's unilateral nasal cavity was classified according to its nasal vestibule shape as Standard or Notched. Inspiratory airflow simulations were performed at 15 L/min, simulating resting inspiration using computational fluid dynamics modeling. Odorant transport simulations for three odorants (limonene, 2,4-dinitrotoluene, and acetaldehyde) were then performed at concentrations of 200 ppm for limonene and acetaldehyde, and 0.2 ppm for dinitrotoluene. Olfactory cleft odorant flux was computed for each simulation. RESULTS AND DISCUSSION AND CONCLUSION: Simulated results showed airflow in the olfactory cleft was greater in the Standard phenotype compared to the Notched phenotype. For Standard, median airflow was greatest in the anterior region (0.5006 L/min) and lowest in the posterior region (0.1009 L/min). Median airflow in Notched was greatest in the medial region (0.3267 L/min) and lowest in the posterior region (0.0756 L/min). Median olfactory odorant flux for acetaldehyde and limonene was greater in Standard (Acetaldehyde: Standard = 140.45 pg/cm2-s; Notched = 122.20 pg/cm2-s. Limonene: Standard = 0.67 pg/cm2-s; Notched = 0.65 pg/cm2-s). Median dinitrotoluene flux was greater in Notched (Standard = 2.86 × 10-4pg/cm2-s; Notched = 4.29 × 10-4 pg/cm2-s). The impact of nasal vestibule morphological variations on odorant flux at the olfactory cleft may have implications on individual differences in olfaction, which should be investigated further.

Role of nasal vestibule morphological variations on olfactory airflow dynamics.

BACKGROUND: The conductive mechanisms of olfaction are typically given little priority in the evaluation of olfactory function. The objective of this study is to investigate the role of nasal vestibule morphological variations on airflow volume at the olfactory recess in healthy subjects. METHODS: Anatomically realistic three-dimensional nasal airway models were constructed from computed tomography scans in five subjects. Each individual's unilateral nasal cavity (10 total) was classified according to the shape of their nasal vestibule: Standard, Notched, or Elongated. Nasal airflow simulations were performed using computational fluid dynamics modeling at two inspiratory flow rates (15 L/min and 30 L/min) to reflect resting and moderate breathing rates. Olfactory airflow volume and cross-sectional flow resistance were computed. FINDINGS: Average olfactory airflow volumes (and percent airflow in olfactory) were: 0.25 L/min to 0.64 L/min (3.0%-7.7%; 15 L/min simulations) and 0.53 L/min to 1.30 L/min (3.2%-7.8%; 30 L/min simulations) for Standard; 0.13 L/min - 0.47 L/min (2.0%-6.8%; 15 L/min simulations) and 0.06 L/min - 0.82 L/min (1.7%-6.1%; 30 L/min simulations) for Notched; and 0.07 L/min - 0.39 L/min (1.2%-5.4%; 15 L/min simulations) and 0.30 L/min - 0.99 L/min (2.1%-6.7%; 30 L/min simulations) for Elongated. On average, relative difference in olfactory resistance between left and right sides was 141.5% for patients with different unilateral phenotypes and 82.2% for patients with identical unilateral phenotype. INTERPRETATION: Olfactory cleft airflow volume was highest in the Standard nasal vestibule phenotype, followed by Notched phenotype for 15 L/min simulations and Elongated phenotype for 30 L/min simulations. Further, intra-patient variation in olfactory cleft airflow resistance differs greatly for patients with different unilateral phenotypes compared to patients with identical unilateral phenotype.