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. Author manuscript; available in PMC: 2024 May 1.
Published in final edited form as: Laryngoscope. 2022 May 13;133(5):1036–1043. doi: 10.1002/lary.30155

Intranasal Spray Characteristics for Best Drug Delivery in Patients with Chronic Rhinosinusitis

Carson Popper 1,2, Hannah Martin 2, Reanna Shah 2, Ryan Sicard 2, Katrina Hodges 2,3, Dennis Frank-Ito 2,4,5
PMCID: PMC9653517  NIHMSID: NIHMS1802930  PMID: 35560998

Abstract

Objectives

To determine parameter combinations for effective drug delivery of intranasal spray steroids to the ostiomeatal complex (OMC) and maxillary sinus (MS) in patients with chronic rhinosinusitis (CRS).

Methods

Each patient’s sinonasal cavity was reconstructed from computed tomography scans. Intranasal airflow and drug particle transport were simulated using computational fluid dynamic modeling. Airflow simulations were performed at 15 Pascal inhalation pressure. Intranasal spray particles of 1–100 microns were simulated at release speeds of 1, 5, and 10 m/s from 6 release locations (Bottom, Center, Top, Lateral, Lateral-Bottom, and Lateral-Top) at a nozzle insertion depth of 15 mm. Drug delivery simulations were performed in the head tilted forward position.

Results

Maximal OMC deposition was 0.78 – 12.44%, while maximal MS deposition was 0.02 – 1.03% across all simulations. In general, particles between 6–10 microns had the best OMC (at 1 m/s particle velocity) and MS (at 10 m/s particle velocity) deposition. Particles ranging from 21–30 microns also had superior OMC deposition. The lateral and lateral-top spray release locations produced maximum OMC deposition, but no one release location demonstrated an increase in MS deposition.

Conclusion

This preliminary study suggests that it is challenging to determine a common set of intranasal spray parameter combinations for effective drug delivery to the ostiomeatal complex and maxillary sinuses. Although drug particle size and spray particle velocity seem to impact particle deposition patterns, spray release location appears to vary with anatomical differences between subjects, particularly when the MS is the target location for particle deposition.

Keywords: Drug Delivery, Chronic Rhinosinusitis, Computational Fluid Dynamics

Introduction

Adult chronic rhinosinusitis (CRS) with or without nasal polyps as defined in the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 (EPOS2020) is the presence of two or more symptoms lasting at least 12 weeks, one of which should be either nasal blockage/obstruction/congestion or nasal discharge; with validation by telephone or interview [1]. CRS according to EPOS2020 can be classified either as primary or secondary and is divided within each classification as localized (unilateral) and diffuse (bilateral) depending on anatomic distribution of the disease [1]. In the case primary CRS, the disease is considered by endotype dominance while secondary CRS is based on four categories dependent on local pathology, mechanical, inflammatory and immunological factors [1].

In certain situations, CRS can be non-responsive to medical management and surgery is usually recommended [1]. Nonetheless, the appropriate timing for surgical intervention remains heavily debated, though a minimum course of eight weeks of nasal corticosteroids is advised before surgery, and the persistent use for post-surgery management is important [1–5]. Medical management options for CRS include intranasal steroids, saline irrigation, antibiotics, and biologicals (monoclonal antibodies). However, topical antibiotics do not appear to be more effective than placebo in reducing CRS symptoms in a meta-analysis of six studies [1, 6–11].

On the other hand, nasal corticosteroids are particularly useful in reducing inflammation and suppressing pro-inflammatory mediators, and they are recommended before and after endoscopic sinus surgery. In other meta-analyses, nasal corticosteroids were preferred to placebo for quality of life (QOL) improvement, which was measured using Sinonasal Outcome Test-22 (SNOT-22), for patients with CRS [1, 12–28]. While patients tended to tolerate nasal corticosteroids relatively well with mostly mild to moderate adverse events, they have been found to increase the risk of epistaxis, which could be attributed to improper usage of the delivery device (intranasal sprays) [1, 13, 20, 21, 23–27, 29–43].

One of the biggest challenges in using nasal corticosteroids is targeting drugs to achieve effective dose of medication at the maxillary sinus (MS), which is important for therapeutic effects; to facilitate draining and ventilation. Part of the difficulty with targeting the MS or the proximal ostiomeatal complex (OMC) with intranasal steroid sprays is the variability in patient self-administration of nasal sprays and the wide array of factors that influence drug particle movement within the nasal passages. Inefficient intranasal drug delivery to the MS and OMC contributes to poor symptom relief and long-term sequelae of CRS.

The current recommendations on package inserts provided by pharmaceutical companies may not be optimal for delivering drugs to target the MS and OMC. Current guidance recommends tilting the head forward with the bottle upright and releasing the spray in a lateral direction when inside the nasal cavity. Intranasal drug deposition patterns are complex and depend highly on administration technique as well as the delivery mechanism. Variables impacting particle deposition patterns include spray release location, head position, spray velocity, drug composition, particle size, airflow, mode of delivery, among others. Even in patients with normal nasal anatomy, intranasal drug delivery to the MS and OMC is challenging due to the arrangement of the turbinates and difficulty with angling the drug nozzle appropriately within the nose during drug administration. In patients with CRS and inflamed mucosa, this becomes even more challenging. With the odds against successful drug delivery to the MS in CRS, it is crucial that contributing variables are evaluated, understood, and optimized in order to successfully deliver drug to the MS and OMC.

This study uses computational fluid dynamics (CFD) to investigate how release location, spray velocity, particle size, and individual nasal anatomy impacts drug deposition on the OMC and MS in five preoperative patients with CRS and no prior history of undergoing endoscopic sinus surgery. The use of CFD and anatomically accurate computational models allows for objective analysis of drug particle transport simulations to be carried out on multiple subjects. The goal of this study is to evaluate the variables that influence intranasal drug delivery to the OMC and MS to provide clinicians with (1) insightful information for patient education in drug administration technique; and (2) determine best intranasal drug delivery techniques to provide symptom relief to patients with CRS.

METHODS

This retrospective study was approved by the Duke University Health System Institutional Review Board for Clinical Investigations. Computed tomography (CT) scans of five eligible preoperative patients with CRS without nasal polyps were selected after conducting a Duke Enterprise Unified Content Explorer (D.E.D.U.C.E.) search on all adult individuals 18 years and over diagnosed and treated for CRS within the Duke University Health System from July 1st, 2008 and March 1st, 2015 (Fig. 1A – 1E). Selected patients have not had prior endoscopic sinus surgery. Figure 1 demonstrates coronal views of CT scans for each of the five subjects: the right side is more diseased in Subjects 1 and 5, while the left side is more diseased in Subjects 2 and 3, and both sides of Subject 4 were mildly diseased. All five subjects (four males and one female, aged 37–66 years) reported normal olfactory ability as indicated by their response of <3 on the smell based question on the Sino-Nasal Outcome Test (SNOT-22) questionnaire; [44, 45] a validated instrument for assessing quality of life related to sinonasal conditions. Although our assertion of patients’ normal olfactory ability is based on their reported SNOT-22 response, SNOT-22 is not a validated instrument for olfactory assessment. The D.E.D.U.C.E. search records showed that these patients were not administered any validated instruments for olfactory assessment.

Figure 1.

Figure 1.

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Coronal views from CT scans of all patients. A. Subject 1, B. Subject 2, C. Subject 3, D. Subject 4, E. Subject 5. F. Schematic diagram of the sinonasal airway.

Airway Reconstruction

CT images of each subject were read into the imaging analysis software Avizo™ (FEI, Burlington, MA) for de-identification and creation of three-dimensional (3D) nasal airway models. The Sinonasal cavities were delineated with subsequent manual editing as needed, to create 3D models in a method similar to previous publications from our group [2, 46–48]. The reconstructed 3D nasal airspace models were exported from Avizo™ in stereolithography file format and imported into the computer aided design and mesh-generating software package ICEM-CFD™ 19.1 (ANSYS, Canonsburg, PA). For each sinonasal cavity model, a box covering the external nose was created and specified as airflow inlet surface and the following regions were defined in the airway models: unilateral left and right nasal passages, left and right MS (unless the sinus was completely opacified), left and right OMC, nasopharynx, and a planer outlet surface (Fig. 1F).

Airflow Simulations

To solve the discretized governing equations of fluid flow, each 3D nasal model geometry was discretized by generating hybrid tetrahedral-prism mesh elements in the nasal airway domain using ICEM-CFD. Approximately 5 million graded tetrahedral elements were generated in the airway models including the external nose with a box covering the nose as the inlet surface. Mesh quality analysis was done to ensure that all tetrahedral elements had an aspect ratio greater than 0.3, to prevent distorted elements from affecting the accuracy of the numerical simulation. A finer three-layer prism-element with a 0.1 mm prism thickness for each layer was created at the airway walls to accurately account for near-wall particle trajectories. The mesh densities and structure chosen were consistent with suggested densities yielding mesh independent results from the mesh refinement study by [49] The conservation of mass and momentum governing equations for laminar, viscous, incompressible, transient inspiratory flow at rest reduces to:

∇⋅u→=0, (1)
ρ(u→⋅∇)u→=−∇p+μ∇2u→, (2)

where u→=u→(x,y,z) is the velocity vector field, ρ = 1.204 kg/m3 is fluid density, μ = 1.825 × 10−5 kg/m − s is dynamic viscosity, and p is pressure. Airflow simulations at inspiratory pressures of 15 Pa were simulated using the CFD software, Fluent™ 19.1 (ANSYS, Inc., Canonsburg, PA, U.S.A). Fluent™ uses the finite volume method to solve the discretized governing equations. The following boundary conditions were specified for our low-to-moderate inspiratory simulations: a no-slip, stationary boundary at the nasal wall; a “pressure-inlet” boundary condition at the inlet surface with gauge pressure set to 0 Pa; and a “pressure-outlet” condition at the outlet with a negative gauge pressure set as −15 Pa. The −15 Pa pressure is specified to target normal resting inhalation. The use of a constant inhalation pressure induces variability in inhalation airflow rate based on the each patient’s nasal anatomical morphology and severity of CRS.

Drug Particle Simulations

The drug particle simulations involved computing particle trajectories in the airway during inhalation. Dispersed particles exchanged momentum and mass with inhaled airflow. Particle trajectories were calculated using the Euler-Lagrange approach via the Lagrangian discrete phase model in Fluent™, assuming unit density and spherical particles with particle density of 1000 kg/m3 and no interactions between particles. Particle sizes ranged from 1–100 microns and particle velocity was set to either 1 m/s, 5 m/s, or 10 m/s.[50, 51] For each particle size, 3500 particles were released into each unilateral airway for a total of 350,000 micron particles. The simulation setup mimics the administration of nasal sprays in the sinonasal passage. A simulated spray nozzle was postioned in the nasal passage 15 mm from the nostril and directed towards six different release locations (Bottom, Center, Top, Lateral, Lateral-Bottom, and Lateral-Top) with the head tilted forward at 45°. Simulated particles were tracked until they either exited the sinonasal passages in the pharynx or until they deposited on the airway mucosa. Subsites of the sinonasal passages were defined as the left or right nasal passage, left or right MS, left or right OMC, and nasopharynx.

RESULTS

Drug Particle Deposition

Across all subjects and simulations tested, maximum drug particle deposition in the MS was 1.03%, which occurred in the right MS of Subject 4 using a lateral spray position at 1 m/s (Fig. 2A). In the OMC (Fig. 2B), drug particle deposition was highest in Subject 5 right side (12.44%) which was accomplished with a lateral top spray position at 1 m/s and lowest in Subject 2 left side (0.01%) from a central release position at 10 m/s.

Figure 2.

Figure 2.

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Drug particle deposition on each side in A. MS, and B. OMC

Figure 3 illustrates particle deposition patterns for each release locations for particles sized 1–20 microns in Subject 1 at 1 m/s particle velocity. The Bottom and Central release locations barely had deposition in the main nasal airway. For all release locations, the right (more diseased) airway had more airway deposition, while most of the particles exited the airway on the left side.

Figure 3.

Figure 3.

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Particle deposition in the paranasal airway by release location.

Drug Deposition by Particle Size Groups

Subject 1:

Particle sizes belonging to group G02 (6 to 10 microns) had the most MS deposition (5.34%) on the left sinus resulting from a lateral top release position at 10 m/s (Fig. 4A). The other particle size groups with non-zero MS drug depositions had between 0.01% (G05) and 0.49% (G03) on the left sinus and between 0.11% (G01) and 0.22% (G02) on the right (more diseased) sinus (Fig. 4A). G03 (11 to 20 microns) particle group had best OMC deposition (5.93%) on the right compared to a much smaller maximum deposition (3.75%) on the left for the same group (Fig. 4B). The right deposition was achieved with a central release location at 5 m/s. The right side had a greater deposition with smaller particle sizes 1.08% to 5.93% for G01 through G04 compared to 0.29% to 0.003% for G05 through G010 (Fig. 4B). The left side had a more even distribution of depositions, from 0.11% to 3.75% from G01 to G11 (Fig. 4B).

Figure 4.

Figure 4.

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Deposition by particle size group. A. Subject 1 MS, B. Subject 1 OMC, C. Subject 2 MS, D. Subject 2 OMC. (G01=1–5 microns, G02=6–10 microns, G03=11–20 microns, G04=21–30 microns, G05=31–40 microns, G06=41–50 microns, G07=51–60 microns, G08=61–70 microns, G09=71–80 microns, G10=81–90 microns, G11=91–100 microns)

Subject 2:

The right MS had a maximal deposition of 1.42% from G02 (6 to 10 microns) at 10 m/s from the top release location (Fig. 4C). The MS only had particle deposition on the right, and only from two size groups (G02 and G03), with a deposition of 0.28% for G03 as the left MS was severely opacified (Fig. 4C). The best group size deposition on the OMC came from G04 (21 to 30 microns), with a deposition of 16.83% on the right OMC (Fig. 4D). This was achieved with a lateral release at 1 m/s. The maximal deposition on the left side was 0.04% with G05 (31 to 40 microns) (Fig. 4D).

Subject 3:

This subject had had zero MS deposition. The best group size deposition for the right OMC was 9.67%, occurring in G02 (6 to 10 microns) compared to 1.68% on the left (diseased side) in G01 (1 to 5 microns) (Fig. 5A). The right OMC deposition was from a lateral release location at 1 m/s. The right OMC had a minimal deposition in G01, maxing out in G02 and then tailing off through G11 (0.22% to 6.88%) (Fig. 5A).

Figure 5.

Figure 5.

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Deposition by particle size group. A. Subject 3 OMC, B. Subject 5 OMC, C. Subject 4 MS, D. Subject 4 OMC. Note Subjects 3 and 5 had zero MS deposition and were not displayed on the plot. (G01=1–5 microns, G02=6–10 microns, G03=11–20 microns, G04=21–30 microns, G05=31–40 microns, G06=41–50 microns, G07=51–60 microns, G08=61–70 microns, G09=71–80 microns, G10=81–90 microns, G11=91–100 microns)

Subject 4:

Maximal OMC on the right occurred at G04 (21 to 30 microns) with a deposition of 28.43% for lateral release location at 1 m/s compared to 8.45% on the left with G03 (11 to 20 microns) (Fig. 5D). Groups G02 through G04 had larger depositions on the right side (18.86% to 28.43%) (Fig. 5D). The left OMC had minimal deposition with G02 and G04 through G11 (0.01% to 4.9%) (Fig. 5D). Best MS deposition on the right was 20.66% occurring at G02 (6 to 10 microns) from the lateral position with 1 m/s (Fig. 5C). This was much greater than all the other subjects. The left MS had a deposition of 0.34% at G02 (6 to 10 microns) (Fig. 5C). There were only three particle group sizes that had non-zero deposition (G01 to G03) (Fig. 5C).

Subject 5:

G03 (11 to 20 microns) had the greatest right (diseased) side OMC deposition (60.72%) (Fig. 5B), occurring at lateral top release position for 1 m/s. On the contrary, the left OMC had minimal deposition in every particle group size (Fig. 5B). As particle size increased beyond G03 group, deposition decreased on the right OMC (21.89% to 2.47%) (Fig. 5B). This large deposition was interesting due to the right side being the diseased side. There was no deposition in the right or left MS.

Discussion

This study demonstrates that it is challenging to determine a common set of intranasal spray parameters for effective drug delivery to the MS and the OMC. Drug particle size range and spray particle velocity seem to have distinguishable trends for each subject, but deposition patterns from various spray release locations appear to vary with the individual anatomy of each subject.

There was no one release location that clearly stood out as the optimal release location across all subjects. The best release location varied from subject to subject, but the lateral and central release locations performed the best overall. In a similar study, Basu et al. found that aiming directly toward the OMC (“line of sight”) had optimal results compared to current use methods of aiming the spray axis closer to the lateral nasal wall [52]. The “line of sight” direction that they found optimal would likely be between the lateral and central locations used in this study. Future studies could help improve our understanding on the optimal release location by including more release locations to see how slight variations may improve delivery, as well as examining more closely the impact of specific anatomic variations such as septal deviation and turbinate hypertrophy on drug deposition patterns.

Particle size does appear to influence the success of drug delivery to the MS, although these trends were less clear for OMC deposition. The G02 (6 to 10 micron) particle size group resulted in the maximal deposition in the MS for each of the subjects that had any MS deposition. Hyo et al. theorized that the optimal particle size for MS deposition was from 3–10 microns, which concurs with our findings [53]. In a different study, Saijo et al. investigated MS deposition in post-ESS cast model using steady-state aerosol flow. That study found that particles of 5.63 microns were deposited at a greater rate than particles with a diameter of 16.37 microns [54, 55]. Wofford et al. examined how MS drug deposition improved post-surgery. They found that the particle size group with the best deposition were sprayed particles from 5–20 microns [47].

When looking specifically at deposition at the OMC, particles ranging from 11–20 microns (G03 group) had optimal deposition in 4 of the 10 simulations with meaningful OMC deposition. All of the other OMC max deposition groups ranged from G01 (1 to 5 microns) to G06 (41 to 50 microns). Our data suggests that particle size may influence drug deposition patterns to the MS and suggest that smaller particles (<50 microns) may provide optimal deposition, although future research in additional subjects is needed to confirm these trends.

Variations in intranasal anatomy and the severity of mucosal inflammation had a profound impact on intranasal drug deposition patterns for each subject. Subjects with severe unilateral disease tended to have better drug delivery to the MS and OMC on the contralateral side. In Subject 4, there was mild bilateral disease, but the deposition on the right was much greater for both the MS and OMC, potentially because there was an accessory ostium on the right side that increased the surface area considered part of the OMC region. In Subject 5, the right side demonstrated more mucosal edema, but also had much greater deposition on the right OMC, potentially because the surface area of the right OMC was greater than that of the left OMC in this subject.

Of the five subjects, only three had deposition on their MS, and one of those subjects only had unilateral deposition. Lack of deposition in the MS could be secondary to either intranasal anatomy that blocks the ability of the drug particles to reach the OMC, such as turbinate hypertrophy, septal deviation, or nasal polyps, or inflammation of the OMC itself that obstructs the maxillary antrum. Even in a healthy, unobstructed nasal passageway, delivery of intranasal particles to the OMC and MS is challenging.

The major limitation of this study was the small sample size, limiting our ability to fully assess the impact of individual subject anatomy and disease severity on our results. Of the 10 MS evaluated, one was excluded as there was no patent OMC in the reconstructed scan, and several others received no drug particle deposition at all, limiting the ability to fully distinguish the impact of each of the many variables involved in particle deposition patterns. Our data suggests the need for larger study, where disease severity and anatomies could be stratified for subgroup analysis, to further evaluate the trends suggested in this preliminary pilot study.

Conclusion

We used computational fluid dynamics to identify variables in intranasal spray administration technique to determine which combination of variables resulted in maximal drug delivery to the OMC and MS in 5 subjects with chronic rhinosinusitis. Our results demonstrate that it is both difficult to successfully delivery intranasal drugs to the OMC in patients with mucosal inflammation secondary to CRS as well as to develop a set of spray parameters that work for every subject. Further work on this topic is warranted to obtain more information on the parameters that optimize drug delivery to the MS. Going forward, this study could be expanded by examining head position as a key variable of improving drug deposition and by increasing the number of subjects in the study.

Acknowledgements:

This research was supported in part by the National Institute of Dental & Craniofacial Research of the National Institutes of Health under Award Number R01DE028554. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. In addition, special thanks to ANSYS, ANSYS Global Academic Program, and Dr. Paolo Maccarini (Duke University) for support and strategic donation. All authors gave final approval for publication.

Funding and Conflict of Interest:

This research was supported in part by the National Institute of Dental & Craniofacial Research of the National Institutes of Health under Award Number R01DE028554. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Meeting: 2022 Triological Combined Sections Meeting 2022, Hotel del Coronado, Coronado, CA, USA

References

  • 1.Fokkens WJ, et al. , European position paper on rhinosinusitis and nasal polyps 2020. Rhinology, 2020. 58: p. I–+. [DOI] [PubMed] [Google Scholar]
  • 2.Frank Dennis O, Z. AM, Dhandha Vishal H, McKinney Kibwei A, Fleischman Gitanjali M, Ebert Charles S Jr, Senior Brent A, Kimbell Julia S, Quantification of airflow into the maxillary sinuses before and after functional endoscopic sinus surgery. International Forum of Allergy & Rhinology, 2013. 3(10): p. 834–840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Rudmik L, et al. Defining appropriateness criteria for endoscopic sinus surgery during management of uncomplicated adult chronic rhinosinusitis: a RAND/UCLA appropriateness study. in International Forum of Allergy & Rhinology. 2016. Wiley Online Library. [DOI] [PubMed] [Google Scholar]
  • 4.Chong LY, et al. , Saline irrigation for chronic rhinosinusitis. Cochrane Database of Systematic Reviews, 2016(4). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Chong LY, et al. , Intranasal steroids versus placebo or no intervention for chronic rhinosinusitis. Cochrane Database of Systematic Reviews, 2016(4). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Sykes D, et al. , Relative importance of antibiotic and improved clearance in topical treatment of chronic mucopurulent rhinosinusitis: a controlled study. The Lancet, 1986. 328(8503): p. 359–360. [DOI] [PubMed] [Google Scholar]
  • 7.Desrosiers MY and Salas-Prato M, Treatment of chronic rhinosinusitis refractory to other treatments with topical antibiotic therapy delivered by means of a large-particle nebulizer: results of a controlled trial. Otolaryngology—Head and Neck Surgery, 2001. 125(3): p. 265–269. [DOI] [PubMed] [Google Scholar]
  • 8.Videler W, et al. , Nebulized bacitracin/colimycin: a treatment option in recalcitrant chronic rhinosinusitis with Staphylococcus aureus? A double-blind, randomized, placebo-controlled, cross-over pilot study. Rhinology, 2008. 46(2): p. 92–98. [PubMed] [Google Scholar]
  • 9.Jervis-Bardy J, et al. , A randomized trial of mupirocin sinonasal rinses versus saline in surgically recalcitrant staphylococcal chronic rhinosinusitis. The Laryngoscope, 2012. 122(10): p. 2148–2153. [DOI] [PubMed] [Google Scholar]
  • 10.Shikani A, et al. , Multimodality topical therapy for refractory chronic rhinosinusitis: our experience in thirteen patients with and twelve patients without nasal polyps. Clinical otolaryngology, 2013. 38(3): p. 254–258. [DOI] [PubMed] [Google Scholar]
  • 11.Bonfils P, et al. , Efficacy of tobramycin aerosol in nasal polyposis. European Annals of Otorhinolaryngology, Head and Neck Diseases, 2015. 132(3): p. 119–123. [DOI] [PubMed] [Google Scholar]
  • 12.Harvey RJ, et al. Corticosteroid nasal irrigations are more effective than simple sprays in a randomized double-blinded placebo-controlled trial for chronic rhinosinusitis after sinus surgery. in International forum of allergy & rhinology. 2018. Wiley Online Library. [DOI] [PubMed] [Google Scholar]
  • 13.Leopold DA, et al. , NAVIGATE II: randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis. Journal of Allergy and Clinical Immunology, 2019. 143(1): p. 126–134. e5. [DOI] [PubMed] [Google Scholar]
  • 14.Kobayashi Y, et al. , HFA-BDP metered-dose inhaler exhaled through the nose improves eosinophilic chronic rhinosinusitis with bronchial asthma: a blinded, placebo-controlled study. Frontiers in immunology, 2018: p. 2192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Research ALAAC, et al. , Efficacy of nasal mometasone for the treatment of chronic sinonasal disease in patients with inadequately controlled asthma. Journal of Allergy and Clinical Immunology, 2015. 135(3): p. 701–709. e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Tait S, et al. , Effect of budesonide added to large-volume, low-pressure saline sinus irrigation for chronic rhinosinusitis: a randomized clinical trial. JAMA Otolaryngology–Head & Neck Surgery, 2018. 144(7): p. 605–612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Rawal RB, et al. , Post-operative budesonide irrigations for patients with polyposis: a blinded, randomized controlled trial. Rhinology, 2015. 53(3): p. 227–234. [DOI] [PubMed] [Google Scholar]
  • 18.Rotenberg BW, et al. , Postoperative care for Samter’s triad patients undergoing endoscopic sinus surgery: a double-blinded, randomized controlled trial. The Laryngoscope, 2011. 121(12): p. 2702–2705. [DOI] [PubMed] [Google Scholar]
  • 19.Zhou B, et al. Mometasone furoate nasal spray in the treatment of nasal polyposis in Chinese patients: a double-blind, randomized, placebo-controlled trial. in International Forum of Allergy & Rhinology. 2016. Wiley Online Library. [DOI] [PubMed] [Google Scholar]
  • 20.Wang C, et al. , Effect of budesonide transnasal nebulization in patients with eosinophilic chronic rhinosinusitis with nasal polyps. Journal of Allergy and Clinical Immunology, 2015. 135(4): p. 922–929. e6. [DOI] [PubMed] [Google Scholar]
  • 21.Mösges R, et al. , Efficacy and safety of mometasone furoate nasal spray in the treatment of chronic rhinosinusitis. Advances in Therapy, 2011. 28(3): p. 238–249. [DOI] [PubMed] [Google Scholar]
  • 22.Hansen F, Djupesland P, and Fokkens W, Preliminary efficacy of fluticasone delivered by a novel device in recalcitrant chronic rhinosinusitis. Rhinology, 2010. 48(3): p. 292. [DOI] [PubMed] [Google Scholar]
  • 23.Jorissen M and Bachert C, Effect of corticosteroids on wound healing after endoscopic sinus surgery. Rhinology, 2009. 47(3): p. 280. [DOI] [PubMed] [Google Scholar]
  • 24.Vlckova I, et al. , Effective treatment of mild-to-moderate nasal polyposis with fluticasone delivered by a novel device. Rhinology, 2009. 47(4): p. 419. [DOI] [PubMed] [Google Scholar]
  • 25.Lund VJ, et al. , Effect of fluticasone in severe polyposis. Archives of Otolaryngology–Head & Neck Surgery, 1998. 124(5): p. 513–518. [DOI] [PubMed] [Google Scholar]
  • 26.Lund VJ, et al. , Efficacy and tolerability of budesonide aqueous nasal spray in chronic rhinosinusitis patients. Rhinology, 2004. 42(2): p. 57–62. [PubMed] [Google Scholar]
  • 27.Filiaci F, et al. , A randomized controlled trial showing efficacy of once daily intranasal budesonide in nasal polyposis. Rhinology, 2000. 38(4): p. 185–190. [PubMed] [Google Scholar]
  • 28.Parikh A, et al. , Topical corticosteroids in chronic rhinosinusitis: a randomized, double-blind, placebo-controlled trial using fluticasone propionate aqueous nasal spray. Rhinology, 2001. 39(2): p. 75–79. [PubMed] [Google Scholar]
  • 29.Tos M, et al. , Efficacy of an aqueous and a powder formulation of nasal budesonide compared in patients with nasal polyps. American Journal of Rhinology, 1998. 12(3): p. 183–190. [DOI] [PubMed] [Google Scholar]
  • 30.JOHANSEN LV, et al. , The effect of budesonide (Rhinocort®) in the treatment of small and medium-sized nasal polyps. Clinical Otolaryngology & Allied Sciences, 1993. 18(6): p. 524–527. [DOI] [PubMed] [Google Scholar]
  • 31.Stjärne P, et al. , The efficacy and safety of once-daily mometasone furoate nasal spray in nasal polyposis: a randomized, double-blind, placebo-controlled study. Acta oto-laryngologica, 2006. 126(6): p. 606–612. [DOI] [PubMed] [Google Scholar]
  • 32.Stjärne P, et al. , A randomized controlled trial of mometasone furoate nasal spray for the treatment of nasal polyposis. Archives of Otolaryngology–Head & Neck Surgery, 2006. 132(2): p. 179–185. [DOI] [PubMed] [Google Scholar]
  • 33.Stjärne P, Olsson P, and Ålenius M, Use of mometasone furoate to prevent polyp relapse after endoscopic sinus surgery. Archives of Otolaryngology–Head & Neck Surgery, 2009. 135(3): p. 296–302. [DOI] [PubMed] [Google Scholar]
  • 34.Ruhno J, et al. , A double-blind comparison of intranasal budesonide with placebo for nasal polyposis. Journal of allergy and clinical immunology, 1990. 86(6): p. 946–953. [DOI] [PubMed] [Google Scholar]
  • 35.Dijkstra M, et al. , Fluticasone propionate aqueous nasal spray does not influence the recurrence rate of chronic rhinosinusitis and nasal polyps 1 year after functional endoscopic sinus surgery. Clinical & Experimental Allergy, 2004. 34(9): p. 1395–1400. [DOI] [PubMed] [Google Scholar]
  • 36.Vento S, et al. , Prevention of relapses of nasal polyposis with intranasal triamcinolone acetonide after polyp surgery: A prospective double-blind, placebo-controlled, randomised study with a 9-month follow-up. Clinical Otolaryngology, 2012. 37(2): p. 117–123. [DOI] [PubMed] [Google Scholar]
  • 37.Keith P, et al. , Efficacy and tolerability of fluticasone propionate nasal drops 400 μg once daily compared with placebo for the treatment of bilateral polyposis in adults. Clinical & Experimental Allergy, 2000. 30(10): p. 1460–1468. [DOI] [PubMed] [Google Scholar]
  • 38.Holmberg K, et al. , Fluticasone propionate aqueous nasal spray in the treatment of nasal polyposis. Annals of Allergy, Asthma & Immunology, 1997. 78(3): p. 270–276. [DOI] [PubMed] [Google Scholar]
  • 39.Jankowski R, et al. , Efficacy and tolerability of budesonide aqueous nasal spray treatment in patients with nasal polyps. Archives of Otolaryngology–Head & Neck Surgery, 2001. 127(4): p. 447–452. [DOI] [PubMed] [Google Scholar]
  • 40.Small CB, et al. , Efficacy and safety of mometasone furoate nasal spray in nasal polyposis. Journal of Allergy and Clinical Immunology, 2005. 116(6): p. 1275–1281. [DOI] [PubMed] [Google Scholar]
  • 41.Pentilla M, Ra utiainen MEP, Pukander JS, Karma PH Endoscopic versus Caldwell–Luc approach in chronic maxillary sinusitis: Comparison of symptoms at one-year follow-up. Rhinology, 1994. 1(994): p. 32. [PubMed] [Google Scholar]
  • 42.Ehnhage A, et al. , Functional endoscopic sinus surgery improved asthma symptoms as well as PEFR and olfaction in patients with nasal polyposis. Allergy, 2009. 64(5): p. 762–769. [DOI] [PubMed] [Google Scholar]
  • 43.Lildholdt T, Rundcrantz H, and Lindqvist N, Efficacy of topical corticosteroid powder for nasal polyps: a double-blind, placebo-controlled study of budesonide. Clinical Otolaryngology & Allied Sciences, 1995. 20(1): p. 26–30. [DOI] [PubMed] [Google Scholar]
  • 44.Piccirillo JF, Merritt MG Jr., and Richards ML, Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg, 2002. 126(1): p. 41–7. [DOI] [PubMed] [Google Scholar]
  • 45.Browne JP, et al. , Health-related quality of life after polypectomy with and without additional surgery. Laryngoscope, 2006. 116(2): p. 297–302. [DOI] [PubMed] [Google Scholar]
  • 46.Choi KJ, et al. , Characterizing airflow profile in the postoperative maxillary sinus by using computational fluid dynamics modeling: A pilot study. Am J Rhinol Allergy, 2016. 30(1): p. 29–36. [DOI] [PubMed] [Google Scholar]
  • 47.Wofford MR, et al. , A computational study of functional endoscopic sinus surgery and maxillary sinus drug delivery. Rhinology, 2015. 53(1): p. 41–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Keeler JA, et al. , A Computational Study of Nasal Spray Deposition Pattern in Four Ethnic Groups. J Aerosol Med Pulm Drug Deliv, 2016. 29(2): p. 153–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Frank-Ito DO, et al. , Influence of Mesh Density on Airflow and Particle Deposition in Sinonasal Airway Modeling. J Aerosol Med Pulm Drug Deliv, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Fluent A, ANSYS Fluent Theory Guide, Release 19.0. Ansys 2017, Inc.
  • 51.Dong J, et al. , Detailed nanoparticle exposure analysis among human nasal cavities with distinct vestibule phenotypes. Journal of Aerosol Science, 2018. 121: p. 54–65. [Google Scholar]
  • 52.Basu S, et al. , Numerical evaluation of spray position for improved nasal drug delivery. Sci Rep, 2020. 10(1): p. 10568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Hyo N, Takano H, and Hyo Y, Particle deposition efficiency of therapeutic aerosols in the human maxillary sinus. Rhinology, 1989. 27(1): p. 17–26. [PubMed] [Google Scholar]
  • 54.Albu S, Novel drug-delivery systems for patients with chronic rhinosinusitis. Drug Des Devel Ther, 2012. 6: p. 125–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Saijo R, et al. , Particle deposition of therapeutic aerosols in the nose and paranasal sinuses after transnasal sinus surgery: a cast model study. Am J Rhinol, 2004. 18(1): p. 1–7. [PubMed] [Google Scholar]

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