{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T04:02:34Z","timestamp":1784865754443,"version":"3.55.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The nasal olfactory region is a potential route for non-invasive delivery of drugs directly from the nasal epithelium to the brain, bypassing the often impermeable blood-brain barrier. However, efficient aerosol delivery to the olfactory region is challenging due to its location in the nose. Here we explore aerosol delivery with bi-directional pulsatile flow conditions for targeted drug delivery to the olfactory region using a computational fluid dynamics (CFD) model on the patient-specific nasal geometry. Aerosols with aerodynamic diameter of 1\u00a0\u00b5m, which is large enough for delivery of large enough drug doses and yet potentially small enough for non-inertial aerosol deposition due to, e.g., particle diffusion and flow oscillations, is inhaled for 1.98\u00a0s through one nostril and exhaled through the other one. The bi-directional aerosol delivery with steady flow rate of 4\u00a0L\/min results in deposition efficiencies (DEs) of 50.9 and 0.48% in the nasal cavity and olfactory region, respectively. Pulsatile flow with average flow rate of 4\u00a0L\/min (frequency: 45\u00a0Hz) reduces these values to 34.4 and 0.12%, respectively, and it mitigates the non-uniformity of right-left deposition in both the cavity (from 1.77- to 1.33-fold) and the olfactory region (from 624- to 53.2-fold). The average drug dose deposited in the nasal cavity and the olfactory epithelium region is very similar in the right nasal cavity independent of pulsation conditions (inhalation side). In contrast, the local aerosol dose in the olfactory region of the left side is at least 100-fold lower than that in the nasal cavity independent of pulsation condition. Hence, while pulsatile flow reduces the right-left (inhalation-exhalation) imbalance, it is not able to overcome it. However, the inhalation side (even with pulsation) allows for relatively high olfactory epithelium drug doses per area reaching the same level as in the total nasal cavity. Due to the relatively low drug deposition in olfactory region on the exhalation side, this allows either very efficient targeting of the inhalation side, or uniform drug delivery by performing bidirectional flow first from the one and then from the other side of the nose.<\/jats:p>","DOI":"10.3389\/fphar.2021.746420","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T12:30:01Z","timestamp":1638275401000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Pulsatile Bi-Directional Aerosol Flow Affects Aerosol Delivery to the Intranasal Olfactory Region: A Patient-Specific Computational Study"],"prefix":"10.3389","volume":"12","author":[{"given":"Ali","family":"Farnoud","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hesam","family":"Tofighian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Baumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad M.","family":"Rashidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micheal P.","family":"Menden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Otmar","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"105911","DOI":"10.1016\/j.ejps.2021.105911","article-title":"Flow Structure and Particle Deposition Analyses for Optimization of a Pressurized Metered Dose Inhaler (pMDI) in a Model of Tracheobronchial Airway","volume":"164","author":"Ahookhosh","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"5705","DOI":"10.2147\/IJN.S35329","article-title":"Development and Evaluation of Thymoquinone-Encapsulated Chitosan Nanoparticles for Nose-To-Brain Targeting: a Pharmacoscintigraphic Study","volume":"7","author":"Alam","year":"2012","journal-title":"Int. J. Nanomedicine"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1016\/j.jaerosci.2006.01.013","article-title":"Prediction of Aerosol Deposition in Bends Using LES and an Efficient Lagrangian Tracking Method","volume":"37","author":"Breuer","year":"2006","journal-title":"J. Aerosol Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1115\/1.1990201","article-title":"Index of Resolution Quality for Large Eddy Simulations","volume":"127","author":"Celik","year":"2005","journal-title":"J. Fluids Eng."},{"key":"B5","doi-asserted-by":"publisher","first-page":"174","DOI":"10.3109\/1061186X.2011.622396","article-title":"Solanum tuberosum Lectin-Conjugated PLGA Nanoparticles for Nose-To-Brain Delivery: In Vivo and In Vitro Evaluations","volume":"20","author":"Chen","year":"2012","journal-title":"J. Drug Target."},{"key":"B6","doi-asserted-by":"publisher","first-page":"119341","DOI":"10.1016\/j.ijpharm.2020.119341","article-title":"In Vitro assessment of an Idealized Nose for Nasal spray Testing: Comparison with Regional Deposition in Realistic Nasal Replicas","volume":"582","author":"Chen","year":"2020","journal-title":"Int. J. Pharm."},{"key":"B7","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1089\/08942680152484199","article-title":"Characterization of Nasal spray Pumps and Deposition Pattern in a Replica of the Human Nasal Airway","volume":"14","author":"Cheng","year":"2001","journal-title":"J. Aerosol Med."},{"key":"B8","doi-asserted-by":"crossref","DOI":"10.1201\/b11103","volume-title":"Multiphase Flows with Droplets and Particles","author":"Crowe","year":"2011"},{"key":"B9","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.jaerosci.2013.12.008","article-title":"CFD Simulation of Total and Regional Fiber Deposition in Human Nasal Cavities","volume":"69","author":"Dastan","year":"2014","journal-title":"J. Aerosol Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1007\/s13346-012-0108-9","article-title":"Nasal Drug Delivery Devices: Characteristics and Performance in a Clinical Perspective-A Review","volume":"3","author":"Djupesland","year":"2013","journal-title":"Drug Deliv. Transl. Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1089\/jamp.2011.0924","article-title":"Nasal Deposition and Clearance in Man: Comparison of a Bidirectional Powder Device and a Traditional Liquid spray Pump","volume":"25","author":"Djupesland","year":"2012","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"B12","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1097\/01.MLG.0000199741.08517.99","article-title":"Breath Actuated Device Improves Delivery to Target Sites beyond the Nasal Valve","volume":"116","author":"Djupesland","year":"2006","journal-title":"Laryngoscope"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1126\/science.276.5320.1868","article-title":"Large Porous Particles for Pulmonary Drug Delivery","volume":"276","author":"Edwards","year":"1997","journal-title":"Science"},{"key":"B14","doi-asserted-by":"publisher","first-page":"103816","DOI":"10.1016\/j.compbiomed.2020.103816","article-title":"Simulation of Patient-specific Bi-directional Pulsating Nasal Aerosol Dispersion and Deposition with Clockwise 45\u00b0 and 90\u00b0 Nosepieces","volume":"123","author":"Farnoud","year":"","journal-title":"Comput. Biol. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1615\/atomizspr.2017020782","article-title":"Numerical Simulation of the Dispersion and Deposition of a Spray Carried by a Pulsating Airflow in a Patient-Specific Human Nasal Cavity","volume":"27","author":"Farnoud","year":"2017","journal-title":"Atomization Sprays."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1063\/5.0024264","article-title":"Large Eddy Simulations of Airflow and Particle Deposition in Pulsating Bi-directional Nasal Drug Delivery","volume":"32","author":"Farnoud","year":"","journal-title":"Phys. Fluids."},{"key":"B17","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.ejps.2012.04.013","article-title":"Development and Evaluation of Rivastigmine Loaded Chitosan Nanoparticles for Brain Targeting","volume":"47","author":"Fazil","year":"2012","journal-title":"Eur. J. Pharm. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"045105","DOI":"10.1063\/1.2717722","article-title":"On the Accuracy of the Two-Fluid Formulation in Direct Numerical Simulation of Bubble-Laden Turbulent Boundary Layers","volume":"19","author":"Ferrante","year":"2007","journal-title":"Phys. Fluids"},{"key":"B19","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3109\/10717549709051878","article-title":"Delivery of125I-NGF to the Brain via the Olfactory Route","volume":"4","author":"Frey","year":"1997","journal-title":"Drug Deliv."},{"key":"B20","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.jaerosci.2013.09.004","article-title":"Numerical Analysis of Stochastic Dispersion of Micro-particles in Turbulent Flows in a Realistic Model of Human Nasal\/upper Airway","volume":"67","author":"Ghahramani","year":"2014","journal-title":"J. Aerosol Sci."},{"key":"B21","volume-title":"Aerosol Technology : Properties, Behavior, and Measurement of Airborne Particles","author":"Hinds","year":"1999"},{"key":"B22","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.ijpharm.2019.04.019","article-title":"An In Vitro Evaluation of Importance of Airway Anatomy in Sub-regional Nasal and Paranasal Drug Delivery with Nebulizers Using Three Different Anatomical Nasal Airway Replicas of 2-, 5- and 50-Year Old Human Subjects","volume":"563","author":"Hosseini","year":"2019","journal-title":"Int. J. Pharm."},{"key":"B23","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1080\/02786826.2011.652749","article-title":"In-vivo Measurements of Micrometer-Sized Particle Deposition in the Nasal Cavities of Taiwanese Adults","volume":"46","author":"Hsu","year":"2012","journal-title":"Aerosol Sci. Tech."},{"key":"B24","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.powtec.2018.12.095","article-title":"A Unifying Correlation for Laminar Particle Deposition in 90-degree Pipe Bends","volume":"345","author":"Inthavong","year":"2019","journal-title":"Powder Tech."},{"key":"B25","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.jaerosci.2010.11.008","article-title":"Simulation of Sprayed Particle Deposition in a Human Nasal Cavity Including a Nasal spray Device","volume":"42","author":"Inthavong","year":"2011","journal-title":"J. Aerosol Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1089\/jamp.2014.1205","article-title":"A Computational Study of Nasal Spray Deposition Pattern in Four Ethnic Groups","volume":"29","author":"Keeler","year":"2016","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1080\/027868290883360","article-title":"Particle Deposition in Human Nasal Airway Replicas Manufactured by Different Methods. Part I: Inertial Regime Particles","volume":"38","author":"Kelly","year":"2004","journal-title":"Aerosol Sci. Tech."},{"key":"B28","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1205\/fbp.04403","article-title":"Using Computational Fluid Dynamics (CFD) to Improve the Bi-directional Nasal Drug Delivery Concept","volume":"83","author":"Kleven","year":"2005","journal-title":"Food Bioproducts Process."},{"key":"B29","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/cnm.1128","article-title":"Particle Tracking in Unstructured, Arbitrary Polyhedral Meshes for Use in CFD and Molecular Dynamics","volume":"25","author":"Macpherson","year":"2009","journal-title":"Commun. Numer. Methods Eng."},{"key":"B30","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.compfluid.2015.05.007","article-title":"Influence of Spatial Discretization Schemes on Accuracy of Explicit LES: Canonical Problems to Engine-like Geometries","volume":"117","author":"Mart\u00ednez","year":"2015","journal-title":"Comput. Fluids"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1515\/156939603322663312","article-title":"Weak First- and Second-Order Numerical Schemes for Stochastic Differential Equations Appearing in Lagrangian Two-phase Flow Modeling","volume":"9","author":"Minier","year":"2003","journal-title":"Monte Carlo Methods Appl."},{"key":"B32","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.ijpharm.2009.06.019","article-title":"Nanoparticles for Direct Nose-To-Brain Delivery of Drugs","volume":"379","author":"Mistry","year":"2009","journal-title":"Int. J. Pharm."},{"key":"B33","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1089\/jamp.2013.1071","article-title":"Drug Delivery to Paranasal Sinuses Using Pulsating Aerosols","volume":"27","author":"M\u00f6ller","year":"2014","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"B34","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-16874-6","volume-title":"The Finite Volume Method in Computational Fluid Dynamics: An Advanced Introduction with OpenFOAM\u00ae and Matlab","author":"Moukalled","year":"2016"},{"key":"B35","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.jaerosci.2016.09.003","article-title":"Characterization of Aerosol Stokes Number in 90\u00b0 Bends and Idealized Extrathoracic Airways","volume":"102","author":"Nicolaou","year":"2016","journal-title":"J. Aerosol Sci."},{"key":"B36","volume-title":"Numerical Heat Transfer and Fluid Flow","author":"Patankar","year":"1980"},{"key":"B37","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1016\/0017-9310(72)90054-3","article-title":"A Calculation Procedure for Heat, Mass and Momentum Transfer in Three-Dimensional Parabolic Flows","volume":"15","author":"Patankar","year":"1972","journal-title":"Int. J. Heat Mass. Transf."},{"key":"B38","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1088\/1367-2630\/6\/1\/035","article-title":"Ten Questions Concerning the Large-Eddy Simulation of Turbulent Flows","volume":"6","author":"Pope","year":"2004","journal-title":"New J. Phys."},{"key":"B39","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1080\/02786828708959166","article-title":"Experimental Study of Particle Deposition in Bends of Circular Cross Section","volume":"7","author":"Pui","year":"1987","journal-title":"Aerosol Sci. Tech."},{"key":"B40","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.jaerosci.2010.11.002","article-title":"Effects of Surface Smoothness on Inertial Particle Deposition in Human Nasal Models","volume":"42","author":"Schroeter","year":"2011","journal-title":"J. Aerosol Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.compfluid.2015.02.020","article-title":"Detailed Micro-particle Deposition Patterns in the Human Nasal Cavity Influenced by the Breathing Zone","volume":"114","author":"Shang","year":"2015","journal-title":"Comput. Fluids"},{"key":"B42","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1115\/1.2244574","article-title":"Laminar Airflow and Nanoparticle or Vapor Deposition in a Human Nasal Cavity Model","volume":"128","author":"Shi","year":"2006","journal-title":"J. Biomech. Eng."},{"key":"B43","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.jaerosci.2007.02.002","article-title":"Modeling of Inertial Particle Transport and Deposition in Human Nasal Cavities with wall Roughness","volume":"38","author":"Shi","year":"2007","journal-title":"J. Aerosol Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.resp.2012.12.005","article-title":"Modeling of Release Position and Ventilation Effects on Olfactory Aerosol Drug Delivery","volume":"186","author":"Si","year":"2013","journal-title":"Respir. Physiol. Neurobiol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1137\/0721062","article-title":"High Resolution Schemes Using Flux Limiters for Hyperbolic Conservation Laws","volume":"21","author":"Sweby","year":"1984","journal-title":"SIAM J. Numer. Anal."},{"key":"B46","doi-asserted-by":"publisher","first-page":"127103","DOI":"10.1063\/1.4997682","article-title":"A Critical Analysis of Some Popular Methods for the Discretisation of the Gradient Operator in Finite Volume Methods","volume":"29","author":"Syrakos","year":"2017","journal-title":"Phys. Fluids"},{"key":"B47","doi-asserted-by":"publisher","first-page":"2451","DOI":"10.1007\/s10237-021-01518-5","article-title":"Effect of Swirling Flow and Particle-Release Pattern on Drug Delivery to Human Tracheobronchial Airways","volume":"20","author":"Taheri","year":"2021","journal-title":"Biomech. Model. Mechanobiol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.jaerosci.2017.08.006","article-title":"Human Nasal Olfactory Deposition of Inhaled Nanoparticles at Low to Moderate Breathing Rate","volume":"113","author":"Tian","year":"2017","journal-title":"J. Aerosol Sci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/j.jcp.2019.02.052","article-title":"Parcel-number-density Control Algorithms for the Efficient Simulation of Particle-Laden Two-phase Flows","volume":"387","author":"Tofighian","year":"2019","journal-title":"J. Comput. Phys."},{"key":"B50","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.resp.2009.02.014","article-title":"Comparison of Micron- and Nanoparticle Deposition Patterns in a Realistic Human Nasal Cavity","volume":"166","author":"Wang","year":"2009","journal-title":"Respir. Physiol. Neurobiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1089\/jamp.2016.1295","article-title":"Nasal and Olfactory Deposition with Normal and Bidirectional Intranasal Delivery Techniques: In Vitro Tests and Numerical Simulations","volume":"30","author":"Xi","year":"2017","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"B52","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.ejps.2018.03.027","article-title":"Nasal Dilation Effects on Olfactory Deposition in Unilateral and Bi-directional Deliveries: In Vitro Tests and Numerical Modeling","volume":"118","author":"Xi","year":"2018","journal-title":"Eur. J. Pharm. Sci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.746420\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T12:30:07Z","timestamp":1638275407000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.746420\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,23]]},"references-count":52,"alternative-id":["10.3389\/fphar.2021.746420"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.746420","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,23]]},"article-number":"746420"}}