{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T01:15:10Z","timestamp":1789089310088,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T00:00:00Z","timestamp":1678406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Subglottic stenosis represents a challenging clinical condition in otolaryngology. Although patients often experience improvement following endoscopic surgery, recurrence rates remain high. Pursuing measures to maintain surgical results and prevent recurrence is thus necessary. Steroids therapy is considered effective in preventing restenosis. Currently, however, the ability of trans-oral steroid inhalation to reach and affect the stenotic subglottic area in a tracheotomized patient is largely negligible. In the present study, we describe a novel trans-tracheostomal retrograde inhalation technique to increase corticosteroid deposition in the subglottic area. We detail our preliminary clinical outcomes in four patients treated with trans-tracheostomal corticosteroid inhalation via a metered dose inhaler (MDI) following surgery. Concurrently, we leverage computational fluid-particle dynamics (CFPD) simulations in an extra-thoracic 3D airway model to gain insight on possible advantages of such a technique over traditional trans-oral inhalation in augmenting aerosol deposition in the stenotic subglottic region. Our numerical simulations show that for an arbitrary inhaled dose (aerosols spanning 1\u201312 \u00b5m), the deposition (mass) fraction in the subglottis is over 30 times higher in the retrograde trans-tracheostomal technique compared to the trans-oral inhalation technique (3.63% vs. 0.11%). Importantly, while a major portion of inhaled aerosols (66.43%) in the trans-oral inhalation maneuver are transported distally past the trachea, the vast majority of aerosols (85.10%) exit through the mouth during trans-tracheostomal inhalation, thereby avoiding undesired deposition in the broader lungs. Overall, the proposed trans-tracheostomal retrograde inhalation technique increases aerosol deposition rates in the subglottis with minor lower-airway deposition compared to the trans-oral inhalation technique. This novel technique could play an important role in preventing restenosis of the subglottis.<\/jats:p>","DOI":"10.3390\/pharmaceutics15030903","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T06:52:13Z","timestamp":1678690333000},"page":"903","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Novel Trans-Tracheostomal Retrograde Inhalation Technique Increases Subglottic Drug Deposition Compared to Traditional Trans-Oral Inhalation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6639-9219","authenticated-orcid":false,"given":"Raviv","family":"Allon","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Kaplan Medical Center, Rehovot 76100, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Bhardwaj","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Technion\u2014Israel Institute of Technology, Haifa 3200003, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8217-3842","authenticated-orcid":false,"given":"Josu\u00e9","family":"Sznitman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Technion\u2014Israel Institute of Technology, Haifa 3200003, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagit","family":"Shoffel-Havakuk","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Rabin Medical Center, Petach-Tikva 4941492, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2598-4929","authenticated-orcid":false,"given":"Sapir","family":"Pinhas","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Kaplan Medical Center, Rehovot 76100, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elchanan","family":"Zloczower","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Kaplan Medical Center, Rehovot 76100, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8349-8534","authenticated-orcid":false,"given":"Yael","family":"Shapira-Galitz","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Kaplan Medical Center, Rehovot 76100, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonatan","family":"Lahav","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Kaplan Medical Center, Rehovot 76100, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1177\/0194599813510867","article-title":"A Systematic Review and Meta-Analysis of Endoscopic Balloon Dilation of Pediatric Subglottic Stenosis","volume":"150","author":"Lang","year":"2014","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1001\/jamaoto.2016.4131","article-title":"Endoscopic Management of Subglottic Stenosis","volume":"143","author":"Feinstein","year":"2017","journal-title":"JAMA Otolaryngol. Neck Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1097\/01.mlg.0000235934.27964.88","article-title":"The Efficacy of Mitomycin-C in the Treatment of Laryngotracheal Stenosis","volume":"116","author":"Simpson","year":"2006","journal-title":"Laryngoscope"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1002\/lary.25708","article-title":"Disease Homogeneity and Treatment Heterogeneity in Idiopathic Subglottic Stenosis","volume":"126","author":"Gelbard","year":"2016","journal-title":"Laryngoscope"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1002\/lary.24410","article-title":"Subglottic Stenosis: A Ten-year Review of Treatment Outcomes","volume":"124","author":"Hseu","year":"2014","journal-title":"Laryngoscope"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1177\/0194599820966978","article-title":"Idiopathic Subglottic Stenosis: An Institutional Review of Outcomes With a Multimodality Surgical Approach","volume":"164","author":"Dwyer","year":"2021","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"646.e1","DOI":"10.1016\/j.jvoice.2014.10.012","article-title":"Acquired Glottic Stenosis\u2014The Ongoing Challenge: A Review of Etiology, Pathogenesis, and Surgical Management","volume":"29","author":"Lahav","year":"2015","journal-title":"J. Voice"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1056\/NEJMra050541","article-title":"Antiinflammatory Action of Glucocorticoids\u2014New Mechanisms for Old Drugs","volume":"353","author":"Rhen","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.otohns.2004.03.001","article-title":"Endoscopic Treatment of Laryngeal and Tracheal Stenosis\u2014Has Mitomycin C Improved the Outcome?","volume":"131","author":"Perepelitsyn","year":"2004","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/S0003-4975(10)64938-7","article-title":"Successful Treatment of Postintubation Subglottic Stenosis with Intralesional Steroid Injections","volume":"15","author":"Bonchek","year":"1973","journal-title":"Ann. Thorac. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2473974X211054842","DOI":"10.1177\/2473974X211054842","article-title":"Serial Intralesional Steroid Injection for Subglottic Stenosis: Systemic Side Effects and Impact on Surgery-Free Interval","volume":"5","author":"Neevel","year":"2021","journal-title":"OTO Open"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1002\/lary.28015","article-title":"Serial Intralesional Steroid Injection for Subglottic Stenosis","volume":"130","author":"Song","year":"2020","journal-title":"Laryngoscope"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1002\/lary.26682","article-title":"Serial Office-based Steroid Injections for Treatment of Idiopathic Subglottic Stenosis","volume":"127","author":"Hoffman","year":"2017","journal-title":"Laryngoscope"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1002\/lary.27673","article-title":"Systemic Safety of Serial Intralesional Steroid Injection for Subglottic Stenosis","volume":"129","author":"Woliansky","year":"2019","journal-title":"Laryngoscope"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1001\/jamaoto.2019.3022","article-title":"Comparative Treatment Outcomes for Patients With Idiopathic Subglottic Stenosis","volume":"146","author":"Gelbard","year":"2020","journal-title":"JAMA Otolaryngol. Neck Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1002\/lary.24287","article-title":"Idiopathic Subglottic Stenosis: An Evolving Therapeutic Algorithm","volume":"124","author":"Maldonado","year":"2014","journal-title":"Laryngoscope"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.jpedsurg.2013.11.041","article-title":"Treatment of Postoperative Tracheal Granulation Tissue with Inhaled Budesonide in Congenital Tracheal Stenosis","volume":"49","author":"Yokoi","year":"2014","journal-title":"J. Pediatr. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1007\/s00405-021-06622-x","article-title":"Effect of Inhaled Fluticasone Propionate on Laryngotracheal Stenosis after Balloon Dilation: A Randomized Controlled Trial","volume":"278","author":"Alrabiah","year":"2021","journal-title":"Eur. Arch. Oto-Rhino-Laryngol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1177\/0194599820959674","article-title":"Orally Inhaled Drug Particle Transport in Computerized Models of Laryngotracheal Stenosis","volume":"164","author":"Cohen","year":"2021","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jclinepi.2013.08.003","article-title":"The CARE Guidelines: Consensus-Based Clinical Case Report Guideline Development","volume":"67","author":"Gagnier","year":"2014","journal-title":"J. Clin. Epidemiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1177\/0954411911430188","article-title":"Development of a Realistic Human Airway Model","volume":"226","author":"Lizal","year":"2012","journal-title":"Proc. Inst. Mech. Eng. Part H J. Eng. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1177\/0954411915600005","article-title":"A Method for in Vitro Regional Aerosol Deposition Measurement in a Model of the Human Tracheobronchial Tree by the Positron Emission Tomography","volume":"229","author":"Lizal","year":"2015","journal-title":"Proc. Inst. Mech. Eng. Part H J. Eng. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ejps.2017.09.003","article-title":"Regional Aerosol Deposition in the Human Airways: The SimInhale Benchmark Case and a Critical Assessment of in Silico Methods","volume":"113","author":"Koullapis","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1115\/1.2798296","article-title":"Measurements of Airway Dimensions and Calculation of Mass Transfer Characteristics of the Human Oral Passage","volume":"119","author":"Cheng","year":"1997","journal-title":"J. Biomech. Eng."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Das, P., Nof, E., Amirav, I., Kassinos, S.C., and Sznitman, J. (2018). Targeting Inhaled Aerosol Delivery to Upper Airways in Children: Insight from Computational Fluid Dynamics (CFD). PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0207711"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.clinbiomech.2017.10.006","article-title":"Geometry and Airflow Dynamics Analysis in the Nasal Cavity during Inhalation","volume":"66","author":"Inthavong","year":"2019","journal-title":"Clin. Biomech."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1146\/annurev-fluid-121108-145453","article-title":"Airflow and Particle Transport in the Human Respiratory System","volume":"42","author":"Kleinstreuer","year":"2010","journal-title":"Annu. Rev. Fluid Mech."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1080\/02786829308959627","article-title":"Fluid Dynamics of the Human Larynx and Upper Tracheobronchial Airways","volume":"19","author":"Martonen","year":"1993","journal-title":"Aerosol Sci. Technol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tu, J., Inthavong, K., and Ahmadi, G. (2012). Computational Fluid and Particle Dynamics in the Human Respiratory System, Springer Science & Business Media.","DOI":"10.1007\/978-94-007-4488-2"},{"key":"ref_30","unstructured":"Oliveira, R.F., Ferreira, A.C., Teixeira, S.F., Teixeira, J.C., and Marques, H.C. (2013, January 3\u20135). PMDI Spray Plume Analysis: A CFD Study. Proceedings of the World Congress on Engineering, London, UK."},{"key":"ref_31","doi-asserted-by":"crossref","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":"ref_32","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/lary.30212","article-title":"Comparison of Inhaled Drug Delivery in Patients With One-and Two-level Laryngotracheal Stenosis","volume":"133","author":"Gosman","year":"2022","journal-title":"Laryngoscope"},{"key":"ref_33","first-page":"011005","article-title":"Particulate Deposition in a Patient With Tracheal Stenosis","volume":"1","author":"Taherian","year":"2017","journal-title":"J. Eng. Sci. Med. Diagn. Ther."},{"key":"ref_34","first-page":"V003T03A096","article-title":"Tracheal Stenosis: A CFD Approach for Evaluation of Drug Delivery","volume":"Volume 57380","author":"Taherian","year":"2015","journal-title":"Proceedings of the ASME International Mechanical Engineering Congress and Exposition"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1007\/s11095-012-0691-y","article-title":"Comparing MDI and DPI Aerosol Deposition Using in Vitro Experiments and a New Stochastic Individual Path (SIP) Model of the Conducting Airways","volume":"29","author":"Longest","year":"2012","journal-title":"Pharm. Res."},{"key":"ref_36","first-page":"158","article-title":"Practical Problems with Aerosol Therapy in COPD","volume":"51","author":"Rau","year":"2006","journal-title":"Respir. Care"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1017\/S0022215121001134","article-title":"Subglottic and Tracheal Stenosis Associated with Coronavirus Disease 2019","volume":"135","author":"Scholfield","year":"2021","journal-title":"J. Laryngol. Otol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1002\/lary.30269","article-title":"Interventions and Outcomes in Glottic Versus Multi-level Airway Stenosis: A Multi-institutional Review","volume":"133","author":"Rao","year":"2022","journal-title":"Laryngoscope"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/lary.26151","article-title":"Systematic Review for Surgical Treatment of Adult and Adolescent Laryngotracheal Stenosis","volume":"127","author":"Lewis","year":"2017","journal-title":"Laryngoscope"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1093\/ejcts\/ezs514","article-title":"The Role of T-Tubes in the Management of Airway Stenosis","volume":"43","author":"Saghebi","year":"2013","journal-title":"Eur. J. Cardio-Thoracic. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7839","DOI":"10.3934\/mbe.2019394","article-title":"Treatment of Secondary Benign Airway Stenosis after Tracheotomy with Montgomery T-Tube","volume":"16","author":"Hu","year":"2019","journal-title":"Math. Biosci. Eng."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1002\/lary.20615","article-title":"Granulation Formation Following Tracheal Stenosis Stenting: Influence of Stent Position","volume":"119","author":"Ko","year":"2009","journal-title":"Laryngoscope"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/3\/903\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:51:58Z","timestamp":1760122318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/3\/903"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,10]]},"references-count":42,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["pharmaceutics15030903"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15030903","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,10]]}}}