{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:44:49Z","timestamp":1788975889696,"version":"build-2803163510"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000317","name":"Action Medical Research","doi-asserted-by":"publisher","award":["GN2779"],"award-info":[{"award-number":["GN2779"]}],"id":[{"id":"10.13039\/501100000317","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/R013942\/1"],"award-info":[{"award-number":["BB\/R013942\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Laryngoscope Investig Oto"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Otitis media is an umbrella term for middle ear inflammation; ranging from acute infection to chronic mucosal disease. It is a leading cause of antimicrobial therapy prescriptions and surgery in children. Despite this, treatments have changed little in over 50\u2009years. Research has been limited by the lack of physiological models of middle ear epithelium.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We develop a novel human middle ear epithelial culture using an air\u2010liquid interface (ALI) system; akin to the healthy ventilated middle ear in vivo. We validate this using immunohistochemistry, immunofluorescence, scanning and transmission electron microscopy, and membrane conductance studies. We also utilize this model to perform a pilot challenge of middle ear epithelial cells with SARS\u2010CoV\u20102.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrate that human middle ear epithelial cells cultured at an ALI undergo mucociliary differentiation to produce diverse epithelial subtypes including basal (p63+), goblet (MUC5AC+, MUC5B+), and ciliated (FOXJ1+) cells. Mature ciliagenesis is visualized and tight junction formation is shown with electron microscopy, and confirmed by membrane conductance. Together, these demonstrate this model reflects the complex epithelial cell types which exist in vivo. Following SARS\u2010CoV\u20102 challenge, human middle ear epithelium shows positive viral uptake, as measured by polymerase chain reaction and immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We describe a novel physiological system to study the human middle ear. This can be utilized for translational research into middle ear diseases. We also demonstrate, for the first time under controlled conditions, that human middle ear epithelium is susceptible to SARS\u2010CoV\u20102 infection, which has important clinical implications for safe otological surgery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Level of Evidence<\/jats:title><jats:p>NA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/lio2.661","type":"journal-article","created":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T08:58:25Z","timestamp":1631955505000},"page":"1167-1174","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Development of a physiological model of human middle ear epithelium"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7972-7111","authenticated-orcid":false,"given":"Michael William","family":"Mather","sequence":"first","affiliation":[{"name":"Faculty of Medical Sciences Biosciences Institute, Newcastle University Newcastle\u2010upon\u2010Tyne UK"},{"name":"Department of Otolaryngology Freeman Hospital Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Verdon","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences Biosciences Institute, Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel Anne","family":"Botting","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences Biosciences Institute, Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Engelbert","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences Biosciences Institute, Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Delpiano","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences Biosciences Institute, Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Xu","sequence":"additional","affiliation":[{"name":"Newcastle Biobank, Faculty of Medical Sciences Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Hatton","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences Translational and Clinical Research Institute, Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"Davey","sequence":"additional","affiliation":[{"name":"Electron Microscopy Research Services, Faculty of Medical Sciences Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Lisgo","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences Biosciences Institute, Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Yates","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Freeman Hospital Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Dawe","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Freeman Hospital Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin D.","family":"Bingle","sequence":"additional","affiliation":[{"name":"Department of Infection, Immunity and Cardiovascular Disease The Medical School Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muzlifah","family":"Haniffa","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences Biosciences Institute, Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Powell","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Freeman Hospital Newcastle\u2010upon\u2010Tyne UK"},{"name":"Faculty of Medical Sciences Translational and Clinical Research Institute, Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Ward","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences Translational and Clinical Research Institute, Newcastle University Newcastle\u2010upon\u2010Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,9,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.63"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036226"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9092137"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9841-8_7"},{"key":"e_1_2_9_6_1","unstructured":"HattonCF BottingRA DuenasME HaqIJ VerdonB.Delayed induction of type I and III interferons and nasal epithelial cell permissiveness to SARS\u2010CoV\u20102.bioRxiv[Internet]. 2021.https:\/\/www.biorxiv.org\/content\/10.1101\/2021.02.17.431591v1.abstract."},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aav7501"},{"issue":"11","key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1242\/dmm.026658","article-title":"An in vitro model of murine middle ear epithelium","volume":"9","author":"Mulay A","year":"2016","journal-title":"Dis Model Mech"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/0194599812449986"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/000348940211100606"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.28687"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/lio2.319"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2020.01.011"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-17888-2_1"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.02.045"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2012.11.016"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00170.2003"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201804-0734OC"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-00477-9"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.5152\/iao.2017.4305"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2005.08.007"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2008.11.012"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31490-9"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2019.04.041"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2020.1922"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjoto.2020.102487"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40463-020-00424-7"}],"container-title":["Laryngoscope Investigative Otolaryngology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/lio2.661","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/lio2.661","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/lio2.661","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,8]],"date-time":"2024-09-08T15:09:49Z","timestamp":1725808189000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/lio2.661"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,18]]},"references-count":26,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,10]]}},"alternative-id":["10.1002\/lio2.661"],"URL":"https:\/\/doi.org\/10.1002\/lio2.661","archive":["Portico"],"relation":{},"ISSN":["2378-8038","2378-8038"],"issn-type":[{"value":"2378-8038","type":"print"},{"value":"2378-8038","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,18]]},"assertion":[{"value":"2021-09-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}