{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T19:26:53Z","timestamp":1787081213875,"version":"build-2736575974"},"reference-count":27,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Orthod Craniofacial Res"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Traditional biocompatibility assessments primarily address cytotoxicity and bulk material properties but often overlook molecular responses that occur below toxicity thresholds. Detecting these subtle effects is crucial for materials intended for prolonged contact with human tissues. This study uses a dual\u2010cell model using MCF\u20107 and THP\u20101 lines to evaluate low\u2010level hormonal and immune responses. In this context, clear aligners\u2014removable thermoplastic devices increasingly used in orthodontics\u2014require careful evaluation due to their extended intraoral use and design\u2010dependent clinical performance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Cell orthodontic aligners manufactured with CNC milling or laser cutting served as test samples. Cell viability and cytotoxicity were monitored using the MTT assay for up to 7\u2009days, while the evaluation of early gene expression response was carried out with RT\u2010PCR. The molecular endpoints included inflammatory markers and hormone sensitive receptors (ER\u03b1, ER\u03b2). Gene expression was detected on known inflammatory and hormone\u2010inducible genes (COX\u20102, IL\u20106, IL\u20108, ER\u03b1\/ER\u03b2), selected as representative indicators of inflammatory and hormone signalling, while other cytokines were also measured to provide more detail to sensitivity profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Despite preserved viability, modest modulation of COX\u20102 was detected in THP\u20101 cell lines in response to milled orthodontic clear aligners, without concomitant induction of IL\u20106 or IL\u20108. The expression of ER\u03b1\/ER\u03b2 did not change under any of the conditions. All the responses remained significantly lower than the EC10 levels established for xenoestrogens and inflammatory mediators, thereby verifying absence of biologically adverse or pathogenic activation of the material.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>THP\u20101 and MCF\u20107 pair is a bioactivity detection sub\u2010threshold system that is both efficient and sensitive as well as a highly effective preclinical test for dental material. The findings of this study confirm that orthodontic clear aligners, even after being trimmed on 3D\u2010printed models, do not exhibit antigenic properties. This supports their continued use in intraoral applications where the absence of immunological reactivity is essential during the development phase.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ocr.70119","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T11:35:35Z","timestamp":1775561735000},"page":"671-679","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Dual Cell\u2010Line Molecular Platform to Assess Sub\u2010Threshold Biocompatibility: Application to Processed Orthodontic Clears Aligners"],"prefix":"10.1111","volume":"29","author":[{"given":"Katia","family":"Barbaro","sequence":"first","affiliation":[{"name":"Istituto Zooprofilattico Sperimentale Del Lazio e Della Toscana \u201cM. Aleandri\u201d  Rome Katia Barbaro Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettore","family":"Candida","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences and Integrated Diagnostics (DISC) Genova University  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Silvestrini","family":"Biavati","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences and Integrated Diagnostics (DISC) Genova University  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Lanteri","sequence":"additional","affiliation":[{"name":"Surgical, Medical and Dental Department University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Ghisellini","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences and Integrated Diagnostics (DISC) Genova University  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Rando","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences and Integrated Diagnostics (DISC) Genova University  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Eggenh\u00f6ffner","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences and Integrated Diagnostics (DISC) Genova University  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Ugolini","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences and Integrated Diagnostics (DISC) Genova University  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ma14071799"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ma13235311"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.2319\/071520\u2010630.1"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.48047\/1yhy8771"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ma17123019"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/00222348.2025.2476852"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dental.2021.09.013"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202007226"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26094386"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2022.10.006"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ma15156533"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.18332\/pht\/155263"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ma18020429"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408444.2020.1762538"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010016\u20101866\u20109"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu15132967"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/ftox.2024.1474792"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031216"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23147962"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.2c05984"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00011\u2010007\u20106115\u20105"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/ftox.2025.1547640"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/fft2.44"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molstruc.2022.133853"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10091371"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.15419\/bmrat.v8i9.693"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/jfb16050173"}],"container-title":["Orthodontics &amp; Craniofacial Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ocr.70119","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/ocr.70119","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ocr.70119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T18:54:53Z","timestamp":1787079293000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ocr.70119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,7]]},"references-count":27,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1111\/ocr.70119"],"URL":"https:\/\/doi.org\/10.1111\/ocr.70119","archive":["Portico"],"relation":{},"ISSN":["1601-6335","1601-6343"],"issn-type":[{"value":"1601-6335","type":"print"},{"value":"1601-6343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,7]]},"assertion":[{"value":"2025-10-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}