{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T01:11:16Z","timestamp":1771895476878,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T00:00:00Z","timestamp":1666828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMW\u2013the Netherlands Organisation for Health Research and Development","doi-asserted-by":"publisher","award":["516001351"],"award-info":[{"award-number":["516001351"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMW\u2013the Netherlands Organisation for Health Research and Development","doi-asserted-by":"publisher","award":["80-83900-98-020"],"award-info":[{"award-number":["80-83900-98-020"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Usage of injectable dermal fillers applied for aesthetic purposes has extensively increased over the years. As such, the number of related adverse reactions has increased, including patients showing severe complications such as product migration, topical swelling and inflammatory reactions of the skin. In order to understand the underlying molecular events of these adverse reactions we performed a genome-wide gene expression study on the multi-cell type human Phenion\u00ae Full-Thickness Skin Model exposed to five experimental hyaluronic acid (HA) preparations with increasing cross-linking degree, four commercial fillers from Perfectha\u00ae, and non-resorbable filler Bio-Alcamid\u00ae. In addition, we evaluated whether cross-linking degree or particle size of the HA-based fillers could be associated with the occurrence of adverse effects. In all cases, exposure to different HA fillers resulted in a clearly elevated gene expression of cytokines and chemokines related to acute inflammation as part of the foreign body response. Furthermore, for one experimental filler genes of OXPHOS complexes I-V were significantly down-regulated (adjusted p-value &lt; 0.05), resulting in mitochondrial dysfunction which can be linked to over-expression of pro-inflammatory cytokines TNF\u03b1 and IL-1\u03b2 and chemokine CCL2. Our hypothesis that cross-linking degree or particle size of the HA-based fillers is related to the biological responses induced by these fillers could only partially be confirmed for particle size. In conclusion, our innovative approach resulted in gene expression changes from a human 3D skin model exposed to dermal fillers that mechanistically substantiate aforementioned adverse reactions, and thereby adds to the weight of evidence that these fillers may induce inflammatory and fibrotic responses.<\/jats:p>","DOI":"10.3390\/ijms232113046","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T20:37:58Z","timestamp":1666903078000},"page":"13046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Transcriptomic Analysis in Human 3D Skin Model Injected with Resorbable Hyaluronic Acid Fillers Reveals Foreign Body Response"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8618-2487","authenticated-orcid":false,"given":"Danyel G. J.","family":"Jennen","sequence":"first","affiliation":[{"name":"Department of Toxicogenomics, GROW School for Oncology and Reproduction, Maastricht University, 6200 Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel","family":"van Herwijnen","sequence":"additional","affiliation":[{"name":"Department of Toxicogenomics, GROW School for Oncology and Reproduction, Maastricht University, 6200 Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marlon","family":"Jetten","sequence":"additional","affiliation":[{"name":"Department of Toxicogenomics, GROW School for Oncology and Reproduction, Maastricht University, 6200 Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9140-952X","authenticated-orcid":false,"given":"Rob J.","family":"Vandebriel","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 Bilthoven, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Keizers","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 Bilthoven, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0979-9077","authenticated-orcid":false,"given":"Robert E.","family":"Geertsma","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 Bilthoven, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wim H.","family":"de Jong","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 Bilthoven, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos C. S.","family":"Kleinjans","sequence":"additional","affiliation":[{"name":"Department of Toxicogenomics, GROW School for Oncology and Reproduction, Maastricht University, 6200 Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,27]]},"reference":[{"key":"ref_1","unstructured":"(2022, October 02). ISAPS\u2019 International survey on Aesthetic\/Cosmetic Procedures Performed in 2019. Available online: https:\/\/www.isaps.org\/wp-content\/uploads\/2020\/12\/Global-Survey-2019.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1111\/jocd.14339","article-title":"Upward trend in number of injectable treatments in the Netherlands 2016\u20132019","volume":"20","author":"Decates","year":"2021","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ryu, H.J., Kwak, S.S., Rhee, C.H., Yang, G.H., Yun, H.Y., and Kang, W.H. (2021). 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B"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13046\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:04:29Z","timestamp":1760144669000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,27]]},"references-count":38,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232113046"],"URL":"https:\/\/doi.org\/10.3390\/ijms232113046","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,27]]}}}