{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T10:18:36Z","timestamp":1794305916105,"version":"4.9.0"},"reference-count":86,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005934","name":"Malm\u00f6 University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005934","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Niacinamide (NIA) is a widely used skincare ingredient with established benefits for skin barrier support, inflammation reduction, and dermal health. However, the mechanisms governing its transdermal delivery remain insufficiently understood, particularly regarding how formulation pH influences its permeation through the stratum corneum (SC). This study investigates how donor phase pH (5.0 vs. 7.4) modulates NIA skin permeation and how these effects relate to pH induced changes in SC electrical properties. Franz cell diffusion experiments were combined with electrical impedance spectroscopy (EIS) using full\u2011thickness human skin and 3D reconstructed epidermal tissue models. Permeation was quantified over 24\u00a0h and in pH switch experiments, while EIS characterized pH dependent changes in membrane resistance (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sub>mem<\/jats:sub>\n                    ) and effective capacitance (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>eff<\/jats:sub>\n                    ). Additional analyses assessed microbial conversion of NIA to nicotinic acid during prolonged exposure. Neutral donor pH (7.4) increased NIA permeation by roughly twofold compared with acidic pH (5.0) in both membrane types. Correspondingly, pH\u202f7.4 decreased\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sub>mem<\/jats:sub>\n                    and increased\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>eff<\/jats:sub>\n                    , indicating pH driven changes in SC lipid organization and dielectric behavior. These effects were reversible and likely stem from alterations in SC lipid domains, including pH dependent partial deprotonation of free fatty acids that modifies the continuous lipid regions and introduce localized structural microdefects. Such changes enhance NIA and ion permeability and increase SC dielectric properties at neutral pH. Although microbial conversion of NIA to nicotinic acid was negligible within the first\u00a024\u00a0h, it became clearly detectable upon prolonged experiments. In conclusion, donor phase pH is a critical determinant of NIA skin permeation, primarily through reversible modulation of SC lipid structure and transport pathways. These findings highlight the importance of pH control in topical formulations and underscore the need to consider microbiota\u2011mediated transformations when evaluating the efficacy and safety of skin care products containing NIA.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-41992-4","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T04:12:20Z","timestamp":1774325540000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Effect of pH on niacinamide skin permeation"],"prefix":"10.1038","volume":"16","author":[{"given":"Thomas","family":"Sj\u00f6berg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Letasiova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skaidre","family":"Jankovskaja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Hrapovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"\u00d6sterlund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emelie","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Engblom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Sp\u00e9gel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Bj\u00f6rklund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"41992_CR1","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1002\/aic.690210522","volume":"21","author":"AS Michaels","year":"1975","unstructured":"Michaels, A. S., Chandrasekaran, S. K. & Shaw, J. E. Drug permeation through human skin. Theory and in vitro experimental measurement. AIChE J. 21, 985\u2013996 (1975).","journal-title":"AIChE J."},{"key":"41992_CR2","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1152\/physrev.1971.51.4.702","volume":"51","author":"RJ Scheuplein","year":"1971","unstructured":"Scheuplein, R. J. & Blank, I. H. Permeability of the skin. Physiol. Rev. 51, 702\u2013747 (1971).","journal-title":"Physiol. Rev."},{"key":"41992_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2023.101252","volume":"92","author":"JA Bouwstra","year":"2023","unstructured":"Bouwstra, J. A. et al. The skin barrier: An extraordinary interface with an exceptional lipid organization. Prog. Lipid Res. 92, 101252. https:\/\/doi.org\/10.1016\/j.plipres.2023.101252 (2023).","journal-title":"Prog. Lipid Res."},{"key":"41992_CR4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cocis.2023.101725","volume":"67","author":"E Sparr","year":"2023","unstructured":"Sparr, E. et al. The stratum corneum barrier\u2014From molecular scale to macroscopic properties. Curr. Opin. Colloid Interface Sci. 67, 101725. https:\/\/doi.org\/10.1016\/j.cocis.2023.101725 (2023).","journal-title":"Curr. Opin. Colloid Interface Sci."},{"key":"41992_CR5","doi-asserted-by":"publisher","DOI":"10.3390\/antiox13040425","author":"C Marques","year":"2024","unstructured":"Marques, C. et al. Mechanistic insights into the multiple functions of niacinamide: Therapeutic implications and cosmeceutical applications in functional skincare products. Antioxidants https:\/\/doi.org\/10.3390\/antiox13040425 (2024).","journal-title":"Antioxidants"},{"key":"41992_CR6","doi-asserted-by":"publisher","first-page":"3512","DOI":"10.1007\/s13346-024-01593-y","volume":"14","author":"RR Ong","year":"2024","unstructured":"Ong, R. R. & Goh, C. F. Niacinamide: A review on dermal delivery strategies and clinical evidence. Drug Deliv. Transl. Res. 14, 3512\u20133548. https:\/\/doi.org\/10.1007\/s13346-024-01593-y (2024).","journal-title":"Drug Deliv. Transl. Res."},{"key":"41992_CR7","doi-asserted-by":"publisher","first-page":"20","DOI":"10.4103\/0378-6323.58674","volume":"76","author":"HR Jerajani","year":"2010","unstructured":"Jerajani, H. R., Mizoguchi, H., Li, J., Whittenbarger, D. J. & Marmor, M. J. The effects of a daily facial lotion containing vitamins B3 and E and provitamin B5 on the facial skin of Indian women: A randomized, double-blind trial. Indian J. Dermatol. Venereol. Leprol. 76, 20\u201326. https:\/\/doi.org\/10.4103\/0378-6323.58674 (2010).","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"41992_CR8","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/j.1365-4632.2004.02375.x","volume":"44","author":"Y Soma","year":"2005","unstructured":"Soma, Y. et al. Moisturizing effects of topical nicotinamide on atopic dry skin. Int. J. Dermatol. 44, 197\u2013202. https:\/\/doi.org\/10.1111\/j.1365-4632.2004.02375.x (2005).","journal-title":"Int. J. Dermatol."},{"key":"41992_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/ics.12499","volume":"41","author":"S Nisbet","year":"2019","unstructured":"Nisbet, S. et al. Cosmetic benefit of a biomimetic lamellar cream formulation on barrier function or the appearance of fine lines and wrinkles in randomized proof-of-concept clinical studies. Int. J. Cosmet. Sci. 41, 1\u201311. https:\/\/doi.org\/10.1111\/ics.12499 (2019).","journal-title":"Int. J. Cosmet. Sci."},{"key":"41992_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-88899-0","volume":"15","author":"T Sj\u00f6berg","year":"2025","unstructured":"Sj\u00f6berg, T. et al. Niacinamide and its impact on stratum corneum hydration and structure. Sci. Rep. 15, 4953. https:\/\/doi.org\/10.1038\/s41598-025-88899-0 (2025).","journal-title":"Sci. Rep."},{"key":"41992_CR11","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1111\/j.1473-2130.2004.00115.x","volume":"3","author":"W Gehring","year":"2004","unstructured":"Gehring, W. Nicotinic acid\/niacinamide and the skin. J. Cosmet. Dermatol. 3, 88\u201393. https:\/\/doi.org\/10.1111\/j.1473-2130.2004.00115.x (2004).","journal-title":"J. Cosmet. Dermatol."},{"key":"41992_CR12","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1016\/j.jid.2021.10.021","volume":"142","author":"CYR Tan","year":"2022","unstructured":"Tan, C. Y. R. et al. Nicotinamide prevents UVB- and oxidative stress-induced photoaging in human primary keratinocytes. J. Invest. Dermatol. 142, 1670-1681.e1612. https:\/\/doi.org\/10.1016\/j.jid.2021.10.021 (2022).","journal-title":"J. Invest. Dermatol."},{"key":"41992_CR13","doi-asserted-by":"publisher","DOI":"10.4061\/2010\/157591","volume":"2010","author":"D Surjana","year":"2010","unstructured":"Surjana, D., Halliday, G. M. & Damian, D. L. Role of nicotinamide in DNA damage, mutagenesis, and DNA repair. J. Nucleic Acids. 2010, 157591. https:\/\/doi.org\/10.4061\/2010\/157591 (2010).","journal-title":"J. Nucleic Acids."},{"key":"41992_CR14","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1111\/j.1467-2494.2004.00228.x","volume":"26","author":"DL Bissett","year":"2004","unstructured":"Bissett, D. L., Miyamoto, K., Sun, P., Li, J. & Berge, C. A. Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin. Int. J. Cosmet. Sci. 26, 231\u2013238. https:\/\/doi.org\/10.1111\/j.1467-2494.2004.00228.x (2004).","journal-title":"Int. J. Cosmet. Sci."},{"key":"41992_CR15","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1111\/j.1473-2165.2007.00342.x","volume":"6","author":"P-C Chiu","year":"2007","unstructured":"Chiu, P.-C., Chan, C.-C., Lin, H.-M. & Chiu, H.-C. The clinical anti-aging effects of topical kinetin and niacinamide in Asians: A randomized, double-blind, placebo-controlled, split-face comparative trial. J. Cosmet. Dermatol. 6, 243\u2013249. https:\/\/doi.org\/10.1111\/j.1473-2165.2007.00342.x (2007).","journal-title":"J. Cosmet. Dermatol."},{"key":"41992_CR16","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1111\/j.1346-8138.2008.00537.x","volume":"35","author":"A Kawada","year":"2008","unstructured":"Kawada, A., Konishi, N., Oiso, N., Kawara, S. & Date, A. Evaluation of anti-wrinkle effects of a novel cosmetic containing niacinamide. J. Dermatol. 35, 637\u2013642. https:\/\/doi.org\/10.1111\/j.1346-8138.2008.00537.x (2008).","journal-title":"J. Dermatol."},{"key":"41992_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-66624-7","volume":"14","author":"P Bogdanowicz","year":"2024","unstructured":"Bogdanowicz, P. et al. Senomorphic activity of a combination of niacinamide and hyaluronic acid: Correlation with clinical improvement of skin aging. Sci. Rep. 14, 16321. https:\/\/doi.org\/10.1038\/s41598-024-66624-7 (2024).","journal-title":"Sci. Rep."},{"key":"41992_CR18","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.ijpharm.2018.11.065","volume":"556","author":"Y Zhang","year":"2019","unstructured":"Zhang, Y. et al. A comparison of the in vitro permeation of niacinamide in mammalian skin and in the Parallel Artificial Membrane Permeation Assay (PAMPA) model. Int. J. Pharm. 556, 142\u2013149. https:\/\/doi.org\/10.1016\/j.ijpharm.2018.11.065 (2019).","journal-title":"Int. J. Pharm."},{"key":"41992_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2020.119137","volume":"579","author":"F Iliopoulos","year":"2020","unstructured":"Iliopoulos, F. et al. Topical delivery of niacinamide: Influence of neat solvents. Int. J. Pharm. 579, 119137. https:\/\/doi.org\/10.1016\/j.ijpharm.2020.119137 (2020).","journal-title":"Int. J. Pharm."},{"key":"41992_CR20","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12090887","volume":"12","author":"F Iliopoulos","year":"2020","unstructured":"Iliopoulos, F., Caspers, P. J., Puppels, G. J. & Lane, M. E. Franz cell diffusion testing and quantitative confocal Raman spectroscopy: In vitro-in vivo correlation. Pharmaceutics 12, 887 (2020).","journal-title":"Pharmaceutics"},{"key":"41992_CR21","doi-asserted-by":"publisher","DOI":"10.3390\/pr12010202","volume":"12","author":"W Zhang","year":"2024","unstructured":"Zhang, W., Shi, X. & Zheng, S. Study on influencing factors of nicotinamide transdermal absorption in vitro and the establishment of an evaluation method. Processes 12, 202 (2024).","journal-title":"Processes"},{"key":"41992_CR22","first-page":"271","volume":"77","author":"A Nowak","year":"2020","unstructured":"Nowak, A. et al. Comparison of artificial hydrophilic and lipophilic membranes and human skin to evaluate niacinamide penetration in vitro. Acta Pol. Pharm. 77, 271\u2013279 (2020).","journal-title":"Acta Pol. Pharm."},{"key":"41992_CR23","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.jid.2024.07.009","volume":"145","author":"SG Brooks","year":"2025","unstructured":"Brooks, S. G., Mahmoud, R. H., Lin, R. R., Fluhr, J. W. & Yosipovitch, G. The skin acid mantle: An update on skin pH. J. Invest. Dermatol. 145, 509\u2013521. https:\/\/doi.org\/10.1016\/j.jid.2024.07.009 (2025).","journal-title":"J. Invest. Dermatol."},{"key":"41992_CR24","doi-asserted-by":"publisher","first-page":"8061","DOI":"10.1021\/la800543r","volume":"24","author":"C \u00c5berg","year":"2008","unstructured":"\u00c5berg, C., Wennerstr\u00f6m, H. & Sparr, E. Transport processes in responding lipid membranes: A possible mechanism for the pH gradient in the stratum corneum. Langmuir 24, 8061\u20138070 (2008).","journal-title":"Langmuir"},{"key":"41992_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.colsurfb.2020.111476","volume":"198","author":"EH Mojumdar","year":"2021","unstructured":"Mojumdar, E. H. & Sparr, E. The effect of pH and salt on the molecular structure and dynamics of the skin. Colloids Surf B Biointerfaces 198, 111476. https:\/\/doi.org\/10.1016\/j.colsurfb.2020.111476 (2021).","journal-title":"Colloids Surf B Biointerfaces"},{"key":"41992_CR26","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1016\/j.jid.2021.02.014","volume":"141","author":"A Nov\u00e1\u010dkov\u00e1","year":"2021","unstructured":"Nov\u00e1\u010dkov\u00e1, A. et al. Acidic pH is required for the multilamellar assembly of skin barrier lipids in vitro. J. Invest. Dermatol. 141, 1915-1921.e1914. https:\/\/doi.org\/10.1016\/j.jid.2021.02.014 (2021).","journal-title":"J. Invest. Dermatol."},{"key":"41992_CR27","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/jidsymp.1998.17","volume":"3","author":"JA Bouwstra","year":"1998","unstructured":"Bouwstra, J. A., Gooris, G. S., Dubbelaar, F. E. R., Ponec, M. & Weerheim, A. M. pH, cholesterol sulfate, and fatty acids affect the stratum corneum lipid organization. J. Invest. Dermatol. Symp. Proc. 3, 69\u201374. https:\/\/doi.org\/10.1038\/jidsymp.1998.17 (1998).","journal-title":"J. Invest. Dermatol. Symp. Proc."},{"key":"41992_CR28","first-page":"151","volume":"14","author":"T Yamamoto","year":"1976","unstructured":"Yamamoto, T. & Yamamoto, Y. Electrical properties of the epidermal stratum corneum. Med. Biol. Eng. Comput. 14, 151\u2013158 (1976).","journal-title":"Med. Biol. Eng. Comput."},{"key":"41992_CR29","doi-asserted-by":"publisher","first-page":"2639","DOI":"10.1016\/j.bpj.2013.05.008","volume":"104","author":"S Bj\u00f6rklund","year":"2013","unstructured":"Bj\u00f6rklund, S. et al. Skin membrane electrical impedance properties under the influence of a varying water gradient. Biophys. J. 104, 2639\u20132650 (2013).","journal-title":"Biophys. J."},{"key":"41992_CR30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2023.122891","volume":"637","author":"M Morin","year":"2023","unstructured":"Morin, M., Runnsj\u00f6, A., Ruzgas, T., Engblom, J. & Bj\u00f6rklund, S. Effects of storage conditions on permeability and electrical impedance properties of the skin barrier. Int. J. Pharm. 637, 122891. https:\/\/doi.org\/10.1016\/j.ijpharm.2023.122891 (2023).","journal-title":"Int. J. Pharm."},{"key":"41992_CR31","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1159\/000441038","volume":"29","author":"AM Barbero","year":"2016","unstructured":"Barbero, A. M. & Frasch, H. F. Effect of frozen human epidermis storage duration and cryoprotectant on barrier function using two model compounds. Skin Pharmacol. Physiol. 29, 31\u201340. https:\/\/doi.org\/10.1159\/000441038 (2016).","journal-title":"Skin Pharmacol. Physiol."},{"key":"41992_CR32","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1016\/j.tiv.2012.11.016","volume":"27","author":"K Dennerlein","year":"2013","unstructured":"Dennerlein, K. et al. Studies on percutaneous penetration of chemicals\u2014Impact of storage conditions for excised human skin. Toxicol. In Vitro 27, 708\u2013713. https:\/\/doi.org\/10.1016\/j.tiv.2012.11.016 (2013).","journal-title":"Toxicol. In Vitro"},{"key":"41992_CR33","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1159\/000322304","volume":"24","author":"JB Nielsen","year":"2011","unstructured":"Nielsen, J. B., Plasencia, I., S\u00f8rensen, J. A. & Bagatolli, L. A. Storage conditions of skin affect tissue structure and subsequent in vitro percutaneous penetration. Skin Pharmacol. Physiol. 24, 93\u2013102. https:\/\/doi.org\/10.1159\/000322304 (2011).","journal-title":"Skin Pharmacol. Physiol."},{"key":"41992_CR34","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/0278-6915(86)90232-2","volume":"24","author":"BW Kemppainen","year":"1986","unstructured":"Kemppainen, B. W., Riley, R. T., Pace, J. G. & Hoerr, F. J. Effects of skin storage conditions and concentration of applied dose on [3H]T-2 toxin penetration through excised human and monkey skin. Food Chem. Toxicol. 24, 221\u2013227. https:\/\/doi.org\/10.1016\/0278-6915(86)90232-2 (1986).","journal-title":"Food Chem. Toxicol."},{"key":"41992_CR35","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1002\/1520-6017(200105)90:5<545::aid-jps1012>3.0.co;2-h","volume":"90","author":"H Tang","year":"2001","unstructured":"Tang, H., Mitragotri, S., Blankschtein, D. & Langer, R. Theoretical description of transdermal transport of hydrophilic permeants: Application to low-frequency sonophoresis. J. Pharm. Sci. 90, 545\u2013568. https:\/\/doi.org\/10.1002\/1520-6017(200105)90:5%3c545::aid-jps1012%3e3.0.co;2-h (2001).","journal-title":"J. Pharm. Sci."},{"key":"41992_CR36","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1002\/jps.2600840813","volume":"84","author":"KD Peck","year":"1995","unstructured":"Peck, K. D., Ghanem, A. H. & Higuchi, W. I. The effect of temperature upon the permeation of polar and ionic solutes through human epidermal membrane. J. Pharm. Sci. 84, 975\u2013982 (1995).","journal-title":"J. Pharm. Sci."},{"key":"41992_CR37","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1002\/jps.10299","volume":"92","author":"A Tezel","year":"2003","unstructured":"Tezel, A., Sens, A. & Mitragotri, S. Description of transdermal transport of hydrophilic solutes during low-frequency sonophoresis based on a modified porous pathway model. J. Pharm. Sci. 92, 381\u2013393. https:\/\/doi.org\/10.1002\/jps.10299 (2003).","journal-title":"J. Pharm. Sci."},{"key":"41992_CR38","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.jconrel.2010.01.005","volume":"143","author":"S Bj\u00f6rklund","year":"2010","unstructured":"Bj\u00f6rklund, S., Engblom, J., Thuresson, K. & Sparr, E. A water gradient can be used to regulate drug transport across skin. J. Control Release 143, 191\u2013200 (2010).","journal-title":"J. Control Release"},{"key":"41992_CR39","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/s41598-020-79903-w","volume":"11","author":"S Jankovskaja","year":"2021","unstructured":"Jankovskaja, S. et al. Non-invasive skin sampling of tryptophan\/kynurenine ratio in vitro towards a skin cancer biomarker. Sci. Rep. 11, 678. https:\/\/doi.org\/10.1038\/s41598-020-79903-w (2021).","journal-title":"Sci. Rep."},{"key":"41992_CR40","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.omtm.2022.04.006","volume":"25","author":"J Huang","year":"2022","unstructured":"Huang, J. et al. The ratio of nicotinic acid to nicotinamide as a microbial biomarker for assessing cell therapy product sterility. Mol. Ther. Methods Clin. Dev. 25, 410\u2013424. https:\/\/doi.org\/10.1016\/j.omtm.2022.04.006 (2022).","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"41992_CR41","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/0378-5173(91)90216-B","volume":"69","author":"SM Sims","year":"1991","unstructured":"Sims, S. M., Higuchi, W. I. & Srinivasan, V. Skin alteration and convective solvent flow effects during iontophoresis: I. Neutral solute transport across human skin. Int. J. Pharm. 69, 109\u2013121. https:\/\/doi.org\/10.1016\/0378-5173(91)90216-B (1991).","journal-title":"Int. J. Pharm."},{"key":"41992_CR42","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1023\/A:1015820600672","volume":"7","author":"GB Kasting","year":"1990","unstructured":"Kasting, G. B. & Bowman, L. A. DC electrical properties of frozen, excised human skin. Pharm. Res. 7, 134\u2013143 (1990).","journal-title":"Pharm. Res."},{"key":"41992_CR43","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.ijpharm.2011.02.023","volume":"418","author":"S Mitragotri","year":"2011","unstructured":"Mitragotri, S. et al. Mathematical models of skin permeability: An overview. Int. J. Pharm. 418, 115\u2013129. https:\/\/doi.org\/10.1016\/j.ijpharm.2011.02.023 (2011).","journal-title":"Int. J. Pharm."},{"key":"41992_CR44","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1023\/A:1015810312465","volume":"9","author":"RO Potts","year":"1992","unstructured":"Potts, R. O. & Guy, R. H. Predicting skin permeability. Pharm. Res. 9, 663\u2013669 (1992).","journal-title":"Pharm. Res."},{"key":"41992_CR45","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/S0168-3659(02)00321-8","volume":"86","author":"S Mitragotri","year":"2003","unstructured":"Mitragotri, S. Modeling skin permeability to hydrophilic and hydrophobic solutes based on four permeation pathways. J. Control Release 86, 69\u201392. https:\/\/doi.org\/10.1016\/S0168-3659(02)00321-8 (2003).","journal-title":"J. Control Release"},{"key":"41992_CR46","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.jconrel.2003.08.002","volume":"93","author":"SN Murthy","year":"2003","unstructured":"Murthy, S. N., Sen, A., Zhao, Y.-L. & Hui, S. W. pH influences the postpulse permeability state of skin after electroporation. J. Control Release 93, 49\u201357. https:\/\/doi.org\/10.1016\/j.jconrel.2003.08.002 (2003).","journal-title":"J. Control Release"},{"key":"41992_CR47","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/S0168-3659(01)00443-6","volume":"76","author":"M Sznitowska","year":"2001","unstructured":"Sznitowska, M., Janicki, S. & Baczek, A. Studies on the effect of pH on the lipoidal route of penetration across stratum corneum. J. Control. Release 76, 327\u2013335. https:\/\/doi.org\/10.1016\/S0168-3659(01)00443-6 (2001).","journal-title":"J. Control. Release"},{"key":"41992_CR48","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1016\/j.bpj.2011.02.001","volume":"100","author":"D Groen","year":"2011","unstructured":"Groen, D. et al. Disposition of ceramide in model lipid membranes determined by neutron diffraction. Biophys. J. 100, 1481\u20131489. https:\/\/doi.org\/10.1016\/j.bpj.2011.02.001 (2011).","journal-title":"Biophys. J."},{"key":"41992_CR49","doi-asserted-by":"publisher","first-page":"3951","DOI":"10.1016\/j.bpj.2024.10.006","volume":"123","author":"I Sagrafena","year":"2024","unstructured":"Sagrafena, I. et al. Structure and function of skin barrier lipids: Effects of hydration and natural moisturizers in vitro. Biophys. J. 123, 3951\u20133963. https:\/\/doi.org\/10.1016\/j.bpj.2024.10.006 (2024).","journal-title":"Biophys. J."},{"key":"41992_CR50","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/S0022-2275(20)40054-9","volume":"36","author":"JA Bouwstra","year":"1995","unstructured":"Bouwstra, J. A., Gooris, G. S., Bras, W. & Downing, D. T. Lipid organization in pig stratum corneum. J. Lipid Res. 36, 685\u2013695 (1995).","journal-title":"J. Lipid Res."},{"key":"41992_CR51","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1021\/acs.jpcb.4c05473","volume":"129","author":"M Martin","year":"2025","unstructured":"Martin, M., Chantemargue, B. & Trouillas, P. Skin hydration by natural moisturizing factors, a story of H-bond networking. J. Phys. Chem. B 129, 844\u2013852. https:\/\/doi.org\/10.1021\/acs.jpcb.4c05473 (2025).","journal-title":"J. Phys. Chem. B"},{"key":"41992_CR52","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.chemphyslip.2004.12.002","volume":"134","author":"ME Rerek","year":"2005","unstructured":"Rerek, M. E., Van Wyck, D., Mendelsohn, R. & Moore, D. J. FTIR spectroscopic studies of lipid dynamics in phytosphingosine ceramide models of the stratum corneum lipid matrix. Chem. Phys. Lipids 134, 51\u201358. https:\/\/doi.org\/10.1016\/j.chemphyslip.2004.12.002 (2005).","journal-title":"Chem. Phys. Lipids"},{"key":"41992_CR53","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1046\/j.1523-1747.2003.12128.x","volume":"120","author":"JA Bouwstra","year":"2003","unstructured":"Bouwstra, J. A. et al. Water distribution and related morphology in human stratum corneum at different hydration levels. J. Invest. Dermatol. 120, 750\u2013758 (2003).","journal-title":"J. Invest. Dermatol."},{"key":"41992_CR54","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1038\/jid.2012.43","volume":"132","author":"I Iwai","year":"2012","unstructured":"Iwai, I. et al. The human skin barrier is organized as stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety. J. Invest. Dermatol. 132, 2215\u20132225 (2012).","journal-title":"J. Invest. Dermatol."},{"key":"41992_CR55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0061889","volume":"8","author":"S Bj\u00f6rklund","year":"2013","unstructured":"Bj\u00f6rklund, S., Nowacka, A., Bouwstra, J. A., Sparr, E. & Topgaard, D. Characterization of Stratum Corneum molecular dynamics by natural-abundance 13C solid-state NMR. PLoS ONE 8, e61889. https:\/\/doi.org\/10.1371\/journal.pone.0061889 (2013).","journal-title":"PLoS ONE"},{"key":"41992_CR56","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1111\/1523-1747.ep12338682","volume":"106","author":"A Alonso","year":"1996","unstructured":"Alonso, A., Meirelles, N. C., Yushmanov, V. E. & Tabak, M. Water increases the fluidity of intercellular membranes of Stratum Corneum: Correlation with water permeability, elastic, and electrical resistance properties. J. Invest. Dermatol. 106, 1058\u20131063. https:\/\/doi.org\/10.1111\/1523-1747.ep12338682 (1996).","journal-title":"J. Invest. Dermatol."},{"key":"41992_CR57","doi-asserted-by":"publisher","first-page":"2647","DOI":"10.1016\/j.bbamem.2007.05.028","volume":"1768","author":"CL Silva","year":"2007","unstructured":"Silva, C. L. et al. Stratum Corneum hydration: Phase transformations and mobility in Stratum Corneum, extracted lipids and isolated corneocytes. Biochim. Biophys. Acta (BBA) 1768, 2647\u20132659 (2007).","journal-title":"Biochim. Biophys. Acta (BBA)"},{"key":"41992_CR58","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1021\/js960198e","volume":"86","author":"ME Johnson","year":"1997","unstructured":"Johnson, M. E., Blankschtein, D. & Langer, R. Evaluation of solute permeation through the Stratum Corneum: Lateral bilayer diffusion as the primary transport mechanism. J. Pharm. Sci. 86, 1162\u20131172 (1997).","journal-title":"J. Pharm. Sci."},{"key":"41992_CR59","doi-asserted-by":"publisher","first-page":"3871","DOI":"10.1073\/pnas.87.10.3871","volume":"87","author":"R Potts","year":"1990","unstructured":"Potts, R. & Francoeur, M. Lipid biophysics of water loss through the skin. Proc. Natl. Acad. Sci. U. S. A. 87, 3871\u20133873 (1990).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"41992_CR60","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/0168-3659(91)90114-S","volume":"15","author":"HE Bodde","year":"1991","unstructured":"Bodde, H. E., Van den Brink, I., Koerten, H. K. & De Haan, F. H. N. Visualization of in vitro percutaneous penetration of mercuric chloride; transport through intercellular space versus cellular uptake through desmosomes. J. Control Release 15, 227\u2013236 (1991).","journal-title":"J. Control Release"},{"key":"41992_CR61","doi-asserted-by":"publisher","first-page":"3725","DOI":"10.1021\/bi00410a031","volume":"27","author":"SH White","year":"1988","unstructured":"White, S. H., Mirejovsky, D. & King, G. I. Structure of lamellar lipid domains and corneocyte envelopes of murine Stratum Corneum. An x-ray diffraction study. Biochemistry 27, 3725\u20133732 (1988).","journal-title":"Biochemistry"},{"key":"41992_CR62","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2340\/00015555741214","volume":"74","author":"B Forslind","year":"1994","unstructured":"Forslind, B. A domain mosaic model of the skin barrier. Acta. Derm. Venereol. 74, 1\u20136 (1994).","journal-title":"Acta. Derm. Venereol."},{"key":"41992_CR63","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2021.05.012","volume":"175","author":"JA Bouwstra","year":"2021","unstructured":"Bouwstra, J. A., Helder, R. W. J. & El Ghalbzouri, A. Human skin equivalents: Impaired barrier function in relation to the lipid and protein properties of the stratum corneum. Adv. Drug Deliv. Rev. 175, 113802. https:\/\/doi.org\/10.1016\/j.addr.2021.05.012 (2021).","journal-title":"Adv. Drug Deliv. Rev."},{"key":"41992_CR64","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/s0022-2275(20)36723-7","volume":"16","author":"AA Spector","year":"1975","unstructured":"Spector, A. A. Fatty acid binding to plasma albumin. J. Lipid Res. 16, 165\u2013179. https:\/\/doi.org\/10.1016\/s0022-2275(20)36723-7 (1975).","journal-title":"J. Lipid Res."},{"key":"41992_CR65","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/0009-3084(92)90050-Y","volume":"62","author":"J Villala\u00edn","year":"1992","unstructured":"Villala\u00edn, J. & G\u00f3mez-Fern\u00e1ndez, J. C. Fourier transform infrared spectroscopic study of mixtures of palmitic acid with dipalmitoylphosphatidylcholine using isotopic substitution. Chem. Phys. Lipids 62, 19\u201329. https:\/\/doi.org\/10.1016\/0009-3084(92)90050-Y (1992).","journal-title":"Chem. Phys. Lipids"},{"key":"41992_CR66","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1021\/bi00406a013","volume":"27","author":"DP Cistola","year":"1988","unstructured":"Cistola, D. P., Hamilton, J. A., Jackson, D. & Small, D. M. Ionization and phase behavior of fatty acids in water: Application of the Gibbs phase rule. Biochemistry 27, 1881\u20131888. https:\/\/doi.org\/10.1021\/bi00406a013 (1988).","journal-title":"Biochemistry"},{"key":"41992_CR67","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1073\/pnas.83.1.82","volume":"83","author":"JA Hamilton","year":"1986","unstructured":"Hamilton, J. A. & Cistola, D. P. Transfer of oleic acid between albumin and phospholipid vesicles. Proc. Natl. Acad. Sci. U. S. A. 83, 82\u201386. https:\/\/doi.org\/10.1073\/pnas.83.1.82 (1986).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"41992_CR68","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1023\/a:1016280714593","volume":"12","author":"R Lieckfeldt","year":"1995","unstructured":"Lieckfeldt, R., Villala\u00edn, J., G\u00f3mez-Fern\u00e1ndez, J. C. & Lee, G. Apparent pKa of the fatty acids within ordered mixtures of model human stratum corneum lipids. Pharm. Res. 12, 1614\u20131617. https:\/\/doi.org\/10.1023\/a:1016280714593 (1995).","journal-title":"Pharm. Res."},{"key":"41992_CR69","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-73684-y","volume":"10","author":"M Morin","year":"2020","unstructured":"Morin, M. et al. Skin hydration dynamics investigated by electrical impedance techniques in vivo and in vitro. Sci. Rep. 10, 17218. https:\/\/doi.org\/10.1038\/s41598-020-73684-y (2020).","journal-title":"Sci. Rep."},{"key":"41992_CR70","doi-asserted-by":"publisher","first-page":"2692","DOI":"10.1016\/s0006-3495(96)79460-2","volume":"71","author":"YN Kalia","year":"1996","unstructured":"Kalia, Y. N., Pirot, F. & Guy, R. H. Homogeneous transport in a heterogeneous membrane: Water diffusion across human stratum corneum in vivo. Biophys. J. 71, 2692\u20132700. https:\/\/doi.org\/10.1016\/s0006-3495(96)79460-2 (1996).","journal-title":"Biophys. J."},{"key":"41992_CR71","doi-asserted-by":"publisher","first-page":"2036","DOI":"10.1007\/s11095-013-1052-1","volume":"30","author":"EA White","year":"2013","unstructured":"White, E. A., Orazem, M. E. & Bunge, A. L. Characterization of damaged skin by impedance spectroscopy: Mechanical damage. Pharm. Res. 30, 2036\u20132049. https:\/\/doi.org\/10.1007\/s11095-013-1052-1 (2013).","journal-title":"Pharm. Res."},{"key":"41992_CR72","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-85604-z","volume":"15","author":"AR Hern\u00e1ndez","year":"2025","unstructured":"Hern\u00e1ndez, A. R. et al. Algae extract-based nanoemulsions for photoprotection against UVB radiation: An electrical impedance spectroscopy study. Sci. Rep. 15, 1911. https:\/\/doi.org\/10.1038\/s41598-025-85604-z (2025).","journal-title":"Sci. Rep."},{"key":"41992_CR73","doi-asserted-by":"publisher","first-page":"2376","DOI":"10.3390\/s19102376","volume":"19","author":"AR Hern\u00e1ndez","year":"2019","unstructured":"Hern\u00e1ndez, A. R., Vallejo, B., Ruzgas, T. & Bj\u00f6rklund, S. The effect of UVB irradiation and oxidative stress on the skin barrier\u2014A new method to evaluate sun protection factor based on electrical impedance spectroscopy. Sensors 19, 2376 (2019).","journal-title":"Sensors"},{"key":"41992_CR74","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/0167-2738(92)90378-3","volume":"53-56","author":"RO Potts","year":"1992","unstructured":"Potts, R. O., Guy, R. H. & Francoeur, M. L. Routes of ionic permeability through mammalian skin. Solid State Ionics 53\u201356, 165\u2013169. https:\/\/doi.org\/10.1016\/0167-2738(92)90378-3 (1992).","journal-title":"Solid State Ionics"},{"key":"41992_CR75","doi-asserted-by":"publisher","first-page":"2470","DOI":"10.1016\/j.bbamem.2013.06.011","volume":"1828","author":"C Alb\u00e9r","year":"2013","unstructured":"Alb\u00e9r, C. et al. Effects of water gradients and use of urea on skin ultrastructure evaluated by confocal Raman microspectroscopy. Biochim. Biophys. Acta (BBA) Biomembranes 1828, 2470\u20132478. https:\/\/doi.org\/10.1016\/j.bbamem.2013.06.011 (2013).","journal-title":"Biochim. Biophys. Acta (BBA) Biomembranes"},{"key":"41992_CR76","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1046\/j.1523-1747.2003.12046.x","volume":"120","author":"RR Warner","year":"2003","unstructured":"Warner, R. R., Stone, K. J. & Boissy, Y. L. Hydration disrupts human stratum corneum ultrastructure. J. Invest. Dermatol. 120, 275\u2013284 (2003).","journal-title":"J. Invest. Dermatol."},{"key":"41992_CR77","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1046\/j.1523-1747.1999.00774.x","volume":"113","author":"RR Warner","year":"1999","unstructured":"Warner, R. R. et al. Water disrupts stratum corneum lipid lamellae: Damage is similar to surfactants. J. Invest. Dermatol. 113, 960\u2013966 (1999).","journal-title":"J. Invest. Dermatol."},{"key":"41992_CR78","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1023\/A:1018915100150","volume":"11","author":"K Kontturi","year":"1994","unstructured":"Kontturi, K. & Murtomaki, L. Impedance spectroscopy in human skin. A refined model. Pharm. Res. 11, 1355\u20131357 (1994).","journal-title":"Pharm. Res."},{"key":"41992_CR79","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1023\/A:1018998529283","volume":"11","author":"KD Peck","year":"1994","unstructured":"Peck, K. D., Ghanem, A.-H. & Higuchi, W. I. Hindered diffusion of polar molecules through and effective pore radii estimates of intact and ethanol treated human epidermal membrane. Pharm. Res. 11, 1306\u20131314 (1994).","journal-title":"Pharm. Res."},{"key":"41992_CR80","doi-asserted-by":"publisher","first-page":"3263","DOI":"10.1002\/jps.20955","volume":"96","author":"J Kushner IV","year":"2007","unstructured":"Kushner, J. IV., Blankschtein, D. & Langer, R. Evaluation of the porosity, the tortuosity, and the hindrance factor for the transdermal delivery of hydrophilic permeants in the context of the aqueous pore pathway hypothesis using dual-radiolabeled permeability experiments. J. Pharm. Sci. 96, 3263\u20133282. https:\/\/doi.org\/10.1002\/jps.20955 (2007).","journal-title":"J. Pharm. Sci."},{"key":"41992_CR81","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1038\/nrmicro2537","volume":"9","author":"EA Grice","year":"2011","unstructured":"Grice, E. A. & Segre, J. A. The skin microbiome. Nat. Rev. Microbiol. 9, 244\u2013253. https:\/\/doi.org\/10.1038\/nrmicro2537 (2011).","journal-title":"Nat. Rev. Microbiol."},{"key":"41992_CR82","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/nrmicro.2017.157","volume":"16","author":"AL Byrd","year":"2018","unstructured":"Byrd, A. L., Belkaid, Y. & Segre, J. A. The human skin microbiome. Nat. Rev. Microbiol. 16, 143\u2013155. https:\/\/doi.org\/10.1038\/nrmicro.2017.157 (2018).","journal-title":"Nat. Rev. Microbiol."},{"key":"41992_CR83","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1111\/exd.14604","volume":"31","author":"N Salgaonkar","year":"2022","unstructured":"Salgaonkar, N. et al. Glycerol fermentation by skin bacteria generates lactic acid and upregulates the expression levels of genes associated with the skin barrier function. Exp. Dermatol. 31, 1364\u20131372. https:\/\/doi.org\/10.1111\/exd.14604 (2022).","journal-title":"Exp. Dermatol."},{"key":"41992_CR84","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1111\/j.1473-2165.2008.00387.x","volume":"7","author":"S-H Bang","year":"2008","unstructured":"Bang, S.-H., Han, S.-J. & Kim, D.-H. Hydrolysis of arbutin to hydroquinone by human skin bacteria and its effect on antioxidant activity. J. Cosmet. Dermatol. 7, 189\u2013193. https:\/\/doi.org\/10.1111\/j.1473-2165.2008.00387.x (2008).","journal-title":"J. Cosmet. Dermatol."},{"key":"41992_CR85","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-04613-8","volume":"6","author":"S Feng","year":"2023","unstructured":"Feng, S., Guo, L., Wang, H., Yang, S. & Liu, H. Bacterial PncA improves diet-induced NAFLD in mice by enabling the transition from nicotinamide to nicotinic acid. Commun. Biol. 6, 235. https:\/\/doi.org\/10.1038\/s42003-023-04613-8 (2023).","journal-title":"Commun. Biol."},{"key":"41992_CR86","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-58377-2","volume":"16","author":"P Wang","year":"2025","unstructured":"Wang, P. et al. Microecology in vitro model replicates the human skin microbiome interactions. Nat. Commun. 16, 3085. https:\/\/doi.org\/10.1038\/s41467-025-58377-2 (2025).","journal-title":"Nat. Commun."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-41992-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-41992-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-41992-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T08:48:44Z","timestamp":1774428524000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-41992-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,24]]},"references-count":86,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["41992"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-41992-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,24]]},"assertion":[{"value":"20 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9821"}}