{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:02:43Z","timestamp":1780531363277,"version":"3.54.1"},"reference-count":126,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"EU Framework Programme for Research and Innovation Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["956851"],"award-info":[{"award-number":["956851"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Toxicology in Vitro"],"published-print":{"date-parts":[[2026,8]]},"DOI":"10.1016\/j.tiv.2026.106221","type":"journal-article","created":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T01:22:02Z","timestamp":1772846522000},"page":"106221","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":1,"special_numbering":"C","title":["Harnessing human colonoid-derived monolayers as an in vitro platform for investigating accumulation, toxicity, and pharmacodynamics of small molecules"],"prefix":"10.1016","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3284-7866","authenticated-orcid":false,"given":"Pedro G.M.","family":"Canh\u00e3o","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anny","family":"Smeuninx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzy","family":"Geerinckx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Evers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Snoeys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Augustijns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Kourula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.tiv.2026.106221_bb0005","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0231423","article-title":"Recapitulation of the accessible interface of biopsy-derived canine intestinal organoids to study epithelial-luminal interactions","volume":"15","author":"Ambrosini","year":"2020","journal-title":"PLoS One"},{"key":"10.1016\/j.tiv.2026.106221_bb0010","first-page":"1","article-title":"Human enteroid monolayers: a novel, functionally-stable model for investigating oral drug disposition","volume":"52","author":"Arian","year":"2024","journal-title":"Drug Metab. Dispos."},{"key":"10.1016\/j.tiv.2026.106221_bb0015","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11095-018-2362-0","article-title":"Human primary cell-based organotypic microtissues for modeling small intestinal drug absorption","volume":"35","author":"Ayehunie","year":"2018","journal-title":"Pharm. Res."},{"issue":"1","key":"10.1016\/j.tiv.2026.106221_bib536","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s40487-022-00215-2","article-title":"Liposomal irinotecan shows a larger therapeutic index than non-liposomal irinotecan in patient-derived xenograft models of pancreatic cancer","volume":"11","author":"Barbier","year":"2023","journal-title":"Oncol. Ther."},{"key":"10.1016\/j.tiv.2026.106221_bb0020","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tiv.2020.104928","article-title":"Human ileal organoid model recapitulates clinical incidence of diarrhea associated with small molecule drugs","volume":"68","author":"Belair","year":"2020","journal-title":"Toxicol. in Vitro"},{"key":"10.1016\/j.tiv.2026.106221_bb0025","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1124\/dmd.110.037663","article-title":"Studies on the metabolism and biological activity of the epimers of sulindac","volume":"39","author":"Brunell","year":"2011","journal-title":"Drug Metab. Dispos."},{"issue":"4","key":"10.1016\/j.tiv.2026.106221_bib539","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1093\/annonc\/mdl495","article-title":"Assessment of erlotinib pharmacodynamics in tumors and skin of patients with head and neck cancer","volume":"18","author":"Calvo","year":"2007","journal-title":"Ann. Oncol."},{"key":"10.1016\/j.tiv.2026.106221_bb9113","first-page":"1","article-title":"Prescribing Information","author":"CAMPTOSAR\u00ae","year":"2014","journal-title":"Pfizer Inc."},{"key":"10.1016\/j.tiv.2026.106221_bb0030","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejps.2025.107025","article-title":"Human organotypic colon in vitro microtissue: unveiling a new window into colonic drug disposition","volume":"209","author":"Canh\u00e3o","year":"2025","journal-title":"Eur. J. Pharm. Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb9114","first-page":"1","article-title":"Prescribing Information","author":"CELEBREX\u00ae","year":"2008","journal-title":"Pfizer Inc."},{"key":"10.1016\/j.tiv.2026.106221_bb9115","first-page":"1","article-title":"Clinical Pharmacology and Biopharmaceutics Review","author":"CELEBREX\u00ae","year":"1998","journal-title":"US FDA"},{"key":"10.1016\/j.tiv.2026.106221_bb9116","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/oxfordjournals.annonc.a059109","article-title":"Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials","volume":"6","author":"Chabot","year":"1995","journal-title":"Ann. Oncol."},{"key":"10.1016\/j.tiv.2026.106221_bb0035","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1039\/C8LC00039E","article-title":"Maximizing the impact of microphysiological systems with in vitro\u2013in vivo translation","volume":"18","author":"Cirit","year":"2018","journal-title":"Lab Chip"},{"key":"10.1016\/j.tiv.2026.106221_bb0040","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.yrtph.2018.04.018","article-title":"A big data approach to the concordance of the toxicity of pharmaceuticals in animals and humans","volume":"96","author":"Clark","year":"2018","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"10.1016\/j.tiv.2026.106221_bb9117","first-page":"1","article-title":"Prescribing Information","author":"CLINORIL\u00ae","year":"2010","journal-title":"Merck Co. Inc"},{"key":"10.1016\/j.tiv.2026.106221_bb9118","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1006379730137","article-title":"In vitro binding and partitioning of irinotecan (CPT-11) and its metabolite, SN-38, in human blood. Invest","volume":"18","author":"Combes","year":"2000","journal-title":"New Drugs"},{"key":"10.1016\/j.tiv.2026.106221_bb0045","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fcell.2020.00363","article-title":"Characterization of human colon organoids from inflammatory bowel disease patients","volume":"8","author":"d\u2019Aldebert","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"10.1016\/j.tiv.2026.106221_bb9119","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00280-009-1008-7","article-title":"Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors","volume":"65","author":"Denlinger","year":"2009","journal-title":"Cancer Chemother. Pharmacol."},{"key":"10.1016\/j.tiv.2026.106221_bb0050","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1158\/1078-0432.CCR-15-0339","article-title":"Toxicity attribution in phase I trials: evaluating the effect of dose on the frequency of related and unrelated toxicities","volume":"22","author":"Eaton","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.tiv.2026.106221_bb0055","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/0016-5085(94)90246-1","article-title":"Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas","volume":"107","author":"Eberhart","year":"1994","journal-title":"Gastroenterology"},{"key":"10.1016\/j.tiv.2026.106221_bb0060","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1177\/2472555220923332","article-title":"Recommended guidelines for developing, qualifying, and implementing complex in vitro models (CIVMs) for drug discovery","volume":"25","author":"Ekert","year":"2020","journal-title":"SLAS Discov."},{"key":"10.1016\/j.tiv.2026.106221_bb0065","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.ejps.2006.04.010","article-title":"Regional levels of drug transporters along the human intestinal tract: Co-expression of ABC and SLC transporters and comparison with Caco-2 cells","volume":"29","author":"Englund","year":"2006","journal-title":"Eur. J. Pharm. Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb0070","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1089\/adt.2016.742","article-title":"Big data mining and adverse event pattern analysis in clinical drug trials","volume":"14","author":"Federer","year":"2016","journal-title":"Assay Drug Dev. Technol."},{"key":"10.1016\/j.tiv.2026.106221_bb0075","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1242\/bio.013235","article-title":"Generation of tissue-engineered small intestine using embryonic stem cell-derived human intestinal organoids","volume":"4","author":"Finkbeiner","year":"2015","journal-title":"Biol. Open"},{"key":"10.1016\/j.tiv.2026.106221_bb0080","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1124\/jpet.113.207118","article-title":"NSAID-induced enteropathy\u00a0: are the currently available selective COX-2 inhibitors all the same?","volume":"348","author":"Fornai","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"10.1016\/j.tiv.2026.106221_bb0085","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1097\/FPC.0b013e32834f94cb","article-title":"Celecoxib pathways: pharmacokinetics and pharmacodynamics","volume":"22","author":"Gong","year":"2012","journal-title":"Pharmacogenet. Genomics"},{"key":"10.1016\/j.tiv.2026.106221_bb0090","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/35094017","article-title":"Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2","volume":"1","author":"Gupta","year":"2001","journal-title":"Nat. Rev. Cancer"},{"key":"10.1016\/j.tiv.2026.106221_bb0095","doi-asserted-by":"crossref","first-page":"48","DOI":"10.21037\/dmr-20-149","article-title":"The epidemiology of inflammatory bowel disease: balance between East and West? A narrative review","volume":"3","author":"Hammer","year":"2020","journal-title":"Dig Med. Res."},{"key":"10.1016\/j.tiv.2026.106221_bb0100","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fddsv.2024.1355044","article-title":"The (misleading) role of animal models in drug development","volume":"4","author":"Hartung","year":"2024","journal-title":"Front. Drug Discov."},{"key":"10.1016\/j.tiv.2026.106221_bb0105","first-page":"183","article-title":"A path forward advancing microphysiological systems","volume":"42","author":"Hartung","year":"2025","journal-title":"ALTEX Alternat. Anim. Exp."},{"key":"10.1016\/j.tiv.2026.106221_bb9120","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.lungcan.2016.01.005","article-title":"Association of pharmacokinetics and pharmacogenomics with safety and efficacy of gefitinib in patients with EGFR mutation positive advanced non-small cell lung cancer","volume":"93","author":"Hirose","year":"2016","journal-title":"Lung Cancer"},{"key":"10.1016\/j.tiv.2026.106221_bb0110","first-page":"1","article-title":"Industry adoption of organoids and organs-on-chip technology\u00a0: toward a paradox of choice","volume":"2200334","author":"Homan","year":"2023","journal-title":"Adv. Biol."},{"key":"10.1016\/j.tiv.2026.106221_bb0115","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/cancers12113322","article-title":"Epithelial transfer of the tyrosine kinase inhibitors erlotinib, gefitinib, afatinib, crizotinib, sorafenib, sunitinib, and dasatinib: implications for clinical resistance","volume":"12","author":"Honeywell","year":"2020","journal-title":"Cancers (Basel)"},{"key":"10.1016\/j.tiv.2026.106221_bb0120","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1038\/nprot.2007.303","article-title":"Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers","volume":"2","author":"Hubatsch","year":"2007","journal-title":"Nat. Protoc."},{"key":"10.1016\/j.tiv.2026.106221_bb9121","first-page":"1","article-title":"Prescribing Information","author":"IRESSA\u00ae","year":"2018","journal-title":"AstraZeneca Pharm. LP"},{"key":"10.1016\/j.tiv.2026.106221_bb0125","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/ibd\/izac212","article-title":"Molecular and functional characterization of human intestinal organoids and monolayers for modeling epithelial barrier","volume":"29","author":"Jelinsky","year":"2023","journal-title":"Inflamm. Bowel Dis."},{"key":"10.1016\/j.tiv.2026.106221_bb0130","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.addr.2020.09.012","article-title":"Engineered tissues and strategies to overcome challenges in drug development","volume":"158","author":"Khalil","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"10.1016\/j.tiv.2026.106221_bb0135","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fcell.2025.1508820","article-title":"The differentiation state of small intestinal organoid models influences prediction of drug-induced toxicity","volume":"13","author":"Klein","year":"2025","journal-title":"Front. Cell Dev. Biol."},{"key":"10.1016\/j.tiv.2026.106221_bb0140","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejps.2023.106481","article-title":"Intestinal organoids as an in vitro platform to characterize disposition, metabolism, and safety profile of small molecules","volume":"188","author":"Kourula","year":"2023","journal-title":"Eur. J. Pharm. Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb0145","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1136\/gutjnl-2017-314817","article-title":"DNA methylation defines regional identity of human intestinal epithelial organoids and undergoes dynamic changes during development","volume":"68","author":"Kraiczy","year":"2019","journal-title":"Gut"},{"key":"10.1016\/j.tiv.2026.106221_bb0150","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/pharmaceutics15112523","article-title":"Caco-2 cell line standardization with pharmaceutical requirements and in vitro model suitability for permeability assays","volume":"15","author":"Kus","year":"2023","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.tiv.2026.106221_bb0155","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1126\/sciadv.abh1586","article-title":"The development of a functional human small intestinal epithelium model for drug absorption","volume":"7","author":"Kwon","year":"2021","journal-title":"Sci. Adv."},{"key":"10.1016\/j.tiv.2026.106221_bb0160","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1208\/s12248-013-9456-8","article-title":"Drug discovery and regulatory considerations for improving in silico and in vitro predictions that use caco-2 as a surrogate for human intestinal permeability measurements","volume":"15","author":"Larregieu","year":"2013","journal-title":"AAPS J."},{"key":"10.1016\/j.tiv.2026.106221_bb0165","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2023.1108289","article-title":"Understanding disruption of the gut barrier during inflammation: should we abandon traditional epithelial cell lines and switch to intestinal organoids?","volume":"14","author":"Lechuga","year":"2023","journal-title":"Front. Immunol."},{"key":"10.1016\/j.tiv.2026.106221_bb0170","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/pharmaceutics13020161","article-title":"Drug disposition in the lower gastrointestinal tract: targeting and monitoring","volume":"13","author":"Lemmens","year":"2021","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.tiv.2026.106221_bb0175","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.apsb.2019.10.001","article-title":"Current trends in drug metabolism and pharmacokinetics","volume":"9","author":"Li","year":"2019","journal-title":"Acta Pharm. Sin. B"},{"key":"10.1016\/j.tiv.2026.106221_bb0180","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1093\/toxsci\/kfr339","article-title":"Evaluation of drugs with specific organ toxicities in organ-specific cell lines","volume":"126","author":"Lin","year":"2012","journal-title":"Toxicol. Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb0185","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2021.785851","article-title":"A microphysiological cell-culturing system for pharmacokinetic drug exposure and high-resolution imaging of arrays of 3D microtissues","volume":"12","author":"Lohasz","year":"2021","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.tiv.2026.106221_bb9122","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1124\/dmd.118.082966","article-title":"Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 1352 drug compounds","volume":"46","author":"Lombardo","year":"2018","journal-title":"Drug Metab. Dispos."},{"key":"10.1016\/j.tiv.2026.106221_bb0190","first-page":"1","article-title":"Establishment of human epithelial enteroids and colonoids from whole tissue and biopsy","volume":"2015","author":"Mahe","year":"2015","journal-title":"J. Vis. Exp."},{"key":"10.1016\/j.tiv.2026.106221_bb0195","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/cancers13040594","article-title":"Non-steroidal anti-inflammatory drugs in colorectal cancer chemoprevention","volume":"13","author":"Maniewska","year":"2021","journal-title":"Cancers (Basel)"},{"key":"10.1016\/j.tiv.2026.106221_bb0200","first-page":"1","article-title":"Colorectal cancer: current updates and future perspectives","volume":"13","author":"Marcellinaro","year":"2024","journal-title":"J. Clin. Med."},{"key":"10.1016\/j.tiv.2026.106221_bb0205","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/s11626-020-00526-6","article-title":"Human small intestinal organotypic culture model for drug permeation, inflammation, and toxicity assays","volume":"57","author":"Markus","year":"2021","journal-title":"In Vitro Cell Dev. Biol. Anim."},{"key":"10.1016\/j.tiv.2026.106221_bb0210","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1021\/mp4000822","article-title":"Rapid measurement of intracellular unbound drug concentrations","volume":"10","author":"Mateus","year":"2013","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.tiv.2026.106221_bb0215","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep43047","article-title":"Intracellular drug bioavailability: a new predictor of system dependent drug disposition","volume":"7","author":"Mateus","year":"2017","journal-title":"Sci. Rep."},{"key":"10.1016\/j.tiv.2026.106221_bb0220","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s10928-005-0074-7","article-title":"How modeling and simulation have enhanced decision making in new drug development","volume":"32","author":"Miller","year":"2005","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"issue":"8","key":"10.1016\/j.tiv.2026.106221_bib540","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/j.stem.2024.05.007","article-title":"Bioengineered human colon organoids with in vivo-like cellular complexity and function","volume":"31","author":"Mitrofanova","year":"2024","journal-title":"Cell Stem Cell"},{"key":"10.1016\/j.tiv.2026.106221_bb0225","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1016\/j.stemcr.2021.07.016","article-title":"Assessing donor-to-donor variability in human intestinal organoid cultures","volume":"16","author":"Mohammadi","year":"2021","journal-title":"Stem Cell Reports"},{"key":"10.1016\/j.tiv.2026.106221_bb0230","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.taap.2017.09.006","article-title":"Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: the IQ consortium nonclinical to clinical translational database","volume":"334","author":"Monticello","year":"2017","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"10.1016\/j.tiv.2026.106221_bb0235","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1177\/0192623312457273","article-title":"Use of animal models of human disease for nonclinical safety assessment of novel pharmaceuticals","volume":"41","author":"Morgan","year":"2013","journal-title":"Toxicol. Pathol."},{"key":"10.1016\/j.tiv.2026.106221_bb0240","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1515\/hsz-2016-0259","article-title":"Expression, regulation and function of intestinal drug transporters: an update","volume":"398","author":"M\u00fcller","year":"2017","journal-title":"Biol. Chem."},{"key":"10.1016\/j.tiv.2026.106221_bb0245","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1021\/acs.molpharmaceut.7b00095","article-title":"Magnetic resonance imaging quantification of fasted state colonic liquid pockets in healthy humans","volume":"14","author":"Murray","year":"2017","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.tiv.2026.106221_bb0250","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.aquatox.2025.107354","article-title":"Metabolic disruptions induced by low concentrations of DMSO in RTgill-W1 fish cells: the importance of solvent controls in in vitro studies","volume":"283","author":"Nguyen","year":"2025","journal-title":"Aquat. Toxicol."},{"key":"10.1016\/j.tiv.2026.106221_bb0255","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/Spectrum.00003-21","article-title":"A versatile human intestinal organoid-derived epithelial monolayer model for the study of enteric pathogens","volume":"9","author":"Nickerson","year":"2021","journal-title":"Microbiol. Spectrum"},{"key":"10.1016\/j.tiv.2026.106221_bb0260","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/BF02056946","article-title":"Tissue prostaglandin levels in familial adenomatous polyposis patients treated with sulindac","volume":"39","author":"Nugent","year":"1996","journal-title":"Dis. Colon Rectum"},{"key":"10.1016\/j.tiv.2026.106221_bb0265","first-page":"1","article-title":"Human intestinal enteroids: nonclinical applications for predicting oral drug disposition, toxicity, and efficacy","volume":"108879","author":"O\u2019Mahony","year":"2025","journal-title":"Pharmacol. Ther."},{"key":"10.1016\/j.tiv.2026.106221_bb0270","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.xphs.2015.10.030","article-title":"The proteome of filter-grown Caco-2 cells with a focus on proteins involved in drug disposition","volume":"105","author":"\u00d6lander","year":"2016","journal-title":"J. Pharm. Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb0275","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1006\/rtph.2000.1399","article-title":"Concordance of the toxicity of pharmaceuticals in humans and in animals","volume":"32","author":"Olson","year":"2000","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"10.1016\/j.tiv.2026.106221_bb0280","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2022.122004","article-title":"The Caco-2 model: modifications and enhancements to improve efficiency and predictive performance","volume":"624","author":"Panse","year":"2022","journal-title":"Int. J. Pharm."},{"key":"10.1016\/j.tiv.2026.106221_bb0285","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lfs.2024.122875","article-title":"Exploring the potential of human intestinal organoids: applications, challenges, and future directions","volume":"352","author":"Parente","year":"2024","journal-title":"Life Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb0290","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1124\/dmd.121.000476","article-title":"Quantitative investigation of irinotecan metabolism, transport, and gut microbiome activation","volume":"49","author":"Parvez","year":"2021","journal-title":"Drug Metab. Dispos."},{"key":"10.1016\/j.tiv.2026.106221_bb0295","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/toxsci\/kfy268","article-title":"Human 3D gastrointestinal microtissue barrier function as a predictor of drug-induced diarrhea","volume":"168","author":"Peters","year":"2019","journal-title":"Toxicol. Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb0300","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1039\/C9LC01107B","article-title":"Developing in vitro assays to transform gastrointestinal safety assessment: potential for microphysiological systems","volume":"20","author":"Peters","year":"2020","journal-title":"Lab Chip"},{"key":"10.1016\/j.tiv.2026.106221_bb0305","first-page":"425","article-title":"Characterization and optimization of variability in a human colonic epithelium culture model","volume":"41","author":"Pike","year":"2024","journal-title":"ALTEX Alternat. Anim. Exp."},{"key":"10.1016\/j.tiv.2026.106221_bb0310","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tiv.2025.106040","article-title":"High-throughput assay for predicting diarrhea risk using a 2D human intestinal stem cell-derived model","volume":"106","author":"Pike","year":"2025","journal-title":"Toxicol. in Vitro"},{"key":"10.1016\/j.tiv.2026.106221_bb0315","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cpim.106","article-title":"Establishment and culture of human intestinal organoids derived from adult stem cells","volume":"130","author":"Pleguezuelos-Manzano","year":"2020","journal-title":"Curr. Protoc. Immunol."},{"issue":"7","key":"10.1016\/j.tiv.2026.106221_bib537","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1002\/cncr.22545","article-title":"A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer","volume":"109","author":"Posadas","year":"2007","journal-title":"Cancer"},{"key":"10.1016\/j.tiv.2026.106221_bb9123","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1215\/S1522851705000451","article-title":"Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma1","volume":"8","author":"Prados","year":"2006","journal-title":"Neuro. Oncol."},{"key":"10.1016\/j.tiv.2026.106221_bb0320","doi-asserted-by":"crossref","first-page":"893","DOI":"10.2174\/138920008786485119","article-title":"Permeability for intestinal absorption: Caco-2 assay and related issues","volume":"9","author":"Press","year":"2008","journal-title":"Curr. Drug Metab."},{"key":"10.1016\/j.tiv.2026.106221_bb0325","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1208\/s12249-009-9207-4","article-title":"Permeation of four oral drugs through human intestinal mucosa","volume":"10","author":"Pretorius","year":"2009","journal-title":"AAPS PharmSciTech"},{"key":"10.1016\/j.tiv.2026.106221_bb0330","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1002\/ijc.22755","article-title":"Prostaglandin F2\u03b1 stimulates motility and invasion in colorectal tumor cells","volume":"121","author":"Qualtrough","year":"2007","journal-title":"Int. J. Cancer"},{"key":"10.1016\/j.tiv.2026.106221_bb9124","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1158\/1055-9965.EPI-07-2510","article-title":"Comparative Bioavailability of Sulindac in Capsule and Tablet Formulations","volume":"17","author":"Reid","year":"2008","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"10.1016\/j.tiv.2026.106221_bb0335","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1124\/dmd.116.071837","article-title":"Determination of unbound partition coefficient and in vitro-in vivo extrapolation for SLC13A transporter-mediated uptake","volume":"44","author":"Riccardi","year":"2016","journal-title":"Drug Metab. Dispos."},{"key":"10.1016\/j.tiv.2026.106221_bb0340","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1124\/dmd.117.079152","article-title":"Comparison of species and cell-type differences in fraction unbound of liver tissues, hepatocytes, and cell lines","volume":"46","author":"Riccardi","year":"2018","journal-title":"Drug Metab. Dispos."},{"key":"10.1016\/j.tiv.2026.106221_bb0345","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1016\/j.xphs.2019.10.060","article-title":"Evaluation of fraction unbound across 7 tissues of 5 species","volume":"109","author":"Ryu","year":"2020","journal-title":"J. Pharm. Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb0350","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nature07935","article-title":"Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche","volume":"459","author":"Sato","year":"2009","journal-title":"Nature"},{"key":"10.1016\/j.tiv.2026.106221_bb0355","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1053\/j.gastro.2011.07.050","article-title":"Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett\u2019s epithelium","volume":"141","author":"Sato","year":"2011","journal-title":"Gastroenterology"},{"key":"10.1016\/j.tiv.2026.106221_bb0360","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1111\/j.1365-2036.2005.02683.x","article-title":"Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging","volume":"22","author":"Schiller","year":"2005","journal-title":"Aliment. Pharmacol. Ther."},{"key":"10.1016\/j.tiv.2026.106221_bb0365","doi-asserted-by":"crossref","first-page":"e216","DOI":"10.1016\/j.cllc.2019.12.003","article-title":"Tyrosine kinase inhibitors for the treatment of EGFR mutation-positive non\u2013small-cell lung cancer: a clash of the generations","volume":"21","author":"Shah","year":"2020","journal-title":"Clin. Lung Cancer"},{"key":"10.1016\/j.tiv.2026.106221_bb0370","first-page":"1","article-title":"Gut-on-Chip microphysiological systems: latest advances in the integration of sensing strategies and adoption of mature detection mechanisms","volume":"33","author":"Signore","year":"2021","journal-title":"Sens. Biosens. Res."},{"key":"10.1016\/j.tiv.2026.106221_bb0375","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1124\/dmd.108.022335","article-title":"The expression of most UDP-glucuronosyltransferases (UGTs) is increased significantly during Caco-2 cell differentiation, whereas UGT1A6 is highly expressed also in undifferentiated cells","volume":"36","author":"Siissalo","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"10.1016\/j.tiv.2026.106221_bb0380","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.tiv.2005.06.045","article-title":"Pharmacogenetics of irinotecan metabolism and transport: an update","volume":"20","author":"Smith","year":"2006","journal-title":"Toxicol. in Vitro"},{"key":"10.1016\/j.tiv.2026.106221_bb0385","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ab.2012.10.022","article-title":"A highly efficient, high-throughput lipidomics platform for the quantitative detection of eicosanoids in human whole blood","volume":"433","author":"Song","year":"2013","journal-title":"Anal. Biochem."},{"key":"10.1016\/j.tiv.2026.106221_bb0390","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1177\/2211068214561025","article-title":"TEER measurement techniques for in vitro barrier model systems","volume":"20","author":"Srinivasan","year":"2015","journal-title":"J. Lab. Autom."},{"key":"10.1016\/j.tiv.2026.106221_bb0395","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fbioe.2020.00725","article-title":"Human microphysiological models of intestinal tissue and gut microbiome","volume":"8","author":"Steinway","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"10.1016\/j.tiv.2026.106221_bb0400","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1517\/17425255.4.4.395","article-title":"The Caco-2 cell monolayer: usefulness and limitations","volume":"4","author":"Sun","year":"2008","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"10.1016\/j.tiv.2026.106221_bb0405","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1016\/j.apsb.2022.02.002","article-title":"Why 90% of clinical drug development fails and how to improve it?","volume":"12","author":"Sun","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"10.1016\/j.tiv.2026.106221_bb0410","doi-asserted-by":"crossref","first-page":"581","DOI":"10.2131\/jts.38.581","article-title":"Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan","volume":"38","author":"Tamaki","year":"2013","journal-title":"J. Toxicol. Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb0415","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.1002\/jps.24433","article-title":"Impact of luminal fluid volume on the drug absorption after oral administration: analysis based on in vivo drug concentration-time profile in the gastrointestinal tract","volume":"104","author":"Tanaka","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb0420","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-025-95823-z","article-title":"Robust and reproducible human intestinal organoid-derived monolayer model for analyzing drug absorption","volume":"15","author":"Tanaka","year":"2025","journal-title":"Sci. Rep."},{"key":"10.1016\/j.tiv.2026.106221_bb0425","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1021\/mp800261a","article-title":"Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment","volume":"6","author":"Tannergren","year":"2009","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.tiv.2026.106221_bb9125","first-page":"1","article-title":"Prescribing Information","author":"TARCEVA\u00ae","year":"2010","journal-title":"OSI Pharm. Inc., Genentech, Inc"},{"key":"10.1016\/j.tiv.2026.106221_bb0430","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/bjc.2015.5","article-title":"OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan-based chemotherapy","volume":"112","author":"Teft","year":"2015","journal-title":"Br. J. Cancer"},{"key":"10.1016\/j.tiv.2026.106221_bb0435","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1093\/jnci\/94.4.252","article-title":"Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues","volume":"94","author":"Thun","year":"2002","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"10.1016\/j.tiv.2026.106221_bb0440","doi-asserted-by":"crossref","first-page":"3331","DOI":"10.1158\/1535-7163.MCT-09-0758","article-title":"Sulindac sulfide selectively inhibits growth and induces apoptosis of human breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP, and activation of protein kinase G","volume":"8","author":"Tinsley","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"10.1016\/j.tiv.2026.106221_bb0445","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1021\/acs.molpharmaceut.8b00064","article-title":"Intracellular drug bioavailability: effect of neutral lipids and phospholipids","volume":"15","author":"Treyer","year":"2018","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.tiv.2026.106221_bb0450","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11095-019-2717-1","article-title":"A cell-free approach based on phospholipid characterization for determination of the cell specific unbound drug fraction (fu,cell)","volume":"36","author":"Treyer","year":"2019","journal-title":"Pharm. Res."},{"key":"10.1016\/j.tiv.2026.106221_bb0455","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2014.00174","article-title":"Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at novartis institute of biomedical research","volume":"5","author":"Tuntland","year":"2014","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.tiv.2026.106221_bb0460","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fcell.2020.00375","article-title":"Congruence of transcription programs in adult stem cell-derived jejunum organoids and original tissue during long-term culture","volume":"8","author":"van der Hee","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"10.1016\/j.tiv.2026.106221_bb0465","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1080\/00365520410006891","article-title":"Real-time PCR of host DNA in feces to study differential exfoliation of colonocytes between rats and humans","volume":"39","author":"Van Lieshout","year":"2004","journal-title":"Scand. J. Gastroenterol."},{"key":"10.1016\/j.tiv.2026.106221_bb0470","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.jacbts.2019.10.008","article-title":"Limitations of animal studies for predicting toxicity in clinical trials: is it time to rethink our current approach?","volume":"4","author":"Van Norman","year":"2019","journal-title":"JACC Basic Transl. Sci."},{"key":"10.1016\/j.tiv.2026.106221_bb0475","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0378-4274(01)00304-6","article-title":"The importance of drug-transporting P-glycoproteins in toxicology","volume":"120","author":"Van Tellingen","year":"2001","journal-title":"Toxicol. Lett."},{"key":"10.1016\/j.tiv.2026.106221_bb0480","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.stem.2023.04.011","article-title":"Human pluripotent-stem-cell-derived organoids for drug discovery and evaluation","volume":"30","author":"Vandana","year":"2023","journal-title":"Cell Stem Cell"},{"key":"10.1016\/j.tiv.2026.106221_bb0485","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1136\/gutjnl-2013-306651","article-title":"Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays","volume":"64","author":"VanDussen","year":"2015","journal-title":"Gut"},{"key":"10.1016\/j.tiv.2026.106221_bb0490","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1053\/j.gastro.2004.09.080","article-title":"The role of prostaglandins and other eicosanoids in the gastrointestinal tract","volume":"128","author":"Wang","year":"2005","journal-title":"Gastroenterology"},{"issue":"21","key":"10.1016\/j.tiv.2026.106221_bib538","first-page":"6045","article-title":"Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models","volume":"60","author":"Williams","year":"2000","journal-title":"Cancer Res."},{"key":"10.1016\/j.tiv.2026.106221_bb0495","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jbspin.2023.105685","article-title":"NSAID: current limits to prescription","volume":"91","author":"Wirth","year":"2024","journal-title":"Joint Bone Spine"},{"issue":"4","key":"10.1016\/j.tiv.2026.106221_bib541","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1021\/acs.biomac.8b01467","article-title":"Molecular characterization of mucus binding","volume":"20","author":"Witten","year":"2019","journal-title":"Biomacromolecules"},{"key":"10.1016\/j.tiv.2026.106221_bb0500","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-023-43656-z","article-title":"Establishment of a 96-well transwell system using primary human gut organoids to capture multiple quantitative pathway readouts","volume":"13","author":"Wright","year":"2023","journal-title":"Sci. Rep."},{"key":"10.1016\/j.tiv.2026.106221_bb0505","doi-asserted-by":"crossref","first-page":"5467","DOI":"10.2147\/OTT.S194870","article-title":"Comparative review of drug\u2013drug interactions with epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer","volume":"12","author":"Xu","year":"2019","journal-title":"Onco. Targets Ther."},{"key":"10.1016\/j.tiv.2026.106221_bb0510","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1093\/annonc\/mdf337","article-title":"Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity","volume":"13","author":"Xu","year":"2002","journal-title":"Ann. Oncol."},{"key":"10.1016\/j.tiv.2026.106221_bb0515","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.omtm.2021.05.005","article-title":"Monolayer platform using human biopsy-derived duodenal organoids for pharmaceutical research","volume":"22","author":"Yamashita","year":"2021","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.tiv.2026.106221_bb0520","first-page":"1","article-title":"Sulindac, a non-steroidal anti-inflammatory drug, mediates breast cancer inhibition as an immune modulator","volume":"6","author":"Yin","year":"2016","journal-title":"Sci. Rep."},{"key":"10.1016\/j.tiv.2026.106221_bb0525","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-63151-z","article-title":"Generation of intestinal organoids derived from human pluripotent stem cells for drug testing","volume":"10","author":"Yoshida","year":"2020","journal-title":"Sci. Rep."},{"key":"10.1016\/j.tiv.2026.106221_bb0530","doi-asserted-by":"crossref","first-page":"3759","DOI":"10.1074\/jbc.R114.635995","article-title":"Human enteroids\/colonoids and intestinal organoids functionally recapitulate normal intestinal physiology and pathophysiology","volume":"291","author":"Zachos","year":"2016","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.tiv.2026.106221_bb0535","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fbioe.2020.577656","article-title":"Organoids to study intestinal nutrient transport, drug uptake and metabolism \u2013 update to the human model and expansion of applications","volume":"8","author":"Zietek","year":"2020","journal-title":"Front. Bioeng. Biotechnol."}],"container-title":["Toxicology in Vitro"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0887233326000299?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0887233326000299?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T23:22:42Z","timestamp":1780528962000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0887233326000299"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":126,"alternative-id":["S0887233326000299"],"URL":"https:\/\/doi.org\/10.1016\/j.tiv.2026.106221","relation":{},"ISSN":["0887-2333"],"issn-type":[{"value":"0887-2333","type":"print"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Harnessing human colonoid-derived monolayers as an in vitro platform for investigating accumulation, toxicity, and pharmacodynamics of small molecules","name":"articletitle","label":"Article Title"},{"value":"Toxicology in Vitro","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.tiv.2026.106221","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Author(s). Published by Elsevier Ltd.","name":"copyright","label":"Copyright"}],"article-number":"106221"}}