{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T16:06:08Z","timestamp":1784217968107,"version":"3.55.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Toxicol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The intestine plays essential roles in digestion, immunity, and metabolism, but is highly sensitive to ionizing radiation during cancer treatment or environmental exposure. Although three-dimensional intestinal models more accurately replicate tissue architecture than conventional monolayers, they are frequently limited by insufficient oxygen delivery, leading to hypoxia-associated functional impairment. Incorporating physiologically relevant oxygenation strategies remains a key challenge in advanced\n                      <jats:italic>in vitro<\/jats:italic>\n                      systems. This study aimed to establish a physiologically relevant\n                      <jats:italic>in vitro<\/jats:italic>\n                      intestinal model by improving oxygen mass transfer within three-dimensional tissue constructs, thereby enhancing structural organization and functional maturation, and subsequently applying the system to investigate radiation-related mechanisms and evaluate potential protective agents.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Based on a microengineered 3D cell-assembly platform, intestinal epithelial cells, endothelial cells, and fibroblasts were spatially organized to form a structured intestinal tissue model. The composition of the cells was optimised to improve tissue uniformity and the function of the epithelial barrier. To alleviate hypoxia in the three-dimensional construct, an oxygen-permeable microwell system was employed to enhance oxygen diffusion and promote epithelial differentiation, as evidenced by the upregulation of\n                      <jats:italic>Isx<\/jats:italic>\n                      ,\n                      <jats:italic>Cyp3a5<\/jats:italic>\n                      , and\n                      <jats:italic>Tff3<\/jats:italic>\n                      . A vascularized chip that recapitulated the\n                      <jats:italic>in vivo<\/jats:italic>\n                      intestinal\u2013stromal\u2013vascular interface was created by incorporating microvascular networks self-assembled from endothelial cells within a hydrogel matrix.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Following radiation exposure, the model exhibited characteristic symptoms of intestinal injury, such as decreased cell viability, impaired E-cadherin signaling, and compromised epithelial barrier integrity. Treatment with dimethyloxalylglycine (DMOG) mitigated these effects, confirming it\u2019s utility for assessing radioprotective drugs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This vascularized intestinal-on-a-chip model closely mimics the structure and function of the human intestinal microenvironment. It serves as a robust\n                      <jats:italic>in vitro<\/jats:italic>\n                      platform for studying radiation-induced intestinal injury and for screening candidate protective agents, offering valuable applications in radiation protection and regenerative medicine research.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/ftox.2026.1863392","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T15:35:18Z","timestamp":1784216118000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Oxygen-enhanced assembloid-based vascularized intestinal-on-a-chip for radioprotective drug evaluation"],"prefix":"10.3389","volume":"8","author":[{"given":"Yuting","family":"Guo","sequence":"first","affiliation":[{"name":"Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University","place":["Beijing, China"]},{"name":"Key Laboratory for Advanced Materials Processing Technology, Ministry of Education","place":["Beijing, China"]},{"name":"Beijing Key Laboratory of Intelligent Organ Biofabrication and Regenerative Repair, Tsinghua University","place":["Beijing, China"]},{"name":"The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiling","family":"Fu","sequence":"additional","affiliation":[{"name":"Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University","place":["Beijing, China"]},{"name":"Key Laboratory for Advanced Materials Processing Technology, Ministry of Education","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Pang","sequence":"additional","affiliation":[{"name":"Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University","place":["Beijing, China"]},{"name":"Key Laboratory for Advanced Materials Processing Technology, Ministry of Education","place":["Beijing, China"]},{"name":"Beijing Key Laboratory of Intelligent Organ Biofabrication and Regenerative Repair, Tsinghua University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13287-017-0763-3","article-title":"BCN057 induces intestinal stem cell repair and mitigates radiation-induced intestinal injury","volume":"9","author":"Bhanja","year":"2018","journal-title":"Stem Cell Res. and Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1055\/s-2008-1056013","article-title":"A radiologic study of chronic radiation-induced injuries of the small intestine and colon","volume":"136","author":"Bruneton","year":"1982","journal-title":"Fortschritte dem Geb. R\u00f6ntgenstrahlen Nukl."},{"key":"B3","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1038\/nprot.2017.018","article-title":"On-chip human microvasculature assay for visualization and quantification of tumor cell extravasation dynamics","volume":"12","author":"Chen","year":"2017","journal-title":"Nat. Protoc."},{"key":"B4","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s13287-023-03629-5","article-title":"Human intestinal organoid-derived PDGFR\u03b1+ mesenchymal stroma enables proliferation and maintenance of LGR4+ epithelial stem cells","volume":"15","author":"Chen","year":"2024","journal-title":"Stem Cell Res. and Ther."},{"key":"B5","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1016\/j.cell.2025.12.025","article-title":"Shifting paradigms in tissue stem cell biology: insights from the intestine","volume":"189","author":"Clevers","year":"2026","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1126\/science.1062892","article-title":"What does radiotherapy do to endothelial cells?","volume":"293","author":"Folkman","year":"2001","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1089\/dna.2024.0105","article-title":"Radiation-induced intestinal injury: molecular mechanisms and therapeutic status","volume":"43","author":"Gao","year":"2024","journal-title":"DNA Cell Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"11360","DOI":"10.1038\/s41598-019-47851-9","article-title":"Hyperosmolar environment and intestinal epithelial cells: impact on mitochondrial oxygen consumption, proliferation, and barrier function in vitro","volume":"9","author":"Grauso","year":"2019","journal-title":"Sci. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e2200863","DOI":"10.1002\/adhm.202200863","article-title":"Scalable formation of highly viable and functional hepatocellular carcinoma spheroids in an oxygen-permeable microwell device for anti-tumor drug evaluation","volume":"11","author":"He","year":"2022","journal-title":"Adv. Healthc. Mater."},{"key":"B10","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1038\/s41385-020-00368-1","article-title":"The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes","volume":"14","author":"Jacobson","year":"2021","journal-title":"Mucosal Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1038\/s41551-019-0397-0","article-title":"A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip","volume":"3","author":"Jalili-Firoozinezhad","year":"2019","journal-title":"Nat. Biomed. Eng."},{"key":"B12","doi-asserted-by":"publisher","first-page":"7335","DOI":"10.1039\/c3cs60040h","article-title":"Designing degradable hydrogels for orthogonal control of cell microenvironments","volume":"42","author":"Kharkar","year":"2013","journal-title":"Chem. Soc. Rev."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.1039\/c2lc40074j","article-title":"Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow","volume":"12","author":"Kim","year":"2012","journal-title":"Lab a Chip"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.3390\/nu10101405","article-title":"The microbiome and radiation induced-bowel injury: evidence for potential mechanistic role in disease pathogenesis","volume":"10","author":"Kumagai","year":"2018","journal-title":"Nutrients"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1247125","DOI":"10.1126\/science.1247125","article-title":"Organogenesis in a dish: modeling development and disease using organoid technologies","volume":"345","author":"Lancaster","year":"2014","journal-title":"Science"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e0161026","DOI":"10.1371\/journal.pone.0161026","article-title":"Reproducible construction of surface tension-mediated honeycomb concave microwell arrays for engineering of 3D microtissues with minimal cell loss","volume":"11","author":"Lee","year":"2016","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"723","DOI":"10.3760\/cma.j.cn.441530-20200513-00276","article-title":"Diagnosis and treatment of radiation intestinal injury: current status and perspectives","volume":"23","author":"Li","year":"2020","journal-title":"Chin. J. Gastrointest. Surg."},{"key":"B17","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1038\/nature16460","article-title":"Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration","volume":"528","author":"Lindemans","year":"2015","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/s41378-025-00956-w","article-title":"Engineering in vitro vascular microsystems","volume":"11","author":"Liu","year":"2025","journal-title":"Microsystems and Nanoeng."},{"key":"B47","doi-asserted-by":"publisher","first-page":"11890","DOI":"10.1038\/s41598-019-48347-2","article-title":"Allometric scaling of physiologically-relevant organoids","volume":"9","author":"Magliaro","year":"2019","journal-title":"Sci Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.stem.2020.01.008","article-title":"Distinct mesenchymal cell populations generate the essential intestinal BMP signaling gradient","volume":"26","author":"McCarthy","year":"2020","journal-title":"Cell Stem Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1089\/ten.TEC.2015.0375","article-title":"Analytic models of oxygen and nutrient diffusion and metabolism dynamics in three-dimensional tissue constructs","volume":"22","author":"McMurtrey","year":"2016","journal-title":"Tissue Eng. Part C. Methods"},{"key":"B21","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.jcmgh.2020.02.007","article-title":"A novel organoid model of damage and repair identifies HNF4\u03b1 as a critical regulator of intestinal epithelial regeneration","volume":"10","author":"Montenegro-Miranda","year":"2020","journal-title":"Cell. Mol. Gastroenterology Hepatology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1242\/jcs.105.4.1013","article-title":"Paracrine induction of angiogenesis in vitro by Swiss 3T3 fibroblasts","volume":"105","author":"Montesano","year":"1993","journal-title":"J. Cell Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/s41598-017-18050-1","article-title":"The microwell-mesh: a high-throughput 3D prostate cancer spheroid and drug-testing platform","volume":"8","author":"Mosaad","year":"2018","journal-title":"Sci. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1016\/j.stem.2023.10.002","article-title":"Development of functional resident macrophages in human pluripotent stem cell-derived colonic organoids and human fetal colon","volume":"30","author":"M\u00fanera","year":"2023","journal-title":"Cell Stem Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1038\/nature05484","article-title":"Gut hormones and the regulation of energy homeostasis","volume":"444","author":"Murphy","year":"2006","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","first-page":"4739","DOI":"10.1016\/j.biomaterials.2014.01.079","article-title":"Effects of angiogenic factors and 3D-microenvironments on vascularization within sandwich cultures","volume":"35","author":"Nishiguchi","year":"2014","journal-title":"Biomaterials"},{"key":"B26","doi-asserted-by":"publisher","first-page":"101674","DOI":"10.1016\/j.redox.2020.101674","article-title":"Mitochondrial electron transport chain: oxidative phosphorylation and oxidant production","volume":"37","author":"Nolfi-Donegan","year":"2020","journal-title":"Redox Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1126\/science.1060191","article-title":"Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice","volume":"293","author":"Paris","year":"2001","journal-title":"Science"},{"key":"B28","doi-asserted-by":"publisher","first-page":"115404","DOI":"10.1016\/j.ecoenv.2023.115404","article-title":"X-ray radiation-induced intestinal barrier dysfunction in human epithelial Caco-2 cell monolayers","volume":"264","author":"Park","year":"2023","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B29","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/nri3608","article-title":"Intestinal epithelial cells: regulators of barrier function and immune homeostasis","volume":"14","author":"Peterson","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/nrm.2017.36","article-title":"Vascular heterogeneity and specialization in development and disease","volume":"18","author":"Potente","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1016\/j.it.2021.05.004","article-title":"Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions","volume":"42","author":"Pral","year":"2021","journal-title":"Trends Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1038\/nature17040","article-title":"Angiocrine functions of organ-specific endothelial cells","volume":"529","author":"Rafii","year":"2016","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3748\/wjg.v19.i2.185","article-title":"Gastrointestinal radiation injury: symptoms, risk factors and mechanisms","volume":"19","author":"Shadad","year":"2013","journal-title":"World J. Gastroenterology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1021\/acs.chemrestox.9b00245","article-title":"Organotypic and microphysiological models of liver, gut, and kidney","volume":"33","author":"Shen","year":"2020","journal-title":"Chem. Res. Toxicol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1002\/btpr.1837","article-title":"Combination of microwell structures and direct oxygenation enables efficient aggregate formation of a pancreatic \u03b2-cell line","volume":"30","author":"Shinohara","year":"2014","journal-title":"Biotechnol. Prog."},{"key":"B36","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1083\/jcb.201610056","article-title":"Organoids: a historical perspective of thinking in three dimensions","volume":"216","author":"Simian","year":"2017","journal-title":"J. Cell Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1517\/14712598.2015.986453","article-title":"Biologics as countermeasures for acute radiation syndrome","volume":"15","author":"Singh","year":"2015","journal-title":"Expert Opin. Biol. Ther."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2127","DOI":"10.1038\/s44318-024-00084-7","article-title":"Limited oxygen in standard cell culture alters metabolism and function of differentiated cells","volume":"43","author":"Tan","year":"2024","journal-title":"EMBO J."},{"key":"B39","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1038\/s41420-024-02015-1","article-title":"Extracellular matrix remodelling and gut permeability in health and disease","volume":"10","author":"Vilardi","year":"2024","journal-title":"Cell Death Discov."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.18240\/ijo.2017.07.01","article-title":"Comparative analysis of different feeder layers with 3T3 fibroblasts for culturing rabbits limbal stem cells","volume":"10","author":"Wang","year":"2017","journal-title":"Int. J. Ophthalmol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"3047","DOI":"10.3748\/wjg.v13.i22.3047","article-title":"Significance of endothelial dysfunction in early and delayed radiation enteropathy","volume":"13","author":"Wang","year":"2007","journal-title":"World J. Gastroenterology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"022011","DOI":"10.1088\/1758-5090\/adb7c1","article-title":"Biofabrication and simulation techniques for gut-on-a-chip","volume":"17","author":"Wang","year":"2025","journal-title":"Biofabrication"},{"key":"B42","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.immuni.2026.01.006","article-title":"Effector differentiation by stem-like intraepithelial \u03b3\u03b4 T cells is required for host defense against infection","volume":"59","author":"Xie","year":"2026","journal-title":"Immunity"},{"key":"B43","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/s13287-024-03738-9","article-title":"Mesenchymal stromal\/stem cells promote intestinal epithelium regeneration after chemotherapy-induced damage","volume":"15","author":"Yetkin-Arik","year":"2024","journal-title":"Stem Cell Res. and Ther."},{"key":"B44","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.stem.2015.12.005","article-title":"Engineering stem cell organoids","volume":"18","author":"Yin","year":"2016","journal-title":"Cell Stem Cell"},{"key":"B45","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1146\/annurev.cellbio.042308.113344","article-title":"Vertebrate endoderm development and organ formation","volume":"25","author":"Zorn","year":"2009","journal-title":"Annu. Rev. Cell Dev. Biol."}],"container-title":["Frontiers in Toxicology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1863392\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T15:35:20Z","timestamp":1784216120000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1863392\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":49,"alternative-id":["10.3389\/ftox.2026.1863392"],"URL":"https:\/\/doi.org\/10.3389\/ftox.2026.1863392","relation":{},"ISSN":["2673-3080"],"issn-type":[{"value":"2673-3080","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]},"article-number":"1863392"}}