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Here a new in vitro model of the small intestine based on primary epithelial cells (i), apically accessible (ii), with native tissue mechanical properties and controlled mesh size (iii), 3D villus\u2010like architecture (iv), and precisely controlled biomolecular gradients of the ISC niche (v) is presented. Biochemical gradients are formed through hydrogel\u2010based scaffolds by free diffusion from a source to a sink chamber. To confirm the establishment of spatiotemporally controlled gradients, light\u2010sheet fluorescence microscopy and in\u2010silico modeling are employed. The ISC niche biochemical gradients coming from the stroma and applied along the villus axis lead to the in vivo\u2010like compartmentalization of the proliferative and differentiated cells, while changing the composition and concentration of the biochemical factors affects the cellular organization along the villus axis. This novel 3D in vitro intestinal model derived from organoids recapitulates both the villus\u2010like architecture and the gradients of ISC biochemical factors, thus opening the possibility to study in vitro the nature of such gradients and the resulting cellular response.<\/jats:p>","DOI":"10.1002\/adhm.202201172","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T02:43:50Z","timestamp":1662605030000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Modeling Biochemical Gradients In Vitro to Control Cell Compartmentalization in a Microengineered 3D Model of the Intestinal Epithelium"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3521-1647","authenticated-orcid":false,"given":"Gizem","family":"Altay","sequence":"first","affiliation":[{"name":"Biomimetic Systems for Cell Engineering Laboratory Institute for Bioengineering of Catalonia (IBEC) Barcelona Institute of Science and Technology (BIST)  Baldiri i Reixac 15\u201021 Barcelona 08028 Spain"},{"name":"Institut de l'Audition Institut Pasteur INSERM Universit\u00e9 de Paris  Paris 75012 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aina","family":"Abad\u2010L\u00e1zaro","sequence":"additional","affiliation":[{"name":"Biomimetic Systems for Cell Engineering Laboratory Institute for Bioengineering of Catalonia (IBEC) Barcelona Institute of Science and Technology (BIST)  Baldiri i Reixac 15\u201021 Barcelona 08028 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5948-5493","authenticated-orcid":false,"given":"Emilio J.","family":"Gualda","sequence":"additional","affiliation":[{"name":"SLN Research Facility Institute of Photonic Sciences (ICFO) Mediterranean Technology Park  Av. 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