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However, most existing in\u00a0vitro models rely on flat monolayers or villus\u2010only hydrogels, limiting their ability to capture stem cell niches and spatial organization. Here, we report silk fibroin scaffolds engineered with physiologically scaled crypt\u2010villus topography through a combination of 3D\u2010printed molds, vacuum\u2010assisted silk infiltration, and water annealing. This approach reproducibly generated scaffolds with well\u2010defined crypt and villus features and an open design that permitted visual inspection prior to seeding. When seeded with human intestinal organoid\u2010derived monolayers, the scaffolds supported polarized epithelia with apical ZO\u20101, organized F\u2010actin, and E\u2010cadherin localization along villus axes. Differentiation protocols yielded all major intestinal lineages, including enterocytes, goblet cells, Paneth cells, and enteroendocrine cells, confirmed by immunostaining and qRT\u2010PCR. Ultrastructural analysis further revealed dense brush\u2010border microvilli on villi, indicative of absorptive maturation. Incorporation of L\u2010WRN feeder cells within the scaffold bulk sustained Ki\u201067 positive proliferative zones and increased LGR5 transcript expression, consistent with prolonged proliferative activity. Collectively, these results establish silk\u2010based crypt\u2010villus scaffolds as a reproducible and versatile platform for generating spatially organized human intestinal epithelium, with potential applications in epithelial biology, host\u2010microbe studies, and intestinal disease modeling.<\/jats:p>","DOI":"10.1002\/jbm.a.70083","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:08:16Z","timestamp":1776834496000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Silk Scaffold Crypt\u2010Villus Geometry Combined With L\u2010\n                    <scp>WRN<\/scp>\n                    Feeder Cells Sustains Spatially Organized Epithelial Proliferation and Multilineage Differentiation"],"prefix":"10.1002","volume":"114","author":[{"given":"Sara E.","family":"Rudolph","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Tufts University  Medford Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke N.","family":"Longo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Tufts University  Medford Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9693-6668","authenticated-orcid":false,"given":"Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Tufts University  Medford Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Tufts University  Medford Massachusetts 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