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Yet the impact of the stiffened matrix on epithelial physiology remains poorly understood. A 2D and 3D microphysiological model of the large intestine was developed using a collagen scaffold with a physiologic or excessive stiffness (Young\u2019s moduli of 2.84 \u00b1 0.85 kPa and 15.9 \u00b1 0.73 kPa) by altering the collagen concentration within the substrate. Diffusion of a 10 and 40 kDa fluorescent dextran was significantly different between the physiologic and stiff scaffold (97.8 vs 79.8\n                    <jats:italic>\u00b5<\/jats:italic>\n                    m\n                    <jats:sup>2<\/jats:sup>\n                    s\n                    <jats:sup>\u22121<\/jats:sup>\n                    [10 kDa] and 68.2 vs 56.8\n                    <jats:italic>\u00b5<\/jats:italic>\n                    m\n                    <jats:sup>2<\/jats:sup>\n                    s\n                    <jats:sup>\u22121<\/jats:sup>\n                    [40 kDa], respectively). When primary human epithelial cells of the large intestine were grown as a 2D monolayer, cultures on the physiologic scaffold grew to a significantly higher density with more proliferative and fewer differentiated cells than cultures on the stiffened scaffold. Three-dimensional crypt arrays were also fabricated with the physiologic and stiff substrates, populated with cells, and a growth factor gradient applied. The cell density, proliferation, and height-to-width ratio was significantly greater for cells on the physiologic scaffold relative to that of cells on the stiffened scaffolds. Placement of a layer of intestinal fibroblasts below the epithelium on the crypt arrays did not mitigate the impact of the stiffened substrate. Bulk-RNA sequencing revealed 378 genes that were significantly upregulated and 385 genes significantly downregulated in the stiffened vs physiologic scaffolds. This work demonstrates that a molded collagen hydrogel can be used to mimic the biophysical characteristics of a stiffened intestinal stroma, recapitulating physiology observed\n                    <jats:italic>in vivo<\/jats:italic>\n                    . This\n                    <jats:italic>in vitro<\/jats:italic>\n                    model of polarized crypts with a tunable underlying substrate will enable an improved understanding of intestinal epithelial cell morphology, stem cell maintenance and lineage allocation within a stiffened environment.\n                  <\/jats:p>","DOI":"10.1088\/1758-5090\/ae2cf2","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T22:59:15Z","timestamp":1765839555000},"page":"015018","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["An\n                    <i>in vitro<\/i>\n                    model of stiffened colonic mucosa exhibits altered epithelial behavior"],"prefix":"10.1088","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0529-4410","authenticated-orcid":false,"given":"Angelo","family":"Massaro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0522-6829","authenticated-orcid":false,"given":"Cecilia","family":"Villegas Novoa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9242-768X","authenticated-orcid":true,"given":"Nancy L","family":"Allbritton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"bfae2cf2bib1","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.diff.2016.05.002","type":"journal-article","article-title":"Fibroblasts and myofibroblasts of the intestinal lamina propria in physiology and disease","volume":"92","author":"Roulis","year":"2016","journal-title":"Differentiation"},{"key":"bfae2cf2bib2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41420-024-02015-1","type":"journal-article","article-title":"Current understanding of the interplay between extracellular matrix remodelling and gut permeability in health and disease","volume":"10","author":"Vilardi","year":"2024","journal-title":"Cell Death Discovery"},{"key":"bfae2cf2bib3","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1097\/MIB.0b013e3182813297","type":"journal-article","article-title":"Matrix stiffness corresponding to strictured bowel induces a fibrogenic response in human colonic fibroblasts","volume":"19","author":"Johnson","year":"2013","journal-title":"Inflamm Bowel. 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