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Studying these hidden stages in patients presents significant technical and ethical challenges, underscoring the need for advanced in vitro models such as organ\u2010on\u2010chip (OoC) platforms. While cell\u2010laden hydrogels can replicate tissue\u2010like 3D\u2010microenvironments, their small mesh size may restrict pathogen migration and cell\u2013pathogen interactions, both critical for establishing infection on\u2010chip. To overcome this limitation, this work develops a \u201creversed\u201d granular hydrogel strategy that creates interconnected microporosity in hydrogels incorporated into organ\u2010on\u2010chip compartments. Sacrificial alginate (ALG) \u00b5gels are embedded as porogens in a fibrin\u2013collagen (FIB\u2010COL) precursor inside a custom BM\u2010on\u2010chip and, after crosslinking, are selectively removed by in situ enzymatic\/chemical leaching to yield highly porous hydrogels (pFIB\u2010COL). The pFIB\u2010COL supports 3D\u2010cultures of mesenchymal stromal cells, endothelial cells, and erythroblasts. Physical and cellular analyses show reduced flow resistance, enhanced particle and cell permeation, more uniform cell distribution and improved endothelial network formation compared with native FIB\u2010COL. This versatile strategy is readily adaptable to other hydrogel systems, providing a valuable tool for the faithful modeling of infection processes in biomimetic 3D\u2010microenvironments within OoC devices.<\/jats:p>","DOI":"10.1002\/smtd.202500652","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T06:21:12Z","timestamp":1762410072000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Advancing Organ\u2010on\u2010Chip Models With a Sacrificial Granular Hydrogel Strategy for Enhanced Permeability and Biomimicry"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7657-7410","authenticated-orcid":false,"given":"Hugo R","family":"Caires","sequence":"first","affiliation":[{"name":"i3S \u2013 Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade Universidade do Porto  Porto 4200\u2010135 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