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While 2D anisotropic topographies guide nerve growth via contact guidance, these models fail to recapitulate the 3D extracellular matrix microenvironment of native nerves. Herein, a microfluidic \u201cnerve\u2010in\u2010a\u2010chip\u201d platform is customized and filled with decellularized nerve matrix hydrogel (DNM\u2010G) to investigate how microchannel dimensions regulate 3D neurite extension and SC dynamics. Mid\u2010sized microchannels optimally enhanced longitudinal neurite growth and fasciculation, whereas excessively narrow microchannels impeded both neurite\/SC penetration. Crucially, a self\u2010directing mechanism is identified wherein fasciculated neurite bundles (&gt;3 \u00b5m diameter) followed trajectories dictated by highly dynamic branches (\u201cpathfinder neurites\u201d &lt;1\u00a0\u00b5m diameter). These tiny neurites exhibited cytoskeletal plasticity to enable exploratory branching and directional shifts. 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This study establishes a biomimetic model for deciphering microenvironmental regulation of nerve regeneration and provides de novo design principles for neural scaffolds, emphasizing the interplay between channel geometry and axonal dynamics.<\/jats:p>","DOI":"10.1002\/smll.202505674","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T10:37:57Z","timestamp":1755081477000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["\"Smart\" Nerves Sprout and Assemble in an Extracellular Matrix\u2010Based 3D Nerve\u2010in\u2010a\u2010Chip Microfluidic Model"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0143-6068","authenticated-orcid":false,"given":"Zilong","family":"Rao","sequence":"first","affiliation":[{"name":"Guangdong Engineering Technology Research Centre for Functional Biomaterials Key Laboratory for Polymeric Composite and Functional Materials 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