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Current surgical interventions fail to restore the native nigrostriatal pathway essential for dopamine regulation. We have developed tissue\u2010engineered nigrostriatal pathways (TE\u2010NSPs) using hyaluronic acid hydrogel microcolumns with a collagen\/laminin core encasing aggregated dopaminergic neurons and long\u2010projecting axon tracts. TE\u2010NSPs fabricated using human iPSC\u2010derived dopaminergic neurons extended bundled axon tracts at a rate of 1\u00a0mm\/day\u2014twice that of neuronal aggregates on planar surfaces. Fully grown engineered microtissue exhibited nigrostriatal\u2010like cytoarchitecture, appropriate dopaminergic phenotypes, evoked dopamine release, and innervation of striatal neurons in vitro. TE\u2010NSPs were then evaluated in a rat 6\u2010OHDA PD model via histology and voltammetry at 3\u2010 and 6 months post\u2010implantation. TE\u2010NSPs showed dopaminergic neuronal survival in the substantia nigra, preserved axon tracts within the microcolumn, and outgrowth into host striatum. Voltammetry on ex vivo brain slices containing the implanted microtissue revealed evoked dopamine release at both 3\u2010 and 6\u2010months post\u2010implant. This study shows engineered microtissue fabricated using human cells with an anatomically\u2010inspired architecture and subsequently used for chronic replacement of a long\u2010distance brain pathway in a preclinical model, potentially offering a promising future treatment for pathway reconstruction in PD.<\/jats:p>","DOI":"10.1002\/adhm.71775","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T06:20:50Z","timestamp":1791094850000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human iPSC\u2010Derived Tissue\u2010Engineered Nigrostriatal Pathway for Chronic Restoration of Dopaminergic Axon Tracts in a Rat Parkinson's Model"],"prefix":"10.1002","author":[{"given":"Wisberty J.","family":"Gordi\u00e1n\u2010V\u00e9lez","sequence":"first","affiliation":[{"name":"Department of Bioengineering School of Engineering and Applied Science University of Pennsylvania  Philadelphia PA USA"},{"name":"Center For Brain Injury &amp; Repair Department of Neurosurgery Perelman School of Medicine University of Pennsylvania  Philadelphia PA USA"},{"name":"Center For Neurotrauma Neurodegeneration &amp; Restoration Corporal Michael Crescenz Veterans Affairs Medical Center  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2633-4343","authenticated-orcid":false,"given":"Dimple","family":"Chouhan","sequence":"additional","affiliation":[{"name":"Center For Brain Injury &amp; Repair Department of Neurosurgery Perelman School of Medicine University of Pennsylvania  Philadelphia PA USA"},{"name":"Center For Neurotrauma Neurodegeneration &amp; Restoration Corporal Michael Crescenz Veterans Affairs Medical Center  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5604-3021","authenticated-orcid":false,"given":"Kevin D.","family":"Browne","sequence":"additional","affiliation":[{"name":"Center For Brain Injury &amp; Repair Department of Neurosurgery Perelman School of Medicine University of Pennsylvania  Philadelphia PA USA"},{"name":"Center For Neurotrauma Neurodegeneration &amp; Restoration Corporal Michael Crescenz Veterans Affairs Medical Center  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Lim","sequence":"additional","affiliation":[{"name":"Center For Brain Injury &amp; Repair Department of Neurosurgery Perelman School of Medicine University of Pennsylvania  Philadelphia PA USA"},{"name":"Center For Neurotrauma Neurodegeneration &amp; Restoration Corporal Michael Crescenz Veterans Affairs Medical Center  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saarang P.","family":"Karandikar","sequence":"additional","affiliation":[{"name":"Department of Bioengineering School of Engineering and Applied Science University of Pennsylvania  Philadelphia PA USA"},{"name":"Center For Brain Injury &amp; Repair Department of Neurosurgery Perelman School of Medicine University of Pennsylvania  Philadelphia PA USA"},{"name":"Center For Neurotrauma Neurodegeneration &amp; Restoration Corporal Michael Crescenz Veterans Affairs Medical Center  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo A.","family":"Espa\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Neurobiology &amp; Anatomy College of Medicine Drexel University  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7282-2201","authenticated-orcid":false,"given":"John E.","family":"Duda","sequence":"additional","affiliation":[{"name":"Center For Neurotrauma Neurodegeneration &amp; Restoration Corporal Michael Crescenz Veterans Affairs Medical Center  Philadelphia PA USA"},{"name":"Department of Neurology Perelman School of Medicine University of Pennsylvania  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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