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Here, we present a novel\n                    <jats:italic>Neuron\u2010on\u2010Chip<\/jats:italic>\n                    microfluidic device and weight\u2010drop impactor\u00a0platform that can be used to mechanically injure mature human prefrontal cortex neurons (hPFCs) embedded in three\u2010dimensional (3D) hydrogels, enabling the study of injury responses in pure neuronal cultures. We assessed real\u2010time calcium dynamics across 13 metrics of single\u2010cell and network activity, revealing a biphasic injury response: an early phase (0.5\u201324\u00a0h) characterized by excitotoxicity, hyper\u2010synchronized bursting, and network collapse; and a late phase (8 d) marked by sustained depolarization and structural remodeling. Secretome profiling revealed progressive elevations in extracellular pT181 and total Tau from days 1 to 5 post\u2010injury. Cytokine analysis identified early (24\u00a0h) elevations in IP\u201010, IL\u201010, IFN\u03b12, and NCAM, and late increases (8 d) in CXCL9 and MPO, linking neuronal activity changes to stage\u2010specific inflammatory signaling. Immunocytochemistry and immunoblotting confirmed temporally ordered upregulation of calpain\u20101 and active caspase\u20103 (days 1\u20133), phosphorylated Tau (AT8+, days 5\u20138), and neurofibrillary tangle\u2010like Tau aggregates (NFT+, day 8). These findings establish our platform as a scalable microphysiological model for probing the dynamic cellular and molecular sequelae of neuronal response to injury, offering insights into neurodegeneration and opportunities for therapeutic discovery.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202503457","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:13:04Z","timestamp":1785406384000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A 3D Human Neuron\u2010on\u2010Chip Platform to Monitor Neuronal Injury Responses"],"prefix":"10.1002","volume":"15","author":[{"given":"Ruiping","family":"Tang","sequence":"first","affiliation":[{"name":"Regenerative Bioscience Center University of Georgia  Athens Georgia USA"},{"name":"Edgar L. 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Woodruff School of Mechanical Engineering Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay M.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Emory University School of Medicine  Atlanta Georgia USA"},{"name":"Department of Biomedical Engineering Georgia Institute of Technology\u2010Emory University  Atlanta Georgia USA"},{"name":"Atlanta VA Medical Center Emory University School of Medicine  Decatur Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Zeltner","sequence":"additional","affiliation":[{"name":"Center For Molecular Medicine University of Georgia  Athens Georgia USA"},{"name":"Department of Biochemistry and Molecular Biology Franklin College of Arts and Sciences University of Georgia  Athens Georgia USA"},{"name":"Division of Neuroscience Biomedical and Translational Sciences Institute University of Georgia  Athens Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven L.","family":"Stice","sequence":"additional","affiliation":[{"name":"Regenerative Bioscience Center University of Georgia  Athens Georgia USA"},{"name":"Edgar L. 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