{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:18:27Z","timestamp":1785421107693,"version":"3.56.0"},"posted":{"date-parts":[[2025,8,9]]},"group-title":"Neuroscience","reference-count":159,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T00:00:00Z","timestamp":1754697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01NS099596"],"award-info":[{"award-number":["R01NS099596"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21NS130468"],"award-info":[{"award-number":["R21NS130468"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01ES033892"],"award-info":[{"award-number":["R01ES033892"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016363","name":"Alliance for Regenerative Rehabilitation Research and Training","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016363","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Dianne Isakson Distinguished Professorship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Traumatic brain injury (TBI) is a major cause of neurological dysfunction and long-term neurodegeneration, yet the intrinsic neuronal contributions to TBI pathophysiology remain incompletely defined. Here, we present a novel\n                  <jats:italic>Neuron-on-Chip<\/jats:italic>\n                  microfluidic platform that can be used to mechanically injure mature human prefrontal cortex neurons (hPFCs) embedded in three-dimensional (3D) hydrogels, enabling the study of injury responses in pure neuronal cultures. We assessed real-time calcium dynamics across 13 metrics of single-cell and network activity, revealing a biphasic injury response: an early phase (0.5\u201324 hr) characterized by excitotoxicity, hyper-synchronized bursting, and network collapse; and a late phase (8 d) marked by sustained depolarization and structural remodeling. Secretome profiling uncovered progressive elevations in extracellular pT181 and total Tau from days 1 to 5 post-injury. Cytokine analyses identified early (24 hr) elevations in IP-10, IL-10, IFN\u03b12, and NCAM, and late increases (8 d) in CXCL9 and MPO, linking neuronal activity changes to stage-specific inflammatory signaling. Immunocytochemistry and immunoblotting confirmed temporally ordered upregulation of calpain-1 and active caspase-3 (days 1\u20133), phosphorylated Tau (AT8+, days 5\u20138), and neurofibrillary tangle-like 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":"10.1101\/2025.08.06.667201","type":"posted-content","created":{"date-parts":[[2025,8,10]],"date-time":"2025-08-10T00:25:11Z","timestamp":1754785511000},"source":"Crossref","is-referenced-by-count":0,"title":["A 3D Human Neuron-on-Chip Platform to Monitor Neuronal Injury Responses"],"prefix":"10.64898","author":[{"given":"Ruiping","family":"Tang","sequence":"first","affiliation":[{"name":"Regenerative Bioscience Center, University of Georgia, Athens, GA, USA"},{"name":"Edgar L. 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Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, 30332, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Liu","sequence":"additional","affiliation":[{"name":"Optics11 Life Inc., Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3498-8355","authenticated-orcid":false,"given":"Isha","family":"Mhatre-Winters","sequence":"additional","affiliation":[{"name":"Isakson Center for Neurological Disease Research, Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0775-3219","authenticated-orcid":false,"given":"Aditya","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of Georgia, Athens, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei G.","family":"Fedorov","sequence":"additional","affiliation":[{"name":"G. 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