{"doi":"10.1101/2025.08.06.667201","title":"A 3D Human Neuron-on-Chip Platform to Monitor Neuronal Injury Responses","abstract":"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 (0.5-24 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, IFNα2, 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 1-3), phosphorylated Tau (AT8+, days 5-8), 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":572463,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9247,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":419575,"name":"Charles-Francois V. Latchoumane","orcid":"0000-0001-7018-0439","position":1,"is_corresponding":false},{"id":1479091,"name":"Avi Chopra","orcid":null,"position":2,"is_corresponding":false},{"id":1478615,"name":"Marzan Sarkar","orcid":"0000-0003-0047-1841","position":3,"is_corresponding":false},{"id":408918,"name":"CK Kim","orcid":"0000-0003-2410-9118","position":4,"is_corresponding":false},{"id":919834,"name":"Nathan Gonsalves","orcid":"0000-0003-1030-1993","position":5,"is_corresponding":false},{"id":877572,"name":"Hsueh‐Fu Wu","orcid":"0000-0001-7892-7154","position":6,"is_corresponding":false},{"id":632605,"name":"Isha Mhatre‐Winters","orcid":"0000-0003-3498-8355","position":7,"is_corresponding":false},{"id":858613,"name":"Aditya K. Mishra","orcid":"0000-0003-0775-3219","position":8,"is_corresponding":false},{"id":355143,"name":"Lohitash Karumbaiah","orcid":"0000-0001-7969-417X","position":11,"is_corresponding":false},{"id":1479092,"name":"Jay M. Patel","orcid":null,"position":12,"is_corresponding":false},{"id":291181,"name":"Nadja Zeltner","orcid":"0000-0002-2978-2507","position":13,"is_corresponding":false},{"id":283054,"name":"Steven L. Stice","orcid":"0000-0002-6420-4892","position":14,"is_corresponding":false},{"id":424949,"name":"Jason R. Richardson","orcid":"0000-0001-6521-610X","position":15,"is_corresponding":false},{"id":1297015,"name":"Ruiping Tang","orcid":"0000-0003-0155-848X","position":0,"is_corresponding":true}],"reference_count":119,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:23.653298Z","pmid":"42427570","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}