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In this review, we focus on intervertebral disc (IVD) degeneration, a leading cause of chronic low back pain, providing a comprehensive overview of the current understanding of IVD anatomy, physiology, and pathogenesis. We review conventional in vitro, ex vivo, and in vivo models, which have expanded our understanding; however, they inadequately reproduce the human phenotype, heterogeneous disc composition and anatomy, which comprises nucleus pulposus (NP) and annulus fibrosus (AF) with neovascularization and sensory innervation within the three\u2010dimensional (3D) degenerative microenvironment. We emphasize a disc\u2010on\u2010a\u2010chip platform to address these limitations, which integrates microfluidics and biomimetic ECM\u2010based hydrogels within a controlled microenvironment to miniaturize the disc. It offers a promising platform to simulate the pathological disc milieu by incorporating gradient control of key signaling molecules implicated in disc degeneration. These include a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMP)\u2010mediated extracellular matrix (ECM) degradation; tumor necrosis factor alpha (TNF\u2010\u03b1) and interleukin\u20101 beta (IL\u20101\u03b2)\u2010driven inflammation via nuclear factor kappa\u2010light\u2010chain\u2010enhancer of activated B cells (NF\u2010\u03baB); vascular endothelial growth factor (VEGF)\u2010promoted angiogenesis; and nerve growth factor (NGF)\u2010 and brain\u2010derived neurotrophic factor (BDNF)\u2010mediated sensory innervation and sensitization, thus contributing to nociception. Collectively, disc\u2010on\u2010a\u2010chip offers a next\u2010generation in vitro model for investigating mechanisms relating to ECM degradation, inflammation, innervation, vascularization, and nociception underlying IVD degeneration, enabling precision preclinical therapeutic evaluations.<\/jats:p>","DOI":"10.1002\/smmd.70051","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T11:14:48Z","timestamp":1787915688000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Organ\u2010on\u2010a\u2010Chip Technology: Advances in Modeling Inflammation, Neurovascularization and Nociception in Human Intervertebral Disc Degeneration"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5493-7876","authenticated-orcid":false,"given":"Izzat","family":"Zulkiflee","sequence":"first","affiliation":[{"name":"C\u00daRAM Research Ireland Centre for Medical Devices University of Galway  Galway Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5661-4559","authenticated-orcid":false,"given":"Nurul Fariha","family":"Za'aba","sequence":"additional","affiliation":[{"name":"Department of Anatomy Faculty of Medicine Universiti Kebangsaan Malaysia  Kuala Lumpur Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6292-4933","authenticated-orcid":false,"given":"Abhay","family":"Pandit","sequence":"additional","affiliation":[{"name":"C\u00daRAM Research Ireland Centre for Medical Devices University of Galway  Galway Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5389-9927","authenticated-orcid":false,"given":"Isma Liza","family":"Mohd Isa","sequence":"additional","affiliation":[{"name":"C\u00daRAM Research Ireland Centre for Medical Devices University of Galway  Galway Ireland"},{"name":"Department of Anatomy Faculty of Medicine Universiti Kebangsaan Malaysia  Kuala Lumpur Malaysia"},{"name":"Pharmacology and Therapeutics University of Galway  Galway Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/healthcare3030838"},{"key":"e_1_2_16_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0b013e3181a01b3f"},{"key":"e_1_2_16_4_1","doi-asserted-by":"publisher","DOI":"10.3171\/2009.5.SPINE08675"},{"key":"e_1_2_16_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spinee.2009.10.018"},{"key":"e_1_2_16_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2022-064119"},{"key":"e_1_2_16_7_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2014.1191"},{"key":"e_1_2_16_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.brs.0000146049.52152.da"},{"key":"e_1_2_16_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics16050615"},{"key":"e_1_2_16_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.841831"},{"key":"e_1_2_16_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2025.1601154"},{"key":"e_1_2_16_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jsp2.1123"},{"key":"e_1_2_16_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40610-018-0100-3"},{"key":"e_1_2_16_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2021.592118"},{"key":"e_1_2_16_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24010208"},{"key":"e_1_2_16_16_1","volume-title":"Benzel\u2019s Spine Surgery: Techniques, Complication Avoidance, and Management","author":"Steinmetz M. 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