Organ‐on‐a‐Chip Technology: Advances in Modeling Inflammation, Neurovascularization and Nociception in Human Intervertebral Disc Degeneration

An organ‐on‐a‐chip platform has emerged as an advanced in vitro model that replicates organ‐level structures within physiologically relevant human microenvironments. 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‐dimensional (3D) degenerative microenvironment. We emphasize a disc‐on‐a‐chip platform to address these limitations, which integrates microfluidics and biomimetic ECM‐based 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)‐mediated extracellular matrix (ECM) degradation; tumor necrosis factor alpha (TNF‐α) and interleukin‐1 beta (IL‐1β)‐driven inflammation via nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB); vascular endothelial growth factor (VEGF)‐promoted angiogenesis; and nerve growth factor (NGF)‐ and brain‐derived neurotrophic factor (BDNF)‐mediated sensory innervation and sensitization, thus contributing to nociception. Collectively, disc‐on‐a‐chip offers a next‐generation in vitro model for investigating mechanisms relating to ECM degradation, inflammation, innervation, vascularization, and nociception underlying IVD degeneration, enabling precision preclinical therapeutic evaluations.