Izzat Zulkiflee, Nurul Fariha Za'aba, Abhay Pandit, Isma Liza Mohd Isa
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.