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Disc-on-a-chip for the modelling of patient specific pathogenesis of intervertebral disc degeneration underlying inflammatory pain

Intervertebral disc (IVD) degeneration is a progressive disease mediated by an imbalance of extracellular matrix (ECM). Increasing inflammation leads to drastic mechanical stress, hyperinnervation, and sensitisation of nociceptive nerve fibres, resulting in low back pain. An advanced in vitro model of the human disc offers a better system to mimic disease states by manipulating cellular responses within the biomimetic niche. This project focuses on developing a human disc-on-a-chip, a disease model-oriented microfluidic gradient device under pathological stimulation tailored for painful disc degeneration. Using a precision medicine approach, the work package (WP) 1 study will adopt a prospective study of genotyping neuro-inflammation in symptomatic IVD degeneration patients, aiming to determine signalling molecules in IVD degeneration associated inflammatory pain. The WP 2 study will highlight the development of disc-on-a-chip using microfluidic bioprinting to model patient-specific IVD degeneration underlying inflammatory pain. The device will be fabricated using two-photon polymerisation coupled with micro-extrusion three-dimensional bioprinting of hydrogel encapsulation with cells (nucleus pulposus (NP), annulus fibrosus (AF), and dorsal root ganglia (DRG)). The identified molecules associated with inflammatory pain will be adopted to mimic a patient-specific pathological painful disc niche. The inflammatory mediator will induce dysregulation of ECM content and inflammation in the AF and NP By tuning gradient concentration. At the same time, a neurotrophic factor will be employed to stimulate nerve in-growth, expression of nociceptors, cellular action potential, trafficking of the voltage-gated sodium channel in axon termini of DRG. Shear stress induced-mechano-nociception will be stimulated by tuning diffusion flow. The WP 3 study aims to validate this model by suppressing ECM degradation and inflammation, thus preventing nociception using anti-inflammatory drugs and analgesics. This project will be the first human “on-chip” model to probe the patient-specific pathogenesis of painful IVD degeneration, enabling a rapid prototyping and high-precision system for pharmacological modulation and tissue regeneration.