## 2 Intervertebral Disc Degeneration  
IDD is an age-related chronic and progressive process, characterized by a gradual loss of proteoglycans and water content in the NP with a reduction in the disc's capacity to withstand compressive loads [17]. The IVD is an avascular organ, and the supply of nutrition occurs by diffusion from its surrounding vasculature through the CEPs [23]. However, IVD aging and mechanical overload progressively foster endplate calcification and capillary obliteration, thus reducing nutrient delivery to the IVD itself [24]. Due to the lack of blood flow, a hypoxic microenvironment is consequently established with higher O\({}_{2}\) concentrations at the surface of the AF (19.5%) and a reduction towards the center of the NP (0.65%). However, low oxygen concentration has not been shown to be detrimental for NPC viability [25]. Another factor involved in making the IVD microenvironment hostile is the low glucose concentration, which ranges from about 5 mM at the periphery to about 0.8 mM at the center of the IVD [26]. pH is another crucial parameter in the IVD microenvironment. Local production of lactic acid by IVD maintains a pH between 2 and 6, with significant effects on cell survival and matrix synthesis, as well as on the expression of proinflammatory cytokines and pain-related factors [27]. The main change in NP during IDD is in the imbalance between anabolic factors, such as insulin-like growth factor 1 (IGF-1), growth differentiation factor 6 (GDF-6), transforming growth factor \(\beta\) (TGF-\(\beta\)), bone morphogenetic proteins ( BMPs) and catabolic enzymes, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) [28]. Aggrecan, the most abundant proteoglycan in the NP matrix, binds to sulphated glycosaminoglycans (GAGs, e.g., keratan and chondro sulfate), and consequently retains hydration and osmotic pressure within the IVD. Negatively charged GAGs regulate the ion balance of the ECM [29]. In a healthy state, osmolarity can range from 430 mOsm/L (isosmotic pressure) to about 496 mOsm/L (hyperosmotic pressure) [30]. In degenerative conditions, due to the progressive loss of proteoglycans, the osmolarity of the IVD decreases until it reaches values of about 300 mOsm/L [31]. [PERSON] et al. reported that high osmolarity can not only decrease the viability and proliferation of disc cells but can also influence the expression levels of collagen type II, SOX-9 and aggrecan in progenitor NPCs [32]. Excessive mechanical loading may be another crucial factor that compromises the biomechanical characteristics of IVD. Static compression stress induces apoptosis, senescence, mitochondrial damage, and matrix catabolism due to a reduction in collagen and aggrecan expression with an increase in MMPs [33]. On the contrary, dynamic compressive loading often triggers an anabolic response and improves the transport of nutrients and growth factors within the NP [34]. The inflammatory response may also contribute to the onset and progression of the degenerative process [35]. The nutritional decrease and accumulation of degraded matrix products promote macrophage-mediated production of pro-inflammatory cytokines such as interleukin (IL)-1\(\beta\) and tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)) through activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway [36]. IL-1\(\beta\) and TNF-\(\alpha\) are involved in the progression and initiation of IDD by regulating inflammatory response, IVD cell proliferation, senescence, apoptosis, pyproptosis, autophagy, ECM destruction, and oxidative stress [37]. TNF-\(\alpha\) is able to amplify the inflammatory response by stimulating IVD cells to synthesize additional cytokines, including IL-6, IL-8, IL-17, IL-1\(\beta\) and numerous chemokines [38]. IL-1\(\beta\) is expressed at higher levels in degenerated IVDs with an increased production of genes and proteins for the IL-1 receptor.