## 5 Discussion and Future Directions  
Discogenic back pain is a prevalent disease described by the degeneration of one or more of the intervertebral discs causing pain, dramatically affecting the quality of life. LBP generation is initiated by low numbers of native IVD cells, which leads to extracellular matrix disintegration, and vascularisation promoting inflammation and low back pain sensation. It was found that pro-inflammatory cytokines such as IFN\(\alpha\) induce cellular arrest and apoptosis of the disc cells through downstream targets such as IFIT3 and IGFBP3; therefore, leading to low cellularity of the disc [12]. Moreover, the up-regulation of different inflammatory cytokines can induce the disintegration of the ECM, synthesis of chemokine and, ultimately, changes in IVD cells [38]. For the ideal HA-based therapeutic to be identified, it needs to be compatible and supportive to the disc microenvironment in general and target inflammation and downstream signalling cascades that lead to innervation, vascularisation and pain sensation in particular. In the last few decades, HA and a combination of HA-based biomaterials were tested in preclinical disc degeneration models and human clinical trials. Multiple cross-linking techniques have been employed, including UV cross-linking [142], chemical cross-linking [145] and combination devices that also utilize molecular self-assembly [146]. There is no apparent consensus on optimal cross-linking methods, nor has there been detailed investigation into the retained bioactivity using these cross-linking methods. Although it could be challenging because of the complexity of the disease, research has focused on a different combination of materials that could be quite promising for IVD degeneration. HA, a sizeable hydrophilic molecule that can absorb shocks, is a fundamental component of ECM which developed to be a promising platform for next-generation therapeutics. Through the use of various combinations of HMW HA and processing techniques, inflammation, innervation, as well as pain, can be reduced in the disc [59; 60; 148]. The material design process must further consider the degradation products of these materials and ensure these metabolites do not induce pro-inflammatory signalling in long-term follow-up. While LMW HA fragments induce inflammation, HA can be modified to resist degradation and mitigate the effects of fragmentation [84; 159]. In this review, we identified a series of studies focused on assessing the effect of different compositions of HA as a therapy for aberrantly expressed enzymes, proteins or signalling pathways identified in the degenerated IVD. It was found that HA was effective in lowering the IFN\(\alpha\) inflammatory signalling pathway and downstream key apoptosis and cell senescence regulators such as IFIT3 and IGFBP3 in the AF [60]. Similarly, HA was found to be capable of lowering the NF-\(\kappa\)B signalling pathway and its downstream targets NGF and BDNF in the NP [59]. In addition to its use as anti-inflammatory, anti-apoptotic and analgesic biomaterial in the disc, HA was also used as a carrier for MSCs in vivo [147; 155]. The results of recent clinical trials [157] supported that the implantation of adipose-derived MSCs embedded in HA derivative (Figure 2) is non-toxic and endurable in LBP and could enhance the patients' quality of life by reducing the back pain and enhancing their function [158]. HA encapsulation of MSCs injected into the disc offers structural integrity and allows for cytoskeletal attachment through CD44 binding [59; 160]. HA may also block noxious signalling pathways present in the degenerated IVD to preserve cell phenotype. Ongoing clinical trials are using HA as a delivery medium for BM-MSCs and disogenic cells to improve cell survival and reduce inflammation [161]. Furthermore, HA has been used as a vehicle to deliver different types of therapeutics (Figure 2) such as TGF-\(\beta\)1 [142], BMP-2/7 [154] and gefitinib [149].