applied sciences Review The Role of Hyaluronic Acid in Intervertebral Disc Regeneration 1, 1,2 1, Zepur Kazezian y, Kieran Joyce and Abhay Pandit * 1 CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, H91 W2TY Galway, Ireland; [email protected] (Z.K.); [email protected] (K.J.) 2 School of Medicine, National University of Ireland Galway, H91 TK33 Galway, Ireland * Correspondence: [email protected] Zepur Kazezian is currently at Imperial College London, London SW7 2AZ, UK. y Received: 17 August 2020; Accepted: 7 September 2020; Published: 9 September 2020 Abstract: Intervertebral disc (IVD) degeneration is a leading cause of low back pain worldwide, incurring a significant burden on the healthcare system and society. IVD degeneration is characterized by an abnormal cell-mediated response leading to the stimulation of different catabolic biomarkers and activation of signalling pathways. In the last few decades, hyaluronic acid (HA), which has been broadly used in tissue-engineering, has popularised due to its anti-inflammatory, analgesic and extracellular matrix enhancing properties. Hence, there is expressed interest in treating the IVD using different HA compositions. An ideal HA-based biomaterial needs to be compatible and supportive of the disc microenvironment in general and inhibit inflammation and downstream cascades leading to the innervation, vascularisation and pain sensation in particular. High molecular weight hyaluronic acid (HMW HA) and HA-based biomaterials used as therapeutic delivery platforms have been trialled in preclinical models and clinical trials. In this paper, we reviewed a series of studies focused on assessing the effect of different compositions of HA as a therapeutic, targeting IVD degeneration. Overall, tremendous advances have been made towards an optimal form of a HA biomaterial to target specific biomarkers associated with IVD degeneration, but further optimization is necessary to address regeneration. Keywords: hyaluronic acid; disc repair; annulus fibrosus repair; biomaterials; inflammatory biomarkers and signalling pathways 1. Introduction A total of 80% of the world population suffer from low back pain (LBP) which is considered the most significant cause of disability, resulting in a negative socioeconomic impact [1,2]. In terms of disability-adjusted life years, LBP incurs a substantial burden over other health-related conditions [3,4]. Although LBP is more common in patients above 65 years old [5,6], it can start as early as in the late teenage years [7]. It is classified as the most expensive healthcare treatment, ranging between 12 to 90 billion dollars in the United States alone [8] and above 500 million pounds in the United Kingdom according to the nice guideline [9]. LBP is frequently associated with the deterioration of the intervertebral disc (IVD) due to abnormal cell-mediated response leading to the stimulation of different catabolic enzymes [10,11] and signalling pathways [12], imbalance in extracellular matrix composition and overexpression of the extracellular matrix-degrading enzymes [13]. The changes in the biomechanical elements, which are represented by unbalanced mechanical loading [14], genetic background [15] and reduced cellular activity, lead to continuous structural failure (Figure1)[ 16]. In terms of biochemical changes, the deficiency in nutrient diffusion into the disc due to the calcified cartilaginous endplate (CEP) is a fundamental cause of IVD Appl. Sci. 2020, 10, 6257; doi:10.3390/app10186257 www.mdpi.com/journal/applsci Appl. Sci. 2020, 10, 6257 2 of 24 Appl. Sci. 2020, 10, x FOR PEER REVIEW 2 of 24 degenerationfundamental [17 ].cause Additionally, of IVD degeneration increased [17]. elastin Additi concentrationsonally, increased in theelastin annulus concentrations fibrosus in (AF) the [18], and augmentedannulus fibrosus proteoglycan (AF) [18], breakdownand augmented in theproteoglycan nucleus pulposus breakdown (NP) in the cause nucleus a dramatic pulposus decrease (NP) in disc heightcause a and dramatic ultimately decrease lead in disc to biomechanical height and ultimately instability lead [to19 biomechanical]. instability [19]. Figure 1. Different hyaluronic acid-based hydrogel platforms to treat the intervertebral disc Figure 1. Different hyaluronic acid-based hydrogel platforms to treat the intervertebral disc degeneration.degeneration. Hydrogel Hydrogel propertiesproperties can can be beoptimized optimized to recapitulate to recapitulate the mechanical the mechanical properties propertiesof the of theintervertebral intervertebral disc disc (IVD), (IVD), deliv deliverer therapeutics therapeutics including including growth growth factors factors and cells and cellsinto the into IVD. the IVD. HydrogelsHydrogels may may be optimized be optimized to to be be injectable injectable for for minimallyminimally invasive invasive treatment treatment of ofthe the IVD. IVD. TreatmentTreatment of LBP of LBP in thein the early early and and moderate moderate stagesstages is is mostly mostly monitored monitored through through conservative conservative treatmentstreatments including including bed bed rest, rest, physiotherapy physiotherapy andand exerciseexercise [20,21] [20,21 which] which is followed is followed by prescribing by prescribing non-steroidalnon-steroidal anti-inflammatory anti-inflammatory drugs drugs (NSAID)s (NSAID)s including including Ibuprofen Ibuprofen and COX-2 and inhibitorsCOX-2 inhibitors (Celecoxib), that are(Celecoxib), effective that in treating are effective acute in andtreating chronic acute LBPand chronic comparing LBP comparing to placebo to [22 placebo]. In addition [22]. In addition to NSAIDs, muscleto relaxantsNSAIDs, muscle such as relaxants cyclobenzaprine such as cyclobenzaprine are also used [23are]. also Moreover, used [23]. opioids Moreover, and benzodiazepinesopioids and benzodiazepines are prescribed to treat LBP. However, they have a short-term effect and need to be are prescribed to treat LBP. However, they have a short-term effect and need to be prescribed for no prescribed for no longer than four weeks because of the risk of developing dependency [24,25]. longer than four weeks because of the risk of developing dependency [24,25]. Furthermore, epidural Furthermore, epidural and systemic corticosteroids are recommended with clinical trials exhibiting and systemicheterogeneous corticosteroids results, with are the recommended latest outcomes with indicating clinical trialsthat glucocorticoid exhibiting heterogeneous receptor-specific results, with thesteroids latest may outcomes be more indicating effective comparing that glucocorticoid to mineralocorticoid-targeting receptor-specific steroids steroids may[26]. be more effective comparingAlthough to mineralocorticoid-targeting most of the LBP patients will steroids recover [26 after]. an acute phase, 10% may develop chronic Althoughlow back pain most [27]. of In the chronic LBP patientsstages, generally, will recover surgery after is required an acute because phase, the 10% IVD may is unable develop to cure chronic low backitself pain[28]. [Existing27]. In chronicsurgical stages,interventions generally, include surgery discectomy is required and spinal because fusion, the or—occasionally IVD is unable toin cure itselfthe [28 ].cervical Existing spine—a surgical total interventions disc replacement include is in discectomydicated [29]. andPatients spinal who fusion, had discectomy or—occasionally show in the cervicalimprovement spine—a when total compared disc replacement to nonsurgical is therapy indicated in short-term [29]. Patients follow-ups; who however, had discectomy long term show follow-ups (beyond two years) indicate no significant difference in the outcomes [30]. Spinal fusion improvement when compared to nonsurgical therapy in short-term follow-ups; however, long term follow-ups (beyond two years) indicate no significant difference in the outcomes [30]. Spinal fusion is the typical surgical approach for chronic LBP. Although nonsurgical treatment for chronic LBP may be useful in a particular cohort, lumbar fusion remains more effective in alleviating pain and decreasing Appl. Sci. 2020, 10, 6257 3 of 24 Appl. Sci. 2020, 10, x FOR PEER REVIEW 3 of 24 disabilityis the typical than commonly surgical approach used nonsurgical for chronic treatmentsLBP. Although [31]. nonsurgical Disc replacement treatment is for also chronic used toLBP tackle the incidencemay be useful of the in a disease particular in thecohort, adjacent lumbar segments fusion remains due to more the acute effective variation in alleviating in motion pain segment and decreasing disability than commonly used nonsurgical treatments [31]. Disc replacement is also used mechanics linked with anterior cervical discectomy and fusion [32]. There is minimal evidence that to tackle the incidence of the disease in the adjacent segments due to the acute variation in motion suggests early surgical intervention improves long-term results in patients with lumbar disc herniation segment mechanics linked with anterior cervical discectomy and fusion [32]. There is minimal andevidence radiculopathy that suggests that did early not surgical progress intervention yet into neurologic improves long-term deficit [30 results,33]. in patients with lumbar discThese herniation treatments and radiculopathy are not deemed that curative,did not progress nor do yet they into reverse neurologic the deficit underlying [30,33]. pathology but rather aimThese to achieve treatments symptomatic