Low Back Pain

One of the most prevalent musculoskeletal disorders in developed Western societies is low back pain. The economic burdens are widespread, and costs are estimated to exceed £12 billion annually [1]. Nearly 70% of individuals will experience some form of back pain during their lifetime, and although not life-threatening, the disease is a hugely important area of focus for regenerative medicine strategies.

 

Low back pain is attributed to a number of medical disorders including hernias, scoliosis, muscle damage and bone damage, although most importantly, degeneration of the intervertebral disc (IVD) is associated with up to 40% of cases [2].

The Intervertebral Disc

The intervertebral disc is the soft tissue located between the vertebrae of the human spine. It can best be described as comprised of three distinct regions: the central nucleus pulposus (NP); the annulus fibrosus (AF) which surrounds the NP, and the cartilaginous endplate which sits between the AF and vertebral bodies, as illustrated by Figure 1.

 

 

The Nucleus Pulposus

The NP is the highly hydrated central region of the IVD, comprised predominantly of proteoglycans (including aggrecan) and type II collagen. The tissue is relatively aceullular compared to other tissues, but the complex ECM serves as load-bearing surface which compresses and expands when load is applied.

 

The Annulus Fibrosus

The AF serves to confine the anatomical boundaries of the NP and is comprised predominantly of type I collagen fibres organised in ~25 concentric lamellae. When the NP compresses and expands under load, the AF acts as a supporting structure, preventing total distortion of the disc.

 

The Cartilaginous Endplate

The function of the CEP is twofold: firstly to confine the NP and AF to their anatomical locations but also to act as a semi-permeable membrane across which nutrients and oxygen must both diffuse in order to reach the central NP.

Figure 1 The Intervertebral Disc



IVD Degeneration

Degeneration of the IVD is an incredibly complex disorder, involving changes at both the morphological and molecular level, particularly in the NP.

 

In terms of changes to the appearance of the tissue, fissure formation is commonly noted, which originate in the NP and extend into the AF [3]. Additionally, the central NP loses its hydrated appearance due to breakdown of the proteoglycan-rich ECM [4]. Cell clusters are noted to form within the NP, and the organised lamellar structure of the AF loses its distinction also. In severe cases, calcification of the CEP may be observed, which in turn prevents proper diffusion of oxygen and nutrients into the disc. Ingrowth of both nervous tissue and blood vessels is also common during degeneration.

 

In terms of molecular alterations, the balance between matrix anabolism and catabolism that exists in the non-degenerate NP is shifted towards catabolism in degeneration, due to the production of matrix degrading enzymes MMPs and ADAMTSs by native NP cells [5]. A reduction in pH is also thought to occur, due to the prevention of metabolic waste products (including lactic acid) from diffusing out of the nucleus [6]. Cells of the degenerate NP have been shown to express markers associated with cellular senescence at increased levels compared to non-degenerate specimens [7]. The most significant molecular alteration is thought to be the upregulated expression of inflammatory cytokines which are postulated to drive the degenerative process. Such mediators include interleukin-1 and tumour necrosis factor-alpha [8]

 

However, it should be noted that there is still much that is unknown regarding the molecular pathways underlying IVD degeneration, thus prompting further investigation.

Molecular Alterations in IVD Degeneration



IVD Regeneration: Cell Sources

Currently, therapeutic interventions for the treatment of LBP and IVD degeneration are largely conservative - aimed at pain and symptomatic relief, rather than treating the underlying diseased tissue. Novel regenerative techiniques have been considered, including the use of gene therapy whereby molecules, such as antagonists against the upregulated pro-inflammatory cytokines, are injected into the degenerate disc in question [9]. However, side effects associated with the use of viral vectors and the need for frequent administration means such techniques are not optimal.

 

Given that aberrant cell biology underlies the aetiology of IVD degeneration, implanting healthy cells into the disc with a view to repair the damaged tissue seems an obvious choice. Initially, autologous NP cell implantation was considered, although the cell numbers obtained are often below that considered clinically-relevant and subsequent degeneration to donor sites has also been reported [10].

 

Thus, the use of stem cells has received increased interest regarding IVD regeneration. Given the chondrocyte-like characteristics of NP cells and the ability of adult mesenchymal stem cells (MSCs) to undergo chondrogenic differentiation, much research has been focussed on these. Common sources of MSCs in IVD research include bone marrow and adipose tissue. There is extensive evidence to suggest such sources have potential to regenerate the degenerate IVD (for example through expression of matrix molecules type II collagen and aggrecan to regenerate the ECM [11]), but what remains unclear is how such cells will survive in the degenerate tissue niche when exposed to low pH, low oxygen, an inflammatory cytokine millieu and mechanical load, and research is therefore ongoing. Additionally, the interactions of these cells with native disc cells is also of interest, and therefore the subject of much study. It is essential for the purposes of tissue regeneration that any implanted cells do not negatively impact an already damaged tissue, and extensive investigation is therefore required before translation of these therapies from the laboratory to the clinic.

IVD Regeneration: Hydrogels and Scaffolds

As the ECM of the degenerate IVD has commonly lost its integrity through degeneration, not only do diseased NP cells require replacement, it is also necessary to regenerate the disc matrix. Although MSCs possess the potential to do so, they need to be implanted into the disc in a material similar to the nucleus pulposus in terms of structure, in order that load-bearing capabilities can still be maintained whilst the tissue is regenerating. Although a solid scaffold would provide structure to the spine and may be suitable when considering replacements for the AF, a softer, more gelatinous substance is required for the NP.

 

Regarding biologically-relevant materials, hydrogels appear the obvious choice. Many, such as alginate and chitosan [12,13] are liquid at room temperature and during processing, but can gel at body temperature, and are therefore ideal for injection into the disc. Also, numerous hydrogels have been developed that possess the ability to dissolve over time; again ideal when you want to repair the disc tissue to a healthy state. Many hydrogels have been tested in vitro for used as IVD regenerative tools. Although none are yet considered ready for use in the clinic, additional adaptations are frequently being tested, in order to optimise the gel for the degenerate disc niche in which it is to be implanted.

 

Once an optimal source of cells for regeneration have been identified, and an appropriate synthetic hydrogel in which to implant them, they can then be assessed in vivo, with a view to repairing the permanent tissue damage suffered by millions globally.

References

[1] Maniadakis N. and Gray A. The economic burden of back pain in the UK. Pain 2000; 84(1): 95-103

[2] Cheung K.M., Karppinen J., Chan D., Ho D.W., Song Y.Q., Sham P., Cheah K.S., Leong J.C. and Luk K.D. Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine 2009; 34(9): 934-940

[3] Boos N., Weissbach S., Rohrbach H., Weiler C., Spratt K.F. and Nerlich A.G. Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science. Spine 2002; 27(23): 2331-2344

[4] Buckwalter J.A. Aging and degeneration of the human intervertebral disc. Spine 1995; 20: 1307-1314

[5] Le Maitre C.L., Pockert A., Buttle D.J., Freemont A.J. and Hoyland J.A. Matrix synthesis and degradation in human intervertebral disc degeneration. Biochemical Society Transactions 2007; 35(4): 652-655

[6] Grunhagen T., Wilde G., Soukane D.M., Shirazi-Adl S.A. and Urban J.P.G. Nutrient supply and intervertebral disc metabolism. The Journal of Bone and Joint Surgery 2006; 88: 30-35

[7] Le Maitre C.L., Freemont A.J. and Hoyland J.A. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Research and Therapy 2007; 9: R45

[8] Hoyland J.A., Le Maitre C.L. and Freemont A.J. Investigating the role of IL-1 and TNF in matrix degradation in the intervertebral disc. Rheumatology 2008; 47(6): 809-814

[9] Vadala G., Sowa G.A. and Kang J.D. Gene therapy for disc degeneration. Expert Opinion on Biological Therapy 2007; 7(2): 185-196

[10] Hegewald A.A., Endres M., Abbushi A., Cabraja M., Woiciechowsky C., Schmieder K., Kaps C. and Thome C. Adequacy of herniated disc tissue as a cell source for nucleus pulposus regeneration. Journal of Neurosurgery Spine 2011; 14(2): 273-280

[11] Ronzière M.C., Perrier E., Mallein-Gerin F. and Freyria A.M. Chondrogenic potential of bone marrow- and adipose tissue-derived adult human mesenchymal stem cells. Biomedical Materials and Engineering 2010; 20(3): 145-158

[12] Richardson S.M., Hughes N., Hunt J.A., Freemont A.J. and Hoyland J.A. Human mesenchymal stem cell differentiation to NP-like cells in chitosan-glycerophosphate hydrogels. Biomaterials 2008; 29(1): 85-93

[13] Bron J.L., Vonk L.A., Smit T.H. and Koederink G.H. Engineering alginate for intervertebral disc repair. Journal of the Mechanical Behavior of Biomedical Materials 2011; 4(7): 1196-1205

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