• This is an A-list topic basic science topic. Some questions would overlap with the general pathology viva, most likely relating to the herniated disc.
• It is important to relate structure to biomechanical function to gain an understanding of the intervertebral disc (IVD) in both health and disease.

• The nervous system consists of the central (brain and spinal cord) and peripheral nervous systems.
• In the adult, the spinal cord extends from the medulla oblongata and terminates at the conus medullaris at the level of the L1 or L2 vertebrae.
• The average adult vertebral column typically consists of 33 vertebrae (seven cervical, 12 thoracic, five lumbar, five fused sacral and four fused coccygeal) and extends from the occipital condyles of the skull at the atlanto-occipital joint to the apex of the coccyx.
• Movement of the vertebral column occurs through the 24 unfused cervical, thoracic and lumbar vertebrae, facilitated through the intervertebral discs.
• A typical vertebra consists of a body and neural arch (consisting of corresponding pedicles and laminae, and seven processes – two transverse processes; four articular processes and a spinous process).
• Accounting for the increasing load-bearing area, vertebrae increase in size from cranial to caudal, up to the sacroiliac joints, where the body’s weight is then transmitted to the pelvic girdle.
• Vertebrae from a specific region (cervical, thoracic, lumbar, sacral or coccygeal) can be identified based on their general features. For instance, the seven cervical vertebrae are the smallest of the 24 unfused vertebrae and are characterised by a foramen transversarium at each transverse process, with C7s being smaller in size and transmitting only the small accessory vertebral veins, while the vertebral arteries, veins and sympathetic plexus pass through the remaining foramina. Furthermore, C3 to C6 have short bifid spinous processes; C7 is characterised by a long palpable process – the vertebra prominens. The atlas (C1) and axis (C2) are atypical to their neighbours, with the atlas articulating with the skull via the occipital condyles of the occipital bone and the superior articular processes of the atlas. The atlas has no body or spinous process; the atlas is made up of anterior and posterior arches with two lateral masses and anterior and posterior tubercles. The axis (C2) has a large bifid spinous process and permits rotation of the head via the large superior articular facets. The odontoid process (tooth-like) extends from the body towards the anterior arch of the atlas, which is stabilised by the transverse ligament.

• Intervertebral joints between adjacent bodies are secondary cartilaginous joints (symphyses), consisting of fibrocartilage. Lumbar intervertebral discs are the largest. The intervertebral space is largely occupied by the IVD, with approximately 5% of the adult space containing cartilage end plates.
• 23 IVDs act as ‘shock absorbers’ and permit movement of the spine (flexion, extension, rotation).
• The IVDs connect the adjoining vertebral bodies of the unfused cervical, thoracic and lumbar vertebrae and contribute towards the secondary curvatures of the spine.
• C1 and C2 have no IVDs that pivot at the specialised atlanto-axial joint. The articulation between C1 and the base of the skull the occipito-atlantal joint also does not contain a disc.
• The most inferior disc is between L5 and S1.

Figure 1. The intervertebral disc.1 Nucleus 2 Annulus 3 Cartilagenous endplate 4 Anterior longitudinal ligament 6 Posterior longitudinal ligament

• Each IVD has three main structures:
• An outer fibrous annulus fibrosus (AF).
• Central gelatinous nucleus pulposus (NP).
• Cartilaginous end plates.
• Nerves and blood vessels are primarily restricted to a small proportion of the outer margin of the annulus fibrosus.
• Disc cells derive their nutrition from diffusion through the end plates.

• The annulus fibrosus is a fibrocartilaginous structure, derived from mesoderm, consisting of concentric lamellae that insert into the articular surface of the vertebral body, hyaline cartilage end plates superiorly and inferiorly and the anterior and longitudinal ligaments.
• The outer annulus fibrosus consists of a number of densely packed layers composed of predominantly type 1 collagen called lamellae. Fibres of each lamella run obliquely between vertebrae, with adjacent fibres typically running at right angles. This arrangement allows the disc to resist both torsional and tensile loads.
• A larger fibrocartilaginous inner annulus fibrosus layer is found more centrally containing chondrocytes and a less dense predominantly type II collagenous matrix lacking lamellar organisation.
• Therefore, on progressing from the outer to the inner annulus, the type I collagen level declines and that of the type II increases.
• Cells within the annulus fibrosus are elongated and “fibroblast-like.”
• In the lumbar spine, there are approximately 15–25 lamellae within each disc. Of note, the lamellae are thinner posteriorly, thus making this region susceptible to posterior disc herniation.

• The nucleus pulposus (NP) (type II collagen) is derived from endoderm, and is an avascular gelatinous posterocentrally located cartilaginous structure that has a greater water content than its outer counterpart. Cells within the nucleus pulposus are oval and ‘chondrocyte-like’.
• The high density of negatively charged sulphate and carboxyl groups on the glycosaminoglycan chains of the main proteoglycan in the disc, aggrecan, is responsible for attracting the high water content. A pressure is generated by swelling from the attraction of water into the IVD from surrounding tissues that results in the vertebral bodies being pushed apart. This pressure is resisted by tension in the collagen fibres of the AF.
• The balance between expansion of the NP and tension in the AF leads the IVD to resist compression.
• Equilibruim between the aggrecan and collagen helps in creating a load bearing and compression resisting tissue that gives stability to the disc.
• The NP resists compressive loads, dampens mechanical loads and evenly distributes forces onto the end plates.

• The anterior longitudinal ligament is a fibrous ligament that reduces hyperextension. It projects from the anterior tubercle of C1 and occipital bone to the pelvic surface of the sacrum, adhering to the anterolateral vertebral bodies and intervertebral discs.
• The posterior longitudinal ligament reduces hyperflexion and strengthens the column posteriorly, running within the neural canal, adhering to the intervertebral discs and bodies from C2 to the sacrum.
• Ligamenta flava.
• Interspinous ligaments.
• Supraspinous ligaments.

• At the interface between the disc and the vertebral bodies is the end plate, which is made up of the cortical bone of the vertebral body and a region of hyaline cartilage.
• The central portion is the major pathway for nutrients from the vertebral bodies to diffuse into the disc.
• The major function of the end plates is to act as a semipermeable membrane that allows nutrients and metabolites to diffuse into the disc from the capillary blood of the vertebral body and allow waste products to diffuse out. It also prevents larger molecules, such as proteoglycan, from diffusing out of the NP.

• The invertebral disc is the largest avascular organ in the body. Small blood vessels are found on the surface of the outer annulus and penetrate 3 mm at most.
• Nutrients are supplied to the disc primarily through diffusion.
• As the disc has a very limited blood supply, invertebral disc cells, particularly those in the centre of the avascular NP, operate in an environment that would be unviable to most other cells. They appear to have adapted to this hypoxic, acidic environment.

Figure 2. Diffusion of nutrients into the intervertebral disc

Figure 3. Blood supply of the intervertebral disc

• The sinuvertebral nerve, which arises from the dorsal root ganglion, innervates the outer annulus fibrosus. The NP is not innervated.

Figure 4. Nerve supply of the intervertebral disc

• The ECM of both the NP and AF contain a small amount of cells but a rich amount of molecules consist of non-collagenous proteins, proteoglycans, collagens and enzymes.

• Proteins
• Collagen
• Proteoglycans
• Proteinases
• Cells

Table 1. Components of the extracellular matrix of mature lumbar IVD

• A variety of proteoglycan molecules form the major component within the ECM in the nucleus. The nucleus pulposus contains the greatest concentration of the largest proteoglycan named aggrecan.
• Aggrecans are critical to attract, retain and maintain the water content giving the nucleus its main function in responding to the mechanical compression loads.
• Loss of aggrecans results in a decrease of hydration and of fluid pressure within the nucleus resulting in major changes in the biomechanical functions of the IVD.
• Biglycan, decorin, fibromodulin and lumican are essential for interacting tightly with the different types of collagen, for assisting in cross-linking of collagen, for the organisation, integrity and stability of the collagen network.
• Biglycan is involved in the interaction with type VI collagen. The presence of increased amounts of biglycan in older and in degenerated discs is the expression of the cells’ inability to repair properly.

• The integrity of the invertebral disc relies on a healthy balance between synthesis and breakdown. When this is disturbedhigher concentrations of aberrant molecules are produced (more destructive proteinases, abnormal proteoglycans and collagens and cytokines) causing an alteration of the structural and functional properties of the extracellular matrix.

• IVD aging and degeneration share many similar features.
• A common factor is the significant hypoxic conditions disc cells work under and associated factors that interfere with disc cell diffusion and nutrition.

• With increasing age, the disk cells produce less aggrecan and type II collagen, leading to decreased proteoglycan and water content.
• The nucleus eventually no longer acts hydrostatically. This means that the annulus and end plate are exposed to high point stresses, which might lead to the cracks and fissures seen in degenerate discs.
• Having a lower fluid content and because hydraulic permeability increases with aggrecan loss, aging and degenerate discs will lose that fluid more quickly under load. As water is the main component of the IVD, loss of fluid leads to a fall in disc height and abnormal loading of other spinal structures such as the apophyseal joints.
• Aging is associated with fragmentation, destruction and reduction of proteoglycans, which then can no longer attract and bind sufficient water molecules. Water content in the nucleus of the IVD declines and the hydrostatic pressure gets lost. This explains why the IVD becomes more and more unable to dissipate spinal forces ultimately resulting in a progressive functional biomechanical failure.

• The rate of synthesis of glycosaminoglycans, proteoglycans, link proteins and hyaluronan decreases progressively with age as they undergo continuous proteolytic degradation (MMPs and ADAMs). At the same time, the production of collagen type I increases. The number of cells diminishes as well.
• This results in a number of changes:
• Aggrecan content in the nucleus pulposus drops significantly, and with it the ability of the ECM to attract, bind and maintain water. The NP becomes progressively more fibrous and opaque, and with increased pigmentation. As the collagen content increases and changes from type II to type I, demarcation between the NP and AF becomes less distinct and separation of adjacent annular laminae occurs. This delamination leads to the development of concentric tears in the annular laminae.

• Degenerative related changes in the structure and composition of disc tissue results in changes in the material and structural properties of the components of the disc. These changes are most profound in the nucleus and end plate.

Nucleus pulposus

• Shear modulus of the NP increases 10 fold (becomes stiffer).
• The NP undergoes a transition from fluid-like to solid-like behaviour.
• Loss of water content and increase in tissue density.
• More anisotopic (orientation dependent) stress state with more non-uniform distribution of stresses.

Annulus fibrosus

• Significant increase in compression.
• Decrease in permeability due to loss of water content and obstruction of pores with debris.
• Diffusion is hindered.
• Moderate increase in shear modulus.

End plate

• Thinning, microfracture or damage to the end plate.
• More non-uniform distribution of load and higher shear stresses resulting in damage to the disc.

• The integrity of the intervertebral disc relies on a healthy balance between synthesis and degradation of the components of the extracellular matrix by the disc cells (especially proteoglycans and collagens type II).
• While the degrading IVD processes progress, higher concentrations of aberrant molecules appear (destructive proteolytic enzymes such as matrix metalloproteinases, abnormal proteoglycans and collagens, more collagens type I and cytokines), which cause alterations in the structure and function of the matrix.
• The mechanical properties of this ECM further become impaired because the nucleus of the IVD starts losing more water under load and becomes more fibrous.
• Moreover, and once the end plates start to sclerose and the transport end plate capillaries obliterate, the healthy balance is adversely influenced by the diminishing nutrient transport (glucose, amino acids, oxygen) and the daily loading patterns (flexion, extension, rotation, etc.).
• When the viscoelastic characteristics of the collagen networks in the nucleus and the annulus start decreasing, compression and tension forces become difficult to resist.
• Constructivedamage occurs in the nucleus, end plates and the annulus. The end plates rupture and in-to-out fissures appear in the annulus.

Figure 5.The integrity of the intervertebral disc relies on a healthy balance between synthesis and degradation of the components of the extracellular matrix by the disc cells (especially proteoglycans and collagens type II).

• Matrix metalloproteinases (MMPs) and proteases of the ADAMs (“a desintegrin and metalloproteinase”) family are the two major classes of degrading enzymes in the ECM of the IVD. Both are involved in the normal turnover of the ECM molecules. Their catabolic genes are strongly upregulated when the IVD starts aging and during the degenerative processes.
• Chondrocytes contain anti-catabolic genes producing tissue inhibitors of MMPs (TIMPs) to counteract the degradative properties of the MMPs and ADAMS (aggrecanases) to prevent loss of the ECM.
• In the normal, healthy and non-degenerated IVDs, TIMPS and MMPs balance their activities to maintain the structural and functional characteristics of the extracellular matrix.
• With age and IVD degeneration the concentration of the entire group of active degradative proteases increases (MMPs and ADAMs) and the anti-catabolic proteases (TIMPs) decrease. This results in interrupting the healthy balance in favour of the destruction of the ECM proteins.

Figure 6. Disc biochemical property alterations

• The relationship between disc degeneration and low back pain is poorly understood.
• Many factors including structural changes in the spine, soluble mediators that sensitise nerve endings and nerve/vessel ingrowth into the outer annulus have been implicated as the possible cause of chronic pain.

The fiber orientation of the AF resists hoop stresses generated by the hydrostatic pressure from the NP. The AF provides the ability to absorb significant hoop stresses and maintain stiffness in the presence of tensile forces induced by bending and twisting of the spine. Animal experiments have demonstrated that even a partial thickness laceration in the annulus rapidly produces advanced disc degeneration

Figure 7. Compressive force from body weight contraction(straight arrows) raises the pressure in the NP.This is turn increases the tension in theAF(curved arrow) and muscle

Figure 8. The increased tension in the AF inhibits radial expansion of the NP. The rising pressure in the NP is also exerted upward and downward against the vertebral endplates. b The weight is partly borne by the AF and NP and is then transmitted across the endplates to neighbouring vertebrae

Figure 9.  Hoop stress. A load of water in a barrel is resisted by the hoops around the barrel. When too great a load is applied, the hoop will break. The annulus functions in a similar manner to that of the hoops around a water barrel.

Protrusion

• Bulging NP (intact AF) into spinal canal.

Extrusion NP

• Burst through AF but contained by the posterior longitudinal ligament.

Sequestration

• Fragment of disc detached and lying free in the canal.

Total disc replacement⁴

• This is intended to be an alternative to spinal fusion with the advantage of restoring flexibility to the intervertebral joint.
• Most designs are ball and socket joints.
• A simple ball and socket joint fixes the axis about which the prosthesis can twist and bend. By contrast, a natural has a flexion/extension axis that is able to shift. As such most artificial joints cannot shift their axis and there is a danger of loosening.

Stem cell therapy

• Some promising preliminary animal studies.
• Concerns regarding whether these cells can survive in the avascular environment of the IVD.
• The indications for its use and the patients who would benefit need to be better defined.

Buzz words/key concepts  

For age related changes these are

1.Reduced proteoglycan content in the NP and therefore reduced hydration

2.Decreased end plate permability

For degenerative changes

1 Increase in matrix degradation factors (TNF-α,IL-I)

2.Reduction in tissue inhibitors