Current perspectives on the role of biomechanical loading and genetics in development of disc degeneration and low back pain; a narrative review.

Degenerative changes in the disc have long been of interest; they are thought to be strongly associated with low back pain and caused by inappropriate loading or through injury. However, independent of the magnitude of occupational spinal loading, twin studies find that the heritability of lumbar disc degeneration is 34-74%. This finding has led to intensive searches for susceptibility genes; some genes associated with disc degeneration have been identified, though all with small effects on the degenerative process. The complex nature of degenerative changes suggests that many different genes are involved, and that interactions with environmental factors are influential in progression of degeneration. Low back pain itself also appears heritable (30-46%). The most important clinical question though, is not how discs degenerate but is disc degeneration related to low back pain. Imaging studies find many people with degenerate discs or even with discs showing pathological features such as herniations, are asymptomatic. However results are obscured by the lack of consistent definitions of the phenotypes of disc degeneration and of low back pain. Epidemiological studies could help disentangle these complex relationships, but they will only be successful once consistent classifications and phenotypes of both disc degeneration and low back pain are developed.

Semi-quantitative evaluation of signal intensity and contrast-enhancement in Modic changes.

BACKGROUND: Semi-quantitative evaluation of Modic changes (MCs) has recently been proposed as a way to standardise and increase repeatability of clinical studies. This study is aimed at developing semi-quantitative measures of enhancement, given by contrast agent injection, on T1-weighted images in MCs, and to investigate their reliability and relation with MC types. METHODS: Thirty-seven subjects suffering from low back pain underwent T1-weighted and T2-weighted turbo spin-echo sequences. Five minutes after the injection of a paramagnetic contrast agent, a second T1-weighted sequence was acquired. Regions of interest (ROIs) corresponding to MCs were selected manually on the unenhanced image; control ROIs in the "healthy" bone marrow were selected. For each ROI, the mean signal intensity (SI) of unenhanced pixels and the mean absolute and normalised difference in SI between unenhanced and contrast-enhanced pixels values were calculated. RESULTS: A total of 103 MCs were recognised and 61 were semi-quantitatively analysed: 16 type I, 34 type II and 11 type I/II. Regarding controls, MCs I showed a lower SI on the unenhanced T1-weighted images and a marked contrast enhancement (CE); MCs II showed a higher SI than controls on unenhanced images and a lower or comparable CE; and MCs I/II presented an intermediate SI on the unenhanced images and a marked CE. Inter-rater and intra-rater agreements were found to be excellent or substantial. CONCLUSIONS: Semi-quantitative measurements could differentiate MC types in terms of unenhanced SI and of CE with respect to "healthy" bone marrow.

The Association Between Body Mass Index (BMI) and Back or Leg Pain in Patients With Spinal Conditions: Results from the Genodisc Study.

STUDY DESIGN: A prospective observational study. OBJECTIVE: The aim of this study was to identify the relationship between obesity, quantified by body mass index (BMI), and both back and leg pain in spinal patients. SUMMARY OF BACKGROUND DATA: Obesity and back pain are massive public health problems. Given the poor correlation between pain and a pathological change in the spine, further investigation is required into other, nonpathological predictors such as obesity. METHODS: The Genodisc Study was one of the largest cross-sectional studies of patients presenting to tertiary spinal units and recruited from six centers in four European countries. In total, 2636 patients were recruited over a 5-year period between 2008 and 2013. Both back and leg pain were scored by patients in the range of 0 to 10. Linear regression was used to model the relationship between BMI and pain. Potential confounders included in the model were age, Zung Depression score, episodes of sport, gender, disability benefit, family history, previous surgery, smoking status, work type, clinical diagnosis, and relevant comorbidities. Back and leg pain outcomes were modeled separately. RESULTS: The study included 1160 men and 1349 women with a mean age of 50.9 years and mean BMI of 27.2 kg/m. In our fully adjusted model, a 5-point increase in BMI was associated with greater leg [0.19 units (95% confidence interval 0.08-0.31)] but not back [0.10 units (95% CI -0.02 to 0.22)] pain scores. Although this relationship was statically significant, given the small magnitude of the relationship, the clinical significance is limited. Similarly, female gender, heavy workload, rheumatoid arthritis, previous spine surgery, and depression were associated with higher back and leg pain. CONCLUSION: In this large observational study of spine patients presenting to tertiary European centers, obesity, as measured by increased BMI, was associated with greater leg pain. LEVEL OF EVIDENCE: 2.

ISSLS Prize Winner: A Detailed Examination of the Elastic Network Leads to a New Understanding of Annulus Fibrosus Organization.

STUDY DESIGN: Investigation of the elastic network in disc annulus and its function. OBJECTIVE: To investigate the involvement of the elastic network in the structural interconnectivity of the annulus and to examine its possible mechanical role. SUMMARY OF BACKGROUND DATA: The lamellae of the disc are now known to consist of bundles of collagen fibers organized into compartments. There is strong interconnectivity between adjacent compartments and between adjacent lamellae, possibly aided by a translamellar bridging network, containing blood vessels. An elastic network exists across the disc annulus and is particularly dense between the lamellae, and forms crossing bridges within the lamellae. METHODS: Blocks of annulus taken from bovine caudal discs were studied in either their unloaded or radially stretched state then fixed and sectioned, and their structure analyzed optically using immunohistology. RESULTS: An elastic network enclosed the collagen compartments, connecting the compartments with each other and with the elastic network of adjacent lamellae, formed an integrated network across the annulus, linking it together. Stretching experiments demonstrated the mechanical interconnectivities of the elastic fibers and the collagen compartments. CONCLUSION: The annulus can be viewed as a modular structure organized into compartments of collagen bundles enclosed by an elastic sheath. The elastic network of these sheaths is interconnected mechanically across the entire annulus. This organization is also seen in the modular structure of tendon and muscle. The results provide a new understanding annulus structure and its interconnectivity, and contribute to fundamental structural information relevant to disc tissue engineering and mechanical modeling. LEVEL OF EVIDENCE: N/A.

Intervertebral disc regeneration: do nutrients lead the way?

Strategies for the biological repair of intervertebral discs derive from the premise that disc degeneration results from impaired cellular activity and, therefore, that these structures can be induced to regenerate by implanting active cells or providing factors that restore normal cellular activity. In vitro and animal studies using this approach have had some success, but whether this success can be reproduced in degenerate human lumbar discs is unknown. Successful repair requires that the disc cells remain viable and active; they therefore need an adequate supply of nutrients. However, as the disc degenerates, the nutrient supply decreases, thereby limiting cell activity and viability. Current biologic approaches might place additional demands on an already precarious nutrient supply. Here, we discuss whether the loss of nutrients associated with disc degeneration limits the effectiveness of biologic approaches, and indicate that this neglected problem requires investigation if clinical application of such therapies is to succeed.

Disc cell therapies: critical issues.

BACKGROUND: Disc cell therapies, in which cells are injected into the degenerate disc in order to regenerate the matrix and restore function, appear to be an attractive, minimally invasive method of treatment. Interest in this area has stimulated research into disc cell biology in particular. However, other important issues, some of which are discussed here, need to be considered if cell-based therapies are to be brought to the clinic. PURPOSE: Firstly, a question which is barely addressed in the literature, is how to identify patients with 'degenerative disc disease' who would benefit from cell therapy. Pain not disc degeneration is the symptom which drives patients to the clinic. Even though there are associations between back pain and disc degeneration, many people with even severely degenerate discs, with herniated discs or with spinal stenosis, are pain-free. It is not possible using currently available techniques to identify whether disc repair or regeneration would remove symptoms or prevent symptoms from occurring in future. Moreover, the repair process in human discs is very slow (years) because of the low cell density which can be supported nutritionally even in healthy human discs. If repair is necessary for relief of symptoms, questions regarding quality of life and rehabilitation during this long process need consideration. Also, some serious technical issues remain. Finding appropriate cell sources and scaffolds have received most attention, but these are not the only issues determining the feasibility of the procedure. There are questions regarding the safety of implanting cells by injection through the annulus whether the nutrient supply to the disc is sufficient to support implanted cells and whether, if cells are able to survive, conditions in a degenerate human disc will allow them to repair the damaged tissue. CONCLUSIONS: If cell therapy for treatment of disc-related disorders is to enter the clinic as a routine treatment, investigations must examine the questions related to patient selection and the feasibility of achieving the desired repair in an acceptable time frame. Few diagnostic tests that examine whether cell therapies are likely to succeed are available at present, but definite exclusion criteria would be evidence of major disc fissures, or disturbance of nutrient pathways as measured by post-contrast MRI.

A needle micro-osmometer for determination of glycosaminoglycan concentration in excised nucleus pulposus tissue.

PURPOSE: Aggrecan is one of the major macromolecular components of the intervertebral disc (IVD) and its loss is an early sign of degeneration. Restoration of aggrecan, and hence of biomechanical properties, is a major objective of biological therapies. At present, assessment of aggrecan concentration via its glycosaminoglycan (GAG) content is accomplished using biochemical and histological methods which require sacrifice of tissue. A minimally invasive method for assessing GAG, and hence aggrecan, which can avoid destruction of tissue, would be of benefit. METHODS: We have developed a needle micro-osmometer that is capable of measuring flux of saline into excised human nucleus pulposus (NP) tissue. Using the isotropic osmotic stress technique to assess the swelling pressure of the excised NP tissue and assuming negligible collagen tensile stress, we were able to relate the flux to the tissue fixed charge density (FCD). GAG concentration is evaluated from its FCD via the radioactive tracer technique. Samples representing different ages (28-59 years) and degeneration grades (1-4) were analyzed. RESULTS: The flux is controlled by both the osmotic pressure difference across the probe's semi-permeable membrane and by the tissue permeability. A linear correlation was found between flux and the tissue FCD. The equation describing the linear fit is FCD/(total tissue hydration) = 1.97 × 10(-4) + 8283 × flux (R = 0.836, p < 10(-4)). Thus, by measuring saline flux, the concentration of GAG can be determined. CONCLUSIONS: Micro-osmometry provides a reliable and minimally invasive tool for assessing GAG content in excised NP tissue. This method may be usefully applied in tissue engineering applications. It may also be useful for in vivo measurements if the question of the degenerative effect of needle puncture can be overcome.

Factors regulating viable cell density in the intervertebral disc: blood supply in relation to disc height.

The intervertebral disc is an avascular tissue, maintained by a small population of cells that obtain nutrients mainly by diffusion from capillaries at the disc-vertebral body interface. Loss of this nutrient supply is thought to lead to disc degeneration, but how nutrient supply influences viable cell density is unclear. We investigated two factors that influence nutrient delivery to disc cells and hence cell viability: disc height and blood supply. We used bovine caudal discs as our model as these show a gradation in disc height. We found that although disc height varied twofold from the largest to the smallest disc studied, it had no significant effect on cell density, unlike the situation found in articular cartilage. The density of blood vessels supplying the discs was markedly greater for the largest disc than the smallest disc, as was the density of pores allowing capillary penetration through the bony endplate. Results indicate that changes in blood vessels in the vertebral bodies supplying the disc, as well as changes in endplate architecture appear to influence density of cells in intervertebral discs.

The distribution of fibrillin-2 and LTBP-2, and their co-localisation with fibrillin-1 in adult bovine tail disc.

We investigated the distribution of fibrillin-2 and LTBP-2 (latent TGF-ß binding protein-2) in the intervertebral disc of the adult bovine tail. The association of fibrillin-2 and of LTBP-2 with fibrillin-1 was examined by dual immunofluorescence staining. Both fibrillin-2 and LTBP-2 were found extensively distributed in all regions of the disc with the organisation of the network varying significantly region to region. In the outer annulus fibrosus (OAF) both fibrillin-2 and LTBP-2 co-localised with fibrillin-1 forming fibres running parallel to the collagen fibres of the lamellae with the microfibrillar network staining densely in between the adjacent lamellae and also at the boundaries of the collagen bundle compartments. In the inner annulus fibrosus (IAF) and nucleus pulposus (NP), co-localised fibrillin-1,2 and LTBP-2 formed a chondron-like structure around the cell. By contrast, the inter-territorial matrix of the IAF and NP contained a dense network of fibrillin-2 but only sparse/filamentous fibres of fibrillin-1 and LTBP-2. Dual immunostaining revealed that in this region, fibrillin-2 was highly colocalised with elastin. The LTBP-2 network co-localised well with that of fibrillin-1 in all regions and indeed is reported to bind strongly to fibrillin-1. However, interestingly LTBP-2 but not fibrillin-1 or fibrillin-2 was removed by hyaluronidase but not collagenase pre-digestion. Our results suggest that fibrillin-2 and LTBP-2 could play an important role in disc function.

Intervertebral disk nutrition: a review of factors influencing concentrations of nutrients and metabolites.

The biomechanical behavior of the intervertebral disk ultimately depends on the viability and activity of a small population of resident cells that make and maintain the disk's extracellular matrix. Nutrients that support these cells are supplied by the blood vessels at the disks' margins and diffuse through the matrix of the avascular disk to the cells. This article reviews pathways of nutrient supply to these cells; examines factors that may interrupt these pathways, and discusses consequences for disk cell survival, disk degeneration, and disk repair.

Differential gene expression profiling of metalloproteinases and their inhibitors: a comparison between bovine intervertebral disc nucleus pulposus cells and articular chondrocytes.

STUDY DESIGN: A comparative in vitro metalloproteinases and their inhibitors gene expression profile. OBJECTIVE: To obtain a complete expression profile of matrix metalloproteinases (MMPs), family of proteases with a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS), and tissue inhibitors of metalloproteinases (TIMPs) in bovine adult nucleus pulposus (NP) cells and to compare this profile with the expression profile obtained from bovine adult articular chondrocytes cultured under identical conditions. SUMMARY OF BACKGROUND DATA: The cells of the NP resemble articular chondrocytes morphologically but produce a matrix which, though consisting of similar components, has very different biomechanical properties. No specific markers for NP cells have yet been identified; they can be distinguished from chondrocytes only by differences in gene expression. Here we compare profiles of gene expression of metalloproteinases and their inhibitors between NP cells and chondrocytes to improve understanding of the differences between these cell types. METHODS: NP cells and articular chondrocytes were harvested respectively from bovine caudal discs and the articular cartilage of metacarpal-phalangeal joints of 18- to 24-month-old steers. These cells were cultured under identical conditions for 96 hours in alginate beads. Expression levels of MMPs, ADAMTSs, and TIMPs were detected by real-time RT-PCR. RESULTS: Gene profiling demonstrated distinct differences between levels of MMPs, ADAMTSs, and TIMPs produced by chondrocytes and NP cells. In particular, NP cells expressed considerably more MMP-2 and MMP-14 than chondrocytes, and expression of ADAMTS-1,-2,-17 and TIMP-1 was also higher. However, expression of MMP-1,-3,-7,-8,-10,-11,-13,-16,-19,-20,-21,-23,-24,-28, ADAMTS-4,-5,-6,-14,-18,-19, and TIMP-3 was lower in NP cells than in chondrocytes. Chondrocytes but not NP cells expressed MMP12 and MMP27; this difference is a potential marker for distinguishing between NP cells and chondrocytes. CONCLUSION: Because culture conditions and animal age were identical, differences in metalloproteinase and inhibitor expression between NP cells and chondrocytes were intrinsic to cell phenotype and not induced by differences in the in situ extracellular environment.

The elastic network of articular cartilage: an immunohistochemical study of elastin fibres and microfibrils.

The elastic network of articular cartilage was investigated by immunohistochemistry using specific antibodies to elastin and fibrillin-1. Articular cartilage was dissected from defined regions of bovine metacarpophalangeal joints. Elastin fibres and microfibrils were dual-immunostained by labelling with distinct fluorescent dyes. A conventional fluorescence microscope combined with a polarized light filter was used to study the organization and degree of colocalization of elastin fibres, microfibrils and of the collagen network. We observed an elaborately organized elastic network. In the uppermost superficial zone, where few cells were present, elastin fibres and microfibrils formed a dense three dimensional network showing some degree of colocalization. The thickness and organization of this elastic network varied dramatically from region to region and was most extensive in the metacarpal palmar region. In the middle and deep zones, very few elastin fibres were observed but microfibrils formed a network in the inter-territorial matrix and dense network around the cells. Our finding of a three dimensional network of dense, well organized elastin fibres and microfibrils in the surface zone of the articular cartilage matrix, and a dense network of microfibrils around the cells deeper into the tissue suggests the elastic network could play both a mechanical and a biological role in articular cartilage.

Notochordal intervertebral disc cells: sensitivity to nutrient deprivation.

OBJECTIVE: The nucleus pulposus (NP) of the intervertebral disc develops from the notochord. Humans and other species in which notochordal cells (NCs) disappear to be replaced by chondrocyte-like mature NP cells (MNPCs) frequently develop disc degeneration, unlike other species that retain NCs. The reasons for NC disappearance are unknown. In humans, the change in cell phenotype (to MNPCs) coincides with changes that decrease nutrient supply to the avascular disc. We undertook this study to test the hypothesis that the consequent nutrient stress could be associated with NC disappearance. METHODS: We measured cell densities and metabolic rates in 3-dimensional cultures of porcine NCs and bovine MNPCs, and we determined survival rates under conditions of nutrient deprivation. We used scanning electron microscopy to examine end plate porosity of discs with NCs and those with MNPCs. Nutrient-metabolite profiles and cell viability were calculated as a function of cell density and disc size in a consumption/diffusion mathematical model. RESULTS: NCs were more active metabolically and more susceptible to nutrient deprivation than were MNPCs. Hypoxia increased rates of glycolysis in NCs but not in MNPCs. Higher end plate porosity in discs with NCs suggested greater nutrient supply in keeping with higher nutritional demands. Mathematical simulations and experiments using an analog disc diffusion chamber indicated that a fall in nutrient concentrations resulting from increased diffusion distance during growth and/or a fall in blood supply through end plate changes could instigate NC disappearance. CONCLUSION: NCs demand more energy and are less resistant to nutritional stress than MNPCs, which may shed light on the fate of NCs in humans. This provides important information about prospective NC tissue engineering approaches.

Tissue engineering and the intervertebral disc: the challenges.

Disc degeneration is a common disorder. Although the back pain that can develop in association with this is rarely life-threatening, the annual cost in terms of morbidity, lost productivity, medical expenses and workers' compensation benefits is significant. Surgical intervention as practised currently is directed towards removing the damaged or altered tissue. Development of new treatment modalities is critical as there is a growing consensus that the strategies used currently for symptomatic degenerative disc disease may not be effective. Accordingly, there is a need to develop an entirely new way to treat this disorder; regenerative medicine and tissue engineering approaches appear particularly promising in this regard. This paper reviews some of the challenges that currently are limiting the clinical application of this approach to the treatment of disc degeneration.

Nutrient gradients in engineered cartilage: metabolic kinetics measurement and mass transfer modeling.

Since tissue-engineered cartilage is avascular, both nutrient supply and metabolic waste removal rely on diffusion. As a result, gradients of nutrients and wastes exist through the construct. Previous models usually calculate gradients of oxygen, glucose, and lactic acid separately, without taking into account the complex interdependence between concentrations of these substrates and rates of metabolism. In this study, these interactions were experimentally examined and incorporated into diffusion models. One-dimensional diffusion-reaction models were developed for three typical culture conditions, that is, static culture, perfusion culture, and suspended culture. The profiles of oxygen, glucose, lactic acid, and pH in the cultured constructs were calculated simultaneously using measured metabolic rates. The maximum construct size and cell density which could be supported before nutrients were depleted in the construct center was identified; a function predicting the relationship between construct dimension and the maximum viable cell density was developed. For constructs incubated under static culture the model demonstrated that the gradients which developed through the medium could not be neglected. Perfusion cultures could support a considerably higher cell density than static cultures, while for batch cultures in a rotating bioreactor, the volume of medium also influences the maximum cell density that could be supported. This study provides useful guidance for design of engineered cartilage constructs.

Bovine explant model of degeneration of the intervertebral disc.

BACKGROUND: Many new treatments for degeneration of the intervertebral disc are being developed which can be delivered through a needle. These require testing in model systems before being used in human patients. Unfortunately, because of differences in anatomy, there are no ideal animal models of disc degeneration. Bovine explant model systems have many advantages but it is not possible to inject any significant volume into an intact disc. Therefore we have attempted to mimic disc degeneration in an explant bovine model via enzymatic digestion. METHODS: Bovine coccygeal discs were incubated with different concentrations of the proteolytic enzymes, trypsin and papain, and maintained in culture for up to 3 weeks. A radio-opaque solution was injected to visualise cavities generated. Degenerative features were monitored histologically and biochemically (water and glycosaminoglycan content, via dimethylmethylene blue). RESULTS AND CONCLUSION: The central region of both papain and trypsin treated discs was macro- and microscopically fragmented, with severe loss of metachromasia. The integrity of the surrounding tissue was mostly in tact with cells in the outer annulus appearing viable. Biochemical analysis demonstrated greatly reduced glycosaminoglycan content in these compared to untreated discs. We have shown that bovine coccygeal discs, treated with proteolytic enzymes can provide a useful in vitro model system for developing and testing potential new treatments of disc degeneration, such as injectable implants or biological therapies.

Effect of extracellular ph on matrix synthesis by chondrocytes in 3D agarose gel.

In cartilage tissue engineering, the determination of the most appropriate cell/tissue culture conditions to maximize extracellular matrix synthesis is of major importance. The extracellular pH plays an important role in affecting energy metabolism and matrix synthesis by chondrocytes. In this study, chondrocytes were isolated from bovine articular cartilage, embedded in agarose gel, and cultured at varied pH levels (7.3-6.6). Rate of lactate production, total glycosaminoglycan (GAG) and collagen synthesis, as well as total cell numbers and cell viability were evaluated after culturing for up to 7 days. The results showed the rate of lactic acid production over the 7-day culture was significantly affected by extracellular pH; acidic pH markedly inhibited the production of lactate. Also, a biphasic response to extracellular pH in regard to total GAG synthesis was observed; the maximum synthesis was seen at pH 7.2. However, the collagen synthesis was not pH-dependent within the pH range explored. In addition, within the conditions studied, total cell numbers and cell viability were not significantly affected by extracellular pH. In conclusion, even minor changes in extracellular pH could markedly affect the metabolic activities and biosynthetic ability of chondrocytes. Consequently, the control of extracellular pH condition is crucially important for successful cartilage tissue engineering and for the study of chondrocyte physiology and functions.

High pressures and asymmetrical stresses in the scoliotic disc in the absence of muscle loading.

BACKGROUND: Loads acting on scoliotic spines are thought to be asymmetric and involved in progression of the scoliotic deformity; abnormal loading patterns lead to changes in bone and disc cell activity and hence to vertebral body and disc wedging. At present however there are no direct measurements of intradiscal stresses or pressures in scoliotic spines. The aim of this study was to obtain quantitative measurements of the intradiscal stress environment in scoliotic intervertebral discs and to determine if loads acting across the scoliotic spine are asymmetric. We performed in vivo measurements of stresses across the intervertebral disc in patients with scoliosis, both parallel (termed horizontal) and perpendicular (termed vertical) to the end plate, using a side mounted pressure transducer (stress profilometry) METHODS: Stress profilometry was used to measure horizontal and vertical stresses at 5 mm intervals across 25 intervertebral discs of 7 scoliotic patients during anterior reconstructive surgery. A state of hydrostatic pressure was defined by identical horizontal and vertical stresses for at least two consecutive readings. Results were compared with similar stress profiles measured during surgery across 10 discs of 4 spines with no lateral curvature and with data from the literature. RESULTS: Profiles across scoliotic discs were very different from those of normal, young, healthy discs of equivalent age previously presented in the literature. Hydrostatic pressure regions were only seen in 14/25 discs, extended only over a short distance. Non-scoliotic discs of equivalent age would be expected to show large centrally placed hydrostatic nuclear regions in all discs. Mean pressures were significantly greater (0.25 MPa) than those measured in other anaesthetised patients (<0.07 MPa). A stress peak was seen in the concave annulus in 13/25 discs. Stresses in the concave annulus were greater than in the convex annulus indicating asymmetric loading in these anaesthetised, recumbent patients. CONCLUSION: Intradiscal pressures and stresses in scoliotic discs are abnormal, asymmetrical and high in magnitude even in the absence of significant applied muscle loading. The origin of these abnormal stresses is unclear.

Pathophysiology of the intervertebral disc and the challenges for MRI.

Through its ability to make relatively noninvasive and repeatable measurements, MRI has a great deal to offer, not only to clinical diagnosis of intervertebral disc disorders but also as a tool for basic research into disc physiology and the etiology of disc degeneration. In this brief review we outline the structure of the disc, the composition and organization of its macromolecules, and the changes that occur during disc degeneration, attempting to summarize features that have been or could become targets of MRI characterization. It is important to recognize, however, the fundamental limitation that most of the changes so far observed in MRI are consequences of alterations in cellular metabolism that occurred months to years previously and provide little insight into the current functional status of the tissue. There is therefore a need to develop MR techniques that directly characterize cellular activity and factors such as nutrient delivery on which it is critically dependent. We therefore briefly review cellular energy metabolism and nutrient transport into the avascular disc and consider the ability of MRI to reveal information about such processes. As a corollary of this discussion we also consider the constraints that the unusual transport properties of the disc impose on the delivery of contrast agents to the disc, since an understanding of these limitations is central to interpretation of the resulting images.