Introduction. Vertebral compression fractures are the most common type of osteoporotic fracture. Though 89% of clinical fractures occur anteriorly, it is challenging to replicate these ex vivo with the underlying intervertebral discs (IVDs) present. Furthermore, the role of disc degeneration in this mechanism is poorly understood. Understanding how disc morphology alters vertebral strain distributions may lead to the utilisation of IVD metrics in fracture prediction, or inform surgical decision-making regarding instrumentation type and placement. Aim. To determine the effect of disc degeneration on the vertebral trabecular bone strain distributions in axial compression and flexion loading. Methods. Eight cadaveric thoracolumbar segments (T11-L3) were prepared (N=4 axial compression, N=4 flexion). µCT-based digital volume correlation was used to quantify trabecular strains. A bespoke loading device fixed specimens at the resultant displacement when loaded to 50N and 800N. Flexion was achieved by adding 6° wedges. Disc degeneration was quantified with Pfirrmann grading and T2 relaxation times. Results. Anterior axial strains were 80.9±39% higher than the posterior region in flexion (p<0.01), the ratio of which was correlated with T2 relaxation time (R. 2. =0.80, p<0.05). In flexion, the central-to-peripheral axial strain ratio in the endplate region was significantly higher when the underlying IVDs were non-degenerated relative to degenerated (+38.1±12%, p<0.05). No significant differences were observed in axial compression. Conclusion. Disc degeneration is a stronger determinant of the trabecular strain distribution when flexion is applied. Load transfer through non-degenerate IVDs under flexion appears to be more centralised, suggesting that disc degeneration predisposes flexion-type compression fractures by shifting high strains anteriorly. Conflicts of interest. The authors declare none. Sources of funding. This work was funded by the Engineering & Physical Sciences Research Council (EP/V029452/1), and Back-to-Back

Purpose of study and background. Degeneration of the intervertebral disc is a strong contributor of low back pain. Studies have shown that both, mechanical unloading and overloading, lead to disc degeneration. This is intuitively clear if one considers that an intervertebral disc essentially is a poro-elastic material embedded with cells, which depend on fluid flow for the transport of nutrients and waste products. As such, mechanical loading is also required for regeneration. It is unclear, however, how much loading is beneficial or detrimental for the healthy or degenerated disc. Methods and Results. We developed a loaded disc culture system for the long-term study of disc physiology. This way we could control both the mechanical and biochemical conditions. If no loading was applied, about half of the cells died within a week. Cells died under a low dynamic loading regime after three weeks. A diurnal loading regime rescued cell viability, gene expression profile and mechanical behavior of the discs. Both static and dynamic overloading induced damage to the discs and led to catabolic and inflammatory gene expressions. Conclusion. Intervertebral discs need a certain dosage of mechanical loading to remain viable. Under overloading, cells deform, change gene expression and become degenerative. The matrix is also remodeled, thereby further decreasing the hydrostatic pressure on the cells and increasing their deformation. This induces a vicious circle of disc degeneration, which needs to be reversed in order to repair the disc. The loaded disc culture system also allows evaluating new therapies for disc degeneration. There are no conflicts of interest. Funded by ZonMW program “Alternatives for live animal testing”, grant #11400090;. BioMedical Materials Program, grant # P2.01 IDiDas; Dutch Arthritis Funds, personal grant KSE

Background

Intervertebral disc degeneration (DD) is a complex age-related condition that constitutes the main risk factor for disabling back pain. DD is assessed using different traits extracted from MR imaging (MRI), normally combined to give summary measures (e.g. Pfirmann score). The aetiology of DD is poorly understood and despite its high heritability (75%), the precise genetic predisposition is yet to be defined. Genome wide association study (GWAS) is used to discover genetic variants associated with a disease or phenotype. It tests variants across the whole genome. It requires large samples to provide adequate but unfortunately there is poor availability of spine imaging data due to the high cost of MRI. We have adopted new methods to examine different MRI traits independently and use the information of those traits to boost GWAS power using specialized statistical software for jointly analyse correlated traits.

Introduction. Risk factors for disc degeneration depend on how the condition is defined, i.e. on the specific disc degeneration “phenotype”. We present evidence that there are two major and largely-distinct types of disc degeneration. Methods. The relevant research literature was reviewed and re-interpreted. Evidence. In the . upper. lumbar and thoracic spine, disc degeneration is closely associated with endplate defects and with inflammatory changes in the vertebral bodies. It has a relatively high heritability (i.e. a strong genetic influence), and its incidence does not increase markedly with age. In the . lower. lumbar spine, disc degeneration is closely associated with radial fissures and nucleus herniation. Here it has a relatively low heritability, and a correspondingly stronger association with mechanical loading, and its incidence increases steadily throughout life. Mechanical experiments on cadaveric spines show that endplate fracture and nucleus herniation can be caused by compressive loading, and by bending combined with compression, respectively. Both lesions cause an immediate decompression of the nucleus, so that it becomes difficult to create subsequently the other lesion in the same disc. This suggests distinct phenotypes. Interpretation. The two types of disc degeneration are not entirely distinct, because disc herniation sometimes occurs at upper lumbar levels. Nevertheless, it may be useful to recognise two phenotypes when it comes to explaining and treating discogenic pain. Some other common disc changes (such as water loss and bulging) are attributable to ageing rather than degeneration, whereas disc narrowing probably represents a final common pathway for both types of disc degeneration. Conflicts of Interest. None. Source of Funding. None. This abstract has not been previously published in whole or in part; nor has it been presented previously at a national meeting

Introduction. Delamination of the annulus fibrosus is an early feature of disc degeneration, and it allows individual lamellae to collapse into the nucleus, or to bulge radially outwards. We . hypothesise. that delamination is driven by high gradients of compressive stress in the annulus. Methods. 102 thoracolumbar motion segments (T8-9 to L5-S1) were dissected from 42 cadavers aged 19–92 yrs. Each specimen was subjected to 1 kN compression, while intradiscal compressive stresses were measured by pulling a pressure transducer along the disc's mid-sagittal diameter. Stress gradients were measured, in the anterior and posterior annulus, as the average rate of increase in compressive stress (MPa/mm) between the nucleus and the region of maximum stress in the annulus. Average nucleus pressure was also recorded. Disc degeneration was assessed macroscopically on a scale of 1–4. Results. Compared to grade 2 discs, moderately degenerated grade 3 discs showed increased stress gradients in the annulus, especially in the posterior annulus where they increased by an average 106%. Nucleus pressure showed minimal changes. However, comparing grade 3 discs with severely degenerated grade 4 discs showed that nucleus pressure fell by 47%, while stress gradients showed little or no further change. Discussion. The results support our hypothesis. In early disc degeneration, a minor reduction in nucleus pressure is sufficient to generate high stress gradients in the annulus. These shear adjacent lamellae, causing delamination and allowing internal displacement of nucleus. As disc degeneration progresses, nucleus migration causes severe decompression, and compressive loading is transferred increasingly to the neural arch. Conflicts of Interest. None. Source of Funding. None. This abstract has not been previously published in whole or in part; nor has it been presented previously at a national meeting

Summary Statement. Spinal flexibility in bending and axial torque has been shown to exhibit very modest changes with advancing disc degeneration. This study is the first to address the possible relationship in pure anterior shear and no clear relationship was observed. Introduction. Disc degeneration (DD) is a risk factor for low back pain. Stable or unstable spine segments may be treated with an isolated decompression or instrumented stabilization, respectively. The effect of DD on spinal flexibility has been addressed by several groups in bending but not in shear; a highly relevant load direction in the lumbar spine is anterior shear. The objective of our study was to determine the effect of DD on anterior translation and specimen stiffness under shear loading in an in vitro model of degenerative spondylolisthesis. Methods. Magnetic resonance images were obtained for human cadaveric lumbar FSUs (N=30). Disc degeneration was assessed with the Pfirrmann five-point grading scale. Three surgeons independently graded the discs and the grade common to at least two of the surgeons was assigned to that specimen. Each specimen was then tested in three sequential states: intact, facet destabilization, and disc destabilization, with the latter two states representing the clinical scenario of degenerative lumbar spondylolisthesis. The specimens were loaded with a constant 300 N axial compressive force, representing body weight, combined with a cyclic anterior shear force (5–250 N). Vertebral translation was tracked with an optoelectronic motion capture system. Kruskal-Wallis ANOVA and multiple comparison Dunn's tests were performed to determine the effect of DD on anterior translation and specimen stiffness. Results. There was only one specimen with disc grade V, and it was grouped with specimens with disc grade IV for the statistical analyses. DD had no effect on anterior translation or specimen stiffness for the intact and disc destabilization conditions. In the facet destabilization condition, specimens with disc grade II translated more than those with disc grades IV and V (p=0.03). Stiffness increased with DD in the facet destabilization condition (ANOVA p=0.04; Dunn's test was not significant). However, we re-analyzed the data with each surgeon's disc grades and found no significant differences in any of the specimen conditions for all three surgeons. Discussion. In the original data analysis, the translation results showed a trend to reduced anterior translation in shear with advancing degeneration only in the facet destabilization condition. These results suggest that shear stiffness of an intact specimen is not affected by overall degeneration, except in the case where the facets are not competent to resist load. In the subsequent data analyses, no significant effects were found. These findings indicate the sensitivity of the analyses to the assignment of disc grade. There are numerous disc grading scales reported in the literature and it is not clear which scale best defines disc degeneration. We are continuing to assess our methods to determine the most appropriate method of defining disc degeneration by disc grade

Purpose & Relevance: To examine the prevalence of degenerative findings in the thoracic spine in a population sample of adult men. Normative data on thoracic degenerative findings provide an essential reference for related observations in patients. Methods & Results: Qualitative and quantitative assessments of thoracic disc degeneration were obtained from MRI (levels T6-L1) for general population sample of 532 men aged 25–70 years. Qualitative assessments of disc degeneration were performed by an experienced spine surgeon and custom-made software was used to acquire quantitative assessments. Descriptive statistics were acquired using SPSS. Moderate or severe disc bulging was present in at least one disc in 7.9% of subjects, with bulging most common at the two lowest levels. The prevalence of disc herniations was 0.8%. Moderate or severe disc height narrowing was present in 2.7% to 9.7% by disc level with 22.4% of subjects having at least one narrowed disc. Four or more wedged vertebrae (≥ 5°) were present in 68 subjects and 13 (2.4%) had coexisting Schmorl’s nodes. Seven subjects (1.3%) met more stringent criteria for Scheuermann’s disease, with three or more wedged vertebrae, endplate changes, sclerosis and disc height narrowing. Of the variables examined, disc signal intensity correlated highest with age (r= 0.31–0.40, depending on disc level). Conclusion: The prevalence of disc degeneration appears lower in the thoracic spine than previously reported in the lumbar spine. However, one-fifth of the subjects have markedly narrowed discs, which have been associated with symptom history in the lumbar spine. Disc signal intensity is the finding most highly associated with age

This short contribution aims to explain how intervertebral disc ‘degeneration’ differs from normal ageing, and to suggest how mechanical loading and constitutional factors interact to cause disc degeneration and prolapse. We suggest that disagreement on these matters in medico-legal practice often arises from a misunderstanding of the nature of ‘soft-tissue injuries’

Mechanical function and failure of intervertebral discs. In a healthy disc, the nucleus pulposus acts like a pressurised fluid which is restrained by tensile stress within the annulus. With increasing age, the nucleus becomes more fibrous, and biochemical changes cause the whole disc to become less elastic, and more yellow in colour. Mechanically, the hydrostatic nucleus shrinks with age, and concentrations of compressive stress appear in the posterior annulus. Experiments on cadaveric spines have shown that healthy discs can prolapse when loaded severely or repetitively in bending and compression, and that internal disruption of the disc probably follows damage to the vertebral endplates. However, mechanical loading is not necessarily harmful to living discs: on the contrary, moderate repetitive loading may lead to disc hypertrophy rather than injury. Disc degeneration. Degeneration represents some mechanical or biological “insult” superimposed on normal ageing. A defining feature of “degeneration” should be structural failure of the annulus or endplate, because all degenerated discs exhibit structural failure whereas many old discs do not. Degeneration creates high stress concentrations within the annulus. Paradoxically, severe degeneration can lead to gross disc narrowing and reduced stresses in the annulus, presumably because it is “stress shielded” by the apophyseal joints. Animal experiments show that disc degeneration always follows mechanical disruption. In some cases, it may possibly precede it. Disc degeneration and back pain. Pain-provocation studies have shown that severe and chronic back pain often originates in the posterior annulus fibrosus, and can be elicited by relatively moderate mechanical pressure. Anatomical studies indicate that the outer annulus is supplied with complex and free nerve endings from the mixed sinuvertebral nerve. MRI and discographic studies show that back pain is closely correlated with structural features of disc degeneration such as radial fissures and prolapse, although age-related changes in composition are clinically irrelevant. The stress-shielding of severely degenerated discs (see above) suggests that discogenic pain may be most closely associated with intermediate stages of degeneration. The localised stress concentrations found in degenerated cadaveric discs have been directly linked to low back pain in living people. Medico-legal implications. The widely-held belief that a disc will not prolapse unless it is degenerated is no longer compatible with the scientific evidence. Severe loading, which in life usually arises from vigorous muscle contractions, can injure normal discs. On the contrary, it seems likely that severely degenerated discs are too fibrous to prolapse, and that many of the cell-mediated changes associated with disc prolapse occur after prolapse, rather than before. However, genetic inheritance is important in disc degeneration and prolapse, suggesting that some discs are more vulnerable than others to mechanical loading. The nature of this vulnerability is largely unknown, but is likely to involve genetic weaknesses in composition, and previous fatigue damage. It would be desirable to distinguish between these last two factors, but this is likely to prove difficult in practice

Introduction: Disc degeneration is consistent with advancing age and in many cases is associated with back pain and restricted mobility. The traditional surgical treatment for chronic back pain has been spinal fusion to immobilize the painful level. Long-term studies, however, suggest that fusion actually promotes degeneration at adjacent levels. One of the hallmarks of disc degeneration is aggregation of chondrocytes in the nucleus of chondrones, and more recently apoptosis has been implicated as a factor controlling the longevity of the cells. Recent research suggests that it may be possible to restore normal function to degenerate discs by introducing a fresh population of cells. This study investigated the potential for autologous costal chondrocyte implantation to prevent lumbar disc degeneration after annular injury in the sheep. Methods: the lumbar spines of eight adult sheep were exposed. In four animals, full thickness annular incisions were made in three alternate discs. No annular incisions were made in the other four sheep. A minimum of 500 mg of cartilaginous tissue was harvested from the twelfth rib of all animals. Tissue was cultured in vitro and the chondrocytes were labelled with a fluorescent marker for retrospective identification. After six weeks the chondrocytes were injected into the lower two alternate discs of all animals, leaving the uppermost discs and those untouched as internal controls. The animals were killed at intervals from three to twenty-four weeks and MRI, plain x-ray, histology and immunocytochemistry were evaluated. Results: MRI at twelve and twenty-four weeks showed apparent preservation of all incised discs that had been transplanted with autologous chondrocytes. Histology revealed clusters of viable chondrocytes of normal appearance within the nucleus. These cells stained positive for the fluorescent label. The same cells and the surrounding matrix were also positive for collagen type II. Serial X-ray measurements suggested that progressive disc degeneration was arrested in the discs that received autologous costal chondrocytes. Discussion: This pilot study showed evidence that cultured autologous costal chondrocytes remained viable and produced extracellular matrix following transplantation into normal and degenerate discs. In contrast to other studies that have used mesenchymal stem cells or chondrocytes harvested directly from discs, this study demonstrated success with cells from a source other than the disc. Costal cartilage is a convenient source of cells for transplantation and this technique warrants further investigation as a potential treatment for degenerative disc disease

Purpose: To evaluate the long term clinical outcomes as well as radiological changes in distal unfused mobile segments and to evaluate factors that may predispose to distal disc degeneration and/or poor outcome. Method: 151 mobile segments in 85 patients (65 female), mean age 43.2 (range 21–68), were studied. Curve type, number of fused levels and pelvic incidence were recorded. Clinical outcome was measured using the Whitecloud function scale and disc degeneration using the UCLA disc degeneration score. Spinal balance, local segmental angulations and lumbar lordosis were measured pre- and post-operatively as well as at the most recent follow up – mean 9.3 years (range 7–19). Results: 62% of patients had a good or excellent outcome. 11 had a poor outcome of which 10 underwent extension of fusion – 5 for pain alone, 3 pain with stenosis and 2 pseudarthroses. Pre-operative disc degeneration was often asymmetric and was slightly greater in older patients. Overall, there was a significant deterioration in disc degeneration (p< 0.0001) that did not correlate with clinical outcome. Disc degeneration correlated with the recent sagittal balance (Anova F=14.285, p< 0.001) and the most recent lordosis (Anova F=4.057, p=0.048). The post-operative sagittal balance and local L5-S1 sagittal angulation correlated to L4 and L5 degeneration respectively. There was no correlation between degeneration and age, pre-operative degenerative score, pelvic incidence, sacral slope, number of fused levels or distal level of fusion. Conclusion: Disc degeneration does occur below an arthrodesis for scoliosis in adults which does not correlate with clinical outcome. The correlation of loss of sagittal balance with disc degeneration may be as a result of degeneration causing the loss of balance or vice versa i.e. sagittal imbalance causing degeneration. Immediate post-operative imbalance correlates with degeneration of the L4/5 disc, which may imply the latter

Osteoporotic fractures are associated with bone loss following hormonal changes and reduced physical activity in middle age. But these systemic changes do not explain why the anterior vertebral body should be such a common site of fracture. We hypothesise that age-related degenerative changes in the intervertebral discs can lead to abnormal load-bearing by the anterior vertebral body. Cadaveric lumbar motion segments (mean age 50 ± 19 yrs, n = 33) were subjected to 2 kN of compressive loading while the distribution of compressive stress was measured along the antero-posterior diameter of the intervertebral disc, using a miniature pressure-transducer. “Stress profiles” were obtained with each motion segment positioned to simulate a) the erect standing posture, and b) a forward stooping posture. Stress measurements were effectively integrated over area in order to calculate the force acting on the anterior and posterior halves of the disc ( . 1. ). These two forces were subtracted from the applied 2 kN to determine the compressive force resisted by the neural arch. Discs were sectioned and their degree of disc degeneration assessed visually on a scale of 1–4. In motion segments with non-degenerated (grade 1) discs, less than 5% of the compressive force was resisted by the neural arch, and forces on the disc were distributed evenly in both postures. However, in the presence of severe disc degeneration, neural arch load-bearing increased to 40% in the erect posture, and the compressive force exerted by the disc on the vertebral body was concentrated anteriorly in flexion, and posteriorly in erect posture. In severely degenerated discs, the proportion of the 2 kN resisted by the anterior disc increased from 18% in the erect posture to 58% in the forward stooped posture. Disc degeneration causes the disc to lose height, so that in erect postures, substantial compressive force is transferred to the neural arch. In addition, the disc loses its ability to distribute stress evenly on the vertebral body, so that the anterior vertebral body is heavily loaded in flexion. These two effects combine to ensure that the anterior vertebral body is stress-shielded in erect postures, and yet severely loaded in flexed postures. This could explain why anterior vertebral body fractures are so common in elderly people with degenerated discs, and why forward bending movements often precipitate the injury

Introduction. Primary cilia are singular structures containing a microtubule-based axoneme which are believed to not only be mechanosensitive but also to co-ordinate many cell functions via signalling pathways including Hedgehog and Wnt. Primary cilia have previously been described on cells of mouse intervertebral discs (IVDs), but not in bovine or human IVDs. Our aim was to examine primary cilia in these species. Methods. Nucleus pulposus cells were obtained from cows with no overt disc degeneration and patients following spine surgery (for herniations and/or degenerative disc disease) and cultured until confluent before maintaining with or without serum for 24h. Primary cilia were visualised with antibodies to the axoneme (acetylated α-tubulin and Arl13b) and/or the basal body (pericentrin) using fluorescent secondary antibodies and ≥200 cells per sample were counted. Results. Primary cilia were detected in the majority of disc cells (81.2±4.1% and 54.8±28.7% with and without serum depletion, respectively, in bovine and 78.9±0.3% and 89.8±7.4% in human cells). Some cilia demonstrated abnormalities, such as bulbous tips or breaks in the axonome. Conclusion. This is the first report of primary cilia being present on human and bovine IVD cells. There remain many other aspects to be investigated, for example, their length has been shown to alter in osteoarthritic chondrocytes. If this, or the incidence of abnormalities, differs in cells from normal and abnormal discs, it could suggest new pathways of disc degeneration, as these organelles are key to so many cell functions. Conflicts of interest: None. Supported by the Orthopaedic Institute Ltd

Summary Statement. DNA damage induced by systemic drugs or local γ-irradiation drives disc degeneration and DNA repair ability is extremely important to help prevent bad effects of genotoxins (DNA damage inducing agents) on disc. Introduction. DNA damage (genotoxic stress) and deficiency of intracellular DNA repair mechanisms strongly contribute to biological aging. Moreover, aging is a primary risk factor for loss of disc matrix proteoglycan (PG) and intervertebral disc degeneration (IDD). Indeed, our previous evidences in DNA repair deficient Ercc1−/Δ mouse model strongly suggest that systemic aging and IDD correlate with nuclear DNA damage. Thus the aim of the current study was to test whether systemic or local (spine) genotoxic stress can induce disc degeneration and how DNA repair ability could help prevent negative effects of DNA damage on IDD. To test this hypothesis a total of twelve Ercc1−/Δ mice (DNA repair deficient) and twelve wild-type mice (DNA repair competent) were challenged with two separate genotoxins to induce DNA damage, i.e. chemotherapeutic crosslinking agent mechlorethamine (MEC) and whole-body gamma irradiation. Local effects of gamma irradiation were also tested in six wild-type mice. Methods. Ercc1. −/Δ. mice (n=6) and their wild-type littermates were chronically exposed to genotoxic stress beginning at 8 wks of age by subcutaneous administration of a subtoxic dose of MEC (8 μg/kg once per week for 6 weeks). Similarly, six Ercc1. −/Δ. mice and their wild-type littermates were exposed to genotoxic stress by whole-body administration of ∼10% radiotherapeutic dose of ionizing radiation (0.5 Gy 1x per week for 10 weeks). A third set of wild-type mice (n=6) were exposed to one shot local spine irradiation at 0, 6, and 10 Gy at 22 weeks old and sacrificed 10 weeks later. Histological staining for proteoglycan (Safranin O) and collagen (Masson's Trichrome), PG synthesis (. 35. S-sulfate incorporation) and GAG content (DMMB assay), disc ADAMTS4, aggrecan and its fragments terminating in NITEGE-. 373. (immunohistochemistry (IHC)) were analyzed. Cellular senescence markers (p16) and apoptosis (TUNEL assay) were also measured. Results. Histological staining revealed substantial reduction in matrix collagen, proteoglycan, and endplate cellularity in the discs of MEC-exposed and irradiated mice. IHC analysis showed decreased aggrecan and increased levels of ADAMTS4 and NITEGE-. 373. containing aggrecan proteolytic fragments. Disc PG synthesis was reduced 2–3 folds in MEC-treated mice and irradiated mice. Locally irradiated mice showed similar effects on disc matrix. Expression of p16 as well as apoptosis significantly increased in MEC-treated and irradiated mice. The overall effect of the treatments on disc matrix and endplate cartilage was more severe in Ercc1−/Δ mice than wild-type mice. Discussion/Conclusion. MEC and IR treatment resulted in loss of disc matrix proteoglycan and collagen in adult wild-type and Ercc1−/Δ mice. The finding that loss of matrix proteoglycan was greater in the DNA repair deficient mice strongly supports the conclusion that DNA damage can drive disc degeneration and DNA repair ability is extremely important to help prevent these effects. Results of this work suggest that patients treated with genotoxic drugs (i.e. long-term cancer survivors) may be at increased risk of IDD

Introduction Disc replacement surgery is being investigated as an alternative to spinal fusion surgery in the hope that maintaining segment spinal motion will not only relieve pain, but also prevent or reduce the likelihood of symptomatic adjacent segment degeneration that is believed to be a consequence of fusion surgery. The aim of this study was to identify evidence in the medical literature that indicates whether or not spinal fusion surgery increases the likelihood of symptomatic adjacent segment degeneration compared to disc replacement surgery or natural history. Methods A search of the Cochrane Controlled Trials Register, Medline and reference lists of retrieved articles was performed. Search terms included arthroplasty replacement, spinal fusion, prognosis, controlled clinical trials and cohort studies, Studies were included if abstracts were available electronically, were published in the English language before1/3/2005 and involved humans. Levels of evidence were determined using the Oxford Centre for Evidence-Based Medicine criteria (. http://www.cebm.net/levels of evidence.asp. ). Discussion The majority of identified studies were case series of patients presenting with adjacent level disc degeneration following spinal fusion surgery (Level 4) and whilst indicating patients can develop adjacent level disc degeneration following fusion surgery, do not indicate the likelihood of doing so. Uncontrolled prospective cohort studies (Level 4) provide conflicting evidence. One retrospective cohort (Level 2b) studying comparing the incidence of adjacent disc degeneration following spinal fusion and discectomy or decompressive surgery alone found that the incidence of degeneration in the superior adjacent disc was increased in the fusion group, but was not associated with differences in functional outcome. No systematic reviews of inception cohort studies (Level 1) were identified. Conclusions Only poor quality evidence has been published to support the proposition that spinal fusion surgery is associated with an increased likelihood of developing symptomatic adjacent level disc degeneration. Long term follow-up of patients enrolled in prospective randomised controlled trials comparing outcomes of spinal fusion and disc replacement surgery is necessary to determine whether or not disc replacement surgery decreases the likelihood of any symptomatic adjacent level disc degeneration that can be attributed to spinal fusion surgery

Study Design: Experimental in vivo study on New Zealand White Rabbits. Summary of Background Data: We have developed an in-vivo rabbit model of lumbar disc degeneration. This model provides a defined loading of one single disc. However, the molecular mechanism that leads to mechanically-induced disc degeneration remains unclear. Objective: To investigate the process of mechanically induced disc degeneration in New Zealand White Rabbits with respect to remodeling on the gene and the level of protein expression. Subjects: Seven animals were treated with an external compression-device applying 200N on segment L3/4. Eight animals underwent sham surgery. Outcome Measures: After 28 days discs were harvested and cut into two pieces in a sagittal plain. One piece was used for protein analysis utilizing immunohistochemical protocols for collagen I, II and aggrecan. The other half of the disc was used for quantitative real-time RT-PCR to determine gene expression of selected matrix genes. Results: In the compression group matrix genes were upregulated: collagen I (6.46x; p=0,018), collagen II (2.14x), biglycan (2.97x; p=0,049), decorin (4.64x; p=0,043), aggrecan (1.2x), osteonectin (2.03x), fibronectin (3.48x), fibromodulin (2.6x; p=0,037). The MMP-13 gene could only be detected in compressed discs. Gene transcripts of the metalloproteinase-inhibitor TIMP-1 were 4.5 times upregulated (p=0,007). Immunohistochemical analysis revealed a decrease of aggrecan and collagen I. Conclusions: In our animal model mechanical loading caused degradation of the matrix proteins collagen I and aggrecan. Metalloproteinases like MMP-13 trigger this degenerative process. The elevated expression of matrix genes and TIMP-1 transcripts may characterize a mechanism of compensation

Objectives. A single degenerate intervertebral disc is suggested to promote rapid degeneration in its adjacent discs. We validated this hypothesis using discordant co-twin case-control design. Methods. 185 pairs of twins were selected from the TwinsUK database having cervical MRI scans at baseline and at follow-up, after 10 years. Isolated disc degeneration (IDD) was diagnosed in subjects having severe loss in disc height (graded 3/3) in a single disc, whilst discs immediately adjacent manifested little or no degeneration (graded 0 or 1). The controls' ‘adjacent discs’ were considered at the same levels as their affected co-twins. Results. Eight twin pairs fulfilled case/control criteria. At follow-up, no significant difference in adjacent disc degeneration between IDD cases and controls remained (p=0.69). Conclusions. Using a highly matched case-control design we did not find evidence that lone IDD has an adverse effect on the natural rate of adjacent disc degeneration in the cervical spine. No conflicts of interest. Acknowledgements. This study was supported by a grant from Globus Inc. Arthritis Research UK supported the imaging costs. TwinsUK. The study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007–2013). The study also receives support from the National Institute for Health Research (NIHR)- funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London

Introduction and Aims: Lower back and/or leg pain is a symptom of a number of pathological conditions involving lumbosacral nerve roots. Disc herniation is one of the most common causes of LBP (after mechanical back pain). There is controversy regarding the progression of disc degeneration and/or lower back pain to symptomatic disc prolapse over time. Method: The aim of the study was to determine the natural progression of patients with lower back pain/disc degeneration established clinically and on MRI to symptomatic disc herniation over three to six years. Total of 970 patients who had an MRI scan between January 1998 and September 2000 were included in the study. Information about disc pathology, level and number of discs involved were recorded from MRI scan reports. A short questionnaire was sent to all patients. It contained 10 questions regarding current status of pain and neurology, any treatment in form of back injection and operation, current occupation and smoking status. Results: The collected data was analysed using standard statistics software (SPSS). The results will be discussed. Conclusion: The information provided by this study will be useful in judging the natural progression of lower back pain and/or disc degeneration to a symptomatic prolapse intervertebral disc. It will also be useful in medico-legal cases where patients had pre-existing disc degeneration and subsequently developed disc herniation over time

Introduction: The development of laboratory techniques in the last ten years has enabled the successful harvest, in vitro selection, culture and transplant of chondrocytes. The study proposes that transplantation of autologous chondrocytes prevents degeneration of the intervertebral disc following outer annular injury in an ovine model. Methods: Eight sheep were anaesthetised and five contiguous lumbar discs were exposed via a left-sided posterolateral approach. Four of the animals were given full thickness annular incisions in three alternate discs. No annular incisions were made in the other 4 sheep. Costal cartilage was harvested from the left twelfth rib of all animals. Tissue was cultured and the chondrocytes were labelled in vitro with CFSE for verification following transplantation. Six weeks later autologous cultured chondrocytes were injected into the lower two alternate discs of all animals, leaving the uppermost discs and those untouched in between as internal controls. Animals were sacrificed after three, six, twelve and twenty-four weeks. Results were based on X rays, histological, and immunocytochemical assessments. Results: Preliminary histological results up to three months showed viability of cultured chondrocytes and matrix production post transplantation. Serial X rays suggested that progressive disc degeneration was arrested in the treated discs. Discussion: In this pilot study we have shown that cultured autologous chondrocytes can remain viable long term in vivo. These preliminary results suggest that these transplanted chondrocytes have the ability to retard and possibly prevent disc degeneration following annular incision. Previous similar studies have reported the use of chondrocytes cultured from disc, whilst this study showed that chondrocytes from a source foreign to the disc can exert positive effects. The encouraging result from this pilot study needs to be further validated to realise its potential as a treatment for degenerative disc disease

INTRODUCTION: The development of laboratory techniques in the last ten years has enabled the successful harvest, in vitro selection, culture and transplant of chondrocytes. The study proposes that transplantation of autologous chondrocytes prevents degeneration of the intervertebral disc following outer annular injury in an ovine model. METHODS: Eight sheep were anaesthetised and five contiguous lumbar discs were exposed via a left-sided posterolateral approach. Four of the animals were given full thickness annular incisions in three alternate discs. No annular incisions were made in the other four sheep. Costal cartilage was harvested from the left twelfth rib of all animals. Tissue was cultured and the chondrocytes were labelled in vitro with CFSE for verification following transplantation. Six weeks later autologous cultured chondrocytes were injected into the lower two alternate discs of all animals, leaving the uppermost discs and those untouched in between as internal controls. Animals were sacrificed after three, six, twelve and twenty-four weeks. Results were based on X-rays, histological, and immunocytochemical assessments. RESULTS: Preliminary histological results up to three months showed viability of cultured chondrocytes and matrix production post transplantation. Serial X-rays suggested that progressive disc degeneration was arrested in the treated discs. DISCUSSION: In this pilot study we have shown that cultured autologous chondrocytes can remain viable long term in vivo. These preliminary results suggest that these transplanted chondrocytes have the ability to retard and possibly prevent disc degeneration following annular incision. Previous similar studies have reported the use of chondrocytes cultured from disc, whilst this study showed that chondrocytes from a source foreign to the disc can exert positive effects. The encouraging result from this pilot study needs to be further validated to realise its potential as a treatment for degenerative disc disease

Study Design and Objectives: The aim of this study is to analyse clinical results of total lumbar disc arthroplasty according to the type of disc degeneration. Summary of Background Data: Lumbar disc degeneration can be associated with different causes of disc disease. Therapeutical management of such pathologies is still controversial between spinal fusion and arthroplasty. Non fusion techniques have been developed to allow a treatment of disc degeneration with a preserved intervertebral mobility. Materials and Methods: 221 patients with a mean age of 42 years were included in this study with a prospective data collection. 54 patients were classified as H0 (primary disc degeneration without previous surgery), 98 were classified as H1 (disc degeneration with associated herniation, without previous surgery), 36 were as H2 (disc degeneration with recurrence of disc herniation, with previous surgery) and 33 patients were H3 (post-discectomy syndrome with previous surgery). Clinical evaluation was based on Oswestry Disability Index (ODI), Lumbar and Radicular Visual Analogic Scale (VAS), each measurement was performed preoperatively, and at 3, 6, 12 and 24 months postoperatively. Results: Mean follow-up of the series was 30 months [24–72 months]. A significant (p< 0.05) clinical improvement was found between preoperative and the last follow-up evaluation for each group. On a multivariate analysis between different groups, a significantly higher ODI was found in the group classified as H3 (post-discectomy syndrome) at the final follow-up. Conclusion: Total lumbar disc arthroplasty provides a significant clinical improvement for patients with disc degenerative disease, with a 2 year minimal follow-up. The poorest results were found in patients with previous surgical procedure on the concerned level (post-discectomy syndrome). These results can be helpful for selection of total disc arthroplasty indications and for the information that a surgeon must give to his or her own patient on the expected result after disc replacement

The lumbar spines of 22 patients were examined for disc degeneration by magnetic resonance imaging (MRI) and by discography. The results from 50 intervertebral discs visualised by both techniques were independently assessed and graded on a five-point scale from normality to gross degeneration and then compared. In 44 discs the results agreed. Of the six discs which gave differing results, four discrepancies were due to observer error and two to incorrect placement of the discographic needle. MRI was shown to be more accurate than discography in the diagnosis of disc degeneration. It has several major advantages, which should make it the investigation of choice

Introduction: The evidence of genetic background as an important causative factor in disc degeneration and osteoporosis is increasing. Defects in the COL2A1 gene coding for type II collagen are known to lead to disturbed chondrogenesis and ossification. Retardation of growth, abnormal shape of vertebral bodies and intervertebral discs and occult spina bifida have been described in young mice with the defect. How the gene defect is manifested later in life has not been described. Purpose of the study: The purpose of this study was to describe, at the microscopic level, the structure of intervertebral discs of transgenic Del1 mice carrying a deletion mutation in the Col2a1 gene, and the effect of the gene defect on the structural properties of bone. In addition, we wanted to see how the gene defect manifests in disc tissue and skeletal bone later in life and if there were differences between sexes. Materials and methods: The study material consisted of transgenic male (n=27) and female (n=21) mice and their age-matched littermate controls (n=22 and 21, respectively). The transgenic mice were offspring of the transgenic founder mouse Del1 harbouring six copies of a mouse type II collagen transgene with a 150-bp deletion. The mice were divided into two age groups, the younger group being 3 to 13 months and the older 15 to 21 months of age. The two major macromolecules of the intervertebral discs, proteoglycans (PGs) and collagen, were studied. The PG concentration of the intervertebral discs’ nucleus pulposus, annulus fibrosus, and the vertebral bodies and end plates was measured from Safranin-O-stained sections using digital densitometry. Collagen orientation of these structures was evaluated using quantitative polarised light microscopy. Bone mineral density (BMD) was measured with dual energy x ray absorptiometry (DXA), and the breaking force of the femoral bone with three point bending test only for nine 14-month-old females (four control mice and five with gene defect) and fourteen 14-month-old male mice (six control mice and eight with gene defect). Results: In the young mice, there were no changes in the measured parameters in the intervertebral discs due to the gene defect. However, Safranin-O density and thus PG concentration of the vertebral trabecular bone was 47 % lower in the young transgenic female mice than in the controls (p< 0.001). Ageing had a significant effect on the measured parameters. The Safranin-O density in the nucleus pulposus of the old transgenic male mice was 35 % higher than in the age-matched controls (p< 0.05). In the females, however, Safranin-O density in the nucleus pulposus was 53 % (p< 0.01) and in the vertebral bone 68 % (p< 0.01) lower in the transgenic mice than in the controls. The Safranin-O density in the annulus fibrosus of the transgenic female mice was not changed as compared to the controls. The collagen orientation in the nucleus pulposus of old transgenic male mice was 27 % higher than in the age-matched controls (p< 0.05). In the old females there was no difference in the collagen orientation of the nucleus pulposus between the transgenic mice and controls but in the annulus fibrosus the orientation was 41 % (p< 0.01) and in the vertebral bone 70 % (p< 0.05) lower in the transgenic mice than in the controls. There was no difference in the BMD and the breaking force of the femurs of 14-month-old male mice as compared with the age-matched controls. However, in the old transgenic female mice, the femoral BMD was 14 % (p=0.05) and the breaking force 27 % (p=0.09) lower than in the controls. Conclusions: The transgene of the Col2a1 gene caused a decrease in the nucleus pulposus PG concentration and in the annulus fibrosus collagen orientation in the old female mice. These features can compromise the structural and load-bearing properties of the discs and thus predispose to disc degeneration. Interestingly enough, the male mice seemed to benefit from the genetic defect in this respect. In addition, in the old transgenic female mice, the PG concentration and the collagen orientation of the vertebral trabecular bone were decreased which contributed to the loss of BMD and breaking force of bone seen in these mice. The fact, that these differences in the bone were not seen in the male mice suggests that this animal model could possibly be used in studies of postmenopausal osteoporosis

Background. The majority of adults will experience an episode of low back pain during their life. Patients with non-specific low back pain and lumbar disc degeneration (LDD) may experience spinal pain and morning stiffness because of a comparable inflammatory process as in patients with osteoarthritis of the knee and/or hip. Therefore, this study assessed the association between spinal morning stiffness, LDD and systemic inflammation in middle aged and elderly patients with low back pain. Methods. This cross-sectional study used the baseline data of the BACE study, including patients aged ≥55 years visiting a general practitioner with a new episode of back pain. The association between spinal morning stiffness, the radiographic features of lumbar disc degeneration and systemic inflammation measured with serum C-reactive protein was assessed with multivariable logistic regression models. Results. At baseline, a total of 661 back pain patients were included. Mean age was 66 years (SD 8), 416 (63%) reported spinal morning stiffness and 108 (16%) showed signs of systemic inflammation measured with CRP. Both LDD definitions were significantly associated with spinal morning stiffness (osteophytes OR=1.5 95% CI 1.1–2.1, narrowing OR=1.7 95% CI 1.2–2.4) and spinal morning stiffness >30 minutes (osteophytes OR=1.9 95% CI 1.2–3.0, narrowing OR=3.0 95% CI 1.7–5.2) For severity of disc space narrowing we found a clear dose response relationship with spinal morning stiffness. We found no associations between spinal morning stiffness and the features of LDD with systemic inflammation. Conclusions. This study demonstrated an association between the presence and duration of spinal morning stiffness and radiographic LDD features. No conflicts of interest. No funding obtained

Introduction The annulus fibrosus of the intervertebral disc is composed of a series of concentric collagenous lamellae that constrain the highly pressurised fluid of the nucleus pulposus. With advancing age and even after physical injury in youth the disc almost invariably becomes progressively degenerate due to the combined effects of dehydration of the nucleus and disruption of the annulus. There is conjecture however, about which of the two compartments shows degenerate changes first. Methods A histological and biochemical review is presented, based on a review of the literature and work carried out in our laboratories. Results Three distinct types of annulus tears are seen histologically. Rim tears are formed by detachment of the peripheral annular fibres from the vertebral rim. Autopsy studies show that these lesions are rare in subjects younger than 30 years but the incidence increases significantly with advancing age. Although granulation tissue grows into the outer layers of the annulus in a normal healing response, these lesions frequently extend deeper into the disc. Radiating tears course radially across several lamellae, most often extending from the vertebral rim across the nucleus to involve the posterior side of the disc. These lesions are seen mostly between the ages of 30 and 50 years. Concentric tears are characterised by separation of adjacent lamellae and may appear as early as the second decade of life. In advanced degeneration nuclear changes may be seen with any combination of annular lesions. Biochemical changes, including dehydration and reduced proteoglycan content of the nucleus, parallel the morphologic changes to the disc. Altered biochemistry is further reflected by MRI studies in which some scanning sequences can detect even modest loss of fluid from the nucleus as early as three months after experimental annular incision. Annular lesions also compromise the biomechanical properties of the disc. While internal fixation that aims to immobilise the injured disc may promote some recovery of the mechanical integrity, degeneration nevertheless advances in the long term. Attempts to seal peripheral annular defects in experimental studies using biocompatible glue have also failed to promote healing and to prevent progression of even minor structural defects. Conclusions Technological developments such as gene transfer into disc cells and direct implantation of either stem cells or more mature cells are emerging as potential candidates for the treatment of disc degeneration

Introduction. The usefulness of markers of non-specific low back pain (NSLBP), including MRI derived measurements of cross-sectional area (CSA) and functional CSA (FCSA, fat free muscle area) of the lumbar musculature, is in doubt. To our knowledge, such markers remain unexplored in Lumbar Disc Degeneration (LDD), which is significantly associated with NSLBP, Modic change and symptom recurrence. This exploratory 3.0-T MRI study addresses this shortfall by comparing asymmetry and composition in asymptomatic older adults with and without Modic change. Methods. A sample of 21 healthy, asymptomatic subjects participated (mean age 56.9 years). T2-weighted axial lumbar images were obtained (L3/L4 to L5/S1), with slices oriented through the centre of each disc. Scans were examined by a Consultant MRI specialist and divided into 2 groups dependent on Modic presence (M) or absence (NM). Bilateral measurements of the CSA and FCSA of the erector spinae, multifidus, psoas major and quadratus lumborum were made using Image-J software. Muscle composition was determined using the equation [(FCSA/CSA)*100] and asymmetry using the equation [(Largest FCSA-smallest FCSA)/largest FCSA*100]. Data were analysed using Mann-Whitney U tests (p value set at). Intrarater reliability was examined using Intraclass Correlations (ICCs). Results. ICCs ranged between 0.74 and 0.96 for all area measurements, indicating excellent reliability. There was no significant difference in TCSA and FCSA asymmetry (P=0.1–1.0) and muscle composition (P=0.1–1.0) between M and NM groups. Conclusion. Modic change in the absence of pain does not appear to influence cross-sectional asymmetry or composition of the lumbar musculature. CSA remains a controversial marker. No conflicts of interest. Funding: This work is funded by an Allied Health Professional Doctoral Fellowship awarded to Janet Deane by Arthritis Research U.K

Thirty-three patients who had undergone anterior cervical fusion for degenerative disc disease were reviewed to determine the efficacy of the procedure. Only patients who were available for examination and who had undergone operation at least one year previously were included in the review. Nearly all had had arm pain and three-quarters neck pain. Diminished neck movement and neurological abnormalities in the arms had been frequent findings. Diagnosis from the clinical features and plain radiographs is described. Myelography was not used routinely and discography was not used at all. Indications for operation and surgical technique are described. Results show that pain in the neck and arm was relieved in a high proportion of cases and that the neurological abnormalities often recovered. It is concluded that this operation is safe and has a definite place in the relief of pain from cervical disc degeneration resistant to conservative treatment

Study Design: Experimental study to assess tissue engineered solutions to disc degeneration. Objectives: To investigate the use of a novel biodegradable hydrogel which is capable of minimally invasive introduction into an intervertebral disc (IVD) and support of cultured nucleus pulposus (NP) cells for the purpose of developing a tissue-engineered solution to retard progression of IVD degeneration. There were 3 objectives: (1) To introduce a slowly polymerising alginate hydrogel into the NP cavity of a bovine vertebral disc model. (2) To demonstrate the viability and metabolic activity of cultured NP cells in the hydrogel in vitro. (3) To determine the effect of Synvisc (hylan G-F 20) on NP cell proliferation and extracellular matrix (ECM) production. Summary of Background Data: The cause of intervertebral disc degeneration (IVDD) is multifactorial. One proposed mechanism is that IVDD originates in the NP and progresses radially to the annulus fibrosis (AF). There is a growing interest in tissue-engineered solutions where a biological repair is induced. By preventing the abnormality at the NP it may be possible to halt progression of IVDD. Injection of NP cells into an early degenerative IVD, where the AF is still intact, may retard the degenerative process. Subjects/Methods: CaSO. 4. and CaCO. 3. alginates were injected into the NP cavity of a bovine tail. After 90 minutes the tail was dissected to reveal the gel. NP cells released from pooled bovine NP tissue were dispersed into the CaSO. 4. and CaCO. 3. alginate gels (10x10. 6. cells.mL. −1. ) with and without Synvisc and cultured for 21 days. Results: Injectable alginate suspensions formed solid viscoelastic gels, filling the exact shape of the NP cavity. NP DNA and ECM synthesis was significantly greater in the CaCO. 3. alginate gel than in the CaSO. 4. alginate gel (p< 0.05). Synvisc significantly increased sulphated GAG (p< 0.01) and collagen (p< 0.05) production. These effects were supported histologically and immunohistologically where cells in the CaCO. 3. and Synvisc gels stained more intensely for proteoglycan and collagen type II. Conclusions: Both CaCO. 3. alginate gel and CaSO. 4. alginate gel are injectable and are capable of sustaining NP cells in-vitro. Cells remain viable, maintain their phenotype, proliferate and produce ECM during the culture period. The CaCO. 3. alginate gel provides a three-dimensional matrix more favourable to NP cellular activity than the CaSO. 4. alginate gel. Synvisc behaves as a chondro-stimulant significantly enhancing NP cell metabolic activity

Background: The healthy, adult human disc is innervated but the nerves are restricted to the outer few millimetres of the annulus fibrosus. In degenerate discs with associated back pain, however, the nerves are more numerous and penetrate further in. We have used a sheep model of intervertebral disc degeneration to monitor the presence and organisation of nerves in the disc as degeneration progresses. This model has been used to study morphological and bio-chemical changes of the disc as it degenerates, in addition to associated alterations in end-plate vascularity and vertebral bone remodelling. One aspect of this model which has not been studied to date is how the innervation of the disc may change with the onset of degeneration. This is the object of the present study. Materials and Methods: Four-year old, skeletally mature Merino wether sheep (n=64) were divided randomly into lesion and control groups. A surgical incision was created in the anterolateral annulus in the L1–L2 and L3–L4 discs of the lesion group. The control group received the same retroperitoneal surgical approach but the annulus was not incised. Intact lumbar discs encompassed by adjacent vertebral bodies were removed at 3,6,12 and 26 months post operation. Specimens were fixed, decalcified and paraffin embedded before sectioning (7μ thick, vertical sagittal sections) and stained immunohistochemically with the neuronal marker, PGP9.5, together with standard histological stains. Results: The incised region of the outer annulus underwent collagenous re-organisation, consistent with an active repair process as early as three months post-operatively. However, the inner annular lesion had a poor repair response and propagated with time, sometimes through to the nucleus. In contrast, remodelling of the outer annular lamellae occurred across the cut region. For example, in one sample at two years post injury there were up to six lamellae “bridging the gap”. Nerves were present in all samples but in the sham animals they were very few and confined to the very outer annulus or longitudinal ligament. In the operated animals, nerves were more extensive, occurring in the matrix adjacent to the fissure where there was often blood vessel ingrowth. The maximum number of nerves was seen at 12 months post-operatively, before diminishing in number at 24 months post-op. This paralleled the presence and extent of blood vessel penetration in this experimental model. Conclusions: We have used an animal model to follow longitudinally the penetration of nerves into the ovine intervertebral disc in association with disc degeneration. Whilst we obviously cannot assess back pain in these animals, and not all nerves are nociceptive, nerves nevertheless are a pre-requisite for the perception of pain. Hence the greater numbers, size and penetration of nerves into degenerate discs demonstrated here has important implications not only for the aetiopathogenesis of degenerative disc disease but also for the treatment of its associated symptoms. Further characterisation of this innervation, i.e. whether autonomic or sensory, may provide an indication as to its nociceptive potential

The pathophysiology of intervertebral disc degeneration has been extensively studied. Various factors have been suggested as influencing its aetiology, including mechanical factors, such as compressive loading, shear stress and vibration, as well as ageing, genetic, systemic and toxic factors, which can lead to degeneration of the disc through biochemical reactions. How are these factors linked? What is their individual importance? There is no clear evidence indicating whether ageing in the presence of repetitive injury or repetitive injury in the absence of ageing plays a greater role in the degenerative process. Mechanical factors can trigger biochemical reactions which, in turn, may promote the normal biological changes of ageing, which can also be accelerated by genetic factors. Degradation of the molecular structure of the disc during ageing renders it more susceptible to superimposed mechanical injuries.

This review supports the theory that degeneration of the disc has a complex multifactorial aetiology. Which factors initiate the events in the degenerative cascade is a question that remains unanswered, but most evidence points to an age-related process influenced primarily by mechanical and genetic factors.

We reviewed the radiographs of 325 unselected patients with defects in the pars interarticularis of L5 to study whether the incidence of vertebral slip in spondylolysis of L5 remained unchanged after the age of 20 years. MRI was also carried out on 111 of the patients to investigate the relationship between the shape of the transverse process of L5 and the degeneration of the discs adjacent to this level. The incidence of spondylolisthesis increased with age from 17% in the second decade to 51% in the sixth. The transverse process was significantly more slender in patients with less degeneration at L4/5 and advanced degeneration at L5/S1 than in patients with advanced degeneration at L4/5 and less degeneration at L5/S1. Vertebral slip secondary to an isthmic defect of L5 after the age of 20 years was confirmed and the adjacent disc degeneration was significantly related to the vertical thickness of the transverse process of L5

Disc degeneration in the human spine is characterised by progressive fraying and dehydration of the nucleus pulposus associated with formation of clefts within the annulus fibrosus. These have been classified on the basis of autopsy studies into radiating, circumferential and peripheral tears (rim lesions). Outer tears allow neovascularisation of the outer third of the annulus fibrosus and ingrowth of nerve fibres. Correlation with discographic findings had suggested the relevance of peripheral defects in the pathogenesis of discogenic pain. Outer annular tears are likely to be linked to tensile strain onto the collagen fibres and, therefore, may have a mechanical aetiology. In the animal model, peripheral tears of the outer annulus were proven to induce degenerative changes within the inner annulus and the nucleus pulposus. The increased understanding of the role of discrete peripheral defects of the annulus in discogenic pain may support the potential therapeutic effects of thermal treatment using radiofrequency waves and specially designed probes. At present, however, no in vivo studies have been able to demonstrate healing of outer annulus defects and reversibility of mechanical lesions to the intervertebral discs by thermal therapy. While it is highly likely that discrete defects of the outer annulus may be responsible for acute episodes of self-limiting low back pain, it is unclear if annular pathology may be as relevant for chronic disabling back pain. Recent studies using discography and other semi-invasive techniques have suggested that the main discriminating factors between benign, self limiting and chronic disabling back pain may not be anatomical but psycho-social. The challenge remains, in the 21st Century as in the past, to devise appropriate strategies that may lessen the socio-economic burden of back pain. Surgery, however, is highly unlikely to play a significant role in the future

Introduction. Patients with recurrent low back pain (LBP) exhibit changes in postural control. Stereotypical muscle activations resulting from external perturbations include anticipatory (APAs) and compensatory (CPAs) postural adjustments. This study aimed to determine differences in postural control strategies (APAs and CPAs) between those with and without lumbar disc degeneration (LDD) and LBP. Methods. Ninety-seven subjects participated in the study (mean age 50 years (SD 12)). 3T MRI was used to acquire T2 weighted images (L1-S1). LDD was determined using Pfirrmann grading and LBP using the numerical rating scale (NRS). A bespoke perturbation platform was designed to deliver postural perturbations. Electrical activity was analysed from 16 trunk and lower limb muscles during four typical APA and CPA epochs. A Kruskal-Wallis H test with Bonferroni correction for multiple comparisons was conducted. Results. Four groups were identified; ‘no LDD no pain’ (n = 19), ‘LDD no pain’ (n =38), ‘LDD pain’ (n =35) and ‘no LDD pain’ (n = 5). There was no significant difference in age or gender between groups. Although, increased BMI was associated with LBP it did not correlate with significant findings. Significant differences in APAs and CPAs were observed between ‘LDD pain’ and ‘LDD no pain’ groups during predicted and unpredicted perturbations (p=0.009–0.049, r=0.31–0.43). Significant CPAs correlated with LBP (p=0.001–0.03) but did not correlate with LDD (p=0.22–0.94). Conclusion. Postural control strategies are different between those with LDD and pain and those without. Differences in compensatory strategy are associated with the presence of pain and not LDD. No conflicts of interest. Sources of Funding: Janet Deane is funded by an Allied Health Professional Doctoral Fellowship awarded by Arthritis Research U.K. (ARUK)

Introduction: A computer model of the L4/5 human intervertebral disc is currently under development. An integral aspect of this model is the material properties assigned to its components. Detailed data on the material properties of the anulus fibrosus ground matrix are not available in the existing literature. To determine these properties, mechanical tests were carried out on specimens of anulus fibrosus harvested from sheep spines. The tests included unconfined uniaxial compression, simple shear and biaxial compression. Data on the strain required to cause permanent damage in the anulus ground matrix and data on the mechanical response of the anulus to repeated loading were obtained. Methods: Intervertebral discs were isolated from the lumbar spines of recently sacrificed sheep. These discs were sectioned into test specimens ensuring there were no continuous collagen fibres bearing load. The edge dimensions of the cubic specimens were 3 ± 0.2mm. To ascertain the strain to initiate tissue damage, the specimens underwent successive loadings, which were carried out 1 hour apart to allow recovery. The maximum strain in each test was increased incrementally by 5% until a reduction in stiffness was observed in the following test. Separate tests were carried out to quantify and characterise the response of the anulus ground matrix in the three modes of loading and to strains greater than that which initiates damage. Results: The strains at which permanent tissue damage occurred were between 20 and 27% in uniaxial compression and between 25 and 35% in simple shear. Testing the specimen beyond these strains showed an obvious reduction in stiffness. The biaxial compression tests showed similar changes but did not result in such pronounced losses in stiffness. The material characteristics were reproducible up to 20% strain. Following deformation to higher strains the altered mechanics were also shown to be reproducible indicating that the matrix had been deranged but not failed. Discussion: Average physiological strains in the L4/5 intervertebral disc are in the order of 10–50% based on maximum deformations observed in vivo. The current results demonstrate that this strain will cause some permanent damage to the anulus ground matrix, however, the matrix will still be capable of carrying stress upon repeated loading. Thompson et. al. 1. found that people over the age of 35 all exhibited signs of disc degeneration. We hypothesise that the regenerative ability of the anulus ceases to function effectively as we age and the continual damage caused to the anulus tissue by daily activities may lead to the degenerative changes seen in the anulus. Knowledge of the material characteristics up to 20% strain and following exposure to higher strains will enable a more realistic model of the intervertebral disc and the effects of degeneration to be studied

INTRODUCTION: A computer model of the L4/5 human intervertebral disc is currently under development. An integral aspect of this model is the material properties assigned to its components. Detailed data on the material properties of the anulus fibrosus ground matrix are not available in the existing literature. To determine these properties, mechanical tests were carried out on specimens of anulus fibrosus harvested from sheep spines. The tests included unconfined uniaxial compression, simple shear and biaxial compression. Data on the strain required to cause permanent damage in the anulus ground matrix and data on the mechanical response of the anulus to repeated loading were obtained. METHODS: Intervertebral discs were isolated from the lumbar spines of recently sacrificed sheep. These discs were sectioned into test specimens ensuring there were no continuous collagen fibres bearing load. The edge dimensions of the cubic specimens were 3 ± 0.2 mm. To ascertain the strain to initiate tissue damage, the specimens underwent successive loadings, which were carried out one hour apart to allow recovery. The maximum strain in each test was increased incrementally by 5% until a reduction in stiffness was observed in the following test. Separate tests were carried out to quantify and characterise the response of the anulus ground matrix in the three modes of loading and to strains greater than that which initiates damage. RESULTS: The strains at which permanent tissue damage occurred were between 20 and 27% in uniaxial compression and between 25 and 35% in simple shear. Testing the specimen beyond these strains showed an obvious reduction in stiffness. The biaxial compression tests showed similar changes but did not result in such pronounced losses in stiffness. The material characteristics were reproducible up to 20% strain. Following deformation to higher strains the altered mechanics were also shown to be reproducible indicating that the matrix had been deranged but not failed. DISCUSSION: Average physiological strains in the L4/5 intervertebral disc are in the order of 10–50% based on maximum deformations observed in vivo. The current results demonstrate that this strain will cause some permanent damage to the anulus ground matrix, however, the matrix will still be capable of carrying stress upon repeated loading. Thompson et. al. 1. found that people over the age of 35 all exhibited signs of disc degeneration. We hypothesise that the regenerative ability of the anulus ceases to function effectively as we age and the continual damage caused to the anulus tissue by daily activities may lead to the degenerative changes seen in the anulus. Knowledge of the material characteristics up to 20% strain and following exposure to higher strains will enable a more realistic model of the intervertebral disc and the effects of degeneration to be studied

Introduction: There are few long-term studies after Zielke ventral derotation spondylodesis (VDS). We present a minimum 17 year follow-up study to assess factors predicting distal adjacent disc degeneration. Material/Methods: Twenty-eight patients with thora-columbar AIS operated in 1982 have been retrospectively evaluated. Mean age 16,3 years, minimum follow-up 15 years. Anterior fusion was performed with rib graft. Results: Mean pre-op Cobb angle was 65 ± 23°, post-op correction rate was 61,2 ± 12,4%. Mean angulation of end vertebra was 32 ± 10°, post-op corrected to a mean of 8° (correction rate 79%). Mean post-op Th10/L2 kyphosis was 10°. Rod breakage was seen in 17 patients. Conclusion: Thoracolumbar kyphosis was associated both with proximal implant breakage and with segmental lordosis and degeneration of the distal adjacent segment. Disc angulation in the AP plane seems to be good tolerated. Anterior support with iliac bone graft or cages is expected to overcome these complications

Low back pain is thought to relate to intervertebral disc (IVD) degeneration. Although the mechanisms have not been clearly identified, exhaustion of nucleus pulposus cells and their producing matrix is regarded as one cause. The matrix of the IVD is continuously replenished and remodeled by tissue-specialized cells and are crucial in supporting the IVD function. However, due to aging, trauma, and genetic and lifestyle factors, the cells can lose their potency and viability, thereby limiting their collective matrix production capacity.

We have discovered the link between loss of angiopoietin-1 receptor (Tie2)-positive human NP progenitor cells (NPPC) and IVD degeneration. Tie2+ cells were characterized as undifferentiated cells with multipotency and possessing high self-renewal abilities. Thus we and others have proposed Tie2+ NPPC as a potent cell source for regenerative cell therapies against IVD degeneration. However, their utilization is hindered by low Tie2-expressing cell yields from NP tissue, in particular from commonly available older and degenerated tissue sources. Moreover, NPPC show a rapid Tie2 decrease due to cell differentiation as part of standard culture processes. As such, a need exists to optimize or develop new culture methods that enable the maintenance of Tie2-expressing NPPC. Trials to overcome these difficulties will be shared.

Background: Over several decades, investigators have been trying to identify the painful degenerate disc. Their work included two main methods. The first was to set criteria on the radiological investigations, mainly the MRI scan, to describe the severity of the degenerative disc disease (DDD); and the second was to perform discographies. Neither of these two methods precluded the need for the other. Purpose: Using Pfirrmann’s classification, we correlated static MRI images, for the severity of segmental disc degeneration, with dynamic lumbar discography, with the aim to improve the identification of painful ‘disco-genic’ intervertebral segments. Study design: Prospective cohort study. Inclusion criteria included patients with mechanical low back pain who exhausted the conservative measures and required surgical treatment. Patient Sample and Methods: We investigated 69 patients (45 females, 24 males). The average age was 38.9 years (range 20–56). All patients had degenerative disc disease (DDD) on lumbar MRI scans. Provocative discographies were performed in all cases as a routine investigation to identify painful levels prior to fusion or disc replacement surgery. The severity of DDD was graded using Pfirrmann’s classification. A total of 162 discographies were performed using the ‘miss the facet joint, double needle technique’. Outcome measures: During discography typical or concordant pain only was regarded as positive. Among each of the five Pfirrmann grades, the percentage of positive discographies was calculated. Significance and correlation then were investigated using the Chi-squared and Spearman’s correlation tests. Results: 24 discs were classified as Pfirrmann grade I, 33 grade II, 63 grade III, 27 grade IV and 15 grade V. The percentages of positive provocative discography for concordant pain among these groups were 0%, 9.1%, 71.4%, 100% and 100% respectively. Statistical analysis showed a high correlation between the severity of DDD on MRI scan and the result of the provocative discography (Chi2 = 32.96, P < 0.001 and correlation coefficient = 0.756). Conclusion: The higher the grade of segmental DDD, the more likely it will be painful on discography. All discs showing Pfirmann grade IV and V disease were painful on discography. We strongly recommend the Pfirrmann classification for use in grading the severity of lumbar DDD especially when assessing for its association with discogenic pain as determined by provocative discography

Background

The factors influencing normal spine curvature in midlife are unknown. We performed an MR and plain radiograph study on well characterised, unselected twin volunteers from the TwinsUK register (www.twinsuk.ac.uk) to determine the relative contributions of genetic and environmental factors to spine curve.

Aims. The presence of facet tropism has been correlated with an elevated susceptibility to lumbar disc pathology. Our objective was to evaluate the impact of facet tropism on chronic lumbosacral discogenic pain through the analysis of clinical data and finite element modelling (FEM). Methods. Retrospective analysis was conducted on clinical data, with a specific focus on the spinal units displaying facet tropism, utilizing FEM analysis for motion simulation. We studied 318 intervertebral levels in 156 patients who had undergone provocation discography. Significant predictors of clinical findings were identified by univariate and multivariate analyses. Loading conditions were applied in FEM simulations to mimic biomechanical effects on intervertebral discs, focusing on maximal displacement and intradiscal pressures, gauged through alterations in disc morphology and physical stress. Results. A total of 144 discs were categorized as ‘positive’ and 174 discs as ‘negative’ by the results of provocation discography. The presence of defined facet tropism (OR 3.451, 95% CI 1.944 to 6.126) and higher Adams classification (OR 2.172, 95% CI 1.523 to 3.097) were important predictive parameters for discography-‘positive’ discs. FEM simulations showcased uneven stress distribution and significant disc displacement in tropism-affected discs, where loading exacerbated stress on facets with greater angles. During varied positions, notably increased stress and displacement were observed in discs with tropism compared to those with normal facet structure. Conclusion. Our findings indicate that facet tropism can contribute to disc herniation and changes in intradiscal pressure, potentially exacerbating disc degeneration due to altered force distribution and increased mechanical stress. Cite this article: Bone Joint Res 2024;13(9):452–461

Aims

The complex relationship between acetabular component position and spinopelvic mobility in patients following total hip arthroplasty (THA) renders it difficult to optimize acetabular component positioning. Mobility of the normal lumbar spine during postural changes results in alterations in pelvic tilt (PT) to maintain the sagittal balance in each posture and, as a consequence, markedly changes the functional component anteversion (FCA). This study aimed to investigate the in vivo association of lumbar degenerative disc disease (DDD) with the PT angle and with FCA during postural changes in THA patients.

One hundred and thirty-nine discs from cadaveric lumbar spines were injected with a mixture of radio-opaque fluid and dye. Discograms were taken and the discs were then sectioned in the sagittal plane. Examination of the sections revealed that injected fluid did not at first mix with the disc matrix but pushed it aside to form pools of injected fluid. The location of these pools, and hence the appearance of a discogram, depended on the stage of degeneration of the disc. It is concluded that useful clinical information can be obtained from discograms.

There are many difficulties associated with the localisation of the symptomatic segment in patients presenting with cervicobrachial pain with no evidence of impaired conduction in the nerve root. Ancillary radiological investigations such as myelography, epidural phlebography, and epidural myelograms are of unreliable diagnostic value. However, discography can be of value if the technique described here is used. Infiltration of the cervical nerve root with local anaesthetic has also proved useful in the localisation of the symptomatic segment. The techniques used in cervical discography and infiltration of the nerve root are described and their reliability is assessed.

Study Purpose: The cause of intervertebral disc degeneration (IVDD) is multifactorial. One proposed mechanism is that IVDD originates in the nucleus pulposus (NP) and progresses radially to the annulus fibrosis (AF). Failure of current treatment modalities in preventing and treating IVDD and thereby low back pain have led to a growing interest in tissue-engineered solutions where a biological repair is induced. By preventing the abnormality at the NP it may be possible to halt further progression of IVDD. Injection of NP cells into an early degenerative IVD, where the AF is still intact, may retard the degenerative process and is presently under investigation. Using a three-dimensional scaffold that could be successfully introduced into the NP cavity through minimally invasive techniques would prevent the loss of chondrocytic phenotype of the cells and be an improvement over the existing technique by which cells are directly injected into the NP cavity.

Methods: (1) CaSO4 and CaCO3 alginates were injected into the NP cavity of a bovine tail. After 90 minutes the tail was dissected to reveal the gel. (2) NP cells released from pooled bovine NP tissue were dispersed into the CaSO4 and CaCO3 alginate gels (10x106 cells.mL-1) with and without Synvisc® and cultured for 21 days.

Results: (1) Injectable alginate suspensions formed solid viscoelastic gels, filling the exact shape of the NP cavity. (2) NP DNA and ECM synthesis was significantly greater in the CaCO3 alginate gel than in the CaSO4 alginate gel (p< 0.05). (3) Synvisc® significantly increased sulphated GAG (p< 0.01) and collagen (p< 0.05) production. These effects were supported histologically and immunohistologically where cells in the CaCO3 and Synvisc® gels stained more intensely for proteoglycan and collagen type II.

Conclusions: Both CaCO3 alginate gel and CaSO4 alginate gel are injectable and are capable of sustaining NP cells in-vitro. Cells remain viable, maintain their phenotype, proliferate and produce ECM during the culture period. The CaCO3 alginate gel provides a three-dimensional matrix more favourable to NP cellular activity than the CaSO4 alginate gel. Synvisc® behaves as a chondro-stimulant significantly enhancing NP cell metabolic activity. This study demonstrates a successful tissue-engineered approach for replacing the NP and, subject to further studies, may be used for retarding mild-to-moderate IVDD, alleviating lower back pain and restoring a functional NP through a minimally invasive technique.

Background: The cause of intervertebral disc degeneration (IVDD) is multifactorial. One proposed mechanism is that IVDD originates in the nucleus pulposus (NP) and progresses radially to the annulus fibrosis (AF). Failure of current treatment modalities in preventing and treating IVDD and thereby low back pain have led to a growing interest in tissue-engineered solutions where a biological repair is induced. By preventing the abnormality at the NP it may be possible to halt further progression of IVDD. Injection of NP cells into an early degenerative IVD, where the AF is still intact, may retard the degenerative process and is presently under investigation. Using a 3-dimensional scaffold that could be successfully introduced into the NP cavity through minimally invasive techniques would prevent the loss of chondrocytic phenotype of the cells and be an improvement over the existing technique by which cells are directly injected into the NP cavity.

Methods:

CaSO4 and CaCO3 3% alginate hydrogels were injected into the NP cavity of a bovine tail. After 90 minutes the tail was dissected to reveal the gel.

Results:

Injectable alginate suspensions formed solid viscoelastic gels, filling the exact shape of the NP cavity.

Discussion: This study demonstrates that slowly polymerising CaCO3 and CaSO4 alginate gels are injectable and capable of sustaining NP cells in-vitro. Cells remain viable, maintain their phenotype, proliferate and produce ECM during the culture period. CaCO3 alginate gel provides a 3-dimensional matrix more favourable to NP cellular activity than the CaSO4 alginate gel. Synvisc® has a chondro-stimulatory effect on NP cells in-vitro. These effects are similar to those observed previously with hyaluronic acid, in that it binds to cell surface CD44 receptors, thereby affecting essential cellular functions and cytoskeleton structure. Synvisc® however has an advantage in that it is highly viscous and can reside longer within an alginate construct thereby having a sustained long-term stimulatory effect. This study demonstrates a successful tissue-engineered approach for replacing the NP and, subject to further studies, may be used for retarding mild-to-moderate IVDD, alleviating lower back pain and restoring a functional NP through a minimally invasive technique.

Purpose: The aim of this study was to examine the intervertebral disc (IVD) biomechanics in a sheep model with concentric tears.

Methods: Fifty two adult merino wethers were randomly allocated into two groups with circumferential tears introduced by injection with saline (group 1) or needle stick with no saline (group 2). They were then sacrificed at 0, 1, 3, 6, 12 and 18 months for biomechanical testing. An additional ten sheep were used as an unoperated control at time 0 (Group 0). Biomechanical tests on each functional spinal unit (FSU) and IVD were performed.

Results: The effect of procedure overall was significant for torsion (P< 0.022), axial compression (P< 0.014), extension (P< 0.001) and left lateral bending (P< 0.004) for both the FSU and IVD. In almost every case, both groups 1 and 2 were significantly stiffer than group 0 but no different to each other. The effect of time overall was significant for flexion (P< 0.0028) and right lateral bending (P< 0.022) for both the FSU and IVD. In torsion, twisting to the left was significant for the intact FSU (P=0.008) and twisting to the right for the isolated IVD (P=0.009).

Discussion: The results of this study show that any intervention in the disc alters the biomechanics compared to an unoperated control group. To our knowledge this has not been shown before and these findings may have relevance to any intervention into the disc in the patient.

We studied 135 lumbar discs from 27 spines removed post-mortem from subjects of an average age of 31.5 years. Defects of the annulus fibrosus were classified as peripheral, circumferential or radiating; the nucleus pulposus as normal, moderately or severely degenerate. Peripheral tears were more frequent in the anterior annulus, except in the L5-S1 disc. Circumferential tears were equally distributed between the anterior and the posterior annulus. Almost all the radiating tears were in the posterior annulus, and closely related to the presence of severe nuclear degeneration. Histology suggested that peripheral tears were due to trauma rather than biochemical degradation, and that they developed independently of nuclear degeneration. The association of peripheral annular lesions with low back pain is uncertain but our study suggests that they may have a role in the pathogenesis of discogenic pain.

Introduction: The age-related reduction of water-trapping proteoglycans needed to maintain optimal disc hydration may be caused by reduced synthetic ability or fewer chondrocytes but there is a paucity of objective quantitative studies of disc cellularity.

Methods: Sagittal sections of L4–5 discs were subdivided into a nucleus zone and 18 annulus zones prior to determining cell density (cells/mm2) in

the mid-sagittal plane of 10 male and 10 female discs aged 13–79 years;

Results:

Most chondrocytes were unicellular but bicellular and multicellular chondrons were common in the margins of large tears and the nucleus in degenerate discs.

Discussion: The findings that cell density is higher in the posterior annulus and in the right half of the disc, tends to be increased if the cartilage end-plate is thicker, and is not uniformly diminished by large tears, indicates that disc cellularity is influenced by a complex interplay of factors which needs to be understood before attempts are made to restore the structural and functional integrity of degenerate discs.

Mesenchymal stem-cell based therapies have been proposed as novel treatments for intervertebral disc degeneration, a prevalent and disabling condition associated with back pain. The development of these treatment strategies, however, has been hindered by the incomplete understanding of the human nucleus pulposus phenotype and by an inaccurate interpretation and translation of animal to human research. This review summarises recent work characterising the nucleus pulposus phenotype in different animal models and in humans and integrates their findings with the anatomical and physiological differences between these species. Understanding this phenotype is paramount to guarantee that implanted cells restore the native functions of the intervertebral disc.

Cite this article: Bone Joint Res 2013;2:169–78.