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Journal ArticleDOI

Cell viability in scoliotic discs in relation to disc deformity and nutrient levels.

15 Oct 2002-Spine (Spine (Phila Pa 1976))-Vol. 27, Iss: 20, pp 2220-2228
TL;DR: Differences in cell viability correlated with changes in nutrient and metabolite levels, and also with disc deformity (convex vs concave and distance from curve apex), thus asymmetrical loads, tissue deformation, and nutrient supply may work separately or in combination to cause cell death.
Abstract: Study design Intervertebral disc tissue was analyzed during or removed at routine surgery for correction of scoliosis. Tissue was analyzed for glucose, lactate, oxygen, glycosaminoglycan, collagen concentrations, and cell viability. Objectives To investigate the cell viability of the scoliotic disc on the concave and convex sides and in relation to curve apex, and to relate cell viability to concentrations of nutrients, metabolites, and extracellular matrix components. Summary of background data Compositional differences have been measured in relation to the deformation of scoliotic discs. However, the causes of these in relation to cellular activity or viability are unknown. Methods Oxygen concentration was measured at surgery using a microelectrode. A segment of disc then was removed and sections at defined locations measured for cell viability and glucose, lactate, glycosaminoglycan, and collagen concentrations. RESULTS Cell viability was lower toward the convex side of the curve, with the greatest difference between the sides in the apical disc. The apical disc had the lowest oxygen and highest lactate concentrations, and lowest total number of cells. Glucose concentration correlated with the number of live cells. Concentrations of glycosaminoglycans and collagen per dry weight of tissue were similar on both sides of the disc. Conclusions Differences in cell viability correlated with changes in nutrient and metabolite levels, and also with disc deformity (convex concave and distance from curve apex). Thus asymmetrical loads, tissue deformation, and nutrient supply may work separately or in combination to cause cell death. A loss of matrix macromolecules was not seen, possibly because the period between cell death and surgery was too short, as compared with long matrix turnover times. Cell death is expected eventually to have a deleterious effect on cell matrix and disc function.
Citations
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Journal ArticleDOI
TL;DR: The intervertebral disc is a cartilaginous structure that resembles articular cartilage in its biochemistry, but morphologically it is clearly different, and shows degenerative and ageing changes earlier than does any other connective tissue in the body.
Abstract: The intervertebral disc is a cartilaginous structure that resembles articular cartilage in its biochemistry, but morphologically it is clearly different. It shows degenerative and ageing changes earlier than does any other connective tissue in the body. It is believed to be important clinically because there is an association of disc degeneration with back pain. Current treatments are predominantly conservative or, less commonly, surgical; in many cases there is no clear diagnosis and therapy is considered inadequate. New developments, such as genetic and biological approaches, may allow better diagnosis and treatments in the future.

1,124 citations


Cites background from "Cell viability in scoliotic discs i..."

  • ...Although little information is available to relate nutrient supply to disc properties in patients, a relationship has been found between loss of cell viability and a fall in nutrient transport in scoliotic discs [80,81]....

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Journal ArticleDOI
01 Dec 2004-Spine
TL;DR: Loss of nutrient supply can lead to cell death, loss of matrix production, and increase in matrix degradation and hence to disc degeneration.
Abstract: Study design A review of the literature on disc nutrition. Objectives To summarize the information on disc nutrition in relation to disc degeneration. Summary of the background data The disc is avascular, and the disc cells depend on diffusion from blood vessels at the disc's margins to supply the nutrients essential for cellular activity and viability and to remove metabolic wastes such as lactic acid. The nutrient supply can fail due to changes in blood supply, sclerosis of the subchondral bone or endplate calcification, all of which can block transport from blood supply to the disc or due to changes in cellular demand. Methods A review of the studies on disc blood supply, solute transport, studies of solute transport in animal and human disc in vitro, and of theoretical modeling studies that have examined factors affecting disc nutrition. Results Small nutrients such as oxygen and glucose are supplied to the disc's cells virtually entirely by diffusion; convective transport, arising from load-induced fluid movement in and out of the disc, has virtually no direct influence on transport of these nutrients. Consequently, there are steep concentration gradients of oxygen, glucose, and lactic acid across the disc; oxygen and glucose concentrations are lowest in the center of the nucleus where lactic acid concentrations are greatest. The actual levels of concentration depend on the balance between diffusive transport and cellular demand and can fall to critical levels if the endplate calcifies or nutritional demand increases. Conclusions Loss of nutrient supply can lead to cell death, loss of matrix production, and increase in matrix degradation and hence to disc degeneration.

904 citations


Cites background from "Cell viability in scoliotic discs i..."

  • ...Loss of nutrient supply could thus lead to cell death, as is seen in scoliotic discs, where endplate calcification(14,47) (Figure 3) appears to lead to cell death.(18,19)...

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  • ...Loss of transport of a gaseous tracer into scoliotic discs correlated with loss of cell viability.(18,19) Thus, the association between disc degeneration and disturbances to nutrient supply are strong....

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Journal ArticleDOI
TL;DR: The intervertebral disc is a highly organized matrix laid down by relatively few cells in a specific manner that allows the discs to facilitate movement and flexibility within what would be an otherwise rigid spine.
Abstract: The intervertebral disc is a highly organized matrix laid down by relatively few cells in a specific manner. The central gelatinous nucleus pulposus is contained within the more collagenous anulus fibrosus laterally and the cartilage end plates inferiorly and superiorly. The anulus consists of concentric rings or lamellae, with fibers in the outer lamellae continuing into the longitudinal ligaments and vertebral bodies. This arrangement allows the discs to facilitate movement and flexibility within what would be an otherwise rigid spine. At birth, the human disc has some vascular supply within both the cartilage end plates and the anulus fibrosus, but these vessels soon recede, leaving the disc with little direct blood supply in the healthy adult. With increasing age, water is lost from the matrix, and the proteoglycan content also changes and diminishes. The disc—particularly the nucleus—becomes less gelatinous and more fibrous, and cracks and fissures eventually form. More blood vessels begin to grow into the disc from the outer areas of the anulus. There is an increase in cell proliferation and formation of cell clusters as well as an increase in cell death. The cartilage end plate undergoes thinning, altered cell density, formation of fissures, and sclerosis of the subchondral bone. These changes are similar to those seen in degenerative disc disease, causing discussion as to whether aging and degeneration are separate processes or the same process occurring over a different timescale. Additional disorders involving the intervertebral disc can demonstrate other changes in morphology. Discs from patients with spinal deformities such as scoliosis have ectopic calcification in the cartilage end plate and sometimes in the disc itself. Cells in these discs and cells from patients with spondylolisthesis have been found to have very long cell processes. Cells in herniated discs appear to have a higher degree of cellular senescence than cells in nonherniated discs and produce a greater abundance of matrix metalloproteinases. The role that abnormalities play in the etiopathogenesis of different disorders is not always clear. Disorders may be caused by a genetic predisposition or a tissue response to an insult or altered mechanical environment. Whatever the initial cause, a change in the morphology of the tissue is likely to alter the physiologic and mechanical functioning of the tissue.

694 citations

Journal ArticleDOI
TL;DR: The finding that the onset of human disc degeneration occurs as early as by adolescence is indicated, because they are the major causes of the biologic changes experienced by disc cells.

358 citations

Journal ArticleDOI
TL;DR: Most evidence points to an age-related process influenced primarily by mechanical and genetic factors, which supports the theory that degeneration of the disc has a complex multifactorial aetiology.
Abstract: 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.

318 citations

References
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Journal ArticleDOI
TL;DR: A modified form of the dim methylmethylene blue assay is described that has improved specificity for sulphated glycosaminoglycans, and it is shown that in conjunction with specific polysaccharidases, the dimethylmethyleneblue assay can be used to quantitate individual sulphated sugarcans.

3,345 citations

Journal ArticleDOI
TL;DR: The metabolism of the canine nucleus pulposus was investigated at different oxygen tensions, and it was found that even at high oxygen tensions the metabolism is mainly anaerobic, only approximately 1.5% of the glucose being converted to carbon dioxide.
Abstract: The metabolism of the canine nucleus pulposus was investigated at different oxygen tensions. It was found that even at high oxygen tensions the metabolism is mainly anaerobic, only approximately 1.5% of the glucose being converted to carbon dioxide. The concentration dependence of oxygen consumption is limited to very low oxygen tensions. Values of oxygen consumption and lactic acid production were used to calculate the concentration profiles of these substances within the nucleus pulposus, using a diffusion theory. The predicted concentration profiles were compared with the experimental measurements of concentration at various positions in the disc. The good agreement in these values found in the nucleus confirms that the main mechanism of metabolite transport is diffusion, and the main route of nutrient supply into the nucleus is via the endplate.

501 citations


"Cell viability in scoliotic discs i..." refers methods in this paper

  • ...These were compared with those estimated for a completely permeable endplate using the diffusion equation; disc dimensions were obtained from radiographs, and values of diffusion coefficients from the literature.(15,42)...

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Journal ArticleDOI
01 Dec 2001-Spine
TL;DR: The results support the idea that maximum cell density in the disc is regulated by nutritional constraints, and that a fall in nutrient supply reduces the number of viable cells in theDisc and thus leads to degeneration.
Abstract: Study design Disc cell viability was analyzed in relation to nutrient supply and cellular demand in vitro in a diffusion chamber. Objective To determine relations among nutrient supply, nutrient concentrations. and cell viability. Summary of background data Although a fall in nutrient supply has long been thought the cause of disc degeneration in vivo, little information exists about the effects of nutrient levels or supply on cell viability and metabolism. Methods Isolated bovine nucleus cells were cultured in agarose gels in a diffusion chamber up to 13 days. Nutrients were supplied to the open sides of the chamber and diffused through the gel to the center, 12.5 mm away from the nutrient supply, in a configuration analogous to that of the disc in vivo. Profiles of cell viability and concentration of glycosaminoglycans across the chamber were measured in relation to cell density and medium composition. Results Cells remained viable across the chamber at low cell densities. However, at higher densities, cells in the center of the chamber died. The viable distance from the nutrient supply fell with an increase in cell density. Glucose was a critical nutrient. Survival was also poor at acidic pH (6.0). At 0% oxygen, disc cells survived up to 13 days with no loss of viability, but produced very little proteoglycan. Conclusions The results support the idea that maximum cell density in the disc is regulated by nutritional constraints, and that a fall in nutrient supply reduces the number of viable cells in the disc and thus leads to degeneration.

433 citations

Journal ArticleDOI
01 Dec 1998-Spine
TL;DR: In this article, an in vivo study of the biologic and biomechanical consequences of static compressive loading on the mouse tail intervertebral disc was carried out and the results indicated that maintenance of appropriate stress within the disc may be an important basis for strategies to mitigate disc degeneration and initiate disc repair.
Abstract: Study design An in vivo study of the biologic and biomechanical consequences of static compressive loading on the mouse tail intervertebral disc. Objectives To determine whether static compression in vivo alters the biologic activity of the disc and leads to diminished biomechanical performance. Summary of background data Static compressive stress that exceeds the disc's swelling pressure is known to change hydration and the intradiscal stress distribution. Alterations in hydration and stress have been associated with changes in disc cell activity in vitro and in other collagenous tissues in vivo. Methods Mouse tail discs were loaded in vivo with an external compression device. After 1 week at one of three different stress levels, the discs were analyzed for their biomechanical performance, morphology, cell activity, and cell viability. A second group of mice were allowed to recuperate for 1 month after the 1-week loading protocol to assess the disc's ability to recover. As an aid to interpreting the histologic and biologic data, finite-element analysis was used to predict region-specific changes in tissue stress caused by the static loading regimen. Results With increasing compressive stress, the inner and middle anulus became progressively more disorganized, and the percentage of cells undergoing apoptosis increased. The expression of Type II collagen was suppressed at all levels of stress, whereas the expression of aggrecan decreased at the highest stress levels in apparent proportion to the decreased nuclear cellularity. Compression for 1 week did not affect the disc bending stiffness or strength but did increase the neutral zone by 33%. As suggested by the finite-element model, during sustained compression, tension is maintained in the outer anulus and lost in the inner and middle regions where the hydrostatic stress was predicted to increased nearly 10-fold. Discs loaded at the lowest stress recovered anular architecture but not cellularity after 1 month of recuperation. Discs loaded at the highest stress did not recover anular architecture, displaying islands of cartilage cells in the middle anulus at sites previously populated by fibroblasts. Conclusions The results of the current project demonstrate that static compressive loading initiates a number of harmful responses in a dose-dependent way: disorganization of the anulus fibrosus; an increase in apoptosis and associated loss of cellularity; and down regulation of collagen II and aggrecan gene expression. The finite element model used in this study predicts loss of collagen fiber tension and increased matrix hydrostatic stress in those anular regions observed to undergo programmed cell death after 1 week of loading and ultimately become populated by chondrocytes after one month of recuperation. This correspondence conforms with the suggestions of others that the cellular phenotype in collagenous tissues is sensitive to the dominant type of tissue stress. Although the specific mechanisms by which alterations in tissue stress lead to apoptosis and variation in cell phenotype remain to be identified, our results suggest that maintenance of appropriate stress within the disc may be an important basis for strategies to mitigate disc degeneration and initiate disc repair.

404 citations

Journal ArticleDOI
15 Feb 1996-Spine
TL;DR: The shape and size of the solutes were found to affect their transport through cartilage matrix, with larger molecules being more highly excluded and diffusing more slowly and long‐chain polymers were able to penetrate the matrix less readily than the more globular molecules.
Abstract: Study Design. The transport properties of solutes of different sizes and conformations were studied in cartilage endplates. Objectives. The results were correlated with the composition of the cartilage matrix to determine if a relationship existed between this and the movement of molecules within it. Summary of Background Data. Solute transport through the hyaline cartilage endplate is important not only for the physiologic and metabolic processes of that tissue, but also for those of the adjacent intervertebral disc. Movement of solutes depends on solute size, shape or charges, and the composition of the matrix itself. Changes in composition of the cartilage endplate, such as those that occur in degeneration or scoliosis, may affect transport. Methods. Partition and diffusion coefficients of solutes ranging in molecular weight from 115 to 70,000 d have been measured on cores of cartilage endplate. Transport properties were assessed in relation to core composition. Results. The shape and size of the solutes were found to affect their transport through cartilage matrix, with larger molecules being more highly excluded and diffusing more slowly. Long-chain polymers were able to penetrate the matrix less readily than the more globular molecules. The more hydrated the matrix, the higher the degree of penetration and the more easily solutes could move, in contrast to the inverse relationship between the other components of the matrix and solute transport. With increased proteoglycan, collagen, or calcification in the tissue, there was greater restriction of solute movement. Conclusions. The proteoglycans normally found in the endplate regulate movement of solutes into and out of the disc. It has been shown previously that removal of proteoglycans from the endplate accelerates the loss of proteoglycans from the nucleus. Hence, a major function of the cartilage endplate may be to prevent fragments of osmotically active proteoglycans from leaving the disc.

364 citations


"Cell viability in scoliotic discs i..." refers background in this paper

  • ...In scoliosis, the cell density also may be compromised because of a fall in nutrient supply.(34,42) The current study focused on cell viability changes in human intervertebral discs of patients with scoliosis to determine whether cell death differs on either side of the disc, contributing to the metabolic changes across scoliotic discs....

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A loss of matrix macromolecules was not seen, possibly because the period between cell death and surgery was too short, as compared with long matrix turnover times.