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PubMed2004

Fluid flow and convective transport of solutes within the intervertebral disc.

Previous experimental and analytical studies of solute transport in the intervertebral disc have demonstrated that for small molecules diffusive transport alone fulfils the nutritional needs of disc cells. It has been often suggested that fluid flow into and within the disc may enhance the transport of larger molecules. The goal of the study was to predict the influence of load-induced interstitial fluid flow on mass transport in the intervertebral disc. An iterative procedure was used to predict the convective transport of physiologically relevant molecules within the disc. An axisymmetric, poroelastic finite-element structural model of the disc was developed. The diurnal loading was divided into discrete time steps. At each time step, the fluid flow within the disc due to compression or swelling was calculated. A sequentially coupled diffusion/convection model was then employed to calculate solute transport, with a constant concentration of solute being provided at the vascularised endplates and outer annulus. Loading was simulated for a complete diurnal cycle, and the relative convective and diffusive transport was compared for solutes with molecular weights ranging from 400 Da to 40 kDa. Consistent with previous studies, fluid flow did not enhance the transport of low-weight solutes. During swelling, interstitial fluid flow increased the unidirectional penetration of large solutes by approximately 100%. Due to the bi-directional temporal nature of disc loading, however, the net effect of convective transport over a full diurnal cycle was more limited (30% increase). Further study is required to determine the significance of large solutes and the timing of their delivery for disc physiology.

Animals↗
PubMed1975

Comparison of intervertebral disc disease treatment by chymopapain injection and open surgery.

Chymopapain chemonucleolysis was performed on 100 patients with primary lumbar intervertebral disc disease. The results were compared with those of 174 patients who underwent laminotomy, foraminotomy, and discectomy. Primary lumbar intervertebral disc disease was arbitrarily divided into degenerative, complex, previous surgical, and simple disc syndromes. No difference was seen between chemonucleolysis and surgery in the first three divisions; between 55 percent and 60 per cent of patients responded successfully to treatment. In the simple disc division 89 per cent of the surgical and 60 per cent of the chemonucleolysis patients had successful results.

Adult↗
PubMed1999

Sensory innervation of the dorsal portion of the lumbar intervertebral disc in rats.

STUDY DESIGN: The vertebral levels of dorsal root ganglia innervating the dorsal portion of the L5-L6 intervertebral disc were investigated in rats using a retrograde transport method. The pathways and functions of nerve fibers supplying the dorsal portion of the disc were determined by denervation and immunohistochemistry. OBJECTIVES: The dorsal portion of the lumbar intervertebral disc has been reported to be innervated segmentally, but anesthetic block of the paravertebral sympathetic trunks and the L2 spinal nerve can relieve discogenic low back pain. In the current study, the sensory innervation of the dorsal portion of the L5-L6 intervertebral disc was investigated, because the disc anatomically corresponds to the L4-L5 disc in humans, and the dorsal portion of the human L4-L5 disc is frequently subject to injury that causes low back pain. METHODS: A retrograde transport of Fluoro-Gold (F-G; Fluorochrome, Denver, CO) was used. Subjects included nontreated control (n = 32) and sympathectomized rats in which paravertebral sympathetic trunks were removed from L2 to L3 (n = 9). In a ventral approach, Fluoro-Gold crystals were placed on the dorsal portion of the L5-L6 disc, and labeled neurons in the bilateral dorsal root ganglia from T10 to L6 were counted. RESULTS: Fluoro-Gold crystals did not leak from the dorsal portion of the L5-L6 disc in 14 of the 32 nontreated rats and in 5 of the 9 sympathectomized rats. These rats were used for analysis. Fluro-Gold-labeled neurons were found in dorsal root ganglia from T13 to L6 in the 14 control rats but only from L2 to L6 in the 5 sympathectomized rats. CONCLUSION: The dorsal portion of the L5-L6 disc of rats was shown to be multisegmentally innervated by the T13 to L6 dorsal root ganglia. The sensory fibers from T13, L1, and L2 dorsal root ganglia were shown to innervate the dorsal portion of the L5-L6 disc through the paravertebral sympathetic trunks. In contrast, those from the L3-L6 dorsal root ganglia may innervate the dorsal portion of the L5-L6 disc through the sinuvertebral nerves.

Animals↗
PubMed2004

Relationship between osteopenia and lumbar intervertebral disc degeneration in ovariectomized rats.

Ovariectomy (OVX) can cause bone loss in rats, but little is known about how it also induces lumbar intervertebral disc degeneration (LVD). This study investigated how estrogen deficiency affected intervertebral discs in OVX rats. Thirty 3-month-old female Sprague-Dawley rats were divided randomly into three equal groups. The baseline control group (BL) was killed at the beginning of the experiment. An ovariectomy was performed in 10 rats (OVX group) and another group of 10 rats was subjected to a sham surgery (Sham group). The OVX rats were untreated after the surgery to allow for the development of moderate osteopenia. Bone mineral density (BMD) measurement and bone histomorphometric analysis were applied to the segments of lumbar spines in all rats killed 6 months after surgery. The pathological changes of intervertebral discs were observed and the degree of LVD was scored by a histological scoring system. The BMD of the spines (L3-L5) in the OVX group decreased significantly compared with the Sham group. The bone volume indices in the OVX group were significantly lower, but the bone turnover rate parameters were significantly higher than those in the Sham group (P < 0.01). The histological scores for LVD in the OVX group were significantly higher than those in the Sham group (P < 0.01). There was a significant negative correlation between the BMD and Grade II discs in the OVX rats (P = 0.042). In conclusion, LVD occurs in the OVX rats and the degeneration of cartilage end plates may be a pathogenic factor in disc degeneration.

Animals↗
PubMed1999

Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy: an in vivo study of adenovirus-mediated transfer of the human transforming growth factor beta 1 encoding gene.

STUDY DESIGN: In vivo studies using a rabbit model to determine the biologic effects of direct, adenovirus-mediated transfer of a therapeutic gene to the intervertebral disc. OBJECTIVES: 1) To deliver an exogenous therapeutic gene to rabbit lumbar intervertebral discs in vivo, 2) to quantify the resulting amount of gene expression, and 3) to determine the effect on the biologic activity of the discs. SUMMARY OF BACKGROUND DATA: Although growth factors such as transforming growth factor beta 1 appear to have promising therapeutic properties, there currently is no practical method for sustained delivery of exogenous growth factors to the disc for the management of certain chronic types of disease (e.g., disc degeneration). A possible solution is to modify the disc cells genetically through gene transfer such that the cells manufacture the desired growth factors endogenously on a continuous basis. METHODS: Saline, with or without virus, was injected directly into lumbar discs of 22 skeletally mature female New Zealand white rabbits. Group 1 (n = 11) received the adenovirus construct Ad/CMV-hTGF beta 1 containing the therapeutic human transforming growth factor beta 1-encoding gene. Group 2 (n = 6) received adenovirus containing the luciferase marker gene. Group 3 (n = 5) received saline only. The rabbits were killed 1 week after injection. Immunohistochemical staining for human transforming growth factor beta 1 was performed on the disc tissues of one rabbit from Group 1. Nucleus pulposus tissues from the remaining rabbits were cultured in serumless medium. Bioassays were performed to determine human transforming growth factor beta 1 production and proteoglycan synthesis. RESULTS: Discs injected with Ad/CMV-hTGF beta 1 exhibited extensive and intense positive immunostaining for transforming growth factor beta 1. The nucleus pulposus tissues from the discs injected with Ad/CMV-hTGF beta 1 exhibited a 30-fold increase in active transforming growth factor beta 1 production, and a 5-fold increase in total (active + latent) transforming growth factor beta 1 production over that from intact control discs (P < 0.05). Furthermore, these tissues exhibited a 100% increase in proteoglycan synthesis compared with intact control tissue, which was statistically significant (P < 0.05). CONCLUSIONS: The results of this study suggest that the intervertebral disc is an appropriate site for adenovirus-mediated transfer of exogenous genes and subsequent production of therapeutic growth factors. Gene therapy therefore may have useful applications for study of the basic science of the intervertebral disc and for clinical management of degenerative disc disease.

Adenoviridae↗
PubMed1981

Biochemical changes in intervertebral disc degeneration.

The distribution of the principal matrix components, collagen, proteoglycans and water, across the diameter of human normal and degenerate intervertebral discs was compared. Little difference in collagen distribution was noted between normal and degenerate tissue but water and proteoglycan content decreased with degeneration, particularly in the centre of the disc. Proteoglycans of the nucleus pulposus and annulus fibrosus of normal and degenerate intervertebral discs were examined. In comparison with monomers of normal tissues, degenerate disc proteoglycans were of larger average hydrodynamic size and had a higher glucosamine to galactosamine ratio. Proteoglycans were digested with chondroitinase ABC and passed over an HS-Sepharose 2B affinity column. A greater proportion of the keratan sulphate-protein cores from degenerate disc were capable of interaction with the immobilized hyaluronate. Loss of aggregating ability was associated with diminution in size of the core. It is suggested that a large proportion of proteoglycans from normal disc have undergone a degree of degradation in the hyaluronate binding region and that proteoglycan synthesis in this tissue is slower than in degenerate tissue.

Adult↗
PubMed1996

Neural connection between the ventral portion of the lumbar intervertebral disc and the groin skin.

This study was designed to investigate neural mechanisms of referred pain in lumbar intervertebral disc lesions. Patients with a degenerative disc in lower lumbar segments occasionally complain of groin pain, which cannot be explained anatomically as having a radicular origin. In rats pretreated with intravenous application of Evans blue dye, the dye extravasation appeared in the groin skin after application of capsaicin to the ventral portion of the L5-6 intervertebral disc. This response occurred even in rats with a sectioned L-5 spinal nerve and sympathetic trunks, but did not occur in rats with a sectioned genitofemoral nerve. Capsaicin topically applied to the sciatic nerve did not cause dye extravasation in the hindpaw. Therefore, groin dye extravasation was not due to a direct effect of capsaicin but, rather, presumably was caused by an "antidromic axon reflex" of dichotomizing C fibers or to a segmental sympathetic reflex causing vascular permeability. The present results indicate that the ventral portion of the lumbar discs is neurally connected to the groin skin via the upper (L-2) lumbar spinal nerves in rats. Groin pain coincident with low-back pain may be explained as referred pain, indicating that a lesion is present in the ventral portion of the lumbar intervertebral disc space.

Animals↗
PubMed2006

Exposure of the nucleus pulposus to the outside of the anulus fibrosus induces nerve injury and regeneration of the afferent fibers innervating the lumbar intervertebral discs in rats.

STUDY DESIGN: Using a retrograde tracing method and immunohistochemistry, we assessed the expression of activating transcription factor 3 (ATF3), a marker of nerve injury, and growth-associated protein 43 (GAP-43), a marker of axonal growth, in dorsal root ganglion (DRG) neurons innervating the lumbar intervertebral discs in rats. OBJECTIVES: To investigate ATF3 and GAP-43 expression in DRGs innervating the intervertebral discs after exposure of the nucleus pulposus to the outside of the anulus fibrosus. SUMMARY OF BACKGROUND DATA: Degeneration of lumbar intervertebral discs is considered as a cause of low back pain. We speculated that exposure of the nucleus pulposus to the outside of the anulus fibrosus may induce nerve injury and ingrowth into the disc. METHODS: A neurotracer, Fluoro-Gold (F-G), was applied to the ventral aspect of L5-L6 intervertebral discs in 20 rats. The rats were classified into 2 groups: an NP group whose disc was punctured to expose the nucleus pulposus (n = 10) and a sham-operated group whose anulus fibrosus surface was scratched superficially (n = 10). Ten days after surgery, bilateral L1-L5 DRGs were processed for staining of ATF3 and GAP-43. RESULTS: In the NP group, 13.9% +/- 2.9% of the F-G-labeled neurons innervating the discs were positive for ATF3, while 19.3% +/- 2.7% were positive for GAP-43. In contrast, in the sham-operated group, only 0.8% +/- 0.4% of the F-G-labeled neurons were positive for ATF3 while 7.4% +/- 1.7% were positive for GAP-43. The percentage of both ATF3-immunoreactive (IR) and GAP-43-IR neurons in the NP group was significantly higher than in the sham-operated group (P < 0.05). CONCLUSIONS: ATF3-IR and GAP-43-IR neurons were significantly increased in the NP group. These results suggested that exposure of the nucleus pulposus to the outside of the anulus fibrosus induced nerve injury and in growth into the discs. These findings may explain discogenic lower back pain in patients with lumbar disc degeneration.

Activating Transcription Factor 3↗
PubMed2001

Type IIA procollagen in development of the human intervertebral disc: regulated expression of the NH(2)-propeptide by enzymic processing reveals a unique developmental pathway.

Type II collagen can be synthesized in two forms generated by alternative splicing of the precursor mRNA. Type IIA procollagen, which contains a cysteine-rich domain in the NH(2)-propeptide (exon 2), is produced by precartilage and noncartilage epithelial and mesenchymal cells, and type IIB procollagen, without the cysteine-rich domain, is characteristic of chondrocytes. Mice lacking type II collagen fail to develop intervertebral discs. We have previously shown that the human intervertebral disc and notochord synthesize primarily the type IIA form of procollagen. Therefore, we investigated the distribution of type IIA procollagen during early disc development in humans. By processes of radioactive in situ hybridization and fluorescence immunohistochemistry, we localized mRNA and protein of type IIA procollagen, type I collagen, and type III collagen in fetal intervertebral disc specimens ranging from day 42 (embryonic stage 17) to day 101 (week 14.5) of gestation. Antibodies to the three distinct domains of type IIA procollagen: the NH(2)-propeptide, the fibrillar domain, and the COOH-propeptide were used. The earliest stage of developing intervertebral disc (42 days, stage 17) was characterized by diffuse synthesis of types I and III collagens in the dense zone (intervertebral area) and synthesis of type IIA procollagen by the chondrocyte progenitor cells surrounding the disc. The notochord cells synthesized and deposited into the notochordal sheath all three fibrillar collagens. By 54 days (stage 22), the developing disc was clearly divided into three regions: 1.) the outer annulus, characterized by synthesis and deposition of types I and III collagens; 2.) the inner annulus, characterized by synthesis and deposition of type IIA collagen containing the NH(2)-propeptide but devoid of the COOH-propeptide (pN-procollagen); and 3.) the notochord, the cells of which synthesized and deposited of all three fibrillar collagens. In later stages of fetal development (72-101 days), a change in type IIA procollagen processing was observed in the cells of the inner annulus: even though these cells continued to synthesize type IIA procollagen, they deposited into the extracellular matrix (ECM) only the processed fibrillar domain, with the NH(2)-propeptide removed. This finding indicates that there is a developmentally regulated change in the processing of type IIA procollagen NH(2)-propeptide in the cells of the inner annulus. This mechanism is in contrast to previously shown developmental regulation of the cysteine-rich domain of the NH(2)-propeptide by alternative splicing of the precursor mRNA. Although the cells of the inner annulus have been identified as chondrocytes, based on their shape and synthesis of characteristic ECM components, they appear to represent a distinct developmental pathway characterized by their synthesis and differential processing of type IIA procollagen. This developmental pattern may prove important for disc regeneration.

Collagen↗
PubMed1988

Human intervertebral disc: structure and function.

This review begins with a brief introduction in which the development, blood supply and innervation of the intervertebral disc is considered, particularly as these may influence the following sections on structure and function. The three regions within the disc--that is, the nucleus pulposus, annulus fibrosus, and cartilage end plates--are considered in some detail. There appears to be no distinct border between the central nucleus pulposus and the outer annulus fibrosus, the main difference being in their fibrous structure. The fluid space is important in the nutrition of the disc, showing plastic deformation and recovery characteristics. The structural elements, both macroscopically and microscopically, together with the biochemical elements, are intimately related to function. The intervertebral disc should not be though of as a homogeneous and static structure; it has a heterogeneous composition and responds dynamically to applied loads. Neither should it be considered as an isolated structure because it interacts with the vertebral bodies, together constituting the vertebral unit. Furthermore, changes within the disc can, and do, have dramatic effects on vertebral column kinematics. The intervertebral disc is not inactive; it is capable of self-maintenance; in injury it can repair itself and has considerable regenerative properties.

Biomechanical Phenomena↗
PubMed1994

Lumbar intervertebral disc transfer. A canine study.

STUDY DESIGN: Degenerative lumbar disc disease has been implicated as a cause of low back pain. Current treatment options for low back pain involve nonphysiologic fusion of the involved segments and have variable success rates. This is an experimental study of lumbar intervertebral disc transplantation using a canine surgical model. OBJECTIVES: This study evaluated the feasibility of lumbar disc transplantation and its effects on disc metabolism and morphology. METHOD: Eight mature mongrel dogs underwent disc transfer surgeries, in which the L2-L3 and L4-L5 intervertebral discs, with a small segment of adjacent superior and inferior vertebral body, were removed and transposed. The transplanted disc were stabilized by plates or by a flexible cable wire construct using Songer cables (DANEK, Inc., Memphis, TN). Unrestricted activity was allowed postoperatively. At 4 months, the spines were harvested, and the transplanted discs were evaluated biochemically and histologically. Intervening nontransplanted discs served as viable controls and thrice-frozen discs served as nonviable controls. Cell viability was assessed by measuring proteoglycan synthesis and DNA content. RESULTS: Proteoglycan synthesis (35S uptake normalized to DNA content) was maintained in transplanted anulus fibrosus tissue, but was decreased in nucleus pulposus samples (P < 0.05). DNA content was not altered significantly in the transplanted discs. Histologic analysis of the transplanted discs showed revascularization and remodeling of the bone adjacent to the disc and preservation of the lamellar architecture of the anulus fibrosus. The transplanted nucleus pulposus samples had chondrocyte-like cells present, but the staining characteristics of the nucleus material was variable. The contour of the transplanted disc endplates was irregular in all specimens. CONCLUSIONS: The structure and function of autograft intervertebral discs were maintained after disc transfer surgery; the transplant discs, however, were not completely normal in either their morphology or their metabolic functioning.

Animals↗
PubMed2000

Potential applications of gene therapy to the treatment of intervertebral disc disorders.

Gene therapy involves the transfer of genes to cells such that the recipient cells express these genes and thereby synthesize the ribonucleic acid and protein that they encode. Recent investigations suggest that gene therapy may have potential applications in the treatment of intervertebral disc disorders, particularly those associated with disc degeneration. The successful in vivo transfer of therapeutic genes to target cells within the intervertebral disc in clinically relevant animal models is one example of the rapid progress that is being made. The purpose of the current review is to address several important technical issues, including choice of vectors and gene delivery strategy and the characteristics of the target tissues, which are relevant to future clinical applications of gene therapy for the treatment of intervertebral disc disorders. It already is apparent from the growing literature that gene therapy has the potential of becoming a valuable clinical treatment mode for intervertebral disc disorders in the twenty-first century.

Adenoviridae↗
PubMed2002

Expression of chondrocyte markers by cells of normal and degenerate intervertebral discs.

AIMS: To investigate the phenotype of cells in normal and degenerate intervertebral discs by studying the expression of molecules characteristic of chondrocytes in situ. METHODS: Human intervertebral discs taken at surgery were graded histologically, and classified on this basis as normal or degenerate. Eighteen of each type were selected, and in situ hybridisation was performed for the chondrocytic markers Sox9 and collagen II using (35)S labelled cDNA probes. Aggrecan was located by immunohistochemistry, using the monoclonal antibody HAG7E1, and visualised with an avidin-biotin peroxidase system. RESULTS: In the normal discs, strong signals for Sox9 and collagen II mRNA, and strong staining for the aggrecan protein were seen for the cells of the nucleus pulposus (NP), but reactions were weak or absent over the cells of the annulus fibrosus (AF). In degenerate discs, the Sox9 and collagen II mRNA signals remained visible over the cells of the NP and were again absent in the AF. Aggrecan staining was not visible in the NP cells, and was again absent in the AF. CONCLUSIONS: Cells of the normal NP showed expression of all three markers, clearly indicating a chondrocytic phenotype. In degeneration, there was evidence of a loss of aggrecan synthesis, which may contribute to the pathogenesis of disc degeneration. AF cells showed no evidence of a chondrocytic phenotype in either normal or degenerate discs.

Adult↗
PubMed1986

Abnormal connective tissue degrading enzyme patterns in prolapsed intervertebral discs.

The collagenolytic enzyme systems in the human, normal, and prolapsed intervertebral discs have been studied. Normal discs obtained postmortem contained a novel collagenase with specificity toward Type II collagen and gelatin but with little or no activity against Type I collagen. A method whereby enzymes are detected quantitatively in extracts of human tissue using specific substrates, without prior chromatographic separation of the enzymes, has been developed and used to study 14 normal discs and 35 surgically excised prolapsed discs. No differences were observed between annulus and nucleus extracts of normal discs either in the pattern of enzymes or the quantity. The intermediate zone between nucleus and annulus was excised and was not tested. Highly significant differences were observed between the enzyme patterns of the normal and prolapsed discs. The major collagenolytic activity of normal discs is against Type II collagen and 1 alpha 2 alpha 3 alpha collagen, there is little activity toward Type I collagen and virtually none toward elastin. Conversely, the prolapsed disc is more highly active against the substrates elastin and Type I collagen than against Type II collagen or 1 alpha 2 alpha 3 alpha collagen. The individual patterns of enzymes of the 35 prolapsed discs were virtually identical. Similarly there was little internal variation between the patterns of enzymes extracted from discs, obtained postmortem, which were apparently normal. The striking difference between the normal and prolapsed disc could be an important factor in the pathogenesis of disc prolapse.

Chromatography, DEAE-Cellulose↗
PubMed2006

Spatially varying material properties of the rat caudal intervertebral disc.

STUDY DESIGN: The use of a microscopy based material testing technique to assess the local material properties of rat caudal intervertebral discs under uniaxial compression. OBJECTIVES: To better understand the cell environment of rat caudal intervertebral discs during mechanical loading and elucidate better the role of the nucleus pulposus to the overall disc material properties. SUMMARY OF BACKGROUND DATA: Rat tail models of disc degeneration have been widely used for their similarity with the degeneration phenomena in human beings. Degenerative patterns in the disc are often inhomogeneous, however, only average material properties of rodent discs have been studied. Knowledge of the spatially varying properties within the disc is necessary to understand the disc cell milieu during tissue loading. METHODS: Rat caudal motion segments were tested intact, sectioned, and with alterations of nucleus pulposus using microscopy based techniques. Local displacements and strains were obtained using digital image correlation. Strains and load measurements were used to get the average apparent Young's modulus, peak stress, local Young's modulus, and local Poisson's ratio. RESULTS: There was no difference observed in the average apparent Young's modulus among experimental groups. Peak stresses decreased significantly when the nucleus pulposus was replaced with extremely fluid-like materials. The axial displacement field showed 3 distinct linear distributions in samples which were sectioned. The center region in all groups had significantly smaller axial strain and showed a higher local Young's modulus. CONCLUSIONS: The average equilibrium Young's modulus may be dependent on short-range ultrastructural organization. Spatially varying material properties within the intervertebral disc may be caused by orientation of fiber bundles in the different regions of the anulus fibrosus. The fiber bundles are better able to resist compressive loads when oriented parallel rather than perpendicular to the loading direction. At equilibrium, the anulus fibrosus also appears to have a shielding effect independent of the material filling up the nucleus pulposus space.

Animals↗
PubMedDate not supplied

Age-related changes in proteoglycans of human intervertebral discs.

The age-related changes in glycosaminoglycan composition of human intervertebral discs were studied. A large number of tissue samples taken from 301 individuals at autopsy or at operation of prolapsed discs were investigated. It was found that the aging process is accompanied by a progressive decrease in GAGs content, both in annulus fibrosus and in nucleus pulposus. The GAG: collagen ratio significantly decreases. The KS and Ch-6-S were found to be the most abundant GAGs in both parts of the disc and their amounts decrease during the aging. A distinct, age-related increase of KS/Ch-S and Ch-6-S/Ch-4-S ratios was observed. Significant quantitative differences between the GAGs contents in normal and prolapsed discs were found. The nuclei pulposi of prolapsed discs contained less GAGs, especially KS and Ch-6-S, in comparison to normal tissue of the same age. Also, the age-related decline of GAGs: collagen ratio is more distinct in prolapsed discs. It seems that these differences in GAGs composition may be important in the mechanism of predisposition to disc prolapse.

Adolescent↗