Human Disc Degeneration Research Articles

In vivo remodeling of intervertebral discs in response to short- and long-term dynamic compression.

This study evaluated how dynamic compression induced changes in gene expression, tissue composition, and structural properties of the intervertebral disc using a rat tail model. We hypothesized that daily exposure to dynamic compression for short durations would result in anabolic remodeling with increased matrix protein expression and proteoglycan content, and that increased daily load exposure time and experiment duration would retain these changes but also accumulate changes representative of mild degeneration. Sprague-Dawley rats (n = 100) were instrumented with an Ilizarov-type device and divided into three dynamic compression (2 week-1.5 h/day, 2 week-8 h/day, 8 week-8 h/day at 1 MPa and 1 Hz) and two sham (2 week, 8 week) groups. Dynamic compression resulted in anabolic remodeling with increased matrix mRNA expression, minimal changes in catabolic genes or disc structure and stiffness, and increased glysosaminoglycans (GAG) content in the nucleus pulposus. Some accumulation of mild degeneration with 8 week-8 h included loss of annulus fibrosus GAG and disc height although 8-week shams also had loss of disc height, water content, and minor structural alterations. We conclude that dynamic compression is consistent with a notion of "healthy" loading that is able to maintain or promote matrix biosynthesis without substantially disrupting disc structural integrity. A slow accumulation of changes similar to human disc degeneration occurred when dynamic compression was applied for excessive durations, but this degenerative shift was mild when compared to static compression, bending, or other interventions that create greater structural disruption.

The roles of apoptosis and proliferation in human cervical disc degeneration

Objective To detect the cell densities,apoptosis rate as well as the expression of PCNA,bax and Caspase-3 in human cervical discs,and analyze their relationships to study the roles that apoptosis and proliferation play in the development of human cervical disc degeneration and the signal transduction pathway of disc cells' apoptosis.Methods Thirty-three herniated human cervical discs were surgically collected from 27 patients undergoing anterior cervical discoidectomy and fusion.The control group consisted of 21 human cervical discs harvested from 6 young men without spine.related eonditiorib immediately after their deaths.Apoptotic disc cells were detected by TUNEL and histomorphology and immunohistoehemical staining was performed to examine the expression of PCNA.bax and Capase-3 in all specimcns.Results The cell densities in experimental group were less than those in control group(In nucleus pulposus:6.30±1.54 vs 8.96±1.14;In cartilaginous end plate:17.27±1.82 vs 25.41±1.89).The number of TUNEL-positive cells in experimental group was more than that in control grouP(In nucleus pulposus:11.73±1.36 vs 7.02±1.26;In cartilaginous end plate:13.04±1.75 vs 6.86±1.42).The number of PCNA positive cells in nucleus pulposus in experimental group was more than that in control group(8.38±1.98 vs 4.55±1.54).The number of cells positive for bax-and Caspase-3 in nucleus pulposus in experimental group was more than t11at in control group(For bax:19.32±1.95 vs 10.94±1.72:For Caspase-3:15.05±1.74 vs 8.92 4-1.48).The number of TUNEL-positive cell8 showed a significandy inverse eorrelation with cell densities(P＜0.01).In nucleus pulposus of experimental group,the number of PCNA-positive cells showed a significant positive correlation with cell densities(P＜0.01).The numher of cells positive for bax-and Caspase-3-showed significant positive correlations with that of TUNEL-positive cells(P＜0.01).Condusion The imbalance between apoptosis and proliferation could contribute to the decrease of cell density in degenerative human cervical disc.The upregulation of expression of bax and Caspase-3 miSht play a role in disc cells' apoptosis in nucleus pulposus of human cervical discs. Key words: Cervical spine; Disc degeneration; Apeptosis:Proliferation

Molecular Changes in the Degenerated Goat Intervertebral Disc

Caprine lumbar intervertebral discs (IVD) were collected from previous studies and categorized as normal, mildly, or severely degenerated. The biochemical composition and the RNA profiles present in both the nucleus pulposus (NP) and the anulus fibrosus (AF) were analyzed. To determine the molecular changes occurring in a disc degeneration model, evaluating the mechanism through which the degeneration develops in this model. Recently we described an IVD degeneration model in the goat by injecting chondroitinase ABC. This results in mild progressive disc degeneration. One hundred nine caprine IVDs were assigned to 3 classes: no degeneration, mild, or severe degeneration. Collagen content, collagen cross-links (hydroxylysyl pyridinoline) and the ratio between the glycosaminoglycans (GAGs) and hydroxyprolines (Hyp) (GAG/Hyp ratio) in the NP and AF samples were studied. Furthermore, the gene expression of collagen type I, type II, and aggrecan as well as a desintegrin and metalloproteinase with thrombospondin motifs (ADAMTIS)-2, ADAMTS-14, and matrix metalloproteinases-13 were studied. Collagen content was increased in severely degenerated NPs and decreased in severely degenerated AFs. Collagen cross-links were decreased in the severely degenerated NPs indicating de novo deposition of immature, reducible cross-linked collagens. The GAG/Hyp ratio found in none-degenerate goat discs was comparable to human ratios and decreased in degenerated discs, similar as in humans. The ADAMTS genes were increasingly detectable in the degenerated discs. The matrix metalloproteinases-13 gene increased significantly in degenerated discs. The expression of collagen type I increased in degenerated discs while aggrecan decreased. Changes in the GAG/Hyp ratio of chemically induced degeneration in goat IVD resemble the changes seen in humans. Gene expression profiles match the pattern of degeneration, suggesting that the injection of chondroitinase ABC might mimic the onset of human disc degeneration.

Collagen Turnover in Normal and Degenerate Human Intervertebral Discs as Determined by the Racemization of Aspartic Acid

Knowledge of rates of protein turnover is important for a quantitative understanding of tissue synthesis and catabolism. In this work, we have used the racemization of aspartic acid as a marker for the turnover of collagen obtained from healthy and pathological human intervertebral disc matrices. We measured the ratio of the d- and l-isomers in collagen extracted from these tissues as a function of age between 16 and 77 years. For collagen taken from healthy discs, the fractional increase of d-Asp was found to be 6.74 x 10(-4)/year; for degenerate discs, the corresponding rate was 5.18 x 10(-4)/year. Using the racemization rate found previously for the stable population of collagen molecules in dentin, we found that the rate of collagen turnover (k(T)) in discs is not constant but rather a decreasing function of age. The average turnover rate in normal disc between the ages of 20 and 40 is 0.00728 +/- 0.00275/year, and that between the ages of 50 and 80 is 0.00323 +/- 0.000947/year, which correspond to average half-lives of 95 and 215 years, respectively. Turnover of collagen from degenerate discs may be more rapid than that found for normal discs; however, statistical analysis leaves this point uncertain. The finding of a similar correlation between the accumulation of d-Asp and that of pentosidine for three normal collagenous tissues further supports the idea that the accumulation of pentosidine in a particular tissue can, along with the racemization of aspartic acid, be used as a reliable measure of protein turnover.

Human cells derived from degenerate intervertebral discs respond differently to those derived from non-degenerate intervertebral discs following application of dynamic hydrostatic pressure

The intervertebral disc (IVD) is one of the body's most important load-bearing structures with the major mechanical force experienced in the nucleus pulposus (NP) being hydrostatic pressure (HP). Physiological levels of HP have an anabolic effect on IVD matrix metabolism in cells derived from non-degenerate animal and herniated IVD while excessive HP has a catabolic effect. However, no studies have investigated the response of non-degenerate and degenerate human disc cells derived from non-herniated discs to HP. Here we investigate the effect of physiological HP on such cells using a novel loading rig. Human IVD cells (both NP and AF) cultured in alginate were subjected to dynamic HP (0.8-1.7 MPa 0.5 Hz) for 2 h. Cell viability was assessed, RNA extracted and qRT-PCR for 18 s, c-fos, Sox-9, collagen type II, aggrecan and MMP-3 performed. Cell viability was unaffected by the loading regime. In non-degenerate NP cells, HP increased c-fos, aggrecan, Sox-9 and collagen type II (significantly so in the case of c-fos and aggrecan), but not MMP-3 gene expression. In contrast, application of HP to AF or degenerate NP cells had no effect on target gene expression. Our data shows that cells obtained from the healthy NP respond to dynamic HP by up-regulating genes indicative of healthy matrix homeostasis. However, responses differed in degenerate NP cells suggesting that an altered mechanotransduction pathway may be operational.

Senescence of Nucleus Pulposus Chondrocytes in Human Intervertebral Discs

Study DesignSenescence-related markers were assessed in surgically obtained human nucleus pulposus (NP) specimens.PurposeTo demonstrate the mechanism and signaling pathway involved in the senescence of NP chondrocytes.Overview of LiteratureThe population of senescent disc cells has been shown to be increased in degenerated or herniated discs. However, the mechanism and signaling pathway involved in the senescence of NP chondrocytes are unknown.MethodsWe examined cell senescence markers [senescence-associated β-galactosidase (SA-β-gal), telomere length, telomerase activity, p53, p21, pRB and p16] and the hydrogen peroxide (H2O2) content in human NP specimens.ResultsThe percentage of SA-β-gal-positive NP chondrocytes increased with age, while the telomere length and telomerase activity declined. However, there was no significant correlation between age and H2O2 content. The NP specimens with grade III or IV degeneration showed significantly higher percentages of SA-β-gal-positive NP chondrocytes than those with grade II degeneration. Immunohistochemistry showed that senescent NP chondrocytes in all specimens expressed p53, p21, and pRB, while a few NP chondrocytes in only two specimens expressed p16.ConclusionsThe present study demonstrates that, with increasing age and advancing disc degeneration, senescent NP chondrocytes increase or accumulate in the NP. Furthermore, the telomere-based p53, p21, pRB pathway, rather than the stress-based p16, pRB pathway, plays a more important role in the senescence of NP chondrocytes in in vivo conditions. Our results suggest that prevention or reversal of senescence of NP chondrocytes can be a novel mechanism by which to prevent human disc degeneration.

Early‐onset degeneration of the intervertebral disc and vertebral end plate in mice deficient in type IX collagen

Type IX collagen is an important component of the intervertebral disc extracellular matrix. Mutations in type IX collagen are associated with premature disc degeneration in mice and a predisposition to disc disorders in humans. The aim of this study was to assess the prevalence and timeline of intervertebral disc degeneration in mice homozygous for an inactivated Col9a1 gene. Intact spine segments were harvested from wild-type (WT) and type IX collagen-knockout (Col9a1(-/-)) mice at 3, 6, and 12 months of age. Sagittal spine sections were evaluated for evidence of histologic changes, by 2 blinded graders, using a semiquantitative grading method. There was evidence of more degeneration of the disc and end plate in the spines of Col9a1(-/-) mice compared with those of WT controls, at most time points. These findings were significant for the disc region at 3 and 6 months (P<0.01) and at 12 months (P<0.10) and for the end plate region only at 6 months (P<0.10). Degenerative changes in the disc consisted of cellular changes and mucous degeneration. Degeneration in the end plates was associated with more cell proliferation, cartilage disorganization, and new bone formation. A deletion mutation for type IX collagen is associated with connective tissue changes characteristic of musculoskeletal degeneration in bony and cartilaginous tissue regions. Some of the observed changes were similar to cartilage changes in osteoarthritis, while others were more similar to disc degenerative changes in humans. The finding of premature onset of intervertebral disc degeneration in this mouse model may be useful in studies of the pathology and treatment of human disc degeneration.

Evidence for Skeletal Progenitor Cells in the Degenerate Human Intervertebral Disc

To identify and characterize endogenous progenitor cell population from intervertebral disc. To determine if progenitor cells exist in degenerate human discs. Back pain, a significant source of morbidity in our society, is directly linked to the pathology of the intervertebral disc. Because disc disease is accompanied by a loss of cellularity, there is considerable interest in regeneration of cells of both the anulus fibrosus (AF) and nucleus pulposus (NP). To determine if skeletal progenitor cells are present in the disc, samples were obtained from the degenerate AF and NP of 5 patients (Thompson grade 2 and 3, mean age 34 +/- 7.6 years) undergoing anterior cervical discectomy and fusion procedures as well as adult rat lumbar spine. Cells isolated from degenerate human tissues expressed CD105, CD166, CD63, CD49a, CD90, CD73, p75 low affinity nerve growth factor receptor, and CD133/1, proteins that are characteristic of marrow mesenchymal stem cells. In osteogenic media, there was an induction of alkaline phosphatase activity and expression of alkaline phosphatase, osteocalcin, and Runx-2 mRNA. When maintained in adipogenic media, a small percentage of cells displayed evidence of adipogenic differentiation: accumulation of cytosolic lipid droplets and increased expression of peroxisome proliferator-activated receptor-gamma2 and lipoprotein lipase mRNA. AF- and NP-derived cells also evidenced chondrogenic differentiation. CD133 (+) cells in the AF were able to commit to either the chondrogenic or adipogenic lineages. The results of the human disc studies were confirmed using cell derived from the NP and AF tissue of the mature rat disc. The analytical data indicated that the pathologically degenerate human disc contained populations of skeletal progenitor cells. These findings suggest that these endogenous progenitors may be used to orchestrate the repair of the intervertebral disc.

The cell biology of intervertebral disc aging and degeneration

Intervertebral disc degeneration, which mimics disc aging but occurs at an accelerated rate, is considered to be related to neck or low back pain and disc herniation. Degenerated discs show breakdown of the extracellular matrix and thus fail to bear the daily loadings exerted on the spine. Rather than a passive process of wear and tear, disc degeneration is an aberrant, cell-mediated response to progressive structural failure due to aging and other environmental factors such as abnormal mechanical stress. With aging and degeneration, disc cells undergo substantially biologic changes, including alternation of cell type in the nucleus pulposus, increased cell density but decreased number of viable cells as a result of increased cell death and increased cell proliferation, increased cell senescence, and altered cell phenotype which is characterized by compromised capability of synthesizing correct matrix components and by enhanced catabolic metabolism. These changes are involved in the process of disc degeneration through the complicated interactions among them. To retard or reverse disc degeneration, the abnormal conditions of the decreased viable cell population and the altered cell phenotype should be corrected. As potential therapies for disc degeneration, intradiscal protein injection, gene transfer and cell implantation are being understudied in vivo. Suppression of excessive apoptosis and accelerated senescence of disc cells may be other choices for treating disc degeneration. When performing a biologic therapy in order to repair or regenerate the degenerated disc, nutrient and biomechanical factors should also be incorporated, because they are the major causes of the biologic changes experienced by disc cells. Moreover, a very early intervention is indicated by the finding that the onset of human disc degeneration occurs as early as by adolescence.

Are animal models useful for studying human disc disorders/degeneration?

Intervertebral disc (IVD) degeneration is an often investigated pathophysiological condition because of its implication in causing low back pain. As human material for such studies is difficult to obtain because of ethical and government regulatory restriction, animal tissue, organs and in vivo models have often been used for this purpose. However, there are many differences in cell population, tissue composition, disc and spine anatomy, development, physiology and mechanical properties, between animal species and human. Both naturally occurring and induced degenerative changes may differ significantly from those seen in humans. This paper reviews the many animal models developed for the study of IVD degeneration aetiopathogenesis and treatments thereof. In particular, the limitations and relevance of these models to the human condition are examined, and some general consensus guidelines are presented. Although animal models are invaluable to increase our understanding of disc biology, because of the differences between species, care must be taken when used to study human disc degeneration and much more effort is needed to facilitate research on human disc material.

A New In Vivo Animal Model to Create Intervertebral Disc Degeneration Characterized by MRI, Radiography, CT/Discogram, Biochemistry, and Histology

A new in vivo sheep model was developed that produced disc degeneration through the injection of 5-bromodeoxyuridine (BrdU) into the intervertebral disc. This process was studied using magnetic resonance imaging (MRI), radiography, CT/discogram, histology, and biochemistry. To develop a sheep model of intervertebral disc degeneration that more faithfully mimics the pathologic hallmarks of human intervertebral disc degeneration. Recent studies have shown age-related alterations in proteoglycan structure and organization in human intervertebral discs. An animal model that involves the use of age-related changes in disc cells can be beneficial over other more invasive degenerative models that involves directly damaging the matrix of disc tissue. Twelve sheep were injected with BrdU or vehicle (phosphate-buffered saline) into the central region of separate lumbar discs. Intact discs were used as controls. At the 2-, 6-, 10-, and 14-week time points, discs underwent MRI, radiography, histology, and biochemical analyses. A CT/discogram study was performed at the 14-week time point. MRI demonstrated a progressive loss of T2-weighted signal intensity at BrdU-injected discs over the 14-week study period. Radiograph findings included osteophyte and disc space narrowing formed by 10 weeks post-BrdU treatment. CT discography demonstrated internal disc disruption in several BrdU-treated discs at the 14-week time point. Histology showed a progressive loss of the normal architecture and cell density of discs from the 2-week time point to the 14-week time point. A progressive loss of cell proliferation capacity, water content, and proteoglycans was also documented. BrdU injection into the central region of sheep discs resulted in degeneration of intervertebral discs. This progressive, degenerative process was confirmed using MRI, histology, and by observing changes in biochemistry. Degeneration occurred in a manner that was similar to that observed in human disc degeneration.

Interaction of Human Mesenchymal Stem Cells With Disc Cells

To evaluate the in vitro interactions between human mesenchymal stem cells (MSCs) and degenerative disc cells. To demonstrate the potential of MSCs in regulating the extracellular matrix synthesis of degenerative disc cells. Culture of degenerative disc cells followed by their reinsertion into a disc can retard the degeneration process in an animal model. However, harvesting cells without accelerating degeneration is problematic. Autologous MSCs can be safely harvested from the bone marrow and transplanted into degenerative discs. Human degenerative nucleus pulposus (NP), anulus fibrosus (AF) cells, and MSCs were cultured as pellets, and coculture pellets were formed by addition of MSCs to disc cells (50:50 ratio). Glycosaminoglycan (GAG) and DNA content were measured. Proteoglycan synthesis was analyzed by RT-PCR and western blot. Type II collagen expression was assessed by immunohistochemistry. Coculture pellets formed by the addition of MSCs to AF cells were superior in size to all other pellets. AF/MSC pellets showed higher experimental GAG content than the predicted values represented by the sum of individual control pellets, with 10.2 versus 5.6 microg/pellet at week 3, respectively. The effect was not observed in the NP/MSC coculture, or when chondrogenic medium was used. Close contact between cells was necessary to obtain this enhancement of GAG content. Proteoglycan and collagen expression in both individual and coculture pellets was confirmed by PCR analysis and western blot. Addition of MSCs to AF cells resulted in an up-regulation of the proteoglycans synthesis. This study provides the rationale for further investigation of the potential of MSC therapy in treating intervertebral disc degeneration.

Assessment of Human Disc Degeneration and Proteoglycan Content Using T1ρ-weighted Magnetic Resonance Imaging

T1rho relaxation was quantified and correlated with intervertebral disc degeneration and proteoglycan content in cadaveric human lumbar spine tissue. To show the use of T1rho-weighted magnetic resonance imaging (MRI) for the assessment of degeneration and proteoglycan content in the human intervertebral disc. Loss of proteoglycan in the nucleus pulposus occurs during early degeneration. Conventional MRI techniques cannot detect these early changes in the extracellular matrix content of the disc. T1rho MRI is sensitive to changes in proteoglycan content of articular cartilage and may, therefore, be sensitive to proteoglycan content in the intervertebral disc. Intact human cadaveric lumbar spines were imaged on a clinical MR scanner. Average T1rho in the nucleus pulposus was calculated from quantitative T1rho maps. After MRI, the spines were dissected, and proteoglycan content of the nucleus pulposus was measured. Finally, the stage of degeneration was graded using conventional T2 images. T1rho decreased linearly with increasing degeneration (r = -0.76, P < 0.01) and age (r = -0.76, P < 0.01). Biochemical analysis revealed a strong linear correlation between T1rho and sulfated-glycosaminoglycan content. T1rho was moderately correlated with water content. Results from this study suggest that T1rho may provide a tool for the diagnosis of early degenerative changes in the disc. T1rho-weighted MRI is a noninvasive technique that may provide higher dynamic range than T2 and does not require a high static field or exogenous contrast agents.

Human disc degeneration is associated with increased MMP 7 expression

During intervertebral disc (IVD) degeneration, normal matrix synthesis decreases and degradation of disc matrix increases. A number of proteases that are increased during disc degeneration are thought to be involved in its pathogenesis. Matrix metalloproteinase 7 (MMP 7) (Matrilysin, PUMP-1) is known to cleave the major matrix molecules found within the IVD, i.e., the proteoglycan aggrecan and collagen type II. To date, however, it is not known how its expression changes with degeneration or its exact location. We investigated the localization of MMP 7 in human, histologically graded, nondegenerate, degenerated and prolapsed discs to ascertain whether MMP 7 is up-regulated during disc degeneration. Samples of human IVD tissue were fixed in neutral buffered formalin, embedded in paraffin, and sections stained with hematoxylin and eosin to score the degree of morphological degeneration. Immunohistochemistry was performed to localize MMP 7 in 41 human IVDs with varying degrees of degeneration. We found that the chondrocyte-like cells of the nucleus pulposus and inner annulus fibrosus were MMP 7 immunopositive; little immunopositivity was observed in the outer annulus. Nondegenerate discs showed few immunopositive cells. A significant increase in the proportion of MMP 7 immunopositive cells was seen in the nucleus pulposus of discs classified as showing intermediate levels of degeneration and a further increase was seen in discs with severe degeneration. Prolapsed discs showed more MMP 7 immunopositive cells compared to nondegenerated discs, but fewer than those seen in cases of severe degeneration.

Human Anulus Fibrosis and Nucleus Pulposus Cells of the Intervertebral Disc

Human intervertebral disc cells were harvested from patients with adolescent idiopathic scoliosis (AIS) and from donors with degenerative disc disease. Anulus fibrosis (AF) was separated from nucleus pulposus (NP), and cells were cultured separately in two different cell culture models. To investigate changes in gene expression of human disc cells during in vitro expansion and to determine whether cells from adolescent idiopathic scoliosis donors show different gene expression profiles compared with cells from patients operated for degenerative disc disease. During in vitro expansion, cells undergo a dedifferentiation process, which is characterized by a switch in gene expression. Markers for the differentiation and dedifferentiation status of human disc cells are not yet known. Moreover, it is not known whether changes in the gene expression pattern occur during the degeneration process. Cells from AF and NP tissues were expanded in monolayer and alginate cultures under controlled and defined conditions. Cells were then harvested, and analysis of phenotype was performed using quantitative real-time polymerase chain reaction (PCR). The mRNA expression of Type I, II, and X collagen, aggrecan, and interleukin-1beta in scoliosis and degenerative human intervertebral disc cells was analyzed. The gene expression of Type II and X collagen and of aggrecan significantly decreased for both cell types during monolayer expansion. Reexpression of all genes was observed when cells were cultured in alginate. Additionally, NP cells from degenerative tissues displayed significant lower levels of Type II collagen compared with NP cells from scoliosis donors. These results provide a better understanding of how the phenotype of human healthy and degenerative disc cells is influenced by in vitro expansion. This may be useful for future tissue engineering purposes.

Correlation of HR-MAS Spectroscopy Derived Metabolite Concentrations With Collagen and Proteoglycan Levels and Thompson Grade in the Degenerative Disc

A quantitative high-resolution magic angle spinning (HR-MAS) NMR study of human lumbar discs was conducted to determine biomarkers of disc degeneration. To correlate HR-MAS quantification of compounds relevant to human lumbar disc degeneration to conventional methods of disc grading such as Thompson grading and biochemical analysis. It has been shown that there is poor correlation between MRI and CT morphologic findings, spinal biomechanics, and patient symptoms in degenerative disc disease and low back pain. There is a need for an objective, quantitative measurement of biochemical status, morphology, and function. A total of 17 cadaveric human lumbar intervertebral discs were harvested from patients ranging from 20 to 85 years of age. Quantitative HR-MAS data were acquired, and proteoglycan and collagen biochemical analyses were conducted on 3-mm biopsy punches taken from the anulus fibrosus and nucleus pulposus of each sample. HR-MAS data were fitted and analyzed for hydroxyproline (3.42 ppm), glycine (3.56 ppm), and the N-acetyl peak (2.04 ppm) associated with proteoglycans in comparison with an internal standard. These concentrations were then compared directly to biochemical analyses and Thompson grade. HR-MAS data correlated well with Thompson grade (P < 0.001). An increase was seen in the levels of unbound hydroxyproline and glycine in annular tissue, which is directly associated to collagen breakdown. This trend also correlates with the changes of total collagen measured by a collagen biochemical assay. HR-MAS also detected a decrease in concentration of nucleus pulposus proteoglycans with degeneration. This proteoglycan decrease was verified by a standard proteoglycan biochemical assay. Changes in disc chemical composition can be accurately quantified using quantitative HR-MAS NMR spectroscopy ex vivo. This noninvasive method of qualitatively and quantitatively assessing disc degeneration supports the utility of these biomarkers and underlines the need for developing in vivo magnetic resonance spectroscopic imaging (MRSI) for characterizing intervertebral disc degeneration.

Animal models for human disc degeneration

Despite the significant impairment associated with degenerative disc disease, a clear understanding of its pathogenesis is still lacking. Currently, no particular model parallels the complex nature of human disc degeneration. Naturally occurring animal models have the drawback that the basis for the high rate of disc degeneration is not known. Although the interventions in artificial animal models that create disc degeneration are known, the relationship of those to the events leading to disc degeneration in humans is not. With the recent progress in biomechanics, cell biology and molecular biology, an easily reproducible and valid animal model may help unlock the complex cascade of events surrounding human disc degeneration.

Cell-based therapy for disc repair

Background context One of the most promising therapies for symptomatic disc degeneration involves the implantation of therapeutic cells into the degenerative disc. Purpose In this article, the rationale and approaches for cell-based tissue engineering of the intervertebral disc are discussed. Study design The scientific literature related to cell-based tissue engineering of the intervertebral disc is reviewed. Methods A variety of cell types have been used in various research models to affect matrix repair of the intervertebral disc. The use of cellular scaffolds and growth factors or genes also appears promising for achieving meaningful tissue repair of the intervertebral disc. Results Disc tissue engineering is a promising approach for achieving repair of the intervertebral disc. Using cell-based approaches, various research models suggest that improvements in the complex matrix of the disc may be achieved. Conclusion A cell-based approach to repair of the intervertebral disc appears promising. More research is needed to define the optimal cell type, cellular scaffold and mixture of growth factors that may allow meaningful repair of the human symptomatic degenerative disc.

Summary Statement

The problems of neurologic injury, disc degeneration, and spinal pain are germane to all physicians who manage spinal deformities. In accordance with this Focus Issue’s theme of “Innovative Treatment Options for Spinal Deformity,” the prior four papers describe novel technologies that encompass biologic, biomechanical, and biophysical approaches. In the area of spinal cord injury, several experimental approaches have shown promise for promoting neurologic recovery in animal models and are emerging as potential therapies ready for human clinical trials. The urgency with which an effective treatment for these devastating injuries are needed, however, should not circumvent the requirement for all potential therapies to undergo rigorous safety and efficacy evaluation in well-designed, controlled clinical trials before their acceptance as a valid treatment in humans. Intervertebral disc matrix degradation and cellular loss are integral to the process of disc degeneration. In recent years, a variety of biologic strategies have been suggested to repair the degenerative disc. The current data suggest that a variety of cell types have the ability to survive transplantation to the disc and produce matrix proteins for at least short periods of time in animal models. At present, it remains unclear whether a cellular approach is capable of producing meaningful, long-term disc repair in humans. A significant hurdle in this line of research is the lack of understanding of the specific etiology of spinal pain, and the elusive correlation between pain and the histologic and morphologic signs of disc degeneration. Substantial future research is required to determine the efficacy of a cellular approach to disc repair and ultimately the effect of such a strategy on symptomatic disc degeneration in humans. Biophysical methods such as heat and ultrasound have been studied for the treatment of spinal pain, although the mechanisms of action and the underlying short- and long-term efficacy of biophysical methods remain undefined. Cryotherapy, which is at a very preliminary stage of investigation, represents a potential, novel approach treatment for spinal pain. Substantial research will be required to characterize the safety and biologic effects of cryotherapy before consideration of clinical trials. Within this section, cervical disc replacement is the farthest along the path to clinical adoption with several FDA IDE trials in progress across North America. Despite the current enthusiasm for motion preservation in the spine, it is not yet clear whether cervical disc replacement will produce a true clinical benefit when compared with cervical fusion. It is worth remembering that anterior cervical decompression and fusion has traditionally been considered one of the most successful of spine surgeries. New complications related to cervical disc replacement are likely to occur, and the longevity of the implant and consequences of wear debris are unknown.

6:06 189. Relationship between annular puncture and disc degeneration following incorrect radiographic marker placement during anterior cervical discectomy and fusion

BACKGROUND CONTEXT: Annular puncture in animal studies reliably produces progressive intervertebral disc degeneration that has been utilized as a model for studying the same disease process in humans. Placement of a spinal needle through the anterior annulus into the disc space is common practice for radiographic identification of the correct disc space during anterior cervical spine procedures. Needle placement at a level that is not incorporated into the planned surgery occurs frequently, but no study has systematically examined the effect of such annular violation in terms of risk for subsequent development of disc degeneration in humans.