|Year : 2015 | Volume
| Issue : 1 | Page : 5-15
Novel treatment strategies for intervertebral disc degeneration
Moattar Raza Rizvi
Department of Nursing, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia
|Date of Web Publication||13-Feb-2015|
Moattar Raza Rizvi
Department of Nursing, College of Applied Medical Sciences, Majmaah University, Majmaah
Source of Support: None, Conflict of Interest: None
Intervertebral disc degenerative (IVDD) is a common orthopaedic condition characterized by a series of cellular, biochemical, structural and functional changes that imparts a large socioeconomic impact on healthcare system. Progressive loss of normal extracellular matrix constituents, namely proteoglycans and water content, is thought to be a key contributor to IVDD. The ability to sustain or augment normal matrix composition may slow down or reverse disc degeneration. Traditional concepts for treatment of lumbar disc degeneration have aimed at symptomatic relief by limiting motion in the lumbar spine, but novel treatment strategies involving direct injection of active substance, stem cells, growth factors and gene therapy have been attracting more attention in respect to prevent, slow or even reverse disc degeneration. Understanding the pathophysiological basis of disc degeneration will lay the foundation for the emergence of exciting new regenerative or reparative biological treatments for this debilitating condition either by inducing disc regeneration or replacing the degenerated disc.
Keywords: Annulus fibrosus, gene therapy, intervertebral disc degeneration, mesenchymal stem cells, nucleus pulposus, spinal fusion surgery
|How to cite this article:|
Rizvi MR. Novel treatment strategies for intervertebral disc degeneration. Saudi J Health Sci 2015;4:5-15
| Introduction|| |
Low back pain (LBP) is a significant cause of morbidity and disability. It is one of the most frequent reasons for clinic visits and surgical treatments, which leads to individual suffering and results in loss of work, time, billions of dollars in treatment expenditure as well as wage compensation every year.  About 80% of the adult population would be subjected to neck or back pain at some points in their lives affecting the quality of life and resulting in serious socioeconomic consequences. ,
LBP is qualified as chronic if the symptoms persist for more than 3 months; in approximately 10-20% of the patients with low back pain, the condition becomes chronic. ,, In 85% of the patients with chronic low back pain, the specific cause of the pain cannot be found.  Although LBP is complex in etiology, histological and magnetic resonance imaging (MRI) data have suggested a chronic LBP is associated with lumber intervertebral disc degeneration, which can develop as early as the second decade of life.  The disease is of widespread prevalence. The main cause of low back pain is intervertebral disc degeneration (IVDD).  Disc degeneration, although in many cases asymptomatic is also associated with sciatica, disc herniation, spinal canal stenosis, spondylolysthesis and degenerative scoliosis. , IVDD is a process which is histologically and radiologically characterized by a loss of disc height, subchondral sclerosis of the endplate, formation of osteophyte and radial bulging.  The incidence is rising exponentially with current demographic changes and an increased aged population.
Preventive measures and surgical treatments of spinal degenerative diseases in the late stage is at huge cost and result in suboptimal clinical outcomes in many situation , musculoskeletal tissues. About 20% of people in their teens have discs with mild signs of degeneration; degeneration increases steeply with age, particularly in males, so that around 10% of 50-year-old discs and 60% of 70-year-old discs are severely degenerated.  Thus, early intervention to prevent the progression of IVDD, or regenerate the degenerative disc is of great necessity.
Strategies for stopping or reversing disc degeneration in the lumbar spine range from mechanical treatment options that rely on the traditional concept of removing the pain generator, the disc, and eliminating pain by stopping motion to more recently emerging and developing treatment options involving gene therapy, growth factors and cell transplantations. The traditional approach of motion-eliminating fusion surgery, which may be effective for the treatment of pain in some cases, may also increase the rate of degeneration at adjacent spinal motion segments. Furthermore, this strategy does not halt the progression of the degenerative cascade of events that leads to pain and disability. So despite its undeniable significance, lumbar fusion surgery as a treatment of LBP has to be regarded suboptimal, as it targets the symptom of pain rather than its causes. 
Although an important public health issue, the pathogenesis of LBP is poorly understood. Only in the last 10-15 years, there exists mechanisms underlying human intervertebral disc (IVD) degeneration been studied in any detail, but the arrival of molecular pathology and similar techniques for examining disease mechanisms in human tissue (e.g. immunohistochemistry,  in situ zymography,  in situ hybridization  and quantitative image analysis  and the advent of biotherapeutics  stem cell therapy  and tissue engineering  have brought both methods for and reasons to investigate IVD degeneration. In this short review, we outline the novel treatment strategies for intervertebral disc degeneration. However, the pathogenesis of IVDD has not been elucidated clearly, although it is acknowledged that programmed cell death (PCD) of IVD cells plays an essential role in this process.  Numerous studies indicate that a variety of cellular events are disturbed in the progression of IVDD, ranging from matrix synthesis to cytokine expression [Figure 1]. 
|Figure 1: Changes involved in degeneration of the intervertebral disc at biochemical and molecular level. TNF-α tumor necrosis factor α; TGF: Transforming growth factor; MMPs: Matrix metalloproteinases; ADAMTs; a disintegrin and metalloproteinases; TIMPs: tissue inhibitor of metalloproteinases|
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Intervertebral discs, also known as intervertebral fibrocartilage or spinal discs, are the padding between each vertebra of the spine. They have an elastic structure, made of fibrocartilage tissue. The intervertebral disc has a complex structure with the nucleus pulposus (NP, soft and gelatinous) encapsulated by endplates and the annulus fibrosus (tough and fibrous, and is composed of several overlapping layers.  NP extracellular matrix (ECM) consists mainly of loosely assembled collagen type II fibres and proteoglycan (mostly aggrecan and versican) in a ratio of 1:20. Aggrecan is highly hydrophilic, which enable the NP to retain water, thereby cushioning and absorbing the considerable loads placed on the vertebral bodies. Imbalanced metabolism of Nucleus pulposus extracellular matrix is closely correlated to IVDD disease.  In a healthy young adult the intervertebral discs consist of about 90% water. As we age, the water content goes down, the padding becomes less thick and the spine becomes slightly shorter as a result. Sometimes the disc might bulge. 
Pathogenesis of intervertebral disc degeneration
With advancing age comes pronounced changes in the composition of the disc ECM. , Decreasing aggrecan content in the NP leads to reduced hydration,  leading in turn to impaired mechanical function. , A less hydrated, more fibrous NP is unable to evenly distribute compressive forces between the vertebral bodies. The forces are instead transferred non-uniformly to the surrounding AF,  which can result in altered AF mechanical properties , and progressive structural deterioration, including the formation of circumferential and radial tears.  On occasion, radial tears can progress to a posterior radial bulge or herniation of NP material,  resulting in painful symptoms. Decreased disc height is also commonly associated with advanced disc degeneration  and results in painful compression of surrounding structures. Multiple interdependent factors, including altered mechanical loading,  reduced nutrient supply  and hereditary factors, have been implicated in the initiation and progression of the degenerative cascade. Changes to disc extracellular matrix composition with age are attributable to alterations in function and increased death of the cells that make up the disc.  The cellular microenvironment of the disc becomes progressively more hostile, and is characterized by upregulated levels of proinflammatory cytokines and associated catabolic enzymes.  This is in part due to a reduction in the diffusion of nutrients through the endplates that accompanies thinning and calcification; the reasons for these endplate changes are not well-understood. , Mechanical loading might also play a direct role in the progression of disc degeneration. Cell survival and matrix synthesis are both sensitive to compressive stress.  Although some mechanical stimulation is necessary to induce nutrient diffusion and to promote matrix synthesis, excessive loading can result in localized tissue injury that is slow to repair and alters strain distribution throughout the extracellular matrix of the entire disc.  Finally, hereditary factors also play a role in an individual's susceptibility to disc degeneration.  Twin studies suggest that genetics predispose individuals to disc degeneration.  Population studies for candidate genes and genome-wide assays are advancing this idea, although the fact that disc degeneration is a multi-factorial process and because large sample sizes are needed for such studies, genetic analyses have been challenging.  Additionally, undertaking gene analyses [polymerase chain reaction (PCR), or microarray] for thousands of individuals becomes prohibitively expensive.
| Changes associated with intervertebral disc degeneration|| |
Macroscopic and microscopic changes
Obvious macroscopic and microscopic changes happen in IVDD and disrupt its structure. Some macroscopic changes include annulus tear,  loss of disc height and hydration,  lamella disorganization of annulus  and formation of osteophytes. Some other microscopic changes include increased clonal cell proliferation, mucous matrix degeneration, increased cell death, obliteration of blood vessels in endplate and decreased vascularization and innervation. These changes are believed to be the result of the underlying molecular changes in the disc. Theoretically, suppressing these changes by the regulation of the related pathways may prevent, arrest or even reversed the progression of IVD degeneration.
Degeneration of IVD has been characterized extensively showing that the degeneration involves changes in the composition of the ECM. Such molecular changes have been widely studied, and obvious alternations in both gene and protein expressions as compared with that of young healthy IVD have been demonstrated. ,, In addition, there are studies suggesting that the molecular changes are the result of an upregulation of matrix degradation enzymes and inflammatory mediators in the degenerated IVD. , The most common changes which related to matrix synthesis, catabolic mechanism, as well as growth factors and cytokines are discussed briefly in this review.
IVDD is believed to be, in part, the result of imbalance between anabolism and catabolism of ECM. 
Concerning the matrix changes related to the anabolic mechanism, proteoglycans (PG) and collagen are two predominant matrixes that involved in the degeneration process. Decrease of PG content in the NP is one of the first signs of disc degeneration. , Among many types of PG in IVD including aggrecan, versican, decorin, biglycan, lumican and perlecan, aggrecan is the most abundant on a weight basis. The overall aggrecan content was found reduced and its gene expression was down regulated in the whole degenerated human disc. , This depletion has been generally suggested to be associated with the proteolytic degradation. Apart from the overall decrease of the aggrecan content, the composition of aggrecan in the discs also undergoes alteration during degeneration. 
Aggrecan possesses both chondroitin sulfate (CS) and keratan sulfate (KS) in mature human IVD,  and the proportion of KS to CS is generally higher in degenerated than normal disc.  This was postulated to be a result of decreased oxygen supply and vasculature during degeneration, as oxidation is a prerequisite for the formation of the glucuronic acid during synthesis of CS, whereas formation of galactose during synthesis of KS does not require oxidation.  This molecular change was considered to be a mechanism strived to maintain the high negative charge density to retain the osmotic properties of the discs. In addition, the proportion of non-aggregating PGs relative to the total proteoglycan content also increases during disc degeneration, particularly in the NP.  These non-aggregating PGs are suggested to be derived from intact aggrecans by proteolytic degradation. The non-aggregating PGs differ in composition, including the CS-rich and KS-rich depending on the sites of cleavage. Other PGs including versican, biglycan and decorin also undergo extensive degradation during aging and degeneration; however, the exact role of the molecular changes and the degradation consequence is still not clear.  Fibronectin, a cell and matrix protein, was found to be elevated in degenerated disc. It was hypothesized that the presence of fibronectin modifies the cell-matrix interaction and results in enhanced proteolytic activity, which subsequently promotes the degeneration of a disc.  Apart from fibronectin, a novel small leucin-rich proteoglycan (SLRP) named asporin has been recently shown to be highly localized in human degenerated disc, and degenerated disc also showed higher gene expression of asporin than non-degenerated one.  Many studies are now underway to elucidate the role of these biomolecules in disc degeneration. Collagen also changes its distribution and composition when IVD is degenerated. In early degeneration, the abundance of Types III, V and VI collagen increases in the NP and that of Type I collagen increases in the AF.  Other studies also found that the gene expression of Type I collagen was upregulated in the whole degenerated discs even in the NP, ,, while Type II collagen was downregulated in NP ,, with more advanced degeneration, furthermore, Types III and VI collagen has also been reported to appear in the NP, and the expression of Type V collagen was slightly upregulated in NP. ,
Apart from molecular changes in terms of matrix synthesis, the alteration in catabolic metabolism also involves during disc degeneration. Matrix metalloproteinases (MMPs) and a desintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) are the most commonly proposed enzymes which are involved in the ECM degradation and have been reported to enhance catabolic metabolism within the discs. This degeneration may be caused by losing a balance between the production and activation of these catabolic enzymes relative to their inhibition by tissue inhibitors.  Metalloproteinase is known to cleave major matrix molecules, mainly that of aggrecan, collagen, versican and link proteins. Many members from this catabolic enzyme family including MMP-1, 3, 7, 9, 13 have been shown to be involved in IVD degeneration. The number of immunopositive cells for MMP-1, 3, 7, 13 increased with the severity of the degeneration in human NP, and gene expression of MMP-1, 7, 9, 13 was found to be increased in rabbit degenerative model and human disc. , A family member of metalloproteinase, referred to as aggrecanase, is involved mainly in the degradation of aggrecan and versican.  Considering ADAMTS, the protein expression for ADAMTS-2 and 14 were found upregulated in degenerated disc in goat,  and same was true for ADAMTS-4, 5, 9 and 15, as confirmed in a recent study using human degenerated discs. 
Numerous growth factors including bone morphogenetic proteins (BMPs), insulin-like growth factor-1 (IGF-1), transforming growth factor-b (TGF-b), etc., have been reported to have therapeutic effect of slowing or reversing IVDD. The upregulation of bFGF, BMP and TGF-β expression has been observed in degenerated discs, and have been supposed to be involved in the degradation processes. ,,,,, Recent genetic evidence has indicated the role of TGF-β and BMP signalling in the pathogenesis of IVDD as well as osteoarthritis. , Members of the TGF-β family are the best-characterized growth factors.  In cartilage, TGF-β has been shown to participate in processes including chondrogensis, production of metalloproteinase and inflammatory responses. , The gene expression of TGF-β was found promoted in osteoarthritic cells, which is similar to that observed in degenerative disc cells.  Both TGF-β and TGF-β receptor type II are generally found in disc cells from specimens of herniated , and non-herniated , degenerated human discs. However, the findings are still contradictory as TGF-β was only found in a minority of the herniated disc tissues.  More recently, two growth factors named nerve growth factor (NGF)  and connective tissue growth factor (CTGF)  have been discovered to be highly associated with degenerative discs which are accompanied with pain. The expression of these growth factors has been shown to be higher in painful human degenerated discs than asympomatic ones.
IL-1α52, 53, IL-1β53, 54, IL-653, 55, 56, IL-852,55 and TNF-α40, 52, 53 are the most commonly studied cytokines in relation to the degeneration of IVD. Disc cells have potential to produce these inflammatory cytokines mainly for mediating and propagating the inflammatory reaction.  All of these cytokines were found upregulated in degenerated IVD, which are believed to be responsible for the enhancement of catabolic degradation of ECM. Downstream to interleukin IL-1β, a mediator named nitric oxide (NO), which has been implicated in osteoarthritis , was reported to be produced in higher quantities in degenerated discs that were associated with herniation, when compared with the normal discs.  The production of NO was increased in response to IL-1β56, and its ability at inhibiting PG synthesis in lumbar discs was also discovered.  Apart from NO, prostaglandin is another mediator of inflammatory reaction which is a possible intermediary in the suppression of PG synthesis. The prostaglandin E2 was also detected in significantly higher amounts in degenerated discs which were associated with herniation.  However, the precise role of these biochemical mediators of inflammation is still not well-understood and is currently being investigated.
Treatment strategies for degenerative disc disease
Currently, the therapeutic strategies for treating IVDD are mainly empirical and concentrates at alleviating symptoms rather than targeting the mechanism of underlying disease. The continually increasing burden of disease and the patient experience suggest that this approach has limited success. It could be argued that therapeutic advances might be facilitated were more known about the causes of back pain and the underlying tissue processes [Figure 2].
Arguably, the two main foci of this work are in restoring the normal environment of the IVD and in regenerating functional IVD tissue. In the former, the major targets are the altered load consequent upon disturbed matrix composition and the abnormal cytokine environment of the degenerate IVD. These have given rise to research on delivery of cytokine modulators to the degenerate IVD, , novel biomaterials to replace the function of the NP  and the use of stem cells to replace deficient IVD cells ,,
|Figure 2: Current strategies to treat intervertebral disc disease consist of conservative measures or surgical decompression. The new treatment strategies can be applied at different stages of intervertebral disc degeneration, with salvage procedures being applied in late-stage degeneration/disease, functional repair being applied in intermediate-stage degeneration, and intervertebral disc regeneration being applied in early-stage degeneration. NP: Nucleus Pulposus; AF: Annulus Fibrosus|
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Reliable new treatments for discogenic back pain based on this new knowledge are a long way off, but the tide of translational research is running in that direction. There are also new research areas developing particularly around mechanotransduction and prevention of degeneration based on recognizing genetically programmed 'at risk' groups. Clinical subtyping of patients to identify those who might benefit from the new therapies is one of the area that has been neglected to some extent. Advance in this area will be essential if the new therapeutics are to be of any value, and will go wider than the history and clinical examination but will also encompass clinical technologies such as novel imaging and the wealth of different 'omics'. This is an exciting time to be working on back pain and there is little doubt that the clinical management of the patient with discogenic back pain and/or IVDD will be distinctly different in 10-years' time.
Conservative or medical treatment
Conservative treatment consists of providing analgesic support, often with non-steroidal anti-inflammatory drugs (NSAIDs) and opioids in the acute phase. Anti-inflammatory medication, consisting of corticosteroids or NSAIDs, is applied to counter the inflammatory response and to treat the spinal pain. NSAIDs are preferred to corticosteroids, because NSAIDs have similar analgesic and anti-inflammatory effects but significantly fewer side effects.  Controlled and dosed exercise and physical therapy is also beneficial. Adjunct treatments, such as nutraceuticals and weight loss, are often used as well. Conservative treatment also consists of restricting activities that could exacerbate the neural compression, to prevent more NP material from herniating and to facilitate consolidation of the (partially) herniated disc. Extruded NP material is resorbed over a period of 4 to 6 weeks and the inflammation will settle, leading to resolution of the clinical signs. In addition, physical therapy can be started to prevent muscle atrophy due to disuse of muscles and to improve muscle tone, to maximize afferent sensory input in areas of deficit and to promote a normal range of movement, motion patterns and function.  Conservative treatment is best suited for mild cases of IVDD. ,,
The decision to treat IVDD patients surgically should be based on several factors, such as the severity of neurological signs, the severity of pain, the type and severity of compressive lesion (s) and the response to conservative therapy. General indications for surgery include clinical signs unresponsive to conservative treatment and the presence of neurological deficits. , The aim of surgery is to remove the compressive lesions and structures, such as the herniated IVDD and hypertrophic ligaments, thereby alleviating neural compression. Once the decision has been made that surgery is the optimal treatment option, a wide array of surgical techniques are available to treat IVDD-related compression. Direct decompressive procedures include ventral slot (cervical disc disease), inverted cone slot (CSM), dorsal laminectomy (DLSS) and haemilaminectomy (thoracolumbar disc disease), pediculotomy, corpectomy. ,,, Also, curettage or fenestration (nuclectomy) of the diseased disc or adjacent discs which may cause future disease is commonly performed.  Indirect decompressive techniques, such as distraction-stabilization/fusion, have also been described as treatment for CSM and DLSS , As decompression involves removing essential stabilizing structures, the decompressed segment can also be re-stabilized. A wide variety of techniques, including bone grafts, pins, screws and cages, have been described for this purpose. ,,,,,,,
Functional repair of the IVDD
The above-described treatments can be regarded as salvage procedures: They are symptomatic and the compressive lesion is removed with or without stabilization of the spinal segment. However, the functionality of the IVDD is not restored. Moreover, these surgical procedures all lead to altered biomechanics of the spinal segment: Decompressive surgery without stabilization results in spinal instability, which may lead to recurrence of clinical signs , While stabilization prevents degeneration of the decompressed spinal segment, it is associated with degeneration of the adjacent spinal segments, a phenomenon referred to as adjacent segment disease or the 'domino effect'. ,, These complications have prompted interest in new technologies to restore the functionality of the IVD following decompression.
If IVD degeneration has not progressed beyond repair, the IVD may be repaired by replacing the diseased NP with a NP prosthesis (NPP).  A novel, biocompatible, hydrogel NPP has recently been developed. ,, It is implanted in dry form, enabling insertion of the NPP through a small annular opening. After insertion, the prosthesis is allowed to expand in situ and reaches its final dimensions within 18 hours of placement. The prosthesis fills up the entire NP cavity created after nuclectomy (confinement), which is essential to achieve a physiological distribution of stress in the disc and to minimize the risk of implant migration. The NPP consists of an intrinsically radiopaque hydrogel, which makes it optimally visible on X-ray fluoroscopy, computed tomography (CT) and MRI. ,,
The physical-mechanical material properties of this NPP have been assessed by means of swelling and diffusion testing, static and dynamic mechanical testing and creep and fatigue testing. ,, However, before this technique can be used in canine IVD patients, the applicability of the surgical technique in the canine spine and the functionality of this concept need to be investigated.
Regeneration of the IVDD
The optimal method for restoring IVDD functionality would be to return the IVDD to its healthy state, i.e. regeneration of the degenerated IVD tissue. Regeneration of the IVD involves the prevention, inhibition and/or reversal of degenerative processes by concomitantly stimulating ECM synthesis and decreasing, and ideally reversing, ECM degradation. , A prerequisite for IVD regeneration is that the IVD cells and environment still have the capability to produce, and thus restore, a healthy ECM.  Different strategies for biological repair of the degenerated IVD can be used, including the use of growth factors and anticatabolic agents, gene therapy and cell-based strategies. ,,,
Cell-based therapies and growth factors in lumbar disc degeneration
Both the application of growth factors such as IGF, TGF and bone morphogenetic protein (BMPs) and alternatively replacement of abnormal IVD cells, either by injection of adult mesenchymal stem cells (MSCs) or autologous IVD cells, have been investigated as potential therapeutic agents aimed at regeneration of the IVD matrix. Growth factors are peptides the function of which is to regulate the stimulation of cellular proliferation, differentiation and migration and to stimulate matrix synthesis. In the IVD, specific growth factors such as IGF, TGF and BMP are produced by the chondrocyte-like cells of the NP and act to stimulate matrix synthesis.  As loss of IVD matrix composition is a characteristic feature of IVDD, growth factors have been investigated as potential therapeutic agents, aimed at promoting matrix synthesis in the degenerated IVD.
In 2002, BMP was approved as a bone graft substitute for anterior lumbar interbody fusion (ALIF), but in addition to its osteoinductive properties, BMP also demonstrated some potential for the treatment of disc disease.  Current human and animal studies have shown upregulation of BMP-2 and -7 in aging discs.  This upregulation has been found to have an antiapoptotic effect on the cells of the nucleus pulposus.  Also, the introduction of BMP-2 into intervertebral discs has resulted in increased extracellular matrix production.  However, the direct introduction of BMP into the intervertebral disc may lead to potential undesired osteogenic effects. In recent years, concerns about the safety of BMP-2 have arisen following reports of adverse reactions attributable to its use in ALIF and its off-label use in other spinal fusions. ,, In 2008, the Food and Drug Administration (FDA) published a public health notification about potentially life-threatening complications associated with use of BMP in cervical spine fusion.  To date, the safety of recombinant BMP-2 as a bone graft substitute remains controversial. Recent studies have shown the potential for the drug simvastatin to induce chondrogenesis and the production of Type II collagen and aggrecan through BMP-mediated pathways. 
A key factor initiating early degeneration, leading to the transformation of an optimal to a less optimal matrix, involves the disappearance of notochordal cells from the NP. ,, Notochordal cells have been shown to positively influence the activity of surrounding chondrocyte-like cells and their homeostasis ,,, and have gained increased attention as a potential NP progenitor cell. ,, Recent animal studies have shown increased extracellular matrix when autologous disc-derived chondrocytes were introduced into a canine disc degeneration model. Furthermore, recent human trial involving the introduction of autologous chondrocytes into postdiscectomy patients has resulted in decreased pain at 2 years compared with controls. Also, there was increased disc hydration at the treated levels and adjacent levels as evidenced by MRI evaluation. 
An alternative technique to chrondrocyte transplantation has been the use of adipocyte progenitor cells. The advantage to this technique is the relative abundance of adipose derived stem cell when compared to chondrocytic stem cells. In a rat degenerative disc disease model, transplanted adipose-derived stem cells resulted in increased extracellular matrix production, minimally decreased disc height, and improved discal hydration when compared to controls. 
Finally, another promising type of stem cells for future investigation are bone-marrow-derived stem cells. In vitro studies have demonstrated that these cells have similar chondrogenic capacity when compared to nucleu-pulposusderived cells.  However, in vivo studies are needed to confirm their potential efficacy, and any strategy involving the introduction of new cells into the human intervertebral disc to induce regeneration would have to account for the increased demand of nutritional supply by the increasing number of cells or the increased activity of previously present cells. 
Platelet-rich plasma (PRP) as a strategy for intervertebral disc degeneration repair and regeneration
PRP contains a variety of proteins and growth factors that are expected to serve as a therapeutic growth factor cocktail, playing a pivotal role in regulating the tissue microenvironment, improving cellular functions and promoting the regeneration of damaged tissues. PRP has been clinically applied for its healing properties,  and now is widely applied in many therapeutic areas. The concept that PRP application would promote IVDD regeneration is based on the role of platelets in wound healing. When activated, platelets can secrete a variety of growth factors, including PDGF, IGF-1, TGF-β, VEGF, bFGF, EGF and CTGF, among others. , All these growth factors might play significant roles in promoting the proliferation of tissues. Platelets also contain antibacterial and bactericidal proteins that may influence the process of inflammatory responses by inducing the synthesis of some molecules, such as integrins, interleukins and chemokines.  Last but not least, platelets may serve as a biological sponge because they can absorb, store and transfer some small molecules that regulate tissue regeneration.  PRP represents a new biotechnology in tissue engineering and has become a popular clinical treatment for various tissue healing applications without any immune rejections. Chen and colleagues  demonstrated that PRP could promote nucleus pulposus regeneration and resulting in increased levels of messenger ribonucleic acids (mRNAs) involved in chondrogenesis and matrix accumulation.
Gene therapy in lumbar disc degeneration
Transduction of genes that have the potential to interfere with disc degeneration or even induce disc regeneration is a concept recently applied to IVDD by researchers. This strategy requires identification of relevant genes that play a role in the disc degeneration cascade, as well as ways of delivering those potentially therapeutic genes into disc cells. This can be obtained by so-called gene vector systems, which include a variety of viral and, more recently, non-viral vectors. ,,
Genetic material can be delivered into host cells by vectors via one of two methods in vivo or ex vivo. In vivo refers to the direct injection or inhalation of the vector. Ex vivo is the process where host cells are removed and the vector is applied in vitro, and then the modified cells are returned to the host. There are two classifications of vectors which can be used in gene therapy: Viral or non-viral vectors. Viral vectors can be further subdivided into two categories: Genome incorporating, which include retroviruses and lentiviruses and non-genome incorporating viruses, such as herpes viruses, adenoviruses and adeno-associated viruses. Viral vectors are genetically modified viruses which have been engineered to lack the genetic material which makes them pathogenic while retaining the genetic information which enables insertion of their genes into host cells. Additionally, a copy of the therapeutic gene is inserted into the viral vector so that it may be transferred into the host cell.
The first gene with potentially beneficial effects on disc degeneration to be experimentally delivered to the IVDD in an animal model was TGF-β1.  A similar approach of initial transduction of a marker gene was taken by Moon et al. to deliver genes into human IVD cells. 
Additionally, other growth factors,  inhibitors of metalloproteinases  and also a transcription factor, Sox-9,  have received consideration as possible targets for gene therapy for IVDD. Following identification of ADAMTS5 as a contributor to cartilage degradation in a mouse model,  ADAMTS5 small interference RNA was successfully used in a rabbit model to suppress degradation of NP tissue.  A similar approach was used to target caspase 3, a main executor of apoptosis, in a rabbit model  Future in vivo studies linking theoretical benefits of any of these gene therapy approaches to situations possibly encountered in clinical practice are desirable  and comprise the long-term perspective of applying gene therapy as a strategy to treat the underlying mechanism of disc degeneration.
In summary, the IVD is an essential stabilizing and mobilizing component of the spine. IVDD involves numerous cellular, biochemical and biomechanical processes. The diagnosis and treatment of IVD degenerative disease can be refined further, thereby facilitating early diagnosis and early treatment of IVDD patients, which could lead to better outcomes and improved quality of life. Preventing the loss of IVD matrix composition would ideally be used in conjunction with an approach aimed at regenerating the IVD matrix in order to begin reversing the matrix composition. Therefore, regeneration of the degenerated IVD matrix must be considered as an additional and equally important factor in the treatment of IVDD. However, much still needs to be learned about the fundamental processes involved in IVD degeneration, knowledge which may aid our understanding of the degenerative process and facilitate the development of novel strategies to regenerate the IVD.
| References|| |
Hart LG, Deyo RA, Cherkin DC. Physician office visits for low-back-pain - Frequency, clinical-evaluation, and treatment patterns from a U.S. national survey. Spine (Phila Pa 1976) 1995;20:11-9.
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al
. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163-96.
Gore M, Sadosky A, Stacey BR, Tai KS, Leslie D. The burden of chronic low back pain: Clinical comorbidities, treatment patterns, and health care costs in usual care settings. Spine (Phila Pa 1976) 2012;37:E668-77.
Anderson GB. Epidemiological features of chronic low-back pain. Lancet 1999;354:581-5.
Scientific approach to the assessment and management of activity-related spinal disorders: A monograph for clinicians. Report of the Quebec Task Force on Spinal Disorders. Spine (Phila Pa 1976) 1987;12:S1-59.
Non-drug management of chronic low back pain. Drug Ther Bull 2009;47:102-7.
Deyo RA, Weinstein JN. Low back pain. N Engl J Med 2001;344:363-70.
Cheung KM, Karppinen J, Chan D, Ho DW, Song YQ, Sham P, et al
. Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine (Phila Pa 1976) 2009;34:934-40.
Balagué F, Mannion AF, Pellisé F, Cedraschi C. Non-specific low back pain. Lancet 2012;379:482-91.
Katz JN. Lumbar disc disorders and low-back pain: Socioeconomic factors and consequences. J Bone Joint Surg Amn 2006;88:21-4.
Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976) 2006;31:2151-61.
Miller JA, Schmatz C, Schultz AB. Lumbar disc degeneration: Correlation with age, sex, and spine level in 600 autopsy specimens. Spine (Phila Pa 1976) 1988;13:173-8.
Taher F, Essig D, Lebl DR, Hughes AP, Sama AA, Cammisa FP, et al
. Lumbar degenerative disc disease: Current and future concepts of diagnosis and management. Adv Orthop 2012;2012:970752.
Le Maitre CL, Freemont AJ, Hoyland JA. Localization of degradative enzymes and their inhibitors in the degenerate human intervertebral disc. J Pathol 2004;204:47-54.
Freemont AJ, Byers RJ, Taiwo YO, Hoyland JA. In situ
zymographic localisation of type II collagen degrading activity in osteoarthritic human articular cartilage. Ann Rheum Dis 1999;58:357-65.
Mee AP, Hoyland JA, Braidman IP, Freemont AJ, Davies M, Mawer EB. Demonstration of vitamin D receptor transcripts in actively resorbing osteoclasts in bone sections. Bone 1996;18:295-9.
Braidman I, Baris C, Wood L, Selby P, Adams J, Freemont A, et al
. Preliminary evidence for impaired estrogen receptor-alpha protein expression in osteoblasts and osteocytes from men with idiopathic osteoporosis. Bone 2000;26:423-7.
Sasaki N, Kikuchi S, Konno S, Sekiguchi M, Watanabe K. Anti-TNF-alpha antibody reduces pain-behavioral changes induced by epidural application of nucleus pulposus in a rat model depending on the timing of administration. Spine (Phila Pa 1976) 2007;32:413-6.
Jandial R, Aryan HE, Park J, Taylor WT, Snyder EY. Stem cell-mediated regeneration of the intervertebral disc: Cellular and molecular challenge. Neurosurg Focus 2008;24:E21.
O′Halloran DM, Pandit AS. Tissue-engineering approach to regenerating the intervertebral disc. Tissue Eng 2007;13:1927-54.
Zhao CQ, Jiang LS, Dai LY. Programmed cell death in intervertebral disc degeneration. Apoptosis 2006;11:2079-88.
Freemont AJ. The cellular pathobiology of the degenerate intervertebral disc and discogenic back pain. Rheumatology (Oxford) 2009;48:5-10.
Minogue BM, Richardson SM, Zeef LA, Freemont AJ, Hoyland JA. Characterization of the human nucleus pulposus cell phenotype and evaluation of novel marker gene expression to define adult stem cell differentiation. Arthritis Rheum 2010;62:3695-705.
Feng H, Danfelter M, Strömqvist B, Heinegård D. Extracellular matrix in disc degeneration. J Bone Joint Surg Am 2006;88:25-9.
Buckwalter JA. Aging and degeneration of the human intervertebral disc. Spine (Phila Pa 1976) 1995;20:1307-14.
Antoniou J, Steffen T, Nelson F, Winterbottom N, Hollander AP, Poole RA, et al
. The human lumbar intervertebral disc: Evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Invest 1996;98:996-1003.
Roughley PJ. Biology of intervertebral disc aging and degeneration: Involvement of the extracellular matrix. Spine (Phila Pa 1976) 2004;29:2691-9.
Boxberger JI, Sen S, Yerramalli CS, Elliott DM. Nucleus pulposus glycosaminoglycan content is correlated with axial mechanics in rat lumbar motion segments. J Orthop Res 2006;24:1906-15.
Costi JJ, Stokes IA, Gardner-Morse MG, Iatridis JC. Frequency dependent behavior of the intervertebral disc in response to each of six degree of freedom dynamic loading: Solid phase and fluid phase contributions. Spine (Phila Pa 1976) 2008;33:1731-8.
Adams MA, McNally DS, Dolan P. ′Stress′ distributions inside intervertebral discs. The effects of age and degeneration. J Bone Joint Surg Br 1996;78:965-72.
Acaroglu ER, Iatridis JC, Setton LA, Foster RJ, Mow VC, Weidenbaum M. Degeneration and aging affect the tensile behavior of human lumbar anulus fibrosus. Spine (Phila Pa 1976) 1995;20:2690-701.
O′Connell GD, Guerin HL, Elliott DM. Theoretical and experimental evaluation of human annulus fibrosus degeneration. J Biomech Eng 2009;131:111007.
Vernon-Roberts B, Moore RJ, Fraser RD. The natural history of age-related disc degeneration: The pathology and sequelae of tears. Spine (Phila Pa 1976) 2007;32:2797-804.
Videman T, Battié MC, Gibbons LE, Maravilla K, Manninen H, Kaprio J. Associations between back pain history and lumbar MRI findings. Spine (Phila Pa 1976) 2003;28:582-8.
Stokes IA, Iatridis JC. Mechanical conditions that accelerate intervertebral disc degeneration: overload versus immobilization. Spine (Phila Pa 1976) 2004;29:2724-32.
Urban JP, Smith S, Fairbank JC. Nutrition of the intervertebral disc. Spine (Phila Pa 1976) 2004;29:2700-9.
Zhao CQ, Wang LM, Jiang LS, Dai LY. The cell biology of intervertebral disc aging and degeneration. Ageing Res Rev 2007;6:247-61.
Le Maitre CL, Freemont AJ, Hoyland JA. A preliminary in vitro
study into the use of IL-1Ra gene therapy for the inhibition of intervertebral disc degeneration. Int J Exp Pathol 2006;87:17-28.
Rajasekaran S, Babu JN, Arun R, Armstrong BR, Shetty AP, Murugan S. ISSLS prize winner: A study of diffusion in human lumbar discs: A serial magnetic resonance imaging study documenting the influence of the endplate on diffusion in normal and degenerate discs. Spine (Phila Pa 1976) 2004;29:2654-67.
Maclean JJ, Lee CR, Alini M, Iatridis JC. Anabolic and catabolic mRNA levels of the intervertebral disc vary with the magnitude and frequency of in vivo dynamic compression. J Orthop Res 2004;22:1193-200.
Battie MC, Videman T. Lumbar disc degeneration: epidemiology and genetics. J Bone Joint Surg Am 2006;88:3-9.
Sambrook PN, MacGregor AJ, Spector TD. Genetic influences on cervical and lumbar disc degeneration: A magnetic resonance imaging study in twins. Arthritis Rheum 1999;42:366-72.
Chan D, Song Y, Sham P, Cheung KM. Genetics of disc degeneration. Eur Spine J 2006;15:S317-25.
Urban JP, McMullin JF. Swelling pressure of the lumber intervertebral disks: Influence of age, spinal level, composition, and degeneration. Spine (Phila Pa 1976) 1988;13:179-87.
Marchand F, Ahmed AM. Investigation of the laminate structure of lumber disk anulus fibrosus. Spine (Phila Pa 1976) 1990;15:402-10.
Anderson DG, Izzo MW, Hall DJ, Vaccaro AR, Hilibrand A, Arnold W, et al
. Comparative gene expression profiling of normal and degenerative discs: Analysis of a rabbit annular laceration model. Spine (Phila Pa 1976) 2002;27:1291-6.
Hoogendoorn R, Doulabi BZ, Huang CL, Wuisman PI, Bank RA, Helder MN, et al
. Molecular changes in the degenerated goat intervertebral disc. Spine (Phila Pa 1976) 2008;33:1714-21.
Guehring T, Omlor GW, Lorenz H, Bertram H, Steck E, Richter W, et al
. Stimulation of gene expression and loss of anular architecture caused by experimental disc degeneration - An in vivo animal study. Spine (Phila Pa 1976) 2005;30:2510-5.
Cs-Szabo G, Ragasa-San Juan D, Turumella V, Masuda K, Thonar EJ, An HS. Changes in mRNA and protein levels of proteoglycans of the anulus fibrosus and nucleus pulposus during intervertebral disc degeneration. Spine (Phila Pa 1976) 2002;27:2212-9.
Mern DS, Fontana J, Beierfuß A, Thomé C, Hegewald AA. A combinatorial relative mass value evaluation of endogenous bioactive proteins in three-dimensional cultured nucleus pulposus cells of herniated intervertebral discs: Identification of potential target proteins for gene therapeutic approaches. PLoS One 2013;8:e81467.
Pearce RH, Grimmer BJ, Adams ME. Degeneration and the chemical-composition of the human lumber intervertebral-disk. J Orthop Res 1987;5:198-205.
Roughley PJ, Alini M, Antoniou J. The role of proteoglycans in aging, degeneration and repair of the intervertebral disc. Biochem Soc Trans 2002;30:869-74.
Roughley PJ, Melching LI, Heathfield TF, Pearce RH, Mort JS. The structure and degradation of aggrecan in human intervertebral disc. Eur Spine J 2006;15:S326-32.
Taylor JR, Scott JE, Cribb AM, Bosworth TR. Human intervertebral-disk acid glycosaminoglycans. J Anat 1992;180:137-41.
Oegema TR Jr, Johnson SL, Aguiar DJ, Ogilvie JW. Fibronectin and its fragments increase with degeneration in the human intervertebral disc. Spine (Phila Pa 1976) 2000;25:2742-7.
Gruber HE, Ingram JA, Hoelscher GL, Zinchenko N, Hanley EN Jr, Sun Y. Asporin, a susceptibility gene in osteoarthritis, is expressed at higher levels in the more degenerate human intervertebral disc. Arthritis Res Ther 2009;11:R47.
Guiot BH, Fessler RG. Molecular biology of degenerative disc disease. Neurosurgery 2000;47:1034-40.
Nerlich AG, Schleicher ED, Boos N. Volvo Award winner in basic science studies. Immunohistologic markers for age-related changes of human lumbar intervertebral discs. Spine (Phila Pa 1976) 1997;22:2781-95.
Nerlich AG, Boos N, Wiest I, Aebi M. Immunolocalization of major interstitial collagen types in human lumbar intervertebral discs of various ages. Virchows Arch 1998;432:67-76.
Goupille P, Jayson MI, Valat JP, Freemont AJ. Matrix metalloproteinases: The clue to intervertebral disc degeneration? Spine (Phila Pa 1976) 1998;23:1612-26.
Le Maitre CL, Freemont AJ, Hoyland JA. Human disc degeneration is associated with increased MMP 7 expression. Biotech Histochem 2006;81:125-31.
Pockert AJ, Richardson SM, Le Maitre CL, Lyon M, Deakin JA, Buttle DJ, et al
. Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degeneration. Arthritis Rheum 2009;60:482-91.
Tolonen J, Grönblad M, Vanharanta H, Virri J, Guyer RD, Rytömaa T, et al
. Growth factor expression in degenerated intervertebral disc tissue. Eur Spine J 2006;15:588-96.
Séguin CA, Pilliar RM, Roughley PJ, Kandel RA. Tumor necrosis factor-alpha modulates matrix production and catabolism in nucleus pulposus tissue. Spine (Phila Pa 1976) 2005;30:1940-8.
Takae R, Matsunaga S, Origuchi N, Yamamoto T, Morimoto N, Suzuki S, et al
. Immunolocalization of bone morphogenetic protein and its receptors in degeneration of intervertebral disc. Spine (Phila Pa 1976) 1999;24:1397-401.
Tolonen J, Grönblad M, Virri J, Seitsalo S, Rytömaa T, Karaharju E. Transforming growth factor beta receptor induction in herniated intervertebral disc tissue: An immunohistochemical study. Eur Spine J 2001;10:172-6.
Nerlich AG, Bachmeier BE, Boos N. Expression of fibronectin and TGF-beta 1 mRNA and protein suggest altered regulation of extracellular matrix in degenerated disc tissue. Eur Spine J 2005;14:17-26.
Weiler C, Nerlich AG, Bachmeier BE, Boos N. Expression and distribution of tumor necrosis factor alpha in human lumbar intervertebral discs: A study in surgical specimen and autopsy controls. Spine (Phila Pa 1976) 2005;30:44-53.
Kizawa H, Kou I, Iida A, Sudo A, Miyamoto Y, Fukuda A, et al
. An aspartic acid repeat polymorphism in aspirin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet 2005;37:138-44.
An HS, Masuda K, Inoue N. Intervertebral disc degeneration: Biological and biomechanical factors. J Orthop Sci 2006;11:541-52.
Paesold G, Nerlich AG, Boos N. Biological treatment strategies for disc degeneration: Potentials and shortcomings. Eur Spine J 2007;16:447-68.
Frenz DA, Liu W, Williams JD, Hatcher V, Galinovic-Schwartz V, Flanders KC, et al
. Induction of chondrogenesis: Requirement for synergistic interaction of basic fibroblast growth-factor and transforming growth-factor-beta. Development 1994;120:415-24.
Wright JK, Cawston TE, Hazleman BL. Transforming growth factor-beta stimulates the production of the tissue inhibitor of metalloproteinases (TIMP) by human synovial and skin fibroblasts. Biochimica Et Biophysica Acta 1991;1094:207-10.
Roughley PJ. Articular cartilage and changes in arthritis: Noncollagenous proteins and proteoglycans in the extracellular matrix of cartilage. Arthritis Res 2001;3:342-7.
Chon BH, Lee EJ, Jing L, Setton LA, Chen J. Human umbilical cord mesenchymal stromal cells exhibit immature nucleus pulposus cell phenotype in a laminin-rich pseudo-three-dimensional culture system. Stem Cell Res Ther 2013;4:120.
Specchia N, Pagnotta A, Toesca A, Greco F. Cytokines and growth factors in the protruded intervertebral disc of the lumbar spine. Eur Spine J 2002;11:145-51.
Purmessur D, Freemont AJ, Hoyland JA. Expression and regulation of neurotrophins in the nondegenerate and degenerate human intervertebral disc. Arthritis Res Ther 2008;10:R99.
Konttinen YT, Kemppinen P, Li TF, Waris E, Pihlajamäki H, Sorsa T, et al
. Transforming and epidermal growth factors in degenerated intervertebral discs. J Bone Joint Surg Br 1999;81B; 1058-63.
Peng B, Chen J, Kuang Z, Li D, Pang X, Zhang X. Expression and Role of Connective tissue growth factor in painful disc fibrosis and degeneration. Spine (Phila Pa 1976) 2009;34:E178-82.
Hickery MS, Bayliss MT. Interleukin-1 induced nitric oxide inhibits sulphation of glycosaminoglycan chains in human articular chondrocytes. Biochim Biophys Acta 1998;1425:282-90.
Stefanovic-Racic M, Stadler J, Evans CH. Nitric-oxide and arthritis. Arthritis Rheum 1993;36:1036-44.
Kang JD, Georgescu HI, McIntyre-Larkin L, Stefanovic-Racic M, Donaldson WF 3 rd
, Evans CH. Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E (2). Spine (Phila Pa 1976) 1996;21:271-7.
Liu GZ, Ishihara H, Osada R, Kimura T, Tsuji H. Nitric oxide mediates the change of proteoglycan synthesis in the human lumbar intervertebral disc in response to hydrostatic pressure. Spine (Phila Pa 1976) 2001;26:134-41.
Levicoff EA, Kim JS, Sobajima S, Wallach CJ, Larson JW 3rd, Robbins PD, et al
. Safety assessment of intradiscal gene therapy II: Effect of dosing and vector choice. Spine (Phila Pa 1976) 2008;33:1509-16.
Le Maitre CL, Hoyland JA, Freemont AJ. Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: An in situ
zymographic and gene therapy study. Arthritis Res Ther 2007;9:R83.
Vernengo J, Fussell GW, Smith NG, Lowman AM. Evaluation of novel injectable hydrogels for nucleus pulposus replacement. J Biomed Mater Res B Appl Biomater 2008;84:64-9.
Crevensten G, Walsh AJ, Ananthakrishnan D, Page P, Wahba GM, Lotz JC, et al
. Intervertebral disc cell therapy for regeneration: Mesenchymal stem cell implantation in rat intervertebral discs. Ann Biomed Eng 2004;32:430-4.
Richardson SM, Hoyland JA. Stem cell regeneration of degenerated intervertebral discs: Current status. Curr Pain Headache Rep 2008;12:83-8.
Richardson SM, Hughes N, Hunt JA, Freemont AJ, Hoyland JA. Human mesenchymal stem cell differentiation to NP-like cells in chitosan-glycerophosphate hydrogels. Biomaterials 2008;29:85-93.
Meij BP, Bergknut N. Degenerative lumbosacral stenosis in dogs. Vet Clin North Am Small Anim Pract 2010;40:983-1009.
da Costa RC, Parent JM, Holmberg DL, Sinclair D, Monteith G. Outcome of medical and surgical treatment in dogs with cervical spondylomyelopathy: 104 cases (1988-2004). J Am Vet Med Assoc 2008;233:1284-90.
Brisson BA. Intervertebral disc disease in dogs. Vet Clin North Am Small Anim Pract 2010;40:829-58.
Levine JM, Levine GJ, Johnson SI, Kerwin SC, Hettlich BF, Fosgate GT. Evaluation of the success of medical management for presumptive thoracolumbar intervertebral disk herniation in dogs. Vet Surg 2007;36:482-91.
Levine JM, Levine GJ, Johnson SI, Kerwin SC, Hettlich BF, Fosgate GT. Evaluation of the success of medical management for presumptive cervical intervertebral disk herniation in dogs. Vet Surg 2007;36:492-9.
Samartzis D, Shen FH, Perez-Cruet MJ, Anderson DG. Minimally invasive spine surgery: A historical perspective. Orthop Clin North Am 2007;38:305-26.
Allen RT, Garfin SR. The economics of minimally invasive spine surgery: The value perspective. Spine (Phila Pa 1976) 2010;35:S375-82.
Slocum B, Devine T. L7-S1 fixation-fusion for treatment of cauda equina compression in the dog. J Am Vet Med Assoc 1986;188:31-5.
Trotter EJ. Cervical spine locking plate fixation for treatment of cervical spondylotic myelopathy in large breed dogs. Vet Surg 2009;38:705-18.
Denny HR, Gibbs C, Gaskell CJ. Cervical spondylopathy in the dog-a review of thirty-five cases. J Small Anim Pract 1977;18:117-32.
Meij BP, Suwankong N, Van der Veen AJ, Hazewinkel HA. Biomechanical flexion-extension forces in normal canine lumbosacral cadaver specimens before and after dorsal laminectomy-discectomy and pedicle screw-rod fixation. Vet Surg 2007;36:742-51.
Ullman SL, Boudrieau RJ. Internal skeletal fixation using a Kirschner apparatus for stabilization of fracture/luxations of the lumbosacral joint in six dogs. A modification of the transilial pin technique. Vet Surg 1993;22:11-7.
Méheust P, Mallet C, Marouze C. A new technique for lumbosacral stabilization: Pedicle screw fusion anatomical considerations. Prat Med Chir Anim Comp 2000;35:193-9.
Méheust P. A new technique for lumbosacral stabilization: Pedicle screw fusion, clinical study of 5 cases. Prat Med Chir Anim Comp 2000;35:201-7.
Macy NB, Les CM, Stover SM, Kass PH. Effect of disk fenestration on sagittal kinematics of the canine C5-C6 intervertebral space. Vet Surg 1999;28:171-9.
Smith ME, Bebchuk TN, Shmon CL. An in vitro biomechanical study of the effects of surgical modification upon the canine lumbosacral spine. Vet Comp Orthop Traumatol 2004;17:17-24.
Lee CK. Accelerated degeneration of the segment adjacent to a lumbar fusion. Spine (Phila Pa 1976) 1988;13:375-7.
MacDougall J, Perra J, Pinto M. Incidence of adjacent segment degeneration at ten years after lumbar spine fusion. Spine J 2003;3:675.
Schlegel JD, Smith JA, Schleusener RL. Lumbar motion segment pathology adjacent to thoracolumbar, lumbar, and lumbosacral fusions. Spine (Phila Pa 1976) 1996;21:970-81.
Boelen EJ, van Hooy-Corstjens CS, Bulstra SK, van Ooij A, van Rhijn LW, Koole LH. Intrinsically radiopaque hydrogels for nucleus pulposus replacement. Biomaterials 2005;26:6674-83.
Boelen EJ, van Hooy-Corstjens CS, Gijbels MJ. Preliminary evaluation of new intrinsically radiopaque hydrogels for replacing the nucleus pulposus. J Mater Chem 2006;16:824-8.
Boelen EJ, Koole LH, van Rhijn LW, van Hooy-Corstjens CS. Towards a functional radiopaque hydrogel for nucleus pulposus replacement. J Biomed Mater Res B Appl Biomater 2007;83:440-50.
Tow BP, Hsu WK, Wang JC. Disc regeneration: A glimpse of the future. Clin Neurosurg 2007;54:122-8.
Yoon ST. Molecular therapy of the intervertebral disc. Spine J 2005;5:280-6S.
Masuda K. Biological repair of the degenerated intervertebral disc by the injection of growth factors. Eur Spine J 2008;17:441-51.
Sakai D. Future perspectives of cell-based therapy for intervertebral disc disease. Eur Spine J 2008;17:452-8.
Chadderdon RC, Shimer AL, Gilbertson LG, Kang JD. Advances in gene therapy for intervertebral disc degeneration. Spine J 2004;4:341-7S.
Than KD, Rahman SU, Vanaman MJ, Wang AC, Lin CY, Zhang H, et al
. Bone morphogenetic proteins and degenerative disk disease. Neurosurgery 2012;70:996-1002.
Wei A, Brisby H, Chung SA, Diwan AD. Bone morphogenetic protein-7 protects human intervertebral disc cells in vitro from apoptosis. Spine J 2008;8:466-74.
Park JS, Nagata K. BMP and LMP-1 for intervertebral disc regeneration. Clin Calcium 2004;14:76-8.
Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: Emerging safety concerns and lessons learned. Spine (Phila Pa 1976) 2011;11:471-91.
Glassman SD, Howard J, Dimar J, Sweet A, Wilson G, Carreon L. Complications with recombinant human bone morphogenic protein-2 in posterolateral spine fusion: A consecutive series of 1037 cases. Spine (Phila Pa 1976) 2011;36:1849-54.
Smucker JD, Rhee JM, Singh K, Yoon ST, Heller JG. Increased swelling complications associated with offlabel usage of rhBMP-2 in the anterior cervical spine. Spine (Phila Pa 1976) 2006;31:2813-9.
Center for Devices and Radiological Health. FDA public health notification: Life-threatening complications associated with recombinant human bone morphogenetic protein in cervical spine fusion; 2011.
Zhang H, Lin CY. Simvastatin stimulates chondrogenic phenotype of intervertebral disc cells partially through BMP-2 pathway. Spine (Phila Pa 1976) 2008;33:E525-31.
Hansen HJ. A pathologic-anatomical study on disc degeneration in dog, with special reference to the so-called enchondrosis intervertebralis. Acta Orthop Scand Suppl 1952;11:1-117.
Braund KG, Ghosh P, Taylor TK, Larsen LH. Morphological studies of the canine intervertebral disc. The assignment of the beagle to the achondroplastic classification. Res Vet Sci 1975;19:167-72.
Cappello R, Bird JL, Pfeiffer D, Bayliss MT, Dudhia J. Notochordal cell produce and assemble extracellular matrix in a distinct manner, which may be responsible for the maintenance of healthy nucleus pulposus. Spine (Phila Pa 1976) 2006;31:873-82.
Aguiar DJ, Johnson SL, Oegema TR. Notochordal cells interact with nucleus pulposus cells: Regulation of proteoglycan synthesis. Exp Cell Res 1999;246:129-37.
Risbud MV, Schaer TP, Shapiro IM. Toward an understanding of the role of notochordal cells in the adult intervertebral disc: From discord to accord. Dev Dyn 2010;239:2141-8.
Risbud MV, Schipani E, Shapiro IM. Hypoxic regulation of nucleus pulposus cell survival: From niche to notch. Am J Pathol 2010;176:1577-83.
Henriksson H, Thornemo M, Karlsson C, Hägg O, Junevik K, Lindahl A, et al
. Identification of cell proliferation zones, progenitor cells and a potential stem cell niche in the intervertebral disc region: A study in four species. Spine (Phila Pa 1976) 2009;34:2278-87.
Hohaus C, Ganey TM, Minkus Y, Meisel HJ. Cell transplantation in lumbar spine disc degeneration disease. Eur Spine J 2008;17:492-503.
Jeong JH, Lee JH, Jin ES, Min JK, Jeon SR, Choi KH. Regeneration of intervertebral discs in a rat disc degeneration model by implanted adipose-tissue-derived stromal cells. Acta Neurochir (Wien) 2010;152:1771-7.
Blanco JF, Graciani IF, Sanchez-Guijo FM, Muntión S, Hernandez-Campo P, Santamaria C, et al
., Isolation and characterization of mesenchymal stromal cells from human degenerated nucleus pulposus: Comparison with bone marrow mesenchymal stromal cells from the same subjects. Spine (Phila Pa 1976) 2010;35:2259-65.
Sánchez-González DJ, Méndez-Bolaina E, Trejo-Bahena NI. Platelet-rich plasma peptides: Key for regeneration. Int J Pept 2012;2012:532519.
Brass L. Understanding and evaluating platelet function. Hematology Am Soc Hematol Educ Program 2010;2010:387-96.
Knighton DR, Hunt TK, Thakral KK, Goodson WH 3rd. Role of platelets and fibrin in the healing sequence: An in vivo study of angiogenesis and collagen synthesis. Ann Surg 1982;196:379-88.
Fréchette JP, Martineau I, Gagnon G. Platelet-rich plasmas: Growth factor content and roles in wound healing. J Dent Res 2005;84:434-9.
Leslie M. Cell biology. Beyond clotting: The powers of platelets. Science 2010;328:562-4.
Chen WH, Lo WC, Lee JJ, Su CH, Lin CT, Liu HY, et al
. Tissue-engineered intervertebral disc and chondrogenesis using human nucleus pulposus regulated through TGF-beta1 in platelet-rich plasma. J Cell Physiol 2006;209:744-54.
Wehling P, Schulitz KP, Robbins PD, Evans CH, Reinecke JA. Transfer of genes to chondrocytic cells of the lumbar spine: Proposal for a treatment strategy of spinal isorders by local gene therapy. Spine (Phila Pa 1976) 1997;22:1092-7.
Hubert MG, Vadala G, Sowa G, Studer RK, Kang JD. Gene therapy for the treatment of degenerative disk disease. J Am Acad Orthop Surg 2008;16:312-9.
Nishida K, Kang JD, Suh JK, Robbins PD, Evans CH, Gilbertson LG. Adenovirus-mediated gene transfer to nucleus pulposus cells implications for the treatment of intervertebral disc degeneration. Spine (Phila Pa 1976) 1998;23:2437-42.
Nishida K, Kang JD, Gilbertson LG, Moon SH, Suh JK, Vogt MT, et al
. 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 β1 encoding gene. Spine (Phila Pa 1976) 1999;24:2419-25.
Moon SH, Gilbertson LG, Nishida K, Knaub M, Muzzonigro T, Robbins PD, et al
. Human intervertebral disc cells are genetically modifiable by adenovirus-mediated gene transfer: Implications for the clinical management of intervertebral disc disorders. Spine (Phila Pa 1976) 2000;25:2573-9.
Cui M, Wan Y, Anderson DG, Shen FH, Leo BM, Laurencin CT, et al
. Mouse growth and differentiation factor-5 protein and DNA therapy potentiates intervertebral disc cell aggregation and chondrogenic gene expression. Spine J 2008;8:287-95.
Wallach CJ, Sobajima S, Watanabe Y, Kim JS, Georgescu HI, Robbins P, et al
. Gene transfer of the catabolic inhibitor TIMP-1 increases measured proteoglycans in cells from degenerated human intervertebral discs. Spine (Phila Pa 1976) 2003;28:2331-7.
Paul R, Haydon RC, Cheng H, Ishikawa A, Nenadovich N, Jiang W, et al
. Potential use of So × 9 gene therapy for intervertebral degenerative disc disease. Spine (Phila Pa 1976) 2003;28:755-63.
Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, et al
. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 2005;434:644-8.
Seki S, Asanuma-Abe Y, Masuda K, Kawaguchi Y, Asanuma K, Muehleman C, et al
. Effect of small interference RNA (siRNA) for ADAMTS5 on intervertebral disc degeneration in the rabbit annular needle-puncture model." Arthritis Res Ther 2009;11:R166.
Sudo H, Minami A. Caspase 3 as a therapeutic target for regulation of intervertebral disc degeneration in rabbits. Arthritis Rheum 2011;63:1648-57.
Nishida K, Suzuki T, Kakutani K, Yurube T, Maeno K, Kurosaka M, et al
. Gene therapy approach for disc degeneration and associated spinal disorders. Eur Spine J 2008;17:459-66.
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