• Cell therapy
• Degenerative disc disease (DDD)
• Low back pain (LBP)
• Mesenchymal stem cells (MSC)
• Nucleus pulposus (NP)
• Regenerative medicine

• degenerative disc disease
• disc pain
• imaging
• molecular therapy
• notochordal cells

• Intervertebral Disc Degeneration/therapy
• Intervertebral Disc Degeneration/metabolism
• Intervertebral Disc Degeneration/pathology
• Humans
• Animals
• Regeneration
• Intervertebral Disc/pathology
• Intervertebral Disc/metabolism

• biomaterials
• nerve guide conduits
• optic nerve crush
• optic neuropathy
• regeneration

• National Key R&D Program of China
• Key R & D Program of Wenzhou Eye Hospital
• YNZD1201902

• Tet-off
• intervertebral disc regeneration
• mesenchymal stem cells
• tetracyclin (Tet) regulatory system

• Humans
• Rats
• Animals
• Intervertebral Disc/metabolism
• Intervertebral Disc Degeneration/genetics
• Intervertebral Disc Degeneration/therapy
• Intervertebral Disc Degeneration/metabolism
• Nucleus Pulposus/metabolism
• Tetracycline/pharmacology
• Anti-Bacterial Agents/pharmacology
• Mesenchymal Stem Cells/metabolism

• 27304C0002 NIEHS NIH HHS
• 27306C0002 NIEHS NIH HHS

• autocrine
• cytokine
• intervertebral disc metabolism

• Humans
• Cytokines/metabolism
• Intervertebral Disc Degeneration/metabolism
• Interleukin 1 Receptor Antagonist Protein/pharmacology
• Interleukin 1 Receptor Antagonist Protein/metabolism
• Intervertebral Disc/metabolism
• Extracellular Matrix/metabolism
• Proteoglycans/metabolism
• Receptors, Interleukin-1/metabolism
• Collagen/metabolism

• P01 AR048152 NIAMS NIH HHS
• R01 AR079484 NIAMS NIH HHS

• 3D in vitro models
• IL-1Ra
• cell therapies
• chondrospheres
• degenerative disc disease
• nucleus pulposus
• spheroids

• biomaterial
• intervertebral disc
• intervertebral disc degeneration
• low back pain
• regenerative medicine
• stem cell

Degenerative disc disease (DDD) is a pathological condition associated with intervertebral discs (IVDs) that causes chronic back pain. IVD degeneration has become a significant issue in contemporary society. To date, numerous biological therapies have been applied to alleviate the progression of DDD, among which therapeutic protein injection is the most direct and convenient. However, there are some limitations to applying direct protein injection therapy, the most significant being that the efficacy of this method has a short duration, which is a major factor in its effectiveness and the resulting patient satisfaction. How do we solve this problem? Or how can the effectiveness of the treatment be enhanced? It has been proved that manganese dioxide (MnO₂) microspheres, widely used in environmental science, not only regulate the expression of cell genes and cytokines in the microenvironment, but also have the ability to release drugs slowly. We propose that direct injection of protein encapsulated in hollow MnO₂ (h-MnO₂) microspheres could solve the problem of rapid drug release. In addition, the use of a MnO₂ and protein injection in the treatment of DDD may have a synergistic effect, which would be highly significant for the degradation of pro-inflammatory factors in the DDD microenvironment. Therefore, the combination of MnO₂ and protein may provide a new therapeutic approach to alleviate the progression of DDD.

• Liaoning Revitalization Talents Program

• Apoptosis
• Exosomes
• Intervertebral disc disease
• MSCs
• Nucleus pulposus cells
• Regeneration

• Exosomes/metabolism
• Humans
• Intervertebral Disc/pathology
• Intervertebral Disc Degeneration/metabolism
• Intervertebral Disc Degeneration/therapy
• Intervertebral Disc Displacement
• Mesenchymal Stem Cells/metabolism
• Nucleus Pulposus/pathology

Previous studies have indicated that chronic intermittent hypobaric hypoxia (CIHH) preconditioning can inhibit TNF-α and other related inflammatory cytokines and exerts protective effect on intervertebral disc degeneration disease (IDD) in rats; however, the mechanism is still unclear. The present study aimed to explore the repair mechanisms of CIHH on IDD in rats. In the experiment, 48 adult Sprague-Dawley rats were selected and randomly divided into an experimental group (CIHH-IDD), a degenerative group (IDD) and a control group (CON). The CIHH-IDD group of rats (n=16) were treated with CIHH (simulated 3000 m altitude, 5 h per day, 28 days; P_O2=108.8 mmHg) before disc degeneration surgery. The IDD group of rats (n=16) underwent tail-vertebral intervertebral disc surgery to establish a model of intervertebral disc degeneration. The CON group of rats (n=16) did not receive any treatments. After surgery, the disc height index was calculated using X-ray analysis of rat tail vertebrae, the degeneration process was observed and repair was evaluated by chemically staining degenerative intervertebral disc tissue slices. The expression levels of basic fibroblast growth factor (bFGF), TGFβ1, Collagen I and Collagen II were measured in the intervertebral disc tissue using western blotting; while the expression levels of bFGF, TGFβ1 and hypoxia-inducible factor 1-α (HIF-1α) were measured in rat serum using ELISA. The results demonstrated that: i) The degree of intervertebral disc height degeneration in CIHH-IDD rats was significantly lower compared with that in IDD rats (P<0.05); ii) the expression levels of bFGF, TGFβ1 and HIF-1α were higher in CIHH-IDD rat serum compared with those in IDD rat serum (P<0.05); iii) optical microscopy revealed that the degree of disc degeneration was relatively mild in CIHH-IDD rats; and iv) the protein expression levels of bFGF, TGFβ1 and collagen II were increased in CIHH-IDD rat intervertebral disc tissues compared with those of IDD rats, while the overexpression of collagen I protein was inhibited. Overall, after CIHH pre-treatment, the expression levels of bFGF and TGFβ1 were up-regulated, which play notable roles in repairing degenerative intervertebral discs in rats.

Intervertebral disc degeneration (IVDD) occurs as a result of an imbalance of the anabolic and catabolic processes in the intervertebral disc, leading to an alteration in the composition of the extracellular matrix (ECM), loss of nucleus pulposus (NP) cells, excessive oxidative stress and inflammation. Degeneration of the IVD occurs naturally with age, but mechanical trauma, lifestyle factors and certain genetic abnormalities can increase the likelihood of symptomatic disease progression. IVDD, often referred to as degenerative disc disease (DDD), poses an increasingly substantial financial burden due to the aging population and increasing incidence of obesity in the United States. Current treatments for IVDD include pharmacological and surgical interventions, but these lack the ability to stop the progression of disease and restore the functionality of the IVD. Biological therapies have been evaluated but show varying degrees of efficacy in reversing disc degeneration long-term. Stem cell-based therapies have shown promising results in the regeneration of the IVD, but face both biological and ethical limitations. Exosomes play an important role in intercellular communication, and stem cell-derived exosomes have been shown to maintain the therapeutic benefit of their origin cells without the associated risks. This review highlights the current state of research on the use of stem-cell derived exosomes in the treatment of IVDD.

• disc degeneration
• disc regeneration
• exosomes
• intervertebral disc
• stem cells

• Animals
• Exosomes/metabolism
• Exosomes/transplantation
• Extracellular Matrix/metabolism
• Extracellular Matrix/pathology
• Humans
• Intervertebral Disc/metabolism
• Intervertebral Disc/pathology
• Intervertebral Disc/physiopathology
• Intervertebral Disc Degeneration/metabolism
• Intervertebral Disc Degeneration/pathology
• Intervertebral Disc Degeneration/physiopathology
• Intervertebral Disc Degeneration/surgery
• Recovery of Function
• Regeneration
• Stem Cell Transplantation

• R01 AR066517 NIAMS NIH HHS

A bibliometric review of the literature.

To identify the most frequently cited articles relating to the repair of intervertebral disc (IVD) and to summarize the key points and findings of these highly cited works, to quantify their impact on the developments of the disc disease treatment.

IVD repair is an ever-growing and multi-disciplinary innovating treatment method for disc diseases. There are numerous literatures and related studies about it, promoting the development of the field. A comprehensive review and analysis of the most influential articles can help clarify the most effective strategy of IVD repair, and discover the promising directions for future research.

The Thomson Reuters Web of Knowledge was searched for citations of all literatures relevant to IVD repair. The number of citations, key points, categories, authorships, years, journals, countries, and institutions of publications were analyzed.

The most highly cited articles in IVD Repair were published over 30 years, between 1991 and 2017. Most works (No. 41) were published between 2005 and 2009. The most-cited article was Sakai’s 2003 article which described the possibility of combining MSC and gel to repair IVD. The three most popular categories involved were Orthopedics [44], Clinical Neurology [34], Engineering, and Biomedical [24]. The three most common topics were regenerative medicine and the progenitor cells [33], biomaterials and cellular scaffolds [29], application of growth factors [25]. Author Masuda and the partners have 4 articles in the top 100 list. The Rush University has 12 articles in the top 100 list.

This report identifies the top 100 articles in IVD repair and acknowledges those individuals who have contributed the most to the study of the IVD repair and the body of knowledge used to the repair strategy making. It allows insight into the trends of this innovative and interdisciplinary subspecialty of spine surgery.

• adipogenesis
• alginate bead
• angiopoietin‐1 receptor
• chondrogenesis
• differentiation
• flow cytometry
• intervertebral disk
• microenvironment
• nucleus pulposus
• osteogenesis
• qPCR
• three‐dimensional culture
• tissue‐specific progenitor cells

Intervertebral disc degeneration is the main contributor to low back pain, now the leading cause of disability worldwide. Gene transfer, either in a therapeutic attempt or in basic research to understand the mechanisms of disc degeneration, is a fascinating and promising tool to manipulate the complex physiology of the disc. Viral vectors based on the adeno-associated virus (AAV) have emerged as powerful transgene delivery vehicles yet a systematic investigation into their respective tropism, transduction efficiency, and relative toxicity have not yet been performed in the disc in vivo. Herein, we used in vivo bioluminescence imaging to systematically compare multiple AAV serotypes, injection volumes, titers, promoters, and luciferase reporters to determine which result in high transduction efficiency of murine nucleus pulposus (NP) cells in vivo. We find that AAV6 using a CAG promoter to drive transgene expression, delivered into the NP of murine caudal discs at a titer of 10¹¹ GC/mL, provides excellent transduction efficiency/kinetics and low toxicity in vivo. We also show, for the first time, that the transduction of NP cells can be significantly boosted in vivo by the use of small cell permeabilization peptides. Finally, to our knowledge, we are the first to demonstrate the use of optical tissue clearing and three-dimensional lightsheet microscopy in the disc, which was used to visualize fine details of tissue and cell architecture in whole intact discs following AAV6 delivery. Taken together, these data will contribute to the success of using AAV-mediated gene delivery for basic and translational studies of the IVD.

• IGF‐1
• PAPPA
• aging
• cellular senescence
• intervertebral disc degeneration
• proteoglycan

• R01 AG044376 NIA NIH HHS
• Commonwealth of Pennsylvania: CURE Program Award
• American Federation for Aging Research

• growth differentiation factor 6
• growth factor signalling
• intervertebral disc degeneration
• nucleus pulposus
• regenerative medicine

• Adult
• Female
• Growth Differentiation Factor 6/pharmacology
• Humans
• Intervertebral Disc Degeneration/drug therapy
• Intervertebral Disc Degeneration/metabolism
• Intervertebral Disc Degeneration/pathology
• MAP Kinase Signaling System/drug effects
• Nucleus Pulposus/pathology
• Nucleus Pulposus/physiology
• Regeneration/drug effects
• Smad Proteins/metabolism

• MC_PC_14112 v.2 Medical Research Council
• MC_PC_14112 Medical Research Council
• MR/K026682/1 Medical Research Council
• MR/K026682/1 Biotechnology and Biological Sciences Research Council

Cellular senescence is a contributor to intervertebral disc (IVD) degeneration and low back pain. Here, we found that RG-7112, a potent mouse double-minute two protein inhibitor, selectively kills senescent IVD cells through apoptosis. Gene expression pathway analysis was used to compare the functional networks of genes affected by RG-7112, a pure synthetic senolytic with o-Vanillin a natural and anti-inflammatory senolytic. Both affected a functional gene network related to cell death and survival. O-Vanillin also affected networks related to cell cycle progression as well as connective tissue development and function. Both senolytics effectively decreased the senescence-associated secretory phenotype (SASP) of IVD cells. Furthermore, bioavailability and efficacy were verified ex vivo in the physiological environment of degenerating intact human discs where a single dose improved disc matrix homeostasis. Matrix improvement correlated with a reduction in senescent cells and SASP, supporting a translational potential of targeting senescent cells as a therapeutic intervention.

Pain in the lower back affects about four in five people during their lifetime. Over time, the discs that provide cushioning between the vertebrae of the spine can degenerate, which can be one of the major causes of lower back pain.

It has been shown that when the cells of these discs are exposed to different stress factors, they stop growing and become irreversibly dormant. Such ‘senescent’ cells release a range of proteins and small molecules that lead to painful inflammation and further degeneration of the discs. Moreover, it is thought that a high number of senescent cells may be linked to other degenerative diseases such as arthritis.

Current treatments can only reduce the severity of the symptoms, but they cannot prevent the degeneration from progressing. Now, Cherif et al. set out to test the effects of two different compounds on human disc cells grown in the laboratory. One of the molecules studied, RG-7112, is a synthetic drug that has been approved for safety by the US Food and Drug Administration and has been shown to remove senescent cells. The other, o-Vanillin, is a natural compound that has anti-inflammatory and anti-senescence properties.

The results showed that both compounds were able to trigger changes to that helped new, healthy cells to grow and at the same time kill senescent cells. They also reduced the production of molecules linked to inflammation and pain.

Further analyses revealed that the compounds were able to strengthen the fibrous matrix that surrounds and supports the discs. Cherif et al. hope that this could form the basis for a new family of drugs for back pain to slow the degeneration of the discs and reduce pain. This may also have benefits for other similar degenerative diseases caused by cell senescence, such as arthritis.

• annulus fibrosus
• cartilage
• cell biology
• human
• intervertebral disc
• medicine
• nucleus pulposus

• cell
• degenerative disc disease
• tissue engineering

With an aging population, there is a proportional increase in the prevalence of intervertebral disc diseases. Intervertebral disc diseases are the leading cause of lower back pain and disability. With a high prevalence of asymptomatic intervertebral disc diseases, there is a need for accurate diagnosis, which is key to management. A thorough understanding of the pathophysiology and clinical manifestation aids in understanding the natural history of these conditions. Recent developments in radiological and biomarker investigations have potential to provide noninvasive alternatives to the gold standard, invasive discogram. There is a large volume of literature on the management of intervertebral disc diseases, which we categorized into five headings: (a) Relief of pain by conservative management, (b) restorative treatment by molecular therapy, (c) reconstructive treatment by percutaneous intervertebral disc techniques, (d) relieving compression and replacement surgery, and (e) rigid fusion surgery. This review article aims to provide an overview on various current diagnostic and treatment options and discuss the interplay between each arms of these scientific and treatment advancements, hence providing an outlook of their potential future developments and collaborations in the management of intervertebral disc diseases.

• degenerative disc disease
• gene therapy
• intervertebral disc
• spinal decompression
• spinal endoscopy
• spinal fusion
• spinal injection
• spinal molecular therapy
• spine pain management
• stem cells

• Stem cell transplantation
• intervertebral disc degeneration
• low back pain
• regenerative medicine
• tissue scaffolds

• degeneration model
• inflammation
• needle stab
• pulsed electromagnetic fields
• rat‐tail disc

• BMP-3
• IL-1beta
• chondrogenesis
• co-culture
• human mesenchymal stem cells
• intervertebral disc cells

• 3D collagen gel culture
• Fibroblast growth factor
• Fibronectin-coated dish
• Micromass culture
• Mouse nucleus pulposus cells
• Transforming growth factor-β

• CTGF
• TGF-β1
• gene transfer
• lumbar disc degeneration
• nucleus pulposus cells

Intervertebral disc degeneration is a major source of back pain. For intervertebral disc regeneration after herniation a fast closure of anulus fibrosus (AF) defects is crucial. Here, the use of the C-C motif chemokine ligand 25 (CCL)25 in comparison to differentiation factors such as transforming growth factor (TGF)β3, bone morphogenetic protein (BMP)2, BMP7, BMP12, and BMP14 (all in concentrations of 10, 50 and 100 ng/mL) was tested in an in vitro micro mass pellet model with isolated and cultivated human AF-cells (n = 3) to induce and enhance AF-matrix formation. The pellets were differentiated (serum-free) with supplementation of the factors. After 28 days all used factors induced proteoglycan production (safranin O staining) and collagen type I production (immunohistochemical staining) in at least one of the tested concentrations. Histomorphometric scoring revealed that TGFβ3 delivered the strongest induction of proteoglycan production in all three concentrations. Furthermore, it was the only factor able to facilitate collagen type II production, even higher than in native tissue samples. CCL25 was also able to induce proteoglycan and collagen type I production comparable to several BMPs. CCL25 could additionally induce migration of AF-cells in a chemotaxis assay and therefore possibly aid in regeneration processes after disc herniation by recruiting AF-cells.

• CCL25
• TECK
• anulus fibrosus
• chemotaxis
• differentiation
• extracellular matrix
• tissue regeneration

• Annulus Fibrosus/cytology
• Annulus Fibrosus/metabolism
• Bone Morphogenetic Proteins/metabolism
• Cell Movement
• Cells, Cultured
• Chemokines, CC/metabolism
• Chemotaxis
• Collagen Type I/metabolism
• Extracellular Matrix/metabolism
• Humans
• Proteoglycans/metabolism
• Transforming Growth Factor beta3/metabolism

• growth factor
• intervertebral disc
• intervertebral disc disease
• tissue engineering

Intervertebral disc degeneration is a disease of the discs connecting adjoining vertebrae in which structural damage leads to loss of disc integrity. Degeneration of the disc can be a normal process of ageing, but can also be precipitated by other factors. Literature has made substantial progress in understanding the biological basis of intervertebral disc, which is reviewed here. Current medical and surgical management strategies have shortcomings that do not lend promise to be effective solutions in the coming years. With advances in understanding the cell biology and characteristics of the intervertebral disc at the molecular and cellular level that have been made, alternative strategies for addressing disc pathology can be discovered. A brief overview of the anatomic, cellular, and molecular structure of the intervertebral disc is provided as well as cellular and molecular pathophysiology surrounding intervertebral disc degeneration. Potential therapeutic strategies involving stem cell, protein, and genetic therapy for intervertebral disc degeneration are further discussed.

• Stem cells
• disc
• disc cells
• intervertebral disc degeneration

• Annulus fibrosis (AF)
• Intervertebral disc degeneration
• Mesenchymal stem cells (MSCs)
• Nucleus pulposus (NP)
• Vertebral body

• bone morphogenetic growth factor-3
• chondrogenesis
• human mesenchymal stem cells
• interleukin-1β
• intervertebral discs

Our study is an analysis of the histological and radiological changes in degenerated lumbar intervertebral discs, after transplantation of fibroblasts in rabbits. With that study we aimed to show the viability of the fibroblasts injected to the degenerated discs, and observe their potential for further studies.

The apoptosis of the cell is one of the factors at the disc degeneration process. Fibroblasts may act as mesenchymal stem cells at the tissue to which they are injected and they may replace the apoptotic cells. The nucleus pulposus of the discs from eight rabbits were aspirated under scopic guidance to induce disc degeneration.

One month later, cultured fibroblasts, which had been taken from the skin, were injected into the disc. The viability and the potential of the injected cells for reproduction were studied histologically and radiologically. Cellular formations and organizations indicating to the histological recovery were observed at the discs to which fibroblasts were transplanted. The histological findings of the discs to which no fibroblasts were transplanted, did not show any histological recovery. Radiologically, no finding of the improvement was found in both groups. The fibroblasts injected to the degenerated discs are viable.

The findings of improvement, observed in this study, suggest that fibroblast transplantation could be an effective method of therapy for the prevention or for the retardation of the degenerative disease of the discs.

• Aging
• Animals
• Cells
• Cultured
• Disease models
• Fibroblasts
• Lumbar disc degeneration
• Pathology
• Rabbit

Back pain is the second leading cause of disability among American adults and is currently treated either with conservative therapy or interventional pain procedures. However, the question that remains is whether we, as physicians, have adequate therapeutic options to offer to the patients who suffer from chronic low back pain but fail both conservative therapy and interventional pain procedures before they consider surgical options such as discectomy, disc arthroplasty, or spinal fusion. The purpose of this article is to review the potential novel therapies that are on the horizon for the treatment of chronic low back pain. We discuss medications that are currently in use through different phases of clinical trials (I–III) for the treatment of low back pain. In this review, we discuss revisiting the concept of chemonucleolysis using chymopapain, as the first drug in an intradiscal injection to reduce herniated disc size, and newer intradiscal therapies, including collagenase, chondroitinase, matrix metalloproteinases, and ethanol gel. We also review an intravenous glial cell-derived neurotrophic growth factor called artemin, which may repair sensory nerves compressed by herniated discs. Another new drug in development for low back pain without radiculopathy is a subcutaneous monoclonal antibody acting as nerve growth factor called tanezumab. Finally, we discuss how platelet-rich plasma and stem cells are being studied for the treatment of low back pain. We believe that with these new therapeutic options, we can bridge the current gap between conservative/interventional procedures and surgeries in patients with chronic back pain.

• PRP
• artemin
• chemonucleolysis
• chronic low back pain
• clinical trials
• new therapy
• stem cells
• tanezumab

• Biologics
• Disk degeneration
• Disk repair
• Gene therapy
• Injectables
• Intervertebral disk
• Spine
• Stem cells
• Tissue engineering

• Animals
• Biological Therapy
• Extracellular Matrix
• Genetic Therapy
• Humans
• Intervertebral Disc Degeneration/complications
• Intervertebral Disc Degeneration/pathology
• Intervertebral Disc Degeneration/therapy
• Low Back Pain/etiology
• Low Back Pain/prevention & control
• Tissue Engineering

• R01 AR057397 NIAMS NIH HHS
• R01 AR064157 NIAMS NIH HHS
• R01 AR069315 NIAMS NIH HHS

• Hyaluronic acid
• glutaraldehyde
• hydrogel
• plugs
• polyaspartic acid

The involvement of growth factors (GFs) in the pathogenesis of lumbar intervertebral disc (ID) herniation and the spontaneous resorption of herniated ID fragments remains only partially elucidated. A simultaneous assessment of the transcript levels of numerous GFs and their association with clinical and epidemiological profiles of human ID herniation would provide valuable insight into the biology and clinical course of the disease. In the present study, we examined simultaneously the transcript levels of vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF-β1), basic fibroblast growth factor 2 (bFGF2), platelet derived growth factor (PDGF) isoforms and receptors, epidermal growth factor (EGF) and insulin growth factor-1 (IGF-1) in herniated and control ID specimens and investigated their correlation with the clinicopathological profiles of patients suffering from symptomatic lumbar ID herniation. GF mRNA expression levels were determined by RT-qPCR in 63 surgical specimens from lumbar herniated discs and 10 control ID specimens. Multiple positive correlations were observed between the transcript levels of the GFs examined in the ID herniation group. VEGF mRNA expression was significantly increased in the protruding compared with the extruded discs. Intense and acute pain significantly upregulated the PDGF transcript levels. Significant negative correlations were observed between the patient body mass index and the transcript levels of VEGF and PDGF receptors. Our findings support the hypothesis of the involvement of GFs in the natural history of ID herniation. GFs synergistically act in herniated IDs. Increased VEGF expression possibly induces the neovascularization process in the earliest stages of ID herniation. PDGF-C and -D play a role in the acute phase of radiculopathy in a metabolic response for tissue healing. A molecular effect, in addition to the biomechanical effect of obesity in the pathogenesis of ID herniation is also implied.

• Intervertebral disc degeneration
• Intervertebral disc regeneration
• Mesenchymal stem cells
• Platelet-rich plasma
• Tissue engineering

Exogenous crosslinking has been shown to have potential for treating disc degeneration and back pain due to its ability to increase the strength and toughness of the annulus fibrosus, increase intervertebral joint stability, decrease intradiscal pressure, and increase fluid flow through the disc. Some results imply that crosslink augmentation may also lead to changes in the compressive load sharing properties of the disc. The objective of the present study was to evaluate directional stress distribution changes of the disc following genipin crosslinking treatment. Bovine lumbar motion segments were randomly divided into control and crosslinked groups. Annular strains were determined from simultaneous deformation measurements at various time points during compressive creep testing. Four stress components of the annulus were then calculated according to the previously measured modulus data. Immediately after the application of a 750-N compressive load, mean axial and radial compressive stresses in the crosslinked group were twofold higher than control means. Conversely, mean lamellae-aligned and circumferential tensile stresses of the crosslinked discs were 8- and threefold lower, respectively, compared to control means. After 1-h creep loading, the two compressive mean stresses in both the control and genipin-crosslinked specimens increased approximately threefold from their initial 750-N-loaded values. The two tensile mean stresses in the crosslinked group remained lower than the respective levels of the control means after creep loading. A greater proportion of annular compressive load support under compressive creep loading, with a commensurate decrease in both tensile stresses and strains, was seen in the discs following exogenous crosslink augmentation.

• Compressive creep loading
• Crosslink augmentation
• Intervertebral disc
• Load sharing
• Stress distribution

• Chitosan
• Intervertebral disc
• Nanoparticles
• Organ culture
• Poly(γ-glutamic acid)

• Animals
• Cattle
• Cells, Cultured
• Chitosan/chemistry
• Chondrocytes/cytology
• Collagen/chemistry
• Collagen Type II/chemistry
• DNA/chemistry
• Glutamic Acid/chemistry
• Glycosaminoglycans/chemistry
• Humans
• Hydrogen-Ion Concentration
• Intervertebral Disc/surgery
• Intervertebral Disc Degeneration/therapy
• Light
• Mesenchymal Stem Cells/cytology
• Microscopy, Electron, Transmission
• Nanocomposites/chemistry
• Nanotechnology
• Polyglutamic Acid/analogs & derivatives
• Polyglutamic Acid/chemistry
• Polymers/chemistry
• Regeneration
• Scattering, Radiation
• Static Electricity

To assess role of some inflammatory mediators in patients with primary and recurrent lumbar disc herniation. Expression of IL-6, transforming growth factor (TGF)-1, insulin-like growth factor (IGF)-1, and Bcl-2-associated X protein (BAX) have been shown to be more intense in the primary group than the recurrent goup, but this mediators may be important aspects prognostic.

19 patients underwent primary and revision operations between June 1, 2009 and June 1, 2014, and they were included in this study. The 19 patients’ intervertebral disc specimens obtained from the primary procedures and reoperations were evaluated. Expression of IL-6, TGF-1, IGF-1, and BAX were examined immunohistochemically in the 38 biopsy tissues obtained from the primary and recurrent herniated intervertebral discs during the operation.

For IL-6 expression in the intervertebral disc specimens, there was no difference between the groups. The immunohistochemical study showed that the intervertebral disc specimens in the primary group were stained intensely by TGF-1 compared with the recurrent group. Expression of IGF-1 in the primary group was found moderate. In contrast, in the recurrent group of patients was mild expression of IGF-1. The primary group intervertebral disc specimens were stained moderately by BAX compared with the recurrent group.

The results of our prognostic evaluation of patients in the recurrent group who were operated due to disc herniation suggest that mediators may be important parameters.

• Disc herniation
• Immunohistochemical
• Inflammatory mediators

• DNA delivery
• electroporation
• intervertebral disc
• nonviral gene therapy
• tissue engineering applications

• Cell carrier
• Chondrogenesis
• Disc degeneration
• Human mesenchymal stem cells
• Hydrogels
• Intervertebral disc

• annular repair
• back pain
• cell therapy
• disk regeneration
• growth factor
• intervertebral disk
• platelet-rich plasma
• tissue engineering