Intervertebral disc regeneration: from the degenerative cascade to molecular therapy and tissue engineering

Low back pain is one of the major health problems in industrialized countries, as a leading source of disability in the working population. Intervertebral disc degeneration has been identified as its main cause, being a progressive process mainly characterized by alteration of extracellular matrix composition and water content. Many factors are involved in the degenerative cascade, such as anabolism/catabolism imbalance, reduction of nutrition supply and progressive cell loss. Currently available treatments are symptomatic, and surgical procedures consisting of disc removal are often necessary. Recent advances in our understanding of intervertebral disc biology led to an increased interest in the development of novel biological treatments aimed at disc regeneration. Growth factors, gene therapy, stem cell transplantation and biomaterials‐based tissue engineering might support intervertebral disc regeneration by overcoming the limitation of the self‐renewal mechanism. The aim of this paper is to overview the literature discussing the current status of our knowledge from the degenerative cascade of the intervertebral disc to the latest molecular, cell‐based therapies and tissue‐engineering strategies for disc regeneration. Copyright © 2013 John Wiley & Sons, Ltd.

[1]  M. Alini,et al.  Injectable thermoreversible hyaluronan-based hydrogels for nucleus pulposus cell encapsulation , 2012, European Spine Journal.

[2]  Bing Wang,et al.  Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model. , 2012, The spine journal : official journal of the North American Spine Society.

[3]  C. Hunter,et al.  Developing an alginate/chitosan hybrid fiber scaffold for annulus fibrosus cells. , 2007, Journal of biomedical materials research. Part A.

[4]  E. Thonar,et al.  Platelet-Rich Plasma (PRP) Stimulates the Extracellular Matrix Metabolism of Porcine Nucleus Pulposus and Anulus Fibrosus Cells Cultured in Alginate Beads , 2006, Spine.

[5]  H. Lorenz,et al.  Multilineage cells from human adipose tissue: implications for cell-based therapies. , 2001, Tissue engineering.

[6]  Rolando Barbucci,et al.  Amidic alginate hydrogel for nucleus pulposus replacement. , 2008, Journal of biomedical materials research. Part A.

[7]  H E Gruber,et al.  Analysis of Aging and Degeneration of the Human Intervertebral Disc: Comparison of Surgical Specimens With Normal Controls , 1998, Spine.

[8]  T. Albert,et al.  Evidence for Skeletal Progenitor Cells in the Degenerate Human Intervertebral Disc , 2007, Spine.

[9]  J. Ott,et al.  An allele of COL9A2 associated with intervertebral disc disease. , 1999, Science.

[10]  K. Yudoh,et al.  Autocrine/paracrine mechanism of insulin‐like growth factor‐1 secretion, and the effect of insulin‐like growth factor‐1 on proteoglycan synthesis in bovine intervertebral discs , 1996, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[11]  A. Lindahl,et al.  Transplantation of Human Mesenchymal Stems Cells Into Intervertebral Discs in a Xenogeneic Porcine Model , 2009, Spine.

[12]  J. Ringe,et al.  Regenerative treatment strategies in spinal surgery. , 2008, Frontiers in bioscience : a journal and virtual library.

[13]  A. Mobasheri,et al.  Mesenchymal stem cells in regenerative medicine: Opportunities and challenges for articular cartilage and intervertebral disc tissue engineering , 2010, Journal of cellular physiology.

[14]  Deli Wang,et al.  Differentiation of human Wharton's jelly cells toward nucleus pulposus-like cells after coculture with nucleus pulposus cells in vitro. , 2012, Tissue engineering. Part A.

[15]  James D. Kang,et al.  Coculture of Bone Marrow Mesenchymal Stem Cells and Nucleus Pulposus Cells Modulate Gene Expression Profile Without Cell Fusion , 2008, Spine.

[16]  H. Blau,et al.  The Evolving Concept of a Stem Cell Entity or Function? , 2001, Cell.

[17]  E. Thonar,et al.  Transplantation of Goat Bone Marrow Stromal Cells to the Degenerating Intervertebral Discin a Goat Disc Injury Model , 2011, Spine.

[18]  A. Salgado,et al.  Angiogenic potential of gellan-gum-based hydrogels for application in nucleus pulposus regeneration: in vivo study. , 2012, Tissue engineering. Part A.

[19]  E. Thonar,et al.  Osteogenic Protein-1 Injection Into a Degenerated Disc Induces the Restoration of Disc Height and Structural Changes in the Rabbit Anular Puncture Model , 2006, Spine.

[20]  A. Vaccaro,et al.  Biologic Solutions for Degenerative Disk Disease , 2009, Journal of spinal disorders & techniques.

[21]  James D. Kang,et al.  Differentiation of Intervertebral Notochordal Cells Through Live Automated Cell Imaging System In Vitro , 2009, Spine.

[22]  Mauro Alini,et al.  The Transpedicular Approach As an Alternative Route for Intervertebral Disc Regeneration , 2013, Spine.

[23]  A. Wallace,et al.  Humoral Regulation of Blood Flow in the Vertebral Endplate , 1994, Spine.

[24]  D. Sakai,et al.  Transplantation of mesenchymal stem cells in a canine disc degeneration model , 2008, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[25]  Soon Hee Kim,et al.  Fibrin and poly(lactic-co-glycolic acid) hybrid scaffold promotes early chondrogenesis of articular chondrocytes: an in vitro study , 2008, Journal of orthopaedic surgery and research.

[26]  D. Sakai,et al.  Upregulation of the Viability of Nucleus Pulposus Cells by Bone Marrow-Derived Stromal Cells: Significance of Direct Cell-to-Cell Contact in Coculture System , 2004, Spine.

[27]  James D. Kang,et al.  Feasibility of a stem cell therapy for intervertebral disc degeneration. , 2008, The spine journal : official journal of the North American Spine Society.

[28]  T. Flotte,et al.  Delayed Expression of Adeno-Associated Virus Vector DNA , 1999, Intervirology.

[29]  J. Lotz,et al.  Innervation, inflammation, and hypermobility may characterize pathologic disc degeneration: review of animal model data. , 2006, The Journal of bone and joint surgery. American volume.

[30]  J. Lotz,et al.  New challenges for intervertebral disc treatment using regenerative medicine. , 2010, Tissue engineering. Part B, Reviews.

[31]  James D. Kang,et al.  In vitro interaction between muscle-derived stem cells and nucleus pulposus cells. , 2008, The spine journal : official journal of the North American Spine Society.

[32]  T. Albert,et al.  Galectin-3 Expression in the Intervertebral Disc: A Useful Marker of the Notochord Phenotype? , 2007, Spine.

[33]  C. Laurencin,et al.  Biphasic scaffold for annulus fibrosus tissue regeneration. , 2008, Biomaterials.

[34]  Arijitt Borthakur,et al.  T1&rgr; Magnetic Resonance Imaging Quantification of Early Lumbar Intervertebral Disc Degeneration in Healthy Young Adults , 2012, Spine.

[35]  Tong-Chuan He,et al.  Potential Use of Sox9 Gene Therapy for Intervertebral Degenerative Disc Disease , 2003, Spine.

[36]  A R Hargens,et al.  Intervertebral disc nutrition. Diffusion versus convection. , 1986, Clinical orthopaedics and related research.

[37]  R. C. Mulholland,et al.  The myth of lumbar instability: the importance of abnormal loading as a cause of low back pain , 2008, European Spine Journal.

[38]  M. Pfeiffer,et al.  Intradiscal application of hyaluronic acid in the non-human primate lumbar spine: radiological results , 2003, European Spine Journal.

[39]  M. Battié,et al.  Lumbar Disc Degeneration: Epidemiology and Genetic Influences , 2004, Spine.

[40]  J. P. Thompson,et al.  Stimulation of Mature Canine Intervertebral Disc by Growth Factors , 1991, Spine.

[41]  M. Endres,et al.  Human intervertebral disc-derived cells are recruited by human serum and form nucleus pulposus-like tissue upon stimulation with TGF-beta3 or hyaluronan in vitro. , 2009, Tissue & cell.

[42]  L. Setton,et al.  Collagen gene expression and mechanical properties of intervertebral disc cell–alginate cultures , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[43]  P. A. Revell,et al.  Tissue engineered intervertebral disc repair in the pig using injectable polymers , 2007, Journal of materials science. Materials in medicine.

[44]  M. Adams,et al.  What is Intervertebral Disc Degeneration, and What Causes It? , 2006, Spine.

[45]  V. Denaro,et al.  Bioactive electrospun scaffold for annulus fibrosus repair and regeneration , 2012, European Spine Journal.

[46]  James D. Kang,et al.  Effect of bupivacaine on intervertebral disc cell viability. , 2010, The spine journal : official journal of the North American Spine Society.

[47]  W. Hutton,et al.  Effect of Bone Morphogenetic Protein-2 (BMP-2) on Matrix Production, Other BMPs, and BMP Receptors in Rat Intervertebral Disc Cells , 2004, Journal of spinal disorders & techniques.

[48]  I. Sekiya,et al.  Intradiscal transplantation of synovial mesenchymal stem cells prevents intervertebral disc degeneration through suppression of matrix metalloproteinase-related genes in nucleus pulposus cells in rabbits , 2010, Arthritis research & therapy.

[49]  A. Mackay-Sim,et al.  Olfactory stem cells can be induced to express chondrogenic phenotype in a rat intervertebral disc injury model. , 2009, The spine journal : official journal of the North American Spine Society.

[50]  M. Aebi,et al.  The Potential and Limitations of a Cell-Seeded Collagen/Hyaluronan Scaffold to Engineer an Intervertebral Disc-Like Matrix , 2003, Spine.

[51]  Xinlin Yang,et al.  Nucleus pulposus tissue engineering: a brief review , 2009, European Spine Journal.

[52]  J. Gough,et al.  In vitro studies of annulus fibrosus disc cell attachment, differentiation and matrix production on PDLLA/45S5 Bioglass composite films. , 2006, Biomaterials.

[53]  J. Urban,et al.  Nutrition of the Intervertebral Disc , 2004, Spine.

[54]  J. Ralphs,et al.  Are animal models useful for studying human disc disorders/degeneration? , 2007, European Spine Journal.

[55]  Johnny Huard,et al.  Clonal Isolation of Muscle-Derived Cells Capable of Enhancing Muscle Regeneration and Bone Healing , 2000, The Journal of cell biology.

[56]  K. Cheung,et al.  Tissue engineering for intervertebral disk degeneration. , 2011, The Orthopedic clinics of North America.

[57]  B. Zheng,et al.  Muscle stem cells differentiate into haematopoietic lineages but retain myogenic potential , 2003, Nature Cell Biology.

[58]  James D. Kang,et al.  p38 MAPK Inhibition in Nucleus Pulposus Cells: A Potential Target for Treating Intervertebral Disc Degeneration , 2007, Spine.

[59]  B. Caterson,et al.  Matrix Metalloproteinases And Aggrecanase: Their Role in Disorders of the Human Intervertebral Disc , 2000, Spine.

[60]  Lars G. Gilbertson,et al.  Biologic Response of Human Intervertebral Disc Cells to Gene Therapy Cocktail , 2008, Spine.

[61]  E. Scott,et al.  Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion , 2002, Nature.

[62]  R. Bank,et al.  Differentiation of adipose stem cells by nucleus pulposus cells: configuration effect. , 2007, Biochemical and biophysical research communications.

[63]  G. Vunjak‐Novakovic,et al.  Porous silk scaffolds can be used for tissue engineering annulus fibrosus , 2007, European Spine Journal.

[64]  H. Uludaǧ,et al.  Carrier systems for bone morphogenetic proteins. , 1999, Clinical orthopaedics and related research.

[65]  James D. Kang,et al.  Safety Assessment of Intradiscal Gene Therapy II: Effect of Dosing and Vector Choice , 2008, Spine.

[66]  A. Wobus.  Potential of embryonic stem cells. , 2001, Molecular aspects of medicine.

[67]  D. Hu,et al.  LMP-1, a LIM-domain protein, mediates BMP-6 effects on bone formation. , 1998, Endocrinology.

[68]  G. Hafner,et al.  Growth factor levels in platelet-rich plasma and correlations with donor age, sex, and platelet count. , 2002, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[69]  Keita Ito,et al.  2004 Young Investigator Award Winner: Vertebral Endplate Marrow Contact Channel Occlusions and Intervertebral Disc Degeneration , 2005, Spine.

[70]  H. An,et al.  Histological Features of the Degenerating Intervertebral Disc in a Goat Disc-Injury Model , 2011, Spine.

[71]  G. Vunjak‐Novakovic,et al.  Enhancing annulus fibrosus tissue formation in porous silk scaffolds. , 2010, Journal of biomedical materials research. Part A.

[72]  H. Matsui,et al.  Association between an aggrecan gene polymorphism and lumbar disc degeneration. , 1999, Spine.

[73]  Charles A Vacanti,et al.  Tissue-Engineered Composites of Anulus Fibrosus and Nucleus Pulposus for Intervertebral Disc Replacement , 2004, Spine.

[74]  Chao Zhang,et al.  Experimental intervertebral disc regeneration with tissue-engineered composite in a canine model. , 2010, Tissue engineering. Part A.

[75]  James D. Kang,et al.  Quantitative analysis of gene expression in a rabbit model of intervertebral disc degeneration by real-time polymerase chain reaction. , 2005, The spine journal : official journal of the North American Spine Society.

[76]  James D. Kang,et al.  Characterization of Intervertebral Disc Aging: Longitudinal Analysis of a Rabbit Model by Magnetic Resonance Imaging, Histology, and Gene Expression , 2008, Spine.

[77]  M. Spector,et al.  Regional variations in certain cellular characteristics in human lumbar intervertebral discs, including the presence of α‐smooth muscle actin , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[78]  Lars G Gilbertson,et al.  A Slowly Progressive and Reproducible Animal Model of Intervertebral Disc Degeneration Characterized by MRI, X-Ray, and Histology , 2005, Spine.

[79]  E. Hurwitz,et al.  2009 ISSLS Prize Winner: Does Discography Cause Accelerated Progression of Degeneration Changes in the Lumbar Disc: A Ten-Year Matched Cohort Study , 2009, Spine.

[80]  J. Urban,et al.  Swelling pressure of the inervertebral disc: influence of proteoglycan and collagen contents. , 1985, Biorheology.

[81]  J A Buckwalter,et al.  Aging and degeneration of the human intervertebral disc. , 1995, Spine.

[82]  M. Alini,et al.  An injectable cross-linked scaffold for nucleus pulposus regeneration. , 2008, Biomaterials.

[83]  Yusuke Nakamura,et al.  A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease , 2005, Nature Genetics.

[84]  A. Freemont,et al.  The role of interleukin-1 in the pathogenesis of human Intervertebral disc degeneration , 2005, Arthritis research & therapy.

[85]  D. Sakai,et al.  Stem cell applications in intervertebral disc repair. , 2008, Cellular and molecular biology.

[86]  Joji Mochida,et al.  Differentiation of Mesenchymal Stem Cells Transplanted to a Rabbit Degenerative Disc Model: Potential and Limitations for Stem Cell Therapy in Disc Regeneration , 2005, Spine.

[87]  J A Buckwalter,et al.  Ultrastructure of the human intervertebral disc. I. Changes in notochordal cells with age. , 1982, Tissue & cell.

[88]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[89]  G. Balian,et al.  Modulation of Chondrocytic Properties of Fat-Derived Mesenchymal Cells in Co-Cultures with Nucleus Pulposus , 2005, Connective Tissue Research.

[90]  Lauren N. Smith,et al.  Regulation of Transgene Expression Using an Inducible System for Improved Safety of Intervertebral Disc Gene Therapy , 2007, Spine.

[91]  H. Haro,et al.  The association of degeneration of the intervertebral disc with 5a/6a polymorphism in the promoter of the human matrix metalloproteinase-3 gene. , 2001, The Journal of bone and joint surgery. British volume.

[92]  Wan-Ju Li,et al.  Intervertebral disc tissue engineering using a novel hyaluronic acid-nanofibrous scaffold (HANFS) amalgam. , 2008, Tissue engineering. Part A.

[93]  Korovessis Pg,et al.  Comparison of surgical specimens with normal controls. , 1999 .

[94]  Alexander R. Vaccaro,et al.  Nucleus Pulposus Replacement: Basic Science and Indications for Clinical Use , 2005, Spine.

[95]  T. Smit,et al.  Repair, regenerative and supportive therapies of the annulus fibrosus: achievements and challenges , 2008, European Spine Journal.

[96]  T. Albert,et al.  Differentiation of Mesenchymal Stem Cells Towards a Nucleus Pulposus-like Phenotype In Vitro: Implications for Cell-Based Transplantation Therapy , 2004, Spine.

[97]  M. Alini,et al.  Tailoring thermoreversible hyaluronan hydrogels by "click" chemistry and RAFT polymerization for cell and drug therapy. , 2010, Biomacromolecules.

[98]  J. García-Sancho,et al.  Intervertebral Disc Repair by Autologous Mesenchymal Bone Marrow Cells: A Pilot Study , 2011, Transplantation.

[99]  J. Matyas,et al.  The notochordal cell in the nucleus pulposus: a review in the context of tissue engineering. , 2003, Tissue engineering.

[100]  Brendon M. Baker,et al.  NANOFIBROUS BIOLOGIC LAMINATES REPLICATE THE FORM AND FUNCTION OF THE ANNULUS FIBROSUS , 2009, Nature materials.

[101]  A. Sadikot,et al.  Isolation of multipotent adult stem cells from the dermis of mammalian skin , 2001, Nature Cell Biology.

[102]  Lars G. Gilbertson,et al.  Gene Transfer of the Catabolic Inhibitor TIMP-1 Increases Measured Proteoglycans in Cells from Degenerated Human Intervertebral Discs , 2003, Spine.

[103]  L. Bonassar,et al.  Self-assembly of aligned tissue-engineered annulus fibrosus and intervertebral disc composite via collagen gel contraction. , 2010, Tissue engineering. Part A.

[104]  James D. Kang,et al.  Gene therapy for the treatment of degenerative disk disease. , 2008, The Journal of the American Academy of Orthopaedic Surgeons.

[105]  Samantha C W Chan,et al.  Intervertebral disc regeneration or repair with biomaterials and stem cell therapy--feasible or fiction? , 2012, Swiss medical weekly.

[106]  J. Gough,et al.  Cell viability, proliferation and extracellular matrix production of human annulus fibrosus cells cultured within PDLLA/Bioglass composite foam scaffolds in vitro. , 2008, Acta biomaterialia.

[107]  James D. Kang,et al.  Gene therapy for disc degeneration , 2007, Expert opinion on biological therapy.

[108]  L G Gilbertson,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 beta 1 encoding gene. , 1999, Spine.

[109]  E. Thonar,et al.  Metabolism of the Extracellular Matrix Formed by Intervertebral Disc Cells Cultured in Alginate , 1997, Spine.

[110]  N. Boos,et al.  Cell-seeded polyurethane-fibrin structures--a possible system for intervertebral disc regeneration. , 2009, European cells & materials.

[111]  H. Bertram,et al.  Matrix-assisted cell transfer for intervertebral disc cell therapy. , 2005, Biochemical and biophysical research communications.

[112]  Ricardo Pietrobon,et al.  Estimates and Patterns of Direct Health Care Expenditures Among Individuals With Back Pain in the United States , 2004, Spine.

[113]  N. Boos,et al.  Age-Related Variation in Cell Density of Human Lumbar Intervertebral Disc , 2011, Spine.

[114]  W. Hutton,et al.  Clinical experience in cell-based therapeutics: intervention and outcome , 2006, European Spine Journal.

[115]  P. Regitnig,et al.  Single lamellar mechanics of the human lumbar anulus fibrosus , 2005, Biomechanics and modeling in mechanobiology.

[116]  N. Boos,et al.  2002 SSE Award Competition in Basic Science: Expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption , 2002, European Spine Journal.

[117]  K. Ando,et al.  Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration. , 2003, Biomaterials.

[118]  S. Richardson,et al.  Stem cell regeneration of degenerated intervertebral discs: Current status , 2008, Current pain and headache reports.

[119]  James D. Kang,et al.  Toward a Biochemical Understanding of Human Intervertebral Disc Degeneration and Herniation: Contributions of Nitric Oxide, Interleukins, Prostaglandin E2, and Matrix Metalloproteinases , 1997, Spine.

[120]  V. Denaro,et al.  Anatomo-Clinical Correlations in Cervical Spondylosis , 1987 .

[121]  D. Kaplan,et al.  Annulus fibrosus tissue engineering using lamellar silk scaffolds , 2012, Journal of tissue engineering and regenerative medicine.

[122]  L. Ala‐Kokko,et al.  Interleukin 1 Polymorphisms and Intervertebral Disc Degeneration , 2004, Epidemiology.

[123]  George M. Wahba,et al.  Intervertebral Disc Cell Therapy for Regeneration: Mesenchymal Stem Cell Implantation in Rat Intervertebral Discs , 2004, Annals of Biomedical Engineering.

[124]  B. Harfe,et al.  Degeneration and regeneration of the intervertebral disc: lessons from development , 2010, Disease Models & Mechanisms.

[125]  H. An,et al.  Growth Factors and Treatment of Intervertebral Disc Degeneration , 2004, Spine.

[126]  V. Denaro,et al.  Poly-l-Lactic Acid/Hydroxyapatite Electrospun Nanocomposites Induce Chondrogenic Differentiation of Human MSC , 2009, Annals of Biomedical Engineering.

[127]  C. Laurencin,et al.  Novel biodegradable poly(1,8-octanediol malate) for annulus fibrosus regeneration. , 2007, Macromolecular bioscience.

[128]  S. Nicoll,et al.  Characterization of novel photocrosslinked carboxymethylcellulose hydrogels for encapsulation of nucleus pulposus cells. , 2010, Acta biomaterialia.

[129]  Vincenzo Denaro,et al.  Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation , 2012, Journal of tissue engineering and regenerative medicine.

[130]  E. Thonar,et al.  Osteogenic protein-1 enhances matrix replenishment by intervertebral disc cells previously exposed to interleukin-1. , 2002, Spine.

[131]  V. Denaro,et al.  Toward an Optimum System for Intervertebral Disc Organ Culture: TGF-β3 Enhances Nucleus Pulposus and Anulus Fibrosus Survival and Function Through Modulation of TGF-β-R Expression and ERK Signaling , 2006, Spine.

[132]  C. Peter Winlove,et al.  Oxygen and Lactate Concentrations Measured in Vivo in the Intervertebral Discs of Patients With Scoliosis and Back Pain , 1998, Spine.

[133]  G. Balian,et al.  Collagen and Proteoglycan Abnormalities in the GDF-5-Deficient Mice and Molecular Changes When Treating Disk Cells With Recombinant Growth Factor , 2004, Spine.

[134]  James D. Kang,et al.  In Vitro and in Vivo Testing of a Novel Regulatory System for Gene Therapy for Intervertebral Disc Degeneration , 2011, Spine.

[135]  K. Ando,et al.  Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc. , 2006, Biomaterials.

[136]  S. Richardson,et al.  Stem Cell Regeneration of Degenerated Intervertebral Discs: Current Status (Update) , 2008, Current Pain and Headache Reports.

[137]  D. Sakai,et al.  Homing of Mesenchymal Stem Cells in Induced Degenerative Intervertebral Discs in a Whole Organ Culture System , 2012, Spine.