'Cell or Not to Cell' that is the Question: For Intervertebral Disc Regeneration?

Low back pain, strongly associated with intervertebral disc degeneration, is one of the most prevalent health problems in the western world today. Current treatments have been directed toward alleviating patient symptoms but have been shown to accelerate degenerative changes in adjacent discs. New approaches in tissue engineering have provided a variety of treatment options including the delivery of regenerative cells, either alone or together with hydrogel scaffolds in order to restore/maintain disc biomechanics whilst simultaneously regenerating the matrix. This review paper discusses the use of cellular and acellular therapeutic strategies for IVD degeneration with an emphasis on the importance of tailoring the treatment strategy with stage of degeneration, thus offering insight into the future clinical options for IVD regeneration.

[1]  D. Hukins,et al.  Effect of Axial Load on the Flexural Properties of an Elastomeric Total Disc Replacement , 2012, Spine.

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

[3]  Jyh-Ping Chen,et al.  Preparation and evaluation of thermo-reversible copolymer hydrogels containing chitosan and hyaluronic acid as injectable cell carriers , 2009 .

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

[5]  C. L. Le Maitre,et al.  Degeneration of the intervertebral disc with new approaches for treating low back pain. , 2015, Journal of neurosurgical sciences.

[6]  James D. Kang,et al.  p38 MAPK inhibition modulates rabbit nucleus pulposus cell response to IL‐1 , 2008, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[7]  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.

[8]  L. Bonassar,et al.  Total disc replacement using a tissue-engineered intervertebral disc in vivo: new animal model and initial results , 2010, Evidence-based spine-care journal.

[9]  A. Freemont,et al.  Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1β and TNFα expression profile , 2007, Arthritis research & therapy.

[10]  S. Richardson,et al.  Bi-Directional Exchange of Membrane Components Occurs during Co-Culture of Mesenchymal Stem Cells and Nucleus Pulposus Cells , 2012, PloS one.

[11]  S. Waldman,et al.  Characterization of cartilagenous tissue formed on calcium polyphosphate substrates in vitro. , 2002, Journal of biomedical materials research.

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

[13]  K. Ha,et al.  Notochordal cells stimulate migration of cartilage end plate chondrocytes of the intervertebral disc in in vitro cell migration assays. , 2009, The spine journal : official journal of the North American Spine Society.

[14]  P. Roughley,et al.  The potential of chitosan-based gels containing intervertebral disc cells for nucleus pulposus supplementation. , 2006, Biomaterials.

[15]  Lawrence J Bonassar,et al.  Image‐based tissue engineering of a total intervertebral disc implant for restoration of function to the rat lumbar spine , 2012, NMR in biomedicine.

[16]  A. Freemont,et al.  Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degeneration. , 2009, Arthritis and rheumatism.

[17]  W. Hitzl,et al.  Mid- to long-term results of total lumbar disc replacement: a prospective analysis with 5- to 10-year follow-up. , 2014, The spine journal : official journal of the North American Spine Society.

[18]  Haeyoun Kang,et al.  Interleukin‐1β induces angiogenesis and innervation in human intervertebral disc degeneration , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[19]  H. Brisby,et al.  The fate of transplanted xenogeneic bone marrow‐derived stem cells in rat intervertebral discs , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[20]  J. Mochida,et al.  Nucleus Pulposus Allograft Retards Intervertebral Disc Degeneration , 2001, Clinical orthopaedics and related research.

[21]  I. Shapiro,et al.  Role of cytokines in intervertebral disc degeneration: pain and disc content , 2014, Nature Reviews Rheumatology.

[22]  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.

[23]  Moe R. Lim,et al.  Does Incorrect Level Needle Localization During Anterior Cervical Discectomy and Fusion Lead to Accelerated Disc Degeneration? , 2009, Spine.

[24]  I. Shapiro,et al.  Inflammatory Cytokines Induce NOTCH Signaling in Nucleus Pulposus Cells , 2013, The Journal of Biological Chemistry.

[25]  Christopher J Hunter,et al.  Cytomorphology of notochordal and chondrocytic cells from the nucleus pulposus: a species comparison , 2004, Journal of anatomy.

[26]  S. Roberts,et al.  Biochemical and Structural Properties of the Cartilage End-Plate and its Relation to the Intervertebral Disc , 1989, Spine.

[27]  M. Risbud,et al.  Understanding nucleus pulposus cell phenotype: a prerequisite for stem cell based therapies to treat intervertebral disc degeneration. , 2015, Current stem cell research & therapy.

[28]  T. Albert,et al.  Cellular Therapy for Disc Degeneration , 2005, Spine.

[29]  A. Freemont,et al.  Intervertebral Disc Cell–Mediated Mesenchymal Stem Cell Differentiation , 2006, Stem cells.

[30]  Y. Joung,et al.  Controlled release of heparin-binding growth factors using heparin-containing particulate systems for tissue regeneration. , 2008, Expert opinion on drug delivery.

[31]  T. Albert,et al.  Differential Gene Expression in Anterior and Posterior Annulus Fibrosus , 2014, Spine.

[32]  Tae-Hong Lim,et al.  Biomechanical Study on the Effect of Cervical Spine Fusion on Adjacent-Level Intradiscal Pressure and Segmental Motion , 2002, Spine.

[33]  Keita Ito,et al.  Advances in the diagnosis of degenerated lumbar discs and their possible clinical application , 2014, European Spine Journal.

[34]  A. Freemont,et al.  Co-culture induces mesenchymal stem cell differentiation and modulation of the degenerate human nucleus pulposus cell phenotype. , 2010, Regenerative medicine.

[35]  P. Roughley,et al.  Distinction between the extracellular matrix of the nucleus pulposus and hyaline cartilage: a requisite for tissue engineering of intervertebral disc. , 2004, European cells & materials.

[36]  A. Lindahl,et al.  Investigation of different cell types and gel carriers for cell‐based intervertebral disc therapy, in vitro and in vivo studies , 2012, Journal of tissue engineering and regenerative medicine.

[37]  J. Matyas,et al.  The three‐dimensional architecture of the notochordal nucleus pulposus: novel observations on cell structures in the canine intervertebral disc , 2003, Journal of anatomy.

[38]  A. Freemont,et al.  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 , 2007, Arthritis research & therapy.

[39]  P. Roughley Biology of Intervertebral Disc Aging and Degeneration: Involvement of the Extracellular Matrix , 2004, Spine.

[40]  C. L. Le Maitre,et al.  Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration , 2014, Arthritis Research & Therapy.

[41]  N. A. van der Gaag,et al.  Total disc replacement for chronic back pain in the presence of disc degeneration. , 2012, The Cochrane database of systematic reviews.

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

[43]  W. Hutton,et al.  The Effect of Bone Morphogenetic Protein-2 on Rat Intervertebral Disc Cells in Vitro , 2003, Spine.

[44]  Mary Murphy,et al.  Type II collagen-hyaluronan hydrogel--a step towards a scaffold for intervertebral disc tissue engineering. , 2010, European cells & materials.

[45]  Fenghua Tao 陶凤华,et al.  Differentiation of mesenchymal stem cells into nucleus pulposus cells in vitro , 2008, Journal of Huazhong University of Science and Technology [Medical Sciences].

[46]  Lori A. Setton,et al.  Molecular phenotypes of notochordal cells purified from immature nucleus pulposus , 2006, European Spine Journal.

[47]  K. Ito,et al.  Potential application of notochordal cells for intervertebral disc regeneration: an in vitro assessment. , 2014, European cells & materials.

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

[49]  W. Hutton,et al.  Clinical experience in cell-based therapeutics: disc chondrocyte transplantation A treatment for degenerated or damaged intervertebral disc. , 2007, Biomolecular engineering.

[50]  Francesco Dell'Accio,et al.  Mesenchymal multipotency of adult human periosteal cells demonstrated by single-cell lineage analysis. , 2006, Arthritis and rheumatism.

[51]  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.

[52]  S. Nicoll,et al.  Characterization of photocrosslinked alginate hydrogels for nucleus pulposus cell encapsulation. , 2009, Journal of biomedical materials research. Part A.

[53]  A. Freemont,et al.  Expression of cartilage-derived morphogenetic protein in human intervertebral discs and its effect on matrix synthesis in degenerate human nucleus pulposus cells , 2009, Arthritis research & therapy.

[54]  F. Luyten,et al.  Multipotent mesenchymal stem cells from adult human synovial membrane. , 2001, Arthritis and rheumatism.

[55]  Gail Haddock,et al.  The cytokine and chemokine expression profile of nucleus pulposus cells: implications for degeneration and regeneration of the intervertebral disc , 2013, Arthritis Research & Therapy.

[56]  A. Freemont,et al.  Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration , 2007, Arthritis research & therapy.

[57]  C. L. Le Maitre,et al.  Potential roles of cytokines and chemokines in human intervertebral disc degeneration: interleukin-1 is a master regulator of catabolic processes. , 2015, Osteoarthritis and cartilage.

[58]  A. Freemont,et al.  Open Access Research Article Transcriptional Profiling of Bovine Intervertebral Disc Cells: Implications for Identification of Normal and Degenerate Human Intervertebral Disc Cell Phenotypes , 2022 .

[59]  Antonios G. Mikos,et al.  Injectable biodegradable hydrogel composites for rabbit marrow mesenchymal stem cell and growth factor delivery for cartilage tissue engineering. , 2007, Biomaterials.

[60]  C. L. Le Maitre,et al.  Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration , 2013, Annals of the rheumatic diseases.

[61]  Fan Ding,et al.  Cell death in intervertebral disc degeneration , 2013, Apoptosis.

[62]  T. Lund,et al.  Adjacent level disk disease--is it really a fusion disease? , 2011, The Orthopedic clinics of North America.

[63]  I. Sekiya,et al.  Comparison of rat mesenchymal stem cells derived from bone marrow, synovium, periosteum, adipose tissue, and muscle , 2007, Cell and Tissue Research.

[64]  Y. Sakaguchi,et al.  Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. , 2005, Arthritis and rheumatism.

[65]  S J Bryant,et al.  Cytocompatibility of UV and visible light photoinitiating systems on cultured NIH/3T3 fibroblasts in vitro , 2000, Journal of biomaterials science. Polymer edition.

[66]  S. Waldman,et al.  Tissue Engineered Nucleus Pulposus Tissue Formed on a Porous Calcium Polyphosphate Substrate , 2004, Spine.

[67]  Chi-Hwa Wang,et al.  Fabrication and characterization of PLGA/HAp composite scaffolds for delivery of BMP-2 plasmid DNA. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[68]  S. Abram,et al.  Anatomy and pathophysiology of intervertebral disc disease , 2009 .

[69]  I. Lieberman,et al.  Mechanical Characterization of a Viscoelastic Disc for Lumbar Total Disc Replacement , 2011 .

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

[71]  A. Freemont,et al.  Matrix synthesis and degradation in human intervertebral disc degeneration. , 2007, Biochemical Society transactions.

[72]  A. Freemont,et al.  Investigation of the role of IL-1 and TNF in matrix degradation in the intervertebral disc. , 2008, Rheumatology.

[73]  T. Albert,et al.  Fibroblast Growth Factor-2 Maintains the Differentiation Potential of Nucleus Pulposus Cells In Vitro: Implications for Cell-Based Transplantation Therapy , 2007, Spine.

[74]  L. Ala‐Kokko,et al.  Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ß gene polymorphisms , 2006, European Spine Journal.

[75]  C. Baird,et al.  The pilot study. , 2000, Orthopedic nursing.

[76]  A. Schultz,et al.  Mechanical Properties of Human Lumbar Spine Motion Segments—Part I: Responses in Flexion, Extension, Lateral Bending, and Torsion , 1979 .

[77]  Mark R. Buckley,et al.  The effects of needle puncture injury on microscale shear strain in the intervertebral disc annulus fibrosus. , 2010, The spine journal : official journal of the North American Spine Society.

[78]  D. Elliott,et al.  ISSLS Prize Winner: Integrating Theoretical and Experimental Methods for Functional Tissue Engineering of the Annulus Fibrosus , 2008, Spine.

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

[80]  L. Setton,et al.  Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. , 2010, Arthritis and rheumatism.

[81]  K. Ha,et al.  Senescence mechanisms of nucleus pulposus chondrocytes in human intervertebral discs. , 2009, The spine journal : official journal of the North American Spine Society.

[82]  T. Kubo,et al.  Intervertebral disc regeneration using platelet-rich plasma and biodegradable gelatin hydrogel microspheres. , 2007, Tissue engineering.

[83]  P. Dolan,et al.  Recent advances in lumbar spinal mechanics and their significance for modelling. , 2001, Clinical biomechanics.

[84]  T. Albert,et al.  Substance P Stimulates Production of Inflammatory Cytokines in Human Disc Cells , 2012, Spine.

[85]  Gail Haddock,et al.  Tumor necrosis factor α- and interleukin-1β-dependent induction of CCL3 expression by nucleus pulposus cells promotes macrophage migration through CCR1. , 2013, Arthritis and rheumatism.

[86]  M. Detamore,et al.  Biomimetic method for combining the nucleus pulposus and annulus fibrosus for intervertebral disc tissue engineering , 2011, Journal of tissue engineering and regenerative medicine.

[87]  A. Gefen,et al.  Thermosensitive hydrogel made of ferulic acid-gelatin and chitosan glycerophosphate. , 2013, Carbohydrate polymers.

[88]  S. Ghanaati,et al.  Biological performance of cell‐encapsulated methacrylated gellan gum‐based hydrogels for nucleus pulposus regeneration , 2017, Journal of tissue engineering and regenerative medicine.

[89]  A. Mcgregor,et al.  The pathogenesis of degeneration of the intervertebral disc and emerging therapies in the management of back pain. , 2012, The Journal of bone and joint surgery. British volume.

[90]  Koichi Masuda,et al.  The Origin of Chondrocytes in the Nucleus Pulposus and Histologic Findings Associated With the Transition of a Notochordal Nucleus Pulposus to a Fibrocartilaginous Nucleus Pulposus in Intact Rabbit Intervertebral Discs , 2003, Spine.

[91]  Xiong Guo,et al.  Bone Mesenchymal Stem Cells Transplanted into Rabbit Intervertebral Discs Can Increase Proteoglycans , 2005, Clinical orthopaedics and related research.

[92]  Marcia Simon,et al.  Hydrogels for Regenerative Medicine , 2016 .

[93]  J. Lotz,et al.  Porcine intervertebral disc repair using allogeneic juvenile articular chondrocytes or mesenchymal stem cells. , 2011, Tissue engineering. Part A.

[94]  P. Leino-Arjas,et al.  Modic changes and interleukin 1 gene locus polymorphisms in occupational cohort of middle-aged men , 2009, European Spine Journal.

[95]  M. Alini,et al.  Thermoreversible hyaluronan-based hydrogel supports in vitro and ex vivo disc-like differentiation of human mesenchymal stem cells. , 2013, The spine journal : official journal of the North American Spine Society.

[96]  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.

[97]  R. Reis,et al.  Rheological and mechanical properties of acellular and cell-laden methacrylated gellan gum hydrogels. , 2013, Journal of biomedical materials research. Part A.

[98]  A. Freemont,et al.  Human mesenchymal stem cell differentiation to NP-like cells in chitosan-glycerophosphate hydrogels. , 2008, Biomaterials.

[99]  K. Luk,et al.  Injury‐induced sequential transformation of notochordal nucleus pulposus to chondrogenic and fibrocartilaginous phenotype in the mouse , 2009, The Journal of pathology.

[100]  R. Reis,et al.  Biocompatibility Evaluation of Ionic‐ and Photo‐Crosslinked Methacrylated Gellan Gum Hydrogels: In Vitro and In Vivo Study , 2013, Advanced healthcare materials.

[101]  Dawn M Elliott,et al.  IL-1ra delivered from poly(lactic-co-glycolic acid) microspheres attenuates IL-1β-mediated degradation of nucleus pulposus in vitro , 2012, Arthritis Research & Therapy.

[102]  J. Urban,et al.  Swelling Pressure of the Lumbar Intervertebral Discs: Influence of Age, Spinal Level, Composition, and Degeneration , 1988, Spine.

[103]  A. Freemont,et al.  Characterization of the human nucleus pulposus cell phenotype and evaluation of novel marker gene expression to define adult stem cell differentiation. , 2010, Arthritis and rheumatism.

[104]  S. M. Naqvi,et al.  Differential response of encapsulated nucleus pulposus and bone marrow stem cells in isolation and coculture in alginate and chitosan hydrogels. , 2015, Tissue engineering. Part A.

[105]  Irving M Shapiro,et al.  Toward an understanding of the role of notochordal cells in the adult intervertebral disc: From discord to accord , 2010, Developmental dynamics : an official publication of the American Association of Anatomists.

[106]  J. Hoyland,et al.  Identification of novel nucleus pulposus markers , 2013, Bone & joint research.

[107]  H. Gruber,et al.  Senescence in Cells of the Aging and Degenerating Intervertebral Disc: Immunolocalization of Senescence-Associated &bgr;-Galactosidase in Human and Sand Rat Discs , 2007, Spine.

[108]  D. Rosenzweig,et al.  Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors , 2014, Journal of cellular and molecular medicine.

[109]  Keita Ito,et al.  Conditioned medium derived from notochordal cell-rich nucleus pulposus tissue stimulates matrix production by canine nucleus pulposus cells and bone marrow-derived stromal cells. , 2015, Tissue engineering. Part A.

[110]  J. Hows,et al.  Bone marrow-derived mesenchymal stem cells , 2005, Leukemia & lymphoma.

[111]  B. Derby,et al.  Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition, and micromechanical properties of nucleus pulposus constructs , 2014, Arthritis Research & Therapy.

[112]  Zachary R. Schoepflin,et al.  Defining the phenotype of young healthy nucleus pulposus cells: Recommendations of the Spine Research Interest Group at the 2014 annual ORS meeting , 2015, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[113]  Yang Liu,et al.  Three-dimensional hypoxic culture of human mesenchymal stem cells encapsulated in a photocurable, biodegradable polymer hydrogel: a potential injectable cellular product for nucleus pulposus regeneration. , 2014, Acta biomaterialia.

[114]  Kai-Chiang Yang,et al.  Thermosensitive chitosan-gelatin-glycerol phosphate hydrogels as a cell carrier for nucleus pulposus regeneration: an in vitro study. , 2010, Tissue engineering. Part A.

[115]  H. Wilke,et al.  In vivo biofunctional evaluation of hydrogels for disc regeneration , 2013, European Spine Journal.

[116]  A. Freemont,et al.  Localization of degradative enzymes and their inhibitors in the degenerate human intervertebral disc , 2004, The Journal of pathology.

[117]  D. Kletsas,et al.  Senescence in human intervertebral discs , 2006, European Spine Journal.

[118]  M. Tammi,et al.  Relative increase of biglycan and decorin and altered chondroitin sulfate epitopes in the degenerating human intervertebral disc. , 1998, The Journal of rheumatology.

[119]  T. Ganey,et al.  Cell transplantation in lumbar spine disc degeneration disease , 2008, European Spine Journal.

[120]  H. Fong,et al.  Electrospun nanofibrous polycaprolactone scaffolds for tissue engineering of annulus fibrosus. , 2011, Macromolecular bioscience.

[121]  Antonios G Mikos,et al.  Thermoresponsive hydrogels in biomedical applications. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

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

[123]  T. Albert,et al.  Expression and Relationship of Proinflammatory Chemokine RANTES/CCL5 and Cytokine IL-1&bgr; in Painful Human Intervertebral Discs , 2013, Spine.

[124]  P. Leino-Arjas,et al.  Possible association of interleukin 1 gene locus polymorphisms with low back pain , 2004, Pain.

[125]  E. Thonar,et al.  Changes in mRNA and Protein Levels of Proteoglycans of the Anulus Fibrosus and Nucleus Pulposus During Intervertebral Disc Degeneration , 2002, Spine.

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

[127]  Catherine M. Verfaillie,et al.  Pluripotency of mesenchymal stem cells derived from adult marrow , 2007, Nature.

[128]  Weibing Teng,et al.  Complete recombinant silk-elastinlike protein-based tissue scaffold. , 2010, Biomacromolecules.

[129]  A. Freemont,et al.  An in vitro study investigating the survival and phenotype of mesenchymal stem cells following injection into nucleus pulposus tissue , 2009, Arthritis research & therapy.

[130]  Anne-Sofie Lagerstedt,et al.  The Dog as an Animal Model for Intervertebral Disc Degeneration? , 2012, Spine.

[131]  S. Milz,et al.  Variations in gene and protein expression in human nucleus pulposus in comparison with annulus fibrosus and cartilage cells: potential associations with aging and degeneration. , 2010, Osteoarthritis and cartilage.