Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 142 No. 2122 (2012)

Intervertebral disc regeneration or repair with biomaterials and stem cell therapy – feasible or fiction?

  • Samantha Chun Wai Chan
  • Benjamin Gantenbein-Ritter
DOI
https://doi.org/10.4414/smw.2012.13598
Cite this as:
Swiss Med Wkly. 2012;142:w13598
Published
20.05.2012

Abstract

The “gold standard” for treatment of intervertebral disc herniations and degenerated discs is still spinal fusion, corresponding to the saying “no disc – no pain”. Mechanical prostheses, which are currently implanted, do only have medium outcome success and have relatively high re-operation rates. Here, we discuss some of the biological intervertebral disc replacement approaches, which can be subdivided into at least two classes in accordance to the two different tissue types, the nucleus pulposus (NP) and the annulus fibrosus (AF). On the side of NP replacement hydrogels have been extensively tested in vitroand in vivo. However, these gels are usually a trade-off between cell biocompatibility and load-bearing capacity, hydrogels which fulfill both are still lacking. On the side of AF repair much less is known and the question of the anchoring of implants is still to be addressed. New hope for cell therapy comes from developmental biology investigations on the existence of intervertebral disc progenitor cells, which would be an ideal cell source for cell therapy. Also notochordal cells (remnants of the embryonic notochord) have been recently pushed back into focus since these cells have regenerative potential and can activate disc cells. Growth factor treatment and molecular therapies could be less problematic. The biological solutions for NP and AF replacement are still more fiction than fact. However, tissue engineering just scratched the tip of the iceberg, more satisfying solutions are yet to be added to the biomedical pipeline.

References

  1. Leung VY, Chan D, Cheung KM. Regeneration of intervertebral disc by mesenchymal stem cells: potentials, limitations, and future direction. Eur Spine J. 2006;15(Suppl 3):S406–13.
  2. Hunter CJ, Matyas JR, Duncan NA. The notochordal cell in the nucleus pulposus: a review in the context of tissue engineering. Tissue Eng. 2003;9:667–77.
  3. Urban JP, Smith S, Fairbank JC. Nutrition of the intervertebral disc. Spine. 2004;29:2700–9.
  4. Wuertz K, Godburn K, Neidlinger-Wilke C, et al. Behavior of mesenchymal stem cells in the chemical microenvironment of the intervertebral disc. Spine. (Phila Pa 1976) 2008;33:1843–9.
  5. Nachemson A. Is there such a thing as degenerative disc disease? In: Gunzburg R, Szpalski M, Andersson GB, ed. Degenerative disc disease. Philadelphia, Lippincott Williams Wilkins, 2004: 1–5.
  6. Kara B, Tulum Z, Acar U. Functional results and the risk factors of reoperations after lumbar disc surgery. Eur Spine J. 2005;14:43–8.
  7. Etebar S, Cahill DW. Risk factors for adjacent-segment failure following lumbar fixation with rigid instrumentation for degenerative instability. J Neurosurg. 1999;90:163–9.
  8. Cheng YH, Yang SH, Su WY, et al. Thermosensitive chitosan-gelatin-glycerol phosphate hydrogels as a cell carrier for nucleus pulposus regeneration: an in vitro study. Tissue Eng Part A. 2010;16:695–703.
  9. Peroglio M, Grad S, Mortisen D, et al. Injectable thermoreversible hyaluronan-based hydrogels for nucleus pulposus cell encapsulation. Eur Spine J. 2011; Epub ahead of print.
  10. Chou AI, Akintoye SO, Nicoll SB. Photo-crosslinked alginate hydrogels support enhanced matrix accumulation by nucleus pulposus cells in vivo. Osteoarthritis Cartilage. 2009;17:1377–84.
  11. Reza AT, Nicoll SB. Characterization of novel photocrosslinked carboxymethylcellulose hydrogels for encapsulation of nucleus pulposus cells. Acta Biomater 2010;6(1):129–86.
  12. Moss IL, Gordon L, Woodhouse KA, et al. A novel thiol-modified hyaluronan and elastin-like polypetide composite material for tissue engineering of the nucleus pulposus of the intervertebral disc. Spine. (Phila Pa 1976) 2011;36:1022–9.
  13. Collin EC, Grad S, Zeugolis DI, et al. An injectable vehicle for nucleus pulposus cell-based therapy. Biomaterials. 2011;32:2862–70.
  14. Huang B, Li CQ, Zhou Y, et al. Collagen II/hyaluronan/chondroitin-6-sulfate tri-copolymer scaffold for nucleus pulposus tissue engineering. J Biomed Mater Res B Appl Biomater. 2010;92:322–31.
  15. Revell PA, Damien E, Di Silvio L, et al. Tissue engineered intervertebral disc repair in the pig using injectable polymers. J Mater Sci Mater Med. 2007;18:303–8.
  16. Calderon L, Collin E, Velasco-Bayon D, et al. Type II collagen-hyaluronan hydrogel – a step towards a scaffold for intervertebral disc tissue engineering. Eur Cell Mater. 2010;20:134–48.
  17. Richardson SM, Hoyland JA, Mobasheri R, et al. Mesenchymal stem cells in regenerative medicine: opportunities and challenges for articular cartilage and intervertebral disc tissue engineering. J Cell Physiol. 2010;222:23–32.
  18. Hoogendoorn RJ, Lu ZF, Kroeze RJ, et al. Adipose stem cells for intervertebral disc regeneration: current status and concepts for the future. J Cell Mol Med. 2008;12:2205–16.
  19. He F, Pei M. Rejuvenation of nucleus pulposus cells using extracellular matrix deposited by synovium-derived stem cells. Spine. (Phila Pa 1976) 2011;37:459–69.
  20. Orozco L, Soler R, Morera C, et al. Intervertebral disc repair by autologous mesenchymal bone marrow cells: A pilot study. Transplantation. 2011;92:822–8.
  21. Serigano K, Sakai D, Hiyama A, et al. Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. J Orthop Res. 2010;28:1267–75.
  22. Chan SCW, Gantenbein-Ritter B, Leung VY, et al. Cryopreserved intervertebral disc with injected bone marrow-derived stromal cells: a feasibility study using organ culture. Spine J. 2010;10(6):486–96.
  23. Gantenbein-Ritter B, Benneker LM, Alini M, et al. Differential response of human bone marrow stromal cells to either TGF-β(1) or rhGDF-5. Eur Spine J. 2011;20:962–71.
  24. Ehlicke F, Freimark D, Heil B, et al. Intervertebral disc regeneration: Influence of growth factors on differentiation of human mesenchymal stem cells (hMSC). Int J Artif Organs. 2010;33:244–52.
  25. Stoyanov JV, Gantenbein-Ritter B, Bertolo A, et al. Role of hypoxia and growth and differentiation factor-5 on differentiation of human mesenchymal stem cells towards intervertebral nucleus pulposus-like cells. Eur Cell Mater. 2011;21:533–47.
  26. Xu J, Wang W, Ludeman M, et al. Chondrogenic differentiation of human mesenchymal stem cells in three-dimensional alginate gels. Tissue Eng Part A. 2008;14:667–80.
  27. Than KD, Rahman SU, Vanaman MJ, Wang AC, Lin CY, Zhang H, et al. Bone morphogenetic proteins and degenerative disc disease. Neurosurgery 2011; Sept. 5. E-pub ahead of print.
  28. Strassburg S, Richardson SM, Freemont AJ, et al. Co-culture induces mesenchymal stem cell differentiation and modulation of the degenerate human nucleus pulposus cell phenotype. Regen Med. 2010;5:701–11.
  29. Richardson SM, Walker RV, Parker S, et al. Intervertebral disc cell-mediated mesenchymal stem cell differentiation. Stem Cells. 2006;24:707–16.
  30. Korecki CL, Taboas JM, Tuan RS, et al. Notochordal cell conditioned medium stimulates mesenchymal stem cell differentiation toward a young nucleus pulposus phenotype. Stem Cell Res Ther. 2010;1:18.
  31. Singh M, Pierpoint M, Mikos AG, et al. Chondrogenic differentiation of neonatal human dermal fibroblasts encapsulated in alginate beads with hydrostatic compression under hypoxic conditions in the presence of bone morphogenetic protein-2. J Biomed Mater Res A. 2011;98:412–24.
  32. Chan SC, Ferguson SJ, Gantenbein-Ritter B. The effects of dynamic loading on the intervertebral disc. Eur Spine J. 2011;20:1796–812.
  33. Potier E, Noailly J, Ito K. Directing bone marrow-derived stromal cell function with mechanics. J Biomech. 2010;43:807–17.
  34. Bertram H, Kroeber M, Wang H, et al. Matrix-assisted cell transfer for intervertebral disc cell therapy. Biochem Biophys Res Commun. 2005;331:1185–92.
  35. Vadalà G, Sowa G, Hubert M, et al. Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med. 2012;6(5):348–55.
  36. Sheikh H, Zakharian K, De La Torre RP, et al. In vivo intervertebral disc regeneration using stem cell-derived chondroprogenitors. J Neurosurg Spine. 2009;10:265–72.
  37. Ruan D, Zhang Y, Wang D, et al. Differentiation of human Wharton’s jelly cells toward nucleus pulposus-like cells after coculture with nucleus pulposus cells in vitro. Tissue Eng Part A. 2011;18(1-2):167–75.
  38. Sakai D. Endogenous/stem progenitor cell population of the intervertebral disc and its implication on ageing and degeneration, in The symbosium of AO Exploratory Research “Where Science meets clinics” 2011, 2–7 September, Davos.
  39. Erwin WM. Intervertebral disc-derived stem cells: Implications for regenerative medicine and neural repair, in Proceedings of ISSLS, June 14–18 2011, Gothenburg
  40. Meisel HJ, Siodla V, Ganey T, et al. Clinical experience in cell-based therapeutics: disc chondrocyte transplantation A treatment for degenerated or damaged intervertebral disc. Biomol Eng. 2007;24:5–21.
  41. Henriksson H, Thornemo M, Karlsson C, 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.
  42. Walmsley R. The development and growth of the intervertebral disc. Edinburgh Med J. 1953;60.
  43. Miyazaki T, Kobayashi S, Takeno K, et al. A phenotypic comparison of proteoglycan production of intervertebral disc cells isolated from rats, rabbits, and bovine tails; which animal model is most suitable to study tissue engineering and biological repair of human disc disorders? Tissue Eng Part A. 2009;15:3835–46.
  44. Smith LJ, Nerurkar NL, Choi KS, et al. Degeneration and regeneration of the intervertebral disc: lessons from development. Dis Model Mech. 2011;4:31–41.
  45. Purmessur D, Schek RM, Abbott RD, et al. Notochordal conditioned media from tissue increases proteoglycan accumulation and promotes a healthy nucleus pulposus phenotype in human mesenchymal stem cells. Arthritis Res Ther. 2011;13:R81.
  46. Lee CR, Sakai D, Nakai T, et al. A phenotypic comparison of intervertebral disc and articular cartilage cells in the rat. Eur Spine J. 2007;16:2174–85.
  47. Minogue BM, Richardson SM, Zeef LA, et al. Transcriptional profiling of bovine intervertebral disc cells: implications for identification of normal and degenerate human intervertebral disc cell phenotypes. Arthritis Res Ther. 2010;12:R22.
  48. Rutges J, Creemers LB, Dhert W, 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. Osteoarthritis and Cartilage. 2010;18:416–23.
  49. Sakai D, Nakai T, Mochida J, et al. Differential phenotype of intervertebral disc cells: microarray and immunohistochemical analysis of canine nucleus pulposus and anulus fibrosus. Spine. (Phila Pa 1976) 2009;34:1448–56.
  50. Shapiro IM, Risbud MV. Transcriptional profiling of the nucleus pulposus: say yes to notochord. Arthritis Res Ther. 2010;12:117.
  51. 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.
  52. Weiler C, Nerlich AG, Schaaf R, et al. Immunohistochemical identification of notochordal markers in cells in the aging human lumbar intervertebral disc. Eur Spine J. 2010; 19(10):1761–70.
  53. Gantenbein-Ritter B, Chan SC. The evolutionary importance of cell ratio between notochordal and nucleus pulposus cells: an experimental 3-D co-culture study. Eur Spine J. 2011; [epub ahead of print].
  54. Vujovic S, Henderson S, Presneau N, et al. Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol. 2006;209:157–65.
  55. Erwin WM, Ashman K, O'Donnel P, et al. Nucleus pulposus notochord cells secrete connective tissue growth factor and up-regulate proteoglycan expression by intervertebral disc chondrocytes. Arthritis Rheum. 2006;54:3859–67.
  56. Zhang Y, An HS, Thonar EJ, et al. Comparative effects of bone morphogenetic proteins and sox9 overexpression on extracellular matrix metabolism of bovine nucleus pulposus cells. Spine. (Phila Pa 1976) 2006;31:2173–9.
  57. Li X, An HS, Ellman M, et al. Action of fibroblast growth factor-2 on the intervertebral disc. Arthritis Res Ther. 2008;10:R48.
  58. Zhang Y, Chee A, Thonar EJ, et al. Intervertebral disk repair by protein, gene, or cell injection: a framework for rehabilitation-focused biologics in the spine. PM R 2011;3:S88–94.
  59. Mwale F, Masuda K, Pichika R, et al. The efficacy of Link N as a mediator of repair in a rabbit model of intervertebral disc degeneration. Arthritis Res Ther. 2011;13:R120.
  60. Haid RW, Branch CL, Alexander JT, et al. Posterior lumbar interbody fusion using recombinant human bone morphogenetic protein type 2 with cylindrical interbody cages. Spine J. 2004; 4:527–38; discussion 538–9.
  61. Benneker LM, Heini PF, Alini M, et al. 2004 young investigator award winner: vertebral endplate marrow contact channel occlusions and intervertebral disc degeneration Spine. (Phila Pa 1976) 2005;30:167–73.
  62. Kurunlahti M, Kerttula L, Jauhiainen J, et al. Correlation of diffusion in lumbar intervertebral disks with occlusion of lumbar arteries: a study in adult volunteers. Radiology. 2001;221:779–86.
  63. Rinkler C, Heuer F, Pedro MT, et al. Influence of low glucose supply on the regulation of gene expression by nucleus pulposus cells and their responsiveness to mechanical loading. J Neurosurg Spine. 2010;13:535–42.
  64. Sekiguchi M, Konno S, Kikuchi S. The effects of a 5-HT2A receptor antagonist on blood flow in lumbar disc herniation: application of nucleus pulposus in a canine model. Eur Spine J. 2008;17:307–13.
  65. Turgut M, Uysal A, Uslu S, et al. The effects of calcium channel antagonist nimodipine on end-plate vascularity of the degenerated intervertebral disc in rats. J Clin Neurosci. 2003;10:219–23.
  66. Bao QB, McCullen GM, Higham PA, et al. The artificial disc: theory, design and materials. Biomaterials 1996;17:1157–67.
  67. Selviaridis P, Foroglou N, Tsitlakidis A, et al. Long-term outcome after implantation of prosthetic disc nucleus device (PDN) in lumbar disc disease. Hippokratia. 2010;14:176–84.
  68. Endres M, Abbushi A, Thomale UW, et al. Intervertebral disc regeneration after implantation of a cell-free bioresorbable implant in a rabbit disc degeneration model. Biomaterials. 2010;31:5836–41.
  69. Bron JL, Helder MN, Meisel HJ, et al. Repair, regenerative and supportive therapies of the annulus fibrosus: achievements and challenges. Eur Spine J. 2009;18:301–13.
  70. Hegewald AA, Knecht S, Baumgartner D, et al. Biomechanical testing of a polymer-based biomaterial for the restoration of spinal stability after nucleotomy. J Orthop Surg Res. 2009;4:25.
  71. Bron JL, van der Veen AJ, Helder MN, et al. Biomechanical and in vivo evaluation of experimental closure devices of the annulus fibrosus designed for a goat nucleus replacement model. Eur Spine J. 2010;19:1347–55.
  72. Alini M, Li W, Markovic P, et al. The potential and limitations of a cell-seeded collagen/hyaluronan scaffold to engineer an intervertebral disc-like matrix. Spine. 2003;28:446–54; discussion 453.
  73. Shao X, Hunter CJ. Developing an alginate/chitosan hybrid fiber scaffold for annulus fibrosus cells. J Biomed Mater Res A. 2007;82:701–10.
  74. Helen W, Gough JE. Cell viability, proliferation and extracellular matrix production of human annulus fibrosus cells cultured within PDLLA/Bioglass composite foam scaffolds in vitro. Acta Biomater. 2008;4:230–43.
  75. Helen W, Merry CL, Blaker JJ, et al. Three-dimensional culture of annulus fibrosus cells within PDLLA/Bioglass composite foam scaffolds: assessment of cell attachment, proliferation and extracellular matrix production. Biomaterials. 2007;28:2010–20.
  76. Wilda H, Gough JE. In vitro studies of annulus fibrosus disc cell attachment, differentiation and matrix production on PDLLA/45S5 Bioglass composite films. Biomaterials. 2006;27:5220–9.
  77. Wan Y, Feng G, Shen FH, et al. Novel biodegradable poly(1,8-octanediol malate) for annulus fibrosus regeneration. Macromol Biosci. 2007;7:1217–24.
  78. Wan Y, Feng G, Shen FH, et al. Biphasic scaffold for annulus fibrosus tissue regeneration. Biomaterials. 2008;29:643–52.
  79. Chang G, Kim HJ, Kaplan D, et al. Porous silk scaffolds can be used for tissue engineering annulus fibrosus. Eur Spine J. 2007;16:1848–57.
  80. Boyd LM, Carter AJ. Injectable biomaterials and vertebral endplate treatment for repair and regeneration of the intervertebral disc. Eur Spine J. 2006;15(Suppl 3):S414–21.
  81. Fielding JW. Complications of anterior cervical disk removal and fusion. Clin Orthop Relat Res. 1992:10–3.
  82. Ebner H, Kraft D. Wild silk-induced asthma. A contribution to the knowledge of inhalation allergies caused by wild and tussah silk-filled bed quilts. Wien Klin Wochenschr. 1987;99:542–6.
  83. Chang G, Kim HJ, Vunjak-Novakovic G, et al. Enhancing annulus fibrosus tissue formation in porous silk scaffolds. J Biomed Mater Res A. 2010;92:43–51.
  84. Park SH, Gil ES, Mandal BB, et al. Annulus fibrosus tissue engineering using lamellar silk scaffolds. J Tissue Eng Regen Med. 2012; [epub ahead of print].
  85. Nerurkar NL, Baker BM, Sen S, et al. Nanofibrous biologic laminates replicate the form and function of the annulus fibrosus. Nat Mater. 2009;8:986–92.
  86. Koepsell L, Zhang L, Neufeld D, et al. Electrospun nanofibrous polycaprolactone scaffolds for tissue engineering of annulus fibrosus. Macromol Biosci. 2011;11:391–9.
  87. Zhang K, Qian Y, Wang H, et al. Electrospun silk fibroin-hydroxybutyl chitosan nanofibrous scaffolds to biomimic extracellular matrix. J Biomater Sci Polym Ed. 2011;22:1069–82.
  88. Zhang K, Mo X, Huang C, et al. Electrospun scaffolds from silk fibroin and their cellular compatibility. J Biomed Mater Res A. 2010;93:976–83.
  89. Qiu W, Huang Y, Teng W, et al. Complete recombinant silk-elastinlike protein-based tissue scaffold. Biomacromolecules. 2010;11:3219–27.
  90. Vadalà G, Mozetic P, Rainer A, et al. Bioactive electrospun scaffold for annulus fibrosus repair and regeneration. Eur Spine J. 2012; [epub ahead of print].
  91. Park SH, Gil ES, Cho H, et al. Intervertebral disc tissue engineering using biphasic silk composite scaffolds. Tissue Eng Part A. 2011;18:447–58.
  92. Lazebnik M, Singh M, Glatt P, et al. Biomimetic method for combining the nucleus pulposus and annulus fibrosus for intervertebral disc tissue engineering. J Tissue Eng Regen Med. 2011;5:e179–87.
  93. Bowles RD, Gebhard HH, Härtl R, et al. Tissue-engineered intervertebral discs produce new matrix, maintain disc height, and restore biomechanical function to the rodent spine. Proc Natl Acad Sci U S A 2011;108:13106–11.
  94. Errington RJ, Puustjarvi K, White IR, et al. Characterisation of cytoplasm-filled processes in cells of the intervertebral disc. J Anat. 1998;192(Pt 3):369–78.
  95. Cassidy JJ, Hiltner A, Baer E. Hierarchical structure of the intervertebral disc. Connect Tissue Res. 1989;23:75–88.
  96. Maroudas A, Stockwell RA, Nachemson A, et al. Factors involved in the nutrition of the human lumbar intervertebral disc: cellularity and diffusion of glucose in vitro J Anat. 1975;120:113–30.
  97. Chou AI, Reza AT, Nicoll SB. Distinct intervertebral disc cell populations adopt similar phenotypes in three-dimensional culture. Tissue Eng Part A. 2008;14:2079–87.
  98. Nesti LJ, Li WJ, Shanti RM, et al. Intervertebral disc tissue engineering using a novel hyaluronic acid-nanofibrous scaffold (HANFS) amalgam. Tissue Eng Part A. 2008;14:1527–37.
  99. Fedorovich NE, Swennen I, Girones J, et al. Evaluation of photocrosslinked Lutrol hydrogel for tissue printing applications. Biomacromolecules. 2009;10:1689–96.
  100. Cui X, Boland T. Human microvasculature fabrication using thermal inkjet printing technology. Biomaterials. 2009;30:6221–7.
  101. Nishiyama Y, Nakamura M, Henmi C, et al. Development of a three-dimensional bioprinter: construction of cell supporting structures using hydrogel and state-of-the-art inkjet technology. J Biomech Eng. 2009;131:035001.