International Orthopaedics

, Volume 43, Issue 4, pp 1011–1025 | Cite as

Cell therapy for intervertebral disc herniation and degenerative disc disease: clinical trials

  • Jordy ScholEmail author
  • Daisuke SakaiEmail author


Low back pain is the primary cause of disability and is highly associated with progression of intervertebral disc degeneration. Current treatment options are limited and fail to address the origin of the problem. New advancements in cellular therapies might offer novel and potent strategies for low back pain patients. In this review, we summarize and discuss the contemporary status of in-human trials investigating cellular transplantation for treatment of low back pain. We aim to highlight current trends, shortcomings, and hurdles for effective clinical trials and consecutive commercialization.


Clinical trials Cell therapy Regenerative medicine Intervertebral disc Degeneration 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V et al (2012) Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the global burden of disease study 2010. Lancet (London, England) 380(9859):2163–2196CrossRefGoogle Scholar
  2. 2.
    Meucci RD, Fassa AG, Faria NM (2015) Prevalence of chronic low back pain: systematic review. Rev Saude Publica 49:1518–8787 (Electronic)CrossRefGoogle Scholar
  3. 3.
    Katz JN (2006) Lumbar disc disorders and low-back pain: socioeconomic factors and consequences. J Bone Joint Surg Am 88 Suppl 2(4):21–24Google Scholar
  4. 4.
    Martin BI, Deyo RA, Mirza SK, Turner JA, Comstock BA, Hollingworth W, Sullivan SD (2008) Expenditures and health status among adults with back and neck problems. Jama 299(6):656–664CrossRefGoogle Scholar
  5. 5.
    Loisel P, Lemaire J, Poitras S, Durand MJ, Champagne F, Stock S, Diallo B, Tremblay C (2002) Cost-benefit and cost-effectiveness analysis of a disability prevention model for back pain management: a six year follow up study. Occup Environ Med 59(12):807–815CrossRefGoogle Scholar
  6. 6.
    Freemont AJ (2009) The cellular pathobiology of the degenerate intervertebral disc and discogenic back pain. Rheumatology (Oxford, England) 48(1):5–10CrossRefGoogle Scholar
  7. 7.
    Ringwalt C, Gugelmann H, Garrettson M, Dasgupta N, Chung AE, Proescholdbell SK, Skinner AC (2014) Differential prescribing of opioid analgesics according to physician specialty for Medicaid patients with chronic noncancer pain diagnoses. Pain Res Manag 19(4):179–185CrossRefGoogle Scholar
  8. 8.
    Yoshihara H, Yoneoka D (2015) National trends in the surgical treatment for lumbar degenerative disc disease: United States, 2000 to 2009. Spine J 15(2):265–271CrossRefGoogle Scholar
  9. 9.
    Deyo RA, Nachemson A, Mirza SK (2004) Spinal-fusion surgery—the case for restraint. N Engl J Med 350(7):722–726CrossRefGoogle Scholar
  10. 10.
    Pettine KA, Suzuki RK, Sand TT, Murphy MB (2017) Autologous bone marrow concentrate intradiscal injection for the treatment of degenerative disc disease with three-year follow-up. Int Orthop 41(10):2097–2103CrossRefGoogle Scholar
  11. 11.
    Fritzell P, Hagg O, Wessberg P, Nordwall A, Swedish Lumbar Spine Study G (2001) 2001 Volvo award winner in clinical studies: lumbar fusion versus nonsurgical treatment for chronic low back pain: a multicenter randomized controlled trial from the Swedish lumbar spine study group. Spine 26(23):2521–2532 discussion 2532-2524 CrossRefGoogle Scholar
  12. 12.
    Nguyen TH, Randolph DC, Talmage J, Succop P, Travis R (2011) Long-term outcomes of lumbar fusion among workers’ compensation subjects: a historical cohort study. Spine 36(4):320–331CrossRefGoogle Scholar
  13. 13.
    Epstein NE (2015) Adjacent level disease following lumbar spine surgery: a review. Surg Neurol Int 6 Suppl 24:S591–S599CrossRefGoogle Scholar
  14. 14.
    Han I, Ropper AE, Konya D, Kabatas S, Toktas Z, Aljuboori Z, Zeng X, Chi JH, Zafonte R, Teng YD (2015) Biological approaches to treating intervertebral disk degeneration: devising stem cell therapies. Cell Transplant 24(11):2197–2208CrossRefGoogle Scholar
  15. 15.
    Buckley CT, Hoyland JA, Fujii K, Pandit A, Iatridis JC, Grad S (2018) Critical aspects and challenges for intervertebral disc repair and regeneration-harnessing advances in tissue engineering. JOR Spine 1:3CrossRefGoogle Scholar
  16. 16.
    Gullbrand SE, Smith LJ, Smith HE, Mauck RL (2018) Promise, progress, and problems in whole disc tissue engineering. JOR Spine 1:2CrossRefGoogle Scholar
  17. 17.
    Sakai D, Schol J (2017) Cell therapy for intervertebral disc repair: clinical perspective. J Orthop Translat 9:8–18CrossRefGoogle Scholar
  18. 18.
    Smith LJ, Silverman L, Sakai D, Le Maitre CL, Mauck RL, Malhotra NR, Lotz JC, Buckley CT (2018) Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: recommendations of the ORS spine section. JOR Spine e1036.
  19. 19.
    Centeno C, Markle J, Dodson E, Stemper I, Williams CJ, Hyzy M, Ichim T, Freeman M (2017) Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy. J Transl Med 15(1):197CrossRefGoogle Scholar
  20. 20.
    Comella K, Silbert R, Parlo M (2017) Effects of the intradiscal implantation of stromal vascular fraction plus platelet rich plasma in patients with degenerative disc disease. J Transl Med 15(1):12CrossRefGoogle Scholar
  21. 21.
    Coric D, Pettine K, Sumich A, Boltes MO (2013) Prospective study of disc repair with allogeneic chondrocytes presented at the 2012 Joint Spine Section Meeting. J Neurosurg Spine 18(1):85–95CrossRefGoogle Scholar
  22. 22.
    Elabd C, Centeno CJ, Schultz JR, Lutz G, Ichim T, Silva FJ (2016) Intra-discal injection of autologous, hypoxic cultured bone marrow-derived mesenchymal stem cells in five patients with chronic lower back pain: a long-term safety and feasibility study. J Transl Med 14:253CrossRefGoogle Scholar
  23. 23.
    Haufe SM, Mork AR (2006) Intradiscal injection of hematopoietic stem cells in an attempt to rejuvenate the intervertebral discs. Stem Cells Dev 15(1):136–137CrossRefGoogle Scholar
  24. 24.
    Kumar H, Ha DH, Lee EJ, Park JH, Shim JH, Ahn TK, Kim KT, Ropper AE, Sohn S, Kim CH et al (2017) Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. Stem Cell Res Ther 8(1):262CrossRefGoogle Scholar
  25. 25.
    Meisel HJ, Ganey T, Hutton WC, Libera J, Minkus Y, Alasevic O (2006) Clinical experience in cell-based therapeutics: intervention and outcome. Eur Spine J 15 Suppl 3:S397–S405CrossRefGoogle Scholar
  26. 26.
    Meisel HJ, Siodla V, Ganey T, Minkus Y, Hutton WC, Alasevic OJ (2007) Clinical experience in cell-based therapeutics: disc chondrocyte transplantation a treatment for degenerated or damaged intervertebral disc. Biomol Eng 24(1):5–21CrossRefGoogle Scholar
  27. 27.
    Mochida J, Sakai D, Nakamura Y, Watanabe T, Yamamoto Y, Kato S (2015) Intervertebral disc repair with activated nucleus pulposus cell transplantation: a three-year, prospective clinical study of its safety. Eur Cell Mater 29:202–212 discussion 212 CrossRefGoogle Scholar
  28. 28.
    Noriega DC, Ardura F, Hernandez-Ramajo R, Martin-Ferrero MA, Sanchez-Lite I, Toribio B, Alberca M, Garcia V, Moraleda JM, Sanchez A et al (2017) Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial. Transplantation 101(8):1945–1951CrossRefGoogle Scholar
  29. 29.
    Orozco L, Soler R, Morera C, Alberca M, Sanchez A, Garcia-Sancho J (2011) Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 92(7):822–828CrossRefGoogle Scholar
  30. 30.
    Pang X, Yang H, Peng B (2014) Human umbilical cord mesenchymal stem cell transplantation for the treatment of chronic discogenic low back pain. Pain Physician 17(4):E525–E530Google Scholar
  31. 31.
    Pettine KA, Murphy MB, Suzuki RK, Sand TT (2015) Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cells 33(1):146–156CrossRefGoogle Scholar
  32. 32.
    Pettine K, Suzuki R, Sand T, Murphy M (2016) Treatment of discogenic back pain with autologous bone marrow concentrate injection with minimum two year follow-up. Int Orthop 40(1):135–140CrossRefGoogle Scholar
  33. 33.
    Tschugg A, Diepers M, Simone S, Michnacs F, Quirbach S, Strowitzki M, Meisel HJ, Thome C (2017) A prospective randomized multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disk plus autologous disk chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disks to avoid secondary disease: safety results of phase I—a short report. Neurosurg Rev 40(1):155–162CrossRefGoogle Scholar
  34. 34.
    Tschugg A, Michnacs F, Strowitzki M, Meisel HJ, Thome C (2016) A prospective multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disc plus autologous disc chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disc to avoid secondary disease: study protocol for a randomized controlled trial. Trials 17(1):108CrossRefGoogle Scholar
  35. 35.
    Yoshikawa T, Ueda Y, Miyazaki K, Koizumi M, Takakura Y (2010) Disc regeneration therapy using marrow mesenchymal cell transplantation: a report of two case studies. Spine 35(11):E475–E480CrossRefGoogle Scholar
  36. 36.
    Thorpe AA, Bach FC, Tryfonidou MA, Le Maitre CL, Mwale F, Diwan AD, Ito K (2018) Leaping the hurdles in developing regenerative treatments for the intervertebral disc from preclinical to clinical. JOR Spine 1:e1027.
  37. 37.
    Holtedahl R, Brox JI, Tjomsland O (2015) Placebo effects in trials evaluating 12 selected minimally invasive interventions: a systematic review and meta-analysis. BMJ Open 5(1):e007331CrossRefGoogle Scholar
  38. 38.
    Harden RN, Saracoglu M, Connolly S, Kirsling A, Comstock K, Khazey K, Gerson T, Burns J (2016) “Managing” the placebo effect: the single-blind placebo lead-in response in two pain models. Pain Med 17(12):2305–2310CrossRefGoogle Scholar
  39. 39.
    Brayda-Bruno M, Tibiletti M, Ito K, Fairbank J, Galbusera F, Zerbi A, Roberts S, Wachtel E, Merkher Y, Sivan SS (2014) Advances in the diagnosis of degenerated lumbar discs and their possible clinical application. Eur Spine J 23(3):315–323CrossRefGoogle Scholar
  40. 40.
    Mader KT, Peeters M, Detiger SE, Helder MN, Smit TH, Le Maitre CL, Sammon C (2016) Investigation of intervertebral disc degeneration using multivariate FTIR spectroscopic imaging. Faraday Discuss 187:393–414CrossRefGoogle Scholar
  41. 41.
    Wang AM, Cao P, Yee A, Chan D, Wu EX (2015) Detection of extracellular matrix degradation in intervertebral disc degeneration by diffusion magnetic resonance spectroscopy. Magn Reson Med 73(5):1703–1712CrossRefGoogle Scholar
  42. 42.
    Grad S, Bow C, Karppinen J, Luk KD, Cheung KM, Alini M, Samartzis D (2016) Systemic blood plasma CCL5 and CXCL6: potential biomarkers for human lumbar disc degeneration. Eur Cell Mater 31:1–10CrossRefGoogle Scholar
  43. 43.
    Davies BM, Atkinson RA, Ludwinski F, Freemont AJ, Hoyland JA, Gnanalingham KK (2016) Qualitative grading of disc degeneration by magnetic resonance in the lumbar and cervical spine: lack of correlation with histology in surgical cases. Br J Neurosurg 30(4):414–421CrossRefGoogle Scholar
  44. 44.
    Nukaga T, Sakai D, Tanaka M, Hiyama A, Nakai T, Mochida J (2016) Transplantation of activated nucleus pulposus cells after cryopreservation: efficacy study in a canine disc degeneration model. Eur Cell Mater 31:1473–2262 (Electronic), 95-106Google Scholar
  45. 45.
    Gantenbein B, Calandriello E, Wuertz-Kozak K, Benneker LM, Keel MJ, Chan SC (2014) Activation of intervertebral disc cells by co-culture with notochordal cells, conditioned medium and hypoxia. BMC Musculoskelet Disord 15(1):422CrossRefGoogle Scholar
  46. 46.
    Hiraishi S, Schol J, Sakai D, Nukaga T, Erickson I, Silverman L, Foley K, Watanabe M (2018) Discogenic cell transplantation directly from a cryopreserved state in an induced intervertebral disc degeneration canine model. JOR Spine 1:2CrossRefGoogle Scholar
  47. 47.
    Ganey T, Libera J, Moos V, Alasevic O, Fritsch KG, Meisel HJ, Hutton WC (2003) Disc chondrocyte transplantation in a canine model: a treatment for degenerated or damaged intervertebral disc. Spine 28(23):2609–2620CrossRefGoogle Scholar
  48. 48.
    Arpinar VE, Rand SD, Klein AP, Maiman DJ, Muftuler LT (2015) Changes in perfusion and diffusion in the endplate regions of degenerating intervertebral discs: a DCE-MRI study. Eur Spine J 24(11):2458–2467CrossRefGoogle Scholar
  49. 49.
    Muftuler LT, Jarman JP, Yu HJ, Gardner VO, Maiman DJ, Arpinar VE (2015) Association between intervertebral disc degeneration and endplate perfusion studied by DCE-MRI. Eur Spine J 24(4):679–685CrossRefGoogle Scholar
  50. 50.
    Clarke LE, McConnell JC, Sherratt MJ, Derby B, Richardson SM, Hoyland JA (2014) Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition, and micromechanical properties of nucleus pulposus constructs. Arthritis Res Ther 16(2):R67CrossRefGoogle Scholar
  51. 51.
    Colombier P, Clouet J, Boyer C, Ruel M, Bonin G, Lesoeur J, Moreau A, Fellah BH, Weiss P, Lescaudron L et al (2016) TGF-beta1 and GDF5 act synergistically to drive the differentiation of human adipose stromal cells toward nucleus pulposus-like cells. Stem Cells 34(3):653–667CrossRefGoogle Scholar
  52. 52.
    Stoyanov JV, Gantenbein-Ritter B, Bertolo A, Aebli N, Baur M, Alini M, Grad S (2011) 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 21:533–547CrossRefGoogle Scholar
  53. 53.
    Mwale F, Roughley P, Antoniou J (2004) Distinction between the extracellular matrix of the nucleus pulposus and hyaline cartilage: a requisite for tissue engineering of intervertebral disc. Eur Cell Mater 8:58–63 discussion 63-54 CrossRefGoogle Scholar
  54. 54.
    Sakai D, Nakamura Y, Nakai T, Mishima T, Kato S, Grad S, Alini M, Risbud MV, Chan D, Cheah KS et al (2012) Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat Commun 3:1264CrossRefGoogle Scholar
  55. 55.
    Sakai D, Schol J, Bach FC, Tekari A, Sagawa N, Nakamura Y, Chan SCW, Nakai T, Creemers LB, Frauchiger DA et al. (2018) Successful fishing for nucleus pulposus progenitor cells of the intervertebral disc across species. JOR Spine 1:e1018.
  56. 56.
    Wu T, Song HX, Dong Y, Li JH (2018) Cell-based therapies for lumbar discogenic low back pain: systematic review and single-arm meta-analysis. Spine 43(1):49–57CrossRefGoogle Scholar
  57. 57.
    Ganguly P, El-Jawhari JJ, Giannoudis PV, Burska AN, Ponchel F, Jones EA (2017) Age-related changes in bone marrow mesenchymal stromal cells: a potential impact on osteoporosis and osteoarthritis development. Cell Transplant 26(9):1520–1529CrossRefGoogle Scholar
  58. 58.
    Serigano K, Sakai D, Hiyama A, Tamura F, Tanaka M, Mochida J (2010) Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. J Orthop Res 28(10):1267–1275CrossRefGoogle Scholar
  59. 59.
    Michalek AJ, Buckley MR, Bonassar LJ, Cohen I, Iatridis JC (2010) The effects of needle puncture injury on microscale shear strain in the intervertebral disc annulus fibrosus. Spine J 10(12):1098–1105CrossRefGoogle Scholar
  60. 60.
    Gullbrand SE, Malhotra NR, Schaer TP, Zawacki Z, Martin JT, Bendigo JR, Milby AH, Dodge GR, Vresilovic EJ, Elliott DM et al (2017) A large animal model that recapitulates the spectrum of human intervertebral disc degeneration. Osteoarthr Cartil 25(1):146–156CrossRefGoogle Scholar
  61. 61.
    Vadala G, Sowa G, Hubert M, Gilbertson LG, Denaro V, Kang JD (2012) Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med 6(5):348–355CrossRefGoogle Scholar
  62. 62.
    Vadala G, Russo F, Pattappa G, Schiuma D, Peroglio M, Benneker LM, Grad S, Alini M, Denaro V (2013) The transpedicular approach as an alternative route for intervertebral disc regeneration. Spine 38(6):E319–E324CrossRefGoogle Scholar
  63. 63.
    Illien-Junger S, Pattappa G, Peroglio M, Benneker LM, Stoddart MJ, Sakai D, Mochida J, Grad S, Alini M (2012) Homing of mesenchymal stem cells in induced degenerative intervertebral discs in a whole organ culture system. Spine 37(22):1865–1873CrossRefGoogle Scholar
  64. 64.
    Sakai D, Schol J, Foldager CB, Sato M, Watanabe M (2017) Regenerative technologies to bed side: evolving the regulatory framework. J Orthop Translat 9:1–7CrossRefGoogle Scholar

Copyright information

© SICOT aisbl 2018

Authors and Affiliations

  1. 1.Department for Orthopaedic SurgeryTokai University School of MedicineIseharaJapan

Personalised recommendations