nach oben

International Orthopaedics

Erschienen in:

29.11.2018 | Review

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

verfasst von: Jordy Schol, Daisuke Sakai

Erschienen in: International Orthopaedics | Ausgabe 4/2019

Einloggen, um Zugang zu erhalten

Abstract

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.

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):2163–2196CrossRef

Meucci RD, Fassa AG, Faria NM (2015) Prevalence of chronic low back pain: systematic review. Rev Saude Publica 49:1518–8787 (Electronic)CrossRef

Katz JN (2006) Lumbar disc disorders and low-back pain: socioeconomic factors and consequences. J Bone Joint Surg Am 88 Suppl 2(4):21–24PubMed

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):656–664PubMedCrossRef

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):807–815PubMedPubMedCentralCrossRef

Freemont AJ (2009) The cellular pathobiology of the degenerate intervertebral disc and discogenic back pain. Rheumatology (Oxford, England) 48(1):5–10CrossRef

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):179–185PubMedPubMedCentralCrossRef

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):265–271PubMedCrossRef

Deyo RA, Nachemson A, Mirza SK (2004) Spinal-fusion surgery—the case for restraint. N Engl J Med 350(7):722–726PubMedCrossRef

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):2097–2103PubMedCrossRef

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 PubMedCrossRef

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):320–331PubMedCrossRef

13.

Epstein NE (2015) Adjacent level disease following lumbar spine surgery: a review. Surg Neurol Int 6 Suppl 24:S591–S599CrossRef

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):2197–2208PubMedCrossRef

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 1:3CrossRef

16.

Gullbrand SE, Smith LJ, Smith HE, Mauck RL (2018) Promise, progress, and problems in whole disc tissue engineering. JOR Spine 1:2CrossRef

17.

Sakai D, Schol J (2017) Cell therapy for intervertebral disc repair: clinical perspective. J Orthop Translat 9:8–18PubMedPubMedCentralCrossRef

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. https://doi.org/10.1002/jsp2.1036

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):197PubMedPubMedCentralCrossRef

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):12PubMedCrossRef

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):85–95PubMedCrossRef

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 14:253PubMedPubMedCentralCrossRef

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):136–137PubMedCrossRef

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):262PubMedPubMedCentralCrossRef

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–S405PubMedCrossRef

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):5–21PubMedCrossRef

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 PubMedCrossRef

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):1945–1951PubMedCrossRef

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):822–828PubMedCrossRef

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–E530PubMed

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):146–156PubMedCrossRef

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):135–140PubMedCrossRef

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):155–162PubMedCrossRef

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):108PubMedPubMedCentralCrossRef

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–E480PubMedCrossRef

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. https://doi.org/10.1002/jsp2.1027

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):e007331PubMedPubMedCentralCrossRef

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):2305–2310PubMedCrossRef

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):315–323CrossRef

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 187:393–414PubMedPubMedCentralCrossRef

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):1703–1712PubMedCrossRef

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 31:1–10PubMedCrossRef

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):414–421PubMedCrossRef

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), 95-106

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):422PubMedPubMedCentralCrossRef

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 1:2CrossRef

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):2609–2620PubMedCrossRef

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):2458–2467PubMedCrossRef

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):679–685PubMedCrossRef

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):R67PubMedPubMedCentralCrossRef

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):653–667PubMedCrossRef

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 21:533–547PubMedCrossRef

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 PubMedCrossRef

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 3:1264PubMedCrossRef

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. https://doi.org/10.1002/jsp2.1018

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):49–57PubMedCrossRef

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):1520–1529PubMedPubMedCentralCrossRef

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):1267–1275PubMedCrossRef

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):1098–1105PubMedPubMedCentralCrossRef

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):146–156CrossRef

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):348–355PubMedCrossRef

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–E324PubMedCrossRef

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):1865–1873PubMedCrossRef

64.

Sakai D, Schol J, Foldager CB, Sato M, Watanabe M (2017) Regenerative technologies to bed side: evolving the regulatory framework. J Orthop Translat 9:1–7PubMedPubMedCentralCrossRef

Titel: Cell therapy for intervertebral disc herniation and degenerative disc disease: clinical trials
verfasst von: Jordy Schol
Daisuke Sakai
Publikationsdatum: 29.11.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: International Orthopaedics / Ausgabe 4/2019
Print ISSN: 0341-2695
Elektronische ISSN: 1432-5195
DOI: https://doi.org/10.1007/s00264-018-4223-1

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, Videos und Abbildungen.
» Jetzt entdecken

Neu im Fachgebiet Orthopädie und Unfallchirurgie

25.04.2024 | Hypertonie | Nachrichten

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

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

Abstract

Arthropedia

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Ärztliche Empathie hilft gegen Rückenschmerzen

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Update Orthopädie und Unfallchirurgie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2019

What every spine surgeon should know about transforaminal lumbar interbody fusion surgery for herniated discs

Preliminary efficacy of inter-spinal distraction fusion which is a new technique for lumbar disc herniation

Risk factors for recurrent lumbar disc herniation after discectomy

Adjacent segment degeneration after fusion spinal surgery—a systematic review

Thoracic disc herniation, avoidance, and management of the surgical complications

Current concepts for lumbar disc herniation

Arthropedia

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Ärztliche Empathie hilft gegen Rückenschmerzen

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Update Orthopädie und Unfallchirurgie