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International Orthopaedics
Erschienen in: International Orthopaedics 4/2019

29.11.2018 | Review Article

Clinical trials of intervertebral disc regeneration: current status and future developments

verfasst von: Yi Sun, Victor Y. Leung, Kenneth M. Cheung

Erschienen in: International Orthopaedics | Ausgabe 4/2019

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Abstract

Intervertebral disc (IVD) degeneration (IDD) is considered as one of the major causes for low back pain (LBP). However, conventional surgical approaches for treating LBP do not aim to counter the degeneration. Biological interventions have been investigated with an attempt to regenerate the IVD by restoring its matrices and cell activities. This review summarizes the current clinical trials that explore the efficacy of covering cell-, growth factor-, and small molecule-based approaches. While investigations of growth factor- and small molecule-based therapies are still preliminary, intradiscal delivery of mesenchymal stromal cells has been more widely adopted and shown positive results in addressing the pain and the associated physical disability, albeit to a lower extent than observed in previous animal studies. Strategies that potentiate the endogenous disc progenitors may offer a valid alternative to the exogenous cell transplantation. Identification of the novel biologics to arrest IDD phenotype may potentiate disc repair in future. Large-scale, high-quality long-term trials should be conducted to clarify the safety and efficacy of these therapies.
Literatur
1.
Cheung KM, Samartzis D, Karppinen J, Luk KD (2012) Are “patterns” of lumbar disc degeneration associated with low back pain?: new insights based on skipped level disc pathology. Spine (Phila Pa 1976) 37(7):E430–E438CrossRef
2.
Samartzis D, Karppinen J, Mok F, Fong DY, Luk KD, Cheung KM (2011) A population-based study of juvenile disc degeneration and its association with overweight and obesity, low back pain, and diminished functional status. J Bone Joint Surg Am 93(7):662–670PubMedCrossRef
3.
Cheung KM (2010) The relationship between disc degeneration, low back pain, and human pain genetics. Spine J 10(11):958–960PubMedCrossRef
4.
Zhao CQ, Wang LM, Jiang LS, Dai LY (2007) The cell biology of intervertebral disc aging and degeneration. Ageing Res Rev 6(3):247–261PubMedCrossRef
5.
Bian Q, Ma L, Jain A, Crane JL, Kebaish K, Wan M, Zhang Z, Edward Guo X, Sponseller PD, Seguin CA et al (2017) Mechanosignaling activation of TGFbeta maintains intervertebral disc homeostasis. Bone Res 5:17008PubMedPubMedCentralCrossRef
6.
Kennon JC, Awad ME, Chutkan N, DeVine J, Fulzele S (2018) Current insights on use of growth factors as therapy for Intervertebral Disc Degeneration. Biomol Concepts 9(1):43–52PubMedCrossRef
7.
Liu ZQ, Zhao S, Fu WQ (2016) Insulin-like growth factor 1 antagonizes lumbar disc degeneration through enhanced autophagy. Am J Transl Res 8(10):4346–4353PubMedPubMedCentral
8.
Risbud MV, Shapiro IM (2014) Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol 10(1):44–56PubMedCrossRef
9.
Wang C, Yu X, Yan Y, Yang W, Zhang S, Xiang Y, Zhang J, Wang W (2017) Tumor necrosis factor-alpha: a key contributor to intervertebral disc degeneration. Acta Biochim Biophys Sin Shanghai 49(1):1–13PubMedCrossRef
10.
Karppinen J, Shen FH, Luk KD, Andersson GB, Cheung KM, Samartzis D (2011) Management of degenerative disk disease and chronic low back pain. Orthop Clin North Am 42(4):513–528 viii PubMedCrossRef
11.
12.
Ghiselli G, Wang JC, Bhatia NN, Hsu WK, Dawson EG (2004) Adjacent segment degeneration in the lumbar spine. J Bone Joint Surg Am 86-A(7):1497–1503CrossRef
13.
Eliasberg CD, Kelly MP, Ajiboye RM, SooHoo NF (2016) Complications and rates of subsequent lumbar surgery following lumbar total disc arthroplasty and lumbar fusion. Spine (Phila Pa 1976) 41(2):173–181CrossRef
14.
Sampara P, Banala RR, Vemuri SK, Av GR, Gpv S (2018) Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration: a review. Gene Ther 25(2):67–82PubMedCrossRef
15.
16.
Basso M, Cavagnaro L, Zanirato A, Divano S, Formica C, Formica M, Felli L (2017) What is the clinical evidence on regenerative medicine in intervertebral disc degeneration? Musculoskelet Surg 101(2):93–104PubMedCrossRef
17.
Potier E, Ito K (2014) Using notochordal cells of developmental origin to stimulate nucleus pulposus cells and bone marrow stromal cells for intervertebral disc regeneration. Eur Spine J 23(3):679–688PubMedCrossRef
18.
Wang W, Deng G, Qiu Y, Huang X, Xi Y, Yu J, Yang X, Ye X (2018) Transplantation of allogenic nucleus pulposus cells attenuates intervertebral disc degeneration by inhibiting apoptosis and increasing migration. Int J Mol Med 41(5):2553–2564PubMedPubMedCentral
19.
Yim RL, Lee JT, Bow CH, Meij B, Leung V, Cheung KM, Vavken P, Samartzis D (2014) A systematic review of the safety and efficacy of mesenchymal stem cells for disc degeneration: insights and future directions for regenerative therapeutics. Stem Cells Dev 23(21):2553–2567PubMedPubMedCentralCrossRef
20.
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
21.
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
22.
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
23.
Hyun W. Bae KA, Coric D, McJunkin TL, Pettine KA, Hong HJ, DePalma MJ, Kim KD, Beckworth WJ, Oehme D, Goldschlager T, Brown RD (2014) A phase II study demonstrating efficacy and safety of mesenchymal precursor cells in low back pain due to disc degeneration. Spine J 14(11):31–32
24.
Garcia-Sancho J, Sanchez A, Vega A, Noriega DC, Nocito M (2017) Influence of HLA matching on the efficacy of allogeneic mesenchymal stromal cell therapies for osteoarthritis and degenerative disc disease. Transplant Direct 3(9):e205PubMedPubMedCentralCrossRef
25.
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
26.
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
27.
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
28.
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
29.
Le Blanc K, Davies LC (2015) Mesenchymal stromal cells and the innate immune response. Immunol Lett 168(2):140–146PubMedCrossRef
30.
Detiger SE, Helder MN, Smit TH, Hoogendoorn RJ (2015) Adverse effects of stromal vascular fraction during regenerative treatment of the intervertebral disc: observations in a goat model. Eur Spine J 24(9):1992–2000PubMedCrossRef
31.
Wang SZ, Jin JY, Guo YD, Ma LY, Chang Q, Peng XG, Guo FF, Zhang HX, Hu XF, Wang C (2016) Intervertebral disc regeneration using platelet-rich plasma-containing bone marrow-derived mesenchymal stem cells: a preliminary investigation. Mol Med Rep 13(4):3475–3481PubMedPubMedCentralCrossRef
32.
Alini M, Eisenstein SM, Ito K, Little C, Kettler AA, Masuda K, Melrose J, Ralphs J, Stokes I, Wilke HJ (2008) Are animal models useful for studying human disc disorders/degeneration? Eur Spine J 17(1):2–19PubMedCrossRef
33.
Yuan M, Yeung CW, Li YY, Diao H, Cheung KM, Chan D, Cheah K, Chan PB (2013) Effects of nucleus pulposus cell-derived acellular matrix on the differentiation of mesenchymal stem cells. Biomaterials 34(16):3948–3961PubMedCrossRef
34.
Leung VY, Aladin DM, Lv F, Tam V, Sun Y, Lau RY, Hung SC, Ngan AH, Tang B, Lim CT et al (2014) Mesenchymal stem cells reduce intervertebral disc fibrosis and facilitate repair. Stem Cells 32(8):2164–2177PubMedCrossRef
35.
Cheng X, Zhang G, Zhang L, Hu Y, Zhang K, Sun X, Zhao C, Li H, Li YM, Zhao J (2018) Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration. J Cell Mol Med 22(1):261–276PubMedCrossRef
36.
Wang F, Shi R, Cai F, Wang YT, Wu XT (2015) Stem cell approaches to intervertebral disc regeneration: obstacles from the disc microenvironment. Stem Cells Dev 24(21):2479–2495PubMedCrossRef
37.
Beeravolu N, Brougham J, Khan I, McKee C, Perez-Cruet M, Chaudhry GR (2018) Human umbilical cord derivatives regenerate intervertebral disc. J Tissue Eng Regen Med 12(1):e579–e591PubMedCrossRef
38.
Yi Z, Guanjun T, Lin C, Zifeng P (2014) Effects of transplantation of hTIMP-1-expressing bone marrow mesenchymal stem cells on the extracellular matrix of degenerative intervertebral discs in an in vivo rabbit model. Spine (Phila Pa 1976) 39(11):E669–E675CrossRef
39.
Oehme D, Ghosh P, Goldschlager T, Itescu S, Shimon S, Wu J, McDonald C, Troupis JM, Rosenfeld JV, Jenkin G (2016) Reconstitution of degenerated ovine lumbar discs by STRO-3-positive allogeneic mesenchymal precursor cells combined with pentosan polysulfate. J Neurosurg Spine 24(5):715–726PubMedCrossRef
40.
Omlor GW, Bertram H, Kleinschmidt K, Fischer J, Brohm K, Guehring T, Anton M, Richter W (2010) Methods to monitor distribution and metabolic activity of mesenchymal stem cells following in vivo injection into nucleotomized porcine intervertebral discs. Eur Spine J 19(4):601–612PubMedCrossRef
41.
Maidhof R, Rafiuddin A, Chowdhury F, Jacobsen T, Chahine NO (2017) Timing of mesenchymal stem cell delivery impacts the fate and therapeutic potential in intervertebral disc repair. J Orthop Res 35(1):32–40PubMedCrossRef
42.
Zhou X, Tao Y, Chen E, Wang J, Fang W, Zhao T, Liang C, Li F, Chen Q (2018) Genipin-cross-linked type II collagen scaffold promotes the differentiation of adipose-derived stem cells into nucleus pulposus-like cells. J Biomed Mater Res A 106(5):1258–1268PubMedCrossRef
43.
Wu Y, Jia Z, Liu L, Zhao Y, Li H, Wang C, Tao H, Tang Y, He Q, Ruan D (2016) Functional self-assembled peptide nanofibers for bone marrow mesenchymal stem cell encapsulation and regeneration in nucleus pulposus. Artif Organs 40(6):E112–E119PubMedCrossRef
44.
Tsaryk R, Gloria A, Russo T, Anspach L, De Santis R, Ghanaati S, Unger RE, Ambrosio L, Kirkpatrick CJ (2015) Collagen-low molecular weight hyaluronic acid semi-interpenetrating network loaded with gelatin microspheres for cell and growth factor delivery for nucleus pulposus regeneration. Acta Biomater 20:10–21PubMedCrossRef
45.
Tam V, Rogers I, Chan D, Leung VY, Cheung KM (2014) A comparison of intravenous and intradiscal delivery of multipotential stem cells on the healing of injured intervertebral disk. J Orthop Res 32(6):819–825PubMedCrossRef
46.
Le Fournier L, Fusellier M, Halgand B, Lesoeur J, Gauthier O, Menei P, Montero-Menei C, Guicheux J, Clouet J (2017) The transpedicular surgical approach for the development of intervertebral disc targeting regenerative strategies in an ovine model. Eur Spine J 26(8):2072–2083PubMedCrossRef
47.
Wu H, Shang Y, Yu J, Zeng X, Lin J, Tu M, Cheang LH, Zhang J (2018) Regenerative potential of human nucleus pulposus resident stem/progenitor cells declines with ageing and intervertebral disc degeneration. Int J Mol Med 42(4):2193–2202PubMed
48.
Tekari A, Chan SC, Sakai D, Grad S, Gantenbein B (2016) Angiopoietin-1 receptor Tie2 distinguishes multipotent differentiation capability in bovine coccygeal nucleus pulposus cells. Stem Cell Res Ther 7(1):75PubMedPubMedCentralCrossRef
49.
Brown S, Matta A, Erwin M, Roberts S, Gruber HE, Hanley EN Jr, Little CB, Melrose J (2018) Cell clusters are indicative of stem cell activity in the degenerate intervertebral disc: can their properties be manipulated to improve intrinsic repair of the disc? Stem Cells Dev 27(3):147–165PubMedCrossRef
50.
Ishii T, Sakai D, Schol J, Nakai T, Suyama K, Watanabe M (2017) Sciatic nerve regeneration by transplantation of in vitro differentiated nucleus pulposus progenitor cells. Regen Med 12(4):365–376PubMedCrossRef
51.
Wu H, Zeng X, Yu J, Shang Y, Tu M, Cheang LH, Zhang J (2017) Comparison of nucleus pulposus stem/progenitor cells isolated from degenerated intervertebral discs with umbilical cord derived mesenchymal stem cells. Exp Cell Res 361(2):324–332PubMedCrossRef
52.
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
53.
Young-Joon Kwon ESK, Kim S-M, Park H, Byun HM, Nam S-Y (2015) Intradiscal injection of YH14618, a first-in-class disease-modifying therapy, reduces pain and improves daily activity in patients with symptomatic lumbar degenerative disc disease. Spine J 15(10):S119CrossRef
54.
Kwon YJ, Lee JW, Moon EJ, Chung YG, Kim OS, Kim HJ (2013) Anabolic effects of Peniel 2000, a peptide that regulates TGF-beta1 signaling on intervertebral disc degeneration. Spine (Phila Pa 1976) 38(2):E49–E58CrossRef
55.
Zheng L, Cao Y, Ni S, Qi H, Ling Z, Xu X, Zou X, Wu T, Deng R, Hu B et al (2018) Ciliary parathyroid hormone signaling activates transforming growth factor-beta to maintain intervertebral disc homeostasis during aging. Bone Res 6:21PubMedPubMedCentralCrossRef
56.
Deshmukh V, Hu H, Barroga C, Bossard C, Kc S, Dellamary L, Stewart J, Chiu K, Ibanez M, Pedraza M et al (2018) A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthr Cartil 26(1):18–27PubMedCrossRef
57.
Lin AC, Seeto BL, Bartoszko JM, Khoury MA, Whetstone H, Ho L, Hsu C, Ali SA, Alman BA (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15(12):1421–1425PubMedCrossRef
58.
Suyama K, Sakai D, Hirayama N, Nakamura Y, Matsushita E, Terayama H, Qu N, Tanaka O, Sakabe K, Watanabe M (2018) Effects of interleukin-17A in nucleus pulposus cells and its small-molecule inhibitors for intervertebral disc disease. J Cell Mol Med 22(11):5539–5551PubMedPubMedCentralCrossRef
59.
60.
Krupkova O, Sekiguchi M, Klasen J, Hausmann O, Konno S, Ferguson SJ, Wuertz-Kozak K (2014) Epigallocatechin 3-gallate suppresses interleukin-1beta-induced inflammatory responses in intervertebral disc cells in vitro and reduces radiculopathic pain in rats. Eur Cell Mater 28:372–386PubMedCrossRef
61.
Shi C, Wu H, Du D, Im HJ, Zhang Y, Hu B, Chen H, Wang X, Liu Y, Cao P et al (2018) Nicotinamide phosphoribosyltransferase inhibitor APO866 prevents IL-1beta-induced human nucleus pulposus cell degeneration via autophagy. Cell Physiol Biochem 49(6):2463–2482PubMedCrossRef
62.
Li K, Li Y, Mi J, Mao L, Han X, Zhao J (2018) Resveratrol protects against sodium nitroprusside induced nucleus pulposus cell apoptosis by scavenging ROS. Int J Mol Med 41(5):2485–2492PubMedPubMedCentral
63.
Liu H, Kang H, Song C, Lei Z, Li L, Guo J, Xu Y, Guan H, Fang Z, Li F (2018) Urolithin a inhibits the catabolic effect of TNFalpha on nucleus pulposus cell and alleviates intervertebral disc degeneration in vivo. Front Pharmacol 9:1043PubMedPubMedCentralCrossRef
64.
Buckwalter JA (1995) Aging and degeneration of the human intervertebral disc. Spine (Phila Pa 1976) 20(11):1307–1314CrossRef
65.
Chan D, Song Y, Sham P, Cheung KM (2006) Genetics of disc degeneration. Eur Spine J 15(Suppl 3):S317–S325PubMedCrossRef
66.
Fogelholm RR, Alho AV (2001) Smoking and intervertebral disc degeneration. Med Hypotheses 56(4):537–539PubMedCrossRef
67.
Liuke M, Solovieva S, Lamminen A, Luoma K, Leino-Arjas P, Luukkonen R, Riihimaki H (2005) Disc degeneration of the lumbar spine in relation to overweight. Int J Obes 29(8):903–908CrossRef
68.
Seidler A, Euler U, Bolm-Audorff U, Ellegast R, Grifka J, Haerting J, Jager M, Michaelis M, Kuss O (2011) Physical workload and accelerated occurrence of lumbar spine diseases: risk and rate advancement periods in a German multicenter case-control study. Scand J Work Environ Health 37(1):30–36PubMedCrossRef
69.
Amelot A, Mazel C (2018) The intervertebral disc: physiology and pathology of a brittle joint. World Neurosurg 120:265–273
Metadaten
Titel
Clinical trials of intervertebral disc regeneration: current status and future developments
verfasst von
Yi Sun
Victor Y. Leung
Kenneth M. Cheung
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/s00264-018-4245-8

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