Autologous mesenchymal stromal cells embedded in tricalcium phosphate for posterolateral spinal fusion: results of a prospective phase I/II clinical trial with long-term follow-up

Juan F Blanco, Eva M Villarón, David Pescador, Carmen da Casa, Victoria Gómez, Alba M Redondo, Olga López-Villar, Miriam López-Parra, Sandra Muntión, Fermín Sánchez-Guijo, Juan F Blanco, Eva M Villarón, David Pescador, Carmen da Casa, Victoria Gómez, Alba M Redondo, Olga López-Villar, Miriam López-Parra, Sandra Muntión, Fermín Sánchez-Guijo

Abstract

Background: Posterolateral spinal fusion with autologous bone graft is considered the "gold standard" for lumbar degenerative disc disease (DDD) when surgical treatment is indicated. The potential role of mesenchymal stromal cells (MSCs) to replace the bone graft in this setting has not been fully addressed.

Objective: To analyze the safety, feasibility and potential clinical efficacy of the implantation of autologous MSCs embedded with tricalcium phosphate as a therapeutic alternative to bone graft in patients with DDD during posterolateral spine fusion.

Study design: Phase I/II single-arm prospective clinical trial.

Methods: Eleven patients with monosegmental DDD at L4-L5 or L5-S1 level were included. Autologous bone marrow-derived MSC were expanded in our Good Manufacturing Practice (GMP) Facility and implanted during spinal surgery embedded in a tricalcium phosphate carrier. Monitoring of patients included a postoperative period of 12 months with four visits (after the 1st, 3rd, 6th, and 12th month), with clinical and radiological assessment that included the visual analog scale (VAS), the Oswestry disability index (ODI), the Short-Form Health Survey (SF-36), the vertebral fusion grade observed through a simple Rx, and the evaluation of possible complications or adverse reactions. In addition, all patients were further followed up to 5 years for outcome.

Results: Median age of patients included was 44 years (range 30-58 years), and male/female ratio was (6/5) L4-L5 and L5-S1 DDD was present five and six patients, respectively. Autologous MSCs were expanded in all cases. There were no adverse effects related to cell implantation. Regarding efficacy, both VAS and ODI scores improved after surgery. Radiologically, 80% of patients achieved lumbar fusion at the end of the follow-up. No adverse effects related to the procedure were recorded.

Conclusions: The use of autologous MSCs for spine fusion in patients with monosegmental degenerative disc disease is feasible, safe, and potentially effective.

Trial registration: no. EudraCT: 2010-018335-17 ; code Identifier: NCT01513694 ( clinicaltrials.gov ).

Keywords: Autologous mesenchymal stromal cells; Bone graft; Cell therapy; DDD; Lumbar degenerative disc disease; MSC; Spinal fusion; Spine surgery.

Conflict of interest statement

Competing interests

The authors declare that they have no competing interests.

Ethics approval and consent to participate

This clinical trial protocol was reviewed and approved by the Ethics Committee of the University Hospital of Salamanca and the Spanish Medicine Agency (AEMPS).

Furthermore, all patients signed the approved informed consent and all the procedures where in accordance to the principles of the Declaration of Helsinki.

Consent for publication

All patients signed de informed consent, including consent for publication. No personal details or contact data of patient was included.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Anteroposterior X-ray of L4–L5 showing bone bridges (asterisk) formation in the intertransverse space for posterolateral spine fusion 1 year after surgery
Fig. 2
Fig. 2
Anteroposterior X-ray of L5–S1 showing bone bridges (asterisk) formation in the intertransverse space for posterolateral spine fusion 1 year after surgery

References

    1. Chan D, Song Y, Sham P, Cheung KM. Genetics of disc degeneration. Eur Spine J. 2006;15(Suppl 3):S317–S325. doi: 10.1007/s00586-006-0171-3.
    1. Setton LA, Chen J. Mechanobiology of the intervertebral disc and relevance to disc degeneration. J Bone Jt Surg Am. 2006;88(Suppl 2):52–57.
    1. Wang J, Tang T, Yang H, Yao X, Chen L, Liu W, et al. The expression of Fas ligand on normal and stabbed-disc cells in a rabbit model of intervertebral disc degeneration: a possible pathogenesis. J Neurosurg Spine. 2007;6(5):425–430. doi: 10.3171/spi.2007.6.5.425.
    1. Bibby SR, Urban JP. Effect of nutrient deprivation on the viability of intervertebral disc cells. Eur Spine J. 2004;13(8):695–701. doi: 10.1007/s00586-003-0616-x.
    1. Blanco JF, Graciani IF, Sanchez-Guijo FM, Muntión S, Hernandez-Campo P, Santamaria C, et al. Isolation and characterization of mesenchymal stromal cells from human degenerated nucleus pulposus: comparison with bone marrow mesenchymal stromal cells from the same subjects. Spine (Phila Pa 1976) 2010;35(26):2259–2265. doi: 10.1097/BRS.0b013e3181cb8828.
    1. Tarpada SP, Morris MT, Burton DA. Spinal fusion surgery: a historical perspective. J Orthop. 2017;14(1):134–136. doi: 10.1016/j.jor.2016.10.029.
    1. Rajaee SS, Bae HW, Kanim LE, Delamarter RB. Spinal fusion in the United States: analysis of trends from 1998 to 2008. Spine (Phila Pa 1976) 2012;37(1):67–76. doi: 10.1097/BRS.0b013e31820cccfb.
    1. Rihn JA, Kirkpatrick K, Albert TJ. Graft options in posterolateral and posterior interbody lumbar fusion. Spine. 2005;35(17):1629–39.
    1. Park JJ, Hershman SH, Kim YH. Updates in the use of bone grafts in the lumbar spine. Bull Hosp Jt Dis. 2013;71(1):39–48.
    1. Dimitriou R, Mataliotakis GI, Angoules AG, Kanakaris NK, Giannoudis PV. Complications following autologous bone graft harvesting from the iliac crest and using the RIA: a systematic review. Injury. 2011;42:S3–15. doi: 10.1016/j.injury.2011.06.015.
    1. An HS, Lynch K, Toth J. Prospective comparison of autograft vs. allograft for adult posterolateral lumbar spine fusion: differences among freeze-dried, frozen, and mixed grafts. J Spinal Disord. 1995;8(2):131–135. doi: 10.1097/00002517-199504000-00007.
    1. Gibson S, McLeod I, Wardlaw D, Urbaniak S. Allograft versus autograft in instrumented posterolateral lumbar spinal fusion: a randomized control trial. Spine (Phila Pa 1976) 2002;27(15):1599–1603. doi: 10.1097/00007632-200208010-00002.
    1. Korovessis P, Koureas G, Zacharatos S, Papazisis Z, Lambiris E. Correlative radiological, self-assessment and clinical analysis of evolution in instrumented dorsal and lateral fusion for degenerative lumbar spine disease. Autograft versus coralline hydroxyapatite. Eur Spine J. 2005;14(7):630–638. doi: 10.1007/s00586-004-0855-5.
    1. Oryan A, Kamali A, Moshiri A, Baghaban Eslaminejad M. Role of mesenchymal stem cells in bone regenerative medicine: what is the evidence? Cells Tissues Organs. 2017;204(2):59–83. doi: 10.1159/000469704.
    1. Uccelli A, de Rosbo NK. The immunomodulatory function of mesenchymal stem cells: mode of action and pathways. Ann N Y Acad Sci. 2015;1351:114–126. doi: 10.1111/nyas.12815.
    1. Sharma RR, Pollock K, Hubel A, McKenna D. Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices. Transfusion. 2014;54(5):1418–1437. doi: 10.1111/trf.12421.
    1. Wang LT, Ting CH, Yen ML, Liu KJ, Sytwu HK, Wu KK, et al. Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials. J Biomed Sci. 2016;23(1):76. doi: 10.1186/s12929-016-0289-5.
    1. Salamanna F, Sartori M, Brodano GB, Griffoni C, Martini L, Boriani S, et al. Mesenchymal stem cells for the treatment of spinal arthrodesis: from preclinical research to clinical scenario. Stem Cells Int. 2017;2017:3537094. doi: 10.1155/2017/3537094.
    1. Blanco JF, García-Briñon J, Benito-Garzón L, Pescador D, Muntión S, Sánchez-Guijo F. Human bone marrow mesenchymal stromal cells promote bone regeneration in a xenogeneic rabbit model: a preclinical study. Stem Cells Int. 2018;2018:7089484. doi: 10.1155/2018/7089484.
    1. Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976) 2001;26(17):1873–1878. doi: 10.1097/00007632-200109010-00011.
    1. Sánchez-Guijo F, Caballero-Velázquez T, López-Villar O, Redondo A, Parody R, Martínez C, et al. Sequential third-party mesenchymal stromal cell therapy for refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20(10):1580–1585. doi: 10.1016/j.bbmt.2014.06.015.
    1. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs. 2005;14(7):798–804. doi: 10.1111/j.1365-2702.2005.01121.x.
    1. Little DG, MacDonald D. The use of the percentage change in Oswestry disability index score as an outcome measure in lumbar spinal surgery. Spine (Phila Pa 1976) 1994;19(19):2139–2143. doi: 10.1097/00007632-199410000-00001.
    1. Walsh TL, Hanscom B, Lurie JD, Weinstein JN. Is a condition-specific instrument for patients with low Back pain/leg symptoms really necessary? Spine (Phila Pa 1976) 2003;28(6):607–615.
    1. Sathiyakumar V, Molina CS, Thakore RV, Obremskey WT, Sethi MK. ASA score as a predictor of 30-day perioperative readmission in patients with orthopaedic trauma injuries: an NSQIP analysis. J Orthop Trauma. 2015;29(3):e127–e132. doi: 10.1097/BOT.0000000000000200.
    1. Werner BC, Li XSF. Stem cells in preclinical spine studies. spine J. 2014;14(3):542–551. doi: 10.1016/j.spinee.2013.08.031.
    1. Weiss AJ, Elixhauser A. Trends in operating room procedures in U.S. Hospitals, 2001–2011: Statistical Brief #171. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. 2006.
    1. Wood GW, Boyd RJ, Carothers TA, Mansfield FL, Rechtine GR, Rozen MJ, et al. The effect of pedicle screw/plate fixation on lumbar/lumbosacral autogenous bone graft fusions in patients with degenerative disc disease. Spine (Phila Pa 1976) 1995;20(7):819–830. doi: 10.1097/00007632-199504000-00017.
    1. Tuchman A, Brodke DS, Youssef JA, Meisel HJ, Dettori JR, Park JB, et al. Iliac crest bone graft versus local autograft or allograft for lumbar spinal fusion: a systematic review. Glob Spine J. 2016;6(6):592–606. doi: 10.1055/s-0035-1570749.
    1. Buser Z, Brodke DS, Youssef JA, Meisel H-J, Myhre SL, Hashimoto R, et al. Synthetic bone graft versus autograft or allograft for spinal fusion: a systematic review. J Neurosurg Spine. 2016;25(4):509–516. doi: 10.3171/2016.1.SPINE151005.
    1. Cahill KS, McCormick PC, Levi AD. A comprehensive assessment of the risk of bone morphogenetic protein use in spinal fusion surgery and postoperative cancer diagnosis. J Neurosurg Spine. 2015;23(1):86–93. doi: 10.3171/2014.10.SPINE14338.
    1. Singh K, Ahmadinia K, Park DK, Nandyala SV, Marquez-Lara A, Patel AA, et al. Complications of spinal fusion with utilization of bone morphogenetic protein. Spine (Phila Pa 1976) 2014;39(1):91–101. doi: 10.1097/BRS.0000000000000004.
    1. Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM. Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med. 2017;6(12):2173–2185. doi: 10.1002/sctm.17-0129.
    1. Pescador D, Ibáñez-Fonseca A, Sánchez-Guijo F, Briñón JG, Arias FJ, Muntión S, et al. Regeneration of hyaline cartilage promoted by xenogeneic mesenchymal stromal cells embedded within elastin-like recombinamer-based bioactive hydrogels. J Mater Sci Mater Med. 2017;28(8)
    1. Blanco B, Herrero-Sánchez M del C, Rodríguez-Serrano C, García-Martínez ML, Blanco JF, Muntión S, et al. Immunomodulatory effects of bone marrow versus adipose tissue-derived mesenchymal stromal cells on NK cells: implications in the transplantation setting. Eur J Haematol. 2016;97(6):528–537. doi: 10.1111/ejh.12765.
    1. Valencia J, Blanco B, Yáñez R, Vázquez M, Herrero Sánchez C, Fernández-García M, et al. Comparative analysis of the immunomodulatory capacities of human bone marrow– and adipose tissue–derived mesenchymal stromal cells from the same donor. Cytotherapy. 2016;18(10):1297–1311. doi: 10.1016/j.jcyt.2016.07.006.
    1. Li Y, Jin D, Xie W, Wen L, Chen W, Xu J, et al. Mesenchymal stem cells-derived exosomes: a possible therapeutic strategy for osteoporosis. Curr Stem Cell Res Ther. 2018;13(5):362–368. doi: 10.2174/1574888X13666180403163456.
    1. Zhang J, Liu X, Li H, Chen C, Hu B, Niu X, et al. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther. 2016;7(1):136. doi: 10.1186/s13287-016-0391-3.
    1. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230–247. doi: 10.1097/00007890-196803000-00009.
    1. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause DS, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317. doi: 10.1080/14653240600855905.
    1. Bora P, Majumdar AS. Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation. Stem Cell Res Ther. 2017;8(1):145. doi: 10.1186/s13287-017-0598-y.
    1. Yousef MAA, La Maida GA, Misaggi B. Long-term radiological and clinical outcomes after using bone marrow mesenchymal stem cells concentrate obtained with selective retention cell technology in posterolateral spinal fusion. Spine (Phila Pa 1976) 2017;42(24):1871–1879. doi: 10.1097/BRS.0000000000002255.
    1. Gan Y, Dai K, Zhang P, Tang T, Zhu Z, Lu J. The clinical use of enriched bone marrow stem cells combined with porous beta-tricalcium phosphate in posterior spinal fusion. Biomaterials. 2008;29(29):3973–3982. doi: 10.1016/j.biomaterials.2008.06.026.
    1. Hendrich C, Engelmaier F, Waertel G, Krebs R, Jäger M. Safety of autologous bone marrow aspiration concentrate transplantation: initial experiences in 101 patients. Orthop Rev (Pavia). 2009;1(1):32. doi: 10.4081/or.2009.e32.
    1. Jäger M, Hernigou P, Zilkens C, Herten M, Li X, Fischer J, et al. Cell therapy in bone healing disorders. Orthop Rev (Pavia). 2010;2(2):e20.
    1. Jäger M, Herten M, Fochtmann U, Fischer J, Hernigou P, Zilkens C, et al. Bridging the gap: bone marrow aspiration concentrate reduces autologous bone grafting in osseous defects. J Orthop Res. 2011;29(2):173–180. doi: 10.1002/jor.21230.
    1. Gessmann J, Köller M, Godry H, Schildhauer TA, Seybold D. Regenerate augmentation with bone marrow concentrate after traumatic bone loss. Orthop Rev (Pavia) 2012;3(2):14. doi: 10.4081/or.2012.e14.
    1. Hyer CF, Berlet GC, Bussewitz BW, Hankins T, Ziegler HL, Philbin TM. Quantitative assessment of the yield of osteoblastic connective tissue progenitors in bone marrow aspirate from the iliac crest, tibia, and calcaneus. J Bone Joint Surg-Am. 2013;95(14):1312–1316. doi: 10.2106/JBJS.L.01529.
    1. Epstein NE. Beta tricalcium phosphate: observation of use in 100 posterolateral lumbar instrumented fusions. Spine J. 2009;9(8):630–638. doi: 10.1016/j.spinee.2009.04.007.
    1. Thaler M, Lechner R, Gstottner M, Kobel C, Bach C. The use of beta-tricalcium phosphate and bone marrow aspirate as a bone graft substitute in posterior lumbar interbody fusion. Eur Spine J. 2013;22(5):1173–1182. doi: 10.1007/s00586-012-2541-3.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner