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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2017

Open Access 01-12-2017 | Research

Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy

Authors: Christopher Centeno, Jason Markle, Ehren Dodson, Ian Stemper, Christopher J. Williams, Matthew Hyzy, Thomas Ichim, Michael Freeman

Published in: Journal of Translational Medicine | Issue 1/2017

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Abstract

Background

Degenerative disc disease (DDD) is a common cause of lower back pain with radicular symptoms and has a significant socioeconomic impact given the associated disability. Limited effective conservative therapeutic options result in many turning to surgical alternatives for management, which vary in the rate of success and also carry an increased risk of morbidity and mortality associated with the procedures. Several animal based studies and a few human pilot studies have demonstrated safety and suggest efficacy in the treatment of DDD with mesenchymal stem cells (MSCs). The use of bone marrow-derived MSCs for the treatment of DDD is promising and in the present study we report on the safety and efficacy findings from a registry based proof of concept study using a percutaneous intradiscal injection of cultured MSCs for the management of DDD with associated radicular symptoms.

Methods

Thirty-three patients with lower back pain and disc degeneration with a posterior disc bulge diagnosed on magnetic resonance imaging (MRI) met the inclusion criteria and were treated with culture-expanded, autologous, bone marrow-derived MSCs. Prospective registry data was obtained at multiple time intervals up to 6 years post-treatment. Collected outcomes included numeric pain score (NPS), a modified single assessment numeric evaluation (SANE) rating, functional rating index (FRI), measurement of the intervertebral disc posterior dimension, and adverse events.

Results

Three patients reported pain related to procedure that resolved. There were no serious adverse events (i.e. death, infection, or tumor) associated with the procedure. NPS change scores relative to baseline were significant at 3, 36, 48, 60, and 72 months post-treatment. The average modified SANE ratings showed a mean improvement of 60% at 3 years post-treatment. FRI post-treatment change score averages exceeded the minimal clinically important difference at all time points except 12 months. Twenty of the patients treated underwent post-treatment MRI and 85% had a reduction in disc bulge size, with an average reduction size of 23% post-treatment.

Conclusions

Patients treated with autologous cultured MSCs for lower back pain with radicular symptoms in the setting of DDD reported minor adverse events and significant improvements in pain, function, and overall subjective improvement through 6 years of follow-up.
Literature
1.
Frank JW, Brooker AS, DeMaio SE, Kerr MS, Maetzel A, Shannon HS, et al. Disability resulting from occupational low back pain. Part I: what do we know about primary prevention? A review of the scientific evidence on prevention before disability begins. Spine. 1996;21:2908–17.CrossRefPubMed
2.
Hart LG, Deyo RA, Cherkin DC. Physician office visits for low back pain. Frequency, clinical evaluation, and treatment patterns from a US national survey. Spine. 1995;20:11–9.CrossRefPubMed
3.
4.
Carragee EJ, Hannibal M. Diagnostic evaluation of low back pain. Orthop Clin N Am. 2004;35:7–16.CrossRef
5.
Manchikanti L, Singh V, Datta S, Cohen SP, Hirsch JA, American Society of Interventional Pain Physicians. Comprehensive review of epidemiology, scope, and impact of spinal pain. Pain Physician. 2009;12:E35–70.PubMed
6.
Skorupska E, Keczmer P, Łochowski RM, Tomal P, Rychlik M, Samborski W. Reliability of MR-based volumetric 3-D analysis of pelvic muscles among subjects with low back with leg pain and healthy volunteers. PLoS ONE. 2016;11:e0159587.CrossRefPubMedPubMedCentral
7.
8.
Schwarzer AC, Aprill CN, Derby R, Fortin J, Kine G, Boqduk N. The prevalence and clinical features of internal disc disruption in patients with chronic low back pain. Spine. 1995;20:1878–83.CrossRefPubMed
9.
Brinjikji W, Luetmer PH, Comstock B, Bresnahan BW, Chen LE, Deyo RA, et al. Systematic literature review of imaging features of spinal degeneration in asymptomatic populations. AJNR Am J Neuroradiol. 2015;36:811–6.CrossRefPubMed
10.
Reith W, Bodea S, Kettner M, Huhl-Benninghausen R, Simgen A. Degenerative and age-related alterations of the spine. Radiologe. 2014;54:1069–77.CrossRefPubMed
11.
Albert HB, Sorensen JS, Christensen BS, Manniche C. Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized clinical controlled trial of efficacy. Eur Spine J. 2013;22:697–707.CrossRefPubMedPubMedCentral
12.
13.
Mochida J, Nishimura K, Nomura T, Toh E, Chiba M. The importance of preserving disc structure in surgical approaches to lumbar disc herniation. Spine. 1996;21:1556–63 (discussion 1563–4).CrossRefPubMed
14.
Deyo RA, Gray DT, Kreuter W, Mirza S, Martin BI. United States trends in lumbar fusion surgery for degenerative conditions. Spine. 2005;30:1441–5.CrossRefPubMed
15.
Yoshihara H, Yoneoka D. National trends in the surgical treatment for lumbar degenerative disc disease: United States, 2000 to 2009. Spine J. 2015;15:265–71.CrossRefPubMed
16.
Madigan L, Vaccaro AR, Spector LR, Milam RA. Management of symptomatic lumbar degenerative disk disease. J Am Acad Orthop Surg. 2009;17:102–11.CrossRefPubMed
17.
Knox BD, Chapman TM. Anterior lumbar interbody fusion for discogram concordant pain. J Spinal Disord. 1993;6:242–4.CrossRefPubMed
18.
Fritzell P, Hägg O, Wessberg P, Nordwall A, Swedish Lumbar Spine Study Group. Chronic low back pain and fusion: a comparison of three surgical techniques: a prospective multicenter randomized study from the Swedish lumbar spine study group. Spine. 2002;27:1131–41.CrossRefPubMed
19.
Herkowitz HN, Sidhu KS. Lumbar spine fusion in the treatment of degenerative conditions: current indications and recommendations. J Am Acad Orthop Surg. 1995;3:123–35.CrossRefPubMed
20.
Basques BA, Diaz-Collado PJ, Geddes BJ, Samuel AM, Lukasiewicz AM, Webb ML, et al. Primary and revision posterior lumbar fusion have similar short-term complication rates. Spine. 2016;41:E101–6.CrossRefPubMed
21.
Ma Y, Passias P, Gaber-Baylis LK, Girardi FP, Memtsoudis SG. Comparative in-hospital morbidity and mortality after revision versus primary thoracic and lumbar spine fusion. Spine J. 2010;10:881–9.CrossRefPubMedPubMedCentral
22.
Sakai D, Mochida J, Iwahina T. Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration. Biomaterials. 2003;24:3531–41.CrossRefPubMed
23.
Gou S, Oxentenko SC, Eldridge JS, Xiao L, Pingree MJ, Wang Z, et al. Stem cell therapy for intervertebral disk regeneration. Am J Phys Med Rehabil. 2014;93:S122–31.CrossRefPubMed
24.
Mochida J, Sakai D, Nakamura Y, Watanabe T, Yamamoto Y, Kato S. Intervertebral disc repair with activated nucleus pulposus cell transplantation: a three-year, prospective clinical study of its safety. Eur Cell Mater. 2015;29:202–12.CrossRefPubMed
25.
Pettine KA, Murphy MB, Suzuki RK, Sand TT. Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cells. 2015;33:146–56.CrossRefPubMed
26.
Yim RL, Lee JT, Bow CH, Meij B, Leung V, Cheung KM, et al. 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. 2014;23:2553–67.CrossRefPubMedPubMedCentral
27.
Amable PR, Carias RB, Teixeira MV, de Cruz Pacheco I, Corrêa do Amaral RJ, Granjeiro JM, et al. Platelet-rich plasma preparation for regenerative medicine: optimization and quantification of cytokines and growth factors. Stem Cell Res Ther. 2013;4:67.CrossRefPubMedPubMedCentral
28.
Monje PV, Rendon S, Athauda G, Bates M, Wood PM, Bunge MB. Non-antagonistic relationship between mitogenic factors and cAMP in adult Schwann cell re-differentiation. Glia. 2009;57(9):947–61.CrossRefPubMedPubMedCentral
29.
Tuakli-Wosornu YA, Terry A, Boachie-Adjei K, Harrison JR, Gribbin CK, LaSalle EE, et al. Lumbar intradiskal platelet-rich plasma (PRP) injections: a prospective, double-blind, randomized controlled study. PMR. 2016;8:1–10.CrossRef
30.
Elabd C, Centeno CJ, Schultz JR, Lutz G, Ichim T, Silva FJ. 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. 2016;14:253.CrossRefPubMedPubMedCentral
31.
32.
Centeno CJ, Pitts J, Al-Sayegh H, Freeman MD. Anterior cruciate ligament tears treated with percutaneous injection of autologous bone marrow nucleated cells: a case series. J Pain Res. 2015;8:437–47.PubMedPubMedCentral
33.
Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B. Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2011;6:368–78.CrossRefPubMed
34.
Centeno CJ, Schultz JR, Cheever M, Robineson B, Freeman M, Marasco W. Safety and complications reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2010;5:81–93.CrossRefPubMed
35.
Shelbourne KD, Barnes AF, Gray T. Correlation of a single assessment numeric evaluation (SANE) rating with modified Cincinnati knee rating system and IKDC subjective total scores for patients after ACL reconstruction or knee arthroscopy. Am J Sports Med. 2012;40:2487–91.CrossRefPubMed
36.
Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: visual analog scale for pain (VAS pain), numeric rating scale for pain (NRS Pain), McGill pain questionnaire (MPQ), short-form McGill pain questionnaire (SF-MPQ), chronic pain grade scale (CPGS), short form-36 bodily pain scale (SF-36 BPS), and measure of intermittent and constant osteoarthritis pain (ICOAP). Arthritis Care Res. 2011;63:S240–52.CrossRef
37.
Nguyen HS, Doan N, Shabani S, Baisden J, Wolfla C, Paskoff G, et al. Upright magnetic resonance imaging of the lumbar spine: back pain and radiculopathy. J Craniovertebr Junction Spine. 2016;7:31–7.CrossRefPubMedPubMedCentral
38.
Iwata T, Miyamoto K, Hioki A, Ohasji M, Inoue N, Shimizu K. In vivo measurement of lumbar foramen during axial loading using a compression device and computed tomography. J Spinal Disord Tech. 2013;26:E177–82.CrossRefPubMed
39.
Tunset A, Kjaer P, Chreiteh SS, Jensen TS. A method for quantitative measurement of lumbar intervertebral disc structures: an intra- and inter-rater agreement and reliability study. Chiropr Man Ther. 2013;21:26.CrossRef
40.
R CoreTeam. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2015.
41.
Childs JD, Piva SR. Psychometric properties of the functional rating index in patients with low back pain. Eur Spine J. 2005;14:1008–12.CrossRefPubMed
42.
Komori H, Shinomiya K, Nakai O, Yamaura I, Takeda S, Furuya K. The natural history of herniated nucleus pulposus with radiculopathy. Spine. 1996;21:225–9.CrossRefPubMed
43.
Smith LJ, Nerurkar NL, Choi KS, Harfe BD, Elliott DM. Degeneration and regeneration of the intervertebral disc: lessons from development. Dis Model Mech. 2011;4:31–41.CrossRefPubMed
44.
Marchand F, Ahmed AM. Investigation of the laminate structure of lumbar disc anulus fibrosus. Spine. 1990;15:402–10.CrossRefPubMed
45.
46.
Sakai D. Stem cell regeneration of the intervertebral disk. Orthop Clin N Am. 2011;42:555–62.CrossRef
47.
Fleming JE Jr, Cornell CN, Muschler GF. Bone cells and matrices in orthopedic tissue engineering. Orthop Clin N Am. 2000;31:357–74.CrossRef
48.
Orozco L, Soler R, Morera C, Alberca M, Sánchez A, Garcia-Sancho J. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation. 2011;92:822–8.CrossRefPubMed
49.
50.
Colombier P, Clouet J, Hamel O, Lescaudron L, Guicheux J. The lumbar intervertebral disc: from embryonic development to degeneration. Joint Bone Spine. 2014;81:125–9.CrossRefPubMed
51.
52.
Lam KS, Carlin D, Mulholland RC. Lumbar disc high-intensity zone: the value and significance of provocative discography in the determination of the discogenic pain source. Eur Spine J. 2000;9:36–41.CrossRefPubMedPubMedCentral
53.
Dongfeng R, Hou S, Wu W, Wang H, Shang W, Tang J, et al. The expression of tumor necrosis factor-alpha and CD68 in high-intensity zone of lumbar intervertebral disc on magnetic resonance image in the patients with low back pain. Spine. 2011;36:E429–33.CrossRefPubMed
54.
de la Fuente R, Bernad A, Garcia-Castro J, Martin MC, Ciqudose JC. Retraction: spontaneous human adult stem cell transformation. Cancer Res. 2010;70:6682.CrossRefPubMed
55.
Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Ciqudosa JC, Lloyd AC, et al. Spontaneous human adult stem cell transformation. Cancer Res. 2005;65:3035–9.CrossRefPubMed
56.
Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, et al. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. 2007;67:9142–9.CrossRefPubMed
57.
Choumerianou DM, Dimitriou H, Perdikogianni C, Martimianaki G, Riminucci M, Kalmanti M. Study of oncogenic transformation in ex vivo expanded mesenchymal cells, from paediatric bone marrow. Cell Prolif. 2008;41:909–22.CrossRefPubMed
58.
Røsland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009;69:5331–9.CrossRefPubMed
59.
Conforti A, Starc N, Biagini S, Tomao L, Pitisci A, Algeri M, et al. Resistance to neoplastic transformation of ex vivo expanded human mesenchymal stromal cells after exposure to supramaximal physical and chemical stress. Oncotarget. 2016;7:77416–29.PubMedPubMedCentral
60.
Lipscomb KE, Sariqul-Klijn N, Klineberg E, Mohan V. Biomechanical effects of human lumbar discography: in-vitro experiments and their finite element validation. J Spinal Disord Tech. 2014.
61.
Lipscomb KE, Sariqul-Klijn N, Klineberg E, Mohan V. Biomechanical effects of human lumbar discography: in-vitro experiments and their finite element validation. Clin Spine Surg. 2016. doi:10.​1097/​BSD.​0000000000000077​.
62.
Abbasipour-Dalivand S, Mohammadi R, Mohammadi V. Effects of local administration of platelet rich plasma on functional recovery after bridging sciatic nerve defect using silicone rubber chamber. An experimental study. Bull Emerg Trauma. 2015;3:1–7.PubMedPubMedCentral
63.
Elgazzar RF, Mutabagani MA, Abdelaal SE, Sadakah AA. Platelet rich plasma may enhance peripheral nerve regeneration after cyanoacrylate reanastomosis: a controlled blind study on rats. Int J Oral Maxillofac Surg. 2008;37:748–55.CrossRefPubMed
64.
Anjayani S, Wirohadidjojo YW, Adam AM, Suwandi D, Seweng A, Amiruddin MD. Sensory improvement of leprosy peripheral neuropathy in patients treated with perineural injection of platelet-rich plasma. Int J Dermatol. 2014;53:109–13.CrossRefPubMed
65.
Hibner M, Castellanos ME, Drachman D, Balducci J. Repeat operation for treatment of persistent pudendal nerve entrapment after pudendal neurolysis. J Minim Invasive Gynecol. 2012;19:325–30.CrossRefPubMed
66.
Kuffler DP, Reyes O, Sosa IJ, Santiago-Figueroa J. Neurological recovery across a 12-cm-long ulnar nerve gap repaired 3.25 years post trauma: case report. Neurosurgery. 2011;69:E1321–6.CrossRefPubMed
67.
Malahias MA, Johnson EO, Babis GC, Nikolaou VS. Single injection of platelet-rich plasma as a novel treatment of carpal tunnel syndrome. Neural Regen Res. 2015;10:1856–9.CrossRefPubMedPubMedCentral
68.
69.
70.
Carragee EJ, Chen Y, Tanner CM, Truong T, Lau E, Brito JL. Provocative discography in patients after limited lumbar discectomy: a controlled, randomized study of pain response in symptomatic and asymptomatic subjects. Spine. 2000;25:3065–71.CrossRefPubMed
71.
Carragee EJ, Tanner CM, Khurana S, Hayward C, Welsh J, Date E, et al. The rates of false-positive lumbar discography in select patients without low back symptoms. Spine. 2000;25:1373–80.CrossRefPubMed
72.
Provenzano DA. Diagnostic discography: what is the clinical utility? Curr Pain Headache Rep. 2012;16:26–34.CrossRefPubMed
73.
Golish SR, Hanna LS, Bowser RP, Montesano PX, Carragee EJ, Scuderi GJ. Outcome of lumbar epidural steroid injection is predicted by assay of a complex of fibronectin and aggrecan from epidural lavage. Spine. 2011;36:1464–9.CrossRefPubMed
74.
Cuellar JM, Golish SR, Leroux EJ, Reuter MW, Carragee EJ, Hanna LS, et al. Does a fibronectin and aggrecan complex play a role in painful vertebral disks? PMR. 2013;5:297–302.CrossRef
Metadata
Title
Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy
Authors
Christopher Centeno
Jason Markle
Ehren Dodson
Ian Stemper
Christopher J. Williams
Matthew Hyzy
Thomas Ichim
Michael Freeman
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2017
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-017-1300-y

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