Mesenchymal Stem Cells for Lumbar Degenerative Disc Disease

Summary

This study seeks to bridge these technologies and obtain data regarding the safety and efficacy of image guided percutaneous needle injection of expanded autologous bone marrow derived mesenchymal stem cells to symptomatic degenerated intervertebral discs in humans. The primary outcome will be to assess the safety and efficacy and monitor for adverse events.

Timeline

Start

2019-06

Primary completion

2021-09-30

Completion

2022-09-30

Publications

• Background Walker J 3rd, El Abd O, Isaac Z, Muzin S. Discography in practice: a clinical and historical review. Curr Rev Musculoskelet Med. 2008 Jun;1(2):69-83. doi: 10.1007/s12178-007-9009-9.
• Background Frymoyer JW, Cats-Baril WL. An overview of the incidences and costs of low back pain. Orthop Clin North Am. 1991 Apr;22(2):263-71.
• Background Cheung KM, Karppinen J, Chan D, Ho DW, Song YQ, Sham P, Cheah KS, Leong JC, Luk KD. Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine (Phila Pa 1976). 2009 Apr 20;34(9):934-40. doi: 10.1097/BRS.0b013e3181a01b3f.
• Background Madigan L, Vaccaro AR, Spector LR, Milam RA. Management of symptomatic lumbar degenerative disk disease. J Am Acad Orthop Surg. 2009 Feb;17(2):102-11. doi: 10.5435/00124635-200902000-00006.
• Background Bogduk N, Karasek M. Two-year follow-up of a controlled trial of intradiscal electrothermal anuloplasty for chronic low back pain resulting from internal disc disruption. Spine J. 2002 Sep-Oct;2(5):343-50. doi: 10.1016/s1529-9430(02)00409-6.
• Background Kvarstein G, Mawe L, Indahl A, Hol PK, Tennoe B, Digernes R, Stubhaug A, Tonnessen TI, Beivik H. A randomized double-blind controlled trial of intra-annular radiofrequency thermal disc therapy--a 12-month follow-up. Pain. 2009 Oct;145(3):279-286. doi: 10.1016/j.pain.2009.05.001. Epub 2009 Aug 3.
• Background Freeman BJ, Fraser RD, Cain CM, Hall DJ, Chapple DC. A randomized, double-blind, controlled trial: intradiscal electrothermal therapy versus placebo for the treatment of chronic discogenic low back pain. Spine (Phila Pa 1976). 2005 Nov 1;30(21):2369-77; discussion 2378. doi: 10.1097/01.brs.0000186587.43373.f2.
• Background Williams JD, P.K., ed. Lower Back Pain and Disorders of Intervertebral Discs. 11 ed. Campbell's Operative Orthopaedics., ed. C.a. Beaty. 2007, Mosby.
• Background Hilibrand AS, Robbins M. Adjacent segment degeneration and adjacent segment disease: the consequences of spinal fusion? Spine J. 2004 Nov-Dec;4(6 Suppl):190S-194S. doi: 10.1016/j.spinee.2004.07.007.
• Background Nesti LJ, Li WJ, Shanti RM, Jiang YJ, Jackson W, Freedman BA, Kuklo TR, Giuliani JR, Tuan RS. Intervertebral disc tissue engineering using a novel hyaluronic acid-nanofibrous scaffold (HANFS) amalgam. Tissue Eng Part A. 2008 Sep;14(9):1527-37. doi: 10.1089/ten.tea.2008.0215.
• Background Shuff C, An HS. Artificial disc replacement: the new solution for discogenic low back pain? Am J Orthop (Belle Mead NJ). 2005 Jan;34(1):8-12.
• Background Solchaga LA, Penick K, Goldberg VM, Caplan AI, Welter JF. Fibroblast growth factor-2 enhances proliferation and delays loss of chondrogenic potential in human adult bone-marrow-derived mesenchymal stem cells. Tissue Eng Part A. 2010 Mar;16(3):1009-19. doi: 10.1089/ten.TEA.2009.0100.
• Background Wang F, Dennis JE, Awadallah A, Solchaga LA, Molter J, Kuang Y, Salem N, Lin Y, Tian H, Kolthammer JA, Kim Y, Love ZB, Gerson SL, Lee Z. Transcriptional profiling of human mesenchymal stem cells transduced with reporter genes for imaging. Physiol Genomics. 2009 Mar 3;37(1):23-34. doi: 10.1152/physiolgenomics.00300.2007. Epub 2008 Dec 30.
• Background Love Z, Wang F, Dennis J, Awadallah A, Salem N, Lin Y, Weisenberger A, Majewski S, Gerson S, Lee Z. Imaging of mesenchymal stem cell transplant by bioluminescence and PET. J Nucl Med. 2007 Dec;48(12):2011-20. doi: 10.2967/jnumed.107.043166. Epub 2007 Nov 15.
• Background Welter JF, Solchaga LA, Penick KJ. Simplification of aggregate culture of human mesenchymal stem cells as a chondrogenic screening assay. Biotechniques. 2007 Jun;42(6):732, 734-7. doi: 10.2144/000112451.
• Background Solchaga LA, Temenoff JS, Gao J, Mikos AG, Caplan AI, Goldberg VM. Repair of osteochondral defects with hyaluronan- and polyester-based scaffolds. Osteoarthritis Cartilage. 2005 Apr;13(4):297-309. doi: 10.1016/j.joca.2004.12.016.
• Background Welter JF, Solchaga LA, Stewart MC. High-efficiency nonviral transfection of primary chondrocytes. Methods Mol Med. 2004;100:129-46. doi: 10.1385/1-59259-810-2:129.
• Background Solchaga LA, Welter JF, Lennon DP, Caplan AI. Generation of pluripotent stem cells and their differentiation to the chondrocytic phenotype. Methods Mol Med. 2004;100:53-68. doi: 10.1385/1-59259-810-2:053.
• Background Solchaga LA, Goldberg VM, Caplan AI. Cartilage regeneration using principles of tissue engineering. Clin Orthop Relat Res. 2001 Oct;(391 Suppl):S161-70. doi: 10.1097/00003086-200110001-00016.
• Background Yoo JU, Barthel TS, Nishimura K, Solchaga L, Caplan AI, Goldberg VM, Johnstone B. The chondrogenic potential of human bone-marrow-derived mesenchymal progenitor cells. J Bone Joint Surg Am. 1998 Dec;80(12):1745-57. doi: 10.2106/00004623-199812000-00004.
• Background Lee Z, Dennis JE, Gerson SL. Imaging stem cell implant for cellular-based therapies. Exp Biol Med (Maywood). 2008 Aug;233(8):930-40. doi: 10.3181/0709-MR-234. Epub 2008 May 14.
• Background Richardson SM, Hoyland JA, Mobasheri R, Csaki C, Shakibaei M, Mobasheri A. Mesenchymal stem cells in regenerative medicine: opportunities and challenges for articular cartilage and intervertebral disc tissue engineering. J Cell Physiol. 2010 Jan;222(1):23-32. doi: 10.1002/jcp.21915.
• Background Sobajima S, Vadala G, Shimer A, Kim JS, Gilbertson LG, Kang JD. Feasibility of a stem cell therapy for intervertebral disc degeneration. Spine J. 2008 Nov-Dec;8(6):888-96. doi: 10.1016/j.spinee.2007.09.011. Epub 2007 Dec 21.
• Background Henriksson HB, Svanvik T, Jonsson M, Hagman M, Horn M, Lindahl A, Brisby H. Transplantation of human mesenchymal stems cells into intervertebral discs in a xenogeneic porcine model. Spine (Phila Pa 1976). 2009 Jan 15;34(2):141-8. doi: 10.1097/BRS.0b013e31818f8c20.
• Background Mobasheri A, Csaki C, Clutterbuck AL, Rahmanzadeh M, Shakibaei M. Mesenchymal stem cells in connective tissue engineering and regenerative medicine: applications in cartilage repair and osteoarthritis therapy. Histol Histopathol. 2009 Mar;24(3):347-66. doi: 10.14670/HH-24.347.
• Background Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008 May-Jun;11(3):343-53.
• Background Sakai D, Mochida J, Iwashina T, Watanabe T, Nakai T, Ando K, Hotta T. Differentiation of mesenchymal stem cells transplanted to a rabbit degenerative disc model: potential and limitations for stem cell therapy in disc regeneration. Spine (Phila Pa 1976). 2005 Nov 1;30(21):2379-87. doi: 10.1097/01.brs.0000184365.28481.e3.
• Background Sakai D, Mochida J, Yamamoto Y, Nomura T, Okuma M, Nishimura K, Nakai T, Ando K, Hotta T. Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration. Biomaterials. 2003 Sep;24(20):3531-41. doi: 10.1016/s0142-9612(03)00222-9.
• Background Crevensten G, Walsh AJ, Ananthakrishnan D, Page P, Wahba GM, Lotz JC, Berven S. Intervertebral disc cell therapy for regeneration: mesenchymal stem cell implantation in rat intervertebral discs. Ann Biomed Eng. 2004 Mar;32(3):430-4. doi: 10.1023/b:abme.0000017545.84833.7c.
• Background Zhang YG, Guo X, Xu P, Kang LL, Li J. Bone mesenchymal stem cells transplanted into rabbit intervertebral discs can increase proteoglycans. Clin Orthop Relat Res. 2005 Jan;(430):219-26. doi: 10.1097/01.blo.0000146534.31120.cf.
• Background Bendtsen M, Bunger CE, Zou X, Foldager C, Jorgensen HS. Autologous stem cell therapy maintains vertebral blood flow and contrast diffusion through the endplate in experimental intervertebral disc degeneration. Spine (Phila Pa 1976). 2011 Mar 15;36(6):E373-9. doi: 10.1097/BRS.0b013e3181dce34c.
• Background Serigano K, Sakai D, Hiyama A, Tamura F, Tanaka M, Mochida J. Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. J Orthop Res. 2010 Oct;28(10):1267-75. doi: 10.1002/jor.21147.
• Background See EY, Toh SL, Goh JC. Simulated intervertebral disc-like assembly using bone marrow-derived mesenchymal stem cell sheets and silk scaffolds for annulus fibrosus regeneration. J Tissue Eng Regen Med. 2012 Jul;6(7):528-35. doi: 10.1002/term.457. Epub 2011 Jul 29.
• Background Luo W, Xiong W, Qiu M, Lv Y, Li Y, Li F. Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype utilizing simulated microgravity In vitro. J Huazhong Univ Sci Technolog Med Sci. 2011 Apr;31(2):199. doi: 10.1007/s11596-011-0252-3. Epub 2011 Apr 20.
• Background Yang H, Wu J, Liu J, Ebraheim M, Castillo S, Liu X, Tang T, Ebraheim NA. Transplanted mesenchymal stem cells with pure fibrinous gelatin-transforming growth factor-beta1 decrease rabbit intervertebral disc degeneration. Spine J. 2010 Sep;10(9):802-10. doi: 10.1016/j.spinee.2010.06.019. Epub 2010 Jul 24.
• Background Orozco L, Soler R, Morera C, Alberca M, Sanchez A, Garcia-Sancho J. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation. 2011 Oct 15;92(7):822-8. doi: 10.1097/TP.0b013e3182298a15.
• Background Yoshikawa T, Ueda Y, Miyazaki K, Koizumi M, Takakura Y. Disc regeneration therapy using marrow mesenchymal cell transplantation: a report of two case studies. Spine (Phila Pa 1976). 2010 May 15;35(11):E475-80. doi: 10.1097/BRS.0b013e3181cd2cf4.
• Background Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 1995 Oct;16(4):557-64.
• Background Koc ON, Peters C, Aubourg P, Raghavan S, Dyhouse S, DeGasperi R, Kolodny EH, Yoseph YB, Gerson SL, Lazarus HM, Caplan AI, Watkins PA, Krivit W. Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp Hematol. 1999 Nov;27(11):1675-81. doi: 10.1016/s0301-472x(99)00101-0.
• Background Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI, Lazarus HM. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol. 2000 Jan;18(2):307-16. doi: 10.1200/JCO.2000.18.2.307.
• Background Koc ON, Lazarus HM. Mesenchymal stem cells: heading into the clinic. Bone Marrow Transplant. 2001 Feb;27(3):235-9. doi: 10.1038/sj.bmt.1702791.
• Background Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant. 2002 Aug;30(4):215-22. doi: 10.1038/sj.bmt.1703650.
• Background Fibbe WE, Noort WA. Mesenchymal stem cells and hematopoietic stem cell transplantation. Ann N Y Acad Sci. 2003 May;996:235-44. doi: 10.1111/j.1749-6632.2003.tb03252.x.
• Background Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, Shpall EJ, McCarthy P, Atkinson K, Cooper BW, Gerson SL, Laughlin MJ, Loberiza FR Jr, Moseley AB, Bacigalupo A. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant. 2005 May;11(5):389-98. doi: 10.1016/j.bbmt.2005.02.001.
• Background Vadala G, Sowa G, Hubert M, Gilbertson LG, Denaro V, Kang JD. Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med. 2012 May;6(5):348-55. doi: 10.1002/term.433. Epub 2011 Jun 13.
• Background Foster NE, Thomas E, Bishop A, Dunn KM, Main CJ. Distinctiveness of psychological obstacles to recovery in low back pain patients in primary care. Pain. 2010 Mar;148(3):398-406. doi: 10.1016/j.pain.2009.11.002. Epub 2009 Dec 22.
• Background Maniadakis N, Gray A. The economic burden of back pain in the UK. Pain. 2000 Jan;84(1):95-103. doi: 10.1016/S0304-3959(99)00187-6.
• Background Sakai D. Future perspectives of cell-based therapy for intervertebral disc disease. Eur Spine J. 2008 Dec;17 Suppl 4(Suppl 4):452-8. doi: 10.1007/s00586-008-0743-5. Epub 2008 Nov 13.
• Background Takahashi K, Aoki Y, Ohtori S. Resolving discogenic pain. Eur Spine J. 2008 Dec;17 Suppl 4(Suppl 4):428-31. doi: 10.1007/s00586-008-0752-4. Epub 2008 Nov 13.
• Background Mwale F, Iatridis JC, Antoniou J. Quantitative MRI as a diagnostic tool of intervertebral disc matrix composition and integrity. Eur Spine J. 2008 Dec;17 Suppl 4(Suppl 4):432-40. doi: 10.1007/s00586-008-0744-4. Epub 2008 Nov 13.
• Background Freimark D, Czermak P. Cell-based regeneration of intervertebral disc defects: review and concepts. Int J Artif Organs. 2009 Apr;32(4):197-203. doi: 10.1177/039139880903200403.
• Background Hiyama A, Mochida J, Sakai D. Stem cell applications in intervertebral disc repair. Cell Mol Biol (Noisy-le-grand). 2008 Oct 26;54(1):24-32.
• Background Leung VY, Chan D, Cheung KM. Regeneration of intervertebral disc by mesenchymal stem cells: potentials, limitations, and future direction. Eur Spine J. 2006 Aug;15 Suppl 3(Suppl 3):S406-13. doi: 10.1007/s00586-006-0183-z. Epub 2006 Jul 15.
• Background Cousins JP, Haughton VM. Magnetic resonance imaging of the spine. J Am Acad Orthop Surg. 2009 Jan;17(1):22-30. doi: 10.5435/00124635-200901000-00004.
• Background Kjaer P, Leboeuf-Yde C, Korsholm L, Sorensen JS, Bendix T. Magnetic resonance imaging and low back pain in adults: a diagnostic imaging study of 40-year-old men and women. Spine (Phila Pa 1976). 2005 May 15;30(10):1173-80. doi: 10.1097/01.brs.0000162396.97739.76.
• Background Modic MT, Masaryk TJ, Ross JS, Carter JR. Imaging of degenerative disk disease. Radiology. 1988 Jul;168(1):177-86. doi: 10.1148/radiology.168.1.3289089. No abstract available.
• Background Kjaer P, Korsholm L, Bendix T, Sorensen JS, Leboeuf-Yde C. Modic changes and their associations with clinical findings. Eur Spine J. 2006 Sep;15(9):1312-9. doi: 10.1007/s00586-006-0185-x. Epub 2006 Aug 9.
• Background Thompson KJ, Dagher AP, Eckel TS, Clark M, Reinig JW. Modic changes on MR images as studied with provocative diskography: clinical relevance--a retrospective study of 2457 disks. Radiology. 2009 Mar;250(3):849-55. doi: 10.1148/radiol.2503080474.
• Background Chou R, Baisden J, Carragee EJ, Resnick DK, Shaffer WO, Loeser JD. Surgery for low back pain: a review of the evidence for an American Pain Society Clinical Practice Guideline. Spine (Phila Pa 1976). 2009 May 1;34(10):1094-109. doi: 10.1097/BRS.0b013e3181a105fc.
• Background Resnick DK, Watters WC. Lumbar disc arthroplasty: a critical review. Clin Neurosurg. 2007;54:83-7.
• Background Freeman BJ, Mehdian R. Intradiscal electrothermal therapy, percutaneous discectomy, and nucleoplasty: what is the current evidence? Curr Pain Headache Rep. 2008 Jan;12(1):14-21. doi: 10.1007/s11916-008-0004-7.
• Background Helm S, Hayek SM, Benyamin RM, Manchikanti L. Systematic review of the effectiveness of thermal annular procedures in treating discogenic low back pain. Pain Physician. 2009 Jan-Feb;12(1):207-32.
• Background Nomura T, Mochida J, Okuma M, Nishimura K, Sakabe K. Nucleus pulposus allograft retards intervertebral disc degeneration. Clin Orthop Relat Res. 2001 Aug;(389):94-101. doi: 10.1097/00003086-200108000-00015.
• Background Okuma M, Mochida J, Nishimura K, Sakabe K, Seiki K. Reinsertion of stimulated nucleus pulposus cells retards intervertebral disc degeneration: an in vitro and in vivo experimental study. J Orthop Res. 2000 Nov;18(6):988-97. doi: 10.1002/jor.1100180620.
• Background Ganey T, Libera J, Moos V, Alasevic O, Fritsch KG, Meisel HJ, Hutton WC. Disc chondrocyte transplantation in a canine model: a treatment for degenerated or damaged intervertebral disc. Spine (Phila Pa 1976). 2003 Dec 1;28(23):2609-20. doi: 10.1097/01.BRS.0000097891.63063.78.
• Background Gruber HE, Johnson TL, Leslie K, Ingram JA, Martin D, Hoelscher G, Banks D, Phieffer L, Coldham G, Hanley EN Jr. Autologous intervertebral disc cell implantation: a model using Psammomys obesus, the sand rat. Spine (Phila Pa 1976). 2002 Aug 1;27(15):1626-33. doi: 10.1097/00007632-200208010-00007.
• Background Gorensek M, Jaksimovic C, Kregar-Velikonja N, Gorensek M, Knezevic M, Jeras M, Pavlovcic V, Cor A. Nucleus pulposus repair with cultured autologous elastic cartilage derived chondrocytes. Cell Mol Biol Lett. 2004;9(2):363-73.
• Background Meisel HJ, Siodla V, Ganey T, Minkus Y, Hutton WC, Alasevic OJ. Clinical experience in cell-based therapeutics: disc chondrocyte transplantation A treatment for degenerated or damaged intervertebral disc. Biomol Eng. 2007 Feb;24(1):5-21. doi: 10.1016/j.bioeng.2006.07.002. Epub 2006 Jul 21.
• Background Meisel HJ, Ganey T, Hutton WC, Libera J, Minkus Y, Alasevic O. Clinical experience in cell-based therapeutics: intervention and outcome. Eur Spine J. 2006 Aug;15 Suppl 3(Suppl 3):S397-405. doi: 10.1007/s00586-006-0169-x. Epub 2006 Jul 19.
• Background Trounson A. New perspectives in human stem cell therapeutic research. BMC Med. 2009 Jun 11;7:29. doi: 10.1186/1741-7015-7-29.
• Background Stoyanov JV, Gantenbein-Ritter B, Bertolo A, Aebli N, Baur M, Alini M, Grad S. 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. 2011 Jun 20;21:533-47. doi: 10.22203/ecm.v021a40.
• Background Thompson JP, Pearce RH, Schechter MT, Adams ME, Tsang IK, Bishop PB. Preliminary evaluation of a scheme for grading the gross morphology of the human intervertebral disc. Spine (Phila Pa 1976). 1990 May;15(5):411-5. doi: 10.1097/00007632-199005000-00012.
• Background Yamamoto Y, Mochida J, Sakai D, Nakai T, Nishimura K, Kawada H, Hotta T. Upregulation of the viability of nucleus pulposus cells by bone marrow-derived stromal cells: significance of direct cell-to-cell contact in coculture system. Spine (Phila Pa 1976). 2004 Jul 15;29(14):1508-14. doi: 10.1097/01.brs.0000131416.90906.20.
• Background Monfort J, Garcia-Giralt N, Lopez-Armada MJ, Monllau JC, Bonilla A, Benito P, Blanco FJ. Decreased metalloproteinase production as a response to mechanical pressure in human cartilage: a mechanism for homeostatic regulation. Arthritis Res Ther. 2006;8(5):R149. doi: 10.1186/ar2042.
• Background Murphy CL, Thoms BL, Vaghjiani RJ, Lafont JE. Hypoxia. HIF-mediated articular chondrocyte function: prospects for cartilage repair. Arthritis Res Ther. 2009;11(1):213. doi: 10.1186/ar2574. Epub 2009 Feb 5.
• Background Salem HK, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells. 2010 Mar 31;28(3):585-96. doi: 10.1002/stem.269.
• Background Ostelo RW, Deyo RA, Stratford P, Waddell G, Croft P, Von Korff M, Bouter LM, de Vet HC. Interpreting change scores for pain and functional status in low back pain: towards international consensus regarding minimal important change. Spine (Phila Pa 1976). 2008 Jan 1;33(1):90-4. doi: 10.1097/BRS.0b013e31815e3a10.
• Background Watanabe A, Benneker LM, Boesch C, Watanabe T, Obata T, Anderson SE. Classification of intervertebral disk degeneration with axial T2 mapping. AJR Am J Roentgenol. 2007 Oct;189(4):936-42. doi: 10.2214/AJR.07.2142.
• Background Maughan EF, Lewis JS. Outcome measures in chronic low back pain. Eur Spine J. 2010 Sep;19(9):1484-94. doi: 10.1007/s00586-010-1353-6. Epub 2010 Apr 17.
• Background Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials. 1989 Dec;10(4):407-15. doi: 10.1016/0197-2456(89)90005-6.
• Background Stratford PW, Binkley JM, Riddle DL, Guyatt GH. Sensitivity to change of the Roland-Morris Back Pain Questionnaire: part 1. Phys Ther. 1998 Nov;78(11):1186-96. doi: 10.1093/ptj/78.11.1186.
• Background Beurskens AJHM, de Vet HCW, Koke AJA. Responsiveness of functional status in low back pain: a comparison of different instruments. Pain. 1996 Apr;65(1):71-76. doi: 10.1016/0304-3959(95)00149-2.
• Background Hagg O, Fritzell P, Nordwall A; Swedish Lumbar Spine Study Group. The clinical importance of changes in outcome scores after treatment for chronic low back pain. Eur Spine J. 2003 Feb;12(1):12-20. doi: 10.1007/s00586-002-0464-0. Epub 2002 Oct 24.
• Background Rocchi MB, Sisti D, Benedetti P, Valentini M, Bellagamba S, Federici A. Critical comparison of nine different self-administered questionnaires for the evaluation of disability caused by low back pain. Eura Medicophys. 2005 Dec;41(4):275-81.
• Background Bombardier C, Hayden J, Beaton DE. Minimal clinically important difference. Low back pain: outcome measures. J Rheumatol. 2001 Feb;28(2):431-8.
• Background Lauridsen HH, Hartvigsen J, Manniche C, Korsholm L, Grunnet-Nilsson N. Responsiveness and minimal clinically important difference for pain and disability instruments in low back pain patients. BMC Musculoskelet Disord. 2006 Oct 25;7:82. doi: 10.1186/1471-2474-7-82.
• Background Perry J, Haughton V, Anderson PA, Wu Y, Fine J, Mistretta C. The value of T2 relaxation times to characterize lumbar intervertebral disks: preliminary results. AJNR Am J Neuroradiol. 2006 Feb;27(2):337-42.
• Background Recommendations of the International Conference on Harmonization. . in Fed Regist. 1997.
• Background Prologo JD, Pirasteh A, Tenley N, Yuan L, Corn D, Hart D, Love Z, Lazarus HM, Lee Z. Percutaneous image-guided delivery for the transplantation of mesenchymal stem cells in the setting of degenerated intervertebral discs. J Vasc Interv Radiol. 2012 Aug;23(8):1084-1088.e6. doi: 10.1016/j.jvir.2012.04.032. Epub 2012 Jun 26.
• Background Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ; Canadian Critical Care Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7(10):e47559. doi: 10.1371/journal.pone.0047559. Epub 2012 Oct 25.
• Background Chinnadurai R, Copland IB, Garcia MA, Petersen CT, Lewis CN, Waller EK, Kirk AD, Galipeau J. Cryopreserved Mesenchymal Stromal Cells Are Susceptible to T-Cell Mediated Apoptosis Which Is Partly Rescued by IFNgamma Licensing. Stem Cells. 2016 Sep;34(9):2429-42. doi: 10.1002/stem.2415. Epub 2016 Jul 4.
• Background Moll G, Alm JJ, Davies LC, von Bahr L, Heldring N, Stenbeck-Funke L, Hamad OA, Hinsch R, Ignatowicz L, Locke M, Lonnies H, Lambris JD, Teramura Y, Nilsson-Ekdahl K, Nilsson B, Le Blanc K. Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells. 2014 Sep;32(9):2430-42. doi: 10.1002/stem.1729.
• Background Xu X, Liu Y, Cui Z, Wei Y, Zhang L. Effects of osmotic and cold shock on adherent human mesenchymal stem cells during cryopreservation. J Biotechnol. 2012 Dec 31;162(2-3):224-31. doi: 10.1016/j.jbiotec.2012.09.004. Epub 2012 Sep 16.
• Background Chinnadurai R, Garcia MA, Sakurai Y, Lam WA, Kirk AD, Galipeau J, Copland IB. Actin cytoskeletal disruption following cryopreservation alters the biodistribution of human mesenchymal stromal cells in vivo. Stem Cell Reports. 2014 Jun 6;3(1):60-72. doi: 10.1016/j.stemcr.2014.05.003. eCollection 2014 Jul 8.
• Background Francois M, Copland IB, Yuan S, Romieu-Mourez R, Waller EK, Galipeau J. Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-gamma licensing. Cytotherapy. 2012 Feb;14(2):147-52. doi: 10.3109/14653249.2011.623691. Epub 2011 Oct 27.
• Background Julious SA, Sample size of 12 per group rule of thumb for a pilot study. Pharmaceutical Statistics. 2005 4:287-291. doi:1 0.1002/pst.185.
• Background Fairbank JC, Pynsent PB. The Oswestry Disability Index. Spine (Phila Pa 1976). 2000 Nov 15;25(22):2940-52; discussion 2952. doi: 10.1097/00007632-200011150-00017.
• Background Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976). 2001 Sep 1;26(17):1873-8. doi: 10.1097/00007632-200109010-00011.

Drugs

Indications