New Strategies in Enhancing Spinal Fusion

Abstract

The biologic steps involved in creating a bony fusion between adjacent segments of the spine are a complex and highly coordinated series of events. There have been significant advancements in bone grafts and bone graft substitutes in order to augment spinal fusion. While autologous bone grafting remains the gold standard, allograft bone grafting, synthetic bone graft substitutes, and bone graft enhancers are appropriate in certain clinical situations. This article provides an overview of the basic biology of spinal fusion and strategies for enhancing fusion through innovations in bone graft material.

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References

  1. 1.

    Ahlmann E, Patzakis M, Roidis N, Shepherd L, Holtom P. Comparison of anterior and posterior iliac crest bone grafts in terms of harvest-site morbidity and functional outcomes. J Bone Joint Surg Am. 2002;84:716–720.

    PubMed  Article  Google Scholar 

  2. 2.

    Alden TD, Varady P, Kallmes DF, Jane JA, Jr., Helm GA. Bone morphogenetic protein gene therapy. Spine (Phila Pa 1976). 2002;27:S87–93.

    PubMed  Article  Google Scholar 

  3. 3.

    Bae HW, Zhao L, Kanim LEA, Wong P, Delamarter RB, Dawson EG. Intervariability and intravariability of bone morphogenetic proteins in commercially available demineralized bone matrix products. Spine (Phila Pa 1976). 2006;31:1299–1306.

    PubMed  Article  Google Scholar 

  4. 4.

    Bjerke BT, Zarrabian M, Aleem IS, et al. Incidence of osteoporosis-related complications following posterior lumbar fusion. Global Spine J. 2018;8:563–569.

    PubMed  Article  Google Scholar 

  5. 5.

    Boden SD, Schimandle JH, Hutton WC, Chen MI. 1995 Volvo Award in basic sciences. The use of an osteoinductive growth factor for lumbar spinal fusion. Part I: Biology of spinal fusion. Spine (Phila Pa 1976). 1995;20:2626-2632.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Boden SD, Zdeblick TA, Sandhu HS, Heim SE. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine (Phila Pa 1976). 2000;25:376–381.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Bosch P, Musgrave D, Ghivizzani S, Latterman C, Day CS, Huard J. The efficiency of muscle-derived cell-mediated bone formation. Cell Transplant. 2000;9:463–470.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Buser Z, Brodke DS, Youssef JA, Rometsch E, Park JB, Yoon ST, Wang JC, Meisel HJ. Allograft versus demineralized bone matrix in instrumented and noninstrumented lumbar fusion: a systematic review. Global Spine J. 2018;8:396–412.

    PubMed  Article  Google Scholar 

  9. 9.

    Cammisa FP, Jr., Lowery G, Garfin SR, Geisler FH, Klara PM, McGuire RA, Sassard WR, Stubbs H, Block JE. Two-year fusion rate equivalency between Grafton DBM gel and autograft in posterolateral spine fusion: a prospective controlled trial employing a side-by-side comparison in the same patient. Spine (Phila Pa 1976). 2004;29:660–666.

    PubMed  Article  Google Scholar 

  10. 10.

    Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011;11:471–491.

    PubMed  Article  Google Scholar 

  11. 11.

    Cunningham BW, Kanayama M, Parker LM, Weis JC, Sefter JC, Fedder IL, McAfee PC. Osteogenic protein versus autologous interbody arthrodesis in the sheep thoracic spine. A comparative endoscopic study using the Bagby and Kuslich interbody fusion device. Spine (Phila Pa 1976). 1999;24:509–518.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    David SM, Gruber HE, Meyer RA, Jr., et al. Lumbar spinal fusion using recombinant human bone morphogenetic protein in the canine. A comparison of three dosages and two carriers. Spine (Phila Pa 1976). 1999;24:1973–1979.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Dimar JR, 2nd, Glassman SD, Burkus JK, Pryor PW, Hardacker JW, Carreon LY. Two-year fusion and clinical outcomes in 224 patients treated with a single-level instrumented posterolateral fusion with iliac crest bone graft. Spine J. 2009;9:880–885.

    PubMed  Article  Google Scholar 

  14. 14.

    Don AS, Carragee E. A brief overview of evidence-informed management of chronic low back pain with surgery. Spine J. 2008;8:258–265.

    PubMed  Article  Google Scholar 

  15. 15.

    Ebara S, Nakayama K. Mechanism for the action of bone morphogenetic proteins and regulation of their activity. Spine (Phila Pa 1976). 2002;27:S10–15.

    PubMed  Article  Google Scholar 

  16. 16.

    Ebraheim NA, Elgafy H, Xu R. Bone-graft harvesting from iliac and fibular donor sites: techniques and complications. J Am Acad Orthop Surg. 2001;9:210–218.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Epstein NE. A preliminary study of the efficacy of Beta Tricalcium Phosphate as a bone expander for instrumented posterolateral lumbar fusions. J Spinal Disord Tech. 2006;19:424–429.

    PubMed  Article  Google Scholar 

  18. 18.

    Friesenbichler J, Maurer-Ertl W, Sadoghi P, Pirker-Fruehauf U, Bodo K, Leithner A. Adverse reactions of artificial bone graft substitutes: lessons learned from using tricalcium phosphate geneX®. Clin Orthop Relat Res. 2014;472:976–982.

    Article  Google Scholar 

  19. 19.

    Gazdag AR, Lane JM, Glaser D, Forster RA. Alternatives to Autogenous Bone Graft: Efficacy and Indications. J Am Acad Orthop Surg. 1995;3:1–8.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Grabowski G, Cornett CA. Bone graft and bone graft substitutes in spine surgery: current concepts and controversies. J Am Acad Orthop Surg. 2013;21:51–60.

    PubMed  Article  Google Scholar 

  21. 21.

    Gupta A, Kukkar N, Sharif K, Main BJ, Albers CE, El-Amin III SF. Bone graft substitutes for spine fusion: A brief review. World J Orthop. 2015;6:449–456.

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    He B, Ou Y, Zhou A, et al. Functionalized D-form self-assembling peptide hydrogels for bone regeneration. Drug Des Devel Ther. 2016;10:1379–1388.

  23. 23.

    He B, Yuan X, Zhou A, Zhang H, Jiang D. Designer functionalised self-assembling peptide nanofibre scaffolds for cartilage tissue engineering. Expert Rev Mol Med. 2014;16:e12.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Helm G, Anderson DG, Andersson GB, et al. Summary statement: bone morphogenetic proteins: basic science. Spine (Phila Pa 1976). 2002;27:S9.

    Article  Google Scholar 

  25. 25.

    Henkel J, Woodruff MA, Epari DR, et al. Bone regeneration based on tissue engineering conceptions—a 21st century perspective. Bone Res. 2013;1:216–248.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Inoue G, Ueno M, Nakazawa T, et al. Teriparatide increases the insertional torque of pedicle screws during fusion surgery in patients with postmenopausal osteoporosis. J Neurosurg Spine. 2014;21:425–431.

    PubMed  Google Scholar 

  27. 27.

    Kelly MP, Savage JW, Bentzen SM, Hsu WK, Ellison SA, Anderson PA. Cancer risk from bone morphogenetic protein exposure in spinal arthrodesis. J Bone Joint Surg Am. 2014;96:1417–1422.

    PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Khan SN, Cammisa FP, Jr., Sandhu HS, Diwan AD, Girardi FP, Lane JM. The biology of bone grafting. J Am Acad Orthop Surg. 2005;13:77–86.

    Article  PubMed  Google Scholar 

  29. 29.

    Khan SN, Fraser JF, Sandhu HS, Cammisa FP, Jr., Girardi FP, Lane JM. Use of osteopromotive growth factors, demineralized bone matrix, and ceramics to enhance spinal fusion. J Am Acad Orthop Surg. 2005;13:129–137.

    PubMed  Article  Google Scholar 

  30. 30.

    Khan SN, Tomin E, Lane JM. Clinical applications of bone graft substitutes. Orthop Clin North Am. 2000;31:389–398.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Kim JW, Park SW, Kim YB, Ko MJ. The effect of postoperative use of teriparatide reducing screw loosening in osteoporotic patients. J Korean Neurosurg Soc. 2018;61:494–502.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    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;14:630–638.

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Kumar CY, Nalini KB, Menon J, Patro DK, Banerji BH. Calcium sulfate as bone graft substitute in the treatment of osseous bone defects, a prospective study. J Clin Diagn Res. 2013;7:2926–2928.

  34. 34.

    Last AR, Hulbert K. Chronic low back pain: evaluation and management. Am Fam Phys. 2009;79:1067–1074.

    Google Scholar 

  35. 35.

    LeGeros RZ. Properties of osteoconductive biomaterials: calcium phosphates. Clin Orthop Relat Res. 2002:81–98.

    Article  Google Scholar 

  36. 36.

    Liu Y, Levack AE, Marty E, Or O, Samuels BP, Redko M, Lane JM. Anabolic agents: what is beyond osteoporosis? Osteoporos Int. 2018;29:1009–1022.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Mata A, Geng Y, Henrikson KJ, Aparicio C, Stock SR, Satcher RL, Stupp SIJB. Bone regeneration mediated by biomimetic mineralization of a nanofiber matrix. Biomaterials. 2010;31:6004–6012.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Miller LE, Block JE. Safety and effectiveness of bone allografts in anterior cervical discectomy and fusion surgery. Spine (Phila Pa 1976). 2011;36:2045–2050.

    PubMed  Article  Google Scholar 

  39. 39.

    Musgrave DS, Bosch P, Ghivizzani S, Robbins PD, Evans CH, Huard J. Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone. Bone. 1999;24:541–547.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Musgrave DS, Bosch P, Lee JY, Pelinkovic D, Ghivizzani SC, Whalen J, Niyibizi C, Huard J. Ex vivo gene therapy to produce bone using different cell types. Clin Orthop Relat Res. 2000:290–305.

    Article  Google Scholar 

  41. 41.

    Nasser R, Yadla S, Maltenfort MG,. Complications in spine surgery. J Neurosurg Spine. 2010;13:144–157.

    PubMed  Article  Google Scholar 

  42. 42.

    O’Loughlin PF, Cunningham ME, Bukata SV, et al. Parathyroid hormone (1-34) augments spinal fusion, fusion mass volume, and fusion mass quality in a rabbit spinal fusion model. Spine (Phila Pa 1976). 2009;34:121–130.

    PubMed  Article  Google Scholar 

  43. 43.

    O’Loughlin PF, Morr S, Bogunovic L, Kim AD, Park B, Lane JM. Selection and development of preclinical models in fracture-healing research. J Bone Joint Surg Am. 2008;90 Suppl 1:79–84.

    PubMed  Article  Google Scholar 

  44. 44.

    Ozkaynak E, Rueger DC, Drier EA, et al. OP-1 cDNA encodes an osteogenic protein in the TGF-beta family. EMBO J. 1990;9:2085–2093.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Park JH, Bae YK, Suh SW, Yang JH, Hong JY. Efficacy of cortico/cancellous composite allograft in treatment of cervical spondylosis. Medicine (Baltimore). 2017;96:e7803.

    PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Polo-Corrales L, Latorre-Esteves M, Ramirez-Vick JE. Scaffold design for bone regeneration. J Nanosci Nanotechnol. 2014;14:15–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Poynton AR, Lane JM. Safety profile for the clinical use of bone morphogenetic proteins in the spine. Spine (Phila Pa 1976). 2002;27:S40–48.

    PubMed  Article  Google Scholar 

  48. 48.

    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;37:67–76.

  49. 49.

    Ramachandran M, ed. Basic orthopaedic sciences. Boca Raton, FL: CRC Press; 2018.

    Google Scholar 

  50. 50.

    Riew KD, Wright NM, Cheng S, Avioli LV, Lou J. Induction of bone formation using a recombinant adenoviral vector carrying the human BMP-2 gene in a rabbit spinal fusion model. Calcif Tissue Int. 1998;63:357–360.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Rihn JA, Kirkpatrick K, Albert TJ. Graft options in posterolateral and posterior interbody lumbar fusion. Spine (Phila Pa 1976). 2010;35:1629–1639.

    PubMed  Article  Google Scholar 

  52. 52.

    Roberts TT, Rosenbaum AJ. Bone grafts, bone substitutes and orthobiologics: the bridge between basic science and clinical advancements in fracture healing. Organogenesis. 2012;8:114–124.

    PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Samartzis D, Shen FH, Matthews DK, Yoon ST, Goldberg EJ, An HS. Comparison of allograft to autograft in multilevel anterior cervical discectomy and fusion with rigid plate fixation. Spine J. 2003;3:451–459.

    PubMed  Article  Google Scholar 

  54. 54.

    Schnee CL, Freese A, Weil RJ, Marcotte PJ. Analysis of harvest morbidity and radiographic outcome using autograft for anterior cervical fusion. Spine (Phila Pa 1976). 1997;22:2222–2227.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Seeherman HJ, Li XJ, Bouxsein ML, Wozney JM. rhBMP-2 induces transient bone resorption followed by bone formation in a nonhuman primate core-defect model. J Bone Joint Surg Am. 2010;92:411–426.

    Article  Google Scholar 

  56. 56.

    Silcox DH, 3rd, Boden SD, Schimandle JH, Johnson P, Whitesides TE, Hutton WC. Reversing the inhibitory effect of nicotine on spinal fusion using an osteoinductive protein extract. Spine (Phila Pa 1976). 1998;23:291–296; discussion 297.

    PubMed  Article  Google Scholar 

  57. 57.

    Simmonds MC, Brown JV, Heirs MK, et al. Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med. 2013;158:877–889.

  58. 58.

    Skovrlj B, Guzman JZ, Al Maaieh M, Cho SK, Iatridis JC, Qureshi SA. Cellular bone matrices: viable stem cell-containing bone graft substitutes. Spine J. 2014;14:2763–2772.

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Smith KA, Russo GS, Vaccaro AR, Arnold PM. Scientific, Clinical, regulatory, and economic aspects of choosing bone graft/biological options in spine surgery. Neurosurgery. 2018;84:827–835.

    Article  Google Scholar 

  60. 60.

    Stone MA, Jakoi AM, Iorio JA, et al. Bisphosphonate’s and intermittent parathyroid hormone’s effect on human spinal fusion: a systematic review of the literature. Asian Spine J. 2017;11:484–493.

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Tomford WW. Bone allografts: past, present and future. Cell Tissue Bank. 2000;1:105–109.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Urist MR, Mikulski A, Lietze A. Solubilized and insolubilized bone morphogenetic protein. Proc Natl Acad Sci U S A. 1979;76:1828–1832.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Vaccaro AR, Stubbs HA, Block JE. Demineralized bone matrix composite grafting for posterolateral spinal fusion. Orthopedics. 2007;30:567–570.

    PubMed  Article  Google Scholar 

  64. 64.

    Vaidya R, Carp J, Sethi A, Bartol S, Craig J, Les CM. Complications of anterior cervical discectomy and fusion using recombinant human bone morphogenetic protein-2. Euro Spine J. 2007;16:1257–1265.

    Article  Google Scholar 

  65. 65.

    Virk SS, Phillips FM, Khan SN. The influence of geography, time, and payer type on the utilization of bone morphogenetic protein (BMP) between 2005 and 2015. Clin Spine Surg. 2018;31:174–179.

    PubMed  Article  Google Scholar 

  66. 66.

    Vo TN, Shah SR, Lu S, Tatara AM, Lee EJ, Roh TT, Tabata Y, Mikos AG. Injectable dual-gelling cell-laden composite hydrogels for bone tissue engineering. Biomaterials. 2016;83:1–11.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Wang EA, Rosen V, Cordes P, et al. Purification and characterization of other distinct bone-inducing factors. Proc Natl Acad Sci U S A. 1988;85:9484–9488.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Wang EA, Rosen V, D’Alessandro JS, et al. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci U S A. 1990;87:2220–2224.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Wang JC, Alanay A, Mark D, Kanim LEA, Campbell PA, Dawson EG, Lieberman JR. A comparison of commercially available demineralized bone matrix for spinal fusion. Euro Spine J. 2007;16:1233–1240.

    Article  Google Scholar 

  70. 70.

    Wang JC, Kanim LE, Yoo S, Campbell PA, Berk AJ, Lieberman JR. Effect of regional gene therapy with bone morphogenetic protein-2-producing bone marrow cells on spinal fusion in rats. J Bone Joint Surg Am. 2003;85:905–911.

    PubMed  Article  Google Scholar 

  71. 71.

    Wozney JM. The bone morphogenetic protein family and osteogenesis. Molecular reproduction and development. 1992;32:160–167.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Wozney JM. Overview of bone morphogenetic proteins. Spine (Phila Pa 1976). 2002;27:S2-S8.

    PubMed  Article  Google Scholar 

  73. 73.

    Wozney JM, Rosen V, Celeste AJ, et al. Novel regulators of bone formation: molecular clones and activities. Science. 1988;242:1528–1534.

    CAS  PubMed  Article  Google Scholar 

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Correspondence to Sohrab Virk MD, MBA.

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Conflict of Interest: Yoshihiro Katsuura, MD, Karim Shafi, MD, Chelsie Jacques, BS, Sohrab Virk, MD, MBA, declare that they have no conflict of interest. Sravisht Iyer, MD, reports personal fees from Globus Medical, outside the submitted work. Matthew Cunningham, MD, PhD, reports material support from DePuy Synthes, outside the submitted work.

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Katsuura, Y., Shafi, K., Jacques, C. et al. New Strategies in Enhancing Spinal Fusion. HSS Jrnl 16, 177–182 (2020). https://doi.org/10.1007/s11420-020-09749-5

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Keywords

  • biology of spinal fusion
  • bone graft
  • BMP
  • hydrogels
  • autograft
  • allograft
  • spinal fusion