Biological Enhancers of Fusion

  • Matthew F. Gary
  • Scott D. Boden


There are over 400,000 spinal fusions performed annually in the United States alone. The reported incidence of nonunion following spinal fusion operations varies widely (5–45%) and is dependent on multiple factors. For instance, Wang et al. found that the number of levels operated on for anterior cervical fusions greatly affected fusion rates (pseudoarthrosis was approximately 10% for single-level and 30% for three-level fusions). Given the large number of fusion operations performed each year, even a low rate of pseudoarthrosis can have profound effects on outcomes and overall costs. A lack of understanding with regard to the basic biology involved with arthrodesis certainly contributes.

The goal of this chapter is to review the basic tenants of bone biology and examine the evidence for currently used enhancers of fusion.


Biological enhancers Fusion Cervical stabilization Arthrodesis Autologous bone grafts Allograft Demineralized bone matrix Bone morphogenetic proteins Electromagnetic bone stimulation Mesenchymal stem cells Platelet-rich plasma 


  1. 1.
    Rajaee SS, Bae HW, Kanim LEA, Delamarter RB. Spinal fusion in the United States: analysis of trends from 1998 to 2008. Spine. 2012;37:67–76.CrossRefGoogle Scholar
  2. 2.
    Boden SD. Overview of the biology of lumbar spine fusion and principles for selecting a bone graft substitute. Spine. 2002;27:S26–31.CrossRefGoogle Scholar
  3. 3.
    Wang JC, McDonough PW, Kanim LE, Endow KK, Delamarter RB. Increased fusion rates with cervical plating for three-level anterior cervical discectomy and fusion. Spine. 2001;26:643–6; discussion 646–647.CrossRefGoogle Scholar
  4. 4.
    Delawi D, Dhert WJA, Castelein RM, Verbout AJ, Oner FC. The incidence of donor site pain after bone graft harvesting from the posterior iliac crest may be overestimated: a study on spine fracture patients. Spine. 2007;32:1865–8.CrossRefGoogle Scholar
  5. 5.
    Fernyhough JC, Schimandle JJ, Weigel MC, Edwards CC, Levine AM. Chronic donor site pain complicating bone graft harvesting from the posterior iliac crest for spinal fusion. Spine. 1992;17:1474–80.CrossRefGoogle Scholar
  6. 6.
    Sasso RC, LeHuec JC, Shaffrey C, Spine Interbody Research Group. Iliac crest bone graft donor site pain after anterior lumbar interbody fusion: a prospective patient satisfaction outcome assessment. J Spinal Disord Tech. 2005;18(Suppl):S77–81.CrossRefGoogle Scholar
  7. 7.
    Oryan A, Monazzah S, Bigham-Sadegh A. Bone injury and fracture healing biology. Biomed Environ Sci BES. 2015;28:57–71.PubMedGoogle Scholar
  8. 8.
    Cottrell JA, Turner JC, Arinzeh TL, O’Connor JP. The biology of bone and ligament healing. Foot Ankle Clin. 2016;21:739–61.CrossRefGoogle Scholar
  9. 9.
    Geris L, Gerisch A, Sloten JV, Weiner R, Oosterwyck HV. Angiogenesis in bone fracture healing: a bioregulatory model. J Theor Biol. 2008;251:137–58.CrossRefGoogle Scholar
  10. 10.
    LaStayo PC, Winters KM, Hardy M. Fracture healing: bone healing, fracture management, and current concepts related to the hand. J Hand Ther Off J Am Soc Hand Ther. 2003;16:81–93.CrossRefGoogle Scholar
  11. 11.
    Pilitsis JG, Lucas DR, Rengachary SS. Bone healing and spinal fusion. Neurosurg Focus. 2002;13:e1.CrossRefGoogle Scholar
  12. 12.
    Goldberg VM, Stevenson S. Natural history of autografts and allografts. Clin Orthop. 1987;225:7–16.Google Scholar
  13. 13.
    Urist MR. Bone: formation by autoinduction. Science. 1965;150:893–9.CrossRefGoogle Scholar
  14. 14.
    Gupta A, et al. Bone graft substitutes for spine fusion: a brief review. World J Orthop. 2015;6:449–56.CrossRefGoogle Scholar
  15. 15.
    Choi Y, Oldenburg FP, Sage L, Johnstone B, Yoo JU. A bridging demineralized bone implant facilitates posterolateral lumbar fusion in New Zealand white rabbits. Spine. 2007;32:36–41.CrossRefGoogle Scholar
  16. 16.
    Louis-Ugbo J, Murakami H, Kim H-S, Minamide A, Boden SD. Evidence of osteoinduction by Grafton demineralized bone matrix in nonhuman primate spinal fusion. Spine. 2004;29:360–6; discussion Z1.CrossRefGoogle Scholar
  17. 17.
    Vaccaro AR, Stubbs HA, Block JE. Demineralized bone matrix composite grafting for posterolateral spinal fusion. Orthopedics. 2007;30:567–70.PubMedGoogle Scholar
  18. 18.
    Cammisa FP, et al. 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. 2004;29:660–6.CrossRefGoogle Scholar
  19. 19.
    Schizas C, Triantafyllopoulos D, Kosmopoulos V, Tzinieris N, Stafylas K. Posterolateral lumbar spine fusion using a novel demineralized bone matrix: a controlled case pilot study. Arch Orthop Trauma Surg. 2008;128:621–5.CrossRefGoogle Scholar
  20. 20.
    Zadegan SA, Abedi A, Jazayeri SB, Vaccaro AR, Rahimi-Movaghar V. Demineralized bone matrix in anterior cervical discectomy and fusion: a systematic review. Eur Spine J Off Publ Eur Spine Soc Eur Spinal Deform Soc Eur Sect Cerv Spine Res Soc. 2016;26:958. Scholar
  21. 21.
    Dai L-Y, Jiang L-S. Single-level instrumented posterolateral fusion of lumbar spine with beta-tricalcium phosphate versus autograft: a prospective, randomized study with 3-year follow-up. Spine. 2008;33:1299–304.CrossRefGoogle Scholar
  22. 22.
    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 Off Publ Eur Spine Soc Eur Spinal Deform Soc Eur Sect Cerv Spine Res Soc. 2005;14:630–8.CrossRefGoogle Scholar
  23. 23.
    Lee JH, et al. A prospective consecutive study of instrumented posterolateral lumbar fusion using synthetic hydroxyapatite (Bongros-HA) as a bone graft extender. J Biomed Mater Res A. 2009;90:804–10.CrossRefGoogle Scholar
  24. 24.
    Chang C-H, Lin M-Z, Chen Y-J, Hsu H-C, Chen H-T. Local autogenous bone mixed with bone expander: an optimal option of bone graft in single-segment posterolateral lumbar fusion. Surg Neurol. 2008;70 Suppl 1:S1:47–9; discussion S1:49.Google Scholar
  25. 25.
    Acharya NK, Kumar RJ, Varma HK, Menon VK. Hydroxyapatite-bioactive glass ceramic composite as stand-alone graft substitute for posterolateral fusion of lumbar spine: a prospective, matched, and controlled study. J Spinal Disord Tech. 2008;21:106–11.CrossRefGoogle Scholar
  26. 26.
    Kaiser MG, et al. Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 17: bone growth stimulators as an adjunct for lumbar fusion. J Neurosurg Spine. 2014;21:133–9.CrossRefGoogle Scholar
  27. 27.
    Ong KL, et al. Off-label use of bone morphogenetic proteins in the United States using administrative data. Spine. 2010;35:1794–800.CrossRefGoogle Scholar
  28. 28.
    Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech. 2002;15:337–49.CrossRefGoogle Scholar
  29. 29.
    Burkus JK, Dorchak JD, Sanders DL. Radiographic assessment of interbody fusion using recombinant human bone morphogenetic protein type 2. Spine. 2003;28:372–7.PubMedGoogle Scholar
  30. 30.
    Haid RW, Branch CL, Alexander JT, Burkus JK. Posterior lumbar interbody fusion using recombinant human bone morphogenetic protein type 2 with cylindrical interbody cages. Spine J Off J North Am Spine Soc. 2004;4:527–38; discussion 538–539.CrossRefGoogle Scholar
  31. 31.
    Dimar JR, Glassman SD, Burkus KJ, Carreon LY. Clinical outcomes and fusion success at 2 years of single-level instrumented posterolateral fusions with recombinant human bone morphogenetic protein-2/compression resistant matrix versus iliac crest bone graft. Spine. 2006;31:2534–9; discussion 2540.CrossRefGoogle Scholar
  32. 32.
    Dawson E, Bae HW, Burkus JK, Stambough JL, Glassman SD. Recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge with an osteoconductive bulking agent in posterolateral arthrodesis with instrumentation. A prospective randomized trial. J Bone Joint Surg Am. 2009;91:1604–13.CrossRefGoogle Scholar
  33. 33.
    Glassman SD, et al. RhBMP-2 versus iliac crest bone graft for lumbar spine fusion: a randomized, controlled trial in patients over sixty years of age. Spine. 2008;33:2843–9.CrossRefGoogle Scholar
  34. 34.
    Baskin DS, Ryan P, Sonntag V, Westmark R, Widmayer MA. A prospective, randomized, controlled cervical fusion study using recombinant human bone morphogenetic protein-2 with the CORNERSTONE-SR allograft ring and the ATLANTIS anterior cervical plate. Spine. 2003;28:1219–24; discussion 1225.PubMedGoogle Scholar
  35. 35.
    Health, C. for D. and R. Public health notifications (medical devices) – FDA public health notification: life-threatening complications associated with recombinant human bone morphogenetic protein in cervical spine fusion. Available at: Accessed 18 Jan 2017.
  36. 36.
    Singh K, et al. Complications of spinal fusion with utilization of bone morphogenetic protein: a systematic review of the literature. Spine. 2014;39:91–101.CrossRefGoogle Scholar
  37. 37.
    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;23:86–93.CrossRefGoogle Scholar
  38. 38.
    Simmons JW. Treatment of failed posterior lumbar interbody fusion (PLIF) of the spine with pulsing electromagnetic fields. Clin Orthop. 1985;193:127–32.Google Scholar
  39. 39.
    Buser Z, Acosta FL Jr. Stem cells and spinal fusion—are we there yet? Spine J. 2016;16:400–1.CrossRefGoogle Scholar
  40. 40.
    Eltorai AEM, Susai CJ, Daniels AH. Mesenchymal stromal cells in spinal fusion: current and future applications. J Orthop. 2017;14:1–3.CrossRefGoogle Scholar
  41. 41.
    Eastlack RK, Garfin SR, Brown CR, Meyer SC. Osteocel plus cellular allograft in anterior cervical discectomy and fusion: evaluation of clinical and radiographic outcomes from a prospective multicenter study. Spine. 2014;39:E1331–7.CrossRefGoogle Scholar
  42. 42.
    Skovrlj B, et al. Cellular bone matrices: viable stem cell-containing bone graft substitutes. Spine J Off J North Am Spine Soc. 2014;14:2763–72.CrossRefGoogle Scholar
  43. 43.
    Civinini R, Macera A, Nistri L, Redl B, Innocenti M. The use of autologous blood-derived growth factors in bone regeneration. Clin Cases Miner Bone Metab. 2011;8:25–31.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Ranly DM, Lohmann CH, Andreacchio D, Boyan BD, Schwartz Z. Platelet-rich plasma inhibits demineralized bone matrix-induced bone formation in nude mice. J Bone Joint Surg Am. 2007;89:139–47.CrossRefGoogle Scholar
  45. 45.
    Scholz M, et al. Cages augmented with mineralized collagen and platelet-rich plasma as an osteoconductive/inductive combination for interbody fusion. Spine. 2010;35:740–6.CrossRefGoogle Scholar
  46. 46.
    Roffi A, Filardo G, Kon E, Marcacci M. Does PRP enhance bone integration with grafts, graft substitutes, or implants? A systematic review. BMC Musculoskelet Disord. 2013;14:330.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Orthopaedic SurgeryEmory University School of MedicineAtlantaUSA

Personalised recommendations