The Biology of Fusion

A healthy spinal segment is a small, mobile mechanism. Two vertebral bodies are separated by an intervertebral disc and linked at the back by a pair of facet joints, and the whole unit is designed to bend, twist and bear load. A fusion sets out to convert that mobile mechanism into a solid, immobile block. The goal is to persuade bone to grow across the gap between adjacent vertebrae so that what were once separate bones, free to move against one another, become one continuous bone that cannot. This is arthrodesis in the literal sense, the fusing of a joint into a single fixed unit.

Crucially, the surgeon does not create the fusion. The surgeon creates the conditions in which a fusion can occur and then relies on the patient's biology to do the actual work. Bone-forming cells must be delivered or recruited to the site, they must be given a scaffold to grow along, they must be stimulated to lay down new bone, they must be supplied with blood, and the whole construct must be held sufficiently still for the fragile new bone to mature rather than be repeatedly torn apart. When all of this succeeds, the result is a continuous bony bridge, remodelled over time into strong, load-bearing bone. When any of it fails, the bridge does not form and a false joint, a pseudarthrosis, remains in its place. The entire history of fusion biology is, in one sense, the history of learning what those conditions are and how to provide them.

Understanding why some grafts work and others do not rests on a framework that has become the common language of bone grafting. Any material placed to encourage fusion can contribute to the process in up to three distinct ways, and the framework of osteogenesis, osteoinduction and osteoconduction captures them.

Osteogenesis is the direct formation of new bone by living cells contained within the graft itself. A graft that carries living osteoblasts and their precursors can, in effect, plant bone-forming cells at the site, and these cells begin to make new bone directly. Only fresh, living tissue such as autograft, the patient's own bone, or a marrow-derived cell preparation, contains such cells; processed and sterilised materials do not.

Osteoinduction is the recruitment and instruction of the patient's own primitive cells to become bone-forming cells. An osteoinductive material contains signalling molecules, above all the bone morphogenetic proteins, that reach into the surrounding tissue and coax uncommitted mesenchymal stem cells to differentiate down the bone-forming lineage. This is a chemical summons rather than a delivery of ready-made cells, and it is the property that Marshall Urist's celebrated experiments first revealed.

Osteoconduction is the provision of a passive scaffold, a three-dimensional lattice of the right shape and surface along which blood vessels and bone-forming cells can grow. An osteoconductive material does not itself make bone or instruct cells to do so; it simply offers a trellis onto which the biological process can climb. Many synthetic materials, such as the calcium phosphate ceramics, are purely osteoconductive. The most complete graft is one that offers all three properties at once, and this is precisely why the patient's own living bone was, for most of the twentieth century, regarded as the gold standard against which everything else was measured.

The healing of a spinal fusion follows a sequence that closely mirrors the healing of a fracture, and the modern account of it draws directly on the biology of fracture repair. It proceeds in overlapping stages, each preparing the ground for the next.

The first stage is inflammation. When the surgeon prepares the bony surfaces, roughening them until they bleed, and lays down the graft, the immediate response is a haematoma, a clot rich in platelets and inflammatory cells. This is not an accident to be avoided but the essential opening act. The clot releases a cascade of signalling molecules and growth factors that summon inflammatory cells and, critically, the mesenchymal stem cells that will become the builders of new bone. Within this early phase the graft is entirely dependent on diffusion from the surrounding fluid, for it has as yet no blood supply of its own.

The second stage is revascularisation. New blood vessels sprout from the host bone and the surrounding soft tissues and grow into the graft, carrying with them oxygen, nutrients and a further supply of cells. This ingrowth of vessels is the rate-limiting step of the whole process, because nothing can be built where blood cannot reach, and it explains why the blood supply of the fusion bed is such a decisive factor in success. A well-vascularised bed of freshly bled bone heals far more readily than a poorly vascularised one.

The third stage is osteoconduction and incorporation, in which new bone is laid down along the scaffold of the graft and the graft becomes structurally and biologically continuous with the host. It is here that the phenomenon of creeping substitution takes centre stage. The fourth and longest stage is remodelling, in which the initially disorganised woven bone is gradually replaced by strong, oriented lamellar bone, sculpted by the ordinary machinery of bone turnover into a shape that can bear the loads placed upon it. Remodelling continues for many months and even years after the fusion is first considered solid.

Of all the concepts in fusion biology, creeping substitution is perhaps the most vivid and the most important to grasp. A block of grafted bone, particularly a piece of the patient's own dense cortical bone or a piece of processed allograft, is at first largely dead scaffold. It is not living tissue that simply reconnects; it is a mineral lattice that must be replaced, piece by piece, by the host.

The process works as follows. Blood vessels and the cells that accompany them advance into the dead graft along its natural channels. Bone-resorbing cells, the osteoclasts, tunnel into the old bone and remove it, and following close behind, bone-forming cells, the osteoblasts, lay down fresh living bone in its place. The front of resorption and new formation creeps slowly through the graft, so that old, dead bone is continuously being substituted by new, living bone, hence the name. Over time the entire graft may be turned over in this way, its original scaffold consumed and replaced by the patient's own vital, remodelled bone. Cancellous graft, being open and porous, is invaded and substituted quickly and thoroughly; dense cortical graft is turned over far more slowly and may remain partly dead for a long time, which is one reason the two behave so differently in practice. The elegance of creeping substitution is that a graft need not itself be alive to do its job; it need only provide a scaffold, and where appropriate a chemical signal, that the living host can follow, dissolve and rebuild.

For most of the twentieth century the material judged best for encouraging fusion was the patient's own bone, autograft, and in spinal surgery this most often meant bone harvested from the crest of the pelvis, the iliac crest. Iliac crest autograft was regarded as the gold standard for a simple reason: it is the only widely available material that offers all three grafting properties together, carrying living cells for osteogenesis, retaining the bone morphogenetic proteins that make it osteoinductive, and providing a mineral scaffold that is osteoconductive. Its drawback is equally well documented. Harvesting bone from the pelvis requires a second surgical site, and studies of donor-site morbidity have repeatedly shown that this can leave persistent pain, along with less common problems such as nerve injury, fracture and infection at the harvest site. The realisation that the gold standard came at a real biological and human cost drove much of the search for alternatives.

Local bone, the fragments removed from the spine itself during the approach, offers similar biological properties without a separate harvest and has become a mainstay, particularly where the volume required is modest. Allograft, bone from a donor, is available in large quantities and avoids any harvest from the patient, but the processing and sterilisation needed to make it safe destroy its living cells and much of its biological signalling, leaving a material that is chiefly osteoconductive and only weakly, if at all, osteoinductive. Demineralised bone matrix, produced by dissolving the mineral from donor bone to expose its embedded proteins, was developed to recover some of that lost osteoinductive capacity, though its potency varies from batch to batch. The synthetic ceramics, based on calcium phosphate compounds such as hydroxyapatite and tricalcium phosphate, are manufactured scaffolds that are purely osteoconductive; they carry no cells and no signals, but they are limitless in supply, carry no risk of disease transmission, and are often used as extenders or carriers alongside a biologically active material. Each choice, in short, is a trade-off between biological completeness on the one hand and supply, safety and the avoidance of a harvest on the other, and the history of graft materials is a history of trying to secure the benefits of autograft without its costs.

The single most transformative discovery in this field began with a deceptively simple observation. In 1965 Marshall Urist, working in Los Angeles, reported in the journal Science that demineralised fragments of bone, when implanted into the muscle of an animal, could induce the formation of entirely new bone at a site where no bone had any business being. This was bone formation by autoinduction, and it implied the existence of a substance within bone matrix capable of instructing ordinary connective tissue cells to become bone. Urist named the hypothesised agent bone morphogenetic protein. For years its identity remained elusive, until in 1988 a team led by John Wozney used the tools of molecular biology to clone the genes for a family of these proteins, confirming that they were real, distinct molecules belonging to a larger family of growth factors and opening the door to producing them artificially.

The ability to manufacture these proteins by recombinant technology promised something remarkable: an osteoinductive signal as powerful as anything in autograft, available in unlimited supply and free of any need to harvest bone. Recombinant human bone morphogenetic protein-2 was studied in rigorous trials, including pivotal studies in anterior lumbar interbody fusion that compared it against iliac crest autograft and led to its regulatory approval for that specific use. For a time it seemed that the age-old problem of the bone graft had been solved. What followed, however, became one of the most important cautionary tales in modern spine surgery. As use expanded rapidly, much of it beyond the narrow indication for which the protein had been approved, reports of complications accumulated, including inflammatory swelling in the neck after cervical use, unwanted bone formation in the wrong places, and other concerns. In 2011 a critical review by Eugene Carragee and colleagues argued that the original industry-sponsored trials had substantially understated the rate of adverse events, and the controversy prompted an unusual step: the underlying trial data were released for independent re-analysis. Two systematic reviews of that individual-patient data, published together in 2013, concluded that the protein was effective at promoting fusion but offered no clear advantage over autograft in overall outcomes and carried its own risks, and that the early published literature had indeed painted an overly favourable picture. The episode reshaped not only how these biologics are used but how the evidence behind surgical products is scrutinised, and it stands as a lesson that a powerful biological signal is not the same thing as a better outcome.

When a fusion fails to unite, the result is a pseudarthrosis, literally a false joint, in which fibrous tissue rather than solid bone occupies the gap and the segment retains some ability to move. Understanding why this happens is really the mirror image of understanding what fusion requires, for a pseudarthrosis is what remains when one or more of the necessary conditions is not met.

Mechanical instability is among the most important causes. New bone is fragile, and if the segment moves too much while the graft is trying to incorporate, the delicate advancing tissue is repeatedly disrupted, and the body defaults to making fibrous tissue or cartilage instead of bone. This is the biological rationale for holding the spine still, and it is why the development of instrumentation that rigidly fixes the segment made such a difference to fusion rates. A deficient blood supply is another cause, since revascularisation is the rate-limiting step and bone cannot form where vessels cannot reach. The biological quality of the graft matters too: a scaffold with no cells and no osteoinductive signal placed in a poorly prepared, poorly bled bed has little to work with.

Beyond these local factors lie powerful systemic influences, and here one stands out. Smoking, and nicotine in particular, has been shown to impair spinal fusion both in clinical studies and in animal experiments; nicotine interferes with the blood supply and the bone-forming response, and studies of cervical fusion have found markedly higher rates of non-union in smokers. Other systemic factors that influence bone healing include poorly controlled diabetes, osteoporosis, malnutrition, and certain medications, notably the non-steroidal anti-inflammatory drugs, which act upon the inflammatory cascade that begins the healing process and which some studies have linked to higher non-union rates when used heavily in the early postoperative period. The picture that emerges is that fusion is a biologically demanding process that can be derailed at many points, and that its success depends on mechanical stability, a good blood supply, a biologically capable graft, and a host whose systemic environment permits bone to heal.

The surgical story of fusion begins in a single remarkable year. In 1911 two American surgeons, working independently, described the first operations designed to fuse the spine. Russell Hibbs, in New York, developed a posterior fusion in which the bony elements at the back of the spine were roughened and overlapped to encourage them to grow together, initially to arrest the deformity of tuberculous spines and progressive curves. In the same year Fred Albee described transplanting a strut of the patient's own tibia into the spine to bridge and stabilise the diseased segments in Pott's disease, the spinal form of tuberculosis. Between them, Hibbs and Albee established the two founding principles that still underpin fusion: the preparation of a bony bed that will heal, and the use of grafted bone to bridge it. For several decades thereafter, fusion meant graft and prolonged immobilisation in plaster, for there was as yet no reliable way to hold the spine still from within.

The next great chapter was the development of internal fixation. Early rod systems introduced in the mid-twentieth century allowed the spine to be corrected and held from within, and the subsequent introduction of screws placed through the pedicles, the strong bony bridges connecting the front and back of each vertebra, gave surgeons a means of gripping the vertebrae rigidly and fixing them relative to one another. This mattered biologically as much as mechanically. By abolishing movement across the segment, instrumentation removed one of the principal causes of pseudarthrosis, and randomised studies confirmed that rigid pedicle-screw fixation improved the rate at which posterolateral fusions united. The evolution of technique also produced different biological environments for fusion: bone laid down across the transverse processes at the back, the posterolateral fusion, sits in a bed of muscle and must bridge a relatively hostile gap, whereas bone placed within the disc space after the disc is removed, the interbody fusion, sits under compression between two broad, well-vascularised vertebral surfaces, a mechanically and biologically favourable environment. Understanding these differences allowed surgeons to match the location and the graft to the biological demands of each situation.

Trace the arc of this history and a clear pattern emerges: each advance in understanding the biology changed what surgeons did. The recognition that fusion is a healing process akin to fracture repair explained why a well-prepared, well-bled bony bed matters, and why the graft must be laid against living bone rather than scar. The framework of osteogenesis, osteoinduction and osteoconduction gave surgeons a rational way to compare materials and to understand why autograft outperformed the alternatives, and why a purely osteoconductive ceramic might need to be combined with something biologically active. The concept of creeping substitution explained why dense cortical grafts turn over so slowly and why porous cancellous bone incorporates so well. The appreciation that mechanical instability defeats bone formation drove the whole enterprise of rigid internal fixation and made reliable fusion possible for the first time. The discovery of bone morphogenetic protein, and the sobering experience that followed its enthusiastic adoption, taught the field both the power of a biological signal and the discipline required to evaluate it honestly.

Where the field stands now reflects all of these lessons. The search continues for a graft material that combines the biological completeness of autograft with limitless supply and freedom from harvest and from the risks that attended the first generation of recombinant proteins. Cell-based approaches, using concentrated bone marrow or preparations of mesenchymal stem cells to restore the osteogenic and osteoinductive properties that processed grafts lack, are an active area of study. Refined delivery systems, better carriers, lower and more targeted doses of osteoinductive proteins, and adjuncts such as electrical stimulation for selected cases, all represent attempts to optimise the same fundamental biology that Hibbs and Albee first harnessed with a roughened bony surface and a strut of living bone. The instruments have changed beyond recognition, but the essential truth has not: a fusion is grown, not built, and everything a surgeon does is ultimately in service of that slow, remarkable biological process by which the body knits a moving segment into a bridge of living bone.

A spinal fusion is one of the oldest and most enduring ideas in the surgery of the backbone, yet at its heart it is not really a surgical event at all. It is a biological one. The instruments, screws and cages that occupy so much of the modern imagination are, in the deepest sense, only a means to an end: to hold two or more vertebrae still and closely apposed for long enough that the body's own bone-forming machinery can knit them into a single, continuous piece of living bone. The word for that end state is arthrodesis, the deliberate abolition of a joint, and the process by which it is achieved is a slow, orchestrated feat of biology that unfolds over many months. This piece is a history and an explanation. It describes what fusion means at the level of cells and tissue, how a graft becomes living bone through the phenomenon known as creeping substitution, why fusions sometimes fail to unite, and how, over more than a century, a growing understanding of the biology reshaped the materials surgeons used, the way they held the spine still, and the discovery of the very proteins that instruct bone to form. It is purely educational. It offers no advice and makes no recommendations.

• —Urist MR. Bone: formation by autoinduction. Science. 1965;150(3698):893-899. PMID: 5319761.
• —Urist MR. Bone: formation by autoinduction. 1965. Clin Orthop Relat Res. 2002;(395):4-10. PMID: 11937861.
• —Hibbs RA. An operation for progressive spinal deformities: a preliminary report of three cases from the service of the orthopaedic hospital. 1911. Clin Orthop Relat Res. 2007;460:17-20. PMID: 17620807.
• —Albee FH. Transplantation of a portion of the tibia into the spine for Pott's disease: a preliminary report. 1911. Clin Orthop Relat Res. 2007;460:14-16. PMID: 17620806.
• —Boden SD. The biology of posterolateral lumbar spinal fusion. Orthop Clin North Am. 1998;29(4):603-619. PMID: 9756958.
• —Boden SD. Overview of the biology of lumbar spine fusion and principles for selecting a bone graft substitute. Spine (Phila Pa 1976). 2002;27(16 Suppl 1):S26-S31. PMID: 12205416.
• —Boden SD. Biology of lumbar spine fusion and use of bone graft substitutes: present, future, and next generation. Tissue Eng. 2000;6(4):383-399. PMID: 10992434.
• —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(24):2626-2632. PMID: 8747240.
• —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(6):471-491. PMID: 21729796.
• —Fillingham Y, Jacobs J. Bone grafts and their substitutes. Bone Joint J. 2016;98-B(1 Suppl A):6-9. PMID: 26733632.
• —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(1):77-86. PMID: 15712985.
• —Goldberg VM, Stevenson S. The biology of bone grafts. Semin Arthroplasty. 1993;4(2):58-63. PMID: 10148544.
• —Delloye C. How to improve the incorporation of massive allografts? Chir Organi Mov. 2003;88(4):335-343. PMID: 15259548.
• —Marsell R, Einhorn TA. The biology of fracture healing. Injury. 2011;42(6):551-555. PMID: 21489527.
• —Banwart JC, Asher MA, Hassanein RS. Iliac crest bone graft harvest donor site morbidity. A statistical evaluation. Spine (Phila Pa 1976). 1995;20(9):1055-1060. PMID: 7631235.
• —Seiler JG 3rd, Johnson J. Iliac crest autogenous bone grafting: donor site complications. J South Orthop Assoc. 2000;9(2):91-97. PMID: 10901646.
• —Hill NM, Horne JG, Devane PA. Donor site morbidity in the iliac crest bone graft. Aust N Z J Surg. 1999;69(10):726-728. PMID: 10527350.
• —Lee SC, Chen JF, Wu CT, Lee ST. In situ local autograft for instrumented lower lumbar or lumbosacral posterolateral fusion. J Clin Neurosci. 2009;16(1):37-43. PMID: 19041246.
• —Kanayama M, Hashimoto T, Shigenobu K, Yamane S, Bauer TW, Togawa D. A prospective randomized study of posterolateral lumbar fusion using osteogenic protein-1 (OP-1) versus local autograft with ceramic bone substitute. Spine (Phila Pa 1976). 2006;31(10):1067-1074. PMID: 16648739.
• —Tuchman A, Brodke DS, Youssef JA, et al. Autograft versus allograft for cervical spinal fusion: a systematic review. Global Spine J. 2017;7(1):59-70. PMID: 28451511.
• —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. PMID: 12163718.
• —Floyd T, Ohnmeiss D. A meta-analysis of autograft versus allograft in anterior cervical fusion. Eur Spine J. 2000;9(5):398-403. PMID: 11057533.
• —Ohyama T, Kubo Y, Iwata H, Taki W. Beta-tricalcium phosphate as a substitute for autograft in interbody fusion cages in the canine lumbar spine. J Neurosurg. 2002;97(3 Suppl):350-354. PMID: 12408391.
• —Spivak JM, Hasharoni A. Use of hydroxyapatite in spine surgery. Eur Spine J. 2001;10(Suppl 2):S197-S204. PMID: 11716019.
• —Louis-Ugbo J, Murakami H, Kim HS, Minamide A, Boden SD. Evidence of osteoinduction by Grafton demineralized bone matrix in nonhuman primate spinal fusion. Spine (Phila Pa 1976). 2004;29(4):360-366. PMID: 15094531.
• —Aghdasi B, Montgomery SR, Daubs MD, Wang JC. A review of demineralized bone matrices for spinal fusion: the evidence for efficacy. Surgeon. 2013;11(1):39-48. PMID: 23040457.
• —Chun DS, Baker KC, Hsu WK. Lumbar pseudarthrosis: a review of current diagnosis and treatment. Neurosurg Focus. 2015;39(4):E10. PMID: 26424334.
• —Larsen JM, Capen DA. Pseudarthrosis of the lumbar spine. J Am Acad Orthop Surg. 1997;5(3):153-162. PMID: 10797217.
• —Hilibrand AS, Fye MA, Emery SE, Palumbo MA, Bohlman HH. Impact of smoking on the outcome of anterior cervical arthrodesis with interbody or strut-grafting. J Bone Joint Surg Am. 2001;83(5):668-673. PMID: 11379735.
• —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(3):291-296. PMID: 9507615.
• —Glassman SD, Rose SM, Dimar JR, Puno RM, Campbell MJ, Johnson JR. The effect of postoperative nonsteroidal anti-inflammatory drug administration on spinal fusion. Spine (Phila Pa 1976). 1998;23(7):834-838. PMID: 9563116.
• —Thomsen K, Christensen FB, Eiskjaer SP, Hansen ES, Fruensgaard S, Bünger CE. 1997 Volvo Award winner in clinical studies. The effect of pedicle screw instrumentation on functional outcome and fusion rates in posterolateral lumbar spinal fusion: a prospective, randomized clinical study. Spine (Phila Pa 1976). 1997;22(24):2813-2822. PMID: 9431617.
• —Fernández-Fairen M, Sala P, Ramírez H, Gil J. A prospective randomized study of unilateral versus bilateral instrumented posterolateral lumbar fusion in degenerative spondylolisthesis. Spine (Phila Pa 1976). 2007;32(4):395-401. PMID: 17304127.
• —Wozney JM, Rosen V, Celeste AJ, et al. Novel regulators of bone formation: molecular clones and activities. Science. 1988;242(4885):1528-1534. PMID: 3201241.
• —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(5):337-349. PMID: 12394656.
• —Fu R, Selph S, McDonagh M, et al. Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med. 2013;158(12):890-902. PMID: 23778906.
• —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(12):877-889. PMID: 23778905.
• —Rodgers MA, Brown JV, Heirs MK, et al. Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion. BMJ. 2013;346:f3981. PMID: 23788229.
• —Virk S, Qureshi S, Sandhu H. History of spinal fusion: where we came from and where we are going. HSS J. 2020;16(2):137-142. PMID: 32523481.
• —Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors. 2004;22(4):233-241. PMID: 15621726.
• —Aleem IS, Aleem I, Evaniew N, et al. Efficacy of electrical stimulation for spinal fusion: a systematic review and meta-analysis of randomized controlled trials. Sci Rep. 2020;10(1):4568. PMID: 32165697.

This information is for general patient education and is not a substitute for an individual consultation. Always seek personalised advice from a qualified spinal specialist.