Autograft

Autogenous iliac crest bone was once considered the gold standard of graft material. Historically, it has been the most successful graft source in spine fusion. Cancellous autograft has the requisite matrix proteins, mineral, and collagen for the ideals of osteogenicity, osteoinductivity, and osteoconductivity. Its large trabecular surface makes it highly connective as well. Donor site complication rates as high as 25% to 30% have been reported, although a rate of 8% seems more realistic and is more commonly cited. Morbidity may be associated with an increased incidence of blood loss, chronic donor site pain, increased operative time, infection, and nerve injury. Furthermore, the quantity of bone available is limited and may be insufficient for long-segment fusions or in patients who have had previous graft harvests.

Autogenous cortical bone is useful when structural support is needed at the graft site. Otherwise, it is less desirable than cancellous bone because of the absence of robust bone marrow and, as a result, fewer osteoprogenitor cells. Additionally, these cells are less likely to survive, because they are embedded in a compact matrix where the diffusion of nutrients essential for cell proliferation is impeded compared with the cancellous environment. Cortical bone also has less surface area per unit weight with matrix proteins exposed and, therefore, connectivity is marginal. Vascular ingrowth into cortical bone is slow. Mechanical strength lags because incorporation takes longer. Although cancellous bone is incorporated fairly rapidly and remodeled, portions of cortical graft may remain necrotic for extended periods. When the likelihood of avascular graft healing is low, as in previously irradiated tissue beds, vascularized grafts may be more desirable due to the presence of greater numbers of osteogenic cells.

Demineralized Bone Matrix

Demineralized bone matrix (DBM) is present in a variety of forms, each of which has a variable degree of osteoinductivity. Current data support its use as a bone graft extender but not as a pure substitute or enhancer. Autogenous and allograft DBMs are osteoinductive due to the presence of low doses of BMPs (~0.1% by weight). Collagenous and noncollagenous proteins serve as osteoconductive material that is left after the demineralization process. Preliminary animal studies have shown efficacy of DBM as a carrier molecule for recombinant human bone morphogenetic protein (rhBMP-2) in ectopic bone formation or as a graft alternative in experimental posterolateral arthrodesis. A study by Louis-Ugbo and colleagues used a nonhuman primate posterolateral fusion model to test a specific formulation of DBM, which was more porous than its predecessor. With this new formulation they found robust fusions and suggested that it exhibited properties of both a graft enhancer and extender. A prospective randomized study by Cammisa and associates looked at 2-year fusion rates in the posterolateral environment in 120 human patients. They concluded that DBM could function as an adequate graft extender and promote adequate fusions when mixed with a small amount of autogenous bone graft.

Allograft

The desire to avoid donor site morbidity led to increased use of allograft bone in spine surgery. This was made practical by advances in procurement, sterilization, preparation, and storage. Although allograft bone is widely used in spine surgery, concerns regarding fusion rates and disease transmission remain. Allograft is not osteogenic, because there are no surviving cells in the graft. Because of the processing and storage requirements of allograft, some of the osteoinductive potential is lost. It also carries a small but real risk of disease transmission and may elicit an immune response from the recipient.

Sterilization, donor screening, and sterile harvesting of donor bone help to keep the risks just cited to a minimum. Bone must be harvested in a sterile fashion within 24 hours of death, cultured, and processed for storage. Large tissue banks are available at most academic institutions.

Immunogenicity and maintenance of osteoinductive and osteoconductive properties are affected by these processing and preservation techniques. Bone usually is frozen or freeze-dried as soon as possible after harvest. Both methods decrease immunogenicity and allow for extended storage. Freezing does not diminish the mechanical properties of the bone, and it may be stored at −70° C for 5 years. Freeze-drying further reduces immunogenicity and inactivates viral agents, but it reduces the mechanical strength of the graft. Freeze-dried bone may be stored under vacuum, at room temperature, for an indefinite period.

The most common sterilization methods are high-dose gamma irradiation and ethylene oxide gas sterilization. Both alter the structure of matrix proteins, decreasing the osteoinductive capacity and mechanical strength of the bone. Other sterilization methods such as autoclaving are even more destructive and generally are not used.

Although allograft usually has performed well in both cervical and lumbar interbody fusions, in which the graft is subject to compression, the results in the posterolateral lumbar environment, in which primary tensile forces exist, have not been as favorable. This result has led many surgeons to use allograft as an autograft expander rather than a pure substitute for posterolateral arthrodeses.

Xenograft

The use of bone graft taken from other species has been reported in the orthopaedic literature, but these alternatives to autograft never were incorporated into widespread use. Despite processing, xenografts remain immunogenic and provoke a host response. The graft may become encapsulated from the host’s response, with resultant blockade to revascularization. Ivory and cow horn resist incorporation into host bone and are no longer used. Bovine bone, both freeze-dried and deproteinized, remains weakly antigenic. Both of these types of xenografts have been used in spine surgery with limited success, and therefore they are not recommended as a graft material.

Ceramics

Calcium phosphate (CaPO ₄ ) ceramics, including hydroxyapatite (HA) and tricalcium phosphate (TCP), have been widely used in orthopaedic surgery and spine surgery. These osteoconductive, biodegradable materials are compatible with the remodeling of bone necessary to achieve optimal strength of a construct. Other, nonresorbable materials remain in the fusion mass, leaving permanent stress risers and prolonging strength deficiencies.

To be useful as a graft material, synthetic materials must have several properties. They must be compatible with local tissues, remain chemically stable in body fluids, and be able to withstand sterilization. Furthermore, they must be available in useful shapes and sizes, be cost-effective, and have reliable quality control. CaPO ₄ ceramics qualify and have been widely used in dentistry and maxillofacial surgery, as well as in animal models for experimental spinal research. A wide body of literature exists discussing the use of these materials in human spine surgery.

Both HA and TCP ceramics are inherently brittle. They may be prepared as either a compact or a porous material. The greater crystallinity and density of the compact form results in greater strength and resistance to dissolution in vivo, whereas porous versions more closely approximate cancellous bone and enhance bony ingrowth (at the expense of more rapid degradation). Under physiologic conditions, HA is resorbed slowly, whereas TCP generally is resorbed within 6 weeks of implantation.

Natural coral has been used to augment or even replace autograft, with some success. The calcium carbonate (CaCO ₃ ) in coral is hydrothermally converted to CaPO ₄ . The structural geometry of coral is similar to that of cancellous bone, making it highly osteoconductive and connective.

Animal Studies: Spinal Instrumentation

The effects of spinal instrumentation and stability have been investigated in various animal models. Although this approach can tell us much about short-term effects of instrumentation failure, caution must be exercised in extrapolating this information to the long-term effects in the human body at the bone/instrumentation interface. McAfee and associates created a canine instability model to study both the effect of spinal instrumentation on fusion success and the radiographic incidence of fusion with respect to spinal stability. At 6 months, radiographs revealed a greater probability of fusion in the instrumented animals than in the noninstrumented animals. The instrumented fusions also were more rigid. Likewise, Zdeblick and coworkers demonstrated both an increased rate of fusion and a more rigid fusion when anterior instrumentation was used in a canine model of an unstable burst fracture at L5. These results also were replicated by Shirado. Kotani and colleagues showed that after solid posterolateral arthrodesis was achieved in a sheep model, transpedicular fixation continued to provide mechanical support.

The biologic activity of the graft material may partly determine the need for internal fixation. Fuller and coworkers showed that rigid fixation improved bone ingrowth into a calcium carbonate block in a canine anterior thoracic interbody fusion model. Because ceramics are not osteoinductive, a mechanically stable environment is crucial for ingrowth. Osteoinductive graft substitutes, on the other hand, may not be as reliant on construct rigidity.

Nagel and coworkers developed a sheep model of delayed union and nonunion. Posterior lumbar laminar and facet fusions with iliac crest graft were performed on seven sheep. Six of the seven sheep developed nonunions at the L6-S1 interspace; all cephalad interspaces fused (21 of 21). Eight normal sheep underwent in vivo flexion-extension radiographs. Five normal sheep spines were studied ex vivo, using displacement transducers to test stiffness, displacement, and strain in flexion-extension. The lumbosacral level demonstrated significantly more motion than the other levels, suggesting that motion was a major factor in determining the success of fusion in this sheep model. Similar observations have been made in dogs. The increased stability and decreased motion that instrumentation provides would seem valuable in such instances.

Human Studies: Spinal Instrumentation

Contradictory human studies of the effects of spinal instrumentation have been widely reported. Zdeblick discussed 124 patients undergoing fusion for different conditions. Patients were randomized into three groups, all having dorsolateral autograft fusions. Patients in group 1 were not instrumented, those in group 2 were instrumented with a semirigid pedicle screw system, and individuals in group 3 had rigid pedicle screw instrumentation implanted. The rigid group had a significantly higher fusion rate (95%) than the noninstrumented group (65%). The instrumented groups together had 95% excellent or good results, whereas the noninstrumented patients had only 71% good or excellent outcomes (a statistically significant result).

Bridwell and colleagues described 44 patients with degenerative spondylolisthesis. Patients were individualized into three groups: no fusion, noninstrumented posterolateral fusion, and pedicle screw instrumented posterolateral fusion. Patients with more than 10 degrees or 3 mm of motion were automatically assigned to the instrumentation group. There was an 87% fusion rate in the instrumented group versus a 30% rate in noninstrumented patients; there was no significant clinical difference in successful outcomes between the noninstrumented and unfused groups (30% versus 33%). Successful outcomes in the instrumented group (83%) were significantly greater than in the nonfusion group. Fischgrund and associates also demonstrated a markedly increased rate of fusion in their patients with instrumentation (83% versus 45%), yet found no difference in clinical outcome.

In their meta-analysis, Mardjetko and colleagues reviewed 25 papers describing 889 patients with degenerative spondylolisthesis. Five of the included studies described patients undergoing decompression and posterolateral arthrodesis with pedicle screw instrumentation. Although there was a trend toward an increased rate of fusion in the instrumented versus noninstrumented patients (93% versus 86%), it did not reach significance ( P = .08). The clinical outcome was better in the uninstrumented group: 90% versus 86%. However, the authors acknowledged several limitations of their review: data from different treatments over 20 years; variable study designs and quality; and possible dilution of data from the stronger, better-designed studies that suggested an advantage to instrumentation.

Fusion success is also affected by the physical stresses placed on the graft. In human beings, 80% of the load at a motion segment is transmitted through the intervertebral disc. Graft placed ventrally, in the interbody region, is thus primarily subjected to compression. This compressive force promotes fusion, presumably by stimulating vascular ingrowth and the proliferation of mesenchymal cells. Dorsally placed graft experiences tensile forces, as does graft placed in the intertransverse process region. Under these less favorable mechanical conditions, fusion is more dependent on biologic factors.

Facet preparation for fusion has been shown to increase motion of the involved segment. Although many surgeons routinely include facet fusion in posterolateral intertransverse process arthrodeses, biomechanical studies have demonstrated a resultant decrease in stability. The developing fusion preparation decreases the surface area incorporated into the fusion mass and may result in a less rigid fusion. Rigid instrumentation allows the facets to be prepared and incorporated without sacrificing stability. However, in the osteoporotic patient, the screw-bone interface often is weak. Even with instrumentation, facet preparation may not be appropriate in these individuals.

Overall, it is generally agreed that spinal instrumentation decreases the rate of pseudarthrosis. However, in some situations, especially with single-level fusions, no significant clinical benefit may be obtained. Additionally, although a positive relation exists between radiographic fusion and clinical outcome, no absolute convincing correlation has been demonstrated. Currently, prospective randomized blinded clinical trials examining the effects of instrumentation have not yet been completed.

Human Studies

Kane published the first large multicenter study of the use of DCES in dorsolateral spine fusion. Eighty-two patients treated with DCES were compared to a historical control population of 150 patients fused without electrical stimulation. The DCES group had a 91% fusion rate, significantly higher than the 81% in the control subjects. Of note, the DCES group had a significantly higher rate of revision surgery for pseudarthroses. The report also described a prospective, randomized control study in a “difficult to fuse” population of patients who had failed one or more previous attempts at fusion, were undergoing multilevel arthrodeses, had grade II spondylolisthesis, or had other risk factors. The 31 patients in the stimulation group had a significantly higher fusion rate of 81%, compared with 54% of the 28 patients in the control population.

More recent work has lent further support to the use of DCES in dorsolateral spine fusion. Reports indicate that DCES increases the percentage rate of fusion in dorsolateral pedicle screw–instrumented fusions. Furthermore, DCES has been shown to increase the fusion rate in smokers from 66% to 83%.

Simmons was the first to report on the use of PEMF in spine fusion. He described treatment of pseudarthroses after posterior lumbar interbody fusion in 13 patients, 77% of whom progressed to fusion without further surgery. In the more demanding environment of posterior pseudarthroses, Lee reported a 67% success rate with PEMF. Bose followed 48 patients who received posterolateral fusion in addition to instrumentation. He reported fusion success of 98%; however, there was no control population in this study. Marks demonstrated twice the percentage of successful lumbar fusions in females when compared with control populations without the device.

Linovitz and colleagues reported on a double-blind, randomized, placebo-controlled population of patients on the use of CMF in noninstrumented fusions. The study found that 64% of patients with active devices had fused by 9 months, compared with 43% of patients with placebo devices. Stratification by gender showed that the difference was significant only for the female patients in the study. The reasons for this remain unclear.

Although there seems to be support for the use of electrical stimulation in spine fusion, not all modalities are equally effective. Currently, DCES appears to have the greatest effect. Furthermore, all of these devices are expensive. Guidelines for determining which patients would best be served by their use have yet to be fully elucidated.

Animal Studies

Preclinical work on the use of BMP in posterolateral spine fusions has been reported by many researchers. Many of these early experimental studies demonstrated faster fusion rates when compared to controls. Cook and colleagues, using osteogenic protein 1 (OP-1) in a canine facet and interlaminar fusion model, obtained solid fusions in 12 weeks, as compared with 26 weeks for autogenous graft. In a similar model, Muschler and colleagues found no difference between autograft and rhBMP-2 at 3 months, though the model was criticized for its intrinsically high fusion rate of the control arm.

A canine intertransverse-process fusion model demonstrated solid fusion with rhBMP-2 within 3 months, whereas autologous iliac crest graft animals had not fused at that point. This same model was used to demonstrate that rhBMP-2 could produce solid fusions without decoration. Using a rabbit intertransverse process fusion model they developed, Schimandle and colleagues achieved 100% fusion with rhBMP-2, compared with 42% fusion in the autograft group. Martin and colleagues demonstrated that rhBMP-2 was further able to overcome the inhibitory effect of ketorolac in the model used by Schimandle and Boden. Grauer and colleagues and Patel and colleagues then established that OP-1 had the same effects in reference to fusion, but required higher dosages of the BMP compound.

Sandhu and colleagues and Fischgrund and colleagues reported improved fusion rates with an rhBMP-2 soaked collagen sponge in a canine model for spine fusion compared to controls. Martin and colleagues, on the other hand, failed to show improvement in posterolateral fusions in nonhuman primates when using the same concentration of rhBMP-2 as in the canine studies. They listed one potential cause of this discrepancy originating from compression of the BMP out of the sponge by the surrounding tissues. A protective shield was then placed over the absorbable collagen sponge (ACS), and they were then able to achieve successful fusions at lower concentrations.

Several other studies also have examined the effectiveness of these agents in nonhuman primates. Boden and colleagues tested bBMPx in the lumbar spine of adult rhesus monkeys. Four of the four animals implanted with 3 mg or more of the bovine protein achieved a posterolateral intertransverse process fusion, whereas none of the six animals implanted with a lower dose fused. However, a second study demonstrated only 40% fusion with this same dose, and 54% with a 5-mg dose, although the autograft animals showed only 21% fusion.

A more robust carrier than the collagen sponge alone may be needed to promote fusion in the posterolateral environment. Boden and colleagues developed a more rigid porous biphasic calcium phosphate (BCP) ceramic carrier that provided a scaffold for new bone and then resorbed over time. They were able to achieve fusion at three different concentrations of rhBMP-2/ACS. Additional carriers have been developed that are based on the original BCP ceramic concept with the same excellent results in the rabbit and primate models.

Akamuru and colleagues and Barnes and colleagues used compression resistant matrix (CRM) carriers (15% hydroxyapatite, 85% β-tricalcium phosphate ceramic collagen matrix) and noted that the carrier, collagen sponge, and concentration of rhBMP-2 are all important in promoting a solid fusion in nonhuman primates. Barnes and colleagues failed to achieve a solid posterolateral arthrodesis when the CRM was not used with rhBMP-2 and the collagen sponge. Like the BCP ceramic carrier in the study by Boden discussed earlier, one explanation for this observation by Barnes and colleagues could be that the CRM provides a better scaffold for bone growth than the ACS alone.

Human Studies

Human trials using rhBMP-7 and rhBMP-2 in posterolateral fusion have been reported, both with and without instrumentation. A safety and efficacy study of OP-1 for posterolateral spinal arthrodesis had been completed by 2001. Sixteen patients with degenerative spondylolisthesis, undergoing noninstrumented posterolateral fusion, were randomized to receive either autograft and OP-1 or autograft alone. At 6 months, 9 of the 12 autograft/OP-1 patients had fused, versus only 2 of 4 autograft-alone patients, although the difference was not statistically significant. Clinically, 83% of the OP-1 patients had 20% or better improvement in their Oswestry score, whereas only 50% of the autograft-alone patients had this level of success. Again, the difference was not statistically significant. Of note, OP-1 had no adverse effects.

This initial pilot study has since turned into a larger prospective series with long-term follow-up. The rhOP-1 (rhBMP-7) data for posterolateral spine fusion support increased rates of fusion in the rhBMP-7 group versus control (55% versus 40%). At 4 years of follow-up, Vaccaro and colleagues have achieved similar fusion results with rhOP-1 when compared with iliac crest autograft in posterolateral fusions.

Luque and Boden and colleagues pioneered early clinical studies of rhBMP-2 in the posterolateral fusion environment. Luque examined two patient cohorts in a prospective, randomized, open-label trial of rhBMP-2, with a BCP carrier in patients undergoing single-level lumbar fusions for degenerative instability. The first group (seven patients) received rhBMP-2/BCP unilaterally, with autograft on the contralateral side. Eighty-six percent of the rhBMP-2 sides fused by 12 months, whereas only 57% of the autograft-treated sides fused. The second group received a higher rhBMP-2/BCP dose bilaterally, without autograft; at 12 months, 100% had fused. Oswestry scores improved by 15 or more points in 85.7% of cohort 1 patients and in 100% of cohort 2 individuals. Boden and colleagues performed a prospective randomized clinical pilot trial of rhBMP-2 with BCP carrier versus autograft. All 20 patients with BMP-2 and the BCP carrier had solid fusions judged by CT scans, as evaluated independently. Nine of these patients had no internal fixation. The BMP-2 patients did better than autograft patients at an average of 17 months of follow-up in terms of fusion success and clinical outcome.

Dimar and colleagues also demonstrated that the rhBMP-2 group had better fusion rates compared with iliac crest bone graft (83% versus 73%, respectively) for patients receiving posterolateral instrumented fusions in a large prospective randomized study comparing rhBMP-2 with iliac crest (98 patients). Outcome measures such as the Oswestry Low Back Pain Disability Index and leg and back pain scores, however, were similar over time. These trends toward improved posterolateral fusion rates and outcome scores also were reported by Dawson and colleagues using rhBMP-2, ACS, and a ceramic bulking agent in a multicenter prospective randomized pilot study without instrumentation.

Ectopic Bone Formation: Animal Studies

Ectopic bone formation and its association with the use of BMP has been documented in both animal and clinical studies. The proposed mechanism is leakage of the molecule into unwanted sites from the carrier causing new both growth over the canal, inside the foramen, or the fusion of unwanted levels. This theory, however, is controversial, and many authors have failed to show any ectopic bone formation in both experimental and human studies, even in the presence of a laminectomy defect. Two studies in lower mammals (rabbits and mice ) examined the effects of high doses of BMPs on the exposed thecal sac. In both models, analysis revealed new bone growth and some compression on the neural elements; however, both studies failed to demonstrate any changes in behavior (e.g., motor) in the experimental animals versus the controls. Hsu and colleagues failed to induce ectopic bone formation in rodents when rhBMP-2 was used in high concentrations without an ACS. They raise the question of the significance of BMP elution without association of a carrier.

Ectopic Bone Formation: Human Studies

Swelling, Hematoma, and Dysphagia in Anterior Cervical Discectomy and Fusion

Neck swelling, hematoma, dysphagia, and respiratory failure have been reported with the use of rhBMP-2/ACS in ACDF surgery. Five clinical reports totaling 264 patients were analyzed by Benglis and colleagues in their review on adverse events of BMPs. The studies were by no means standardized, varying in the concentrations of rhBMP-2/ACS used, types of interbody, location of the rhBMP-2, levels fused, and type of anterior construct (discectomy versus corpectomy). The reported complication rates associated with these studies ranged from 5% to 27%, which were higher than historical controls examining complications following ACDF without the use of BMPs. These adverse events, in general, appear to be related to the use of increased dosages and the potential initiation of inflammatory cascades in the soft tissues of anterior cervical procedures. As noted in a study by Baskin and colleagues, only very small doses of rhBMP-2 are needed per level to induce postoperative fusion (one seventh of a small Infuse kit, Medtronic Sofamor Danek, Memphis, TN). Frenkel and colleagues conducted a retrospective cohort study comparing overall fusion rates in patient’s undergoing multilevel ACDF with or without BMP-2. The overall fusion rate was 82.6% without BMP (n = 23) and 100% with BMP (n = 22). Complications associated with BMP was dose related (range used, 0.26 to 2.1 mg/level) with none observed at doses less or equal to 1.1 mg/level.

Bony Resorption and Graft Subsidence

Some in vitro studies have shown that BMPs also may exhibit some osteoclastic activity. This phenomenon could be a function of its interaction with certain interleukins. Various groups are beginning to note robust bone loss during the resorption phase of bone growth associated with the use of BMPs in interbody fusions of the lumbar spine, ranging from resultant instrumentation failure, graft loosening, and subsidence, to migration.

Helgeson and colleagues performed a retrospective analysis of 23 patients who underwent TLIF with 6 mg of rhBMP-2. At 3 to 6 months, the incidence of vertebral body osteolysis was 54%, declining to 41% at 2 years. The interbody fusion rate of 83% did not appear affected by the presence of osteolysis. Mannion and colleagues reported on the rate of radiologic and clinical adverse events associated with very low-dose BMP-2. In this observational study, 36 spinal levels were instrumented in 30 patients. There was one case of nonunion at 12 months with associated vertebral body osteolysis, two cases of asymptomatic heterotopic ossification and two cases of perineural cyst formation.

Cancer-Related Risks

Development of neoplastic lesions is a complex and multifactorial process that, all too often, involves the spine as it is the most common site of bony metastases. Common sources include paired organs such as the breast, the lung, the thyroid, and the prostate (multilobed). Primary spinal tumors are also a concern considering the role bone morphogenic protein has on cellular lineage commitment, differentiation, proliferation, morphogenesis, cellular survival, and apoptosis.

In Poynton and Lane’s review of 570 individuals receiving rhBMP-7 (OP-1) for spine surgery, 5 patients developed cancer (4 nonosseous cancers and 1 recurrent chondrosarcoma). This incidence is similar to that expected in the general population. The Yale Open Data Access (YODA) project analyzing outcomes of 11 randomized controlled trials (RCTs) observed that cancer was twice as common in rhBMP-2 recipients (RR, 1.98 [CI, 0.81 to 4.16]). However, due to the small number of events, the authors could not precluded definite conclusions. A retrospective analysis of 467,916 Medicare patients undergoing spinal arthrodesis by Kelly and colleagues found that the clinical use of BMP was not associated with an increased risk of cancer within a 2.9-year follow-up. As of January 2015, the FDA’s published Summary of Safety and Effectiveness Data recommends INFUSE Bone Graft (rhBMP-2) should not be used in the vicinity of a resected or extant tumor, in patients with any active malignancy or patients undergoing treatment for a malignancy.

Painful Seroma and Mass Effect in Minimally Invasive Lumbar Spine Surgery

Levi and Wang conducted an informal survey with several minimal access surgeons who revealed that a painful seroma from rhBMP-2 is another potential complication (Levi AD, Wang MY, unpublished data, 2010). On reexploration or aspiration of the collection, clear fluid is found, and, following its release, the patient’s symptoms disappear. Origins may be due to inflammatory cascades induced by the BMP within a relatively small contained space.