Interbody material composition and bone morphogenetic protein-2—risks and benefits of utilization: a narrative review

Introduction

Background

As the global population ages, the prevalence of symptomatic spinal pathology requiring surgical intervention is predicted to increase substantially (1-4). Spinal stenosis and degenerative disc disease are among the most common degenerative spinal pathologies. For patients unable to obtain significant relief of their symptoms with non-operative management, surgical decompression with or without fusion is the mainstay of treatment. Incorporating interbody devices can be effective in both restoring anatomical alignment and achieving indirect decompression of the neuroforamen and this has become a popular technique with both open and minimally invasive procedures (5).

Rationale and knowledge gap

Historically, lumbar interbody fusions were performed from an anterior approach with autologous bone graft being the material of choice (6). In the 1980s and 1990s posterior-based interbody fusions were introduced, decreasing morbidity associated with a second surgical site (7). Since then, the popularity and indication for posterior lumbar interbody fusion (PLIF) and transforaminal interbody fusion (TLIF) has increased dramatically (8).

Advances in materials and bioengineering have produced a variety of interbody materials available on the market for surgeons to choose from. Presently, the most commonly used interbody devices are made from polyetheretherketone (PEEK), titanium-alloy, and allogeneic bone graft (9-12). Newer devices include porous PEEK, titanium, and other metal alloys. Interbody cage surface treatments, implant design, and novel materials further add to the array of available options (13).

An ideal interbody device should have adequate strength to withstand the load bearing of the lumbar spine, have low corrosion properties, the biocompatibility to promote bony growth, and a similar modulus of elasticity to minimize subsidence into the vertebral body. A multitude of studies have evaluated the risks and benefits of one material versus another (9,10,14,15). Beyond the implant material composition—shape, footprint size, implant height, ligamentous/disc release and cage positioning are important considerations (16). Additionally, bone morphogenetic protein 2 (BMP-2) is a commonly used adjunct to interbody devices to augment fusion, as numerous studies have shown improved fusion rates, though it is not without controversy and complication (17,18). From a surgical technique perspective, proper preparation of the disc space, such that the cartilaginous endplate is removed without violating the bony endplate, is critical to decreasing the risk of osteolysis or subsidence.

Objective

With consideration to the seemingly daunting number of options available, we review the basics of interbody cage materials and the use of BMP-2, which is often placed within the contained space of the cage, to help spine surgeons select optimal device to best suit the needs of their patients. This review aims to be expansive and provide summative generalizations for the most popular materials and devices, and therefore represents a knowledge gap on specific implants as well as newly emerged technologies. We present this article in accordance with the Narrative Review reporting checklist (available at https://asj.amegroups.com/article/view/10.21037/asj-24-15/rc).

Methods

Studies relevant to this review were identified through a literature search of PubMed. Search terms are listed in Table 1, with various combinations of these terms used in 2023. Additionally, landmark publications and other references found within relevant studies were used. Summative and pertinent data was extracted from primary studies and reported in this review when relevant.

Autograft and allograft

Iliac crest bone graft (ICBG) harvesting was historically the gold standard for interbody graft material in a structural fashion, whereas when used for posterior fusion it is non-structural (16,19). It was touted for being biocompatible, nonimmunogenic, and having excellent fusion results. Over time ICBG harvest for elective spinal fusion procedures has fallen out of favor due to longer procedure times for the graft harvest and due to the morbidity of the graft harvest which can substantially increase the overall complication profile for the surgery (20). With advancements in alternative materials to use as biologic support for the spinal column, there has been a substantial reduction in ICBG harvesting, although it remains the gold-standard across which many synthetic materials are compared against given its high rate of spinal fusion success.

A variety of allograft materials are commercially available (13). This includes femoral ring allograft, cortical bone dowel, demineralized bone matrix, corticocancellous allograft, dense cancellous graft, and others (6). These grafts can be used in either the cervical spine for anterior cervical discectomy and fusion (ACDF) but are also used for anterior-based approaches to the lumbar and thoracic spine. Many surgeons prefer using allograft for its similar elastic modulus to native bone and improved visualization of fusion through follow-up (6,21).

Allograft being non-native tissue carries a demonstrated risk of resorption, potentially leading to pseudarthrosis and recurrent radiculopathy. Although disc height loss, in approximately 50% of cases utilizing conticocancellous allograft should be expected, this is not predictive of revision surgery (6,22). However, it does portend worse patients reported outcomes (22) likely due to some recurrent neuroforaminal impingement. A similar finding was identified by Rhee et al. who reported that dense cancellous allograft in ACDFs had some radiographic evidence of resorption in 53% of levels fused. Despite this, fusion rate was reported as 82% and no patient required revision (23). Lee et al. collected computed tomography (CT) scans on 53 patients immediately after posterior cervical fusion and at 1-year follow-up to evaluate for graft resorption. Patients that received only allograft demonstrated 91% resorption of their allograft on CT scan. Despite this, the fusion rate was still 98.2% (24). This suggests that while graft resorption does occur, it may not necessarily affect fusion results. In fact, it is likely part of the bony remodeling process.

BMP-2

Bone morphogenic proteins are part of the greater transcription growth factor-β (TGF-B) family of proteins and were first discovered in 1965 (17). These proteins are known to promote restoration of cartilage and bone. Recombinant human bone morphogenic protein 2 (rhBMP-2) first achieved Food and Drug Administration (FDA) approval in 2002 for anterior lumbar interbody fusions between L4 and S1 as a replacement for autograft (25). Four years after its introduction into the spine market, it was used in 24.89% of all fusions (18). Its approval for ALIF led to a substantial increase in its off-label usage for posterior thoracolumbar and anterior and posterior spinal fusion procedures. Critics of widespread rhBMP-2 use cite several concerns, including costs, radiculitis, risk of seroma formation, osteolysis, graft subsidence, dysphagia (for anterior cervical fusions), and famously a reported risk of malignancy (17,18). This has been a point of discussion and controversy throughout the spine community, and a risk-benefit discussion with the patient is mandatory especially when using rhBMP-2 for off-label purposes.

rhBMP-2 is widely used in adult spinal deformity surgery, with surgeons touting superior fusion rates and lower rates of mechanical complication compared to bone grafting alone, particularly when performing three column osteotomies or in revision settings (26). A meta-analysis performed by Mariscal et al. showed superior fusion rates in posterolateral lumbar fusion when compared to ICBG at 24 months (94% vs. 83% respectively) (27). Further, in patients at high risk for a pseudarthrosis including smokers and osteoporotic patients, rhBMP-2 is known to improve fusion rates (28). In comparison to a second surgical site, that carries its own risk of complications, many spine surgeons prefer using rhBMP-2 instead of harvesting iliac crest autograft.

In 2010 the FDA reported an increase cancer rate amongst patients that received rhBMP-2. This was further supported by studies that demonstrated increased growth of cancer cells in-vitro when exposed to rhBMP-2 (29). However since then, numerous studies including studies with >300,000 patients in a healthcare claims database, have evaluated the risk of new malignancy after rhBMP-2 use and actually found a non-significant decreased association between rhBMP-2 and new-onset malignancy (30). In fact, BMP-2 has become more popular in patients with a high-risk of pseudarthrosis who are undergoing an ACDF. However, surgeons should be careful when employing this approach given the for anterior soft tissue complications [risk ratio (RR) =1.43, P<0.001] and for postoperative dysphagia (RR =1.39). While non-significant, the relative risk of pseudarthrosis was 0.5 (P=0.9) (31). Further, the most recent AO Spine guideline suggests close monitoring for complication when using rhBMP-2 for ACDF, and if needed using a lower dose to reduce the risk of complication (32).

Titanium

Titanium and titanium alloy materials have become increasingly popular choices for interbody fusion devices. This is due to its numerous benefits, including its elastic modulus, strength, relative cost, and biocompatibility. Despite these benefits, it is important to note that titanium is radiopaque, making fusion assessment more challenging on imaging throughout clinical follow-up (13,33).

From a biomechanical perspective, titanium has a substantially higher elastic modulus than that of bone, meaning it is much more resistant to deformation when under stress, but this comes with a theoretical increased risk of subsidence (33). The elastic modulus of titanium is approximately 1,101,140 GPa, whereas the modulus of corticocancellous bone is 10–40 GPa (34). While increased strength may be beneficial, a greater difference between the elastic modulus of native bone and interbody devices also increases the rate of stress shielding. This can be problematic as this increases the chance of implant subsidence, bony resorption, and subsequent implant loosening (10).

This is further validated by studies demonstrating modified titanium alloys with decreased modulus producing decreased subsidence on axial loading (34).

Some surgeons have a preference for titanium based interbody for its benefit of biocompatibility. Several in-vitro studies have shown titanium’s biocompatible properties, including osteogenesis, osteoblast differentiation, and expression of osteogenic genes (35,36). Olivares-Navarette et al. showed that rough titanium is superior to smooth titanium and PEEK in promoting bone growth through increased levels of osteoprotegerin, TGF-b1, vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), and angiopoietin-1 (35). This promotes bony fusion in the intervertebral disc space, facilitating increased stability. From a surgical technique perspective, placing autograft or biologics in front of the cage is important for promoting fusion.

Surface and structural modifications to titanium cages further alter biomechanical and fusion properties (13). This primarily encompasses the porous structure of the cage and surface modifications to promote fusion. Interconnected micropore structure promotes osteoconduction and proliferation of osteoblasts. Porosity greater than 50% of the structure has been shown to reduce elastic modulus, reducing it closer to that of bone (37). This helps mitigate the stress between the interbody device endplate, decreasing stress shielding and implant subsidence. Further, porous titanium has been shown to produce lower levels of inflammatory, necrosis-inducing, and apoptotic factors (38). Increased surface roughness has been shown to promote osteoblast maturation via expression of BMP-2 and BMP-4 (39). Together, engineering surface and internal structure of titanium cages allows for optimal fusion and biomechanical properties.

PEEK

PEEK, a high molecular-weight semi-crystalline polymer, is another very popular material used for interbody devices. Importantly, PEEK is radiolucent, allowing direct visualization of bony fusion. Metal radiographic markers are often incorporated into PEEK implants to allow easier identification on plain radiographs (11,13).

The elastic modulus of PEEK is very similar to bone, theoretically decreasing the risk of stress shielding and subsidence (40). However, the surface of PEEK is bioinert and does not inherently promote osteointegration. Several studies have shown the surface of solid PEEK can be hydrophobic and form a biofilm which prevents a solid fusion (41). Further, studies have demonstrated pro-inflammatory effects of PEEK. Fibrotic tissue develops around the implant inhibiting bony growth and fusion (42). Further, the pro-inflammatory environment creates an increased risk of osteolysis and implant failure (13). This concern has borne out in retrospective clinical studies identifying greater pseudoarthrosis rates for PEEK cages, which may potentially be six times greater than structural allograft cages (43,44).

The biocompatibility of PEEK is improved by the addition of other polymers or inorganic materials. PEEK has a high melting point, allowing several techniques of surface modifications to be performed. This includes plasma and laser treatments, as well as deposition techniques aiming to deposit other polymers or inorganic matter on the surface to promote bioactivity (12,13,45). Several “hybrid” cages have emerged in the marketplace combining PEEK with calcium silicate, titanium, and hydroxyapatite. These modifications have been shown to improve biocompatibility and promote bony fusion while retaining the biomechanical advantages of PEEK. One study found increased levels of angiogenic and osteogenic growth factors in a titanium-coated PEEK implant, suggesting improved fusion potential (46).

Other materials

Tantalum has been used in the orthopedic treatment of oncologic and infectious processes, particularly porous tantalum (47). This is due to the internal structure being similar to that of bone. Studies have demonstrated bony growth onto and into the porous structure, providing good osteoconductivity and fusion capacity. Additionally, tantalum was shown to promote proliferation of osteoblasts promoting fusion. Tantalum holds promise as a material for interbody devices with further studies needed to delineate timing of fusion, complications, and long-term follow-up (13,48).

Bioabsorbable materials initially held promise for their biocompatibility and gradual absorption over time, gradually transferring stress and load onto healing bone. However, these technologies have substantial complication risk including osteolysis, soft-tissue reaction, and rapid degradation leading to mechanical failure. Magnesium-based implants were studied as a potential material for interbody devices, citing favorable osteoconductive and biomechanical properties to native bone. Similar to other absorbable compounds, magnesium also carried a substantial risk of rapid degradation, osteolysis, and severe foreign body reaction (49). Presently, there are several concerns to be addressed prior to widespread adoption of bioabsorbable materials in spinal implants.

Comparative outcomes of interbody material in the cervical and lumbar spine

Cervical spine

Numerous studies have evaluated the long-term clinical and radiographic outcomes associated with PEEK, titanium, and allograft interbody materials, as well as their performance in the cervical and lumbar spine. Between 2002 and 2004, Chen et al. conducted a 1:1 randomized controlled trial of 80 patients comparing outcomes of titanium versus PEEK cages for patients undergoing multilevel ACDF. Through an average 7 years of follow-up, titanium cages were found to have a higher subsidence rate than PEEK cages (34.5% vs. 5.4%). Radiographic fusion was observed in all 80 patients, and there was no difference in long-term clinical outcomes of these patients (50).

In 2018, Krause et al. reported a fivefold greater rate of radiographic pseudoarthrosis single-level ACDF patients in patients that received a PEEK interbody device compared to structural allograft (51.8% vs. 10%) (51). In light of these dramatic findings, several research groups sought to validate these findings.

Menon et al. compared 1-year outcomes for patients undergoing single and multilevel ACDFs and assessed differences based on interbody material. Pseudoarthrosis rates were similar between structural allograft and synthetic interbody groups in both single (15.2% and 14.1%) and multilevel ACDFs (21.2% and 23.5%). For single level ACDF patients, no significant difference was found for dysphagia or revision surgery when comparing structural allograft to synthetic interbody devices. For multilevel ACDF patients, synthetic interbody devices had a significantly higher rate of reoperation compared to structural allograft (7.3% vs. 3.8%, P<0.001). However, dysphagia rates were higher in patients that received structural allograft compared to synthetic devices (15.9% vs. 12.9% respectively) (14).

Jain et al. conducted a systematic review comparing PEEK to allograft in ACDFs. Allograft had fusion rates of 82% to 100% and 88% to 98% for PEEK interbody devices (15). However, this review also reported a reoperation rate of 0.7% to 13.9% when structural allograft was used as the interbody device. Subsidence rates for structural allograft was reported from 0% to 4.3%. PEEK interbody devices were found to have a higher rate of subsidence, ranging from 14% to 18%.

In a single institution retrospective cohort study, D’Antonio et al. evaluated the rates of pseudoarthrosis one year after ACDF. Using propensity matching analysis, PEEK implants were found to be predictive of pseudoarthrosis compared to structural allograft [odds ratio (OR), 3.34; P=0.007], whereas titanium-based interbody cages were not predictive (OR, 1.64; P=0.156) (43). Importantly, this was based on radiographic evidence of pseudoarthrosis, and there was no significant difference in revision rates between PEEK, titanium, and structural allograft devices. Further, there was no significant difference in patient reported outcomes was observed between implant groups. These findings were directionally consistent with prior clinical studies, and reflective of what is known from biomechanical and material studies.

Lumbar spine

Cutler et al. performed a retrospective review of 39 patients undergoing single-level TLIF between 2001 and 2004 showing similar fusion rates between PEEK cages and femoral cortical allograft. Further, there was no significant difference in Oswestry Disability Index (ODI) scores at 12-month follow-up, suggesting that PEEK and femoral allograft are effective in producing interbody fusion (52). Campbell et al. compared PEEK and titanium implants for patients that underwent lateral interbody fusion. Significantly higher rates of subsidence was found for PEEK compared to titanium devices through 1-year follow-up, however with similar rates in the early post-operative period (10). A meta-analysis of 11 studies and 1,094 patients found PEEK had a significantly lower fusion rate compared to titaniumbased interbody devices [OR, 0.62; 95% confidence interval (CI): 0.41–0.93; P=0.02] but had no difference in subsidence (OR, 0.91; 95% CI: 0.54–1.52; P=0.71) (53).

Comparing titanium to PEEK, clinical studies showed superior rates of fusion in titanium but higher rates of subsidence compared to PEEK (50,54). A 2017 meta-analysis found higher fusion rates in the lumbar spine for titanium compared to PEEK, however the difference was not significant.

Further, there was greater subsidence rates for titanium compared to PEEK (9).

Authors preference

Given the current available literature, either structural allograft or titanium appear to be feasible options for anterior column support in the cervical and thoracolumbar spine. Given the risk of graft resorption, and the potential for loss of neuroforaminal height and deformity correction, the authors typically utilize titanium interbody cages for elective patients undergoing spinal fusion without infection. The authors’ preference in patients with an active spinal infection, remains ICBG harvest to minimize foreign material, while still achieving a high likelihood of spinal fusion with a low rate of potential graft resorption. Given the high risk of morbidity, the authors do not utilize BMP-2 in anterior cervical cages at this time. However, given the relatively low complication profile in the lumbar spine, it is an option for anteriorly (either via a lateral or direct anterior approach) placed cages in the lumbar spine after an appropriate risk-benefit discussion with the patient. Since it is off-label use and has potential side effects, the authors rarely use rhBMP-2 for short construct primary posterolateral lumbar fusions or TLIF procedures. However, the authors will consider using it in the posterolateral gutters in revision cases due to a pseudarthrosis. Since it can cause ectopic neuroforaminal bone growth, the authors do not place rhBMP-2 in TLIF cages given that fusion is most likely to occur first in the contralateral facet and then the intertransverse region with subsequent fusion occurring across the disc space.

Conclusions

At present, PEEK, titanium, and allograft are the mainstays for interbody devices. Each offer a low risk for revision surgery, with known risks and benefits for each material, shown through multiple clinical studies. Titanium offers excellent fusion rates, whereas PEEK has decreased risk of subsidence (9). The evolution and future of interbody devices is promising, with 3D printed, hybrid materials, and patient-specific devices purporting more optimal biomechanical properties with greater capacity for fusion (13). Surgeons should carefully select an appropriate interbody device based on familiarity, prior experience with a device, procedure type, and factors specific to the patient.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://asj.amegroups.com/article/view/10.21037/asj-24-15/rc

Peer Review File: Available at https://asj.amegroups.com/article/view/10.21037/asj-24-15/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://asj.amegroups.com/article/view/10.21037/asj-24-15/coif). B.J.N. reported receiving honoraria from Baxter and payment from Duane Fielder, Attorney. M.J.L. serves as the co-Editor-in-Chief of AME Surgical Journal from December 2024 to December 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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