Biologic Options in Interbody Fusion

Introduction

Interbody fusion devices aim to provide anterior column support as bony fusion between adjacent vertebral bodies progresses. Irrespective of the material utilized for structural support, depending on exact surgical technique, supplemental graft material should be placed within and/or around the allograft or cages in order to achieve a solid fusion. Achieving a solid arthrodesis can be directly correlated to long-term clinical outcomes and the durability of the procedure. Spine biologics can aid in facilitating arthrodesis by altering the existing environment by enhancing specific cellular and molecular activity. As a result, the field of biologics has expanded rapidly over recent years to include not only autogenous bone graft but also allograft, demineralized bone matrix, ceramic carriers, recombinant growth factors, and tissue engineering therapies.

The ideal bone graft substitute possesses three distinct properties: osteogenesis, osteoconduction, and osteoinduction. Osteogenic grafts contain osteoprogenitor or osteogenic precursor cells capable of directly forming bone. Osteoinduction is the mechanism whereby these precursor cells are stimulated to differentiate into mature osteoblasts, whereas osteoconductive materials provide a biocompatible physical structure or scaffold that supports the formation of new bone ( Table 17.1 ). One additional feature of bone grafts, which is more commonly discussed in maxillofacial surgery, is that of osseointegration. This refers to an implant’s ability to bind to bone without any intervening tissue. Surgeons should assess the biologic requirements of the respective fusion site and select a bone graft strategy based on these properties.

TABLE 17.1

Review of the Osteoinductive, Osteoconductive, and Osteogenic Properties of Various Bone Graft Substitutes and Extenders

Bone Graft	Osteoinductive	Osteoconductive	Osteogenic
Autograft	√	√	√
Allograft		√
DBM	√	√
Ceramic		√
rhBMP	√
Platelet		√
MSCs			√

DBM , demineralized bone matrix; MSCs, mesenchymal stem cells; rhBMP, recombinant human bone morphogenetic protein.

Autograft

Iliac crest autograft contains all three properties for bone formation and remains the gold standard for fusion procedures as it has a number of advantages. Depending on the procedure, it can be obtained anteriorly or posteriorly as well as through the same incision versus a separate incision. It is cost effective, readily available, and is biocompatible without risk of antigenicity. The main drawback of its use is related to donor site morbidity, which can include pain, paresthesias, hematoma, and infection with an incidence rate as high as 50% in some series. In one multicenter prospective study, Sasso et al. found that 31% of patients reported pain even at 2 years postoperatively, suggesting that the duration is not merely transient in many patients. Of note, there was no significant difference in pain scores when comparing posterior versus anterior harvest sites.

One alternative to iliac crest bone graft (ICBG) and its potential harvest-related complications is local autograft. This can be harvested from the spinous processes, lamina, and facets during both open and minimally invasive procedures. A systematic review of clinical studies demonstrated similar fusion rates when comparing local bone autograft with ICBG, 79% and 89%, respectively. One primary limitation of local autograft is the potential for volume constraints, particularly in single-level fusions. Sengupta et al. compared ICBG with local autograft in a retrospective review and found similar healing rates in one-level fusions; however, local bone autograft had a significantly lower fusion rate compared with ICBG in multilevel fusions, 20% vs. 66%, respectively ( P = .029). As a result, a number of bone graft extenders have subsequently been developed to remedy this volume-related limitation.

Allograft

Allograft, bone obtained from human donors, serves as an osteoconductive agent, providing a scaffold for bone formation. Allograft is processed and preserved through freeze-drying or freezing. The osteogenic potential of the graft is sacrificed as bone cells are eliminated during its processing which decreases the risk of disease transmission, antigenicity, and infection. Therefore, it is recommended that allograft should always be applied in conjunction with autograft or another osteoinductive agent in the lumbar spine. Nonetheless, allograft is incredibly versatile as it is available in multiple forms including powder, strips, bone chips, and cage-type formulations. Femoral ring allograft has historically been one of the most common materials utilized in anterior lumbar interbody fusions. Thalgott et al. compared freeze-dried with frozen allografts from a single manufacturer in a prospective, randomized study with a minimum follow-up of 24 months. Frozen grafts were cooled and stored at -70°C and dehydrated via lyophilization, whereas freeze-dried grafts were stored at room temperature. They found freeze-dried allografts more likely to break intraoperatively and were also more likely to require reoperation for pseudarthrosis ( P = .026). Over 85% of the revision surgeries were performed in the freeze-dried group; however, most of these patients were noted to be smokers. Despite this disparity, there was no difference in Oswestry disability index (ODI), Short Form-36 (SF-36), and pain scale scores.

Demineralized Bone Matrix

Demineralized bone matrix (DBM) is a bone graft extender developed from human cadaveric bone by means of acid extraction. This process results in a matrix containing a type I collagen framework in addition to a number of growth factors such as bone morphogenetic proteins, transforming growth factor-β (TGF-β), insulin-like growth factor, and fibroblast growth factor. These components make DBM both osteoinductive and osteoconductive. However, DBM comes in a variety of formulations with over 50 commercial DBM products available for use in the lumbar spine. Bae et al. evaluated the quantity of bone morphogenetic protein (BMP) in different products in addition to the variability of BMP in varying lots from the same manufacturer. Utilizing enzyme-linked immunosorbent assay, they identified BMP-2, BMP-4, and BMP-7. Both BMP-2 and BMP-7 were found in all DBM products in low concentrations (∼20 to 200 ng/g); however, BMP-4 was not detected in all samples. Additionally, the variability of BMP concentrations among different lots of the same DBM formulation was higher than the variability of concentrations among different DBM formulations.

Despite the questionable reliability of providing consistent osteoinduction, evidence in the literature supports the use of DBM as a bone graft extender in posterolateral lumbar spine fusion surgery. However, it should be noted that DBM lacks the structural stability needed for lumbar interbody fusion procedures and, in this setting, should be used in combination with a structural spacer. Thalgott et al. reported a 96% fusion rate in their series of 50 patients who underwent anterior lumbar interbody fusion with the use of titanium mesh cages, coralline hydroxyapatite, and DBM as part of a circumferential fusion.

Ceramics

Ceramic-based bone grafts are a type of synthetic graft with osteoconductive properties, supporting new bone ingrowth but lack any osteoinductive potential. They convey numerous advantages including nearly unlimited supply, easy sterilization, and lack immunogenicity as they are biologically inert and generally do not induce an inflammatory response. Drawbacks include their brittle structure and low tensile strength obviating the need for protection from excessive force until a solid fusion has occurred. Calcium sulfate is resorbed in only a few weeks after implantation and therefore should not be used as a scaffold in lumbar fusion surgery. Ideally, the scaffold should facilitate bony ingrowth and then resorb as the fusion develops. As a result, more commonly used compounds include β-tricalcium phosphate and hydroxyapatite. β-tricalcium phosphate is resorbed over a period of months, making it more suitable for use in lumbar spine fusions, whereas hydroxyapatite is resorbed over the course of years. In a recent systematic review with a collective population of 1332 patients, ceramics demonstrated an overall fusion rate in the lumbar spine of 86.4%. All interbody fusion studies reviewed included posterior instrumentation and were subsequently grouped together as circumferential fusions, which included anterior, posterior, and transforaminal techniques. The overall fusion rate for interbody fusions was not statistically different from the posterolateral technique, 88.8% versus 85.6%, respectively ( P = .64). This review suggests that ceramic-based scaffolds are an effective bone graft extender in each of these techniques; however, variability in assessing fusion status and the number of included patients may have led to the lack of difference between the two groups.

Bone Morphogenetic Proteins

Bone morphogenetic proteins belong to the TGF-β superfamily of growth factors. They act through serine-threonine kinase receptors and transduce their signal via the SMAD pathway ( Fig. 17.1 ). This subsequently results in the induction of bone formation through the differentiation, maturation, and proliferation of mesenchymal precursor cells into osteogenic cells. More than 20 types are described; however, only 2 commercial forms are available for clinical use: recombinant human bone morphogenetic protein-2 (rhBMP-2; Infuse) and rhBMP-7 (OP-1). The family of proteins were first discovered by Dr. Marshall Urist in 1965, but not until 2002 did the US Food and Drug Administration (FDA) approve their utilization clinically. Specifically, the use of rhBMP-2 is currently approved as a component of a titanium cage for anterior lumbar interbody fusion. Despite this single FDA-approved indication, rhBMP-2 is frequently used for a number of off-label applications, including posterolateral spine fusions, posterior lumbar interbody fusions, transforaminal lumber interbody fusions, and cervical spine procedures. Only two commercial forms of recombinant BMP are available for clinical use: rhBMP-2 (Infuse) (Medtronic, Memphis, TN) and rhBMP-7 (OP-1) (Stryker, Kalamazoo, MI). These proteins are water-soluble and are rapidly diffused from the surgical site when used independently. As a result, matrix carriers or scaffolds are required to decrease diffusion away from the desired site of application. The most common carrier currently utilized is a type-1 absorbable collagen sponge. It is deformable and can be easily inserted into a cage for interbody fusions. In 2002, Burkus et al. reported their results in an FDA-regulated, multicenter prospective randomized study of 279 patients who underwent anterior lumbar interbody fusion using two tapered titanium threaded fusion cages. The rhBMP-2 group showed a statistically significant improvement in clinical outcomes, including back and leg pain scores as well as the ODI. Additionally, 32% of patients in the ICBG group reported graft site discomfort at 2-year follow-up. In a systematic review, Galimberti et al. also echoed favorable results for rhBMP-2 in anterior lumbar interbody fusion procedures, showing a significant improvement in fusion rates. However, they did not find any statistically significant improvement in fusion rates in posterior lumbar interbody fusion and transforaminal lumbar interbody fusion procedures. It should be noted that these conclusions are limited by the heterogeneity of rhBMP-2 dosing and varying levels of evidence.