Abstract
An estimated 200,000 spinal fusion are performed in the United States on annually for a large range of pathologic conditions. The goal of spinal fusion is to restore or enhance spinal stability by establishing bony union between two or more vertebrae. Pseudoarthrosis, failure of spinal fusion, can lead to persistent symptoms and disability, often requiring revision surgery. The biology of spinal fusion is a complex process involving steps similar to bone healing after fracture. Multiple technique are utilized to enhance the success of spinal fusion, including stabilization with metallic or polymeric implants, grafting with bone products, and augmentation with a variety of biologic agents. Bone grafts utilized can be autologous or allogenic and are often manipulated to remove mineral content and/or maintain a cell population to enhance fusion. Synthetic biologics products are generally composed of ceramic or bioactive glass. Recombinant growth factors, most commonly bone morphogenic protein-2, are potent stimulator of bone formation, but may a have significant risk profile. Research is currently underway to develop biologic treatment to prevent or reverse intervertebral disc degeneration and may obviate the need for spina fusion in the future.
Keywords
disc degeneration, Ðpondylolisthesis, intervertebral disc, Spinal fusion, spine surgery
Introduction
As the medical community has developed a greater understanding of the critical steps necessary for tissue healing, biologics, both natural and synthesized, have become an important adjunct to many orthopedic procedures. Much research is underway to devise biologic strategies to repair or prevent many pathologies of the vertebral column. However, currently the most widely used application for biologics in spinal surgeries is to improve the success of spinal fusion. Spinal fusion procedures are performed for a variety of reasons including degenerative conditions, deformity, trauma, and tumors. There are estimates of up to 200,000 fusion procedures performed in the United States annually. According to a retrospective cohort study, rates of lumbar spine fusion alone have increased upward of 220% from 1990 to 2001. The goal of spinal fusion surgery is to augment or restore spinal stability by achieving solid bony union between two or more vertebral motion segments. Fusion procedures generally provide temporary mechanical support with implants and initiate the biological process necessary for osseous growth and eventual long-term stability. Failure of this process, referred to as a pseudoarthrosis, can result in persistent pain, loss of deformity correction, and eventual mechanical failure of the fusion construct.
The biology of spinal fusion is a complex process with steps similar to what occurs in natural bone fracture healing. However, in the case of fusion, the goal is to achieve bone growth in an environment not originally developed for this purpose, i.e., the disc space or the intertransverse space. Therefore modification of the biologic microenvironment is necessary to stimulate the bone growth process. This augmentation is often achieved with combination of enhanced mechanical stability with metallic or polymeric implants and the addition of graft material and biologic agents that function through osteoconductive, osteoinductive, and/or osteogenic mechanisms. ( Fig. 15.1 ) These three essential mechanisms are necessary for the integration of the graft material and host bone. Biologic agents with osteoconductive properties provide a structural scaffold or framework that is conducive to cellular growth and tissue formation. Osteoinductive agents facilitate the recruitment of immature cells and stimulate their transformation into bone-forming cells that can effect de novo bone formation. Finally, osteogenic materials contain live bone-forming cells that can be implanted for bone regeneration. In addition, an adequate vascular supply to allow for the migration of stem cells and nutrients to the fusion site is of paramount importance for successful fusion to occur. Furthermore, the environment required needs to be a low-strain environment with mechanical stability to prevent excessive strain and adverse effects on the bone formation process. Osteogenic signals, such as growth factors, are needed for the stem cells to proliferate, recruit, and differentiate in a conducive microenvironment for new bone formation. The end product is replacement of the grafted bone with a new bone matrix that can endure the physiologic loads applied to the spine during normal activities of daily living.
Despite our improved understanding of the mechanisms underlying bone healing and modern surgical techniques and technologies, failure of spine fusion is not uncommon with rates of up to 17% in primary fusion surgeries performed in adult populations. Augmentation with biologics provides an additional strategy to limit the rate of pseudoarthrosis by acting to alter the environment and making it more conducive for osteogenesis.
Bone Grafting
Use of bone grafts to augment healing is one of the most common adjuncts to many orthopedic procedures, with greater than 500,000 grafting procedures performed annually in the United States. The rationale for the use of bone graft is to stimulate bone healing by osteoconduction and, depending on the type of graft used, potentially provide osteogenic and/or osteoinductive properties. Bone grafting options can be divided into autograft, allograft, and synthetic grafts. A variety of graft types and material are available; however, the ideal graft should have low immunogenicity, have desirable biologic activity, bioresorbability, and bioconductivty, and be cost-effective.
Autograft Bone
Autograft is considered the gold standard as it provides all three essential properties (osteogenic, osteoconductive, and osteoinductive) required for new bone formation and is easily integrated in the host bone. Autografts are divided into three types: cancellous, cortical, and vascularized cortical grafts. Cancellous grafts provide an abundance of cells for bone regeneration, whereas cortical grafts provide enhanced mechanical and structural integrity.
Iliac crest is one of the most frequently used and favored bone graft harvest sites. The site is easily accessible and provides a graft with excellent bone quality and quantity. Iliac crest bone graft possesses all three essential properties needed for bone regeneration. Studies have demonstrated fusion rates as high as 93% with the use of iliac crest bone graft. However, donor site morbidity including infection, chronic pain, scarring, and propagation of a fracture at harvest site, can occur with complications ranging from 10% to 39%. To avoid the complications of donor site morbidity, local bone autograft can be obtained from various sites such as the spinous processes, lamina, and facet joints, often removed during spinal canal decompression at the time of fusion surgery. Obtaining local bone graft avoids the complications of another site surgery and reduces surgical time as no additional surgical exposure time is required. Fusion rates are as high as 80% with the use of local graft, and in some studies it has been quoted to be equivalent to iliac crest bone graft.
Cancellous grafts are the most common autografts used and provide excellent osteoconductivity allowing for bone growth. Harvesting cortical and/or corticocancellous grafts results in greater morbidity due to the increased surgical exposure required; however, these grafts provide the advantage of immediate load sharing secondary to their structural integrity. As demonstrated by Enneking et al., cortical bone grafts lose significant strength around 6 weeks secondary to bone remodeling; however, they recover by about 1 year. The use of vascularized cortical bone grafts can counteract the loss of strength secondary to remodeling as a vascular pedicle is anastomosed to the graft at the fusion site, thus providing vascular supply needed for osteointegration. Use of a vascularized cortical graft is beneficial for bridging large bony defects; however, there is a significant increase in the operative time and is a very technically demanding procedure requiring larger surgical exposure and potential for increased donor site morbidity. Thus it is not a technique often used in spinal surgery.
Allograft Bone
Allogenic bone graft, harvested from another human, is another common adjuvant to spinal fusion. Use of an allograft is advantageous as it avoids the complications of donor site morbidity, readily available, and able to provide bone graft in varying forms and large quantity. Although all allografts have osteoconductive properties, the osteoinductivity of various grafts is highly dependent on preparation and sterilization techniques. Allografts, however, have an inherent weakness in that they are costly and tend to have a slower osteointegration rate, increased resorption, and infection risk as compared to autografts. Allografts can be broadly categorized into fresh or processed, with fresh allografts being transplanted immediately after procurement and processed allografts being generally treated and then stored to be available for transplantation at a later time point. The form of allograft used can be dependent on the function or application anticipated for the graft. Immunogenicity is a concern while using allograft as cell surface antigens present on the allograft can entice an adverse immune response and result in rejection. The immunogenicity of the graft can be tailored during allograft processing via immunosuppression, histocompatibility matching, freeze-drying, or fresh-freezing. The freeze-dried allografts are the least immunogenic, and fresh vascularized composite grafts are the most immunogenic.
Bone graft extenders are a form of allografts that are used as viable substitutes, with the most common being demineralized bone matrix (DBM). DBM is prepared via an elaborate process involving harvesting and cleaning of cortical bone that is subsequently ground and demineralized through acid extraction, generating a noncollagenous proteinaceous product with varying levels of osteoinductive cytokines. When present, these cytokines are released during the demineralization process and act on various cellular cascades to promote bone repair and regeneration. The DBM can be combined and modified with various different carriers depending on its application and is commercially available in powder, granule, putty, gel, or chips form. DBM is one of the least immunogenic allografts, and studies have shown induction of new bone formation in animal fusion models.
Cellular Allograft
In recent years, processed cellularized allografts have come to market in an effort to increase the efficacy of allograft bone. These products are processed to remove immunogenic cells while retaining mesenchymal stem cells within a demineralized matrix and are designed to simulate human autograft bone and promote bone regeneration while avoiding the complications associated with harvesting autograft. The cellular allografts have the three essential properties (osteogenic, osteoconductive, and osteoinductive) needed for bone regeneration as they contain mesenchymal stem cells, DBM, and cancellous bone. Osteocel Plus (Nuvasive, San Diego, CA), a minimally modified human allograft, is one of the most well-studied products in this category and has been demonstrated to contain viable cells capable of self-renewal and multipotential differentiation. Tomeh et al. conducted a radiographic and clinical outcome study in patients who had an extreme lateral interbody fusion with Osteocel Plus and demonstrated a 90.2% complete interbody fusion with the remaining 9.8% being partially consolidated and progression toward fusion. Ammerman et al. conducted a retrospective chart review on patients undergoing a minimally invasive transformational lumbar interbody fusion with Osteocel Plus and demonstrated that 91.3% of the patients were able to achieve bony arthrodesis by 12 months.
Trinity Evolution (Orthofix, Lewisville, TX) is another cellular allograft designed as an alternative to autograft. It contains supraphysiologic concentrations of mesenchymal stem cells in a cancellous bone matrix and a demineralized bone component. It had been studied with positive results demonstrated in the foot and ankle surgery. Bio4 (Stryker, Mahwah, NJ) is another cellular allograft that is angiogenic in addition to being osteoconductive, osteoinductive, and osteogenic. It contains mesenchymal stem cells, osteoprogenitor cells, osteoblasts, and osteoinductive and angiogenic growth factors, making it a theoretically attractive choice for an allograft; however, clinical efficacy has not yet been demonstrated in the literature.
Synthetic Grafts
Ceramics
Ceramic compounds are an often-used substitute for both autogeneic and allogeneic bone graft and have several properties that promote osteogenesis. These products are categorized into three types: sintered, replamiform, and collagen mesh. Sintered ceramics are synthetic porous compounds made of hydroxyapatite. Although the ability to mass produce synthetic sintered ceramics is advantageous, these compounds do not have the interconnectivity seen in trabecular bone. Conversely, replamiform ceramics, made from sea coral, have more structural similarity to bone. All ceramics serve an osteoinductive role allowing for bone repair and regeneration. They do not generate an inflammatory response; however, ceramics may lead to formation of a seroma secondary to a nonimmune inflammatory response. Yuan et al. investigated the osteogenic potential of porous ceramic materials and demonstrated that after implantation in a large bone defect in sheep, the porous ceramic materials led to equally efficient bone repair as autologous bone graft.
Bioactive Glass
Bioactive glasses are another alternative to autografts which have gained significant interest in recent years. In particular, bioactive glass 45S5 and Bioglass were composed of 46.1 mol% SiO 2 , 24.4 mol% Na 2 O, 26.9 mol% CaO, and 2.6 mol% P 2 O 5 . This is now sold and known as PerioGlas (Novabone, Alachua, FL). It is osteoconductive with significant initial mechanical strength as compared to other grafts types. When first created by Hench, it was found to form a strong bond with bone. lharreborde et al. investigated bioactive glass in a comparative study with iliac crest bone graft as a bone graft substitute for the treatment of idiopathic scoliosis. The study demonstrated that bioactive glass was indeed as effective as iliac crest bone graft in achieving fusion and maintaining correction, thus, being a viable bone graft alternative for spinal fusion. Bioactive glass has also been combined with ceramics, in products such as Vitoss BA (Stryker, Mawah, NJ), to take advantage of the favorable properties of both materials.
Growth Factors
Growth factors have been among the most extensively studied biologics in spine surgery to promote successful fusion and prevention of a pseudoarthrosis. Of particular interest, bone morphogenetic proteins (BMPs) have been studied at length in spine fusion due to their substantial osteoinductive properties. BMPs were initially discovered by Marshall Urist in 1965. They belong to the transforming growth factor β (TGF-β) superfamily and play an important role in postnatal bone development. BMPs are important in recruiting mesenchymal stem cells and stimulating their differentiation into osteoblasts. BMPs act upon cell membrane receptors to activate various intracellular signaling cascades resulting in target gene expression and ultimately bone matrix formation.
Concentrations of BMPs and BMP receptors are upregulated and play a vital role in fracture healing and bone formation. Studies of the use of BMPs for spinal fusion have shown excellent fusion rates and have been marketed as a stand-alone product to promote the proliferation of mesenchymal stem cells and formation of osteoprogenitor cells, resulting in bone remodeling and formation. Recombinant BMP-2 (rhBMP-2), marketed as INFUSE (Medtronic, Minneapolis, Mn), has been approved by the FDA for use in anterior lumbar interbody spine fusions; however, it has been widely used in an off-label capacity for a variety of other spinal fusion techniques. In its current formulation, a supraphysiologic extremely high loading dose of rhBMP-2 is required for bone formation, which can result in variety of adverse side effects. The nature of these side effects could not be predicted initially as rhBMP-2 acted on a number of different physiological pathways leading to a wide variety of adverse events including tissue reaction, osteolysis, ectopic bone formation, bony overgrowth, systemic toxicity, and inflammation. Although initial clinical studies demonstrated the positive effects of rhBMP-2 on inducing bone formation, study design biases were later discovered which brought several safety concerns to the forefront. The studies were industry funded and shared similar findings with regards to safety, reporting a very low risk of adverse events. This perceived absence of a significant incidence of complications led to a widespread use of rhBMP-2 for spine arthrodesis, rising from use in 0.7% of spinal fusions after its FDA approval in 2002 to 25% in 2006 in the United States. After the widespread use of both on-label and off-label applications, a wide array of complications were seen ( Fig. 15.2 ) and led to investigations of original studies reporting minimal complications. These complications included neck and soft tissue swelling, injury to neurological structures, dysphagia requiring intubation, antiinflammatories, tracheostomy, and additional surgeries.
Carragee et al. conducted a systematic review evaluating the safety concerns with the use of rhBMP-2 in spine surgery. The use of rhBMP-2 was investigated in posterolateral lumbar fusion, and Boden et al. demonstrated greater leg pain, inferior early functional outcome scores, and wound complications in the rhBMP-2 group versus iliac crest bone graft. Review of the Scoliosis Research Society database by Williams et al. revealed a 500% higher rate of wound complication and epidural hematoma with the use of rhBMP-2 and posterior approach. Vaidya et al. revealed a significant graft subsidence rate in patients undergoing Anterior lumbar interbody fusion (ALIF) with rhBMP-2. Carragee et al. demonstrated greater subsidence and higher rate of reoperation in patients with use of rhBMP-2 with interbody fusion versus allograft. Other studies demonstrated retrograde ejaculation rates of 5%–7% in male patients undergoing ALIF surgery with rhBMP-2, rates which were greater than those in the original published studies. Osteolytic defects associated with the use of rhBMP-2 are common and have led to bone loss, implant migration, and kyphosis secondary to bone collapse. Incidence as high as 56% has been demonstrated with very low resolution at long-term follow-up. Use of BMPs and their association with development of neoplasms has been questioned and studied at length. Thawani et al. performed a review of the literature on BMPs and neoplasms in which there was no definitive association noted between the use of BMPs and promotion of neoplasm. Even though there was no definitive association, they did recommend practicing caution against widespread use.
The high-dose rhBMP-2 formulation (AMPLIFY, Medtronic) used for posterolateral fusion in lumbar spine was initially noted to have no adverse events. However, a recent FDA Executive Summary revealed major back pain and leg pain in the AMPLIFY group at 4 and 8 weeks after surgery, and as a result, the product is not commercially available. Despite the identified risks, rhBMP is still currently in use as an adjunct to spinal fusion, especially in patients with physiology which may reduce their chance of successful fusion. Most surgeons will limit the use to the lowest dose possible as this may reduce the risk of complications; however, data to support this hypothesis are not currently available.
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