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Biologics in Spinal Fusion
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.
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