Bone Graft Substitutes for the Promotion of Spinal Arthrodesis
In the prototypical method for inducing spinal fusion, autologous bone graft is harvested from the iliac crest or local bone removed during the spinal decompression. Although autologous bone remains the "gold standard" for stimulating bone repair and regeneration, modern molecular biology and bioengineering techniques have produced unique materials that have potent osteogenic activities. Recombinant human osteogenic growth factors, such as bone morphogenetic proteins, transforming growth factor, and platelet-derived growth factor are now produced in highly concentrated and pure forms and have been shown to be extremely potent bone-inducing agents when delivered in vivo in rats, dogs, primates, and humans. The delivery of pluripotent mesenchymal stem cells (MSCs) to regions requiring bone formation is also compelling, and it has been shown to be successful in inducing osteogenesis in numerous preclinical studies in rats and dogs. Finally, the identification of biological and nonbiological scaffolding materials is a crucial component of future bone graft substitutes, not only as a delivery vehicle for bone growth factors and MSCs but also as an osteoconductive matrix to stimulate bone deposition directly. In this paper, the currently available bone graft substitutes will be reviewed and the authors will discuss the novel therapeutic approaches that are currently being developed for use in the clinical setting.
A variety of internal fixation techniques can be used in most patients to achieve immediate spinal stability; however, long-term stability typically requires bone fusion of the involved region. A solid bone fusion is usually achieved after placement of autologous or allogenic bone grafts, each of which has specific advantages and disadvantages. Although autologous bone is the "gold standard" graft material, donor-site morbidity (pain, infection), limited supply, and inconsistent osteogenic activity continue to be associated problems. Allogenic bone grafts are significantly less osteogenic than autologous bone, mainly because allogenic bone typically acts only as a passive scaffold for vascular ingrowth and bone deposition. Because of these limitations, basic science and clinical researchers are aggressively developing biosynthetic bone grafts as an alternative to autologous and allogenic bone grafts. Research has also focused on defining the physiological mechanisms involved in bone repair and regeneration. These mechanisms have only been partially elucidated but appear to involve complex interactions between a variety of different angiogenic and osteogenic growth factors, ECM proteins, and pluripotent MSCs. Typical biosynthetic bone grafts rely on one, or a combination, of these components of the osteogenic cascade for their activity.
The three processes by which bone can be repaired or regenerated are osteoinduction, osteoconduction, and osteogenesis. Osteoinduction is defined as the ability to stimulate the proliferation and differentiation of pluripotent MSCs. In endochondral bone formation, stem cells differentiate into chondroblasts and chondrocytes, laying down a cartilaginous ECM, which subsequently calcifies and is remodeled into lamellar bone. In intramembranous bone formation, the stem cells differentiate directly into osteoblasts, which form bone through direct mechanisms. Osteoinduction can be stimulated by osteogenic growth factors, although some ECM proteins can also drive progenitor cells toward the osteogenic phenotype. Osteoconduction is defined as the ability to stimulate the attachment, migration, and distribution of vascular and osteogenic cells within the graft material. The physical characteristics that affect the graft's osteoconductive activity include porosity, pore size, and three-dimensional architecture. In addition, direct biochemical interactions between matrix proteins and cell surface receptors play a major role in the host's response to the graft material. The ability of a graft material to produce bone independently is termed its direct osteogenic potential. To have direct osteogenic activity, the graft must contain cellular components that directly induce bone formation. For example, a collagen matrix seeded with activated MSCs would have the potential to induce bone formation directly, without recruitment and activation of host MSC populations. Because many osteoconductive scaffolds also have the ability to bind and deliver bioactive molecules, their osteoinductive potential will be greatly enhanced.
In the prototypical method for inducing spinal fusion, autologous bone graft is harvested from the iliac crest or local bone removed during the spinal decompression. Although autologous bone remains the "gold standard" for stimulating bone repair and regeneration, modern molecular biology and bioengineering techniques have produced unique materials that have potent osteogenic activities. Recombinant human osteogenic growth factors, such as bone morphogenetic proteins, transforming growth factor, and platelet-derived growth factor are now produced in highly concentrated and pure forms and have been shown to be extremely potent bone-inducing agents when delivered in vivo in rats, dogs, primates, and humans. The delivery of pluripotent mesenchymal stem cells (MSCs) to regions requiring bone formation is also compelling, and it has been shown to be successful in inducing osteogenesis in numerous preclinical studies in rats and dogs. Finally, the identification of biological and nonbiological scaffolding materials is a crucial component of future bone graft substitutes, not only as a delivery vehicle for bone growth factors and MSCs but also as an osteoconductive matrix to stimulate bone deposition directly. In this paper, the currently available bone graft substitutes will be reviewed and the authors will discuss the novel therapeutic approaches that are currently being developed for use in the clinical setting.
A variety of internal fixation techniques can be used in most patients to achieve immediate spinal stability; however, long-term stability typically requires bone fusion of the involved region. A solid bone fusion is usually achieved after placement of autologous or allogenic bone grafts, each of which has specific advantages and disadvantages. Although autologous bone is the "gold standard" graft material, donor-site morbidity (pain, infection), limited supply, and inconsistent osteogenic activity continue to be associated problems. Allogenic bone grafts are significantly less osteogenic than autologous bone, mainly because allogenic bone typically acts only as a passive scaffold for vascular ingrowth and bone deposition. Because of these limitations, basic science and clinical researchers are aggressively developing biosynthetic bone grafts as an alternative to autologous and allogenic bone grafts. Research has also focused on defining the physiological mechanisms involved in bone repair and regeneration. These mechanisms have only been partially elucidated but appear to involve complex interactions between a variety of different angiogenic and osteogenic growth factors, ECM proteins, and pluripotent MSCs. Typical biosynthetic bone grafts rely on one, or a combination, of these components of the osteogenic cascade for their activity.
The three processes by which bone can be repaired or regenerated are osteoinduction, osteoconduction, and osteogenesis. Osteoinduction is defined as the ability to stimulate the proliferation and differentiation of pluripotent MSCs. In endochondral bone formation, stem cells differentiate into chondroblasts and chondrocytes, laying down a cartilaginous ECM, which subsequently calcifies and is remodeled into lamellar bone. In intramembranous bone formation, the stem cells differentiate directly into osteoblasts, which form bone through direct mechanisms. Osteoinduction can be stimulated by osteogenic growth factors, although some ECM proteins can also drive progenitor cells toward the osteogenic phenotype. Osteoconduction is defined as the ability to stimulate the attachment, migration, and distribution of vascular and osteogenic cells within the graft material. The physical characteristics that affect the graft's osteoconductive activity include porosity, pore size, and three-dimensional architecture. In addition, direct biochemical interactions between matrix proteins and cell surface receptors play a major role in the host's response to the graft material. The ability of a graft material to produce bone independently is termed its direct osteogenic potential. To have direct osteogenic activity, the graft must contain cellular components that directly induce bone formation. For example, a collagen matrix seeded with activated MSCs would have the potential to induce bone formation directly, without recruitment and activation of host MSC populations. Because many osteoconductive scaffolds also have the ability to bind and deliver bioactive molecules, their osteoinductive potential will be greatly enhanced.
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