Neurosurg Focus 14 (2):Article 8, 2003, Click here to return to Table of Contents Bone grafting GREGORY J. ZIPFEL, M.D., BERNARD H. GUIOT, M.D., AND RICHARD G. FESSLER, M.D., PH.D. Department of Neurosurgery, University of Florida, Gainesville, Florida; Rocky Mountain Neurosurgical Alliance, Aurora, Colorado; and Section of Neurosurgery, University of Chicago, Chicago, Illinois In recent years our understanding of spinal fusion biology has improved. This includes the continued elucidation of the step-by-step cellular and molecular events involved in the prototypic bone induction cascade, as well as the identifi- cation and characterization of the various critical growth factors governing the process of bone formation and bone graft incorporation. Based on these fundamental principles, growth factor technology has been exploited in an attempt to improve rates of spinal fusion, and promising results have been realized in preclinical animal studies and initial clinical human studies. In this article the authors review the recent advances in the biology of bone fusion and provide a per- spective on the future of spinal fusion, a future that will very likely include increased graft fusion rates and improved patient outcome as a result of the successful translation of fundamental bone fusion principles to the bedside. KEY WORDS • bone graft • spinal fusion • bone morphogenetic protein • bone graft Spinal fusion is a critical element in many spinal pro- BONE FORMATION cedures. The incidence of nonunion ranges from 5 to 7,8,20,38 A firm grasp of the two different embryonic modes of 35%, and failed spinal fusions are a significant con- osteogenesis is critical in understanding the biological tributor to the morbidity associated with spinal surgery. In principles of bone graft incorporation and spinal fusion. recent years our understanding of spinal fusion biology As illustrated by these two models, bone always develops has improved, including the identification and characteri- by the replacement of preexisting connective tissue. Both zation of various local and systemic growth factors. This modes of ossification are likely involved in spinal fusion, argues well for improved spinal fusion rates in the future. as will be described. Investigators of recent in vivo studies have shown the util- ity of this growth factor technology in multiple spinal Intramembranous Ossification 3,24,32,34 fusion models, thus underscoring its bright future. Intramembranous ossification is bone formation pro- The aim of this article is to describe and illustrate the duced by the direct differentiation of mesenchymal cells chronology of events occurring during the incorporation into osteoblasts. There is no cartilage intermediate. Cer- of bone grafts into a stable spinal fusion. First, the crucial tain flat bones of the skull and part of the mandible de- topics of bone formation, bone graft physiology, and typ- velop in this manner. Initially, the primitive mesenchymal ical bone graft options are reviewed. Second, the step-by- cells condense into a rich, vascularized layer of connec- step cellular and molecular events involved in the pro- tive tissue. The cells are embedded in an extracellular totypic bone induction cascade are delineated. Third, a matrix composed of fine bundles of collagen fibrils and a lumbar spinal fusion animal model is sequentially de- gellike ground substance composed of proteoglycans. A scribed, illustrating the bone induction cascade as it relates trabeculated pattern of early bone matrix is then produced, to the clinically relevant setting of spinal fusion. Finally, concurrent with the differentiation of primitive mesenchy- conclusions are drawn regarding the potential application mal cells into osteoblasts. Maturation of the bone matrix of bone fusion principles, particularly the use of growth occurs through cellular synthesis and secretion of bone factors, in the clinical setting of spinal fusion. matrix components such as collagen, producing thickened and lengthened trabeculae. Shortly thereafter, the bone Abbreviations used in this paper: BMP = bone morphogenetic matrix becomes the site of calcium phosphate deposition protein; DBM = demineralized bone matrix; PDGF = platelet- in the form of hydroxyapatite crystals. The trabeculae derived growth factor; PMNL = polymorphonuclear leukocyte; continue to thicken during this mineralization process and TGF = transforming growth factor; TP = transverse process. ultimately sequester the osteoblasts in lacunae, forming Neurosurg. Focus / Volume 14 / February, 2003 1 Unauthenticated | Downloaded 09/30/21 11:13 AM UTC G. J. Zipfel, B. H. Guiot, and R. G. Fessler osteocytes. In those areas destined to become compact motaxis of host mesenchymal cells to the graft site. There- bone, the trabeculae continue to thicken, eventually adopt- after, the primitive host cells differentiate into chondro- ing a lamellar pattern of organization (not true lamellar blasts and osteoblasts, a process under the influence of bone, however). In those areas destined to become spongy various osteoinductive factors. The additional processes bone, the trabeculae stop thickening and hemopoietic tis- of bone graft revascularization and necrotic graft resorp- sue develops.36 tion occur concurrently. Finally, bone production from the osteoblasts onto the graft’s three-dimensional framework Endochondral Ossification occurs, followed by bone remodeling in response to mech- 11 Endochondral ossification involves bone formation anical stress. through a cartilage intermediate and is by far the most An ideal bone graft would provide all elements required common mechanism of primary bone formation. The during these phases of graft incorporation and lend struc- skull base, vertebral column, pelvis, and extremities are tural support during the process. This ideal graft would formed in this manner. Initially, a hyaline cartilage model possess the following: 1) an osteoconductive matrix that develops, which subsequently undergoes a highly specific provides a nonviable three-dimensional framework amen- maturation process in preparation for its replacement by able to the ingrowth of blood vessels and osteoprogenitor bone. This maturation initially involves the hypertrophy cells required for bone formation; 2) osteoinductive fac- of chondrocytes, which impinges upon the intervening tors that recruit the recipient’s mesenchymal cells through osseous matrix leading to matrix erosion. The cartilage chemotaxis and then induce or modulate bone formation; matrix that remains then mineralizes, a crucial prerequi- 3) osteogenic cells that are graft cells with the potential to differentiate into osteoblasts; and 4) structural integrity site step in the replacement of cartilage by bone. Even- 10 tually, the chondrocytes regress and die, and blood ves- that provides mechanical support to the spinal fusion. sels, carrying primitive mesenchymal stem cells in their Many bone graft types are available to the spine surgeon perivascular tissue, invade the calcified cartilage model. today, and each possesses some of the aforementioned These stem cells populate the calcified cartilage and then properties. The surgeon’s choice of graft material depends differentiate into osteoblasts or hemopoietic tissue. The greatly on which of the four elements are most crucial to osteoblasts congregate on the calcified cartilage trabecu- the particular surgical application. For example, an inter- lae and deposit bone matrix, a process that forms early tra- body graft site would require structural integrity, whereas beculae composed of a calcified cartilage core and outer an intertransverse process graft site would place more osseous layer. The deposition of bone matrix continues, emphasis on the osteogenic and osteoinductive properties producing thickened and lengthened osseous trabeculae. of a graft. The osseous matrix deposition either continues and forms cortical bone or halts and forms cancellous bone with BONE GRAFT TYPES 36 intermixed hemopoietic tissue. Various bone graft types including autografts, allo- Bone Remodeling grafts, synthetic grafts, and others have been characterized and applied clinically. Of these, the most effective is that Bone remodeling is the replacement of primary bone of the autologous cancellous variety, which possesses (formed through intramembranous or endochondral ossi- three of the four primary graft elements (Table 1). First, it fication) by more precisely ordered lamellar or secondary has a collagen and hydroxyapatite osteoconductive frame- bone, referred to as definitive haversian systems. At var- work that is superior to all other graft types. Second, its ious sites in primary bone, osteoclast-produced bone re- stroma is populated with various cells with osteogenic po- sorption occurs and forms cavities. As this resorption pro- tential. Third, many osteoinductive factors including the gresses, long cylindrical cavities housing blood vessels fundamental BMPs are found within this graft. The autol- and embryonic bone marrow develop. Eventually the ogous cortical bone graft has a more limited osteoconduc- resorption ceases and osteoblastic activity takes over. The tive, -inductive, and -genic profile than cancellous grafts, osteoblasts produce concentric lamellae of bone in the but it has the attractive feature of providing initial stabili- walls of the cavity producing a typical osteon. These pre- ty to the spinal fusion. Finally, the autologous vascular- cisely organized lamellar osteons of secondary bone even- ized free