Bone is a highly vascularized tissue and, under normal circumstances, even large defects heal with bone because of the local supply of mesenchymal stem cells within the bone marrow environment and the presence of osteoinductive agents within the bone matrix. In addition, factors released at the wound site or present within the hematoma enhance osteogenesis by recruiting progenitor cells and stimulating their proliferation and differentiation. When this process becomes dysregulated, either because of the size of the defect or because of other host-dependent factors, some form of bone tissue engineering may be necessary. Addition of multipotent autologous cells, such as those in bone marrow, and the addition of autologous bone as a structural element provide the optimal therapeutic approach. Often one or both of these are in limited supply and alternative approaches are needed. The lessons learned from the authors' study of DFDBA-induced bone formation illustrate those features of osteogenesis that may confound the use of tissue engineering strategies. • The behavior of material may be different orthotopically and heterotopically. Factors that promote osteoinduction in muscle likely are effective in a bone site, but those factors that inhibit osteoinduction may have usefulness orthotopically as long as the site is not overly compromised. • Simply adding a growth factor or cell attachment ligand may be sufficient in fresh fractures in healthy rats but may not be effective in patients, especially when confounding variables are present, in particular those involving age and pharmacology. • The rate of graft resorption may be a critical variable depending on the intended use of a material and should be considered when designing any kind of bone graft substitute. • Each bioactive factor acts through a distinct mechanism that influences its relative function when used clinically. Understanding those mechanisms is important when selecting a material for a specific application.
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