This response appears to be highly sensitive to the timing and dosage, as there are also many reports of the anti-angiogenic effects of TNF. In the case of bone, TNF has been shown to improve bone fracture healing in vivo and osteogenic differentiation of stem cells in vitro. The current study aims to understand whether TNF may benefit the development and maintenance of vascular networks within engineered osteogenic tissue. In particular, we study the effects of TNF dose and timing, as well as its combined effects with PDGF. In addition, we generate osteogenic grafts within composite scaffolds to study tissue maturation and integration in vivo. We demonstrate that recapitulating the biochemical environment within normal bone healing cascades through the inclusion of the inflammatory mediator TNF improves vascularization of tissue engineered osteogenic grafts. PDGF is a key regenerative cue that is released by activated platelets following bone injury, raising the question of how other elements of normal bone repair may affect bone tissue engineering. Immediately following bone injury, there is an acute inflammatory phase in which activated platelets and macrophages release a host of factors, CWHM-12 including PDGF and pro-inflammatory cytokines. These factors play a critical role in the initiation of healing through the recruitment and activation of regenerative cells, as well as promoting re-vascularization. While normally thought of as intrinsically damaging to tissue repair, proinflammatory cytokines such as tumor necrosis factor-a have been shown to promote tissue-healing processes in some cases. For example, exogenously applied TNF has been shown to promote angiogenesis in vivo and in vitro by inducing the endothelial tip cell Monastrol phenotype. Bone is a resilient tissue that has the potential to fully heal itself after moderate injuries. When this happens, normal healing progresses towards full recovery through a tightly regulated cascade of inflammation, cellular and vascular recruitment, and a complex host of signaling molecules.