As implantation of biomaterials is performed under sterile surgical these conditions the environment at the implantation site is expected to contain only few pathogen associated molecular patterns (PAMPs) but to be enriched on damage associated molecular patterns (DAMPs). These signals activate tissue cells and resident immune cells to release inflammatory cytokines, chemokines and proteins which determine the monocyte to macrophage differentiation outcome.14,15 The complex interplay of these mediators resulting in monocyte differentiation and macrophage activation thought to occur under conditions of sterile tissue injury is illustrated in Figure 1. It is suggested that these chemokines and cytokines are sequentially and differentially released to promote phase-specific infiltration and activation of leukocyte subsets during the healing response.
16 A study of wound healing of adult skin demonstrated that monocyte infiltration peaks at day two of the healing response and is paralleled by strong MCP-1 expression in the wound area.17 Besides MCP-1, which is crucial for the attraction of monocytes, inflammatory cytokines like interferon �� (IFN��), tumor necrosis factor �� (TNF��), IL-1�� and IL-6 regulate monocyte differentiation and macrophage activation in the early phase of inflammation during wound repair.18-20 Activated lymphocytes and natual killer cells are a major source of IFN��, which has pleiotropic effects on monocytes and macrophages. An essential involvement of IFN�� in the wound healing process has been demonstrated by Ishida et al.
20 They detected IFN�� in sterile wounds 3 d post-injury and showed that the absence of IFN�� may accelerate the healing process through increased TGF-�� production. Implications for wound healing and regulation of monocyte activation have also been shown for MCP-1 and IL-6 secreted by activated tissue cells including keratinocytes, fibroblasts and endothelial cells.21,22 TNF�� and IL-1�� are released by a variety of activated cells post-injury but predominantly by monocytes and macrophages themselves.23 Both cytokines are regarded as amplifiers of the inflammatory response and to impair wound healing through persistent paracrine/autocrine signaling to monocytes and macrophages.18,24,25 Figure 1. Interplay of inflammatory mediators involved in the process of monocyte to macrophage differentiation under condition of sterile tissue injury.
Chemokines and cytokines Anacetrapib released from activated tissue cells and lymphocytes attract monocytes … To mimic monocyte to macrophage differentiation under conditions resembling those of a sterile tissue injury at biomaterial implantation sites in vivo we used a cytokine cocktail composed of MCP-1, IL-6 and IFN��. These mediators are not preferentially released by monocytes and macrophages and are therefore suggested to be crucial for initial monocyte activation and differentiation into macrophages (Fig. 1).