The biomaterial implantation leads to an immune / inflammatory response that may be decisive for clinical success. Titanium (Ti) devices, such as osseointegrated implants, when implanted result in a transient low magnitude inflammatory process, compatible with the constructive inflammation, essential for triggering the osseointegration process. Previous results demonstrate the presence of M2 (F4 / 80 + CD206 +) macrophages in Ti device implantation sites, which, within the context of their role in repair / regeneration processes described in the general introduction of this project, allows us to assume their active involvement in the tissue repair process in biomaterials implantation. Similar to that described in subproject 3, such assumption is reinforced by the expression of the M2 Arg-1 and Fizz markers at the repair sites, which are shown to be associated with (yet unpolarized) macrophage migration during the repair of different tissues. Also, changes in the M2 response pattern possibly derived from changes in the structure / composition of biomaterials can negatively affect the repair response, as suggested by the previous results of the Thematic project, (from which this subproject is derived), in which it was observed that biological aging experimental study of Ti devices changes the pattern of local inflammatory immune response. In this context, although the results of the biological effects of experimental Ti aging are still preliminary, we observed that such modifications result in a more exaggerated inflammatory response, with an apparent deviation of the M1 / M2 pattern observed in the presence of unchanged Ti (normal) implantation. Thus, we believe in such a context, with an exacerbated inflammatory process and with a different pattern from that which characterizes the 'normal' response to the implantation of Ti devices, the use of M2 polarization strategies can be effective, similar to that observed in the model of periapical lesions, which may thereby 'reverse' the response to its normal pattern. Considering also that it claims participation of macrophages M2 in the repair process and osseointegration associated with biomaterials, such as Ti devices, is basically associative to the present moment, since even using strategies to potentiate M2 polarization, or to reverse changes in the balance M1 / M2, rather than potentiate a naturally occurring process, we propose an additional approach to establish a direct cause-and-effect relationship between M2 macrophages polarization and the repair / osseointegration process, using as research strategy the blockage of such phenotypic change. Thus, blocking the M1 / M2 transition that seems to occur naturally throughout the repair / osseointegration process associated with biomaterials, we can determine if the acquisition of an M2 phenotype is indeed involved in such a process. Specifically, we will have as an experimental strategy the blockade of MEK1 / 2 and STAT6, intracellular signaling elements described as essential for macrophage polarization to an M2 phenotype. This subproject 4 has the general objective to investigate the role of macrophage polarization to an M2 profile in the response to the implantation of classical biomaterials (Ti) and its impact on the repair and osseointegration process. To do so, we will use complementary models of implantation of Ti devices in the subcutaneous tissue (Ti disk) and in the bone tissue (Ti bolt, in osseointegration model); in which we initially performed cause-and-effect functional analyzes using C57B1 / 6-WT animals treated with FTY720 and VIP, since they are inducing drugs for the M2 polarization, as well as inhibiting the MEK1 / 2 and STAT6 pathways in additional groups. which are essential for macrophage polarization to an M2 phenotype; thus determining the impact of M2 responses on local immunoregulation and on tissue repair and osseointegration.
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