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Role of MSCs in the response to the implantation of titanium devices and its impact on the repair and osseointegration process

Grant number: 18/08741-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2018
Effective date (End): December 31, 2020
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Gustavo Pompermaier Garlet
Grantee:Carolina Fávaro Francisconi Mortari
Home Institution: Faculdade de Odontologia de Bauru (FOB). Universidade de São Paulo (USP). Bauru , SP, Brazil
Associated research grant:15/24637-3 - MSCs and m2 as determinants of the constructive or destructive nature of inflammatory microenvironments associated with bone tissue, AP.TEM

Abstract

The implantation of titanium (Ti) devices results in a transient inflammatory process of low magnitude, compatible with constructive inflammation, leading to osseointegration. The presence of mesenchymal stem cells (MSCs) at the sites of implantation, apart from their immunoregulatory characteristics, and the participation of the CXCL12-CXCR4 axis, suggests their involvement in this process. However, it is unknown how this response is generated, and the DAMPs (Damage-associated molecular patterns) are possible mediators. Indeed, several DAMPs, like HMGB1, are released at biomaterial implantation sites; suggesting the participation of the HMGB1/TLRs/MyD88 axis. Also, alterations in the structure of the biomaterials can impair the response, being possible to test such hypothesis by the biological aging of Ti, and the use of other biomaterials (PET-polyethylene terephthalate). So, the aim of this study is to investigate the role of MSCs in the response to the implantation of classical biomaterials (Ti) and their impact on the repair and osseointegration process. We will perform two experimental models in C57Bl/6-WT mice: osseointegration in the maxilla (installation of Ti spins); and the subcutaneous (PET discs (negative control) and Ti discs). We will use pharmacological inhibitors (from HMGB1, MyD88 and CXCR4), and CXCL12 HAP hydrogel (controlled release of CXCL12) to determine the role of each factor in the migration of MSCs and their impact on repair as well as the aging of Ti. Samples with 0h, 1, 3, 7, 14 and 21 days post implantation will be collected for comparative analysis through microtomography, histomorphometry and birefringence; as well as gene expression (RealTimePCRarray; ELISA/multiplex) and quantification of MSCs (Immunohistochemistry). Furthermore, we will isolate MSCs from the subcutaneous sites (flow cytometry), and the isolation and culture of SCAPs and BM-MSCs, followed by in vitro analyzes (co-culture with lymphocytes and culture under conditions of osteoblastic differentiation), and multiparametric test (viability/cytotoxicity). The results will provide subsidies for the development of new biomaterials, as well as the improvement of the clinical performance of already established biomaterials.