Role of DAMPs in the modulation of macrophage response after classical biomaterial (Ti) implantation and its impact in the subsequent repair and osseointegration processes

• Grant number: 14/09590-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): August 01, 2014
• Effective date (End): January 16, 2018
• Field of knowledge: Health Sciences - Dentistry
• Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Gustavo Pompermaier Garlet
• Grantee: Claudia Cristina Biguetti
• Host Institution: Faculdade de Odontologia de Bauru (FOB). Universidade de São Paulo (USP). Bauru , SP, Brazil
• Associated scholarship(s): 15/18162-2 - Influence of biomaterial (Ti) experimental biological aging in the outcome of host response to biomaterial grafting in vivo and stem cells (SCAPs) differentiation in vitro, BE.EP.DR

Abstract

Biomaterial implantation leads to an inflammatory response that may play a crucial role in the clinical success or failure outcome. In this process, monocytes/macrophages are supposed to play a central role, since these cells are considered the main body sensors related to biocompatibility. However, this interaction between host/biomaterial is poorly understood at the cellular and molecular levels, even in an ideal condition with proved clinical effectiveness, as observed in the integration of classic biomaterials devices such as titanium (Ti). As known, tissue trauma leads to releasing of DAMPs (damage-associated molecular patterns), molecules that interact with macrophages by binding to specific receptors triggering the immune/inflammatory response in aseptic conditions such as biomaterials implantation. However, the role of DAMPs on macrophage response, specifically in macrophage polarization to inflammatory (M1) or regulatory and wound-healing macrophage (M2) phenotypes in the interface tissue/biomaterial remains unknown. In this sense, it is supposed that the understanding of relationship DAMPs/Ti on modulation of macrophage response could be a key point for understanding the interaction host/biomaterial in ideal conditions and to improve biomaterials development and application. Thus, the aim of this study is evaluate the role of DAMPs in the modulation of macrophage response after implantation of a classic biomaterial (Ti) and its impact on repair and osseointegration processes. For this purpose, the possible adsorption of DAMPs on Ti surface, as well the presence of DAMPs in the inflammatory exudate at biomaterial implantation site will be analyzed by ELISA, in different times after subcutaneous Ti discs implantation in C57BL/6-WT mice. Subsequently, we will analyze the phenotype of macrophages, specifically M1/M2 profiles polarization, as well the patterns of inflammatory/immune mediators expression, in tissues surrounding the Ti disk implantation site (subcutaneous tissue) in C57BL/6-WT mice, by means of flow cytometry, ELISA and PCRArray. To assess the direct impact of DAMPs and macrophages in the wound healing subsequent to biomaterial implantation in vivo, Ti devices will be implant at the dorsum (Ti disk implanted in a subcutaneous tissue repair model) and jaw-bone (Ti 'implant-like device' in a osseointegration model) of C57BL /6-WT mice, which will be divided in control group (untreated), and groups treated with DAMPs inhibitors and its receptors, by three methods: inhibition of HMGB1 by the administration of glycyrrhizin (GR); inhibition of RAGE by administration of S100P-derived RAGE antagonistic peptide; and indirect inhibition of TLR signaling pathway through inhibition of the adapter molecule MyD88 by administration of IMG5005. Specimens will be removed after 72 hour, 7, 14 and 21 days subsequent to biomaterial implantation for histomorphometric and molecular analysis of repair/osseointegration, as well for the expression of bone and inflammatory markers (PCRArray). Parallel with in vivo assays, the role of DAMPs will be assess on macrophage modulation response to development of M1/M2 phenotype in vitro, by exposure of these cells to the surface of Ti in the absence or presence of DAMPs (HMGB1, SP100 and HSP60) commercially available. These cells and their supernatant will be analyzed by flow cytometry, ELISA and PCR Array. We believe that the combined analysis of such data from in vivo and in vitro studies, will allow a direct analysis of the DAMPs and macrophages role in the tissue repair and subsequent osseointegration. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CLAUDIA CRISTINA BIGUETTI; FRANCO CAVALLA; ELCIA M. SILVEIRA; ANGÉLICA CRISTINA FONSECA; ANDREIA ESPINDOLA VIEIRA; ANDRE PETENUCI TABANEZ; DANIELI C. RODRIGUES; ANA PAULA FAVARO TROMBONE; GUSTAVO POMPERMAIER GARLET. Oral implant osseointegration model in C57Bl/6 mice: microtomographic, histological, histomorphometric and molecular characterization. Journal of Applied Oral Science, v. 26, 2018-06-11. (14/09590-8, 15/24637-3, 15/18162-2)

BIGUETTI, CLAUDIA CRISTINA; CAVALLA, FRANCO; FONSECA, ANGELICA CRISTINA; TABANEZ, ANDRE PETENUCCI; SIDDIQUI, DANYAL A.; WHEELIS, SUTTON E.; TAGA, RUMIO; FAKHOURI, WALID D.; SILVA, RENATO MENEZES; RODRIGUES, DANIELI C.; et al. Effects of Titanium Corrosion Products on In Vivo Biological Response: A Basis for the Understanding of Osseointegration Failures Mechanisms. FRONTIERS IN MATERIALS, v. 8, MAY 14 2021. (15/24637-3, 14/09590-8, 15/18162-2)

BIGUETTI, CLAUDIA CRISTINA; CAVALLA, FRANCO; SILVEIRA, ELCIA VARIZE; TABANEZ, ANDRE PETENUCI; FRANCISCONI, CAROLINA FAVARO; TAGA, RUMIO; CAMPANELLII, ANA PAULA; TROMBONE, ANA PAULA FAVARO; RODRIGUES, DANIELI C.; GARLET, GUSTAVO POMPERMAIER. HGMB1 and RAGE as Essential Components of Ti Osseointegration Process in Mice. FRONTIERS IN IMMUNOLOGY, v. 10, APR 5 2019. (14/09590-8, 15/18162-2, 15/24637-3)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

BIGUETTI, Claudia Cristina. Role of DAMPS on the modulation of macrophage response after classical biomaterial (Ti) implantation and its impact on the subsequent repair and osseointegration processes. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Odontologia de Bauru (FOB/SDB) Bauru.