Abstract
Despite the successful clinical application of titanium (Ti) as a biomaterial, the exact cellular and molecular mechanisms responsible for Ti osseointegration remains unclear, especially because of the limited methodological tools available in this field.Objective:In this study, we present a microscopic and molecular characterization of an oral implant osseointegration model using C57Bl/6 mice.Material and Methods:Forty-eight male wild-type mice received a Ti implant on the edentulous alveolar crest and the peri-implant sites were evaluated through microscopic (μCT, histological and birefringence) and molecular (RealTimePCRarray) analysis in different points in time after surgery (3, 7, 14 and 21 days).Results:The early stages of osseointegration were marked by an increased expression of growth factors and MSC markers. Subsequently, a provisional granulation tissue was formed, with high expression of VEGFb and earlier osteogenic markers (BMPs, ALP and Runx2). The immune/inflammatory phase was evidenced by an increased density of inflammatory cells, and high expression of cytokines (TNF, IL6, IL1) chemokines (CXCL3, CCL2, CCL5 and CXC3CL1) and chemokine receptors (CCR2 and CCR5). Also, iNOS expression remained low, while ARG1 was upregulated, indicating predominance of a M2-type response. At later points in time, the bone matrix density and volume were increased, in agreement with a high expression of Col1a1 and Col21a2. The remodelling process was marked by peaks of MMPs, RANKL and OPG expression at 14 days, and an increased density of osteoclasts. At 21 days, intimate Ti/bone contact was observed, with expression of final osteoblast differentiation markers (PHEX, SOST), as well as red spectrum collagen fibers.Conclusions:This study demonstrated a unique molecular view of oral osseointegration kinetics in C57Bl/6 mice, evidencing potential elements responsible for orchestrating cell migration, proliferation, ECM deposition and maturation, angiogenesis, bone formation and remodeling at the bone-implant interface in parallel with a novel microscopic analysis.
Highlights
Despite the successful clinical application of titanium (Ti) as a biomaterial, the exact cellular and molecular mechanisms responsible for Ti osseointegration remains unclear, especially because of the limited methodological tools available in this field
This study demonstrated a unique molecular view of oral osseointegration kinetics in C57Bl/6 mice, evidencing potential elements responsible for orchestrating cell migration, proliferation, ECM deposition and maturation, angiogenesis, bone formation and remodeling at the boneimplant interface in parallel with a novel microscopic analysis
Ti is currently regarded as an immunomodulatory biomaterial rather than an inert metal, since Ti implantation in bone is associated with a transitory small degree of inflammation, which seems to contribute to the activation of host pathways that leads to osseointegration2,4
Summary
Despite the successful clinical application of titanium (Ti) as a biomaterial, the exact cellular and molecular mechanisms responsible for Ti osseointegration remains unclear, especially because of the limited methodological tools available in this field. In vivo preclinical evaluation of bone formation and remodelling on Ti surfaces are usually performed in animals with robust skeletal bones, such as minipigs and dogs, which can recapitulate the architecture of human craniofacial bones and allow the analysis of implant modification (i.e. shapes, coatings and/or surface topographies) in osseointegration9 While such large animal-based models are useful for certain applications, inherent factors such as animal size/weight, lack of specific experimental tools for cause-and-effect experiments, as well as absent or restricted molecular assays, limit the possibilities of understanding the biological basis of osseointegration. The use of mice in the Osteoimmunology field as an experimental model host results in additional advantages due to the extensive knowledge on the inflammatory and immunological responses of mice9,13 In this context, endochondral long bones osseointegration models have been developed in mice with different approaches, such as for investigation of molecular and cellular regulation of osseointegration under micromotion stimuli, implant stability and insertion torque, and acceleration of osseointegration. While these studies are useful to better understand the osseointegration process in orthopaedics applications, they cannot be fully translated for the Dentistry (i.e. maxillary/mandibular implants) context
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