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Osseointegration and foreign body reaction: Titanium implants activate the immune system and suppress bone resorption during the first 4 weeks after implantation

Journal article
Authors Ricardo Trindade
Tomas Albrektsson
Silvia Galli
Zdenka Prgomet
Pentti Tengvall
Ann Wennerberg
Published in Clinical Implant Dentistry and Related Research
Volume 20
Issue 1
Pages 82-91
ISSN 1523-0899
Publication year 2018
Published at Institute of Odontology
Institute of Clinical Sciences, Department of Biomaterials
Pages 82-91
Language en
Keywords animal study, bone, foreign body reaction, immunology, osseointegration, titanium
Subject categories Medical Biotechnology


© 2017 Wiley Periodicals, Inc. Background: Osseointegration mechanisms are still not entirely understood. Purpose: The present pilot study aims at demonstrating the involvement of the immune system in the process of osseointegration around titanium implants, comparing bone healing in the presence and absence of a titanium implant. Materials and Methods: Fifteen New Zealand White rabbits had one osteotomy performed at each of the distal femurs; on one side, no implant was placed (sham) and on the other side a titanium implant was introduced. Subjects were sacrificed at 10 and 28 days for gene expression analysis (three subjects each time point) and for decalcified qualitative histology (six subjects each time point). At 10 days, the three subjects for gene expression analysis were part of the six subjects for histology. Results: Gene expression analysis: at 10 days, ARG1 was significantly up-regulated around titanium, indicating an activation of M2-macrophages. At 28 days CD11b, ARG1, NCF-1, and C5aR1 were significantly up-regulated, indicating activation of the innate immune system, respectively M1-macrophages, M2-macrophages and group 2-innate lymphoid cells, neutrophils, and the complement system; on the other hand, the bone resorption markers RANKL, OPG, cathepsin K, and TRAP were significantly down-regulated around titanium. Histology: at 10 days new bone formation is seen around both sham and titanium sites, separating bone marrow from the osteotomy/implant site; at 28 days no bone trabeculae is seen on the sham site, which is healing at the original cortical level, whereas around titanium implants, bone continues into organization of more mature cortical-like bone, forming a layer between the implant and the bone marrow. Conclusions: The presence of a titanium implant during bone healing activates the immune system and displays type 2 inflammation, which is likely to guide the host-biomaterial relationship. At the same time, bone resorption is suppressed around titanium sites compared to sham sites after 4 weeks of implantation, suggesting a shift to a more pronounced bone forming environment. This suggests two important steps in osseointegration: identification of the titanium foreign body by the immune system and the development of a bone forming environment, that at tissue level translates into bone build-up on the titanium surface and can be perceived as an attempt to isolate the foreign body from the bone marrow space.

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