Abstract: Osseointegration is likely the result of an immunologically driven bone reaction to materials such as titanium. Osseointegration has resulted in the clinical possibility to anchor oral implants in jaw bone tissue. However, the mechanisms behind bony anchorage are not fully understood and complications over a longer period of time have been reported. The current study aims at exploring possible differences between copper (Cu) and polyetheretherketone (PEEK) materials that do not osseointegrate, with osseointegrating cp titanium as control. The implants were placed in rabbit tibia and selected immune markers were evaluated at 10 and 28 days of follow-up. Cu and PEEK demonstrated at both time points a higher immune activation than cp titanium. Cu demonstrated distance osteogenesis due to a maintained proinflammatory environment over time, and PEEK failed to osseointegrate due to an immunologically defined preferential adipose tissue formation on its surface. The here presented results suggest the description of two different mechanisms for failed osseointegration, both of which are correlated to the immune system.

Bone anchored biomaterials have become an indispensable solution for the restoration of lost dental elements and for skeletal joint replacements. However, a thorough understanding is still lacking in terms of the biological mechanisms leading to osseointegration and its contrast, unwanted peri-implant bone loss. We have previously hypothesized on the participation of immune mechanisms in such processes, and later demonstrated enhanced bone immune activation up to 4 weeks around titanium implants. The current experimental study explored and compared in a rabbit tibia model after 10 days of healing time, the bone inflammation/immunological reaction at mRNA level towards titanium, polyether ether ketone (PEEK) and copper compared to a Sham control. Samples from the test and control sites were, after a healing period, processed for gene expression analysis (polymerase chain reaction, (qPCR)) and decalcified histology tissue analysis. All materials displayed immune activation and suppression of bone resorption, when compared to sham. The M1 (inflammatory)/M2 (reparative) -macrophage phenotype balance was correlated to the proximity and volume of bone growth at the implant vicinity, with titanium demonstrating a M2-phenotype at 10 days, whereas copper and PEEK were still dealing with a mixed M1- and M2-phenotype environment. Titanium was the only material showing adequate bone growth and proximity inside the implant threads. There was a consistent upregulation of (T-cell surface glycoprotein CD4) CD4 and downregulation of (T-cell transmembrane glycoprotein CD8) CD8, indicating a CD4-lymphocyte phenotype driven reaction around all materials at 10 days.

Background: Osseointegration mechanisms are still not entirely understood. PurposeThe 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.

Background: the last few decades have seen a progressive shift in paradigm, replacing the notion of body implants as inert biomaterials for that of immune-modulating interactions with the host. Purpose: this text represents an attempt at understanding the current knowledge on the healing mechanisms controlling implant-host interactions, thus interpreting osseointegration and the peri-implant bone loss phenomena also from an immunological point of view. Materials and Methods: a Narrative Review approach was taken in the development of this article. Results: Osseointegration, actually representing a foreign body reaction (FBR) to biomaterials, is an immune-modulated, multifactorial and complex healing process where a number of cells and mediators are involved. The build-up of osseointegration seems to be an immunologically and inflammatory driven process, with the ultimate end to shield off the foreign material placed in the body, triggered by surface protein adsorption, complement activation and build-up of a fibrin matrix, followed by recruitment of granulocytes, mesenchymal stem cells (MSCs) and monocytes/macrophages, with the latter largely controlling the longer term response, further fusing into foreign body giant cells (FBGC), while bone cells make and remodel hydroxyl apatite. The above sequence results in the FBR that we call osseointegration and use for clinical purposes. However, the long term clinical function is dependent on a foreign body equilibrium, that if disturbed may lead to impaired clinical function of the implant, through a breakdown process where macrophages are again activated and may further fuse into FBGCs, now seen in much greater numbers, resulting in the start of bone resorption- due to cells such as osteoclasts with different origins and possibly even macrophages degrading more bone than what is formed via osteoblastic activity- and rupture of mucosal seals, through complex mechanisms in need of further understanding. Infection may follow as a secondary event, further complicating the clinical scenario. Implant failure may ensue. Conclusions: dentistry is still to embrace the concept of the biomaterials healing- and immune-modulating effect when in contact with body tissues. The presented knowledge has the potential to open the door for a different interpretation of past, current and future observations in dental implant science. From a clinical standpoint it seems recommendable to react as rapidly as possible when facing peri-implant bone loss, trying to re-establish a foreign body equilibrium if with some bone resorption.

To understand the biological basis of osseointegration, one has to understand the 2 main sides of the implant host interaction: tissue and biomaterial characteristics. This article addresses osseous tissue characteristics and the potential role of soft tissues in the osseointegration of dental implants. Successful integration is driven by an inflammatory process. Protein adsorption is key for tissue integration with biomaterials. Osseointegration dynamics relate to the in vivo lifetime of the implant. Understanding this biology is important; it opens the door to putting aside heuristic methods and replaces them by methods that produce solutions to achieve a specific biological goal.