Osteoimmune regulation underlies oral implant osseointegration and its perturbation

Abstract

In the field of biomaterials, an endosseous implant is now recognized as an osteoimmunomodulatory but not bioinert biomaterial. Scientific advances in bone cell biology and in immunology have revealed a close relationship between the bone and immune systems resulting in a field of science called osteoimmunology. These discoveries have allowed for a novel interpretation of osseointegration as representing an osteoimmune reaction rather than a classic bone healing response, in which the activation state of macrophages ((M1-M2 polarization) appears to play a critical role. Through this viewpoint, the immune system is responsible for isolating the implant biomaterial foreign body by forming bone around the oral implant effectively shielding off the implant from the host bone system, i.e. osseointegration becomes a continuous and dynamic host defense reaction. At the same time, this has led to the proposal of a new model of osseointegration, the foreign body equilibrium (FBE). In addition, as an oral wound, the soft tissues are involved with all their innate immune characteristics. When implant integration is viewed as an osteoimmune reaction, this has implications for how marginal bone is regulated. For example, while bacteria are constitutive components of the soft tissue sulcus, if the inflammatory front and immune reaction is at some distance from the marginal bone, an equilibrium is established. If however, this inflammation approaches the marginal bone, an immune osteoclastic reaction occurs and marginal bone is removed. A number of clinical scenarios can be envisioned whereby the osteoimmune equilibrium is disturbed and marginal bone loss occurs, such as complications of aseptic nature and the synergistic activation of pro-inflammatory pathways (implant/wear debris, DAMPs, and PAMPs). Understanding that an implant is a foreign body and that the host reacts osteoimmunologically to shield off the implant allows for a distinction to be drawn between osteoimmunological conditions and peri-implant bone loss. This review will examine dental implant placement as an osteoimmune reaction and its implications for marginal bone loss.

Keywords: bone healing; bone regeneration; immune reaction; osteoimmunology; osteomechanobiology; osteometabolics; osteoneurology; revascularization.

Figure 1

A general overview of immune system actions in relation to oral implants. Computerized image of human face.

Figure 2

Hypothetical model for osseointegration dynamics. FBGC: foreign body giant cells. From Trindade, et al. Ref. (27).

Figure 3

(A) This figure depicts the performance of one individual surgeon with respect to the cumulative, average, annual loss in marginal bone that was associated to this clinician (squares) whereas the triangles depict the average annual performance of another oral surgeon who saw much greater accumulated bone loss than his peer, despite them using the same implant type in similar patients. Both these surgeons were active at the University of Toronto, Canada. (B) The squares in this figure represent the cumulative, annual loss in marginal bone associated to two restorative dentists active at the University of Toronto, Canada some 20 years ago. The bone loss curves were constructed so that they started from zero levels by the investigator S Ross Bryant. Figures (A, B) indicate that if a given patient had the poor luck to be treated by the least good surgeon and followed up by the least good prosthodontist, this meant an average accumulated loss of marginal bone of 2 millimeters at about 3-4 years after implant treatment. These curves support the notion that marginal bone loss around oral implants need not always have a septic background.  Created using data from S R Bryant, Ph D thesis, University of Toronto Canada.

Figure 4

Implant-Osteoimmune interaction. Osseointegration is a condition of continuous and dynamic implant-osteoimmune interaction. If the implant surface evokes an initial and long-term immunomodulation, interfacial bone is formed to shield off the implant from the tissues (FBE). In addition, the M2 anti-inflammatory environment would induce adequate defense reactions to handle transient septic and aseptic threats (PAMPs, DAMPs, Implant-derived Titanium particles (i-TiPs) ), which is clinically reflected with 10 year failure rates varying between 0-4%. However, if it is continuous and of considerable size, the provocation and the consequent M1 inflammatory environment can generate Inflammatory cytokines that alters the expression of RANK/RANKL axis, counteracting the ability of implant surface osteoimmunomodulation, then a partial, progressive or total FBR can occur. Modified from Zetao Cheng, et al (ref.20).

Figure 5

Two critical sites involved in marginal bone loss exist at the coronal aspect of the implant where it emerges through the bone and soft tissues.

Figure 6

Common molecular pathways and environmental signals. (A, B) Toll-like receptors (TLRs) and other types of pattern recognition receptors recognize PAMPs and DAMPs and trigger inflammation via the activation of the transcription factor NF-Kb. Signaling pathway that requires the adaptor molecule MyD88. (C)  In addition, inflammation in response to necrotic cells is mostly mediated by IL-1 receptor (IL-1R), which leads to NF-kB activation.  (D) On the other hand, titanium particles can induce acute inflammation due to activation of the NALP3 inflammasome, which leads to increased IL-1  secretion and IL-1-associated signaling. Process mediated by protein complexes such as the Arp 2/3 complex. Also, titanium ions can bind to proteins, such as albumin or transferrin, creating a bioavailable metalloprotein that could serve as an antigen in immunological reactions. (E) Activation of NF-κB , the master inflammatory transcription factor. (F) Macrophages and other cells of the innate immune system respond to a large number of signals emanating from their local environment, therefore, the inflammatory potential can be multiplied due to the synergistic activation of pro-inflammatory pathways.  In this sense, it is known that the crosstalk between the skeletal system and the immune system can lead to osteoclastogenesis, for example, through IL-1. A specific biologic response of either inflammation or tolerance in a particular patient could be related to local and systemic oxidative stress, and other basal states, such as the state of local innervation. All these possible cellular and molecular mechanisms would be constantly counteracted/balanced by both the long-term immunomodulatory capacity of the implant and the dynamic osteo immune environment. (Modified from Goodman SB, et al. ref. 66).