REVIEW S37 Tomas Albrektsson, Bruno Chrcanovic, Johan Mölne, Ann Wennerberg Foreign body reactions, marginal bone loss and allergies in relation to titanium implants Tomas Albrektsson Key words foreign body reactions, marginal bone loss, titanium allergy Department of Biomaterials, University of Gothenburg, Sweden; Department of Aim: To describe general observations of immunological reactions to foreign materials and to real- Prosthodontics, Malmö Uni- versity, Sweden ize that CP titanium gives rise to a foreign body reaction with subsequent bone embedment when placed as oral implants. To analyse the possibility of titanium allergy. Bruno Chrcanovic Department of Prostho- Materials and methods: The present paper is of a narrative review type. Hand and Medline searches dontics, Malmö University, were performed to evaluate marginal bone loss of oral implants and the potential of titanium allergy. Sweden Results: Immunological reactions to foreign substances include Type I hypersensitivity reactions such Johan Mölne Department of Pathology as allergy, Type II hypersensitivity reactions characterised by IgM or IgG antibodies that may react and Genetics, Sahlgren- with blood group antigens at transfusion, and Type III hypersensitivity caused by antigen-antibody ska Academy; University of Gothenburg, Sweden immune complexes exemplified by acute serum sickness. There is also Type IV hypersensitivity, or delayed hypersensitivity, which is typically found in drug and foreign body reactions. It proved very Ann Wennerberg Department of Prostho- difficult to find a universally acceptable definition of reasons for marginal bone loss around oral dontics, Malmö University, implants, which lead to most varying figures of so-called peri-implantitis being 1% to 2% in some Sweden; Department of Prosthodontics, University of 10-year follow-up papers to between 28% and 56% of all placed implants in other papers. It was Gothenburg, Sweden recognised that bone resorption to oral as well as orthopaedic implants may be due to immunological Correspondence to: reactions. Today, osseointegration is seen as an immune-modulated inflammatory process where the Tomas Albrektsson, Dept of Biomaterials, immune system is locally either up- or downregulated. Titanium implant allergy is a rare condition, if Box 412, it exists. The authors found only two papers presenting strong evidence of allergy to CP titanium, but 40530 Göteborg, Sweden Email: tomas.albrektsson@ with the lack of universally accepted and tested patch tests, the precise diagnosis is difficult. biomaterials.gu.se Conclusions: CP titanium acts as a foreign body when placed in live tissues. There may be immuno- logical reasons behind marginal bone loss. Titanium allergy may exist in rare cases, but there is a lack of properly designed and analysed patch tests at present. Introduction IgE antibodies to an allergen (a Th2 driven process). When the allergen is encountered, it is taken up General observations on immunological on mucus membranes and exposed to mast cells. reactions to foreign substances Mast cells have bound IgE on their surface and when the antigen crosslink IgE antibodies, sev- These reactions have traditionally been called type eral substances – most importantly histamine – are I to IV reactions, but can also be classified as acute, released. Histamine dilates and permeabilises capil- allergic or chronic inflammation. laries and small veins, resulting in fluid leakage and Type I hypersensitivity is characterised by allergic reddening of the area. An example of this is con- reactions, including anaphylactic reactions. A typical junctivitis. There is also a later phase when other example is a sensitised patient who has developed mediators mobilise cells, particularly eosinophils and Eur J Oral Implantol 2018;11(Suppl1):S37–S46 S38 Albrektsson et al Foreign body reactions, marginal bone loss and allergies to titanium implants T-cells, leading to a prolonged diseased state and including IL-12. In turn, IL-12 stimulates the T-cells. resulting in asthma in susceptible individuals. The The macrophage phenotypic change is called epith- normal protective reaction in the body using this eloid cells since the macrophages become larger with reaction is the defence against extracellular parasites. abundant, granular cytoplasm simulating epithelial Type II hypersensitivity is characterised by IgM cells. This reaction can be seen in autoimmune dis- or IgG antibodies binding to cells or the extracellular eases such as rheumatoid arthritis, drug and foreign matrix. A typical example is antibodies reacting with body reactions, inflammatory bowel diseases and blood group antigens in transfusion or transplanta- organ transplantation. tion, leading to destruction of red blood cells or the Gell and Coombs1 introduced the hypersen- transplanted organ. Antibodies can also be directed sitivity classification in 1963 and it focuses on the at self-antigens in autoimmune diseases such as vas- negative, host-destructive effects of immunity and culitis, cased by ANCA, or autoimmune haemolytic inflammation. Today, it is evident that these reac- anaemia. In other situations the tions partly overlap and further that they are mainly Autoantibodies can block or stimulate receptors protective, but that tissues can be destroyed in without causing inflammation, such as in myasthenia uncontrolled inflammation or in allergy and auto- gravis and Graves’ disease, respectively. immune processes. Furthermore, the type III reac- Type III hypersensitivity is caused by antigen- tion is uncommon and the main function of immune antibody (immune) complexes formed in the circu- complexes might be to immobilise circulating viral lation and deposited in the microvasculature. Nor- particles in viremia. A more straightforward view is mally, this reaction is broken up by the complement the classification used by pathologists. Allergy is a system and pure type III hypersensitivity is uncom- type I reaction and is driven by allergens, such as mon. Immune complexes are instead formed where pollen. Acute inflammation is a process driven by antigens are trapped in the circulation in small ves- danger or alarm signals from invading extracellular sels, typically in the glomeruli, joints or small cutane- microorganisms, resulting in vascular dilatation and ous blood vessels, resulting in vasculitis. The classical leakage in order to accumulate mediators from the example of type III hypersensitivity is acute serum blood, including complement and neutrophils that sickness caused by administration of large amounts will ingest and destruct the invading organisms. IgM of foreign serum from horses to treat diphtheria, a and IgG antibodies will help the neutrophils to ingest treatment that is no longer used. the microorganism via specific Ig-receptors on their Type IV hypersensitivity is also called delayed surface (type II reaction). Chronic inflammation is type hypersensitivity (DTH) by immunologists, since an equivalent of the type IV reaction and driven by this reaction typically takes several days to develop, antigens on either microorganisms or other foreign in contrast to type I hypersensitivity. This reaction particles, including transplanted organs or cells. This involves cells, mainly T-helper cells (Th1) and mac- reaction is normally aimed at intracellular organisms rophages and cytokines. When a pathogen, such as including bacteria and viruses, where infected cells tuberculosis, is difficult to destroy due to bacterial are destroyed by cytotoxic, CD8+ T-cells. defence mechanisms, the macrophage needs help from T-cells to augment its functions. Antigens are presented on MHC-class II molecules to T-helper cells, Materials and methods together with amplifying signals (co-stimulatory mol- ecules) stimulating the T-cells to produce cytokines, Type of review chosen mainly IL-2 and interferon gamma (IFN-γ). IL-2 is an autocrine growth factor for T-cells multiplying anti- The initial ambition of the present authors was to gen specific T-cells, while IFN-γ changes macrophage present a systematic review of foreign body reac- functions and phenotype. IFN-γ stimulated mac- tions to titanium (type IV hypersensitivity or chronic rophages produce more NO, bactericidal enzymes, inflammation, marginal bone loss/peri-implantitis upregulate MHC-class II, produce matrix degrad- (= acute inflammation) and titanium allergy (type I ing enzymes (metalloproteinases) and cytokines, or allergic inflammation). Eur J Oral Implantol 2018;11(Suppl1):S37–S46 Albrektsson et al Foreign body reactions, marginal bone loss and allergies to titanium implants S39 However, our initial ambition had to be aban- are manufactured from CP titanium. Most of the doned due to lack of universally acceptable stand- remaining 5% of oral implants are made from tita- ards in the case of marginal bone loss (MBL) and its nium alloys, particularly Ti6Al4V. Extraoral, crani- possible relation to a disease entitled peri-implantitis. ofacial implants are generally made from CP tita- It would, of course, have been tempting to use the nium. Several hundred thousand of such implants definition of peri-implantitis presented by Lindhe and have been manufactured and used on indications Meyle2 and apply those criteria to long-term reports such as congenital malformations, acquired facial in the literature. However, whereas Smeets et al3 bone deficiencies or as a fixation of directly bone- based on the Lindhe and Meyle criteria, reported an anchored hearing aids. By contrast, titanium alloys, incidence of peri-implantitis