## 3 General and Local Implications of Titanium Alloys
### Inducing Oxidative Stress and Cell Damage  
Titanium alloys miniplates and screws have multiple advantages associated with the treatment of maxillofacial trauma, orthognathic surgery or oncological reconstructive treatment. However, several studies raise an important question regarding reported negative outcomes [46; 47]. Research has investigated the hypothesis that the chronic inflammation around titanium alloys miniplates and screws can induce an increased production of reactive nitrogen species and oxygen-free radicals [48; 49; 50]. The problem associated with the activation of the reactive oxygen species and the production of reactive nitrogen ones is the damage that follows, affecting the normal cell function and influencing the production of the proinflammatory mediators with a consequence upon the growth, differentiation and apoptosis functions of the normal cells [51]. As far as it was investigated, oxidative stress is one of the inductive mechanisms of the titanium toxicity [52], but the exact amount of damage that it can produce cannot yet be quantified. A study was conducted by [PERSON] et al. [1], being the only one that aimed to evaluate the effect that titanium alloys materials used for osteosynthesis had upon the redox balance found at the placement of the material and upon the systemic health. The results of the study showed that several of the oxidative damage products were increased in the mandibular periosteum of patients with mandibular fractures that were treated with titanium alloy osteosynthesis materials compared to the control group. The results showed that the advanced glycation end products (AGE) fluorescence was increased in the mandibular periosteum of the target group compared to the control, the advanced oxidation protein products (AOPP) and 4-HNE levels were significantly higher also in the target group. At the same time, the concentration of 8-OHdG in the target group compared to the control showed similar values [1]. In the same study, the evaluation of the antioxidant -defence mechanisms showed that the catalase (CAT) activity was lower in the mandibular periosteum of the target group and higher in the erythrocytes of the same group compared to the control one [1]. Also, the superoxide dismutase (SOD) activity showed an increased value in the evaluated group compared to the healthy one, while it showed no influence upon the erythrocytes. The uric acid (UA) concentration was higher both in the periosteum and plasma of the patients with mandibular fractures when compared to the controls [1]. These results suggest an increased imbalance of the redox homeostasis and oxidative stress management associated to the patients with mandibular fractures that were treated with titanium alloys miniplates and screws. The alterations could be identified in the periosteum nearby the titanium alloys by an increased level of lipid metabolism and oxidative protein products in comparison to the healthy control group. Several changes related to the activity of enzymatic and nonenzymatic antioxidants were also observed in the erythrocytes and plasma of the target group. A study conducted by [PERSON] et al. [53] outlined the fact that the released titanium ions from the materials could influence the osteoclasts and phagocytes to increase the production of reactive oxidative species and reactive nitrogen species. Through this mechanism the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity is higher, producing a large number of free radicals. The high level of reactive oxygen species can influence the beginning of an inflammatory process near the titanium material [52; 53; 54; 55]. An imbalance in the normal redox value can determine a high production of free radicals and peroxides, causing damage upon all cell components, especially DNA. Besides local side effects, oxidative stress can be a cause for neurodegenerative conditions. Involving the oral cavity, the alterations of the small nerve fibres of the oral mucosa have been reported, inducing dysgseusia and burning pain [56].