## 3 General and Local Implications of Titanium Alloys
### Modifications of the Surrounding Tissue  
Although titanium is described as having a good acceptance, the long-term interaction between it and the surrounding tissue is still debated and unclear [70]. Taking into consideration the potential consequences, the removal of the titanium-based materials after the healing is complete is still a subject of many research topics. The release of metal in the tissue is explained to be secondary to contamination, corrosion or during the insertion or removal manoeuvres [71; 72; 73]. A study performed by [PERSON] et al. [69] concluded that the metal that was released from the titanium plates used for maxillofacial osteosynthesis is associated with the surgical part of the process. And the metal that has been released during the time that the plates were in situ was a minor quantity.  
[PERSON] et al. [74] conducted a study in which they analysed the surface of retrieved titanium plates and the surrounding tissue after their removal. After the analysis, they identified deposits of silica and aluminium on the surface, suggesting that a contamination might have occurred during the manufacture process by polishing the titanium plate, through atmospheric contamination or during the autoclaving process before their intraperatory use. Overall, the conclusions of their research pointed out the fact that the surgical manipulation and the existing defects of manufacture are a more probable source of potential metal release in the tissue [74]. Other studies also reported the existence of silica and aluminium on the titanium plates surface and in the nearby soft tissue [75; 76; 77]. The potential influence of aluminium has been reported in several studies and associated with the incidence of osteomalacia, Parkinson's and Alzheimer's diseases [78].  
In their study, [PERSON] et al. [79] aimed to examine and quantify the microscopic changes that occur in the soft tissue that covers the titanium plates used for osteosynthesis, in order to identify any presence of metallic deposits. After examining the soft tissue samples that were in contact with the titanium plates, they concluded that in all cases, the titanium plates were covered in fibrotic tissue, without any inflammatory signs. A dark-grey pigmentation was visually observed in the majority of the samples (16 out of 20), and under microscopic examination pigmented debris were found in all the soft tissue samples [79]. Other studied presented that titanium particles can be transported with the help of the lymphatic vessels into the local lymph nodes [80]. However, [PERSON] et al. in their study reported also the encounter of titanium particles in the lungs, kidneys, spleen and liver [80]. Metallic particles in the adjacent soft tissue were also reported by [PERSON] et al. [81], finding after optical microscopic examination, pigmented deposits of a dark brown colour, having intra and extracellular localization. Pigmentation of the nearby connective tissue of a black-grey colour was observed also by [PERSON] et al. [82], in seven of the enrolled patients in their study. The samples were analysed, and the results showed that the pigmented deposits could be found both intracellular and extracellular, surrounded by an apparent foreign body reaction, as shown in Table 3.  
Research showed that metallic particles can be transferred into the surrounding soft tissue as a result of corrosion, defect of manufacture, mechanical damage during insertion or removal, surface contamination or while in situ during a wear process [74; 75; 76; 77; 78; 79; 80; 81; 82; 83].