## 5 Discussion
Nevertheless, a proliferation promoting effect of NIPP on mesenchymal stem cells in vitro has been described by other authors [47]. Since the wound healing effect of NIPP has been demonstrated in vitro, in vivo, and in randomised clinical trials by other authors [30; 48; 49], we treated the patient with this technology. The NIPP application was intended to minimize the risk of developing MRONJ. Various devices are currently used in surgical practice. NIPP is generated in different ways, either by using noble gases such as argon or helium, or by using the ambient air, as shown in our case [13; 14; 31]. In the present study, only a 60 s treatment was performed once a week. Although the device is a certified medical device, there is little evidence-based information on the exact application therapy, except for an application time between 30 s and 120 s. In previous in vitro studies, we found that NIPP has a proliferation-promoting effect when applied for 60 s [13; 32; 39]. A significant increase in wound healing in patients with diabetic foot ulcers by eight applications of NIPP has been shown by [PERSON] et al. In this study, treatment with an argon-based NIPP device is performed for 30 s per cm\({}^{2}\)[30]. Other authors applied a treatment-time of 2 min for 14 patients with chronically infected wounds using argon generated NIPP [37]. Just a few clinical studies have shown that intraoral wound healing can be improved by NIPP: [PERSON] et al. have proven that a single application of NIPP significantly improves gingival wound healing after gingjectomy [50] and [PERSON] et al. have shown that gingival epithelization after surgery can be significantly accelerated by a single application of NIPP [51]. In these studies, application times of 60 s and 120 s, respectively, have been described. Further systematic studies with NIPP treatments of varying duration are needed to reveal the effects of NIPP on intraoral wound healing. Other approaches to prevent MRONJ also exist. For example, it has been shown that dental pulp stem cell conditioned medium or platelet rich fibrin could also be used to prevent MRONJ [52; 53]. However, the NIPP-based treatment modality would be a very cost-effective and easy-to-use method for MRONJ prevention that could also be applied in dental practices. As wound healing problems can only indicate MRONJ at least 8 weeks after surgery under current or previous treatment with antiresorptive drugs with exposed bone and without any history of radiation therapy [4], we wanted to prevent the development of MRONJ by starting NIPP therapy 2 weeks after surgery. In our case, necrotic bone that regularly accompanied MRONJ, was not evident clinically or on radiograph. It has also been described in the literature that the duration of taking antiresorptive drugs seems to have an important influence on the occurrence of MRONJ [54; 55]: Patients receiving antiresorptive drugs for longer than 8 months have a significantly higher incidence of MRONJ than patients receiving these drugs for a shorter period of time [54]. This might suggest that NIPP treatment was only possible because the side effects of zoledronate were not yet very pronounced. However, as the patient we presented had been taking zoledronate for a period of more than 8 months and all primary surgically closed wounds had become dehiscent, we considered the risk of developing MRONJ to be high. However, it may be possible that extensive MRONJ cannot be treated with NIPP. Although a proliferation-promoting effect of NIPP has also been shown in hard tissue cells [32; 56], further studies are needed to decipher the exact effect of NIPP in MRONJ. A limitation of our case report, as with all observational studies, is the possibility of bias and the risk of overinterpretation because it is impossible to control for all variability in a retrospective design. For ethical reasons, we decided not to use a split mouth design. Therefore, no statement can be made about what the healing would have been without NIPP.