## 5 Discussion  
Over the last two decades, drug therapies have been frequently associated with osteonecrosis of the jaw. Thus, these diseases are no longer solely called bisphosphonate associated osteonecrosis, but MRONJ. Bisphosphonates administered for oncologic reasons are associated with the development of osteonecrosis. The risk of developing MRONJ in oncologic patients is 1.3-1.8% [20]. Especially patients treated for multiple myeloma have a rather high incidence for MRONJ [21]. Thus, in these patients, it is mandatory to ensure primary wound healing when surgery is performed. In cases of wound dehiscence, it is very important that the wound is covered with a mucoperiosteal flap with sufficiently stable tissue [22]. We report about a conservative treatment option of a wound dehiscence using NIPP with successful healing of the affected tissue in a patient under bisphosphonate therapy for multiple myeloma. Zoledronate is an intravenous bisphosphonate used to treat multiple myeloma, metastatic breast and prostate cancer, Paget's disease, and osteoporosis [23]. It has a high affinity for mineralised bone, more pronounced than other bisphosphonates, and accumulates particularly at sites of high bone turnover [24; 25]. The effect of bisphosphonates is characterised by reducing bone turnover and increasing osteoblast function [26]. However, zoledronate has been shown to impair wound healing after dental surgery, such as tooth extraction [27]. In our case, the wound healing took about 5-9 weeks in total. Additionally, zoledronate is known to negatively affect wound healing by causing mucosal lesions, inflammatory infiltrates and non-vital bone after tooth extraction [28; 29]. The application of NIPP has been described as a promising method for delayed wound healing and in cancer therapy [14; 30], and a proliferation-promoting effect has been shown in many in vitro, in vivo and even clinical studies [13; 31; 32; 33; 34; 35; 36; 37; 38]. The exact mode of action of NIPP is not known; however, a number of reactive oxygen and nitrogen species have an effect on the cells and tissues involved. In the in vitro part of our study, we were able to demonstrate a proliferation-promoting effect of NIPP on keratinocytes, in terms of upregulation of proliferation markers Ki67 and PCNA mRNA. Additionally, higher metabolic activity of the cells by XTT and improved cell migration by scratch assay has  
Figure 5: The 60 s NIPP treatment of primary human gingival keratinocytes (HPGK) at one day. (**a**) Influence of NIPP on cell viability, shown by XTT assay, \(n=6\); (**b**) impact of NIPP on mRNA level of proliferation markers Ki67 and PCNA, \(n=6\); (**c**) in vitro wound healing assay, displayed by scratch assay, \(n=5\); (**d**) representative images are visualized. * statistical significance (\(p<0.05\)). been shown. However, the NIPP effect was not as pronounced in keratinocytes as in cementoblasts or periodontal ligament cells [13; 39]. A reason might be that keratinocytes are slow-proliferating cells [40]. It is possible that a study after longer incubation times (after 2 or 3 d) would have shown even stronger effects. Nevertheless, a significant positive effect of NIPP was evident, which may explain the successful clinical response observed in the case report. However, since mesenchymal stem cells in particular provide key factors that accelerate healing during wound healing [41; 42], it may be that NIPP influences these cells during tissue stimulation. On the other hand, NIPP is also able to stimulate certain cytokines and chemokines and MMPs [13; 32], which are also components of the mesenchymal stem cell sectrome and modulate immune processes as well as cell migration and proliferation [43; 44; 45]. However, the cellular processes involved in NIPP-induced tissue regeneration and wound healing are still poorly understood. Additionally, as it is also known that microtrauma can influence the secretome of the cells, a detailed investigation of the influence on tissue healing is necessary [46].