# Clinical Applications of Low-Intensity Pulsed Ultrasound and Its Underlying Mechanisms in Dentistry
## 1 Introduction
In a word, LIPUS promotes periodontal regeneration mainly through increasing osteogenic differentiation and inhibiting inflammatory responses (Figure 3). By further exploration of LIPUS, it's possible to find diverse insights and targets in periodontal regeneration. Many conclusions of present studies are based on vitro studies. According to the discrepancy, more research in vivo needs to be designed and conducted in order to have a more accurate understanding of the functions of LIPUS. Figure 3: LIPUS plays a dual role in periodontitis. By applying LIPUS, inflammatory factors including IL-6, IL-8, TNF decrease while osteogenesis-related factors increase. Therefore, the inflammatory response and alveolar resorption of periodontitis can be significantly improved. 3 LIPUS Plays a Significant Role in Orthodontic Treatment via Accelerating OTM and Alleviating OITRR  
Malocclusion is a common oral problem which may influence not only oral health and function, but also facial esthetics and even mental health [49]. With the propagation of facial and dental aesthetics, more and more patients choose orthodontic treatment to improve their appearance. However, due to the different speeds of orthodontic tooth movement (OTM), the usual duration time of orthodontic treatment ranges from one year to three years and some patients even have to bear longer periods [50]. Such a long time becomes a scruple for patients and some side effects of orthodontic treatment are more possible to happen, including caries, inflammation, and orthodontically induced tooth root resorption (OITRR) [45; 51]. Besides, during orthodontic treatment, patients will experience various degrees of pain which may affect appetite and moods [52]. The above scenarios immensely affect patient compliance and block the progress and effect of orthodontic treatment. Therefore, finding an adjuvant therapy is urgent to improve these problems. LIPUS has become a hopeful candidate in expediting OTM, reducing OITRR [8]. The wires and brackets or clear aligners in teeth can respond to external mechanical forces, and then OTM will happen, which is a complicated process of bone remodeling. During OTM, tooth can be divided into pressure zone and tension zone. The former is in the movement direction of the tooth while the other is opposite [53]. In the pressure side, bone resorption will occur which as a rate-limiting factor to OTM [54]. LIPUS was demonstrated to promote OTM in both human and animal. A randomized controlled trial (RCT) found whether applying LIPUS decreased the treatment time to 49% and the patient compliance increased to about 66% by comparing patients using LIPUS and Invaslalign SmartTrack(r) clear aligners with those only using the aligners [55]. Another RCT also obtained a similar outcome in that the average rate of tooth movement rose 29% by exposure to LIPUS [56]. The above two RCTs all suggested that LIPUS have a vital impact on promoting OTM. RANK, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), and RUNX-2 are relative to osteogenesis and bone remodeling. In rats, the expression of these factors would increase by applying LIPUS [57]. Actually, in ovariectomized osteoporotic rats, LIPUS was able to maintain normal OTM, which indicated that LIPUS may also have an effect on postmenopausal women [58]. In fact, the mechanism of LIPUS in promoting OTM is still unclear. A study found that after the stimulation of LIPUS, the number of BMP-2 positive cells and the expression of RANKL were obviously rising. The Hepatocyte growth factor (HGF)/Rurnx2/BMP-2 signaling pathway and RANKL may participate in LIPUS-induced OTM improvement [59] (Figure 4). In fact, low-level laser therapy (LLLT) can promote bone remodeling similarly, so it is also applied in orthodontic treatment [60; 61]. While LIPUS has a greater effect on osteoblast, LLLT mainly aims at osteoclast.