# Clinical Applications of Low-Intensity Pulsed Ultrasound and Its Underlying Mechanisms in Dentistry
## 1 Introduction
These expressed factors equip PDLCs with osteogenic differentiation capacity and play an important role in the regeneration and repair of periodontal tissue [32]. It was demonstrated that LIPUS had an anabolic effect on PDLCs and increased their pluripotent characteristics [18]. Multiple signaling pathways take part in the osteogenic differentiation of PDLCs induced by LIPUS. A research team found that the p38 MASK pathway, integrin \(\beta\)1-dependent signaling transduction, and Runt-related transcription factor 2 (Runx2) were all concerned with the osteogenic differentiation of PDLCs [33; 34]. By inhibiting the p38 MASK pathway and integrin \(\beta\)1, the expression of bone-associated factors was decreased, e.g., alkaline phosphatase (ALP), Runx2, and osteoclastin [33; 34]. Bone morphogenetic protein (BMP) can induce bone-associated factors including Runx2 and \(\beta\)-catenin to gather to the osteoclastin promoter [35]. When Smad serves as an effector of BMP, the osteogenic differentiation of PDLCs can be greatly promoted [36]. In addition to positive regulation, LIPUS also plays a negative regulating role. After post-transcriptional regulation, miR-182 was able to act as the inhibitor of transcription factor Forkhead box O1 (FOXO1) and then reduce the activation of ALP and Runx2 [37; 38]. LIPUS was shown to restrain miR-182 expression [39]. Since periodontal ligament fibroblasts (PDLFs) were also able to express bone-associated proteins, they acted as the target of growth and differentiation factors [40]. Further, in periodontal tissue metabolism, PDLFs can serve as either osteoprogenitor cells or immunoulatory cells [41]. LIPUS has two types of adjustment to the osteogenic differentiation of PDLFs. On one hand, through the ROCK signaling pathway, LIPUS reduced the inhibiting effect of lipopolysaccharide (LPS), interleukin (IL-1\(\beta\)), and tumor necrosis factor (TNF\(\alpha\)) on PDLFs osteogenic differentiation [10]. On the other hand, the stimulation of LIPUS increased the incentive function of BMP-9 to PDLFs osteogenic differentiation [10; 42]. In addition to PDLFs, LIPUS can enhance the potency of human gingival fibroblasts (HGF) osteogenic differentiation through increasing the activation of ALP and the expression of osteopenia (OPN) [43]. BMSCs are also able to differentiate into osteoblasts in a specific condition. Through comparing the BMSCs with LIPUS exposure and without LIPUS exposure, it was proven that BMSCs with LIPUS exposure had more alveolar bone formation, and the expression of COL and OPN also increased. This phenomenon indicated that the combination of LIPUS and BMSCs contributed to periodontal alveolar bone regeneration [19]. In fact, LIPUS also plays a crucial role in controlling the inflammatory response. The periodontal inflammatory response has a negative influence on periodontal tissue regeneration so reducing inflammatory response is necessary [44,45]. The periodontal inflammatory response was mainly caused by LPS, which promoted the expression of various inflammatory cytokines [46]. It was demonstrated that the LIPUS-inhibited NF-kB signaling pathway can reduce the expression of LPS-promoted inflammatory cytokines, including IL-6 and IL-8 [18]. LIPUS can inhibit NF-kB pathway through diverse upstream signals. Angiotensin II receptor type 1 (AT1) can respond to LIPUS and then activate the PLC\(\updelta\)-Ca\({}^{2+}\) pathway [47]. By using AT1 antagonist Losartan, all the functions of LIPUS to LPS-induce IL-1a and NF-kB nuclear translocation were restrained, while using PLC\(\updelta\) inhibitor U73122 may regain the NF-kB nuclear translocation. This phenomenon suggested that LIPUS inhibits the activation of NF-kB and the expression of LPS-induced IL-1a through the AT1-PLC8 pathway [48]. Besides, LIPUS can also reduce LPS directly and inhibit inflammatory signals induced by IL-1\(\updelta\) and TNF\(\upalpha\). This mechanism was possibly related to ROCK1 and other small G-proteins [10].