# Clinical Applications of Low-Intensity Pulsed Ultrasound and Its Underlying Mechanisms in Dentistry
## 1 Introduction
LIPUS Promotes Periodontal Regeneration via Increasing Osteogenic Differentiation and Inhibiting the Inflammatory Response  
As one of the most common oral diseases, periodontitis is a kind of devastating disease and relative to microorganisms which is one of the barriers to periodontal regeneration [16]. During periodontitis, broken periodontal tissues (alveolar bone, gingiva, and periodontium), progressive inflammatory reactions, and even tooth loss can be observed, which would significantly influence the supporting function of the periodontal structures, and bring a great deal of discomfort to patients. The conventional treatments for periodontitis include debridement, anti-inflammatory therapy, and allotriodontia [16]. However, the effect of anti-inflammatory is unsatisfactory and traditional tissue regeneration therapy is time-consuming [15]. Based on these existing limitations, it's necessary to discover a new therapy that not only has an influence on anti-inflammatory, but also contributes to periodontal tissue regeneration. Studies have proven that LIPUS has broad prospects in periodontal diseases. During periodontal wound healing, periodontal ligament cells, osteoblasts of mandibular, and gingival epithelial cells can respond to LIPUS. At the same time, through applying LIPUS, the expression of heat shock protein 70 (HSP 70) was increase, which contributes to wound healing [4]. Presently, LIPUS is considered to have huge potency in periodontal tissue regeneration. Periodontal tissue regeneration can be divided into alveolar bone regeneration,  
Figure 2: The general devices of LIPUS apply to different oral diseases. gingiva regeneration, and periodontium regeneration. It has been demonstrated that LIPUS can promote alveolar bone regeneration, suggesting that it can accelerate periodontal tissue repair [15]. However, several studies found that LIPUS's capacity of promoting periodontal tissue regeneration was mainly relative to the osteogenic differentiation of various cells, including osteogenic differentiations of human periodontal ligament stem cells (hPDLSCs), human periodontal ligament cells (hPDLSCs), fibroblasts, and bone marrow stromal cells (BMSCs) [17; 18; 19]. HPDLSCs participate in periodontal tissue regeneration owing to their ability to differentiate into osteoblast, mechanocyte, and cementoblast [20]. Moreover, it has been proven that PDLSCs can construct a cementum-periodonium-like composite structure in rats [21]. The application of LIPUS was able to enhance the osteogenic differentiation of hPDLSCs and promote the regeneration of periodontal ligament (PDL) like tissue [14]. Through using LIPUS, more extracellular matrix (ECM)-related genes were found, including constans-like (COL-1, COL-3), fibronectin [22], integrin\(\beta\)-1, and laminin (LN). These genes contributed to cell differentiation, cell growth, and cell proliferation. Specially, COL-1 participated in forming PDL, which is also called periodonotiny [23; 24; 25]. The increasing genes can promote the synthesis of ECM and the growing ECM enhanced the functions of hPDLSCs [14]. Besides, another study supposed that LIPUS played an important role in inhibiting endoplasmic reticulum stress (ERS) and then reducing unfolded protein response (UPR), and finally facilitating PDLSCs osteogenic differentiation [17]. The nuclear translocation of NF-kB can inhibit PDLSCs osteogenic differentiation. LIPUS is able to inhibit the NF-kB pathway to block nuclear translocation [26]. In addition to osteogenic differentiation, LIPUS also has an influence on the migration of PDLSCs. LIPUS may promote PDLSCs through the stromal cell-derived factor-1 (SDF-1)/C-X-C motif chemokine receptor 4 (CXCR4) signaling pathway. In this process, twist family bHLH transcription factor 1 (TWIST1) serves as the upstream factor of SDF-1 [27; 28; 29]. Moreover, the migrated PDLSCs contributed to PDL regeneration and repair [30]. PDLSCs could express bone-associated molecules and stimulate growth factors [31].