# Clinical Applications of Low-Intensity Pulsed Ultrasound and Its Underlying Mechanisms in Dentistry
## 1 Introduction  
Low-intensity pulsed ultrasound (LIPUS) is a non-invasive acoustic radiation generally acknowledge to play a significant role in osteogenesis [1]. The intensity of LIPUS ranges from 30 mW/cm\({}^{2}\) to 100 mW/cm\({}^{2}\). LIPUS shows mechanical vibrations at frequencies above the detection limit of human sound [2]. For avoiding tissue overheating, frequencies of 1-3 MHz and intensity of 30-90 mW/cm\({}^{2}\) for 5-30 min/day were often adopted in previous studies [3]. Interestingly, LIPUS appears to have diverse optimal parameters in different tissues and there is still no unified usage specification of LIPUS at present. According to the low-intensity and pulsed pattern, LIPUS not only has the lowest heating effect, but also contributes to transmitting sound waves into specific areas [4]. The pressure waves can serve as mechanical stimulation and activate downstream signals through signal transduction [5]. At present, it's universally acknowledged that the signal transduction is stimulated due to the influence of mechanical stress and/or fluid micro-streaming on the cellular plasma membrane, focal adhesion, and cytoskeletal structures [6, 7]. Integrin was found able to serve as the mechanoreceptor on the cell membrane and conduct mechanicalstimulation into cells [8]. When integrin was stimulated by LIPUS signals, the adhesions of focal adhesion adaptor proteins were enhanced. Then, the focal adhesion kinase (FAK) was phosphorylated and promoted signal transduction [9]. After that, the mechanical signal was transformed into electrical or biological signals and then contributed to various biological processes, such as osteogenic differentiation, bone healing, cytokine secretion, and angiogenesis [10; 11; 12]. Besides, LIPUS has been implicated to reduce the inflammatory response and mediate tissue regeneration through various signal pathways (Figure 1). As for dentistry, oral diseases have influenced a massive number of humans worldwide. In recent years, LIPUS had emerged as a burgeoning therapy in oral diseases and made great advances. The applications of LIPUS in the dental field mainly concentrate on periodontal regeneration, alveolar bone healing, orthodontic bone remodeling, temporomandibular joint cartilage regeneration, and dentin-pulp repair [13; 14; 15] (Figure 2). In this review, we integrally elaborated on the clinical application progress and the specific mechanisms of LIPUS in dentistry and expound on the application prospect of LIPUS. In fact, a review concerning recent advances of LIPUS in dentistry for the past five years is lacking. Thus, this summary may bring new insights into the current research state  
Figure 1: LIPUS alleviates oral diseases by modulating multiple signaling pathways. LIPUS can regulate diverse signaling pathways. Integrin and FAK mainly participate in the signal transduction of LIPUS. Through the integrin/FAK complex, the p38 MASK pathway and the PI3K-AKT pathway can be activated to promote osteogenic differentiation. LIPUS also inhibits NF-kB directly. Besides, LIPUS contributes to the AT1-PLC8-Ca2+ pathway and calcium influx. And the increased Ca2+ further suppresses the nuclear translocation of NF-kB which promotes the reduction of inflammatory response. LIPUS also accelerates FOXOO1 transcription by inhibiting miR-182 and then activates osteogenesis-related factors. Interestingly, Smad has a double effect. On one hand, Smad, which is assembled by LIPUS-activated BMP, plays a role in osteogenesis. On the other hand, LIPUS can stimulate the TGF-ß-Smad pathway to repair the dentin-pulp complex. of LIPUS. Furthermore, we systematically concluded the targets, parameters, and effects of LIPUS in various oral diseases. The limitations and study defects of LIPUS were also set forth. Overall, this paper aims to provide direction for future research on LIPUS in dentistry, find the usage specification of LIPUS to apply this tool more securely and more effectively, and broaden the treatment thoughts for oral diseases.