# Clinical Applications of Low-Intensity Pulsed Ultrasound and Its Underlying Mechanisms in Dentistry
## 4 LIPUS Contributes to the Stability of Implants via Facilitating Osseointegration
Since LIPUS can promote bone formation, it was applied to enhance the stability of MSIs. Through illuminating LIPUS, not only Ti-6 Al-4V MSIs, but also stainless steel (SS) MSIs contacted more closely with the surrounding bone. Besides, the cortical bone density, cortical bone thickness, and cortical bone rate all increased after applying LIPUS [87]. Another controlled experiment observed that the incorporation of MSIs and surrounding bone in the group with LIPUS exposure was stronger than that in the group without LIPUS exposure [88]. These two studies all demonstrated that LIPUS was able to reduce MSIs looseness and promote bone healing in implanting position. As a matter of fact, due to the limited human experiment, the use of LIPUS in implants is still immature. Moreover, at present, most animal experiments are based on tibia rather than jaws. More animal jaw implant models are necessary to be built and more jaw-based animal experiments need to be expanded. Further human trials are urgent to ensure the feasibility of LIPUS in humans and explore the optimal frequency of LIPUS for human implant osseointegration. LIPUS Makes an Effect on TMJ-Involved Diseases via Expediting Bone Formation and Defending Chondrocytes  
The temporomandibular joint (TMJ) mainly consists of the mandibular condylar, the articular surface of the temporal bone, and the articular disc [89]. As the only left and right linked joint in the maxillofacial region, the TMJ plays an important role in chewing, speaking, and facial movements. However, on account of the scarce oxygen, the only cells that exist in the condylar tissue of the joint are chondrocytes [90]. Many TMJ-involved diseases are relative to the bone and articular cartilage. LIPUS was proven to contribute to bone healing and the repair of cartilage injury [91; 92]. So, applying LIPUS in TMJ-involved disease anesis may be a potential approach. TMJ osteoarthritis (TMJ-OA) is a usual disease in the maxillofacial region, which may occur cartilage degradation, subchondoral bone remodeling, and bone wear [93]. TMJ-OA may result in pain and difficulty in the opening mouth due to the interaction between the generated blood vessel and invading nerves [94]. In this process, chondrocytes in TMJ generally undergo apoptosis and the cartilage matrix is easily degraded [95]. According to a direct mechanical injury and hypoxia/reperfusion injury model, a lack of oxygen in the articular cavity is able to induce the production of oxygen radicals and the oxygen radicals could result in joint injury and inflammatory response [96]. Owing to the ability of tissue regeneration, LIPUS gradually comes into view. LIPUS was demonstrated to not only protect the cartilage, but also reduce the inflammatory response through various approaches. In a simulative oxygen-deficient environment, through applying tandem mass tag (TMT) technology, it was observed that LIPUS increased the expression of chondrogenicfactors, including sox9, collagen II and aggrecan, while reducing the expression of vascular endothelial growth factor (VEGF), which suggested that LIPUS can promote chondrocytes growth and inhibit angiogenesis in hypoxia-Induced TMJ-OA. Besides, the study also found that extracellular Matrix (ECM) proteins may become fresh treatment targets [97]. However, hypoxia contributes to activating the hypoxia-inducible factor pathway, and the expression of hypoxia inducible factor (HIF) existing in chondrocytes increases. Interestingly, LIPUS was found to decrease the expression of HIF-2. This outcome indicated that HIF-2 may be the downstream targets of LIPUS in TMJ-OA [98]. In addition, through RNA sequencing, matrix-degrading enzyme (ADAMTS-8) and circadian gene (Per-2, Dbp, Npas2, and Arntl) were also considered to have a close relationship with TMJ-OA [99,100]. Through LIPUS, the expression of Per-2 increased while the expression of ADAMTS-8 decreased. In a rat TMJ-OA model, Zn\({}^{2+}\)exorter-9 (ZNT-9) could be activated by LIPUS.