# Clinical Applications of Low-Intensity Pulsed Ultrasound and Its Underlying Mechanisms in Dentistry
## 4 LIPUS Contributes to the Stability of Implants via Facilitating Osseointegration
The increased ZNT-9 had an effect on down-regulating ADAMTS-8 and up-regulating aggrecan in chondrocytes, which contributed to the protection of chondrocytes [99]. Based on the above results, studies of ZNT-9 or ADAMTS-8 and LIPUS may provide novel insights into the treatment of TMJ-OA. Moreover, in the rabbit TMJ-OA model, LIPUS was proven to inhibit inflammatory cytokine interleukin-6 to anti-inflammation and this inhibiting effect was mediated by the transforming growth factor-\(\beta\)1 (TGF-\(\beta\)1)/Smad3 pathway [101]. Synovial tissue plays a significant role in TMJ nutrition and lubrication. LIPUS can lower the expression of matrix metalloproteinase-9 (MMP-9) which participates in the production of cytokines and tissue injury in inflammation [102]. Moreover, immunohistochemistry indicated that MMP-9 is over-expressed in the synovial tissue of OA patients [103]. Thus, LIPUS may have potency in reducing the inflammation of synovial tissue in TMJ by inhibiting MMP-9 expression. Therefore, LIPUS was considered as a hopeful therapeutic tool of TMJ-OA on account of protecting articular cartilage/chondrocytes, reducing ECM degradation, and alleviating inflammatory reactions. Mandibular deficiency, which is characterized by mandibular retrusion, is one of the usual reasons for class II malocclusions [104]. Mandibular deficiency influences the appearance and function of TMJ, so it's necessary to stimulate bone formation in the mandible [105]. However, some studies demonstrated that LIPUS was able to accelerate bone formation in conde. Applying LIPUS in TMJ of rats for 20 min/day, it could be observed that both the thickness of fibrous cartilage and the number of cells increased. Endochondral bone formation and subchondral trabecular bone remodeling in condey were also promoted obviously. These phenomena suggested that LIPUS contribute to cartilage and bone formation of condey [106]. Thus, the application of LIPUS in mandibular deficiency is feasible. Besides, Micro-CT analysis showed that the bone volume fraction in rats with LIPUS treated was higher than that in rats without disposal. Interestingly, the bone volume in rats with LIPUS and basic fibroblast growth factor (bFGF) treated was uppermost [107]. This study not only showed that LIPUS can stimulate the growth of mandibular condey, but also revealed that there is a synergistic effect between LIPUS and bFGF. Similarly, through histological examination and Micro-CT, it was demonstrated that the cooperation of LIPUS and functional appliances had a positive influence on condey growth and chondrocytes proliferation [108]. However, the usage time of LIPUS can also affect the effect of condey growth. When TMJ was irradiated with LIPUS for 10 min/day, 20 min/day, and 40 min/day, the greatest increase in trabecular perimeter was observed in rats with LIPUS treated at 20 min per day, implying the best effect on condayl growth [109,110]. Taken together, LIPUS can improve mandibular deficiency, especially the growth of the condey, and it works best when used for 20 min/day. Mandible fracture is the second most common fracture in the maxillofacial region [111]. It had been demonstrated that the cells in mandibular fracture hematomas had the potency of osteogenesis [112]. In an animal experiment, LIPUS had been found that had the prospect in mandible fracture treatment. In the rabbit unilateral mandibular interceptive model, after the application of LIPUS, the rigidity of healing bone became stronger, meaning greater mechanical property. Besides, according to histomorphometric analysis, both bone volume and bone densities all remarkably increased in LIPUS-treated rabbits [113]. Mandibular fracture hematoma-derived cells (MHCs) had the capacity for osteogenic differentiation and may contribute to bone healing in mandibular fracture. Increased expression of osteogenic-related factors, such as ALP, Runx2, and OPN, can be observed in human MHCs irradiated with LIPUS.