Application of Mechanical Vibration to Enhance Orthodontic Tooth Movement

描述(由申请人提供)：正畸治疗中的一个关键挑战是需要很长的治疗时间才能达到足够的效果。为这一挑战制定解决方案将对正畸护理的质量产生积极影响。为了更快地移动牙齿，已经探索了两种策略，即局部注射PGE2和RANKL等生物分子，以及手术切除牙槽骨(去皮质)。然而，这两种方法因其侵袭性而未能转化为临床应用。该项目的长期目标是应用机械振动(MV)来增强正畸患者的牙齿移动，以缩短整体治疗时间。本项目的总体目标是使用小鼠模型更好地了解MV对正畸牙移动(OTM)的影响，并确定其对牙槽骨建模的影响作为这种影响的潜在机制。OTM是一种机械诱导的牙周组织建模过程，其中骨在压缩侧被吸收，并在牙周膜(PDL)的张力侧形成。无论力有多轻，由于牙根和牙槽窝壁的不规则表面，PDL内的血管都会受到一定程度的闭塞，导致组织损伤，这种损伤被称为“玻璃化”，导致OTM的滞后期。因此，在不堵塞血管的情况下增加牙齿的运动是移动牙齿更快的关键。实现这一点的可能方法之一是使用MV来修改静态正畸力。最近，共振振动被证明能够增加大鼠的OTM率(Nishimura，2008)。然而，导致这种效应的机制尚不清楚。我们在小鼠身上的初步数据表明，MV增加了OTM。基于这些发现，我们推测MV可能是一种有效的非侵入性工具来增强OTM，其机制可能是通过调节OPG/RANKL和SOST信号通路来实现的。为了验证我们的假设，我们计划完成以下具体目标(SA)。SA1：确定生理频率的MV对OTM率的影响。为了达到这一特定的目的，我们将每隔3天对小鼠上颌骨第一磨牙进行正畸移动，连续28天。为了量化OTM的发生率，将在第28天进行每周X线片和显微CT扫描。我们的工作假设是MV提高了OTM率。SA2：证明MV通过改变牙槽骨的造模率来影响OTM。为了达到这一特定目的，将对未脱钙的组织进行切片，以评估组织形态计量学参数和组织学染色。为了深入了解这一机制，将用免疫组织化学方法检测三个关键的骨代谢调节分子-OPG、RANKL和SOST蛋白的产生情况。我们的工作假设是，MV通过增加RANKL/OPG的比率和SOST蛋白的产生来增加PDL受压侧的骨吸收。如果我们的假设被证明是正确的，合乎逻辑的下一步将是进一步研究这种现象的机制，并将目前的发现从动物转化为人类临床研究。

DESCRIPTION (provided by applicant): One of the key challenges in orthodontics is the long treatment time necessary to achieve adequate results. Developing solutions to this challenge would have a positive impact on the quality of orthodontic care. In an attempt to move teeth faster, two strategies had been explored, namely local injections of biomolecules such as PGE2 and RANKL, and surgical severance (decortication) of the alveolar bone. However, both methods have failed to be translated to clinical application because of their invasiveness. The long-term goal of this project is to apply mechanical vibration (MV) to enhance tooth movement in orthodontic patients to shorten overall treatment time. The overall objective of this project is to use a mouse model to better understand the effect of MV on orthodontic tooth movement (OTM) and to determine its effect on alveolar bone modeling as the underlying mechanism of this effect. OTM is a process of mechanically-induced modeling of periodontium wherein bone is resorbed on the compression side and formed on the tension side of the periodontal ligament (PDL). No matter how "light" a force is, due to the irregular surfaces of the dental root and alveolar socket wall, the blood vessels in the PDL are occluded to some extent, inducing a tissue damage called "hyalinization" and leading to a lag phase of OTM. Thus, increasing tooth motion without blood vessel blockage is the key to move teeth faster. One of the possible means of achieving this is to use MV to modify static orthodontic forces. Recently, resonance vibration has been shown to be able to increase OTM rate in rats (Nishimura, 2008). The mechanism leading to the effect, however, is not known. Our preliminary data in mice suggest increased OTM with MV. Based on these findings, we hypothesize that MV may be a powerful and non-invasive tool to enhance OTM and that the mechanism of this effect may be through the modulation of the OPG/RANKL and SOST signaling pathways. To test our hypotheses, we plan to complete the following specific aims (SA). SA1: To determine the effects of MV at physiological frequency on OTM rates. To target this specific aim, we will apply MV to the orthodontically moved maxillary 1st molars in mice every 3 days for 28 consecutive days. To quantify the rate of OTM, weekly radiographs and a microCT scan on the 28th day will be taken. Our working hypothesis is that MV enhances OTM rates. SA2: To prove that MV affects OTM by altering the modeling rates of the alveolar bone. To target this specific aim, undecalcified tissues will be sectioned to evaluate the histomorphometric parameters as well as histological staining. To gain insights into the mechanism, the production profile of three key bone metabolic regulatory molecules - OPG, RANKL and SOST proteins will be examined Immunohistochemically. Our working hypothesis is that MV increases bone resorption at the compression side of PDL by increasing the ratio of RANKL/OPG and the production of SOST protein. If our hypotheses prove to be correct, the logical next step will be to further investigate the mechanism of this phenomenon as well as to translate the current findings from animals to human clinical studies.