Integrating Biomechanics and Cell Biology to Understand TMJ Pathology

描述（由申请人提供）：颞下颌关节疾病（TMJD）是一个重要的国家健康问题，影响超过3500万人在美国。颞下颌关节盘的机械功能障碍，特别是由于组织变性引起的移位，是许多颞下颌关节疾病的核心。通常认为，病理性机械负荷，例如持续的咬紧牙关或咬合不正，触发导致TMJ椎间盘退变的分子事件级联。然而，人们对这一机制知之甚少。正常的颞下颌关节盘是一个大的无血管结构，营养供应是维持关节盘健康的关键。本项目的目的是开发一种非侵入性集成动态测量系统（包括TMJ成像、颌骨跟踪和TMJ椎间盘有限元模型），以建立TMJ椎间盘中颌骨负荷（模式和大小）、营养浓度分布（氧/葡萄糖/乳酸）和代谢率（氧/葡萄糖使用和ATP/乳酸产生）之间的定量关系。我们推测TMJ椎间盘中的营养物质浓度和细胞代谢率对下颌功能期间的机械负荷的模式和大小敏感，因此是评估机械负荷对TMJD影响的潜在早期生物指标。为了检验这一假设，将追求四个具体目标。目的1：确定猪颞下颌关节盘的运输性能与机械应变。目的2：测定猪颞下颌关节盘细胞能量代谢率与营养浓度的关系。目标3：建立一种无创性的综合动态测量系统，以测定颞下颌关节盘内营养物质浓度和细胞代谢率的分布。目标4：测试机械负荷模式和强度对TMJ椎间盘中营养物质浓度和细胞代谢率的影响，并根据其机械敏感性识别潜在的生物指示剂。将使用机械-电化学信号分析仪（即，经验证的有限元模型），输入目标3的动态TMJ解剖结构以及目标1的组织传输特性和目标2的细胞能量代谢率。成功完成所提出的目标将1）建立一种新的方法来理解与关节负荷、组织营养和细胞代谢相关的TMJ病理学; 2）确定早期TMJ椎间盘退变的潜在生物指标; 3）建立一种新的动态测量系统来确定用于早期诊断的患者特异性生物指标; 4）提供TMJ椎间盘组织再生的基础运输和能量代谢数据，因为营养是软骨组织工程的关键先决条件;和5）证明采取这种多尺度方法来研究关节机械生物学的可行性和重要性。虽然我们的重点将是猪模型，因为它是最接近人类颞下颌关节的特性，生物指标和测量系统将在未来直接转化为人类研究，证明了这个拟议的项目在颞下颌关节研究的长期和重大影响。

DESCRIPTION (provided by applicant): Temporomandibular joint disorders (TMJD) are an important national health problem affecting more than 35 million people in the United States. Mechanical dysfunction of TMJ disc, especially displacement due to tissue degeneration, is central to many TMJ disorders. It is generally believed that pathological mechanical loadings, e.g. sustained jaw clenching or malocclusion, trigger a cascade of molecular events leading to TMJ disc degeneration. However, the mechanism is poorly understood. The normal TMJ disc is a large avascular structure and nutrient supply is crucial for maintaining disc health. The objective of this project is to develop a non-invasive integrated dynamic measuring system (with TMJ imaging, jaw tracking, and TMJ disc finite element model) to establish quantitative relationships between jaw loading (pattern and magnitude), nutrient concentration profiles (oxygen/glucose/lactate), and metabolic rates (oxygen/glucose use and ATP/Lactate production) in TMJ disc. We hypothesize that the nutrient concentrations and cell metabolic rates in TMJ disc are sensitive to the pattern and magnitude of the mechanical loading during jaw function and are therefore potential early bio-indicators for evaluating the impact of mechanical loading on TMJD. Four specific aims will be pursued to test this hypothesis. Aim 1: Determine transport properties of porcine TMJ discs in relation to mechanical strains. Aim 2: Determine porcine TMJ disc cell energy metabolic rates in relation to nutrient concentrations. Aim 3: Develop a non-invasive integrated dynamic measuring system to determine the profiles of nutrient concentrations and cell metabolic rates in TMJ disc. Aim 4: Test the impact of mechanical loading pattern and magnitude on nutrient concentrations and cell metabolic rates in TMJ disc and identify potential bio-indicators based on their mechanical sensitivities. Subject-specific nutrient environment and corresponding cell metabolic rates in TMJ disc during jaw function (Aim 4) will be determined using a mechano-electrochemical signal analyzer (i.e., validated finite element model) with inputs of dynamic TMJ anatomy from Aim 3 as well as tissue transport properties from Aim 1 and cell energy metabolic rates from Aim 2. Successful completion of the proposed aims will 1) establish a new approach to our understanding of TMJ pathology related to joint loading, tissue nutrition, and cell metabolism; 2) identify potential bio-indicators of early TMJ disc degeneration; 3) establish a novel dynamic measuring system to patient-specifically determine those bio-indicators for early diagnosis; 4) provide foundational transport and energy metabolic data for TMJ disc tissue regeneration since nutrition is a key prerequisite for cartilaginous tissue engineering; and 5) demonstrate the feasibility and importance to take this multiscale approach to study joint mechanobiology in general. Although our focus will be on the porcine model, since it is the closest to human TMJ properties, the bio-indicators and measuring systems will all be directly translated to human studies in the future, demonstrating the long term and significant impact of this proposed project in TMJ research.