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）是影响美国3500多万人的重要国家健康问题。TMJ椎间盘的机械功能障碍，特别是由于组织退变引起的移位，是许多TMJ疾病的中心。一般认为，病理性机械负荷，如持续的颌紧咬合或错颌合，会引发一系列分子事件，导致TMJ椎间盘退变。然而，人们对其机制知之甚少。正常的颞下颌关节椎间盘是一个大的无血管结构，营养供应对维持椎间盘健康至关重要。本项目的目标是开发一种非侵入式集成动态测量系统（包括TMJ成像、下颌跟踪和TMJ椎间盘有限元模型），以建立下颌负荷（模式和大小）、营养物质浓度分布（氧气/葡萄糖/乳酸）和TMJ椎间盘代谢率（氧气/葡萄糖使用和ATP/乳酸产生）之间的定量关系。我们假设TMJ椎间盘中的营养物质浓度和细胞代谢率对颌骨功能期间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。为了验证这一假设，将追求四个具体目标。目的1：确定猪TMJ椎间盘在机械应变下的运输特性。目的2：确定猪TMJ椎间盘细胞能量代谢率与营养物质浓度的关系。目的3：开发一种非侵入式综合动态测量系统，以确定TMJ椎间盘中营养物质浓度和细胞代谢率的概况。目的4：测试机械负荷模式和强度对TMJ椎间盘营养物质浓度和细胞代谢率的影响，并根据其机械敏感性确定潜在的生物指标。在颌骨功能（Aim 4）期间，受试者特定的营养环境和相应的TMJ椎间盘细胞代谢率将使用机械电化学信号分析仪（即经过验证的有限元模型）来确定，该信号分析仪的输入来自Aim 3的动态TMJ解剖，以及Aim 1的组织运输特性和Aim 2的细胞能量代谢率。成功完成所提出的目标将1)为我们理解与关节负荷、组织营养和细胞代谢相关的TMJ病理建立新的途径；2)识别早期TMJ椎间盘退变的潜在生物指标；3)建立一种新型的动态测量系统，对患者进行特异性的生物指标测定，以进行早期诊断；4)为TMJ椎间盘组织再生提供基础的转运和能量代谢数据，因为营养是软骨组织工程的关键前提；5)从总体上论证了采用多尺度方法研究关节力学生物学的可行性和重要性。虽然我们的重点将放在猪模型上，但由于它是最接近人类TMJ特性的，生物指标和测量系统都将在未来直接转化为人类研究，证明本项目在TMJ研究中的长期和重大影响。

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.