Biophysical Modeling of Fluid and Solute Transport in the TMJ Disc

描述（由申请人提供）：颞下颌关节疾病（TMDs）是影响美国1000多万人的重要国家健康问题。虽然TMDs的确切原因尚不清楚，但颞下颌关节（TMJ）椎间盘病理生理（即椎间盘紊乱和退变）是许多TMDs的核心。病理性机械负荷导致的TMJ椎间盘营养供应不足和机械功能失效被认为是导致TMJ椎间盘紊乱和退变的主要生物力学机制。本项目的长期目标是阐明液体和溶质转运在TMJ椎间盘力学功能和细胞营养中的作用，以描述TMDs的生物力学病因，从而制定恢复组织功能的新策略。由于TMJ椎间盘内材料的独特组成和结构，以及其力学-电化学耦合现象的复杂性，对TMJ椎间盘的输运特性和系统研究流体和营养物质在TMJ椎间盘内输运的理论模型缺乏认识。因此，本课题的具体目的是：1)评估机械应变对TMJ椎间盘输运特性的影响，建立输运特性与组织生化组成之间的本构关系；2)研究流体输运特性的变化对组织力学功能的影响，建立流体流动对圆盘加载支撑和润滑的依赖机制。为了实现Specific Aim 1，我们将：a)测定不同机械应变下猪TMJ椎间盘的水力渗透率、固定电荷密度和电导率；B)从电导率数据中获得离子扩散系数，并在输运性质（水力渗透率和溶质扩散系数）和组织水化之间建立新的本构关系，以建立应变依赖的输运性质。为了完成具体目标2，我们将确定持续机械载荷下猪TMJ椎间盘的间隙流体压力、流体负载支持和摩擦系数随时间的变化，并将流体负载支持和摩擦系数与间隙流体压力联系起来。这些研究将为椎间盘退变的生物转运相关机制提供新的见解，并为建立生物力学模型提供基础材料特性，以充分了解TMJ椎间盘的功能和病理。这项工作将支持未来的R01应用，我们将提出开发一种新的TMJ椎间盘的多相力学-电化学有限元模型，该模型将提供生理或病理负载条件下TMJ椎间盘内机械应力、应变、流体压力、营养物质浓度、电势、流体流动和营养物质运输的详细信息。我们也将建议研究椎间盘细胞对这些物理化学信号的生物学反应，以充分阐明TMJ椎间盘退变的生物力学病因。公共卫生相关性：本项目的目标是阐明液体和溶质转运在颞下颌关节（TMJ）椎间盘的组织力学功能和细胞营养中的作用，以描述TMJ疾病的生物力学病因，并开发新的、低侵入性的诊断工具和恢复组织功能的新策略。因此，该项目将为猪建立基线测量，并生成可测试的生物力学模型。在未来的研究中，我们将使用猪进一步测试这些模型，比较不同的再生方案，以及设计和评估人类替代TMJ组织。

DESCRIPTION (provided by applicant): Temporomandibular joint disorders (TMDs) are an important national health problem affecting more than 10 million people in the United States. Although the exact cause of TMDs is unclear, the temporomandibular joint (TMJ) disc pathophysiology (i.e., disc derangement and degeneration) is central to many TMDs. Poor nutritional supply to the TMJ disc as well as failure of mechanical function caused by pathological mechanical loading are believed to be the major biomechanical mechanisms for TMJ disc derangement and degeneration. The long-term goal of this project is to elucidate the roles of fluid and solute transport in TMJ disc mechanical function and cell nutrition for delineating the biomechanical etiology of TMDs in order to develop new strategies for restoring tissue function. Due to the unique composition and structure of the materials in the TMJ disc, as well as the complexity of the mechano-electrochemical coupling phenomena, there is a lack of knowledge about transport properties of the TMJ disc and appropriate theoretical models for investigating fluid and nutrient transport in the TMJ disc systematically. Therefore, the Specific Aims of this proposal are to: 1) evaluate the effect of mechanical strain on the transport properties of the TMJ disc and develop constitutive relationships between transport properties and tissue biochemical composition; 2) examine the effect of changes in fluid transport properties on the tissue mechanical function and establish fluid flow dependent mechanisms for disc loading support and lubrication. To accomplish Specific Aim 1, we will: a) determine hydraulic permeability, fixed charge density, and electrical conductivity of porcine TMJ disc under various mechanical strains; b) obtain ion diffusivities from electrical conductivity data and develop new constitutive relationships between transport properties (hydraulic permeability and solute diffusivity) and tissue hydration to establish strain-dependent transport properties. To accomplish Specific Aim 2, we will determine time-dependent interstitial fluid pressure, fluid load support, and friction coefficient of porcine TMJ disc under sustained mechanical loading, and correlate fluid load support and friction coefficient to interstitial fluid pressure. These studies will provide new insights into a bio-transport related mechanism for disc degeneration and provide baseline material properties for developing biomechanical model to fully understand TMJ disc function and pathology. This work will support future R01 applications in which we will propose to develop a new multiphasic mechano-electrochemical finite element model of the TMJ disc which will provide details of mechanical stress, strain, fluid pressure, nutrient concentrations, electrical potential, fluid flow, and transport of nutrients within the TMJ disc under physiological or pathological loading conditions. We will also propose to study the biological response of disc cells to these physicochemical signals for fully elucidating biomechanical etiology of TMJ disc degeneration. Public Health Relevance: The goal of this project is to elucidate the roles of fluid and solute transport in tissue mechanical function and cell nutrition of the temporomandibular joint (TMJ) disc in order to delineate the biomechanical etiology of TMJ disorders and to develop novel, less-invasive diagnostic tools and new strategies for restoring tissue function. Therefore, this project will establish baseline measurements for the pig and generate biomechanical models that can be tested. In future studies we will use the pig to test these models further, compare different regenerative regimens, as well as design and evaluate human replacement TMJ tissues.