Biophysical Modeling of Fluid and Solute Transport in the TMJ Disc

描述（由申请人提供）：颞下颌关节紊乱病（TMD）是一个重要的国家健康问题，影响美国1000多万人。虽然TMD的确切原因尚不清楚，但颞下颌关节（TMJ）椎间盘病理生理学（即，椎间盘紊乱和退化）是许多TMD的核心。颞下颌关节盘的营养供应不足以及病理性机械负荷导致的机械功能衰竭被认为是颞下颌关节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椎间盘机械功能和细胞营养中的作用，以描绘TMD的生物力学病因，从而制定恢复组织功能的新策略。由于颞下颌关节盘内物质组成和结构的独特性，以及机械-电化学耦合现象的复杂性，目前还缺乏对颞下颌关节盘内流体和营养物质输运特性的认识，缺乏系统研究流体和营养物质在颞下颌关节盘内输运的理论模型。因此，本提案的具体目的是：1）评价机械应变对TMJ盘传输特性的影响，并建立传输特性与组织生化成分之间的本构关系; 2）检查流体传输特性变化对组织机械功能的影响，并建立盘负载支持和润滑的流体流动依赖性机制。为了实现具体目标1，我们将：a）确定猪TMJ盘在各种机械应变下的水力渗透率、固定电荷密度和电导率; B）从电导率数据获得离子扩散率，并开发运输特性（水力渗透率和溶质扩散率）与组织水合作用之间的新本构关系，以建立应变依赖性运输特性。为了实现特定目标2，我们将确定持续机械负荷下猪TMJ盘的时间依赖性间质流体压力、流体负荷支持和摩擦系数，并将流体负荷支持和摩擦系数与间质流体压力相关联。这些研究将为椎间盘退变的生物运输相关机制提供新的见解，并为开发生物力学模型提供基线材料特性，以充分了解TMJ椎间盘功能和病理。这项工作将支持未来的R 01应用，其中我们将提议开发一种新的颞下颌关节盘多相机械-电化学有限元模型，该模型将提供机械应力、应变、流体压力、营养浓度、电位、流体流动和营养素运输的详细信息生理或病理负荷条件下颞下颌关节盘内。我们也将提出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颞下颌关节（TMJ）盘的组织机械功能和细胞营养中的流体和溶质运输的作用，以描绘TMJ疾病的生物力学病因，并开发新的，微创的诊断工具和恢复组织功能的新策略。因此，本项目将建立猪的基线测量值，并生成可供测试的生物力学模型。在未来的研究中，我们将使用猪来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.