Multiscale mechanisms of lingual mechanical function

描述（由申请人提供）：舌头是一个结构复杂的肌肉器官，在吞咽过程中起着至关重要的作用，首先配置，然后将摄入的药丸从口腔推进到咽部。舌机械功能障碍在老年人和神经系统疾病患者中非常常见，可能是这些患者营养不良和吸入性肺炎风险增加的原因。尽管如此，人们对舌部肌肉组织对组织生理功能的贡献方式了解甚少。要想确定舌头在吞咽过程中是如何起作用的，就需要了解舌头的运动与外部结构的关系，以及内部结构和功能的基本关系。这些关系集中体现了更普遍的生理原理，即舌关节运动是由肌细胞作用和产生的内力（收缩力）和外力（粘连力、机械栓系力）的复杂平衡造成的。我们的方法考虑了舌力学和运动的多尺度属性，并旨在定义舌的精密复杂的组件阵列在吞咽过程中协调和良好控制力产生的机制。为了实现这一目标，我们的实验室开发了新技术，包括高分辨率MRI，分析和表示肌丝和细胞力学的方法，以及能够跨空间尺度量化机械性能的计算框架。MRI从中尺度（即中观尺度）的解剖结构（肌纤维束）定义了复杂组织的肌肉结构和力学，并为舌功能的有限元多尺度分析提供了解剖学和生物力学输入。我们假设由扩散加权MRI定义的中尺度肌纤维束阵列决定了吞咽过程中协调力产生和变形的模式。构成这些肌纤维束的材料和激活特性依次主要来源于肌丝生物学和与底层骨骼肌细胞相关的关系。我们的研究将集中于生成语言功能的有限元模型，并通过不断发展的知识来证实其潜在的生物物理、机械和生理属性。为了实现这一目标，我们提出以下具体目标：目标1：结合细胞几何、细胞骨架结构和肌丝相互作用，建立舌骨骼肌收缩性的生物物理模型。目的2：通过人体吞咽过程中多细胞肌纤维束的力学，推导出排列的肌细胞收缩性和组织变形之间的三维关系。目的3：基于骨骼肌功能的生物物理原理和MRI获得的肌纤维束力学，建立吞咽过程中舌部变形的有限元模型。基于本文提出的概念，从肌肉结构和力学的定量测量角度考虑吞咽过程中的舌力学应该是可行的。了解与舌力产生相关的潜在机械机制，可以设计更具体的治疗方法来解决口腔和咽吞咽困难。

DESCRIPTION (provided by applicant): The tongue is an intricately configured muscular organ that plays a vital role during swallowing, first to configure and then to propel the ingested bolus from the oral cavity to the pharynx. Disorders of lingual mechanical function are exceedingly common in the elderly and patients with neurological diseases, and may be responsible for malnutrition and increased risk of aspiration pneumonia in these patients. Notwithstanding, there is little understanding of the way in which the lingual musculature contributes to the tissue's physiological function. Determining how the tongue functions during swallowing requires an understanding of the organ's movements in relation to extrinsic structures as well as fundamental relationships involving intramural structure and function. These relationships epitomize the more general physiological tenet that articulated tongue motion results from the intricate balance of internal (contractile) and external (adhesion, mechanical tethering) forces acting on and generated by myocytes. Our approach considers lingual mechanics and motion in terms of its multiscale attributes, and is intended to define the mechanism by which the tongue's exquisitely complex array of components contribute to coordinated and well controlled force generation during swallowing. To address this goal, our laboratory has developed new technologies, including high resolution MRI, methods to assay and represent myofilament and cell mechanics, and a computational framework capable of quantifying mechanical performance across spatial scales. MRI defines complex tissue myoarchitecture and mechanics in terms of intermediate-scale, i.e. meso-scale, anatomical structures (myofiber tracts) and provides anatomical and biomechanical input into FE multiscale analysis of tongue function. We postulate that mesoscale myofiber tract arrays defined by diffusion weighted MRI dictate patterns of coordinated force generation and deformation during swallowing. The material and activation properties constituting these myofiber tracts are in turn derived principally from myofilament biology and relationships associated with the underlying skeletal myocytes. Our research will focus on the generation of a finite element model of lingual function, substantiated by evolving knowledge of its underlying biophysical, mechanical, and physiological attributes. To address this goal, we propose the following Specific Aims: Aim 1: To formulate a biophysical model of lingual skeletal muscle contractility combining cell geometry, cytoskeletal structures and myofilament interactions. Aim 2: To derive 3D relationships between the contractility of aligned myocytes and tissue deformation via the mechanics of multi-cellular myofiber tracts during human swallowing. Aim 3: To develop a finite element model (FEM) of lingual deformation during swallowing based on biophysical principles of skeletal muscle function and the mechanics of myofiber tracts derived by MRI. Based on the concepts proposed here, it should be feasible to consider lingual mechanics during swallowing in terms of quantitative measures of myoarchitecture and mechanics. Knowledge of the underlying mechanical mechanisms associated with lingual force production should allow the design of more specific therapies to address oral and pharyngeal dysphagia.