Multiscale Modeling of Facet CapsuleMechanobiology

摘要 颈部和背部疼痛的年发病率和相关费用巨大。关节囊韧带 (FCL)包围脊椎骨的双侧关节，并有丰富的神经支配， 脊柱运动过程中的本体感觉。FCL也受到伤害感受器的支配，并可能充当疼痛传感器 在异常情况下，如受伤和重复加载。尽管脊柱运动异常和病理性 虽然这些条件与疼痛有关，但组织负荷与伤害感受器激活之间的关系尚不清楚 由于FCL在长度尺度上涉及复杂的力学和生理学。准确 将脊柱运动与FCL内的神经元功能联系起来需要多尺度建模和实验， 确定相关的mechanotransductionmechanisms组织负载介导的神经元功能。 在U 01更新下，我们将扩展我们先前的工作，定义神经元反应如何由以下因素支配： 来自其局部环境的力，这些力由宏观环境的复杂相互作用决定。 载荷和FCL的微观结构。我们通过改进我们的多尺度模型来扩展这项工作， 组织、胶原纤维网络和神经元尺度的FCL力学。我们将使用这些模型来研究 组织中神经元及其胶原基质的力学环境，并预测 损伤和病理状况。在组织和细胞尺度上的补充实验将表征 神经元和矩阵结构和神经元的架构描述，以及定义速率效应和 FCL、胶原纤维和神经元之间的机械相互作用。我们将整合建模和 在协调的具体目标下的实验工作，以确定纤维和非纤维的组织如何 FCL中的材料控制其对不同负载情况的机械响应， 运动转化为神经元上的力，以及这些力如何影响神经元的结构、信号传导和 功能在目标1中，我们将使用先进的生物成像，图像处理和分析工具来完善我们现有的 多尺度模型和捕捉复杂的几何形状和结构的矩阵和神经元的FCL。在 目标2，我们将定义在加载过程中当其周围矩阵变形时神经元上的力;目标3包括 在我们的模型中加入粘弹性和间质流，并研究速率对组织、基质和 神经元最后，在目标4中，我们将把我们的细胞/基质模型（微米到纳米尺度）插入到整个脊柱模型中 (mm-μm尺度），以将实际宏观载荷与临床相关背景下的神经元变形联系起来。通过 连接组织和细胞的尺度，该项目将促进努力，包括相关的生理数据 在损伤和临床相关的脊髓条件与传入神经元功能， 将促进对病理运动期间关节的体内反应的理解， 增强我们对FCL中变性、关节炎和损伤的理解，同时也提供了对其他 具有复杂结构和几何形状的神经支配的软组织和推测性疼痛病因。

Abstract Neck and back pain have a tremendous annual incidence and associated costs. The facet capsular ligament (FCL) encloses the bilateral articulating joints of the spinal vertebrae and is richly innervated to provide proprioception during spinal motions. The FCL is also innervated by nociceptors and may act as a pain sensor during abnormal conditions like injury and repeated loading. Although aberrant spinal motions and pathologic conditions are associated with pain, the relationship between tissue loading and nociceptor activation is unclear due to the complicated involvement of mechanics and physiology in the FCL across length scales. Accurately relating spinal motions to neuronal function within the FCL requires multi-scale modeling and experiments to identify the relevant mechanotransduction mechanisms by which tissue loading mediates neuronal function. Under this U01 renewal, we will expand our prior work defining how the neuronal response is governed by the forces from its local environment, which are determined by the complex interaction of macroscopic loads and the microscopic structure of the FCL. We extend that work by improving our multiscale models of FCL mechanics at the tissue, collagen fiber network, and neuronal scales. We will use those models to study the mechanical environment of neurons in the tissue and its collagen matrix and to predict responses under injury and pathologic conditions. Complementary experiments at the tissue and cell scales will characterize neuron and matrix structure and architectural descriptions of neurons, as well as define rate effects and the mechanical interactions between the FCL, collagen fibers, and neurons. We will integrate modeling and experimental work under coordinated specific aims to define how the organization of fibrillar and non-fibrillar material in the FCL govern its mechanical response to different loading scenarios, how the micro-scale fiber motion translates into forces on neurons, and how those forces affect neuronal architecture, signaling and function. In Aim 1, we will use advanced bioimaging, image-processing, and analytical tools to refine our existing multiscale model and capture the complex geometry and architecture of the matrix and neurons in the FCL. In Aim 2, we will define forces on the neurons during loading when its surrounding matrix deforms; Aim 3 includes adding viscoelasticity and interstitial flow to our model and studying rate effects on both the tissue, matrix and neurons. Finally, in Aim 4, we will insert our cellular/matrix model (µm-to-nm scale) into a whole-spine model (mm-µm scale) to link realistic macroscopic loading to neuronal deformation in clinically relevant contexts. By connecting the tissue and cellular scales, the project will facilitate efforts to include relevant physiological data on joint mechanics during injury and clinically relevant-spinal conditions with afferent neuronal function, which will promote understanding of the in vivo responses of the joints during pathologic motions and will not only enhance our understanding of degeneration, arthritis, and injury in the FCL but also provide insight into other innervated soft tissues with complex structure and geometry and speculative pain etiology.