Multiscale Modeling of Facet CapsuleMechanobiology

摘要 颈部和背部疼痛每年的发病率和相关费用都很高。小关节囊韧带 (FCL) 包围脊柱的双侧关节，神经支配丰富，可提供 脊柱运动时的本体感觉。 FCL 也受伤害感受器支配，可以充当疼痛传感器 在受伤和重复负载等异常情况下。尽管脊柱运动异常和病理性 状况与疼痛相关，但组织负荷和伤害感受器激活之间的关系尚不清楚 由于 FCL 跨长度尺度的力学和生理学的复杂参与。准确地 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 确定组织负荷介导神经元功能的相关机械转导机制。 在这次 U01 更新中，我们将扩展之前的工作，定义神经元反应如何受 来自当地环境的力量，这些力量是由宏观环境的复杂相互作用决定的 FCL 的载荷和微观结构。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 组织及其胶原基质中神经元的机械环境并预测在 损伤和病理状况。组织和细胞尺度的补充实验将表征 神经元和矩阵结构以及神经元的架构描述，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 协调具体目标下的实验工作，以确定纤维状和非纤维状的组织如何 FCL 中的材料控制其对不同负载情况的机械响应，微米级纤维如何 运动转化为作用在神经元上的力，以及这些力如何影响神经元结构、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 多尺度模型并捕获 FCL 中矩阵和神经元的复杂几何形状和架构。在 目标 2，我们将定义加载期间神经元周围矩阵变形时作用在神经元上的力；目标 3 包括 在我们的模型中添加粘弹性和间隙流，并研究速率对组织、基质和 神经元。最后，在目标 4 中，我们将把细胞/矩阵模型（微米到纳米尺度）插入到整个脊柱模型中 （毫米-微米尺度）将现实的宏观负载与临床相关环境中的神经元变形联系起来。由 连接组织和细胞尺度，该项目将促进纳入相关生理数据的努力 损伤期间的关节力学以及具有传入神经元功能的临床相关脊柱状况， 将促进对病理运动期间关节的体内反应的理解，并且不仅 增强我们对 FCL 退化、关节炎和损伤的理解，同时也提供了对其他方面的见解 受神经支配的软组织具有复杂的结构和几何形状以及推测的疼痛病因。

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.