Multiscale Modeling of Facet CapsuleMechanobiology

摘要 颈部和背部疼痛每年的发病率和相关成本都很高。小关节囊韧带 (FCL)包围脊柱的两侧关节，并被丰富的神经支配以提供 脊椎运动时的本体感觉。FCL也由伤害性感受器支配，可能起到疼痛传感器的作用 在非正常情况下，如受伤和重复加载。尽管脊柱异常运动和病理 条件与疼痛有关，组织负荷和伤害性感受器激活之间的关系尚不清楚 由于FCL涉及复杂的力学和生理因素，涉及的长度范围很广。准确地 将脊髓运动与FCL内的神经元功能联系起来需要多尺度的建模和实验来 确定组织负荷调节神经功能的相关机械转导机制。 在这次的U01更新中，我们将扩展我们之前的工作，定义神经元反应是如何由 来自当地环境的力量，这是由宏观因素的复杂相互作用决定的 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 FCL在组织、胶原纤维网络和神经元尺度上的力学。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力学环境和预测在 伤情和病理情况。组织和细胞规模的互补性实验将表征 神经元和矩阵结构以及神经元的体系结构描述，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。我们将把建模和 协调下的实验工作的具体目的是确定纤维和非纤维的组织如何 材料在整箱中支配着其对不同加载情况的机械响应，微尺度的纤维如何 运动转化为对神经元的力，以及这些力如何影响神经元的结构、信号和 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 多尺度建模和捕捉FCL中的基质和神经元的复杂几何和架构。在……里面 目标2，我们将定义在加载过程中当其周围的矩阵变形时对神经元的力；目标3包括 在我们的模型中加入了粘弹性和间质流动，并研究了速率对组织、基质和 神经元。最后，在目标4中，我们将把我们的细胞/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)，将真实的宏观负荷与临床相关环境中的神经元变形联系起来。通过 将组织和细胞尺度连接起来，该项目将促进包括相关生理数据的努力 关于损伤过程中的关节力学和临床相关-脊髓状况与传入神经元功能， 将促进对关节在病理性运动中的活体反应的理解，不仅 增强我们对FCL中的退行性变、关节炎和损伤的了解，同时也提供对其他 神经支配的软组织具有复杂的结构和几何形状，并推测疼痛的病因。

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.