Multiscale Modeling of Facet Capsule Mechanobiology

描述（由申请人提供）：颈部和背部疼痛有一个巨大的年度发病率和相关的费用。小关节囊韧带（FCL），它包围了脊柱的双侧关节，是丰富的神经支配，提供本体感觉在正常的运动。FCL还具有伤害性神经支配，并且在异常情况下可以充当疼痛传感器。虽然异常的脊柱运动和病理状况长期以来一直与疼痛有关，但组织负荷和伤害感受器激活之间的关系尚不清楚，因为FCL功能涉及整个长度尺度的力学和生理学。将脊柱运动与FCL内的神经元功能相关联需要多尺度建模和实验来确定组织负荷可能介导神经元功能的机制。在此U 01下，我们将检验神经元反应受神经元上的局部力支配的假设，该局部力由宏观负载和其所在组织的微观结构的复杂相互作用决定。为此，我们将在组织和胶原纤维网络尺度上创建FCL力学的新的多尺度模型。我们将使用这些模型来研究组织中神经元细胞的力学环境，并预测从胶原纤维传递到神经元的力。在组织和细胞尺度上的补充实验将定义FCL，胶原纤维和神经元之间的机械相互作用，同时还描述了局部应变和神经元反应之间的关系。我们将在协调的具体目标下整合建模和实验工作，以了解FCL中纤维和非纤维材料的组织 控制其机械响应，微尺度纤维运动如何转化为神经元上的力，以及这些力如何影响神经元信号和功能。在目标1中，我们将把我们现有的生物工程组织的多尺度模型扩展到FCL的复杂几何形状和结构;在目标2中，我们将研究细胞填充的胶原凝胶模型，以预测和评估神经元在其所在的基质变形时如何受到影响。最后，在目标3中，我们将使用目标1的机械功能模型（mm到um尺度）和目标2的细胞响应模型（um到nm尺度）来创建组织加载期间神经元机械环境和响应的真实模型。该模型桥接临床显著组织中的长度尺度，将用于双重目的。首先，我们将测试上面的中心假设。其次，通过连接组织和细胞尺度，该项目将促进 努力包括关节力学和传入神经元功能的相关生理数据，这将促进对病理性脊柱运动期间小关节囊的体内反应的理解。正在开发的多尺度预测模型不仅将增强我们对关节囊退行性变、关节炎和损伤的理解，而且还将提供对具有复杂结构和几何形状以及推测性疼痛病因的其他神经支配软组织的深入了解。

DESCRIPTION (provided by applicant): Neck and back pain have a tremendous annual incidence and associated cost. The facet capsular ligament (FCL), which encloses the bilateral articulating joints of the spinal vertebrae, is richly innervated to provide proprioception during normal motions. The FCL also has nociceptive innervation and may act as a pain sensor during abnormal conditions. Although aberrant spinal motions and pathologic conditions have long been associated with pain, the relationship between tissue loading and nociceptor activation is unclear because FCL function involves mechanics and physiology across length scales. Relating spinal motions to neuronal function within the FCL requires multi-scale modeling and experiments to identify mechanisms by which tissue loading may mediate neuronal function. Under this U01, we will test the hypothesis that the neuronal response is governed by local forces on the neurons, which are determined by the complex interaction of the macroscopic load and the microscopic structure of the tissue in which it resides. To do so, we will create new, multiscale models of FCL mechanics at the tissue and collagen fiber network scales. We will use those models to study the mechanical environment of neuronal cells in the tissue and to predict the forces transmitted from the collagen fibers to the neurons. Complementary experiments at the tissue and cell scales will define mechanical interactions between the FCL, collagen fibers, and neurons while also describing the relationship between local strain and the neuronal response. We will integrate modeling and experimental work under coordinated specific aims to understand how the organization of fibrillar and non-fibrillar material in the FCL govern its mechanical response, how the micro-scale fiber motion translates into forces on neurons, and how those forces affect neuronal signaling and function. In Aim 1, we will extend our existing multiscale model of bioengineered tissues to the complex geometry and architecture of the FCL; in Aim 2, we will study a cell- populated collagen gel model to predict and assess how a neuron is affected when the matrix in which it resides is deformed. Finally, in Aim 3, we will use the mechanical function model (mm-to-um scale) of Aim 1 and the cellular response model (um-to-nm scale) of Aim 2 to create a realistic model of the neuronal mechanical environment and response during tissue loading. This model, bridging length scales in a clinically significant tissue, will serve a twofold purpose. First, we will test the central hypothesis above. Second, by connecting the tissue and cellular scales, the project will facilitate efforts to include relevant physiological data on joint mechanics and afferent neuronal function, which will promote understanding of the in vivo responses of the facet capsule during pathologic spinal motions. The multiscale predictive models being developed not only will enhance our understanding of degeneration, arthritis, and injury in the facet capsule but also will provide insight into other innervated soft tissues with complex structure and geometry and speculative pain etiology.