Multiscale Modeling of Facet Capsule Mechanobiology

描述（由申请人提供）：颈部和背部疼痛每年有巨大的发病率和相关费用。小关节囊韧带（FCL）包裹双侧脊椎骨关节，神经丰富，在正常运动时提供本体感觉。FCL也有伤害神经支配，在异常情况下可能作为疼痛传感器。尽管异常的脊柱运动和病理状况长期以来与疼痛有关，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。将脊髓运动与FCL内的神经元功能联系起来需要多尺度建模和实验，以确定组织负荷可能介导神经元功能的机制。在此U01下，我们将测试神经元反应由神经元上的局部力控制的假设，这是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的。为此，我们将在组织和胶原纤维网络尺度上创建新的FCL力学多尺度模型。我们将使用这些模型来研究组织中神经元细胞的机械环境，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，同时也描述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，以了解纤维和非纤维材料在FCL中的组织方式

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.