Multiscale Modeling of Facet Capsule Mechanobiology

描述(由申请者提供)：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)包裹着脊柱两侧的关节，在正常运动时有丰富的神经支配以提供本体感觉。FCL也有伤害性神经支配，在异常情况下可能起到疼痛传感器的作用。尽管脊柱异常运动和病理条件长期以来与疼痛有关，但组织负荷和伤害性感受器激活之间的关系尚不清楚，因为FCL功能涉及到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，需要多尺度的建模和实验来确定组织负荷可能调节神经元功能的机制。根据这一U01，我们将测试假设，即神经元的反应是由神经元上的局部作用力决定的，这是由宏观载荷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、多尺度的FCL力学模型。我们将使用这些模型来研究组织中神经细胞的力学环境，并预测从胶原纤维传递到神经元的力。组织和细胞尺度的互补性实验将定义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中的组织结构 控制其机械反应，微尺度纤维运动如何转化为对神经元的力，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，以预测和评估当神经元所在的基质变形时它将如何受到影响。最后，在目标3中，我们将使用目标1的机械功能模型(mm-to-um Scale)和目标2的细胞响应模型(um-to-nm Scale)来创建组织加载过程中神经元力学环境和响应的逼真模型。这个模型，在临床上有意义的组织中桥接长度尺度，将起到双重作用。首先，我们将检验上面的中心假设。其次，通过将组织和细胞尺度连接起来，该项目将促进 努力包括有关关节力学和传入神经元功能的相关生理数据，这将促进对小关节囊在病理性脊髓运动中的体内反应的了解。正在开发的多尺度预测模型不仅将增强我们对小关节囊内退行性变、关节炎和损伤的了解，还将为了解其他具有复杂结构和几何形状的神经支配软组织和推测疼痛原因提供帮助。

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.