Multiscale Modeling of Facet Capsule Mechanobiology

小面胶囊力学生物学的多尺度建模

• 批准号: 8698747
• 负责人: VICTOR H BAROCAS
• 金额: $ 46.56万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698747
• 关键词: Address; Affect; American; Architecture; Arthritis; Back Pain; Behavior; Bilateral; Biological Assay; Biomedical Engineering; Cell Survival; Cells; Cervical; Clinical Pathology; Collagen; Collagen Fiber; Complex; DNA Sequence Rearrangement; Data; Environment; Etiology; Experimental Models; Facet joint structure; Fiber; Gel; Geometry; Incidence; Injury; Intervertebral disc structure; Joints; Knee; Length; Ligaments; Location; Measures; Mechanics; Mediating; Microscopic; Modeling; Motion; Neck Pain; Neurons; Nociception; Nociceptors; Pain; Pathologic; Physiological; Physiology; Proprioception; Receptor Activation; Research; Risk; Shoulder; Signal Transduction; Simulate; Specific qualifier value; Specificity; Specimen; Spinal; Spinal Ganglia; Structure; Testing; Tissues; Translating; Vertebral column; Work; base; capsular ligament; capsule; clinically significant; cost; experience; in vivo; insight; joint loading; mechanical behavior; multi-scale modeling; nerve supply; pain receptor; predictive modeling; public health relevance; research study; response; sensor; soft tissue; spine bone structure

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.

描述（由申请人提供）：颈部和背部疼痛的年发病率和相关费用非常高。小关节囊韧带 (FCL) 包围脊柱的双侧关节，神经支配丰富，可在正常运动期间提供本体感觉。 FCL 还具有伤害性神经支配，在异常情况下可以充当疼痛传感器。尽管异常的脊柱运动和病理状况长期以来一直与疼痛相关，但组织负荷和伤害感受器激活之间的关系尚不清楚，因为 FCL 功能涉及跨长度尺度的力学和生理学。将脊柱运动与 FCL 内的神经元功能联系起来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。在这个 U01 中，我们将测试这样的假设：神经元反应是由神经元上的局部力控制的，而局部力是由宏观负载与其所在组织的微观结构之间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元细胞的机械环境，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 中纤维状和非纤维状材料的组织方式 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传导和功能。在目标 1 中，我们将把现有的生物工程组织多尺度模型扩展到 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所在基质变形时受到的影响。最后，在目标 3 中，我们将使用目标 1 的机械功能模型（毫米到微米尺度）和目标 2 的细胞响应模型（微米到纳米尺度）来创建神经元力学环境的真实模型和组织加载期间的反应。该模型桥接了具有临床意义的组织中的长度尺度，将具有双重目的。首先，我们将检验上面的中心假设。其次，通过连接组织和细胞尺度，该项目将促进 努力纳入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小关节囊退化、关节炎和损伤的理解，而且还将提供对其他具有复杂结构和几何形状的神经支配软组织以及推测疼痛病因学的深入了解。