Bone Fluid Flow and its Regulatory Role in Adaptation

骨液流动及其在适应中的调节作用

• 批准号: 6944033
• 负责人: Yi-Xian Qin
• 金额: $ 29.2万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-18 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6944033
• 关键词: biological signal transduction; biomechanics; biosynthesis; computed axial tomography; fluid flow; morphometry; nuclear magnetic resonance spectroscopy; osteogenesis; osteoporosis; physical model; scanning electron microscopy; shear stress; substantia spongiosa; transmission electron microscopy; turkeys

DESCRIPTION (provided by applicant): Musculoskeletal complications, such as osteoporosis and aging related osteopenia, are major societal and health problems. Load-induced intracortical bone fluid flow is proposed as a critical mediator in initiating and regulating bone surface and osteonal adaptation. Using oscillatory pressurized marrow fluid flow stimuli, the physiological fluid stimulus was found to initiate new bone formation and reduce intracortical bone porosities caused by disuse, even in the absence of direct tissue strain. The new bone formation and inhibition of resorption were found to correlate with quantified flow parameters, i.e., fluid pressure gradients. This flow initiated bone adaptation occurs at a specific frequency range, i.e., 20-30 Hz, and is interdependent with the dose of anabolic fluid pressure. While bone remodeling was demonstrated to be sensitive to high strain frequency and low intensity physiological loading, the role of fluid flow perhaps explains, at least in part, the cellular response mechanism to anabolic stimuli. In the work proposed, we will examine the general hypothesis that bone fluid flow, mediated at specific physiological magnitudes and high frequencies, promotes osteogenic adaptation. Indeed, improving our understanding in which mechanical signals influence the temporal and spatial dynamics of bone remodeling may help to devise a biomechanically based intervention for treating osteoporosis, accelerating fracture healing or promoting bony ingrowth into prostheses. In this revised application (1-R01-AR049286-01), the goal will be achieved by a series of sub-hypotheses and specific aims: (1) The role of anabolic fluid flow, driven by daily intramedullary pressure (IMP), can initiate surface adaptive response and inhibit intracortical bone loss in a disuse bone. The remodeling response will be evaluated in a disuse in-vivo model in the absence of matrix strain following 4-week exposure of a short period of daily stimuli, consisting of a series of frequencies (0.5,1,5,10,20 & 40 Hz). (2) Osteogenic response to anabolic fluid flow stimuli is fluid pressure sensitive associated with the rate/frequency of loading. The anabolic potential response to hydraulic intensity will be evaluated in a disuse model following 4-week of daily ImP at 10, 20 and 80 mmHg with 1,5, and 20 Hz. (3) The potentials of fluid flow initiated adaptation are interdependent with specific fluid components, i.e., pressure gradient and fluid shear stress, which are responsible for restoring or inhibiting bone loss and new surface bone formation. A poroelastic finite element analysis will be developed, which will evaluate the correlation between fluid flow and resultant adaptation. (4) The osteogenic potentials response to fluid flow stimuli is initiated by osteoblastic activation of bone lining cells, following a daily but short duration (e.g., <10 days) of loading. Ultrastructural osteoblastic features of cell and nuclei will be examined via histomorphometric analysis of cell area, nuclear area, cell number, cell and nuclei shapes, in which associated fluid components will be identified.

描述（由申请人提供）： 肌肉骨骼并发症，如骨质疏松症和衰老相关的骨质减少，是主要的社会和健康问题。负荷诱导的皮质内骨液流动被认为是启动和调节骨表面和骨细胞适应的关键介质。使用振荡加压骨髓液流刺激，生理流体刺激被发现启动新骨形成和减少皮质内的废用引起的骨孔隙度，即使在没有直接的组织应变。发现新骨形成和再吸收抑制与定量流动参数相关，即，流体压力梯度这种流动引发的骨适应发生在特定的频率范围，即，20-30赫兹，并且与合成代谢流体压力的剂量相互依赖。虽然骨重建被证明是敏感的高应变频率和低强度的生理负荷，流体流动的作用可能解释，至少部分，细胞反应机制的合成代谢刺激。在这项工作中，我们将研究的一般假设，即骨液流动，介导的特定生理幅度和高频率，促进成骨适应。事实上，提高我们对机械信号影响骨重建的时间和空间动力学的理解，可能有助于设计基于生物力学的干预措施，用于治疗骨质疏松症，加速骨折愈合或促进骨长入假体。在本修订申请（1-R 01-AR 049286 -01）中，将通过一系列子假设和特定目标实现目标：（1）由每日髓内压（IMP）驱动的合成代谢液流的作用可以启动表面适应性反应并抑制废用骨中的皮质内骨丢失。在不存在基质应变的情况下，在4周暴露于由一系列频率（0.5、1、5、10、20和40 Hz）组成的短时间的每日刺激后，在废用体内模型中评估重塑反应。(2)对合成代谢流体流动刺激的成骨反应是与加载速率/频率相关的流体压力敏感性。在10、20和80 mmHg、1、5和20 Hz下每日ImP 4周后，将在废用模型中评价对水力强度的合成代谢潜力反应。(3)流体流动引发的适应的潜力与特定的流体组分相互依赖，即，压力梯度和流体剪切应力，它们负责恢复或抑制骨丢失和新的表面骨形成。将开发一个多孔弹性有限元分析，这将评估流体流动和由此产生的适应之间的相关性。(4)对流体流动刺激的成骨电位响应是由骨衬里细胞的成骨细胞活化引发的，在每天但短的持续时间（例如，<10天）的装载量。通过对细胞面积、细胞核面积、细胞数量、细胞和细胞核形状进行组织形态计量学分析，检查细胞和细胞核的超微结构成骨细胞特征，其中将识别相关的液体成分。