Bone Fluid Flow and its Regulatory Role in Adaptation

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量减少，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适应的关键介质。使用振荡加压骨髓液体流动刺激，发现生理液体刺激可启动新骨形成，并减少因废弃而引起的皮质内骨疏松，即使在没有直接组织应变的情况下也是如此。新骨形成和抑制吸收被发现与量化的流动参数，即流体压力梯度相关。这种血流启动的骨适应发生在一个特定的频率范围，即20-30赫兹，并与合成代谢液压力的剂量相互依赖。虽然骨重建被证明对高应变频率和低强度的生理负荷敏感，但流体流动的作用可能至少部分解释了细胞对合成代谢刺激的反应机制。在这项拟议的工作中，我们将检验一般假设，即在特定生理水平和高频下调节的骨液流动促进成骨适应。事实上，提高我们对力学信号影响骨重建的时间和空间动力学的理解，可能有助于设计出一种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假体内的骨生长。在本修订申请(1-R01-AR049286-01)中，该目标将通过一系列假设和具体目标来实现：(1)在每日髓内压力(IMP)的驱动下，合成液流的作用可以启动表面适应性反应并抑制废弃骨中的皮质内骨丢失。在一种废弃的体内模型中，在没有基质应变的情况下，在暴露于由一系列频率(0.5，1，5，10，20和40赫兹)组成的短时间的每日刺激4周后，将评估重塑反应。(2)对同化液体流动刺激的成骨反应是流体压力敏感的，与加载速率/频率有关。在每天10、20和80毫米汞柱、1、5和20赫兹的4周IMP后，将在废弃模型中评估合成代谢电位对水力强度的响应。(3)流体启动适应的潜力与特定的流体成分相互依赖，即压力梯度和流体剪应力，它们负责恢复或抑制骨丢失和新骨形成。将开发一种多孔弹性有限元分析，以评估流体流动和所产生的适应之间的相关性。(4)成骨潜能对流体流动刺激的反应是由骨衬里细胞的成骨细胞激活启动的，在每天但很短的时间(例如，10天)的加载之后。细胞和细胞核的超微结构成骨细胞特征将通过对细胞面积、核面积、细胞数量、细胞和核形状的组织形态计量学分析来检测，其中相关的流体成分将被识别。

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.