Musculo-Dynamics in Bone Fluid Flow, Circulation and Ada

描述(申请人提供)：肌肉骨骼微血管循环向肌肉和骨骼提供营养、氧气和生理流动，并从肌肉和骨骼中转移废物。肌肉骨骼并发症是由损伤期间微循环减少和功能性废用(如卧床休息和微重力)引起的，在肌肉萎缩和骨量减少方面具有显著的生理效应。运动，如肌肉收缩，似乎增加了流向骨骼组织，即骨骼和肌肉的血流量。肌肉动力学诱导的骨液流动被认为是启动和调节骨适应的关键介质。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。虽然骨重建被证明对高速率的动态生理刺激很敏感，但骨骼和肌肉中的液体流动可能至少部分解释了细胞对合成代谢刺激的反应机制。在拟议的工作中，我们将检验一般假设，即骨骼肌循环在动态功能刺激下作为动态肌泵和骨液流动的关键媒介，控制和促进成骨和肌肉适应。事实上，提高我们对肌肉动力学(例如，肌肉收缩的频率和幅度)、循环和通过骨骼的液体流动的作用的了解，可能有助于设计一种基于生物力学的干预措施，用于治疗骨质疏松症、肌肉萎缩，促进骨折愈合或促进假体内的骨生长。 在这一应用中，这一目标将通过一系列的亚假设和具体目标来实现：(1)骨骼肌的功能性收缩可以启动和增强动态的间质液体流动。功能性肌肉收缩是产生髓内压力的动力泵，并调节静脉回流，从而启动骨骼内的液体流动。(2)肌肉动力刺激诱导的骨液流动可以启动表面适应性反应，抑制废弃骨皮质内的骨丢失。自适应响应将对加载模式的速率敏感。(3)肌泵对合成液体流动刺激的成骨反应依赖于产生的液体压力大小和加载时间。(4)肌肉刺激的动态模式能启动肌肉适应，在生理水平诱导的负荷会增加肌肉的毛细血管密度，显著增加肌肉的血流量，而超负荷则会导致骨血流缺血后的部分肌肉血管萎缩。(5)在动态负荷过程中加入静止期，可优化肌肉和骨骼的液体渗透，降低液体饱和度，改善血液灌注量。(6)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 microvascular circulations supply nutrients, oxygen and physiological flow to and move waste from muscle and bone. Musculoskeletal complications, induced by reduced microcirculation in the condition during injury and functional disuse (e.g., bedrest and microgravity), have significant physiological effects in muscle atrophy and osteopenia. Exercise such as muscle contraction appears to increase blood flow to the skeletal tissues, i.e., bone and muscle. Musculo-dynamics induced bone fluid flow is proposed as a critical mediator in initiating and regulating 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. While bone remodeling was demonstrated to be sensitive to high rate of dynamic physiological stimulation, the role of fluid flow in both bone and muscle perhaps explains, at least in part, the cellular response mechanism to anabolic stimuli. In the work proposed, we will examine the general hypothesis that skeletal musculocirculation, mediated at dynamic functional stimulation, serves as a dynamic muscle pump and a critical mediator for bone fluid flow, which controls and promotes osteogenic and muscular adaptation. Indeed, improving our understanding the roles of muscular dynamics (e.g., frequency and magnitude of muscle contraction), circulations, and fluid flow through bone may help to devise a biomechanically based intervention for treating osteoporosis, muscle atrophy, and accelerating fracture healing or promoting bony ingrowth into prostheses. In this application, the goal will be achieved by a series of sub-hypotheses and specific aims: (1) Dynamic interstitial fluid flow can be initiated and enhanced by functional contraction of skeletal muscle. Functional muscle contraction serves as a dynamic pump to generate intramedullary pressure and regulates venous return, which initiate fluid flow in bone. (2) Bone fluid flow induced by musculo-dynamic stimulation can initiate surface adaptive response and inhibit intracortical bone loss in a disuse bone. The adaptive response will be sensitive to the rate of loading patterns. (3) Osteogenic response to anabolic fluid flow stimuli induced by muscle-pump is dependent on generated fluid pressure magnitude and loading duration. (4) The potentials of dynamic patterns of muscle stimuli can initiate muscular adaptation, in which loads induced at the physiological level will increase capillary density and substantially increase blood flow in muscle, while overloading will cause partial musculovascular atrophy following bone bloodflow ischemia. (5) Fluid infiltration in muscle and bone can be optimized by insertion of rest preiod during dynamic loading, which reduce the fluid saturation and improve perfusion. (6) 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.