Musculo-Dynamics in Bone Fluid Flow, Circulation and Ada

描述（由申请人提供）：肌肉骨骼微血管循环向肌肉和骨骼提供营养、氧气和生理流量，并从肌肉和骨骼中清除废物。肌肉骨骼并发症是由损伤和功能废用（例如卧床休息和微重力）期间微循环减少引起的，对肌肉萎缩和骨质减少具有显着的生理影响。肌肉收缩等运动似乎会增加流向骨骼组织（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流刺激，即使在没有直接组织应变的情况下，生理液体刺激也能引发新骨形成并减少因废弃而引起的皮质内骨孔隙率。虽然骨重塑被证明对高速率的动态生理刺激敏感，但骨和肌肉中液体流动的作用也许至少部分解释了细胞对合成代谢刺激的反应机制。在提出的工作中，我们将研究一般假设，即动态功能刺激介导的骨骼肌循环充当动态肌肉泵和骨液流动的关键介质，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）、循环和骨中液体流动的作用的理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、加速骨折愈合或促进骨向假体内生长。 在本申请中，该目标将通过一系列子假设和具体目标来实现：（1）动态间质液流动可以通过骨骼肌的功能性收缩来启动和增强。功能性肌肉收缩充当动态泵，产生髓内压力并调节静脉回流，从而启动骨中的液体流动。 (2)肌肉动力刺激引起的骨液流动可以启动表面适应性反应并抑制废用骨的皮质内骨丢失。自适应响应将对加载模式的速率敏感。 (3) 对肌肉泵引起的合成代谢流体流刺激的成骨反应取决于产生的流体压力大小和加载持续时间。 (4)肌肉刺激的动态模式的电位可以启动肌肉适应，其中生理水平引起的负荷会增加毛细血管密度并大幅增加肌肉的血流量，而超负荷会导致骨血流缺血后部分肌血管萎缩。 (5)动态加载期间插入休息时间可以优化肌肉和骨骼中的液体浸润，从而降低液体饱和度并改善灌注。 (6) 在每天但持续时间较短（例如<10天）的负荷后，骨内衬细胞的成骨细胞活化引发对流体流动刺激的成骨电位反应。将通过细胞面积、核面积、细胞数量、细胞和细胞核形状的组织形态计量学分析来检查细胞和细胞核的超微结构成骨细胞特征，其中将识别相关的流体成分。

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.