Osmotic and functional determinants of skeletal biomechanics

构成活体框架的骨骼和肌肉(肌肉骨骼系统)是进化和生活方式层面适应的产物。在野外，有机体的生活方式与其进化适应是一致的。然而，在现代西方社会，生活方式与人类数百万年来一直在适应的生活方式是不一致的。虽然我们可能担心在微重力的影响下宇航员会发生什么，但就骨骼健康而言，城市、久坐不动的长寿人类确实可能更接近从长途太空飞行归来的人，而不是最近的历史祖先，作为他们生存策略的一部分，他们经常从事剧烈的身体活动。今天，我们的骨骼系统自史前猎人时代以来一直在进化的机械刺激的强度，与西方世界人类面临的缺乏机械刺激之间存在差距。这项研究计划沿着两个轴描述了我的兴趣：水与渗透活性大分子组件的相互作用，以及骨组织三维结构的长期累积塑造。这项研究将在纳米和宏观水平上将体力活动、衰老和pH动态平衡的影响与骨骼生物力学联系起来。在纳米尺度上，在骨骼等结缔组织中，有机和无机成分与无处不在的水相互作用。刚性结合的间质水的量控制着骨骼组织的硬度、韧性和非线性粘弹性行为。然而，结合水的量取决于间质的pH值，而间质的pH值本身取决于呼吸和肾脏功能，以及有氧/无氧能量途径。量化和解开这些对组织微观力学的卷积和相互复合的影响可以通过逐步研究矿化和非矿化的非细胞仿生结构来实现。我们的发现可以转化为暴露在实验性久坐和活动条件下的正常和衰老的动物模型。在宏观尺度上，骨的负荷反映在关节中的骨小梁的纹理上。重复的、可预测的加载和/或较老的年龄导致明显的各向异性(定向)应力轨迹，而不是多样的、不可预测的加载和/或较小的年龄。然而，过于单调的习惯性加载会使骨组织过于专业化，不适合随机和意外的加载。对20-90岁健壮的膝关节标本(使用微CT扫描)的骨小梁3D纹理的研究将探索各向异性骨小梁纹理、功能和年龄之间的关系。这项关于系统发育适应(进化设计)和个体发育适应(手术或生活方式)之间差异的研究，是理解困扰西方社会的退化性身体退化的关键，尤其是随着寿命的延长。

The skeleton and the muscles forming the framework of a living body (the musculoskeletal system) is a product of adaptation at the evolutionary and lifestyle levels. In the wild, an organism's lifestyle is congruous with its evolutionary adaptation. However, in modern Western society, lifestyle is at odds with what humans had been adapting to over millions of years. While we may be concerned with what happens to astronauts under the influence of microgravity, in terms of skeletal fitness, an urban, sedentary and long-living human might indeed be closer to an individual returning from a long spaceflight rather than to a recent historic ancestor routinely engaged in strenuous physical activity as part of their survival strategy. Today, there is a gap between the intensity of mechanical stimuli that our skeletal system has evolved for since the prehistoric time of persistence hunters, versus the lack of mechanical stimulation that is faced by humans in the Western world. This research proposal describes my interests along two axes: the interactions of water with osmotically active macromolecular assemblies, and the long-term cumulative shaping of the 3D architecture of bone tissue. This research will link the effects of physical activity, aging and pH homeostasis to skeletal biomechanics, at both the nanoscale and macroscale levels. At the nanoscale, in connective tissues such as bone, organic and inorganic components interact with ubiquitous water. The amount of rigidly bound interstitial water governs stiffness, toughness and nonlinear viscoelastic behavior of skeletal tissues. However, the amount of bound water depends on interstitial pH, which itself hinges upon respiratory and renal functions, and upon aerobic/anaerobic energy pathways. Quantifying and unraveling these convolved and mutually-compounding effects on tissue micromechanics can be achieved through stepwise investigation of mineralized and unmineralized acellular biomimetic constructs. Our findings can be translated to normal and aging animal models exposed to experimental sedentary and active conditions. At the macroscale, loading of bone is mirrored by the texture of trabecular bone in the joints. Repetitive, predictable loading and/or older age result in pronounced anisotropic (oriented) stress trajectories, as opposed to diverse, unpredictable loading and/or younger age. However, too monotonous habitual loading renders bone tissue overspecialized and unfit for random and unexpected loads. A study of the 3D texture of trabecular bone in knee joint specimens (using µCT scans) of a robust age series spanning 20-90 years will probe the relations amongst anisotropic trabecular texture, function and age. This study on the discrepancy between phylogenetic adaptation (evolutionary design) and ontogenetic adaptation (operation, or lifestyle) is key to understanding the degenerative physical deconditioning that plagues Western societies, especially as longevity increases.