Osmotic and functional determinants of skeletal biomechanics

骨骼和肌肉构成了一个生命体的框架（肌肉骨骼系统），是进化和生活方式水平适应的产物。在野外，生物的生活方式与其进化适应是一致的。然而，在现代西方社会，生活方式与人类已经适应了数百万年的生活方式不一致。虽然我们可能会关心宇航员在微重力的影响下会发生什么，但就骨骼健康而言，一个城市里久坐不动的长寿人类可能确实更接近于一个从长期太空飞行中返回的人，而不是一个最近的历史祖先，他们经常进行剧烈的体育活动，作为他们生存策略的一部分。今天，在我们的骨骼系统从史前时代的持久猎人进化而来的机械刺激强度与西方世界人类所面临的机械刺激缺乏之间存在着差距。这个研究计划描述了我在两个轴上的兴趣：水与渗透活性大分子组装的相互作用，以及骨组织三维结构的长期累积塑造。这项研究将在纳米尺度和宏观尺度上将身体活动、衰老和pH稳态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。刚体结合水的量决定了骨组织的刚度、韧性和非线性粘弹性行为。然而，结合水的数量取决于间质pH值，其本身取决于呼吸和肾脏功能，以及有氧/厌氧能量途径。通过对矿化和非矿化脱细胞仿生结构的逐步研究，可以量化和揭示这些复杂的、相互复合的组织微观力学效应。我们的发现可以转化为正常和衰老的动物模型暴露在实验久坐和活动的条件下。在宏观尺度上，骨的载荷反映在关节小梁骨的纹理上。重复的、可预测的载荷和/或更大的年龄导致明显的各向异性（定向）应力轨迹，而不是多样化的、不可预测的载荷和/或更小的年龄。然而，过于单调的习惯性负荷会使骨组织过度专业化，不适合随机和意外负荷。一项对20-90岁强健年龄序列膝关节标本（使用微CT扫描）小梁骨三维纹理的研究将探讨各向异性小梁纹理、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（操作或生活方式）之间差异的研究是理解困扰西方社会的退行性身体条件失调的关键，特别是随着寿命的增加。

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.