Post-yield Behavior vs. Bone Quality

描述（由申请人提供）：骨折是老年人和女性人群健康护理的主要问题。骨折的一个主要原因是除了骨矿物质密度和结构的变化之外，组织质量的恶化（表现为其韧性）。最近的证据表明，骨可能会经历两个不同的阶段，在屈服后变形：它开始与急性增加的微损伤积累和粘性响应（阶段I），其次是塑性变形和饱和的粘性响应（阶段II）。更有趣的是，在个别矿物和胶原蛋白相的内部应变似乎是不同的，这种差异大大增加骨屈服，这表明可能的界面变形之间的两个阶段。此外，骨的水化状态在维持骨的韧性方面表现出显著作用，但这种作用对于老年骨减弱。此外，有证据表明，与年龄相关的骨中非酶胶原交联的积累可能对骨的韧性有显着影响。在这些情况下，与年轻的骨骼相比，老年人的骨骼往往会过早地发生永久性（或塑性）变形。基于这些最新发现，本研究的中心假设是，骨中屈服后能量耗散的能力主要由矿物质相和胶原相之间的相互作用决定，并且这种相互作用中的任何不利变化都会导致骨脆性增加。本研究的目的有四：目的1：确定不同载荷模式下骨屈服后行为的机制。工作假设：骨的屈服后行为开始于微损伤累积的急剧增加，粘性响应的变化较大（第一阶段），随后是与大塑性变形相关的饱和粘性响应（第二阶段）;并且这种行为与加载模式无关。目的2：确定骨的矿物/胶原相互作用与屈服后变形和能量耗散的相关性。工作假设：在骨的屈服后变形过程中，矿物质和胶原界面处的变形是能量耗散的主要机制。目标3：确定脱水对骨中矿物相和胶原相之间界面行为的影响及其与年龄的相关性。工作假设：骨的矿物质和胶原相之间的界面相互作用受到脱水的显著影响，并且这种影响随着年龄的增加而减弱。目标4：确定非酶胶原交联（AGEs）在影响骨屈服后行为（韧性）中的作用及其与年龄的相关性。工作假设：AGEs的骨相关积累显著影响矿物和胶原相之间的界面行为，从而导致骨在屈服后变形期间耗散能量的能力显著降低。通过这项研究，我们希望阐明后屈服和失败的行为，骨的超微结构水平，并确定超微结构的因素，支配骨的脆弱性。这些信息将有助于未来开发预测和预防骨折的临床治疗和策略。 公共卫生相关性：本研究的科学和临床意义体现在以下几个方面：本研究将有助于在超微结构水平上阐明骨的屈服后和失效行为的潜在机制，从而允许在肌肉骨骼和植入系统中准确建模和预测骨失效。此外，这项研究的新技术将提供一种独特的手段，以帮助确定在病理过程中导致骨超微结构变化的细胞/分子途径，并评估骨疾病的临床治疗效果。最后，通过进一步的修改，这种方法可以扩展到定量评估活检骨组织的超微结构变化，从而帮助医生做出更准确的骨折风险评估。

DESCRIPTION (provided by applicant): Bone fractures are a major concern for the health care of elderly and women populations. One leading reason for bone fractures is deterioration of tissue quality (manifested by its toughness) in addition to changes in bone mineral density and architecture. Recent evidence has evinced that bone may experience two distinct stages in the post-yield deformation: it begins with acute increases in microdamage accumulation and viscous response (Stage I), followed by plastic deformation and saturation of the viscous response (Stage II). More intriguingly, the internal strains in individual mineral and collagen phases appear to be different and such a discrepancy increases considerably as bones yield, suggesting a possible interfacial deformation between the two phases. In addition, hydration state of bone exhibits a significant role in sustaining the toughness of bone, but such effects diminish for elderly bones. Moreover, evidence has shown that age-related accumulation of non-enzymatic collagen crosslinks in bone may have significant effects on the toughness of bone. In these cases, elderly bones tend to fail prematurely with very limited permanent (or plastic) deformation compared with the younger bones. Based on these recent findings, the central hypothesis of this study is that the capacity of post-yield energy dissipation in bone is mainly determined by the interaction between the mineral and collagen phases, and any adverse changes in such a interaction would consequently lead to an increased fragility of bone. Four specific aims will be addressed: Aim 1: To determine the mechanism of the post-yield behavior of bone under different loading modes. Working hypothesis: The post-yield behavior of bone is initiated with an acute increase in microdamage accumulation with large variation in viscous response (Stage I) and followed by a saturated viscous response associated with large plastic deformation (Stage II); and such a behavior is independent of loading modes. Aim 2: To determine the correlation of mineral/collagen interaction with the post-yield deformation and energy dissipation of bone. Working hypothesis: Deformation at the mineral and collagen interface is a major mechanism for energy dissipation during the post-yield deformation of bone. Aim 3: To determine the effect of dehydration on the interfacial behavior between the mineral and collagen phases in bone and its correlation with age. Working hypothesis: The interfacial interaction between the mineral and collagen phase of bone is significantly affected by dehydration, and such an effect diminishes with increasing age. Aim 4: To determine the role of non-enzymatic collagen crosslinks (AGEs) in affecting the post-yield behavior (toughness) of bone and its correlation with age. Working hypothesis: Age-related accumulation of AGEs significantly affects the interfacial behavior between the mineral and collagen phases, thus leading to the significantly reduced capacity for bone to dissipate energy during the post-yield deformation. Through this study, we expect to elucidate the post-yield and failure behavior of bone at ultrastructural levels, and to determine the ultrastructural factors that govern the fragility of bone. Such information would facilitate future development of clinical treatments and strategies for predicting and preventing bone fractures. PUBLIC HEALTH RELEVANCE: The scientific and clinical relevance of this study is manifested in the following aspects: This study will help elucidate the underlying mechanism of the post-yield and failure behavior of bone at ultrastructural levels, thus allowing for accurate modeling and failure prediction of bone in musculoskeletal and implant systems. In addition, the novel techniques of this study will provide a unique means to help identify the cellular/molecular pathways that cause such ultrastructural changes in bone during pathological processes and to evaluate the efficacy of clinical treatments to bone disorders. Finally, by further modifications this approach can be extended to assess ultrastructural changes in biopsy bone tissues quantitatively, thus helping physicians to make more accurate risk assessments of bone fractures.