Influence of the ultrastructure on the fracture characteristics of human bone in physiological and pathological conditions

已知疾病和衰老相关的肌肉骨骼系统变化会增加其对骨折的易感性。这种变化对老年人尤其重要，因为随之而来的骨折可能导致生活质量的限制以及显著的死亡率。关于骨骼老化和疾病退化的传统思想主要集中在骨量问题上，目前在临床环境中，骨量被用作骨折风险的预测指标。然而，随着年龄和疾病增加的骨折风险并不仅仅取决于骨量；事实上，抗骨折性还受到描述骨质量的形态和成分变化的影响。了解骨折的性质如何受到骨质量的影响，需要表征骨复杂层次结构各层次的组成和形态学特征，这些特征具有从毫米到纳米的特征，特别是从由胶原和矿物质组成的纳米结构（<500 nm）以及由片层、骨细胞腔隙（3-20 μm）和骨细胞（100-300 μm）组成的微观结构演变到宏观形态（> -3 mm）。我们相信，对衰老和患病骨骼的分层表征将有助于更好地理解这些情况是如何导致骨折风险增加的。我们将利用显微计算机断层扫描、同步加速器小角x射线散射/广角x射线散射、背散射电子成像、深紫外拉曼/傅立叶变换红外光谱、高效液相色谱和酶联免疫吸附分析等综合方法，结合骨骼质量评估技术，表征骨骼完整和病变骨骼的不同层次结构。在这方面，我们想要解决的问题是，骨病中胶原蛋白和矿物质特征的超微结构是否发生了显著改变，结构和材料特征是否发生了明显变化（例如，纤维间和纤维内交联），以及这些变化如何影响骨折机制，从而影响骨的强度和韧性。我们的假设是，影响骨抗骨折的主要机制可能与矿化胶原纤维在纳米尺度上滑动的可塑性机制、微观尺度上的断裂路径特性以及两种尺度上的微开裂有关。我们的目的是提供关于不同超微结构特征如何影响骨组织力学行为的新信息。此外，由于这是对传统的生物工程和骨折医学研究的背离，我们希望这种基于材料科学的研究能够通过为骨骼相关疾病提供新的和不同的见解来积极影响医学领域，从而有助于寻找新的治疗方法和治疗方案。

Disease- and aging-related changes to the musculoskeletal system are known to increase its susceptibility to fracture. Such changes are especially critical in the elderly as the consequent fractures can lead to restrictions on quality of life as well as significant mortality. Traditional thinking on the deterioration of bone with aging and disease has focused predominantly on the question of bone quantity, which is currently used as a predictor of fracture risk in clinical settings. However, the increased fracture risk of bone with aging and disease is not solely dependent on bone quantity; indeed, the fracture resistance is additionally affected by both morphological and compositional changes, which describe the bone quality. Understanding how the nature of fracture is affected by bone quality requires characterization of the compositional and morphological features at each level of bone’s complex hierarchical structure, which has characteristic features from millimeter to nanometer levels, specifically evolving to its macroscopic form (>3 mm) from a nanostructure comprised of collagen and mineral (<500 nm) and a microstructure of lamellae, osteocyte lacunae (3-20 μm) and osteons (100-300 μm). We believe that a hierarchical characterization of aged and diseased bone will lead to a greater understanding of how these conditions cause an increase in fracture risk.We will use an integrated approach combining bone quality assessment techniques by using microcomputed tomography, synchrotron small-angle X-ray scattering/wide-angle X-ray scattering, backscattered electron imaging, deep ultraviolet Raman/Fourier transform infrared spectroscopy, high-performance liquid chromatography and enzyme-linked immunosorbent assay to characterize various levels of the hierarchical structure of skeletally intact and diseased bones. In this connection, we would like to address whether the ultrastructure in terms of the collagen and mineral’s characteristics is significantly altered in bone diseases, whether there are distinct changes in structural and material characteristics (e.g., inter- and intrafibrillar crosslinking), and how these changes can affect the mechanisms of fracture and hence the bone strength and toughness. Our hypothesis is that the primary mechanisms influencing fracture resistance in bone can be associated with the plasticity mechanisms of mineralized collagen fibril sliding at the nanoscale, fracture path properties at the microscale, and microcracking at both scales. Our aim is to provide new information on how distinct ultrastructural features affect the mechanical behavior of bone tissue. Additionally, as this is a departure from traditional bioengineering and medical studies of bone fracture, we hope that such materials-science-based studies can positively impact the medical field by providing new and different insights into bone-related diseases, and as such can help in the search for new cures and treatment options for bone diseases.