EAGER: Which Mechanical Signals do Bone Micro Damage near Microcracks Send to Osteocytes?

这一早期概念探索性研究奖助金(AGER)的研究目标是验证矿化纤维水平上关于骨失效机制的理论假设，以便精确测量传递给骨细胞(骨细胞)的原位机械信号，并检测人类之间在胶原和矿物质强度方面可能存在的差异。骨是一种具有复杂和高度异质微结构的活组织，它是由称为重塑的持续自我修复过程产生的。骨细胞是机械敏感的细胞，一旦检测到其环境中的微小损伤，就可能启动重塑，该环境由由羟基磷灰石晶体矿化的非胶原蛋白和胶原纤维组成的有机相组成。该奖项下的研究将遵循自上而下的方法，应用双重实验和数值方法来测试和模拟新鲜人类骨骼中生长的微裂纹和微损伤。该方法将原位量化在机械载荷作用下骨细胞附近的微裂纹和微损伤所产生的局部力学应力场。如果成功，这项研究将确定人类骨骼如何在胶原和羟基磷灰石水平上机械地承受载荷，以及微观损伤在原位产生的机械信号如何可能刺激骨细胞启动组织生物反应。精确测量骨细胞自然环境中微损伤的机械效应具有变革性，因为它促进了对机械刺激在细胞生物学中作用的一般理解。当应用于老年患者时，这将进一步有助于从基因上追踪骨骼不同成分的组织力学变化，以促进再生治疗和骨组织工程。该教育计划包括对骨骼微观生物力学研究生的指导，以及与领先的骨骼实验研究机构的国际合作。

The research objective of this EArly-Concept Grant for Exploratory Research (EAGER) is to validate theoretical hypotheses on bone failure mechanism at the mineralised fibril level in order to precisely measure the in situ mechanical signals to bone cells (osteocytes) and to detect possible variations among humans in collagen and mineral strengths. Bone is a living tissue with a complex and highly heterogeneous microstructure resulting from the continuous self-healing process called remodeling. Osteocytes are mechano-sensitive cells suspected to initiate remodeling upon detection of micro damage in their environment that is composed of an organic phase of non-collagen proteins and collagen fibrils that are mineralised by hydroxyapatite crystals. Studies under this award will follow a top-down approach applying a dual experimental and numerical method to test and model micro cracks and micro damage growing in fresh human bone. The method will quantify in situ the local mechanical stress field created by progressing micro cracks and micro damage near osteocytes in bone under mechanical load. If successful, this research will determine how human bone mechanically bears load at the collagen and hydroxyapatite level and how the mechanical signals produced in situ by micro damage could possibly stimulate osteocytes to initiate the tissue biological response. The precise measurement of the mechanical effects of micro damage in the osteocyte's natural environment is transformative in that it advances the general understanding of the role of mechanical stimuli in cell biology. When applied to elderly patients this will further help to genetically trace the tissue mechanics changes in different components of bone to advance regenerative therapies and bone tissue engineering. The educational plan includes the mentoring of graduate students in bone micro biomechanics and an international collaboration with leading institutions in bone experimental research.