Multimodal Failure Mechanics in the Collagen Fibril

胶原蛋白的进化寿命是对其复杂的、自我组装的结构的生存价值的致敬。虽然在结缔组织中，弹性损伤和过载损伤已经在光学显微镜水平上进行了广泛的研究，但在纳米尺度上，机械载荷的承受却低于这一尺度。正是在那里，胶原蛋白的强度得以实现，也许对生存更为重要，因为它的韧性是由那里决定的。在过去10年左右的时间里，我一直对两个基本问题感兴趣：*** (I)胶原蛋白的机械损伤在最基本的层面上是什么样的？*** (ii)胶原损伤是否存在激活生理上适当的细胞修复或替换的结构基序？这些问题对于理解胶原原纤维的生物力学进化和合理设计加工的胶原蛋白产品具有深远的意义，这些产品可以模仿天然韧性，调节炎症和愈合。***我们最近证明，肌腱胶原蛋白超载会产生一种特征性的、局部的、纳米级的胶原原纤维“扭结”（直径5200纳米）。原纤维水平的损伤导致填充的胶原蛋白分子的热力学不稳定，与局部变性一致。超负荷肌腱的酶解和高倍率扫描电镜（50-70kX）显示，扭结区亚原纤维的一小部分（仅）被破坏，而其他部分则保持不变。无断裂的重复塑性过载产生沿单个受损原纤维的扭结的线性致密化。胶原原纤维因此被揭示出出乎意料的异质性：在其直径和长度上都是如此。我们有一个有效的理论，局部“扭结”失效机制具有两种进化价值：增强肌腱等组织以防止灾难性失效，同时提供指导吸收和/或修复受损原纤维的结构线索。我相信这些知识是有用的。***我建议进一步探索从我们的工作到目前为止出现的基本结构力学问题，应用SEM，低温透射电镜和AFM加上更细尺度的拉伸保留样品来减少损伤的异质性，从而可视化弹性反弹之前的扭结区失效。我们还将生产实验室挤出的胶原纤维，以研究胶原蛋白固有的离散可塑性机制所必需的异质纤维组装的程度，以及必须采用哪些干预措施来生产具有技术价值的胶原纤维。最后，我们将研究在受损原纤维中形成的系列扭结区是周期性的还是随机确定的问题。有了这些知识，我们将探索扭结形成的纤维到纤维的传播，并寻求建立一个模型，可以将纳米级分子/纤维损伤与微米级纤维失效耦合在一起

Collagen's evolutionary longevity is a tribute to the survival value of its complex, self--assembled structure. While both elasticity and overload damage have been studied extensively at the light microscope level in connective tissues, it is below that scalereally at the nanometer scalewhere mechanical load is borne. It is there that collagen's strength is achievedand perhaps more important for survival, where its toughness is determined. For the last 10 years or so, I have been interested in two fundamental questions:*** (i) What does mechanical damage in collagen look like at its most fundamental levels?*** (ii) Are there structural motifs for damage in collagen that activate physiologically appropriate cellular repair or replacement? These are questions of deep import for understanding the biomechanical evolution of the collagen fibril and for rational design of processed collagen products which can mimic native toughness and modulate inflammation and healing.*** We recently demonstrated that overloading of tendon collagen produces a characteristic, local, nano-scaled “kinking” of collagen fibrils (5200 nm dia.). Fibril-level damage leads to thermodynamic instability of the packed collagen molecules, consistent with local denaturation. Enzymolysis and very high magnification SEM (50-70kX) of overloaded tendons have shown that a sub-set (only) of the sub-fibrils at the kink zones are disrupted while others remain. Repeated plastic overload without rupture produces a linear densification of the kinks along individual damaged fibrils. The collagen fibril has thus been revealed to be unexpectedly heterogeneous: both across its diameter and along its length. We have a working theory that the local “kink” failure mechanism has 2--way evolutionary value: toughening tissues like tendons to prevent catastrophic failure while providing the structural cues that guide resorption and/or repair of damaged fibrils. I believe this knowledge can be used.*** I propose to further explore the fundamental structuro--mechanical questions which have emerged from our work to date, applying SEM, cryo-TEM, and AFM plus finer-scale, stretch-retained samples to reduce heterogeneity of damage, thereby visualizing kink zone failures before elastic rebound. We will also produce laboratory-extruded collagen fibres to study the extent to which the heterogeneous fibril assembly necessary to the discrete plasticity mechanism is innate to collagen, and what interventions must be applied to produce it for technological value. Finally, we will study the question of whether the serial kink zones which form in damaged fibrils are periodic in nature or stochastically determined. With that knowledge, we will explore fibril-to-fibril propagation of kink formation and seek to produce a model which can couple nanoscale molecular/fibril damage to micron-scale fibre failure.**