OReilly Adam, Hankenson Kurt D, Kelly Daniel J
Trinity Centre for Bioengineering, Trinity Biomedical Sciences, Trinity College Dublin, Dublin, Ireland.
Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland.
Biomech Model Mechanobiol. 2016 Oct;15(5):1279-94. doi: 10.1007/s10237-016-0759-4. Epub 2016 Jan 29.
While it is well established that an adequate blood supply is critical to successful bone regeneration, it remains poorly understood how progenitor cell fate is affected by the altered conditions present in fractures with disrupted vasculature. In this study, computational models were used to explore how angiogenic impairment impacts oxygen availability within a fracture callus and hence regulates mesenchymal stem cell (MSC) differentiation and bone regeneration. Tissue differentiation was predicted using a previously developed algorithm which assumed that MSC fate is governed by oxygen tension and substrate stiffness. This model was updated based on the hypothesis that cell death, chondrocyte hypertrophy and endochondral ossification are regulated by oxygen availability. To test this, the updated model was used to simulate the time course of normal fracture healing, where it successfully predicted the observed quantity and spatial distribution of bone and cartilage at 10 and 20 days post-fracture (dpf). It also predicted the ratio of cartilage which had become hypertrophic at 10 dpf. Following this, three models of fracture healing with increasing levels of angiogenic impairment were developed. Under mild impairment, the model predicted experimentally observed reductions in hypertrophic cartilage at 10 dpf as well as the persistence of cartilage at 20 dpf. Models of more severe impairment predicted apoptosis and the development of fibrous tissue. These results provide insight into how factors specific to an ischemic callus regulate tissue regeneration and provide support for the hypothesis that chondrocyte hypertrophy and endochondral ossification during tissue regeneration are inhibited by low oxygen.
虽然充足的血液供应对成功的骨再生至关重要这一点已得到充分证实，但对于脉管系统受损的骨折中存在的改变条件如何影响祖细胞命运，人们仍知之甚少。在本研究中，使用计算模型来探究血管生成受损如何影响骨折痂内的氧供应，进而调节间充质干细胞（MSC）分化和骨再生。使用先前开发的算法预测组织分化，该算法假设MSC命运受氧张力和底物硬度控制。基于细胞死亡、软骨细胞肥大和软骨内成骨受氧供应调节的假设对该模型进行了更新。为了验证这一点，使用更新后的模型模拟正常骨折愈合的时间进程，该模型成功预测了骨折后10天和20天（dpf）观察到的骨和软骨的数量及空间分布。它还预测了在10 dpf时已肥大的软骨比例。在此之后，开发了三种血管生成受损程度逐渐增加的骨折愈合模型。在轻度受损情况下，该模型预测在10 dpf时实验观察到的肥大软骨减少以及在20 dpf时软骨的持续存在。更严重受损的模型预测了细胞凋亡和纤维组织的形成。这些结果深入了解了缺血性骨痂特有的因素如何调节组织再生，并为组织再生过程中软骨细胞肥大和软骨内成骨受低氧抑制这一假设提供了支持。
