Mechanical regulation of endochondral bone regeneration

摘要 由创伤性损伤或肿瘤切除引起的大骨缺损构成了重大的临床挑战，因为它们 如果不进行干预就不能愈合，并且目前的骨移植疗法是有限的。组织工程是一种 有前途的替代品。许多骨组织工程策略使用设计成匹配结构的支架 和成熟骨骼的特性。然而，自然骨折愈合是最有效的（90-95%的成功率）， 它通过软骨内骨化来再现骨发育。一种组织工程疗法 使大的缺损能够以与自然骨折愈合相同的保真度愈合，这将是变革性的。 在这里，我们将这些发育和内源性修复机制应用于具有挑战性的再生。 与单纯骨折不同，缺损不会形成骨痂，也不能自行愈合。在这两个发展 和修复，软骨内骨化需要机械线索。最近，开发了一种无支架的方法 它概括了发育中肢芽的细胞组织， 大面积骨缺损我们发现，在体内机械负荷显着增强内软骨 再生，在软骨细胞肥大时通过负荷启动诱导功能性再生， 骨化转变然而，目前尚不清楚细胞分化状态或组成如何， 细胞外基质的性质影响这种机械传导的软骨内分泌反应。 该项目的目标是了解细胞谱系和细胞外基质 影响软骨内骨缺损再生力学调节。我们的主要假设是 软骨内骨缺损再生的机械刺激依赖于软骨细胞谱系 成熟和细胞外基质组成通过雅普/TAZ机械感觉。康贝特人将以 软骨内分化状态、基质组成和性质以及雅普/TAZ信号转导对 使用生物反应器和大骨缺损的组合的软骨内骨化的机械调节 模型这些结果将确定机械刺激何时以及如何诱导软骨内再生， 可能为其他组织中的发育启发组织工程策略提供见解。

Abstract Large bone defects caused by traumatic injury or tumor resection pose a significant clinical challenge as they cannot not heal without intervention, and current bone grafting therapies are limited. Tissue engineering is a promising alternative. Many bone tissue engineering strategies use scaffolds designed to match the structure and properties of mature bone. However, natural fracture healing is most efficient (90-95% success rate) when it recapitulates bone development through endochondral ossification. A tissue engineering therapy that enabled large defects to heal with the same fidelity as natural fracture healing would be transformative. Here, we apply these developmental and endogenous repair mechanisms to the regeneration of challenging defects, which, unlike simple fractures, do not form a callus and cannot heal on their own. In both development and repair, endochondral ossification requires mechanical cues. Recently, developed a scaffold-free approach that recapitulates the cellular organization of the developing limb bud to induce endochondral ossification in large bone defects. We found that in vivo mechanical loading significantly enhanced endochondral regeneration, with functional regeneration induced by load initiation at the time of chondrocyte hypertrophy-to- ossification transition. However, it remains unclear how the cellular differentiation state or the composition and properties of the extracellular matrix influence this mechanotransductive endochondral response. The goal of this project is to understand the mechanisms by which cellular lineage and extracellular matrix influence mechanical regulation of endochondral bone defect regeneration. Our governing hypothesis is that mechanical stimulation of endochondral bone defect regeneration depends on chondrogenic cell lineage maturation and extracellular matrix composition through YAP/TAZ mechanosensation. We will determine the influence of endochondral differentiation state, matrix composition and properties, and YAP/TAZ signaling on mechanical regulation of endochondral ossification using a combination of bioreactor and large bone defect models. These results will identify when and how mechanical stimuli induce endochondral regeneration and may provide insights for development-inspired tissue engineering strategies in other tissues.