Mechanical regulation of endochondral bone regeneration

软骨内骨再生的机械调节

• 批准号: 10585917
• 负责人: Joel D Boerckel
• 金额: $ 34.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10585917
• 关键词: Bioreactors; Bone Development; Bone Regeneration; Bone Tissue; Bone Transplantation; Bone callus; Cell Lineage; Cell Separation; Cell Transplantation; Cells; Cellular Structures; Chondrocytes; Chondrogenesis; Chondroitin Sulfates; Clinical; Collagen; Collagen Gene; Complication; Defect; Development; Developmental Process; Embryo; Engineering; Environment; Excision; Exhibits; Extracellular Matrix; Fracture; Functional Regeneration; Gene Activation; Gene Expression; Genetic Transcription; Genetically Engineered Mouse; Goals; Hyaluronic Acid; Hypertrophy; Imaging Techniques; In Vitro; Intervention; Knockout Mice; Limb Bud; Limb structure; Mature Bone; Measures; Mechanical Stimulation; Mechanics; Mesenchymal; Modeling; Molecular; Natural regeneration; Osteogenesis; Physical condensation; Physiologic Ossification; Positioning Attribute; Production; Productivity; Property; Proteins; Proteoglycan; Qualifying; Rattus; Regulation; Reporter; Reporter Genes; Research; Role; Signal Transduction; Structure; Testing; Time; Tissue Engineering; Tissues; Transcription Coactivator; Transgenic Organisms; Transplantation; Traumatic injury; bone; bone fracture repair; conditional knockout; contrast enhanced; design; healing; in vivo; in vivo regeneration; innovation; insight; mechanical load; mechanical signal; mechanical stimulus; mechanotransduction; mimetics; mimicry; morphogens; multiplexed imaging; osteogenic; osteoprogenitor cell; programs; regenerative approach; repaired; response; sample fixation; scaffold; self assembly; success; tumor

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.

摘要 由创伤或肿瘤切除引起的大型骨缺损是一个重大的临床挑战，因为它们 如果不介入就无法治愈，目前的植骨疗法有限。组织工程是一种 前景看好的替代方案。许多骨组织工程策略使用与结构相匹配的支架 以及成熟骨的特性。然而，在以下情况下，自然骨折愈合最有效(成功率为90-95%) 它通过软骨内骨化重现骨骼的发育。一种组织工程疗法， 使大的缺陷能够像自然骨折一样保真度地愈合将是变革性的。 在这里，我们应用这些发育和内源性修复机制来再生具有挑战性的 与简单的骨折不同，这些缺陷不会形成骨痂，也不能自行愈合。在这两个开发项目中 而修复，软骨内骨化需要机械提示。最近，开发了一种无脚手架方法 重述了发育中的肢芽的细胞组织以诱导软骨内成骨 大块的骨缺损处。我们发现，在活体机械负荷显著增强软骨内 再生，在软骨细胞肥大到软骨细胞肥大时通过负荷启动诱导功能再生。 骨化转变。然而，目前尚不清楚细胞分化状态或组成和 细胞外基质的性质影响这种机械传导的软骨内反应。 这个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的力学调节。我们的主导假设是 机械刺激软骨内骨缺损再生依赖于软骨细胞系 成熟和细胞外基质组成通过YAP/TAZ机械感觉。我们将确定 软骨内分化状态、基质成分和性质以及YAP/TAZ信号转导途径对软骨细胞分化的影响 生物反应器与大段骨缺损联合应用对软骨内成骨的力学调节 模特们。这些结果将确定机械刺激何时以及如何诱导软骨内再生和 可能会为其他组织中受发育启发的组织工程策略提供见解。