Mechanical regulation of endochondral bone regeneration

软骨内骨再生的机械调节

基本信息

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
项目类别：
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

项目摘要

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.

抽象的由外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无法愈合，并且目前的骨移植疗法是有限的。组织工程是一门有希望的替代方案。许多骨组织工程策略使用与结构相匹配的支架和成熟骨的特性。然而，在以下情况下，自然骨折愈合是最有效的（成功率 90-95%）：它通过软骨内骨化概括了骨骼的发育。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简单骨折不同，缺陷不会形成骨痂，也无法自行愈合。在双方发展中和修复，软骨内骨化需要机械线索。最近开发了一种无脚手架的方法概括了发育中肢芽的细胞组织，以诱导软骨内骨化大骨缺损。我们发现体内机械负荷显着增强软骨内再生，在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特性影响这种机械传导软骨内反应。该项目的目标是了解细胞谱系和细胞外基质的机制影响软骨内骨缺损再生的机械调节。我们的主导假设是软骨内骨缺损再生的机械刺激取决于软骨细胞谱系通过 YAP/TAZ 机械感觉测定成熟和细胞外基质组成。我们将确定软骨内分化状态、基质组成和特性以及 YAP/TAZ 信号传导的影响结合生物反应器和大骨缺损对软骨内骨化进行机械调节模型。这些结果将确定机械刺激何时以及如何诱导软骨内再生和可能为其他组织中受发育启发的组织工程策略提供见解。