Studying Mechanotransduction in Late Embryonic Development to Inform Tendon Tissue Engineering
研究胚胎发育晚期的力转导为肌腱组织工程提供信息
基本信息
- 批准号:9808374
- 负责人:
- 金额:$ 18.81万
- 依托单位:
- 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:2019-07-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:AllogenicAreaAutologousAutomobile DrivingBiocompatible MaterialsBiologicalBiological ProductsCRISPR/Cas technologyCell VolumesCellsChick EmbryoChickensCollagen FibrilComputer SimulationCuesDevelopmentDiseaseEmbryoEmbryonic DevelopmentEngineeringEventExperimental ModelsFailureFoundationsFutureGenesHarvestHumanImageImaging TechniquesIn VitroInstructionInvestigationKnock-outKnowledgeLengthLigamentsMechanical StimulationMechanicsMediatingMetatarsal bone structureModulusMorbidity - disease rateMuscleMusculoskeletal DiseasesPTK2 genePainPhasePropertyProtocols documentationQuality of lifeRuptureSignal TransductionSiteSlideStimulusStructureTechniquesTendon InjuriesTendon structureTestingTimeTissue EngineeringTissuesTransplanted tissueUnited StatesWeight-Bearing stateWorkbasecell behaviordesigndisabilitydisease transmissiondisorder riskextracellularfallshatchingimprovedin vivoinjuredinnovationknockout geneligament injurymechanical drivemechanical loadmechanical propertiesmechanotransductionnovelpreventrepairedresponsescaffoldself assemblyself organizationtendon developmenttissue culture
项目摘要
Project Summary/Abstract
Tendon and ligament injuries are a common cause of disability and pain. In many cases, the injured tissue cannot
be repaired directly and must be replaced with a graft material. Ideally, a tissue engineered biomaterial could be
used for this purpose; however, no tissue engineered construct has been successfully used to reconstruct human
tendon or ligament ruptures. A primary reason for the failure in producing successful tendon replacements is that
most tissue engineering approaches do not replicate normal tendon development. Scaffold-free techniques
based on cellular self-assembly are able to generate tissues that that match the structure and mechanics of early
embryonic tendon. However, they are unable to undergo a critical phase in late tendon development where the
collagen fibrils elongate and fuse together generating a substantially stiffer and stronger material. One reason
for this is that the constructs lacked the mechanical stimulation normally provided in vivo by muscles. In fact,
chick embryo muscle activity peaks during late tendon development and this muscle activity is responsible for
increasing the modulus of embryonic tendons. Nevertheless, while mechanical loading of constructs does
improve tissue mechanics, they still fail to match the order-of-magnitude increase in mechanical properties
observed in embryonic chick tendons. A critical barrier is the lack of knowledge regarding the
mechanotransduction mechanisms that determine the cellular response to mechanical stimulation and drive late
tendon development. Understanding how tendon cells respond to mechanical stimuli due to not only muscle
loading but also the local changes in tissue structure and mechanics that occur during development is necessary
to develop biomaterials that can successfully replicate tendon function. Therefore, the objective of this project is
to identify the mechanotransduction mechanisms that mediate the multiscale changes in tissue structure and
mechanics observed during late tendon development. Specifically, this project will (1) identify the multiscale
structural and mechanical changes that occur during late tendon development and (2) determine the
mechanotransduction mechanisms driving these changes. The overall hypothesis is that cells sense mechanical
stimuli through a combination of cell-cell and cell-matrix interactions and that these mechanotransduction events
are essential for driving proper tendon development. This will be evaluated by inhibiting embryonic muscle
activity and perturbing mechanotransduction signaling in embryonic tendons via site-specific gene knockout
during ex ovo culture of chicken embryos. The effects of these manipulations on tendon structure and mechanics
will be determined by a novel combination of multiscale mechanical testing, computational modeling, and
ultrastructural imaging. This work is the first investigation of the mechanotransduction mechanisms driving the
structural and mechanical changes observed during late tendon development. The findings will provide the
foundation for enhancing tissue engineered constructs to develop biomaterials that can successfully replace
diseased tendons and ligaments.
项目概要/摘要
肌腱和韧带损伤是导致残疾和疼痛的常见原因。在许多情况下,受伤的组织无法
直接修复,必须用移植材料代替。理想情况下,组织工程生物材料可以是
用于此目的;然而,还没有组织工程结构被成功地用于重建人类
肌腱或韧带断裂。未能成功生产肌腱替代品的主要原因是
大多数组织工程方法不能复制正常的肌腱发育。无支架技术
基于细胞自组装的技术能够产生与早期细胞的结构和力学相匹配的组织
胚胎肌腱。然而,它们无法经历肌腱发育后期的关键阶段,即
胶原原纤维伸长并融合在一起,产生更硬、更坚固的材料。原因之一
这是因为该结构缺乏通常由肌肉在体内提供的机械刺激。实际上,
鸡胚肌肉活动在肌腱发育后期达到峰值,这种肌肉活动负责
增加胚胎肌腱的模量。然而,虽然结构的机械加载确实
改善组织力学,但它们仍然无法匹配机械性能的数量级增长
在胚胎鸡肌腱中观察到。一个关键障碍是缺乏相关知识
决定细胞对机械刺激的反应并驱动迟到的机械转导机制
肌腱发育。了解肌腱细胞如何响应不仅来自肌肉的机械刺激
负荷以及发育过程中发生的组织结构和力学的局部变化都是必要的
开发能够成功复制肌腱功能的生物材料。因此,该项目的目标是
确定介导组织结构多尺度变化的机械传导机制
在肌腱发育后期观察到的力学。具体来说,该项目将(1)确定多尺度
肌腱发育后期发生的结构和机械变化以及(2)决定了
驱动这些变化的力传导机制。总体假设是细胞感知机械
通过细胞-细胞和细胞-基质相互作用的组合产生刺激,并且这些机械转导事件
对于驱动肌腱的正常发育至关重要。这将通过抑制胚胎肌肉来评估
通过位点特异性基因敲除胚胎肌腱的活性和扰动机械转导信号
在鸡胚胎的离卵培养过程中。这些操作对肌腱结构和力学的影响
将通过多尺度机械测试、计算建模和
超微结构成像。这项工作是对驱动机械力传导机制的首次研究
在肌腱发育后期观察到的结构和机械变化。研究结果将提供
为增强组织工程结构以开发可以成功替代的生物材料奠定了基础
患病的肌腱和韧带。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Spencer Szczesny', 18)}}的其他基金
Colocalization of gene expression and microscale tissue strains in live tendon explants using barcoded biosensors
使用条形码生物传感器对活体肌腱外植体中的基因表达和微型组织菌株进行共定位
- 批准号:
10558584 - 财政年份:2022
- 资助金额:
$ 18.81万 - 项目类别:
Colocalization of gene expression and microscale tissue strains in live tendon explants using barcoded biosensors
使用条形码生物传感器对活体肌腱外植体中的基因表达和微型组织菌株进行共定位
- 批准号:
10373315 - 财政年份:2022
- 资助金额:
$ 18.81万 - 项目类别:
Role of Mechanical Loading and Stem Cell Mechanotransduction in Tendon Degeneration
机械负荷和干细胞力转导在肌腱退变中的作用
- 批准号:
9320001 - 财政年份:2016
- 资助金额:
$ 18.81万 - 项目类别:
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