Advanced Tissue Engineered Models of Human Cartilage for Studying Joint Disease

用于研究关节疾病的先进人体软骨组织工程模型

• 批准号: 10403942
• 负责人: Josephine Wu
• 金额: $ 2.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403942
• 关键词: Address; Affect; Alcian Blue; Anatomy; Architecture; Benchmarking; Biochemical; Biological Availability; Biology; Biomechanics; Bioreactors; Bone Matrix; Cartilage; Cartilage Diseases; Chemicals; Chondrogenesis; Clinical Data; Collagen; Computer Models; Connective Tissue Diseases; Critical Pathways; Cues; Data; Defect; Degenerative polyarthritis; Development; Disease; Disease Progression; Disease model; Electron Microscopy; Encapsulated; Engineering; Exhibits; Friction; Generations; Health; Histology; Human; Hydrogels; In Vitro; Injury; Joints; Label; Ligands; Light; Maintenance; Marfan Syndrome; Mediating; Mendelian disorder; Metabolic; Methodology; Methods; Modeling; Molecular; Musculoskeletal Development; Nature; Outcome; Patients; Perfusion; Physiological; Play; Proteoglycan; Quality of life; Regimen; Regulation; Resolution; Rodent; Rodent Model; Role; Sepharose; Signal Transduction; Specificity; Structure; Study models; System; Testing; Thick; Tissue Engineering; Tissue Model; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Trauma; Work; arthropathies; articular cartilage; base; bone; bone engineering; bone quality; cartilage development; design; disease phenotype; fibrillin; healing; human model; human tissue; in vitro Model; in vivo Model; molecular marker; novel; novel therapeutics; optogenetics; osteochondral tissue; osteogenic; progenitor; repaired; spatiotemporal; subchondral bone; tool

PROJECT SUMMARY / ABSTRACT Disease and trauma of articular cartilage are highly debilitating to the quality of life, as damaged cartilage has a very limited ability for self-repair. The management of articular cartilage defects continues to be a prevalent and challenging problem with limited treatment options, in part due to the lack of high-fidelity models that would advance our understanding of disease/injury progression and enable testing of novel therapeutics. Rodents are commonly used to study joint disease and development, yet they fail to recapitulate key aspects of human cartilage anatomy and biology, in particular the intricate zonal organization of human cartilage. While engineered in vitro models can be biologically faithful, they generally lack the complexity offered by in vivo models, including the interactions with other tissues. To address this gap, I propose to engineer zonally organized human cartilage in vitro by applying the appropriate spatiotemporal gradients of TGF-β signaling (Aim 1), while concurrently including living subchondral bone for enhanced osteochondral interactions (Aim 2). I seek to demonstrate the utility of this human cartilage model for studying joint disease using a monogenic connective tissue disorder, Marfan syndrome (MFS), in which fibrillin defects affect TGF-β bioavailability and musculoskeletal development (Aim 3). I hypothesize that the precise regulation of TGF-β signaling and the inclusion of a subchondral bone substrate will generate native-like human articular cartilage with zonal organization and cartilage-bone interactions, which can be used to model diseases such as MFS. Optogenetics presents a strategy by which we can control TGF-β signaling by light with unprecedented precision. At the osteochondral junction, biochemical and biomechanical interactions mediate cartilage health and disease, yet most established cartilage models fail to incorporate bone due to the complexity of supporting both tissue types. Our lab has designed perfusion bioreactors which can provide separate physical and chemical cues to each tissue type to overcome this challenge. Using MFS patient-derived hiPSCs, the advanced engineered cartilage model will be used to recapitulate functional and structural features of disease, benchmarked to clinical data and compared to data from existing in vitro models of chondrogenic micromass cultures. The proposed work will establish a novel method for cartilage tissue engineering and provide an advanced human tissue model for studying joint diseases.

项目摘要 /摘要 关节软骨的疾病和创伤使生活质量高度衰弱，因为受损的软骨具有 自我修复的能力非常有限。关节软骨缺陷的管理仍然是普遍的， 有限治疗选择的挑战性问题，部分原因是缺乏高保真模型 促进我们对疾病/损伤进展的理解，并能够测试新型治疗。啮齿动物是 通常用于研究联合疾病和发育，但他们无法概括人类的关键方面 软骨解剖学和生物学，尤其是人类软骨的复杂区域组织。在设计时 体外模型在生物学上可能是忠实的，它们通常缺乏体内模型所提供的复杂性，包括 与其他组织的相互作用。为了解决这一差距，我建议对矿体组织的人体软骨进行设计 在体外应用TGF-β信号的适当时空梯度（AIM 1），同时同时 包括生命的软骨下骨可增强骨软骨相互作用（AIM 2）。我试图证明 这种人软骨模型用于使用单基因连接的组织疾病研究关节疾病的效用， Marfan综合征（MFS），其中纤维蛋白缺陷会影响TGF-β生物利用度和肌肉骨骼发育 （目标3）。我假设TGF-β信号的精确调节和软骨下骨的包含 底物将通过区域组织和软骨骨产生类似土著的人类关节软骨 相互作用，可用于建模MF等疾病。光遗传学提出了一种策略 可以以前所未有的精度来控制TGF-β信号传导。在骨软化连接处的生化 生物力学相互作用介导软骨健康和疾病，但大多数已建立的软骨模型失败 由于支撑两种组织类型的复杂性，要​​结合骨头。我们的实验室设计了灌注 可以为每种组织类型提供单独的物理和化学线索的生物反应器来克服这一点 挑战。使用MFS患者衍生的HIPSC，高级工程软骨模型将用于 概括疾病的功能和结构特征，基准与临床数据进行了比较 来自现有的软骨微生物培养的体外模型。拟议的工作将建立小说 软骨组织工程的方法，并提供了用于研究关节疾病的先进人体组织模型。