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: 10156307
• 负责人: Josephine Wu
• 金额: $ 4.6万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10156307
• 关键词: Address; Affect; Alcian Blue; Anatomy; Architecture; Benchmarking; Biochemical; Biological; 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.

项目概要/摘要 关节软骨的疾病和创伤会严重影响生活质量，因为受损的软骨具有 自我修复能力非常有限。关节软骨缺损的治疗仍然是一个普遍且有效的方法 治疗选择有限，这是一个具有挑战性的问题，部分原因是缺乏高保真模型 增进我们对疾病/损伤进展的理解并能够测试新疗法。啮齿动物是 通常用于研究关节疾病和发育，但它们未能概括人类的关键方面 软骨解剖学和生物学，特别是人类软骨复杂的带状组织。在设计的同时 体外模型在生物学上是忠实的，但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，我建议设计按区域组织的人类软骨 在体外通过应用适当的 TGF-β 信号传导时空梯度（目标 1），同时 包括活体软骨下骨以增强骨软骨相互作用（目标 2）。我试图证明 使用这种人类软骨模型来研究单基因结缔组织疾病的关节疾病， 马凡综合征 (MFS)，其中原纤维蛋白缺陷影响 TGF-β 生物利用度和肌肉骨骼发育 （目标 3）。我假设 TGF-β 信号传导的精确调节和软骨下骨的包含 基质将产生类似天然的人类关节软骨，具有带状组织和软骨骨 相互作用，可用于模拟 MFS 等疾病。光遗传学提出了一种策略，我们可以通过该策略 可以通过光以前所未有的精度控制 TGF-β 信号传导。在骨软骨交界处，生化 和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都失败了 由于支持两种组织类型的复杂性，因此需要合并骨骼。我们实验室设计了灌注 生物反应器可以为每种组织类型提供单独的物理和化学线索以克服这一问题 挑战。使用 MFS 患者来源的 hiPSC，先进的工程软骨模型将用于 以临床数据为基准并与数据进行比较，概括疾病的功能和结构特征 来自现有的软骨形成微团培养的体外模型。拟议的工作将建立一个新颖的 软骨组织工程方法，为研究关节疾病提供先进的人体组织模型。