Multi-Scale In Vitro 3D Tissue Model of Vascularized Bone-Cartilage Interactions

血管化骨软骨相互作用的多尺度体外 3D 组织模型

• 批准号: 9376268
• 负责人: BALABHASKAR PRABHAKARPANDIAN
• 金额: $ 22.5万
• 依托单位: CFD RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9376268
• 关键词: Animal Model; Animals; Architecture; Basic Science; Behavior; Biological; Biological Assay; Biological Factors; Biological Markers; Biology; Blood Vessels; Bone Tissue; Cartilage; Cell Communication; Cells; Cellular Morphology; Chondrocytes; Chronic Disease; Clinical; Coculture Techniques; Collaborations; Collagen Type II; Communication; Complex; Degenerative polyarthritis; Development; Disease; Disease Progression; Disease model; EDN1 gene; Elements; Endothelial Cells; Engineering; Environment; Ethics; Evaluation; Exposure to; Fibroblasts; Gap Junctions; Harvest; Imagery; Immune; In Vitro; Individual; Industrialization; Industry; Inflammatory; Interleukin-6; Investigation; Mediating; Microfluidic Microchips; Microfluidics; Modeling; Monitor; Morphology; Musculoskeletal; Nature; Optics; Osteoblasts; Osteocalcin; Osteoclasts; Pharmaceutical Preparations; Phase; Physiological; Plasticizers; Protocols documentation; Side; Signal Transduction; Signaling Molecule; Skeletal Development; Stromal Cells; System; TNF gene; TNFSF11 gene; Therapeutic; Therapeutic Equivalency; Time; Tissue Engineering; Tissue Model; Tissues; Universities; Vascular Endothelial Cell; adalimumab; aggrecan; arthropathies; base; bone; bone cell; cadherin 5; cartilage cell; cartilage degradation; cell behavior; cell type; cytokine; design; drug development; experimental study; feeding; improved; in vitro Model; in vivo; inhibitor/antagonist; macrophage; multi-scale modeling; multidisciplinary; novel therapeutics; osteochondral tissue; phase 2 study; physiologic model; predictive modeling; response; screening; small molecule therapeutics; tissue regeneration

Abstract Current in vitro models of vascularized bone tissues do not mimic the in vivo microenvironment comprising of diverse cell types in communication with each other through stromal barriers. In addition, they are hampered by lack of real-time visualization and quantitation of vasculature-bone as well as bone-cartilage interactions. In contrast, animal models while providing useful information are time consuming, expensive and in recent years, have increasingly raised ethical concerns. Furthermore, animal studies provide limited understanding of mechanistic behavior compared to well-controlled in vitro studies. Thus, there is an unmet need for an in vitro platform for improved monitoring and analysis of vascularized bone-cartilage interactions. We propose to develop and demonstrate a multi-scale model of vascularized bone-cartilage tissue for the understanding of cellular signaling with a Phase I focus on the interactions between endothelial cells, bone cells, specifically osteoblasts (bone-building cells) and osteoclasts (bone-degrading cells), and chondrocytes (cartilage cells). The multi-scale nature of the proposed approach is based on the use of (a) a microscale based vascular bone-cartilage model using microfluidics and tissue engineering to study cell signaling, which informs (b) a meso-scale vascular bone-cartilage model interrogating both engineered constructs and native tissues for structural and functional studies. Phase I will clearly and unequivocally demonstrate the use of this multiscale model of vascularized osteochondral tissue interactions for cell signaling. The developed platform will mimic the morphology, physiological flow and 3D multi-cellular compositions observed in vivo and enable an easy and robust system for evaluation of cellular responses. In Phase II, the platform will be expanded to include other stromal cells (e.g., fibroblasts), and immune cells (e.g., macrophages), followed by detailed characterization of the signaling molecules and therapeutic screening. A multi-disciplinary industry-academic partnership with expertise in microfluidics cell based assays and musculoskeletal biology and tissue regeneration has been assembled for successful completion of this project. By providing an accurate, quantitative and predictive model of physiological interactions, the developed multi-scale platform promises to establish a new paradigm for in vitro assessment of the physiological response to therapeutics.

抽象的 当前的血管化骨组织的体外模型不模仿由体内微环境组成的。 通过基质屏障相互通信的各种细胞类型。此外，他们受到阻碍 由于缺乏实时可视化和脉管骨的定量以及骨骼相互作用。在 对比，提供有用信息的动物模型是耗时，昂贵且近年来的， 越来越提出了道德问题。此外，动物研究提供了有限的了解 与体外研究良好的机械行为相比。因此，没有满足的体外需求 用于改善血管化骨 - 骨折相互作用的监测和分析的平台。 我们建议开发和展示一种多尺度模型的血管化骨 - 骨骼组织的模型 通过I期对细胞信号的了解，重点是内皮细胞之间的相互作用 细胞，特定的成骨细胞（骨建造细胞）和破骨细胞（降解细胞）和软骨细胞 （软骨细胞）。所提出方法的多尺度性质是基于（a）微观的使用 使用微流体和组织工程研究细胞信号的基于基于血管骨 - 骨折模型，这些模型 通知（b）一种中尺度的血管骨 - 骨 - 骨骼模型，询问工程结构和本地 结构和功能研究的组织。 第一阶段将清楚，明确地证明使用这种多尺度模型的血管化模型 细胞信号传导的骨软骨组织相互作用。开发的平台将模仿形态， 在体内观察到的生理流量和3D多细胞组成，并启用一个简单稳健的系统 用于评估细胞反应。在第二阶段，该平台将扩展到包括其他基质细胞 （例如，成纤维细胞）和免疫细胞（例如巨噬细胞），然后详细表征信号传导 分子和治疗性筛查。具有专业知识的多学科行业学术伙伴关系 基于微流体细胞的测定和肌肉骨骼生物学和组织再生 已经组装了成功完成该项目。通过提供准确，定量和 生理互动的预测模型，开发的多尺度平台有望建立一个新的 用于体外评估治疗剂的体外评估的范例。