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.

摘要 目前血管化骨组织的体外模型不能模拟体内微环境， 不同的细胞类型通过基质屏障相互通讯。此外，他们还受到阻碍， 缺乏血管-骨以及骨-软骨相互作用的实时可视化和定量。在 相比之下，动物模型在提供有用信息的同时既耗时又昂贵，而且近年来， 越来越多地引起了道德上的关注。此外，动物研究提供了有限的理解， 与良好对照的体外研究相比，因此，存在对体外免疫的未满足的需求。 用于改善血管化骨-软骨相互作用的监测和分析的平台。 我们建议开发和展示一个多尺度的血管化骨软骨组织模型， 了解细胞信号传导，第一阶段重点关注内皮细胞、骨骼之间的相互作用 细胞，特别是成骨细胞（骨生成细胞）和破骨细胞（骨降解细胞），以及软骨细胞 （软骨细胞）。所提出的方法的多尺度性质是基于使用（a）微尺度 基于血管的骨软骨模型，使用微流体和组织工程来研究细胞信号传导， 告知（B）询问工程化构建体和天然骨-软骨的中尺度血管骨-软骨模型， 用于结构和功能研究的组织。 第一阶段将清楚和明确地证明使用这种多尺度模型的血管化， 骨软骨组织相互作用的细胞信号。开发的平台将模仿形态学， 在体内观察到的生理流动和3D多细胞组成，并实现简单和稳健的系统 用于评估细胞反应。在第二阶段，该平台将扩大到包括其他基质细胞 (e.g.,成纤维细胞），和免疫细胞（例如，巨噬细胞），然后详细表征信号转导 分子和治疗筛选。一个多学科的行业和学术合作伙伴关系， 微流控细胞分析和肌肉骨骼生物学和组织再生 为成功完成这个项目而进行的。通过提供准确、定量和 生理相互作用的预测模型，开发的多尺度平台有望建立一个新的 用于体外评估对治疗剂的生理反应的范例。