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: 10259212
• 负责人: BALABHASKAR PRABHAKARPANDIAN
• 金额: $ 89.4万
• 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: 2017-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259212
• 关键词: 3-Dimensional; Acute; Animal Model; Animals; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Automation; Basic Science; Behavior; Biological; Biological Assay; Biology; Bioreactors; Blood Vessels; Bone Tissue; Cartilage; Cell physiology; Cells; Chronic Disease; Collaborations; Communication; Consumption; Degenerative polyarthritis; Development; Disease Progression; Drug Delivery Systems; Drug usage; Elements; Engineering; Ethics; Genomics; Goals; Human; Immune; In Vitro; Industry; Inflammation Mediators; Inflammatory; Inflammatory Response; Infrastructure; Injury; Interleukin-1 beta; Interleukin-6; Intervention; Manuals; Measures; Mesenchymal Stem Cells; Microfluidic Microchips; Microfluidics; Modeling; Monitor; Musculoskeletal; Neurologic; Outcome; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Play; Proteomics; Reactive Oxygen Species; Research; Scientist; Signal Transduction; Stream; Synovial Fluid; System; TNF gene; Testing; Therapeutic; Time; Tissue Model; Tissues; Universities; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Visualization; analog; arthropathies; base; bone; cartilage degradation; cell type; clinically relevant; commercialization; cytokine; drug candidate; drug discovery; effectiveness testing; experimental study; improved; in vitro Model; in vivo; macrophage; multidisciplinary; multiplex assay; novel therapeutics; osteochondral tissue; osteogenic; phase 1 study; physiologic model; predictive modeling; response; screening; tissue regeneration; user-friendly

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. In Phase I we successfully developed and demonstrated a multi-scale in vitro model comprising of a micro scale microfluidic device and a meso scale bioreactor to mimic the in vivo conditions. We successfully differentiated in the platform patient derived human mesenchymal stem cells (hMSCs) towards osteogenic and chondrogenic lineages highlighting interactions with vascular endothelial cells. Following detailed functional characterizations, we demonstrated the capability of the platform to evaluate functionality for an anti-inflammatory therapeutic. In Phase II we will test additional pro-inflammatory components that mimic the native osteochondral microenvironment. We will also use our multi-scale system for (a) mechanistic understanding and (b) therapeutic screening of candidate treatments following inflammatory insults. Finally, we will develop the infrastructure to increase the throughput capability by multiplexing the platform for automation. 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 目前的血管化骨组织体外模型不能模拟体内微环境 包括通过基质屏障彼此通讯的不同细胞类型。在 此外，它们还受到缺乏实时可视化和脉管系统定量的阻碍， 骨以及骨-软骨相互作用。相比之下，动物模型虽然提供了有用的 信息是耗时、昂贵的，近年来， 性问题此外，动物研究提供了有限的理解机械行为 与对照良好的体外研究相比。因此，存在对体外平台的未满足的需求。 用于改善血管化骨-软骨相互作用的监测和分析。 在第一阶段，我们成功地开发和证明了多尺度体外模型，包括 微尺度微流体装置和中尺度生物反应器的组合以模拟体内条件。 我们成功地在患者来源的人间充质干细胞的平台上分化， （hMSCs）向成骨和软骨细胞谱系的分化，突出了与血管的相互作用 内皮细胞在详细的功能表征之后，我们展示了 以评估抗炎治疗的功能。在第二阶段，我们将 测试模拟天然骨软骨炎的其他促炎成分 微环境我们还将使用我们的多尺度系统（a）机械理解 和（B）炎症损伤后候选治疗的治疗筛选。最后我们 将开发基础设施，通过多路复用平台来提高吞吐能力 for automation自动化. 一个多学科的行业-学术合作伙伴关系，拥有基于细胞的微流体专业知识 分析和肌肉骨骼生物学和组织再生已经组装成功 完成这个项目。通过提供一个准确的，定量的和预测的模型， 生理相互作用，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。