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.

抽象的 目前血管化骨组织的体外模型不能模拟体内微环境 由不同类型的细胞组成，通过基质屏障相互通讯。在 此外，他们还因缺乏脉管系统的实时可视化和定量而受到阻碍 - 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 信息既耗时又昂贵，而且近年来，道德问题日益受到重视 的担忧。此外，动物研究对机械行为的理解有限 与良好对照的体外研究相比。因此，对体外平台的需求尚未得到满足 用于改进对血管化骨-软骨相互作用的监测和分析。 在第一阶段，我们成功开发并展示了一个多尺度体外模型，包括 微型微流体装置和介观尺度生物反应器来模拟体内条件。 我们在平台上成功分化了患者来源的人间充质干细胞 （hMSC）朝向成骨和软骨形成谱系，强调与血管的相互作用 内皮细胞。根据详细的功能特征，我们展示了该功能 评估抗炎治疗功能的平台。在第二阶段我们将 测试模拟天然骨软骨的其他促炎成分 微环境。我们还将使用我们的多尺度系统来进行（a）机械理解 (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，通过复用平台来提高吞吐量 用于自动化。 具有基于细胞的微流体专业知识的多学科行业学术合作伙伴关系 分析、肌肉骨骼生物学和组织再生已成功完成 该项目的完成。通过提供准确、定量和预测的模型 生理相互作用，开发的多尺度平台有望建立一个新的 体外评估治疗生理反应的范例。