An Integrated In Vitro 3D Model of Human Bone Marrow and Peripheral Infection

项目总结 对外周感染的免疫反应是人类免疫系统的一个基本特征， 提供强大的保护，免受各种感染源的侵袭。响应必然会调用先天的 免疫系统，但这种精心安排的反应的许多特征尚不清楚，限制了我们的能力 加强对新的和不断变化的威胁的响应。特别是，与生俱来的反应与骨骼接触 骨髓来调整反应的大小和动态。两者之间有重要的区别 小鼠(研究先天免疫反应的主要模型)和人类先天免疫反应 独特的规模和动态，以及3D细胞和组织培养的新技术提供了令人兴奋的 这一领域的机遇被称为“芯片上的器官”。该项目的主要目标是设计、建造和 验证一个集成的人类“免疫芯片”平台，该平台模拟生产和生产的关键动态特征 多形核白细胞(PMN，即中性粒细胞)在骨髓之间的运输，系统性 循环和细菌感染的外周部位。开发这项技术很重要，因为 抗生素耐药性细菌的惊人扩张，这将需要创造性和替代方法来 战斗。具体目标是：1)设计、制造和测试微流控免疫芯片，该芯片模拟 骨髓、体循环和无菌皮肤模型之间的动态平衡相互作用；2)建立 免疫芯片中HSPC扩增、PMN转运和抗菌防御的动态平衡电路 对细菌感染的可溶介质做出反应；以及3)表现出适当的反应，以包含 免疫芯片内耐甲氧西林(和敏感)金黄色葡萄球菌外周感染，并生产测试- 用于抗击感染的新生物策略的床。体外模型将能够唯一地模拟 外周感染-骨髓沟通的动态变化，包括转运障碍、滞留时间 由于隔室大小的巨大差异而造成的循环和稀释。完成我们的任务 主要目标是创造一种技术，推动一类新的模型系统来理解人类 对外周感染的反应。

PROJECT SUMMARY The immune response to a peripheral infection is a fundamental feature of the human immune system, providing robust protection from a myriad of infectious agents. The response necessarily invokes the innate immune system, but many features of this orchestrated response are poorly understood, limiting our ability to augment the response to new and ever evolving threats. In particular, the innate response engages the bone marrow to modify the magnitude and dynamics of the response. There are important differences between the mouse (primary model to study the innate immune response) and human innate immune responses, in particular scale and dynamics, and new technologies in 3D cell and tissue culture provide exciting opportunities in the field known as “organ-on-a-chip”. The primary goal of this project is to design, build, and validate an integrated human “ImmuneChip” platform that mimics key dynamic features of the production and trafficking of polymorphonuclear leukocytes (PMN, i.e., neutrophils) between the bone marrow, systemic circulation, and peripheral site of bacterial infection. Developing this technology is important because of the alarming expansion of antibiotic resistance bacteria which will demand creative and alternative approaches to combat. The specific aims are to: 1) design, build, and test a microfluidic ImmuneChip that simulates the homeostatic interaction between bone marrow, systemic circulation, and a sterile skin model; 2) establish a homeostatic circuit in the ImmuneChip in which HSPC expansion, PMN trafficking, and antimicrobial defenses respond to soluble mediators of bacterial infection; and 3) demonstrate an appropriate response to contain a methicillin-resistant (and sensitive) S. aureus peripheral infection within the ImmuneChip, and produce a test- bed for novel biological strategies to combat infection. The in vitro model will be able to uniquely simulate the dynamics of peripheral infection-bone marrow communication including transport barriers, residence time in the circulation, and dilution due to the large difference in the size of the compartments. Accomplishing our primary goal will create a technology that advances a new class of model systems to understand the human response to peripheral infection.