An Advanced Lung Organomimetic to Reproduce Human Airway Pathophysiology

项目摘要 全球人类五大死因中有三个与肺有关;慢性阻塞性肺病 慢性阻塞性肺疾病（COPD）、下呼吸道感染和肺癌每年总共造成800多万人死亡。 目前，在临床前环境中，静态细胞培养物和动物模型是最广泛使用的系统， 机制和翻译研究。然而，这些系统的关键局限性往往阻碍了翻译， 人类的发现。因此，在临床转化、药物开发、生物标志物 在肺领域，特别是COPD，由于缺乏可靠的发现和机制研究， 人类和疾病相关的临床前模型。在这里，我们建议应用组织微工程原理 从新兴的“器官芯片”技术，开发和商业化的“下一代生物人工人类” “肺”作为一种改进的实验研究工具，在体外评估人类肺气道病理生理学。这 高度创新的微流控细胞培养装置将包含人居住的微米大小的中空通道， 衍生的（健康和患病）活细胞，将重建多细胞结构，组织-组织界面， 人肺气道的理化微环境，并将使体内观察到的生殖 血管灌注对于向这种器官模拟培养物提供营养、氧气和生长因子至关重要 系统我们的商业假设是，对于进行肺部研究的实验室研究人员来说， 生物人工肺提供了一个实验研究工具，使他们能够大大加快 他们的基础科学的临床翻译，优于动物模型，静态2D培养系统，甚至 目前可用的微流体系统，通过增强复杂的人体器官的复制， 体外病理生理学为了验证这一假设，在项目的第一阶段，我们将实现以下具体目标：（1） 证明生物人工人肺的可行制造和组装，以及（2）提供 建立含有细胞外基质和基质包埋的活的多细胞共培养物的基本数据 我们提出的微型装置中的基质细胞。在第一阶段完成后，我们预计将有 能够一致且可重复地生产申报的生物人工人肺和原代培养物 在该装置中从人气道分离的细胞，并使它们保持存活和功能数周。这将允许 过渡到第二阶段，应用新的芯片技术重现各种肺部病变， 通过可重复性和成本最小化实现规模化生产能力。最终，一个商业产品， 能够增强肺部领域的临床转化，促进更快的药物开发， 生物标志物发现，将作为最终用户的现成产品。

PROJECT SUMMARY Three of top five causes of death in humans globally are lung-related; chronic obstructive pulmonary disease (COPD), lower respiratory infections and lung cancers collectively account for over eight million deaths annually. Currently, in preclinical setting, static cell cultures and animal models are the most widely used systems for mechanistic and translational studies. However, critical limitations of these systems often hinder the translation of findings to humans. As such, there is a bottleneck on clinical translation, drug development, biomarker discovery and mechanistic studies in pulmonary field, particularly COPD, due to lack of reliable, and human- and disease-relevant preclinical models. Here, we propose to apply tissue microengineering principles from emerging ‘Organ-on-Chip’ technology, to develop and commercialize ‘Next-Generation Bioartificial Human Lung’ as an improved experimental research tool to evaluate human lung airway pathophysiology in vitro. This highly innovative microfluidic cell culture device will contain micrometer-sized hollow channels inhabited by human- derived (healthy and diseased) living cells that will recreate multicellular architecture, tissue-tissue interfaces, and physicochemical microenvironment of the human lung airway, and will enable reproduction of in vivo-observed vascular perfusion that is crucial for providing nutrients, oxygen and growth factors to this organomimetic culture system. Our business hypothesis is that for laboratory investigators who conduct pulmonary research, the Bioartificial Human Lung provides an experimental research tool that enables them to considerably accelerate clinical translation of their basic science, better than animal models, static 2D culture systems and even currently available microfluidic systems, by enhanced reproduction of complex human organ pathophysiology in vitro. To test this hypothesis, in Phase I of the project, we will pursue these specific aims: (1) to demonstrate feasible fabrication and assembly of the Bioartificial Human Lung, and (2) to provide proof-of- principle data on establishing a living multi-cellular co-culture containing extracellular matrix and matrix-embedded stromal cells in our proposed microdevice. At the completion of Phase I, it is our expectation that we will have the capability to consistently and reproducibly manufacture the proposed Bioartificial Human Lung and culture primary cells isolated from the human airway in this device and maintain them viable and functional for weeks. This will allow for transition to Phase II to apply the new chip technology to reproduce various lung pathologies, and refine mass scale production capabilities through reproducibility and cost minimization. Ultimately, a commercial product, which enables enhanced clinical translation in the pulmonary field and facilitates faster-paced drug development and biomarker discovery, will be available as end-user off-the-shelf product.