An Advanced Lung Organomimetic to Reproduce Human Airway Pathophysiology

项目总结 全球人类前五大死因中有三个与肺有关；慢性阻塞性肺病 每年有800多万人死于慢性阻塞性肺病、下呼吸道感染和肺癌。 目前，在临床前环境中，静态细胞培养和动物模型是最广泛使用的系统 机械论和翻译研究。然而，这些系统的严重限制经常阻碍翻译 给人类的发现。因此，在临床翻译、药物开发、生物标志物等方面存在瓶颈 肺领域，特别是COPD的发现和机制研究，由于缺乏可靠的，和 与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学原理 从新兴的“芯片器官”技术到“下一代生物人造人类”的开发和商业化 肺作为一种改进的实验研究工具，在体外评价人肺的呼吸道病理生理学。这 高度创新的微流控细胞培养设备将包含微米大小的中空通道，供人类- 衍生(健康的和患病的)活细胞，将重建多细胞结构、组织-组织界面和 人体肺气道的物理化学微环境，并将使体内观察到的 血管灌流对于为这种有机仿生培养提供营养、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调查人员来说， 生物人工肺提供了一种实验研究工具，使它们能够显著加速 临床翻译其基础科学，优于动物模型、静态2D培养系统甚至 目前可用的微流控系统，通过增强复杂人体器官的复制 体外病理生理学。为了验证这一假设，在项目的第一阶段，我们将追求以下具体目标：(1) 演示生物人工肺的可行制造和组装，以及(2)提供以下证据： 建立含细胞外基质和基质包埋的活体多细胞共培养的基本资料 我们提出的微型设备中的基质细胞。在第一阶段完成后，我们期望我们将拥有 可持续且可重复地制造所建议的生物人工肺和原代培养的能力 在这个设备中从人类呼吸道中分离出细胞，并保持它们的活性和功能数周。这将允许 为了过渡到第二阶段，应用新的芯片技术来复制各种肺部病变，并提炼质量 通过可再生性和成本最小化来扩大生产能力。归根结底，这是一个商业产品， 增强肺部领域的临床翻译，促进更快节奏的药物开发和 生物标记物发现，将作为终端用户现成的产品提供。

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.