Airflow limitation is the hallmark of obstructive pulmonary diseases, with the distal airways representing a major site of obstruction. Although numerous in vitro models of bronchi already exist, there is currently no culture system for obstructive diseases that reproduces the architecture and function of small airways. Here, we aimed to engineer a model of distal airways to overcome the limitations of current culture systems.

We developed a so-called bronchioid model by encapsulating human bronchial adult stem cells derived from clinical samples in a tubular scaffold made of alginate gel.

This template drives the spontaneous self-organisation of epithelial cells into a tubular structure. Fine control of the level of contraction is required to establish a model of the bronchiole, which has a physiologically relevant shape and size. Three-dimensional imaging, gene expression and single-cell RNA-sequencing analysis of bronchioids made of bronchial epithelial cells revealed tubular organisation, epithelial junction formation and differentiation into ciliated and goblet cells. Ciliary beating was observed, at a decreased frequency in bronchioids made of cells from COPD patients. The bronchioid could be infected by rhinovirus. An air–liquid interface was introduced that modulated gene expression.

Here, we provide a proof of concept of a perfusable bronchioid with proper mucociliary and contractile functions. The key advantages of our approach, such as the air-liquid interface, lumen accessibility, recapitulation of pathological features and possible assessment of clinically relevant end-points, will make our pulmonary organoid-like model a powerful tool for preclinical studies.

气流受限是阻塞性肺疾病的标志，远端气道是阻塞的主要部位。尽管已经存在许多支气管的体外模型，但目前还没有重现小气道结构和功能的阻塞性疾病培养系统。在这里，我们旨在设计一个远端气道模型，以克服当前培养系统的局限性。

我们通过将来自临床样本的人支气管成体干细胞封装在由藻酸盐凝胶制成的管状支架中，开发了一种所谓的支气管样模型。

该模板驱动上皮细胞自发自组织成管状结构。需要精细控制收缩水平以建立细支气管模型，该模型具有生理相关的形状和大小。由支气管上皮细胞制成的支气管类化合物的三维成像、基因表达和单细胞 RNA 测序分析揭示了肾小管组织、上皮连接形成和分化为纤毛细胞和杯状细胞。观察到睫状跳动，在 COPD 患者细胞制成的支气管样气管中频率降低。支气管样气管可能被鼻病毒感染。引入了调节基因表达的气-液界面。

在这里，我们提供了具有适当粘膜纤毛和收缩功能的可灌注支气管的概念证明。我们方法的主要优势，例如气液界面、管腔可及性、病理特征的概括以及临床相关终点的可能评估，将使我们的肺类器官样模型成为临床前研究的有力工具。