Currently used animal and cellular models for pulmonary arterial hypertension (PAH) only partially recapitulate its pathophysiology in humans and are thus inadequate in reproducing the hallmarks of the disease, inconsistent in portraying the sex-disparity, and unyielding to combinatorial study designs. Here we sought to deploy the ingenuity of microengineering in developing and validating a tissue chip model for human PAH. We designed and fabricated a microfluidic device to emulate the luminal, intimal, medial, adventitial, and perivascular layers of a pulmonary artery. By growing three types of pulmonary arterial cells (PACs)-endothelial, smooth muscle, and adventitial cells, we recreated the PAH pathophysiology on the device. Diseased (PAH) PACs, when grown on the chips, moved of out their designated layers and created phenomena similar to the major pathologies of human PAH: intimal thickening, muscularization, and arterial remodeling and show an endothelial to mesenchymal transition. Flow-induced stress caused control cells, grown on the chips, to undergo morphological changes and elicit arterial remodeling. Our data also suggest that the newly developed chips can be used to elucidate the sex disparity in PAH and to study the therapeutic efficacy of existing and investigational anti-PAH drugs. We believe this miniaturized device can be deployed for testing various prevailing and new hypotheses regarding the pathobiology and drug therapy in human PAH.

中文翻译：

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片上肺动脉高压（PAH）：制造，验证和应用。

当前用于肺动脉高压（PAH）的动物和细胞模型仅部分概括了其在人类中的病理生理，因此不足以重现该疾病的标志，描述性别差异不一致，并且不屈服于组合研究设计。在这里，我们试图在开发和验证人类PAH的组织芯片模型中运用微工程学的独创性。我们设计和制造了一种微流控设备，以模拟肺动脉的腔，内膜，内膜，外膜和血管周层。通过生长三种类型的肺动脉细胞（PAC）-内皮细胞，平滑肌和外膜细胞，我们在设备上重建了PAH的病理生理学。病态（PAH）PAC在芯片上生长时，移出其指定的层并产生与人类PAH的主要病理相似的现象：内膜增厚，肌肉增生和动脉重塑，并显示内皮向间质的转变。流诱导的压力导致生长在芯片上的控制细胞发生形态变化并引起动脉重塑。我们的数据还表明，新开发的芯片可用于阐明PAH中的性别差异，并研究现有和研究中的抗PAH药物的治疗功效。我们相信，这种小型设备可以部署用于测试有关人类PAH病理生物学和药物治疗的各种流行和新假设。流诱导的压力导致生长在芯片上的控制细胞发生形态变化并引起动脉重塑。我们的数据还表明，新开发的芯片可用于阐明PAH中的性别差异，并研究现有和研究中的抗PAH药物的治疗功效。我们相信，这种小型设备可以部署用于测试有关人类PAH病理生物学和药物治疗的各种流行和新假设。流诱导的压力导致生长在芯片上的控制细胞发生形态变化并引起动脉重塑。我们的数据还表明，新开发的芯片可用于阐明PAH中的性别差异，并研究现有和研究中的抗PAH药物的治疗功效。我们相信，这种小型设备可以部署用于测试有关人类PAH病理生物学和药物治疗的各种流行和新假设。