An inflammation-induced fibrosis-on-chip system for the testing of anti-fibrosis drugs

特发性肺纤维化（IPF）是一种严重的肺纤维化，其特征在于肺组织的进行性硬化， 无法治愈的疾病对IPF发病机制的理解尚不完全，但炎症已被广泛接受。 已被确定为主要介质之一，并已被提议作为发展的治疗靶点。 抗IPF药物。然而，由于现有的体外纤维化模型由有限的细胞类型组成，并且利用了 刚性的2D培养形式，它们不能再现多个促纤维化细胞（巨噬细胞， 肌纤维母细胞）和生理应力（剪切流，基质硬化，组织收缩）在纤维化 组织.因此，这些模型不能提供关于药物的“治疗靶标”的功效读数。 抗纤维化药物本更新项目的目标是开发一种共培养的纤维化微组织系统 其可以模拟由炎症引起的纤维发生事件并预测免疫调节剂的治疗功效。 针对炎症通路的抗纤维化药物。研究人员以前开发了一种静态的，单声道的， 培养的纤维化微组织系统，其可以再现组织中的晚期纤维化变化 肌成纤维细胞分化引起的生物力学和组织学变化。然而，该系统局限于 预测靶向重要的早期纤维发生事件的药物的功效。在目前的项目中， 研究人员建议通过包括早期阶段的纤维化模型来扩展现有系统的纤维化建模能力， 纤维发生事件，如流动介导的巨噬细胞的促纤维化活化和炎症诱导的纤维化。 肌成纤维细胞分化有了这种改进的建模能力，新系统将允许检查 药物对炎症通路的功效，从而验证药物对炎症通路的作用机制。 预定目标。其目标将包括开发一种共培养的纤维化微组织系统， 炎症诱导的肺间质组织纤维化，并评估筛选能力， 微组织系统的抗纤维化药物的目标炎症途径。预期这样的 系统将能够模拟候选药物对炎症途径的治疗效果， 从而能够描述药物的治疗机制。这种新方法可以大大 加快抗纤维化疗法从实验室向诊所的转化。 1

Idiopathic pulmonary fibrosis (IPF), characterized by the progressive stiffening of lung tissues, is a severe disease with no cure. The understanding of the IPF pathogenesis is incomplete, but inflammation has been identified as one of the major mediators and has been proposed as a therapeutic target for the development of anti-IPF drugs. However, since existing in vitro fibrosis models are composed of limited cell types and utilize rigid 2D culture formats, they cannot recapitulate the interaction between multiple profibrotic cells (macrophage, myofibroblast) and the physiological stresses (shear flow, matrix stiffening, tissue contraction) in the fibrotic tissue. As a result, these models are not able to provide the efficacy readout on the “therapeutic targets” of the anti-fibrosis drugs. The objective of this renewal project is to develop a co-cultured fibrotic microtissue system that can model the fibrogenesis event caused by the inflammation and predict the therapeutic efficacy of the anti-fibrotic drugs that target inflammation pathways. Investigators have previously developed a static, mono- cultured fibrotic microtissue system that can recapitulate the late-stage fibrogenic changes in tissue biomechanics and histology caused by myofibroblast differentiation. However, this system is limited in predicting the efficacy of drugs that target important early stage fibrogenesis events. In the current project, investigators propose to expand the fibrosis modeling capacity of the existing system by including early-stage fibrogenesis events, such as flow-mediated profibrotic activation of the macrophages and inflammation induced myofibroblast differentiation. With this improved modeling capability, the new system will allow the examination of the drug efficacy on the inflammatory pathways, thus validating the mechanism of action of the drug on the intended target. The aims will include to develop a co-cultured fibrotic microtissue system that can model inflammation-induced fibrogenesis of the lung interstitial tissue and to evaluate the screening capacity of the microtissue system for anti-fibrosis drugs that target the inflammatory pathway. It is expected that such a system will be able to simulate the therapeutic effects of the drug candidates on inflammatory pathways, thus allowing the delineation of the therapeutic mechanism of the drug. Such a new approach can significantly expedite the translation of anti-fibrotic therapies from the laboratories to the clinics. 1