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

特发性肺纤维化(IPF)以肺组织进行性硬化为特征，是一种严重的 无法治愈的疾病。IPF的发病机制目前尚不完全清楚，但炎症反应已被证实。 被确定为主要的介体之一，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和利用 严格的2D培养格式，它们不能概括多个促纤维化细胞(巨噬细胞， 肌成纤维细胞)和生理应力(剪切流、基质硬化、组织收缩)。 组织。因此，这些模型不能提供关于治疗靶点的疗效读数 抗纤维化药物。这一更新项目的目标是开发一种共培养的纤维化微组织系统 可以对炎症引起的纤维化事件进行建模，并预测该药的疗效 针对炎症途径的抗纤维化药物。调查人员此前已经开发出一种静态、单声道- 可概括组织晚期纤维化改变的培养纤维微组织系统 肌成纤维细胞分化引起的生物力学和组织学研究。然而，该系统仅限于 预测针对重要的早期纤维化事件的药物的疗效。在当前的项目中， 研究人员建议通过包括早期阶段来扩展现有系统的纤维化建模能力 纤维形成事件，如血流介导的巨噬细胞促纤维化激活和诱导的炎症 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 药物对炎症途径的疗效，从而验证了药物对炎症反应的作用机制。 预定目标。其目标将包括开发一种共培养的纤维微组织系统，该系统可以 炎症诱导肺间质纤维化及其筛查能力的评价 针对炎症途径的抗纤维化药物的微组织系统。预计这样的一个 系统将能够模拟候选药物在炎症途径上的治疗效果，从而 从而能够描述该药物的治疗机制。这样的新方法可以显著地 加快将抗纤维化疗法从实验室转移到诊所。 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