Fibrotic microtissue chips for screening of anti-fibrotic therapies

 产品说明：纤维化，如在终末期特发性肺纤维化（IPF）、心力衰竭、肝硬化和肾病中所见，导致器官衰竭，并且目前没有治愈方法。抗纤维化疗法的候选药物已经确定;然而，这些实验室发现转化为临床实践受到疾病进展缓慢和与临床试验相关的高成本的阻碍。为了证明在长期和昂贵的临床试验中开发新疗法的合理性，需要能够提供抗纤维化疗法功效的早期证据的体外筛选平台。然而，现有的失败 体外模型可以充分概括纤维化疾病的生理病理特征， 例如肺纤维化中用力肺活量（FVC）和主要细胞外基质（ECM）重塑的降低，显著延迟了急需的抗纤维化疗法的发展。本项目的目的是开发一种微生理肺“纤维化”， 微组织芯片”设备，可以使抗纤维化治疗的早期筛选。我们最近采用微加工技术组装成纤维细胞填充的亚毫米级微组织的聚（二甲基硅氧烷）（PDMS）微孔阵列。在每个微孔中，成纤维细胞自发地收缩并将基质蛋白（如胶原蛋白）组装成对齐的微组织，该微组织锚在一对杠杆之间。我们最近的初步数据表明，由于边界条件引导的细胞和ECM的自组装，可以在微组织中形成不同的上皮和ECM层。通过适当的生物化学和机械刺激，可以在这些微组织中进一步诱导驻留细胞的纤维化分化。在本项目中，我们将充分表征诱导的微组织的纤维化特性，例如其在模拟强制通气下的顺应性和ECM的沉积。然后，我们将测试其对FDA最近批准用于治疗IPF的两种药物的效用。本申请的具体目的是：1）制造微组织阵列并诱导纤维化转变; 2）校准纤维化微组织的机械和组织学特性并使用一小组训练抗纤维化药物优化系统;以及3）评估所开发的纤维化组织芯片在筛选抗纤维化药物中的效用。 化合物.该项目完成后，我们期望开发出一种新方法，可以显著加快抗纤维化疗法从实验室到诊所的转化。我们相信，这种技术进步将对防治纤维化疾病的实践产生积极影响。

 DESCRIPTION: Fibrosis, as seen in end-stage idiopathic pulmonary fibrosis (IPF), heart failure, liver cirrhosis and kidney disease, leads to organ failure and currently has no cure. Candidates for anti-fibrotic therapies have been identified; however, the translation of these laboratory discoveries to clinical practice is hindered by the slow disease progression and the high cost associated with the clinical trials. To justify the development of new therapies in prolonged and expensive clinical trials, an in-vitro screening platform that can provide early evidence of efficacy of the anti-fibrotic therapies is desired. However, failure of the existing in vitro models to fully recapitulate the physio-pathological characteristics of the fibrotic disease, such as the reduced Forced vital capacity (FVC) and major extracellular matrix (ECM) remodeling in lung fibrosis, has significantly delayed the development of much needed anti-fibrotic therapies. The objective of this project is to develop a microphysiological lung "fibrotic micro-tissue chip" device that can enable the early screening of anti-fibrotic therapies. We have recently adopted micro-fabrication techniques to assemble 3D fibroblast-populated submillimeter micro-tissues in arrays of poly (dimethylsiloxane) (PDMS) micro-wells. In each micro-well, fibroblasts spontaneously contract and assemble the matrix proteins, such as collagen, into aligned micro-tissues that anchor between a pair of cantilevers. Our recent preliminary data have shown that distinct epithelium and ECM layers can be formed in micro-tissues due to boundary condition guided self-assembly of the cells and ECMs. With appropriate biochemical and mechanical stimuli, fibrotic differentiation of the resident cells can be further induced in these micro-tissues. In this project, we will fully characterize the fibrotic propertiesof the induced micro-tissue, such as its compliance under simulated forced ventilation and the deposition of ECM. We will then test its utility against two drugs that are very recently approved by FDA to treat IPF. The Specific Aims of this application are: 1) Fabricate arrays of micro-tissues and induce fibrotic transition; 2) Calibrate the mechanical and histological characteristic of the fibrotic micro-tissues and optimize the system using a small set of training anti-fibrotic drugs; and 3) Evaluate the utility of the developed fibrotic tissue-chip in screening anti-fibrotic compounds. Upon completion of this project, it is our expectation that we will have developed a new approach that can significantly expedite the translation of anti-fibrotic therapies from the laboratories to the clinics. We are confident that such advancement in the technology will positively impact the practices to combat fibrotic diseases.