Fibrotic microtissue chips for screening of anti-fibrotic therapies

用于筛选抗纤维化疗法的纤维化微组织芯片

基本信息

批准号：
8964276
负责人：
Ruogang Zhao
金额：
$ 35.3万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8964276
关键词：
Actins Adopted Animals Biochemical Biological Markers Biology Buffaloes Caring Cells Cessation of life Characteristics Clinic Clinical Trials Collagen Contracts Data Deposition Development Device or Instrument Development Devices Disease Disease Progression Drug Delivery Systems Environmental air flow Epithelial Epithelial Cells Epithelium Extracellular Matrix FDA approved Failure Fibroblasts Fibrosis Goals Hamman-Rich syndrome Heart failure Human In Vitro Joints Kidney Diseases Laboratories Liver Cirrhosis Liver diseases Lung Measures Mechanics Medical Membrane Messenger RNA Microfabrication Modeling Mus Myofibroblast Myosin ATPase Organ failure Pathology Performance Pharmaceutical Preparations Physiological Production Property Proteins Research Research Personnel Roswell Park Cancer Institute Sample Size Sampling Staging Stimulus Stretching System Techniques Technology Testing Therapeutic Tissue Microarray Tissues Training Transforming Growth Factor beta Translations Universities Vital capacity base cantilever clinical practice combat comparative efficacy cost drug discovery epithelial to mesenchymal transition expectation in vitro Model inhibitor/antagonist innovation nanomedicine new technology novel strategies poly(dimethylsiloxane)public health relevance response screening self assembly

项目摘要

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.

描述：纤维化，如终末期特发性肺纤维化（IPF）、心力衰竭、肝硬化和肾脏疾病，会导致器官衰竭，目前尚无抗纤维化疗法的治疗方法。这些实验室发现的临床实践受到疾病进展缓慢和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，体外筛选平台可以。需要提供抗纤维化疗法功效的早期证据，然而现有的疗法却失败了。体外模型全面概括纤维化疾病的生理病理学特征，例如肺纤维化中用力肺活量（FVC）的降低和主要细胞外基质（ECM）的重塑，显着延迟了急需的抗纤维化疗法的开发。该项目的目标是开发微生理学肺“纤维化”。微组织芯片”装置，可以实现抗纤维化治疗的早期筛选。我们最近采用微制造技术，将 3D 成纤维细胞填充的亚毫米微组织组装在聚（二甲基硅氧烷）（PDMS）微孔阵列中。在每个微孔中，成纤维细胞自发收缩并将胶原蛋白等基质蛋白组装成固定在一对悬臂之间的对齐微组织。初步数据表明，由于边界条件引导细胞和 ECM 的自组装，可以在微组织中形成不同的上皮和 ECM 层，通过适当的生化和机械刺激，可以进一步诱导这些常驻细胞的纤维化分化。在这个项目中，我们将充分表征诱导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两种非常有效的药物的效用。最近获得 FDA 批准用于治疗 IPF。该应用的具体目标是：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征并使用小型系统优化系统。一套训练抗纤维化药物；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该项目完成后，我们期望开发出一种新方法，可以显着加快抗纤维化疗法从实验室到临床的转化，我们相信这种技术进步将产生积极影响。对抗纤维化疾病的做法。