Biomimetic Alveolar Interstitium Model for Investigation of Nanomaterials-induced Fibrogenesis

用于研究纳米材料诱导纤维形成的仿生肺泡间质模型

• 批准号: 9581765
• 负责人: Yong Yang
• 金额: $ 28.08万
• 依托单位: UNIVERSITY OF NORTH TEXAS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9581765
• 关键词: Biomimetic; Alveolar; Interstitium; Model; Investigation

PROJECT SUMMARY/ABSTRACT While the rapidly evolving nanotechnology has shown promise in electronics, energy, healthcare and many other fields, there is an increasing concern about the adverse health consequences of engineered nanomaterials. In vivo studies have shown that inhaled carbon nanotubes can rapidly enter the lung interstitium to stimulate collagen production and induce progressive interstitial lung fibrosis, which is a fatal and incurable disease with no known effective treatment. To evaluate the toxicity of nanomaterials, animal studies are necessary but costly, time-consuming and facility limited; while the majority of current in vitro models suffer from a series of drawbacks, most importantly, they lack characteristics of in vivo microenvironment, leading to losses of critical in vivo cell phenotypes and responsiveness. There is, therefore, a critical need to develop in vitro models of physiological relevance to provide reliable, rapid and inexpensive methods for toxicology studies and risk assessment of nanomaterials. The extracellular matrix of lung interstitium manifests significant nanoscale topographies, exhibits various degrees of stiffness, and is enriched with interstitial fluids. The physiological breathing movements also provide cyclic mechanical strain. Although the physical (substrate nanotopography and stiffness) and mechanical (fluid-induced forces and mechanical strain) cues critically influence numerous developmental, physiological and pathological processes in vivo and have a profound influence on cell phenotype and function in vitro, there has been no effort reported on integrating these factors into a single platform for toxicology studies. Our hypothesis is that the interstitial fibrotic response to nanomaterials in vitro can be more accurately evaluated in a physiologically relevant microenvironment. Therefore, the objective of this project is to develop an alveolar interstitium model integrated with the physical and mechanical cues of physiological relevance to investigate nanomaterials induced lung fibrogenesis. We have assembled an interdisciplinary research team to carry out nanotoxicology studies both in vivo and in vitro, and provided strong evidence that nanotopography, stiffness and fluidic shear stress have profound influences on cell behavior. Based on the compelling preliminary results, we propose two Specific Aims in this project: (1) dissect substrate nanotopography and stiff modulated human lung fibroblast sensing nanomaterials, and (2) build a microfluidic platform integrated with key physical, mechanical and structural characteristics of lung interstitium to assess nanomaterials induced fibrogenesis. Successful completion of this project will advance our fundamental understanding of physical and mechanical modulation of cell behavior and develops a novel, biomimetic interstitium microenvironment to advances over the “classic” in vitro cytotoxicity methods. This biomimetic model is expected to fill the knowledge and technology gaps between current in vitro models and animal studies, and potentially promote sustainable development of nanotechnology.

项目概要/摘要 虽然快速发展的纳米技术已在电子、能源、医疗保健和许多领域显示出前景 在其他领域，人们越来越担心工程技术对健康造成的不利后果 纳米材料。体内研究表明，吸入碳纳米管可以快速进入肺部 间质刺激胶原蛋白产生并诱导进行性间质性肺纤维化，这是一种致命的、 没有已知有效治疗方法的不治之症。为了评估纳米材料的毒性，动物研究 是必要的，但成本高昂、耗时且设施有限；而目前大多数体外模型都受到影响 存在一系列的缺点，最重要的是它们缺乏体内微环境的特征，导致 关键体内细胞表型和反应性的丧失。因此，迫切需要开发 生理相关的体外模型为毒理学提供可靠、快速且廉价的方法 纳米材料的研究和风险评估。肺间质细胞外基质表现显着 纳米级的形貌，表现出不同程度的刚度，并且富含间质液。这 生理呼吸运动也提供周期性机械应变。尽管物理（基材 纳米形貌和刚度）和机械（流体引起的力和机械应变）至关重要 影响体内众多的发育、生理和病理过程，并具有深远的影响 体外对细胞表型和功能的影响，尚未有关于整合这些因素的报道 整合到毒理学研究的单一平台中。我们的假设是间质纤维化反应 可以在生理相关的微环境中更准确地评估体外纳米材料。 因此，该项目的目标是开发一种与物理结合的肺泡间质模型 和生理相关的机械线索来研究纳米材料诱导的肺纤维化。我们 组建了一个跨学科研究团队，开展体内和体外纳米毒理学研究， 并提供了强有力的证据表明纳米形貌、刚度和流体剪切应力具有深远的影响 关于细胞行为。基于令人信服的初步结果，我们提出了该项目的两个具体目标：(1) 解剖基底纳米形貌和刚性调制人肺成纤维细胞传感纳米材料，以及（2） 构建集成肺关键物理、机械和结构特征的微流控平台 间质来评估纳米材料诱导的纤维发生。该项目的顺利完成将推进 我们对细胞行为的物理和机械调节的基本理解，并开发了一种新颖的、 仿生间质微环境比“经典”体外细胞毒性方法取得了进步。这 仿生模型有望填补当前体外模型和生物模型之间的知识和技术空白。 动物研究，并有可能促进纳米技术的可持续发展。

项目成果

Microphysiological Systems: Design, Fabrication, and Applications.

• DOI: 10.1021/acsbiomaterials.9b01667
• 发表时间: 2020-06-08
• 期刊: ACS biomaterials science & engineering
• 影响因子: 5.8
• 作者: Wang K;Man K;Liu J;Liu Y;Chen Q;Zhou Y;Yang Y
• 通讯作者: Yang Y

Biophysical Regulation of Cell Behavior-Cross Talk between Substrate Stiffness and Nanotopography.

• DOI: 10.1016/j.eng.2017.01.014
• 发表时间: 2017-03
• 期刊: Engineering (Beijing, China)
• 作者: Yang Y;Wang K;Gu X;Leong KW
• 通讯作者: Leong KW

Piezo1 plays a role in optic nerve head astrocyte reactivity.

• DOI: 10.1016/j.exer.2021.108445
• 发表时间: 2021-03
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: Liu J;Yang Y;Liu Y
• 通讯作者: Liu Y

Dimensionality-Dependent Mechanical Stretch Regulation of Cell Behavior.

• DOI: 10.1021/acsami.2c01266
• 发表时间: 2022-04
• 期刊: ACS applied materials & interfaces
• 影响因子: 9.5
• 作者: Kun Man;Jiafeng Liu;Khang Phan;Kai Wang;Jung Yeon Lee;Xiankai Sun;Michael’s Story;D. Saha;Jun Liao;Hamid Sadat;Yong Yang