微流控技术脑肿瘤微环境仿生构建及初步应用

发布时间：2018-05-21 06:58

本文选题：微流控技术 + 脑肿瘤微环境　；参考：《大连理工大学》2017年博士论文

【摘要】：脑微环境是体内一种复杂的、动态的微系统,其功能异常与脑肿瘤的发生、发展和转移密切相关。传统体外模型难以反映体内脑微环境复杂结构和功能特点。本论文以前沿微流控芯片为核心技术,以常见脑肿瘤研究为对象,通过体外多细胞、多成分和多条件因素调控,模拟构建脑肿瘤复杂微环境,研究多种化学因子和生物力学等因素对脑肿瘤侵袭和转移的影响及调控机制,以期为脑肿瘤研究提供一种全新思路,分述如下:一、设计并构建了一系列基于微流控芯片的脑肿瘤微环境仿生新体系,分别用于研究三维环境下肿瘤血管外渗、肿瘤侵袭和肿瘤脑转移等动态过程,并开展了体外构建复杂三维动态血脑屏障的方法学研究和抗肿瘤药效评价,为研究脑肿瘤的发生、发展和机制研究奠定了基础。二、利用脑微血管炎症仿生芯片,研究了流体剪切力作用下,肺癌细胞在炎性脑微血管内皮细胞表面的滚动和粘附现象,考察了生物化学因素和机械力学因素对肿瘤细胞外转移的影响,验证了 Rho/ROCK信号通路对肺癌细胞外转移的调控机制,为研究循环肿瘤细胞转移入脑提供了新方法。三、利用肿瘤侵袭仿生芯片,研究了缺氧条件对脑胶质瘤细胞运动行为的影响,结果证实缺氧条件可促进脑胶质瘤细胞在三维基质中的侵袭和上皮间质化行为,并且能够促进缺氧诱导因子(HIF)通路下游EMT和血管新生相关基因的表达,提示了缺氧条件通过HIF信号通路促进脑胶质瘤细胞的运动和侵袭,为研究脑肿瘤发展机制提供了新的思路。四、创新性构建体外复杂的三维动态血脑屏障芯片体系,包含多种脑细胞、三维基质和流体等多种核心要素,具备近生理条件的结构和功能;在此基础上,研究了复杂脑微环境条件下,肿瘤脑转移和脑胶质瘤发展的动态过程,并考察了多种临床抗肿瘤药物穿越血脑屏障的能力。为体外脑肿瘤微环境的仿生构建和抗肿瘤药物评价提供了新方法,也为探索脑肿瘤的发生机制提供了新思路。
[Abstract]:Brain microenvironment is a complex and dynamic microsystem in vivo. Its abnormal function is closely related to the occurrence, development and metastasis of brain tumors. The traditional in vitro model can hardly reflect the complex structure and functional characteristics of brain microenvironment in vivo. In this paper, the advanced microfluidic chip is used as the core technology, and the common brain tumors are studied as objects. The complex microenvironment of brain tumors is simulated and constructed by in vitro multicellular, multi-component and multi-conditional regulation. To study the effects and regulatory mechanisms of various chemical factors and biomechanics on the invasion and metastasis of brain tumors in order to provide a new way of thinking for the study of brain tumors. A series of novel microenvironment bionic systems based on microfluidic chip were designed and constructed to study the dynamic processes of tumor vascular extravasation tumor invasion and tumor brain metastasis respectively. The complex three-dimensional dynamic blood-brain barrier was constructed in vitro and the evaluation of anti-tumor effect was carried out, which laid a foundation for the study of the occurrence, development and mechanism of brain tumors. Secondly, the phenomenon of rolling and adhesion of lung cancer cells on the surface of inflammatory cerebral microvascular endothelial cells under fluid shear stress was studied by using biomimetic microarray of cerebral microvascular inflammation. The effects of biochemical and mechanical factors on the extracellular metastasis of lung cancer were investigated. The regulatory mechanism of Rho/ROCK signaling pathway on the extracellular metastasis of lung cancer was verified, which provided a new method for studying the metastasis of circulating tumor cells into the brain. Thirdly, the effect of hypoxia on the motion behavior of glioma cells was studied by using tumor invasion biomimetic chip. The results showed that hypoxia could promote the invasion and epithelial interstitial behavior of glioma cells in three-dimensional matrix. It can promote the expression of EMT and angiogenesis related genes downstream of hypoxia inducible factor (HIF) pathway, suggesting that hypoxia can promote the movement and invasion of glioma cells through HIF signaling pathway. It provides a new idea for studying the development mechanism of brain tumor. Fourth, the complex three-dimensional dynamic blood-brain barrier microarray system in vitro is constructed innovatively. It contains many kinds of core elements, such as brain cells, three-dimensional matrix and fluid, and has the structure and function of near physiological conditions. The dynamic processes of tumor metastasis and glioma development under complex brain microenvironment were studied and the ability of various clinical antitumor drugs to cross the blood-brain barrier was investigated. It provides a new method for the bionic construction of brain tumor microenvironment in vitro and the evaluation of antitumor drugs. It also provides a new idea for exploring the mechanism of brain tumor.
【学位授予单位】：大连理工大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R730.5

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