本文選題：微流控技術(shù) + 腦腫瘤微環(huán)境�。� 參考：《大連理工大學(xué)》2017年博士論文

【摘要】：腦微環(huán)境是體內(nèi)一種復(fù)雜的、動態(tài)的微系統(tǒng),其功能異常與腦腫瘤的發(fā)生、發(fā)展和轉(zhuǎn)移密切相關(guān)。傳統(tǒng)體外模型難以反映體內(nèi)腦微環(huán)境復(fù)雜結(jié)構(gòu)和功能特點(diǎn)。本論文以前沿微流控芯片為核心技術(shù),以常見腦腫瘤研究為對象,通過體外多細(xì)胞、多成分和多條件因素調(diào)控,模擬構(gòu)建腦腫瘤復(fù)雜微環(huán)境,研究多種化學(xué)因子和生物力學(xué)等因素對腦腫瘤侵襲和轉(zhuǎn)移的影響及調(diào)控機(jī)制,以期為腦腫瘤研究提供一種全新思路,分述如下:一、設(shè)計并構(gòu)建了一系列基于微流控芯片的腦腫瘤微環(huán)境仿生新體系,分別用于研究三維環(huán)境下腫瘤血管外滲、腫瘤侵襲和腫瘤腦轉(zhuǎn)移等動態(tài)過程,并開展了體外構(gòu)建復(fù)雜三維動態(tài)血腦屏障的方法學(xué)研究和抗腫瘤藥效評價,為研究腦腫瘤的發(fā)生、發(fā)展和機(jī)制研究奠定了基礎(chǔ)。二、利用腦微血管炎癥仿生芯片,研究了流體剪切力作用下,肺癌細(xì)胞在炎性腦微血管內(nèi)皮細(xì)胞表面的滾動和粘附現(xiàn)象,考察了生物化學(xué)因素和機(jī)械力學(xué)因素對腫瘤細(xì)胞外轉(zhuǎn)移的影響,驗證了 Rho/ROCK信號通路對肺癌細(xì)胞外轉(zhuǎn)移的調(diào)控機(jī)制,為研究循環(huán)腫瘤細(xì)胞轉(zhuǎn)移入腦提供了新方法。三、利用腫瘤侵襲仿生芯片,研究了缺氧條件對腦膠質(zhì)瘤細(xì)胞運(yùn)動行為的影響,結(jié)果證實缺氧條件可促進(jìn)腦膠質(zhì)瘤細(xì)胞在三維基質(zhì)中的侵襲和上皮間質(zhì)化行為,并且能夠促進(jìn)缺氧誘導(dǎo)因子(HIF)通路下游EMT和血管新生相關(guān)基因的表達(dá),提示了缺氧條件通過HIF信號通路促進(jìn)腦膠質(zhì)瘤細(xì)胞的運(yùn)動和侵襲,為研究腦腫瘤發(fā)展機(jī)制提供了新的思路。四、創(chuàng)新性構(gòu)建體外復(fù)雜的三維動態(tài)血腦屏障芯片體系,包含多種腦細(xì)胞、三維基質(zhì)和流體等多種核心要素,具備近生理條件的結(jié)構(gòu)和功能;在此基礎(chǔ)上,研究了復(fù)雜腦微環(huán)境條件下,腫瘤腦轉(zhuǎn)移和腦膠質(zhì)瘤發(fā)展的動態(tài)過程,并考察了多種臨床抗腫瘤藥物穿越血腦屏障的能力。為體外腦腫瘤微環(huán)境的仿生構(gòu)建和抗腫瘤藥物評價提供了新方法,也為探索腦腫瘤的發(fā)生機(jī)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.
【學(xué)位授予單位】：大連理工大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R730.5

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本文編號：1918207