磁共振成像的對比度提升研究-從磁共振弛緩理論到磁共振成像應用

The Study of MRI Contrast Enhancement-From NMR Relaxation Theory to MRI Application

陳育文(Yu-Wen Chen)

指導教授 ： 黃聖言

國立中正大學/理學院/化學暨生物化學系/博士(2016年)

摘要

磁共振成像（MRI）是一種重要的非侵入性技術並且廣泛的應用於醫療診斷中。MRI對比度改進MRI發展的一個重要問題。我們研究的主題在於增強MRI對比度，並且從核磁共振弛豫理論和自旋動態學的理論基礎出發，發展可實際應用於生物體的新式方法。基於此基礎，我的研究論文的內容可分為三個相關主題：“NMR弛豫研究在重要的生物學系統”，“新的MRI方法開發-頻率鎖定抑制技術”與“新型造影劑的設計與合成”。
本文的第一部分為使用核磁共振弛豫理論探討細胞環境中的分子動力學。
其中包含在不同生物分子作用環境中的生物膜動力學系統與造影劑在細胞環境中的行為進行了討論。第一個部分我們研究了不同的生物分子，包括膽固醇和抗菌胜肽與生物膜的作用。在膽固醇系統中，根據膜的彈性的活化能，具有和不具有膽固醇微包被認為具有相同的相位。膽固醇的作用主要作用於脂質膜的擴散運動與秩序性擾動。此外，增加膽固醇的比率時脂質分子間的距離會變得更接近。而在抗菌胜肽和脂質膜的作用部分，結果表明蜂毒素的孔形成機制有兩個步驟，而在pardaxin系統，孔形成的過程只需一個步驟。這是來自徐不同胜肽的親疏水分布不同。另一個部分我們研究了水分子的NMR弛豫表現在不同顯影劑細胞環境中，水微胞環境的詳細的貢獻可藉由D2O替換H2O被詳細的討論，我們分析水的貢獻在微胞內部與外部，發現微胞內部的水會導致橫向弛豫的非線性鐵濃度依賴性。在模擬中還表明，微胞會使超順磁性氧化鐵顆粒形成聚集體的結構，導致微胞內R2 *和R2弛豫具有不同的趨勢，以上的結論證明了顯影劑的開發需要考慮細胞系統對顯影劑環境的影響，這對新式造影劑的開發是非常有幫助的。
第二部分我們根據NMR弛豫理論和水分子動力學設計一種新型造影劑，此顯影劑為鐵/釓的納米環。 在弛豫時間的測量結果中顯示，此顯影劑比商用的顯影劑具有五倍以上的顯影效果。此外，鐵/釓的納米環生物體影像顯示，同時在T1與 T2加權圖像都有優良的顯影劑果，因此可預期此顯影劑可以有非常好的生物應用價值。
在第三部分中我們開發一個新的MRI成像方法-鎖頻放大技術，在結果中此方法已被證明可用於加強與小敏感性頻率差異並組織之間的對比度。此技術以成功應用到腫瘤和腦結構分析，並增強MRI對比。腫瘤結構可以藉由此方法容易地區分成長部分和壞死區域，這是不能在常規的質子密度和T2加權影像可以達到的。此外在腦結構的分析結果中，針對CA1區域，，比較一般的T2加權圖像，鎖頻放大技術可以得到超過五倍的對比度增強。

關鍵字

磁共振弛緩理論 ； 磁共振成像 ； 顯影劑

並列摘要

Magnetic resonance imaging (MRI) is an important non-invasive technique widely used in medical diagnosis. Improvement of MRI contrast is an important issue for MRI development. The main theme of my research is to employ both the NMR relaxation theory and the spin dynamics to enhance MRI contrast. Herein, I re-organized the contents of my seven research papers into three correlative topics: “NMR relaxation study of important biological system”, “Design of a new type of contrast agent”, and “New frequency lock-in suppression technique MRI method”.
The first part of this dissertation focuses on the molecular dynamics in the cellular environment by NMR relaxation. The biomembrane dynamics and contrast agent behavior in the cellular environment are discussed. The membrane dynamics with different bio-molecules including cholesterol and antimicrobial peptide have been shown. In the cholesterol system, according to the activation energy of membrane elasticity, the vesicles with and without cholesterol contained is believed to be at the same phase. The effect of cholesterol is mainly on the order fluctuation of membrane and diffusion motion of lipid molecules. In addition, the distance between lipid molecules become closer when the ratio of cholesterol increases. Moreover, the effects of antimicrobial peptides on the lamellar phase and the dynamics of phospholipids on liposomes were investigated. In the antimicrobial peptides system, the results show there are two steps for melittin pore formation while itis one step for the pore formation in pardaxin system. Furthermore, the NMR relaxation of water molecules behaves differently for a contrast agent solution compared to contrast agent loaded cells. The detailed contribution of water in each compartment of mimic cellular environment was shown. By replacing H2O with D2O, we clarified the contributions of water inside and outside the vesicles and found that water inside the vesicles causes a nonlinear iron concentration dependence. In the simulations, the assumed model also suggests that the vesicles form aggregate structures, causing deviation of R2* and R2 relaxation of water in vesicles in the presence of the SPIO particles. It is believed to be useful for the new contrast agent design.
The second part is to design a new type of contrast agent, Fe/Gd nanorings, in accordance with NMR relaxation theory and water molecular dynamics. The field dependent relaxivityindicated ofFe/Gd nanorings is five times faster than commercial CAs, e.g. Magnevist®. Moreover, phantom images of Fe/Gd nanorings showed significant contrast enhancement in T1- and T2-weighted images compared with that observed for commercial CAs.
In the third part a new MRI method, the frequency lock-in technique, has been demonstrated to enhance the contrast between adjoint tissues with small susceptibility difference. The frequency lock-in technique was developed and successfully applied to the tumor and brain structure analysis and enhances MRI contrast. Tumor structure can be easily refined into growing part and necrosis, which cannot be distinguished in conventional proton density and T2-weighted images. Moreover, more than five times contrast to noise ratio enhancement, comparing to conventional T2-weighted images, in the brain structure for the CA1 region was obtained by frequency lock-in imaging.

並列關鍵字

Contrast agent ； NMR Relaxation ； MRI

參考文獻

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