结构光照明超分辨微分干涉相衬显微成像技术
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摘要
微分干涉相衬（Differential interference contrast, DIC）显微镜，是60年前发展起来的用于观察未染色透明的生物样品（相位样品）。目前，其已经成为使用最广泛的显微成像技术中的一种技术，且在生物医学研究领域具有广泛的应用。DIC成像技术是将样品中相位梯度的变化转化为强度变化，并且由两束横向上有略微距离（几百纳米）的光干涉产生相位的一阶导数信息。对比于荧光显微成像技术，DIC显微镜具有非侵入性和无需样品标记或染色的优点，可以允许人们观察没有处理过的天然的样品，在实际应用中很有意义。而对比于相衬显微镜，DIC显微镜具有以下优点：高空间分辨率；无光晕伪像；光学层析能力。然而，作为一种远场光学显微镜，DIC显微镜的空间分辨率受到了光学成像中衍射法则的限制，这使得许多小于衍射极限的生物结构在DIC成像中不可分辨。因此，为了观察更加精细的结构并且理解它们的功能，提高DIC成像的空间分辨率（打破分辨率衍射极限）显得极为重要。
我们提出了一种打破分辨率衍射极限的DIC成像技术，称之为结构光照明DIC（structured illumination DIC, SI-DIC）显微镜。此技术的物理思想是将结构光照明的观念应用于传统的DIC显微镜来扩宽DIC成像系统的相干传递函数（coherent transferfunction, CTF）的带宽，从而使重构得到的DIC图像的分辨率明显优于传统DIC显微镜的成像分辨率。接着，我们进一步发展了结构光照明超分辨DIC成像技术，提出了基于空间光调制器DIC的结构光照明成像技术。此技术在实现超分辨DIC成像的同时，具有结构相对简单且DIC的重要参数（剪切方向、大小及基延迟）很容易变换的优点。
本文取得的主要创新研究结果如下：
（1）提出了结构光照明DIC超分辨显微成像技术。发展了结构光照明DIC成像理论，并通过计算机仿真的方法，验证了提出的结构光照明DIC成像理论。设计并建立了结构光照明DIC超分辨显微成像系统。使用数值孔径为0.8的聚光镜与物镜，以53nm聚苯乙烯小球样品，测量系统成像分辨率，获得了190nm的成像分辨率，打破了传统DIC成像分辨率衍射极限（380nm）。较传统DIC成像，结构光照明DIC成像的分辨率提高了两倍。并使用结构光照明DIC成像系统观察了生物样品（人脐静脉内皮细胞），同样获得了超分辨的实验结果，展示了此技术在生物学方面的应用。
（2）提出了基于空间光调制器DIC的结构光照明成像技术。研究了基于空间光调制器的DIC成像原理，建立了基于空间光调制器DIC的结构光照明成像系统。由于空间光调制器的灵活性，应用此成像系统可以方便地获得各种DIC重要参数（剪切方向、大小及基延迟）的DIC成像结果。使用数值孔径为0.8的聚光镜与物镜，以53nm聚苯乙烯小球样品，测量基于空间光调制器DIC的结构光照明成像系统分辨率，获得了211nm的成像分辨率，同样打破了DIC成像分辨率极限。较基于空间光调制器的DIC成像（435nm），基于空间光调制器的DIC结构光照明成像的分辨率提高了两倍。
Differential interference contrast (DIC) microscopy is developed60years ago forobserving unstained and transparent biological specimens (phase object). Recently, it hasbeen one of the most widely used techniques and gained broad application in thebiomedical community. The DIC microscopy converts the variations of phase gradients inthe specimen into intensity variations, and produces the first-order derivative of the phaseby the interference of two identical but laterally displaced beams. In contrast tofluorescence microscopy, DIC microscopy is valuable owing to the non-invasive andlabel-free advantages that allow us to observe untreated ‘native’ samples. Compared tophase contrast (PhC) microscopy, DIC microscopy has several benefits, including highspatial resolution, free of halo and shade-off artifacts and optical sectioning capability.However, since DIC microscopy is one kind of far-field optical microscopy, its spatialresolution is limited by the law of diffraction. This makes many biological structuressmaller than the diffraction limit unresolvable. Therefore, the enhancement of spatialresolution below the classical diffraction limit is critically important to reveal the finerstructures for an increasing understanding of their functions.
We present a method termed as structured illumination differential interferencecontrast (SI-DIC) microscopy to break the diffraction resolution limit of the DICmicroscopy. The idea is to apply the concept of structured illumination to the conventionalDIC microscopy to expand the bandwidth of coherent transfer function (CTF) of DICimaging system, and thus reconstruct DIC image with resolution significantly better thanthe diffraction limit. Then, we further develop the structured illumination differentialinterference contrast microscopy, and propose structured illumination SLM-based DICmicroscopy. The technique can realize super-resolution DIC imaging, meanwhile, itsstructure is relatively simple and the important parameters (the direction and size of theshear and bias retardation) of DIC imaging can be changed easily.
The main innovative results of this thesis are as follows:
(1) We propose a structured illumination DIC super-resolution microscopy. Wedevelop the theory of the structured illumination DIC. By computer simulation, we verifythe theory of the structured illumination DIC. We design and constructe the structuredillumination DIC super-resolution imaging system. With0.8numerical aperture condenserand objective, we use53nm polystyrene beads to measure the imaging resolution of the system, and obtain190nm spatial resolution, breaking the resolution diffraction limit (380nm) of traditional DIC microscopy. The imaging resolution of structured illumination DICmicroscopy doubles that of the conventional DIC microscopy. With this system, weobserve biological sample (Human umbilical vein endothelial cells), and also obtainsuper-resolution imaging results, demonstrating biological application of this technique.
(2) We introduce structured illumination spatial light modulator (SLM) based DICmicroscopy. We study the image formation principle of SLM-based DIC. We buildstructured illumination SLM-based DIC imaging system. Because of the flexibility ofSLM, with this imaging system, we can easily achieve DIC imaging with all kinds ofimportant parameters (the direction and size of the shear and bias retardation) of DIC.With0.8numerical aperture condenser and objective, we use53nm polystyrene beads tomeasure the imaging resolution of this system, and obtain211nm spatial resolution,breaking the resolution limit (435nm) of SLM-based DIC microscopy. The imagingresolution of structured illumination SLM-based DIC microscopy doubles that of theSLM-based DIC microscopy.
我们提出了一种打破分辨率衍射极限的DIC成像技术，称之为结构光照明DIC（structured illumination DIC, SI-DIC）显微镜。此技术的物理思想是将结构光照明的观念应用于传统的DIC显微镜来扩宽DIC成像系统的相干传递函数（coherent transferfunction, CTF）的带宽，从而使重构得到的DIC图像的分辨率明显优于传统DIC显微镜的成像分辨率。接着，我们进一步发展了结构光照明超分辨DIC成像技术，提出了基于空间光调制器DIC的结构光照明成像技术。此技术在实现超分辨DIC成像的同时，具有结构相对简单且DIC的重要参数（剪切方向、大小及基延迟）很容易变换的优点。
本文取得的主要创新研究结果如下：
（1）提出了结构光照明DIC超分辨显微成像技术。发展了结构光照明DIC成像理论，并通过计算机仿真的方法，验证了提出的结构光照明DIC成像理论。设计并建立了结构光照明DIC超分辨显微成像系统。使用数值孔径为0.8的聚光镜与物镜，以53nm聚苯乙烯小球样品，测量系统成像分辨率，获得了190nm的成像分辨率，打破了传统DIC成像分辨率衍射极限（380nm）。较传统DIC成像，结构光照明DIC成像的分辨率提高了两倍。并使用结构光照明DIC成像系统观察了生物样品（人脐静脉内皮细胞），同样获得了超分辨的实验结果，展示了此技术在生物学方面的应用。
（2）提出了基于空间光调制器DIC的结构光照明成像技术。研究了基于空间光调制器的DIC成像原理，建立了基于空间光调制器DIC的结构光照明成像系统。由于空间光调制器的灵活性，应用此成像系统可以方便地获得各种DIC重要参数（剪切方向、大小及基延迟）的DIC成像结果。使用数值孔径为0.8的聚光镜与物镜，以53nm聚苯乙烯小球样品，测量基于空间光调制器DIC的结构光照明成像系统分辨率，获得了211nm的成像分辨率，同样打破了DIC成像分辨率极限。较基于空间光调制器的DIC成像（435nm），基于空间光调制器的DIC结构光照明成像的分辨率提高了两倍。
Differential interference contrast (DIC) microscopy is developed60years ago forobserving unstained and transparent biological specimens (phase object). Recently, it hasbeen one of the most widely used techniques and gained broad application in thebiomedical community. The DIC microscopy converts the variations of phase gradients inthe specimen into intensity variations, and produces the first-order derivative of the phaseby the interference of two identical but laterally displaced beams. In contrast tofluorescence microscopy, DIC microscopy is valuable owing to the non-invasive andlabel-free advantages that allow us to observe untreated ‘native’ samples. Compared tophase contrast (PhC) microscopy, DIC microscopy has several benefits, including highspatial resolution, free of halo and shade-off artifacts and optical sectioning capability.However, since DIC microscopy is one kind of far-field optical microscopy, its spatialresolution is limited by the law of diffraction. This makes many biological structuressmaller than the diffraction limit unresolvable. Therefore, the enhancement of spatialresolution below the classical diffraction limit is critically important to reveal the finerstructures for an increasing understanding of their functions.
We present a method termed as structured illumination differential interferencecontrast (SI-DIC) microscopy to break the diffraction resolution limit of the DICmicroscopy. The idea is to apply the concept of structured illumination to the conventionalDIC microscopy to expand the bandwidth of coherent transfer function (CTF) of DICimaging system, and thus reconstruct DIC image with resolution significantly better thanthe diffraction limit. Then, we further develop the structured illumination differentialinterference contrast microscopy, and propose structured illumination SLM-based DICmicroscopy. The technique can realize super-resolution DIC imaging, meanwhile, itsstructure is relatively simple and the important parameters (the direction and size of theshear and bias retardation) of DIC imaging can be changed easily.
The main innovative results of this thesis are as follows:
(1) We propose a structured illumination DIC super-resolution microscopy. Wedevelop the theory of the structured illumination DIC. By computer simulation, we verifythe theory of the structured illumination DIC. We design and constructe the structuredillumination DIC super-resolution imaging system. With0.8numerical aperture condenserand objective, we use53nm polystyrene beads to measure the imaging resolution of the system, and obtain190nm spatial resolution, breaking the resolution diffraction limit (380nm) of traditional DIC microscopy. The imaging resolution of structured illumination DICmicroscopy doubles that of the conventional DIC microscopy. With this system, weobserve biological sample (Human umbilical vein endothelial cells), and also obtainsuper-resolution imaging results, demonstrating biological application of this technique.
(2) We introduce structured illumination spatial light modulator (SLM) based DICmicroscopy. We study the image formation principle of SLM-based DIC. We buildstructured illumination SLM-based DIC imaging system. Because of the flexibility ofSLM, with this imaging system, we can easily achieve DIC imaging with all kinds ofimportant parameters (the direction and size of the shear and bias retardation) of DIC.With0.8numerical aperture condenser and objective, we use53nm polystyrene beads tomeasure the imaging resolution of this system, and obtain211nm spatial resolution,breaking the resolution limit (435nm) of SLM-based DIC microscopy. The imagingresolution of structured illumination SLM-based DIC microscopy doubles that of theSLM-based DIC microscopy.
引文
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