强约束型微纳光子结构的特性研究及其在生物传感和成像中的应用
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摘要
本论文以微纳米尺度下的若干强约束型光子结构为对象,对它们的设计制作以及光学特性进行了研究,并探讨了它们在生物医学传感及成像中的应用。集成光学领域中的平面光波导是一类典型的强约束型光子结构,本文针对它们的小型化和在传感领域的应用做了详细的分析,并结合金属表面等离子体谐振效应,提出了平面波导与金属微纳结构结合的可能性。另一方面,纳米尺度下的光子学由于其给众多领域带来的巨大影响,近年来也越发受到关注,纳米颗粒作为纳米尺度下的强约束光子结构在其中起到了决定性的作用。本文对两类纳米颗粒进行了制作、表征和表面修饰,并研究了它们在生物传感、生物体外及体内成像中的应用。
在微米尺度下的强约束结构研究中,利用有限差分法对两种导波结构进行了设计和分析。首先,设计了一种基于二氧化硅材料的小型光波导结构,这种波导以空气作为上包层用来提高折射率差从而减小波导的截面尺寸;下包层为深刻蚀型的反谐振反射结构用以减小向硅基底的泄露损耗。根据理论模拟,通过引入三个周期的反谐振反射层的设计,得到了具有很小传输损耗的直波导(＜0.01dB/cm)和超小弯曲半径(15μm)的弯曲波导。另外一种波导结构是基于聚合物材料SU-8的小截面强约束型脊形光波导,本文对其单模条件,模式双折射以及弯曲特性进行了系统的分析,通过优化设计得到了75μm的弯曲半径。在此基础上,本文在SU-8波导制作方面也开展了一些工作,对制作的波导结构特性进行了测试及表征,并获得了SU-8波导制作工艺方面的一些研究结果。同时对金属表面等离子谐振效应做了相关的理论和实验研究,提出了进一步增强微米尺度下强约束结构传感灵敏度的几种方式,这些结果为微米尺度下强约束结构在集成光学传感器方面的研究提供了理论和实验基础。
在纳米尺度强约束光子结构研究方面,本文主要对金属以及半导体纳米颗粒的制作及其在生物医学方面的应用做了相应的研究。介绍了金、银纳米颗粒的合成,通过在合成反应中控制纳米颗粒的大小、形状、组分以及结构得到了不同的光学特性。制作得到的这些纳米颗粒,比如银纳米球、金纳米棒以及金-银核壳结构的纳米棒被进一步用生物分子进行修饰并应用到生物医学体外研究中,包括对肿瘤细胞的探测、靶向标记和多颜色的暗场成像,以及对药物成瘾的基因转染法治疗等等。利用金纳米棒在动物体内的试验结果也显示了它们在小型动物活体实验中具有很好的生物兼容性。本文的研究证明了上述的金属纳米颗粒能够为未来疾病的诊断和治疗提供一个很好的纳米尺度的平台,在生物医学的传感及其它研究中发挥更大的作用。本文还介绍了半导体纳米颗粒在活体肿瘤靶向及成像中的应用。合成了高亮度的CdSe/CdS/ZnS量子棒,用聚乙二醇修饰的磷脂胶束将其包覆,并在其表面修饰了对肿瘤新生血管具有靶向性的生物分子。利用这种纳米材料对两种肿瘤模型小鼠(皮下植入肿瘤以及原位移植肿瘤模型)进行了肿瘤的活体追踪检测及成像研究。对量子棒材料详细的毒性研究没有发现它们在细胞以及组织水平有可见的毒性表现。本文的相关结果表明量子棒能够作为一种具有高荧光亮度、高稳定性并具有高生物兼容性的生物探针,在癌症的早期探测研究中发挥巨大的作用。这些研究结果大大的拓宽了纳米尺度强约束结构在生物传感和生物成像中的应用范围。
This dissertation is mainly about the design and fabrication of the strong confinment elements in micro- and nano- photonics for sensing and imaging applications,especially in biomedical research.As typical strong confinement elements in the micro-scale photonics, planar optical waveguides are studied and designed in a way to be more compact in size and better suited for sensing applications.Metallic structures are proposed to be introduced so as to improve the sensitivity due to the strong enhancement from the surface plasmon resonance.On the othe hand,nano-scale photonics,where nanoparticles as the strong confinement elements play as a key role,have been attracting great attention during the last few years due to the extraordinary opportunities it offered in a variety of research fields.Two kinds of nanoparticles have been synthesized,characterized and engineered for biosensing,in vitro and in vivo bioimaging.
In micro-scale strong confinement photonics structure studies,two types of waveguides are designed and analized using finite difference method.A minimized silicon dioxide optical waveguide with an etch-through antiresonant reflecting buffer and an air cladding is presented. The air cladding is used to achieve a high refractive index contrast thus to minimize the lateral size of the waveguide,while the antiresonant reflecting buffer is used to reduce the leakage loss due to the silicon substrate.According to the design,by introducing three periods of etch-through antiresonant reflecting strutures,a straight SiO_2 waveguide with a low leakage loss (＜0.01 dB/cm) and a bending radius as small as 15μm is obtained.The other waveguide structure is based on a commercially available polymer SU-8,which also has an air cladding.In order to redcue the leakage and bending losses,the SiO_2 buffer layer is etched partially.Systematic analysis on the waveguide including the single-mode condition,birefrigence and especially the bending behavior are performed.The numerical simulations indicate that the transition loss between the straight and bending sections dominants the bending loss and can be greatly reduced by introducing a lateral offset.Following the design,straight and bending waveguides are fabricated and characterized,which set basis for the future development in the integrated sensing applications.
As for the strong confinement structures in nano-scale photonics,functionalized metallic and semiconductor nanoparticles have been synthesized,characterized and engineered for different biomedical applications.Gold and silver nanoparticles with different optical properties are obtained by manipulating their size,shape,composition and structure during the synthesis. The as-synthesized nanoparticles,such as silver nanospheres,gold nanorods and gold/silver core/shell nanorods are then functionalized with biomolecules for in vitro studies,including detecting,targeted labeling and multi-colored dark field imaing of human cancer cells,and gene delivery for drug addiction therapy.In vivo studies are also carried out with preliminary results showing that the gold nanorods are highly biocompatible to small animals even with an extremely high dosadge.The demonstration of several applications in biomedical research shows that these metallic nanoparticles are able to provide a powerful and promising nanosized platform for the diagnosis and therapy of desease.On the other hand,in vivo tumor targeting and imaging studies with functionalized semiconductor anisotropic nanocrystals are performed. Highly luminescent CdSe/CdS/ZnS quantum rods(QRs) are synthesized and encapsulated with PEGylated phospholipids,followed by conjugation with cyclic RGD peptides which specifically target the tumor vasculature.These functionalized QRs are then used for targeting and imaging the tumors in nude mice bearing pancreatic cancer xenografts(both subcutaneously and orthotopically planted).Detailed cytotoxicity studies are also performed with results indicating that the functionalized QRs have no observable toxic effect in the cellular and tissue levels, which reflects the vast potential of QRs as bright,photostable and biocompatible luminescent probes for the early diagnosis of cancer.These results greatly expanded the sensing and imaging aplicaitons of the nano-scale strong confinement structures in biomedical research.
在微米尺度下的强约束结构研究中,利用有限差分法对两种导波结构进行了设计和分析。首先,设计了一种基于二氧化硅材料的小型光波导结构,这种波导以空气作为上包层用来提高折射率差从而减小波导的截面尺寸;下包层为深刻蚀型的反谐振反射结构用以减小向硅基底的泄露损耗。根据理论模拟,通过引入三个周期的反谐振反射层的设计,得到了具有很小传输损耗的直波导(＜0.01dB/cm)和超小弯曲半径(15μm)的弯曲波导。另外一种波导结构是基于聚合物材料SU-8的小截面强约束型脊形光波导,本文对其单模条件,模式双折射以及弯曲特性进行了系统的分析,通过优化设计得到了75μm的弯曲半径。在此基础上,本文在SU-8波导制作方面也开展了一些工作,对制作的波导结构特性进行了测试及表征,并获得了SU-8波导制作工艺方面的一些研究结果。同时对金属表面等离子谐振效应做了相关的理论和实验研究,提出了进一步增强微米尺度下强约束结构传感灵敏度的几种方式,这些结果为微米尺度下强约束结构在集成光学传感器方面的研究提供了理论和实验基础。
在纳米尺度强约束光子结构研究方面,本文主要对金属以及半导体纳米颗粒的制作及其在生物医学方面的应用做了相应的研究。介绍了金、银纳米颗粒的合成,通过在合成反应中控制纳米颗粒的大小、形状、组分以及结构得到了不同的光学特性。制作得到的这些纳米颗粒,比如银纳米球、金纳米棒以及金-银核壳结构的纳米棒被进一步用生物分子进行修饰并应用到生物医学体外研究中,包括对肿瘤细胞的探测、靶向标记和多颜色的暗场成像,以及对药物成瘾的基因转染法治疗等等。利用金纳米棒在动物体内的试验结果也显示了它们在小型动物活体实验中具有很好的生物兼容性。本文的研究证明了上述的金属纳米颗粒能够为未来疾病的诊断和治疗提供一个很好的纳米尺度的平台,在生物医学的传感及其它研究中发挥更大的作用。本文还介绍了半导体纳米颗粒在活体肿瘤靶向及成像中的应用。合成了高亮度的CdSe/CdS/ZnS量子棒,用聚乙二醇修饰的磷脂胶束将其包覆,并在其表面修饰了对肿瘤新生血管具有靶向性的生物分子。利用这种纳米材料对两种肿瘤模型小鼠(皮下植入肿瘤以及原位移植肿瘤模型)进行了肿瘤的活体追踪检测及成像研究。对量子棒材料详细的毒性研究没有发现它们在细胞以及组织水平有可见的毒性表现。本文的相关结果表明量子棒能够作为一种具有高荧光亮度、高稳定性并具有高生物兼容性的生物探针,在癌症的早期探测研究中发挥巨大的作用。这些研究结果大大的拓宽了纳米尺度强约束结构在生物传感和生物成像中的应用范围。
This dissertation is mainly about the design and fabrication of the strong confinment elements in micro- and nano- photonics for sensing and imaging applications,especially in biomedical research.As typical strong confinement elements in the micro-scale photonics, planar optical waveguides are studied and designed in a way to be more compact in size and better suited for sensing applications.Metallic structures are proposed to be introduced so as to improve the sensitivity due to the strong enhancement from the surface plasmon resonance.On the othe hand,nano-scale photonics,where nanoparticles as the strong confinement elements play as a key role,have been attracting great attention during the last few years due to the extraordinary opportunities it offered in a variety of research fields.Two kinds of nanoparticles have been synthesized,characterized and engineered for biosensing,in vitro and in vivo bioimaging.
In micro-scale strong confinement photonics structure studies,two types of waveguides are designed and analized using finite difference method.A minimized silicon dioxide optical waveguide with an etch-through antiresonant reflecting buffer and an air cladding is presented. The air cladding is used to achieve a high refractive index contrast thus to minimize the lateral size of the waveguide,while the antiresonant reflecting buffer is used to reduce the leakage loss due to the silicon substrate.According to the design,by introducing three periods of etch-through antiresonant reflecting strutures,a straight SiO_2 waveguide with a low leakage loss (＜0.01 dB/cm) and a bending radius as small as 15μm is obtained.The other waveguide structure is based on a commercially available polymer SU-8,which also has an air cladding.In order to redcue the leakage and bending losses,the SiO_2 buffer layer is etched partially.Systematic analysis on the waveguide including the single-mode condition,birefrigence and especially the bending behavior are performed.The numerical simulations indicate that the transition loss between the straight and bending sections dominants the bending loss and can be greatly reduced by introducing a lateral offset.Following the design,straight and bending waveguides are fabricated and characterized,which set basis for the future development in the integrated sensing applications.
As for the strong confinement structures in nano-scale photonics,functionalized metallic and semiconductor nanoparticles have been synthesized,characterized and engineered for different biomedical applications.Gold and silver nanoparticles with different optical properties are obtained by manipulating their size,shape,composition and structure during the synthesis. The as-synthesized nanoparticles,such as silver nanospheres,gold nanorods and gold/silver core/shell nanorods are then functionalized with biomolecules for in vitro studies,including detecting,targeted labeling and multi-colored dark field imaing of human cancer cells,and gene delivery for drug addiction therapy.In vivo studies are also carried out with preliminary results showing that the gold nanorods are highly biocompatible to small animals even with an extremely high dosadge.The demonstration of several applications in biomedical research shows that these metallic nanoparticles are able to provide a powerful and promising nanosized platform for the diagnosis and therapy of desease.On the other hand,in vivo tumor targeting and imaging studies with functionalized semiconductor anisotropic nanocrystals are performed. Highly luminescent CdSe/CdS/ZnS quantum rods(QRs) are synthesized and encapsulated with PEGylated phospholipids,followed by conjugation with cyclic RGD peptides which specifically target the tumor vasculature.These functionalized QRs are then used for targeting and imaging the tumors in nude mice bearing pancreatic cancer xenografts(both subcutaneously and orthotopically planted).Detailed cytotoxicity studies are also performed with results indicating that the functionalized QRs have no observable toxic effect in the cellular and tissue levels, which reflects the vast potential of QRs as bright,photostable and biocompatible luminescent probes for the early diagnosis of cancer.These results greatly expanded the sensing and imaging aplicaitons of the nano-scale strong confinement structures in biomedical research.
引文
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