Optical coherence tomography OCT) is a novel technique that enables noninvasive or minimally invasive, cross-sectional imaging of biological tissue at sub-10mum spatial resolution and up to 2-3mm imaging depth. Numerous technological advances have emerged in recent years that have shown great potential to develop OCT into a powerful imaging and diagnostic tools. In particular, the implementation of Fourier-domain OCT FDOCT) is a major step forward that leads to greatly improved imaging rate and image fidelity of OCT. This dissertation summarizes the work that focuses on enhancing the performances and functionalities of spectral radar based FDOCT SDOCT) for pathological and functional applications. More specifically, chapters 1-4 emphasize on the development of SDOCT and its utility in pathological studies, including cancer diagnosis. The principle of SDOCT is first briefly outlined, followed by the design of our bench-top SDOCT systems with emphasis on spectral linear interpolation, calibration and system dispersion compensation. For ultrahigh-resolution SDOCT, time-lapse image registration and frame averaging is introduced to effectively reduce speckle noise and uncover subcellular details, showing great promise for enhancing the diagnosis of carcinoma in situ. To overcome the image depth limitation of OCT, a dual-modal imaging method combing SDOCT with high-frequency ultrasound is proposed and examined in animal cancer models to enhance the sensitivity and staging capabilities for bladder cancer diagnosis. Chapters 5-7 summarize the work on developing Doppler SDOCT for functional studies. Digital-frequency-ramping OCT DFR-OCT) is developed in the study, which has demonstrated the ability to significantly improve the signal-to-noise ratio and thus sensitivity for retrieving subsurface blood flow imaging. New DFR algorithms and imaging processing methods are discussed to further enhance cortical CBF imaging. Applications of DFR-OCT for brain functional studies are presented and laser speckle imaging is combined to enable quantitative cerebral blood flow CBF) imaging at high spatiotemporal resolutions. An angiography-enhanced Doppler optical coherence tomography aDFR-OCT) was also demonstrated to enable quantitative imaging of capillary changes for brain functional studies. Lastly, future work on technological development and potential biomedical applications is briefly outlined.

X-rays are excellent for imaging thick samples at high resolution because of their large penetration depth compared to electrons and their short wavelength relative to visible light. To image biological material, the absorption contrast of soft X-rays, especially between the carbon and oxygen K-shell absorption edges, can be utilized to give high contrast, high resolution images without the need for stains or labels. Because of radiation damage and the desire for high resolution tomography, live cell imaging is not feasible. However, cells can be frozen in vitrified ice, which reduces the effect of radiation damage while maintaining their natural hydrated state. X-ray diffraction microscopy XDM) is an imaging technique which eliminates the limitations imposed by current focusing optics simply by removing them entirely. Far-field coherent diffraction intensity patterns are collected on a pixelated detector allowing every scattered photon to be collected within the limits of the detectors efficiency and physical size. An iterative computer algorithm is then used to invert the diffraction intensity into a real space image with both absorption and phase information. This technique transfers the emphasis away from fabrication and alignment of optics, and towards data processing. We have used this method to image a pair of freeze-dried, immuno-labeled yeast cells to the highest resolution 13 nm) yet obtained for a whole eukaryotic cell. We discuss successes and challenges in working with frozen hydrated specimens and efforts aimed at high resolution imaging of vitrified eukaryotic cells in 3D.

Pulsed, optical fields are treated theoretically within the framework of cyclostationary random processes. Propagation-induced effects for stochastic, pulsed fields that are either beam-like or plane waves are examined in the context of interferometric and spectroscopic measurements. Propagation of fields from more general sources is considered in relation to the spectral or polarimetric properties observed. A new scheme for measuring cyclostationary effects is proposed.

Single cycle electromagnetic pulses have been difficult to experimentally generate and to theoretically analyze. With the recent development of terahertz systems based on near infrared femtosecond lasers it has become possible to perform single cycle experiments using picosecond pulses. The work presented in this thesis lays the groundwork for the transition from investigations of ultrafast optical pulse propagation in water to similar work at terahertz frequencies. In this thesis a variety of terahertz generation and detection methods are reviewed. Two commercial terahertz spectroscopy systems are examined in detail, improved upon and put into use. The design of a sample holder for thin, variable thickness samples of water or other highly absorbing liquid is detailed and the constructed holder is utilized in preliminary pulse measurements over a range of paths lengths. How the measured terahertz pulses spectrally and temporally change as they propagate through water is analyzed and used to extract the complex refractive index and attenuation coefficient of the tested water. Current knowledge of the molecular behavior of water in the THz frequency range of 300 GHz to 3 THz is discussed and related to experimental results. This information is also used in the preliminary development of two models. One model examines the molecular energy levels in liquid water, their effect on the propagating pulse, and the potential for the formation of precursors. The other model is based on the double Debye theory and can compare the calculated and measured pulses after propagation in both the time and frequency domains.

This dissertation is concerned with design, fabrication, and mathematical modeling of three different microactuators driven by light. Compared to electricity, electromagnetic wave is a wireless source of power. A distant light source can be delivered, absorbed, and converted to generate a driving force for a microactuator. The study of light-driven microsystems, still at its early stage, is already expanding the horizon for the research of microsystems. The microactuators of this dissertation include micro-cantilevers driven by pulsed laser, photo-deformable microshells coated with gold nanospheres, and a nano-particles coated micro-turbine driven by visible light. Experimental investigation and theoretical analysis of these microactuators showed interesting results. These microactuators were functioned based on cross-linked, multiple physics phenomenon, such as photo-heating, thermal expansion, photo-chemistry effect, plasomonics enhancement, and thermal convection in rarefied gas. These multiple physics effects dominate the function of a mechanical system, when the system size becomes small. The modeling results of the microactuators suggest that, to simulate a microscale mechanical system accurately, one has to take account the minimum dimension of the system and to consider the validity of a theoretical model. Examples of the building of different microstructures were shown to demonstrate the capacity of a digital-micromirror-device DMD) based apparatus for three-dimensional, heterogeneous fabrication of polymeric microstructures.

Many of the advances in cavity quantum electrodynamics (cavity QED) in the last decade have come by controlling the position and motion of atoms coupled to high finesse optical resonators with greater precision. Our experiment uses clouds of ultracold atomic gas confined in the miniaturized magnetic traps of a microfabricated atom chip to achieve high precision positioning of atoms relative to the optical standing wave mode of a high finesse Fabry-Perot cavity. The atom chip consists of micropatterned copper wires buried in a micromachined silicon substrata Up to several thousand ultracold 87 Rb atoms are placed in the mode of our Fabry-Perot optical cavity, which attains the single-atom, strong-coupling regime of cavity QED for the D2 transition of 87Rb. We study the atom-cavity system in the dispersive coupling limit, where the cavity resonance frequency is far detuned from the atomic transition. In this limit the mechanical effects on the atoms of the light used to probe the cavity are explored. We report observations of optical histability in this system as the mechanical potential from probing light induces a shift in the position atomic cloud and thus a shift in the spatially dependent atom-cavity coupling. The design, construction, and operation of this combined cavity QED atom chip are also described.

The minimum spacing of a plasma waveguide was calculated and applied to the formation of periodic nanocracks. The minimum spacing decreased with decreasing plasma frequency but was found to have limited effect on the spacing of the nanocracks. An extension to a standard Finite-Difference Time-Domain method was created to include nonlinear processes and the dynamic build up of the electron plasma. The ionized area produced in the simulation agrees with experiment. The existence of a self-limited absorption effect on a Gaussian pulse in time was verified in the simulations. The region was elongated along the direction parallel to the polarization of the light. The multiphoton absorption was found to be the main cause of the distinct shape of the damaged area. Plasma dispersion and self-focusing create larger electron densities and a shift in the location of the electron density peak, but did not affect the general shape.

In this thesis, studies on the applications of digital micro-mirror devices DMD) to enhancement of digital optical microscope images are presented. This involves adaptation of the fast switching capability and high optical efficiency of DMD to control the spatial illumination of the specimen. The first study focuses on a method of using DMD to enhance the dynamic range of a digital optical microscope. Our adaptive feedback illumination control method generates a high dynamic range image through an algorithm that combines the DMD-to-camera pixel geometrical mapping and a feedback operation. The feedback process automatically generates an illumination pattern in an iterative fashion that spatially modulates the DMD array elements on a pixel-by-pixel level. Via experiment, we demonstrate a transmitted-light microscope system that uses precise DMD control of a DMD-based projector to enhance the dynamic range ideally by a factor of 573. Results are presented showing approximately 5 times the camera dynamic range, enabling visualization over a wide range of specimen characteristics. The second study presents a technique for programming the source of the spherical reference illumination in a digital in-line holographic microscope using DMD. The programmable point source is achieved by individually addressing the elements of a DMD to spatially control the illumination of the object located at some distance from the source of the spherical reference field. Translation of the ON-state DMD mirror element changes the spatial location of the point source and consequently generates a sequence of translated holograms of the object. The experimental results obtained through numerical reconstruction of translated holograms of Latex microspheres shows the possibility of expanding the field of view by about 263% and also extracting depth information between features in an object volume. The common challenges associated with the use of DMD in coherent and broadband illumination control in both studies are discussed.

The sensitive and specific detection of biomolecular interactions is at the heart of many routine analyses in fundamental research, medical diagnosis and environmental monitoring. In contrast to laborious and costly multiwell plate assays, recent years have witnessed a significant progress in miniaturized and integrated biosensors, such as surface plasmon resonance SPR), tailored to these applications. While the design of various SPR biosensors has been described in literature, a robust, multichannel, low-cost and highly sensitive solution has not yet been presented. Specifically, an integrated system that can allow surface functionalization in array format, low-volume multichannel fluidic interfacing, and increased sensitivity is sought. This thesis describes a novel electro-wetting-on-dielectric EWOD) digital microfluidic device with integrated nanostructured biosensor interface that addresses the aforementioned issues for enhanced surface plasmon resonance imaging SPRi) detection. We have taken the opportunity of the most recent advances in microfabrication, nanotechnology and SPR technique to develop this integrated platform. EWOD device is employed for the dynamic immobilization of bioreceptors on SPRi biosensor surface in an array fashion from sub-muL volume solutions. Programmable EWOD electric interface allows the application of an electric field at the biosensor surface for active control of the immobilized probe density and orientation, enhancing SPRi detection. Two-dimensional SPRi detection is achieved by coupling the EWOD device to SPRi instrumentation. Parallel manipulation of individual droplets allows more efficient exploitation of the biosensor surface by separating different samples for simultaneous and selective SPRi detection. Periodic gold structures nanoposts, nanogratings and nanogrooves) residing on a surface of glass and plastic substrates are investigated to improve the SPRi sensitivity. The corresponding electromagnetic field enhancements lead to up to a five-fold increase in SPRi response and provide an order of magnitude improvement in the limit of detection. This optimized nanostructure design is integrated with the EWOD platform to increase the capability and enhance SPRi detection. The integrated platform is successfully employed for parallel detection of ii multiple DNA hybridization reactions in 90 nL droplets. More than a two-fold SPRi signal amplification is achieved within 15 min, while the detection time could be further reduced to 2 min for a simple “yes” or “no” answers for the presence of the target DNA in a sample. The proposed system holds a great potential for ultra-low volume, sensitive and rapid detection of biomolecules, such as DNA and proteins, for clinical diagnosis and other bioanalysis applications.

The shear force mechanism has been utilized as a distance regulation method in scanning probe microscopes. However, the origin of shear force is still unclear. One of the most important reasons for the shear-force damping is due to the presence of a water contamination layer at the sample surface in ambient conditions. Understanding the behavior of such mesoscopic fluid-like films is of significance for studies of not only scanning probe microscopy but also other complex surface phenomena, such as nanotribology, lubrication, adhesion, wetting, and the microfluidity of biological membranes. This thesis investigates, in particular, the dynamics of mesoscopic fluids confined between two sliding solid boundaries. When fluids are constrained to nanometer-sized regions, their physical properties can greatly differ from those displayed by bulk liquids. To gain an insight into the fundamental characteristics of the confined fluid films, we exploit the versatile capabilities of the novel shear-force/acoustic near-field microscope (SANM), which is able to concurrently and independently monitor the effects of the fluid-mediated interactions acting on both the microscope’s probe and the sample to be analyzed. Two signals are monitored simultaneously during each experimental cycle: the tuning fork signal, which is the oscillation amplitude of the probe and gives access to the shear force； and acoustic signal, which is detected by an acoustic sensor placed under the sample. Systematic experiments are carried out to investigate the effects of probe geometry, environmental humidity, and chemical properties of probe and sample surface (water affinity: hydrophobicity or hydrophilicity) on the probe-sample interactions, expressing the influence of the fluid-like contamination films.