Polarization Sensor Design for Biomedical Applications

Advances in fabrication technology have enabled the development of compact, rigid polarization image sensors by integrating pixelated polarization filters with standard image sensing arrays. These compact sensors have the capability for allowing new applications across a variety of disciplines, however their design and use may be influenced by many factors. The underlying image sensor, the pixelated polarization filters, and the incident lighting conditions all directly impact how the sensor performs. In this research endeavor, I illustrate how a complete understanding of these factors can lead to both new technologies and applications in polarization sensing. To investigate the performance of the underlying image sensor, I present a new CMOS image sensor architecture with a pixel capable of operation using either measured voltages or currents. I show a detailed noise analysis of both modes, and that, as designed, voltage mode operates with lower noise than current mode. Further, I integrated aluminum nanowires with this sensor post fabrication, realizing the design of a compact CMOS sensor with polarization sensitivity. I describe a full set of experiments designed as a benchmark to evaluate the performance of compact, integrated polarization sensors. I use these tests to evaluate for incident intensity, wavelength, focus, and polarization state, demonstrating the accuracy and limitations of polarization measurements with such a compact sensor. Using these as guides, I present two novel biomedical applications that rely on the compact, real-time nature of compact integrated polarimeters. I first demonstrate how these sensors can be used to measure the dynamics of soft tissue in real-time, with no moving parts or complex optical alignment. I used a 2 megapixel integrated polarization sensor to measure the direction and strength of alignment in a bovine flexor tendon at over 20 frames per second, with results that match the current method of rotating polarizers. Secondly, I present a new technique for optical neural recording that uses intrinsic polarization reflectance and requires no fluorescent dyes or electrodes. Exposing the antennal lobe of the locust Schistocerca americana, I was able to measure a change in the polarization reflectance during the introduction of the odors hexanol and octanol with the integrated CMOS polarization sensor

FIBER-OPTIC BUNDLE FLUORESCENCE MICROSCOPY FOR FUNCTIONAL BRAIN ACTIVITY MAPPING

Understanding the relationship between cellular activities in the animal brain and the emerging patterns of animal behavior is a critical step toward completing the Brain Activity Map. This dissertation describes the development of fiber-bundle microscopy capable of high-resolution cellular imaging, for mapping of functional brain activity in freely moving mice. As a part of this work, several fiber-bundle microscope systems and image processing algorithms were proposed and developed. These optical imaging methods and system performance were tested and evaluated by performing in vivo animal brain imaging. Several fiber-bundle imaging devices, including a dual-mode confocal reflectance and fluorescence micro-endoscope, a single ball-lens imaging probe, and a spatially multiplexed fiber-bundle imager, were designed and developed for high-resolution imaging of brain cells and visualization of brain activity. A dual-mode micro-endoscope, simultaneously achieving laser scanning confocal reflectance and fluorescence imaging, was developed to quantitatively assess gene transfection efficacy using human cervical cancer cells. A single ball-lens integrated imaging probe was designed for endoscopic brain imaging. Lastly, a spatially multiplexed fiber-bundle imager that allows concurrent monitoring of astrocytic activities in multiple brain regions and enables optical manipulation with cell-specific targeting was proposed and experimentally demonstrated. Novel image-processing algorithms were used along with the developed imaging systems. Structured illumination employing a digital micro-mirror device (DMD) was integrated into the system to achieve depth-resolved imaging with a wide-field illumination fiber-bundle microscope. Data from super-resolution fiber-bundle microscopy based on the linear structured illumination were numerically processed to extend the lateral resolution beyond the diffraction limit. To evaluate the performance of the developed fiber-bundle microscope systems and image reconstruction algorithms, the systems and methods were each tested and validated on in vivo animal models, namely transgenic mice expressing a genetically encoded Calcium indicator (GCaMP3) within astrocytes. We showed that locomotion triggers simultaneous activation of astrocyte networks in multiple brain regions in mice. We have also demonstrated real-time cellular-resolution dual-color functional brain imaging in mice. Finally, we established a platform that allows real-time and non-invasive imaging of the intact central nervous system of freely behaving mice. Using this platform, we observed, for the first time, physiologically relevant activation of astrocytes during behaviorally relevant tasks and in the natural setting. In addition, we present a proof-of-concept study by using a fiber-bundle ring light-guided portable multispectral imaging (MSI) platform capable of tissue characterization and preoperative surgical planning for intestinal anastomosis

Smart Sensor Networks For Sensor-Neural Interface

One in every fifty Americans suffers from paralysis, and approximately 23% of paralysis cases are caused by spinal cord injury. To help the spinal cord injured gain functionality of their paralyzed or lost body parts, a sensor-neural-actuator system is commonly used. The system includes: 1) sensor nodes, 2) a central control unit, 3) the neural-computer interface and 4) actuators. This thesis focuses on a sensor-neural interface and presents the research related to circuits for the sensor-neural interface. In Chapter 2, three sensor designs are discussed, including a compressive sampling image sensor, an optical force sensor and a passive scattering force sensor. Chapter 3 discusses the design of the analog front-end circuit for the wireless sensor network system. A low-noise low-power analog front-end circuit in 0.5μm CMOS technology, a 12-bit 1MS/s successive approximation register (SAR) analog-to-digital converter (ADC) in 0.18μm CMOS process and a 6-bit asynchronous level-crossing ADC realized in 0.18μm CMOS process are presented. Chapter 4 shows the design of a low-power impulse-radio ultra-wide-band (IR-UWB) transceiver (TRx) that operates at a data rate of up to 10Mbps, with a power consumption of 4.9pJ/bit transmitted for the transmitter and 1.12nJ/bit received for the receiver. In Chapter 5, a wireless fully event-driven electrogoniometer is presented. The electrogoniometer is implemented using a pair of ultra-wide band (UWB) wireless smart sensor nodes interfacing with low power 3-axis accelerometers. The two smart sensor nodes are configured into a master node and a slave node, respectively. An experimental scenario data analysis shows higher than 90% reduction of the total data throughput using the proposed fully event-driven electrogoniometer to measure joint angle movements when compared with a synchronous Nyquist-rate sampling system. The main contribution of this thesis includes: 1) the sensor designs that emphasize power efficiency and data throughput efficiency; 2) the fully event-driven wireless sensor network system design that minimizes data throughput and optimizes power consumption

Recent Advances and Future Trends in Nanophotonics

Nanophotonics has emerged as a multidisciplinary frontier of science and engineering. Due to its high potential to contribute to breakthroughs in many areas of technology, nanophotonics is capturing the interest of many researchers from different fields. This Special Issue of Applied Sciences on “Recent advances and future trends in nanophotonics” aims to give an overview on the latest developments in nanophotonics and its roles in different application domains. Topics of discussion include, but are not limited to, the exploration of new directions of nanophotonic science and technology that enable technological breakthroughs in high-impact areas mainly regarding diffraction elements, detection, imaging, spectroscopy, optical communications, and computing

NOVEL TECHNOLOGIES AND APPLICATIONS FOR FLUORESCENT LAMINAR OPTICAL TOMOGRAPHY

Laminar optical tomography (LOT) is a mesoscopic three-dimensional (3D) optical imaging technique that can achieve both a resolution of 100-200 µm and a penetration depth of 2-3 mm based either on absorption or fluorescence contrast. Fluorescence laminar optical tomography (FLOT) can also provide large field-of-view (FOV) and high acquisition speed. All of these advantages make FLOT suitable for 3D depth-resolved imaging in tissue engineering, neuroscience, and oncology. In this study, by incorporating the high-dynamic-range (HDR) method widely used in digital cameras, we presented the HDR-FLOT. HDR-FLOT can moderate the limited dynamic range of the charge-coupled device-based system in FLOT and thus increase penetration depth and improve the ability to image fluorescent samples with a large concentration difference. For functional mapping of brain activities, we applied FLOT to record 3D neural activities evoked in the whisker system of mice by deflection of a single whisker in vivo. We utilized FLOT to investigate the cell viability, migration, and bone mineralization within bone tissue engineering scaffolds in situ, which allows depth-resolved molecular characterization of engineered tissues in 3D. Moreover, we investigated the feasibility of the multi-modal optical imaging approach including high-resolution optical coherence tomography (OCT) and high-sensitivity FLOT for structural and molecular imaging of colon tumors, which has demonstrated more accurate diagnosis with 88.23% (82.35%) for sensitivity (specificity) compared to either modality alone. We further applied the multi-modal imaging system to monitor the drug distribution and therapeutic effects during and after Photo-immunotherapy (PIT) in situ and in vivo, which is a novel low-side-effect targeted cancer therapy. A minimally-invasive two-channel fluorescence fiber bundle imaging system and a two-photon microscopy system combined with a micro-prism were also developed to verify the results

Optical Methods in Sensing and Imaging for Medical and Biological Applications

The recent advances in optical sources and detectors have opened up new opportunities for sensing and imaging techniques which can be successfully used in biomedical and healthcare applications. This book, entitled ‘Optical Methods in Sensing and Imaging for Medical and Biological Applications’, focuses on various aspects of the research and development related to these areas. The book will be a valuable source of information presenting the recent advances in optical methods and novel techniques, as well as their applications in the fields of biomedicine and healthcare, to anyone interested in this subject

Functional Connectivity of the Rodent Brain Using Optical Imaging

RÉSUMÉ L'objectif de cette thèse de doctorat est d’appliquer la connectivité fonctionnelle dans une variété de modèles animaux, à l’aide de plusieurs techniques d’imagerie optique. Le cerveau, même au repos, montre une activité métabolique élevée : la corrélation des fluctuations spontanées lentes permet d’identifier des régions cérébrales distantes mais connectées; d’où le terme connectivité fonctionnelle. Les changements dans l’activité spontanée peuvent donner un aperçu des processus neuronaux qui comprennent la majorité de l’activité métabolique du cerveau, et constituent en conséquent une vaste source de changements reliés aux maladies. L’hémodynamique du cerveau peut être modifiée grâce à des affections neurovasculaires et avoir un effet sur l’activité au repos. Cette thèse vise la compréhension des changements de connectivité fonctionnelle induits par des maladies, à l’aide de l’imagerie optique fonctionnelle. Les techniques d’imagerie explorées dans les deux premières contributions de cette thèse sont l’Imagerie Optique Intrinsèque et l’Imagerie par Granularité Laser. Ensemble, elles peuvent estimer les changements de consommation d'oxygène, étroitement liés à l’activité neuronale. Ces techniques possèdent des résolutions temporelles et spatiales adéquates et bien adaptées pour imager la convexité du cortex cérébral. Dans le dernier article, une modalité d’imagerie en profondeur, la Tomographie Photoacoustique a été utilisée chez le rat nouveau-né. La Tomographie par Cohérence Optique et la Tomographie Laminaire Optique font également partie de la gamme des techniques d’imagerie développées et appliquées dans d’autres collaborations. La première partie des résultats mesure les changements de connectivité fonctionnelle dans un modèle d’activité épileptiforme aiguë chez le rongeur. Il y a des augmentations ainsi que des diminutions entre les corrélations homologues, avec une faible dépendance aux crises épileptiques. Ces changements suggèrent un découplage potentiel entre les paramètres hémodynamiques dans les réseaux au repos, en soulignant l’importance d’investiguer les réseaux épileptiques à l’aide de plusieurs mesures hémodynamiques indépendantes. La deuxième partie des travaux étudie un nouveau modèle de rigidité artérielle chez la souris : la calcification unilatérale de la carotide droite. L’analyse de connectivité basé sur les régions d’intérêt montre une tendance décroissante de corrélation homologue dans les cortex moteur et cingulum. L’analyse de graphes montre une randomisation des réseaux corticaux, ce qui suggère une perte de connectivité; plus spécifiquement, dans le cortex moteur ipsilateral à la carotide----------ABSTRACT The aim of this thesis is to apply functional connectivity in a variety of animal models, using several optical imaging modalities. Even at rest, the brain shows high metabolic activity: the correlation in slow spontaneous fluctuations identifies remotely connected areas of the brain; hence the term “functional connectivity”. Ongoing changes in spontaneous activity may provide insight into the neural processing that takes most of the brain metabolic activity, and so may provide a vast source of disease related changes. Brain hemodynamics may be modified during disease and affect resting-state activity. The thesis aims to better understand these changes in functional connectivity due to disease, using functional optical imaging. The optical imaging techniques explored in the first two contributions of this thesis are Optical Imaging of Intrinsic Signals and Laser Speckle Contrast Imaging, together they can estimate the metabolic rate of oxygen consumption, that closely parallels neural activity. They both have adequate spatial and temporal resolution and are well adapted to image the convexity of the mouse cortex. In the last article, a depth-sensitive modality called photoacoustic tomography was used in the newborn rat. Optical coherence tomography and laminar optical tomography were also part of the array of imaging techniques developed and applied in other collaborations. The first article of this work shows the changes in functional connectivity in an acute murine model of epileptiform activity. Homologous correlations are both increased and decreased with a small dependence on seizure duration. These changes suggest a potential decoupling between the hemodynamic parameters in resting-state networks, underlining the importance to investigate epileptic networks with several independent hemodynamic measures. The second study examines a novel murine model of arterial stiffness: the unilateral calcification of the right carotid. Seed-based connectivity analysis showed a decreasing trend of homologous correlation in the motor and cingulate cortices. Graph analyses showed a randomization of the cortex functional networks, suggesting a loss of connectivity, more specifically in the motor cortex ipsilateral to the treated carotid; however these changes are not reflected in differentiated metabolic estimates. Confounds remain due to the fact that carotid rigidification gives rise to neural decline in the hippocampus as well as unilateral alteration of vascular pulsatility; howeve

Microscale Infrared Technologies for Spectral Filtering and Wireless Neural Dust

Pivotal technologies, such as optical computing, autonomous vehicles, and biomedical implantables, motivate microscale infrared (IR) components. Hyperspectral imagers (HSI), for example, require compact and narrowband filters to obtain high-spatial and -spectral resolution images. HSIs acquire continuous spectra at each pixel, enabling non-destructive analyses by resolving IR scattering/absorption signatures. Toward this end, dielectric subwavelength gratings (SWG) are intriguing filter candidates since they are low-loss, have no moving parts, and exhibit narrow spectral features. Wireless neural implantables are another apropos microscale IR technology. Wireless IR data and power transfer disposes of infection-prone percutaneous wires by leveraging the IR transparency window in biological tissue. This dissertation contains two related topics. The first details SWG IR filters, and the second studies progress toward wireless neural motes. This work extends the capabilities of SWG IR filters. Following a theoretical overview, mid-wave infrared (MWIR, 3-7 um) transmittance filters are experimentally demonstrated using the zero-contrast grating scheme. Via a facile silicon fabrication process, we realize narrowband polarization-dependent and polarization-independent MWIR transmittance filters with some of the highest Q observed in MWIR SWGs. An empirical study confirms the relationship between filter performance and grating size, an important trade-off for HSIs. We then demonstrate GaAs SWG filters for monolithic integration with active optoelectronic devices. The GaAs SWGs perform comparably to their silicon counterparts. To enable narrowband filtering at normal incidence, we investigate symmetry-breaking in geometrically asymmetric gratings. The presented SWG geometries access quasi-bound states in the continuum (BIC). Studies in Fano resonance and diffraction efficiency symmetry provide physical insight. Asymmetric 1D and 2D SWGs furnish polarization-dependent and -independent filtering, respectively. We experimentally demonstrate normal incidence long-wave IR (LWIR, 7-12 um) transmittance filtering in asymmetric SWGs and confirm symmetry-breaking implications. A reduced-symmetry hexagonal pattern presents an early design for truly polarization-independent quasi-BIC coupling in SWGs. Advancements in implantable neural devices promise great leaps in brain mapping and therapeutic intervention. To meet this challenge, we investigated a wireless neural mote system using near-infrared (NIR, 800 nm – 3 um) photovoltaics and LEDs to wirelessly harvest power and transmit data. The neural recorders consist of three subsystems: an epitaxial GaAs-based optoelectronic chip, a Si CMOS IC, and a carbon fiber probe. Though this work encompasses the efforts of many, this dissertation outlines contributions in a few critical areas. To overcome low-flux LED emission, we devise an optical setup with ≈0.1% photon detection efficiency. Monte Carlo techniques model NIR scattering in biological tissue. Another steep challenge is the heterogeneous integration of the three material systems in a compact (200x170x150 um^3) package. To relay data and power between the GaAs and CMOS chips, through-wafer vias are critical. Using a novel selective copper plating technique, we demonstrate through-wafer GaAs vias with <2 Ohm series resistance. Additionally, conductive blind vias are presented for carbon fiber probe insertion. A self-aligned parylene etch mask permits sub-kOhm connection to a buried metal contact while maintaining GOhm substrate isolation. Both via structures meet the requirements of being low-resistance, insulated from the substrate, and amendable to thinned wafer processing. Finally, we demonstrate extensive processing on thinned chips and advances toward full heterogeneous integration via flip-chip alignment and solder bump bonding.PHDElectrical and Computer EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/169986/1/barrowm_1.pd

Seeing the Big Picture: System Architecture Trends in Endoscopy and LED-Based hyperspectral Subsystem Intergration

Early-stage colorectal lesions remain difficult to detect. Early development of neoplasia tends to be small (less than 10 mm) and flat and difficult to distinguish from surrounding mucosa. Additionally, optical diagnosis of neoplasia as benign or malignant is problematic. Low rates of detection of these lesions allow for continued growth in the colorectum and increased risk of cancer formation. Therefore, it is crucial to detect neoplasia and other non-neoplastic lesions to determine risk and guide future treatment. Technology for detection needs to enhance contrast of subtle tissue differences in the colorectum and track multiple biomarkers simultaneously. This work implements one such technology with the potential to achieve the desired multi-contrast outcome for endoscopic screenings: hyperspectral imaging. Traditional endoscopic imaging uses a white light source and a RGB detector to visualize the colorectum using reflected light. Hyperspectral imaging (HSI) acquires an image over a range of individual wavelength bands to create an image hypercube with a wavelength dimension much deeper and more sensitive than that of an RGB image. A hypercube can consist of reflectance or fluorescence (or both) spectra depending on the filtering optics involved. Prior studies using HSI in endoscopy have normally involved ex vivo tissues or xiv optics that created a trade-off between spatial resolution, spectral discrimination and temporal sampling. This dissertation describes the systems design of an alternative HSI endoscopic imaging technology that can provide high spatial resolution, high spectral distinction and video-rate acquisition in vivo. The hyperspectral endoscopic system consists of a novel spectral illumination source for image acquisition dependent on the fluorescence excitation (instead of emission). Therefore, this work represents a novel contribution to the field of endoscopy in combining excitation-scanning hyperspectral imaging and endoscopy. This dissertation describes: 1) systems architecture of the endoscopic system in review of previous iterations and theoretical next-generation options, 2) feasibility testing of a LED-based hyperspectral endoscope system and 3) another LED-based spectral illuminator on a microscope platform to test multi-spectral contrast imaging. The results of the architecture point towards an endoscopic system with more complex imaging and increased computational capabilities. The hyperspectral endoscope platform proved feasibility of a LED-based spectral light source with a multi-furcated solid light guide. Another LED-based design was tested successfully on a microscope platform with a dual mirror array similar to telescope designs. Both feasibility tests emphasized optimization of coupling optics and combining multiple diffuse light sources to a common output. These results should lead to enhanced imagery for endoscopic tissue discrimination and future optical diagnosis for routine colonoscopy

Structural and functional brain imaging using extended-focus optical coherence tomography and microscopy

Neuroimaging techniques aim at revealing the anatomy and functional organisation of cerebral structures. Over the past decades, functional magnetic resonance imaging (fMRI) has revolutionized our understanding of human cerebral physiology through its ability to probe neural activity throughout the entire brain in a non-invasive fashion. Nevertheless, despite recent technological improvements, the spatial resolution of fMRI remains limited to a few hundreds of microns, restricting its use to macroscopic studies. Microscopic imaging solutions have been proposed to circumvent this limitation and have enabled revealing the existence of various cerebral structures, such as neuronal and vascular networks and their contribution to information processing and blood flow regulation within the brain. Optical imaging has proven, through its increased resolution and available contrast mechanisms, to be a valuable complement to fMRI for cellular-scale imaging. In this context, we demonstrate here the capabilities of an extension of optical coherence tomography, termed extended-focus optical coherence tomography (xf-OCT), in imaging cerebral structure and function at high resolution and very high acquisitions rates. Optical coherence tomography is an interferometric imaging technique using a low-coherence illumination source to provide fast, three-dimensional imaging of the back-scattering of tissue and cells. By multiplexing the interferometric ranging over several spectral channels, Fourier-domain OCT performs depth-resolved imaging at very high acquisition rates and high sensitivity. Increasing the lateral resolution of optical systems typically reduces the available depth-of-field and thus hampers this depth multiplexing advantage of OCT. Extended-focus systems aim at alleviating this trade-off between imaging depth and lateral resolution through the use of diffraction-less beams such as Bessel beams, providing high resolution imaging over large depths. The xf-OCT system therefore combines fast acquisition rates and high resolution, both characteristics required to image and study the structure and function of microscopic constituents of cerebral tissue. In this work, we performed functional brain imaging using the ability of xf-OCT to obtain quantita- tive measurements of blood flow in the brain. Changes in blood velocity evoked by neuronal activation were monitored and maps of hemodynamic activity were generated by adapting tools routinely used in fMRI to xf-OCT imaging. Additionally, three novel xf-OCT instruments are presented, wherein the advantages of different spectral ranges are exploited to reach specific imaging parameters. The increased contrast and resolution afforded by an illumination in the visible spectral range was used in two extended-focus optical coherence microscopy (xf-OCM) implementations for subcellular imaging of ex-vivo brain slices and cellular imaging of neurons, capillaries and myelinated axons in the superficial cortex in-vivo. Subsequently, an xf-OCT system is presented, operating in the infrared spectral range, wherein the reduced scattering enabled imaging the smallest capillaries deep in the murine cortex in-vivo