Enhancing the color gamut of waveguide displays for augmented reality head-mounted displays through spatially modulated diffraction grating.

Augmented reality (AR) applications require displays with an extended color gamut to facilitate the presentation of increasingly immersive content. The waveguide (WG) display technology, which is typical AR demonstration method, is a critical constraint on the color gamut of AR systems because of the intrinsic properties of the holographic optical elements (HOEs) used in this technology. To overcome this limitation, we introduce a method of spatially modulated diffractive optics that can expand the color gamut of HOE-based WG displays. This approach involves spatial modulation using sub-pixelized HOEs, which enables the diffraction of red, green, and blue rays along identical directions. The proposed structure considers both the characteristics of the HOE and the wavelength sensitivity of the observer to optimize the color gamut. Consequently, an expanded color gamut was achieved. The results of the theoretical and experimental analyses substantiate the effectiveness and practicality of this method in enhancing the color gamut of HOE-based WG displays. Thus, the proposed method can facilitate the implementation of more immersive AR displays.

Smartphone-Based Rigid Endoscopy Device with Hemodynamic Response Imaging and Laser Speckle Contrast Imaging.

Modern smartphones have been employed as key elements in point-of-care (POC) devices due to remarkable advances in their form factor, computing, and display performances. Recently, we reported a combination of the smartphone with a handheld endoscope using laser speckle contrast imaging (LSCI), suggesting potential for functional POC endoscopy. Here, we extended our work to develop a smartphone-combined multifunctional handheld endoscope using dual-wavelength LSCI. Dual-wavelength LSCI is used to monitor the changes in dynamic blood flow as well as changes in the concentration of oxygenated (HbO2), deoxygenated (Hbr), and total hemoglobin (HbT). The smartphone in the device performs fast acquisition and computation of the raw LSCI data to map the blood perfusion parameters. The flow imaging performance of the proposed device was tested with a tissue-like flow phantom, exhibiting a speckle flow index map representing the blood perfusion. Furthermore, the device was employed to assess the blood perfusion status from an exteriorized intestine model of rat in vivo during and after local ischemia, showing that blood flow and HbO2 gradually decreased in the ischemic region whereas hyperemia and excess increases in HbO2 were observed in the same region right after reperfusion. The results indicate that the combination of LSCI with smartphone endoscopy delivers a valuable platform for better understanding of the functional hemodynamic changes in the vasculatures of the internal organs, which may benefit POC testing for diagnosis and treatment of vascular diseases.

Stadium-type resonator sensor based on a multi-mode waveguide with mode discrimination phenomenon.

In this work, we present a multi-mode resonator based on SU-8 polymer and experimentally verify that the resonator showed mode discrimination can be used as a sensor with high performance. According to field emission scanning electron microscopy (FE-SEM) images, the fabricated resonator shows sidewall roughness which is canonically considered to be undesirable after a typical development process. In order to analyze the effect of sidewall roughness, we conduct the resonator simulation considering the roughness under various conditions. Mode discrimination still occurs even in the presence of sidewall roughness. In addition, waveguide width controllable by UV exposure time effectively contributes to mode discrimination. To verify the resonator as a sensor, we perform a temperature variation experiment, which results in a high sensitivity of about 630.8 nm/RIU. This result shows that the multi-mode resonator sensor fabricated via a simple process is competitive with other single-mode waveguide sensors.

Non-Invasive Monitoring of Cutaneous Wound Healing in Non-Diabetic and Diabetic Model of Adult Zebrafish Using OCT Angiography.

A diabetic wound presents a severe risk of infections and other complications because of its slow healing. Evaluating the pathophysiology during wound healing is imperative for wound care, necessitating a proper diabetic wound model and assay for monitoring. The adult zebrafish is a rapid and robust model for studying human cutaneous wound healing because of its fecundity and high similarities to human wound repair. OCTA as an assay can provide three-dimensional (3D) imaging of the tissue structure and vasculature in the epidermis, enabling monitoring of the pathophysiologic alterations in the zebrafish skin wound. We present a longitudinal study for assessing the cutaneous wound healing of the diabetic adult zebrafish model using OCTA, which is of importance for the diabetes research using the alternative animal models. We used non-diabetic (n = 9) and type 1 diabetes mellitus (DM) adult zebrafish models (n = 9). The full-thickness wound was generated on the fish skin, and the wound healing was monitored with OCTA for 15 days. The OCTA results demonstrated significant differences between diabetic and non-diabetic wound healing, involving delayed tissue remodeling and impaired angiogenesis for the diabetic wound, leading to slow wound recovery. The adult zebrafish model and OCTA technique may benefit long-term metabolic disease studies using zebrafish for drug development.

Health Status and Activity Discomfort among Elderly Drivers: Reality of Health Awareness.

As the number of elderly drivers rapidly increases worldwide, interest in the dangers of driving is growing as accidents rise. The purpose of this study was to conduct a statistical analysis of the driving risk factors of elderly drivers. In this analysis, data from the government organization's open data were used for the secondary processing of 10,097 people. Of the 9990 respondents, 2168 were current drivers, 1552 were past drivers but were not driving presently, and 6270 did not have a driver's license; the participants were divided into groups accordingly. The elderly drivers who were current drivers had a better subjective health status than those who were not. Visual and hearing aids were used in the current driving group, and their depression symptoms reduced as they drove. The elderly who were current drivers experienced difficulties while driving in terms of decreased vision, hearing loss, reduced arm/leg reaction speed, decreased judgment of the road conditions such as signals and intersections, and a decreased sense of speed. The results suggest that elderly drivers are unaware of the medical conditions that can negatively affect their driving. This study contributes to the safety management of elderly drivers by understanding their mental and physical status.

Compact Smartphone-Based Laser Speckle Contrast Imaging Endoscope Device for Point-of-Care Blood Flow Monitoring.

Laser speckle contrast imaging (LSCI) is a powerful visualization tool for quantifying blood flow in tissues, providing simplicity of configuration, ease of use, and intuitive results. With recent advancements, smartphone and camera technologies are suitable for the development of smartphone-based LSCI applications for point-of-care (POC) diagnosis. A smartphone-based portable LSCI endoscope system was validated for POC diagnosis of vascular disorders. The endoscope consisted of compact LED and laser illumination, imaging optics, and a flexible fiberscope assembled in a 3D-printed hand-held cartridge for access to body cavities and organs. A smartphone's rear camera was mounted thereto, enabling endoscopy, LSCI image acquisition, and processing. Blood flow imaging was calibrated in a perfused tissue phantom consisting of a microparticle solution pumped at known rates through tissue-mimicking gel and validated in a live rat model of BBN-induced bladder cancer. Raw LSCI images successfully visualized phantom flow: speckle flow index showed linearity with the pump flow rate. In the rat model, healthy and cancerous bladders were distinguishable in structure and vasculature. The smartphone-based low-cost portable mobile endoscope for monitoring blood flow and perfusion shows promise for preclinical applications and may be suitable for primary diagnosis at home or as a cost-effective POC testing assay.

Automated counting of cerebral penetrating vessels using optical coherence tomography images of a mouse brain in vivo.

RATIONALE AND OBJECTIVES: Penetrating blood vessels emanating from cortical surface vasculature and lying deep in the cortex are essential vascular conduits for the shuttling of blood from superficial pial vessels to the capillary beds in parenchyma for the nourishment of neuronal brain tissues. Locating and counting the penetrating vessels is beneficial for the quantification of a course of ischemia in blood occlusive events such as stroke. This paper seeks to demonstrate and validate a method for automated penetrating vessel counting that uses optical coherence tomography (OCT). MATERIALS AND METHODS: This paper proposes an OCT method that effectively identifies and grades the cortical penetrating vessels in perfusion. The key to the proposed method is the harnessing of vascular features found in the penetrating vessels, which are distinctive from those of other vessels. In particular, with an increase in the light attenuation and flow turbulence, the contrast in the mean projection of the OCT datacube decreases, whereas that in the maximum projection of the Doppler frequency variance datacube increases. By multiplying the inversion of the former with the latter, its binary thresholding is sufficient to highlight the penetrating vessels and allows for their counting over the projection image. RESULTS: A computational method that leverages the decrease in mean OCT projection intensity and the increase in Doppler frequency variance at the penetrating vessel is developed. It successfully identifies and counts penetrating vessels with a high accuracy of over 87%. The penetrating vessel density is observed to be significantly reduced in the mouse model of focal ischemic stroke. CONCLUSION: The OCT analysis is effective for counting penetrating blood vessels in mice brains and may be applied to the rapid diagnosis and treatment of stroke in stroke models of small animals.

Integrated deep learning framework for accelerated optical coherence tomography angiography.

Label-free optical coherence tomography angiography (OCTA) has become a premium imaging tool in clinics to obtain structural and functional information of microvasculatures. One primary technical drawback for OCTA, however, is its imaging speed. The current protocols require high sampling density and multiple acquisitions of cross-sectional B-scans to form one image frame, resulting in low acquisition speed. Recently, deep learning (DL)-based methods have gained attention in accelerating the OCTA acquisition process. They achieve faster acquisition using two independent reconstructing approaches: high-quality angiograms from a few repeated B-scans and high-resolution angiograms from undersampled data. While these approaches have shown promising results, they provide limited solutions that only partially account for the OCTA scanning mechanism. Herein, we propose an integrated DL method to simultaneously tackle both factors and further enhance the reconstruction performance in speed and quality. We designed an end-to-end deep neural network (DNN) framework with a two-staged adversarial training scheme to reconstruct fully-sampled, high-quality (8 repeated B-scans) angiograms from their corresponding undersampled, low-quality (2 repeated B-scans) counterparts by successively enhancing the pixel resolution and the image quality. Using an in-vivo mouse brain vasculature dataset, we evaluate our proposed framework through quantitative and qualitative assessments and demonstrate that our method can achieve superior reconstruction performance compared to the conventional means. Our DL-based framework can accelerate the OCTA imaging speed from 16 to 256[Formula: see text] while preserving the image quality, thus enabling a convenient software-only solution to enhance preclinical and clinical studies.

Image Correlation-Based Method to Assess Ciliary Beat Frequency in Human Airway Organoids.

Ciliary movements within the human airway are essential for maintaining a clean lung environment. Motile cilia have a characteristic ciliary beat frequency (CBF). However, CBF measurement with current video microscopic techniques can be error-prone due to the use of the single-point Fourier transformation, which is often biased for ciliary measurements. Herein, we describe a new video microscopy technique that harnesses a metric of motion-contrast imaging and image correlation for CBF analysis. It can provide objective and selective CBF measurements for individual motile cilia and generate CBF maps for the imaged area. The measurement performance of our methodology was validated with in vitro human airway organoid models that simulated an actual human airway epithelium. The CBF determined for the region of interest (ROI) was equal to that obtained with manual counting. The signal redundancy problem of conventional methods was not observed. Moreover, the obtained CBF measurements were robust to optical focal shifts, and exhibited spatial heterogeneity and temperature dependence. This technique can be used to evaluate ciliary movement in respiratory tracts and determine whether it is non-synchronous or aperiodic in patients. Therefore, our observations suggest that the proposed method can be clinically adapted as a screening tool to diagnose ciliopathies.

Quadruple ultrasound, photoacoustic, optical coherence, and fluorescence fusion imaging with a transparent ultrasound transducer.

Ultrasound and optical imagers are used widely in a variety of biological and medical applications. In particular, multimodal implementations combining light and sound have been actively investigated to improve imaging quality. However, the integration of optical sensors with opaque ultrasound transducers suffers from low signal-to-noise ratios, high complexity, and bulky form factors, significantly limiting its applications. Here, we demonstrate a quadruple fusion imaging system using a spherically focused transparent ultrasound transducer that enables seamless integration of ultrasound imaging with photoacoustic imaging, optical coherence tomography, and fluorescence imaging. As a first application, we comprehensively monitored multiparametric responses to chemical and suture injuries in rats' eyes in vivo, such as corneal neovascularization, structural changes, cataracts, and inflammation. As a second application, we successfully performed multimodal imaging of tumors in vivo, visualizing melanomas without using labels and visualizing 4T1 mammary carcinomas using PEGylated gold nanorods. We strongly believe that the seamlessly integrated multimodal system can be used not only in ophthalmology and oncology but also in other healthcare applications with broad impact and interest.

Imaging Motion: A Comprehensive Review of Optical Coherence Tomography Angiography.

Optical coherence tomography (OCT) is a three-dimensional (3-D) optical imaging technology that provides noninvasive, micrometer resolution images of structural interiors within biological samples with an approximately 1 ~ 2 mm penetration depth. Over the last decades, advances in OCT have revolutionized biomedical imaging by demonstrating a potential of optical biopsy in preclinical and clinical settings. Recently, functional OCT imaging has shown a promise as angiography to visualize cell-perfused vasculatures in the tissue bed in vivo without requiring any exogenous contrast agents. This new technology termed OCT angiography (OCTA) possesses a unique imaging capability of delineating tissue morphology and blood or lymphatic vessels down to capillaries at real-time acquisition rates. For the past 10 years since 2007, OCTA has been proven to be a useful tool to identify disorder or dysfunction in tissue microcirculation from both experimental animal studies and clinical studies in ophthalmology and dermatology. In this section, we overview about OCTA including a basic principle of OCTA explained with simple optical physics, and its scan protocols and post-processing algorithms for acquisition of angiography. Then, potential and challenge of OCTA for clinical settings are shown with outcomes of human studies.

Mean-Subtraction Method for De-shadowing of Tail Artifacts in Cerebral OCTA Images: A Proof of Concept.

When imaging brain vasculature with optical coherence tomography angiography (OCTA), volumetric analysis of cortical vascular networks in OCTA datasets is frequently challenging due to the presence of artifacts, which appear as multiple-scattering tails beneath superficial large vessels in OCTA images. These tails shadow underlying small vessels, making the assessment of vascular morphology in the deep cortex difficult. In this work, we introduce an image processing technique based on mean subtraction of the depth profile that can effectively reduce these tails to better reveal small hidden vessels compared to the current tail removal approach. With the improved vascular image quality, we demonstrate that this simple method can provide better visualization of three-dimensional vascular network topology for quantitative cerebrovascular studies.

Optical coherence tomography angiography in preclinical neuroimaging.

Preclinical neuroimaging allows for the assessment of brain anatomy, connectivity, and function in laboratory animals, such as mice and this imaging field has been a rapidly growing aimed at bridging the translation gap between animal and human research. The progress in the animal research could be accelerated by high-resolution in vivo optical imaging technologies. Optical coherence tomography-based angiography (OCTA) estimates the scattering from moving red blood cells, providing the visualization of functional micro-vessel networks within tissue beds in vivo without a need for exogenous contrast agents. Recent advancement of OCTA methods have expanded its application to neuroimaging of small animal models of brain disorders. In this paper, we overview the recent development of OCTA techniques for blood flow imaging and its preclinical applications in neuroimaging. In specific, a summary of preclinical OCTA studies for traumatic brain injury, cerebral stroke, and aging brain on mice is reviewed.

Monitoring Acute Stroke Progression: Multi-Parametric OCT Imaging of Cortical Perfusion, Flow, and Tissue Scattering in a Mouse Model of Permanent Focal Ischemia.

Cerebral ischemic stroke causes injury to brain tissue characterized by a complex cascade of neuronal and vascular events. Imaging during the early stages of its development allows prediction of tissue infarction and penumbra so that optimal intervention can be determined in order to salvage brain function impairment. Therefore, there is a critical need for novel imaging techniques that can characterize brain injury in the earliest phases of the ischemic stroke. This paper examined optical coherence tomography (OCT) for imaging acute injury in experimental ischemic stroke in vivo. Based on endogenous optical scattering signals provided by OCT imaging, we have developed a single, integrated imaging platform enabling the measurement of changes in blood perfusion, blood flow, erythrocyte velocity, and light attenuation within a cortical tissue, during focal cerebral ischemia in a mouse model. During the acute phase (from 5 min to the first few hours following the blood occlusion), the multi-parametric OCT imaging revealed multiple hemodynamic and tissue scattering responses in vivo, including cerebral blood flow deficits, capillary non-perfusion, displacement of penetrating vessels, and increased light attenuation in the cortical tissue at risk that are spatially correlated with the infarct core, as determined by postmortem staining with triphenyltetrazolium chloride. The use of multi-parametric OCT imaging may aid in the comprehensive evaluation of ischemic lesions during the early stages of stroke, thereby providing essential knowledge for guiding treatment decisions.

Aging-associated changes in cerebral vasculature and blood flow as determined by quantitative optical coherence tomography angiography.

Normal aging is associated with significant alterations in brain's vascular structure and function, which can lead to compromised cerebral circulation and increased risk of neurodegeneration. The in vivo examination of cerebral blood flow (CBF), including capillary beds, in aging brains with sufficient spatial detail remains challenging with current imaging modalities. In the present study, we use 3-dimensional (3-D) quantitative optical coherence tomography angiography (OCTA) to examine characteristic differences of the cerebral vasculatures and hemodynamics at the somatosensory cortex between old (16 months old) and young mice (2 months old) in vivo. The quantitative metrics include cortical vascular morphology, CBF, and capillary flow velocity. We show that compared with young mice, the pial arterial tortuosity increases by 14%, the capillary vessel density decreases by 15%, and the CBF reduces by 33% in the old mice. Most importantly, changes in capillary velocity and heterogeneity with aging are quantified for the first time with sufficiently high statistical power between young and old populations, with a 21% (p < 0.05) increase in capillary mean velocity and 19% (p ≤ 0.05) increase in velocity heterogeneity in the latter. Our findings through noninvasive imaging are in line with previous studies of vascular structure modification with aging, with additional quantitative assessment in capillary velocity enabled by advanced OCTA algorithms on a single imaging platform. The results offer OCTA as a promising neuroimaging tool to study vascular aging, which may shed new light on the investigations of vascular factors contributing to the pathophysiology of age-related neurodegenerative disorders.

Multifunctional in vivo imaging for monitoring wound healing using swept-source polarization-sensitive optical coherence tomography.

BACKGROUND AND OBJECTIVE: Wound healing involves a complex and dynamic biological process in response to tissue injury. Monitoring of the cascade of cellular events is useful for wound management and treatment. The aim of this study is to demonstrate the potential of multifunctional polarization-sensitive optical coherence tomography (PS-OCT) to longitudinally monitor the self-healing process in a murine cutaneous wound model. MATERIALS AND METHODS: A multi-functional PS-OCT system based on swept source OCT configuration (1,310 nm central wavelength) was designed to obtain simultaneously microstructural, blood perfusion, and birefringent information of a biological tissue in vivo. A 1-mm-diameter wound was generated in a mouse pinna with a complete biopsy punch. Afterwards, the self-healing process of the injured tissue was observed every week over 6-week period using the multifunctional system to measure changes in the tissue birefringence. Further OCT angiography (OCTA) was used in post data processing to obtain blood perfusion information over the injured tissue. RESULTS: Three complementary images indicating the changes in anatomical, vascular, and birefringent information of tissue around wound were simultaneously provided from a 3-dimensional (3-D) PS-OCT data set during the wound repair over 1 month. Specifically, inflammatory and proliferative phases of wound healing were characterized by thickened epidermal tissue (from OCT images) and angiogenesis (from OCT angiography images) around wound. Also, it was observed that the regenerating tissues had highly realigned birefringent structures (from PS-OCT images). CONCLUSION: This preliminary study suggests that the proposed multi-functional imaging modality has a great potential to improve the understanding of wound healing through non-invasive, serial monitoring of vascular and tissue responses to injury. Lasers Surg. Med. 50:213-221, 2018. © 2017 Wiley Periodicals, Inc.

Microvascular imaging and monitoring of human oral cavity lesions in vivo by swept-source OCT-based angiography.

We report the development of optical coherence tomography- (OCT) based angiography (OCTA) to image blood flow within microcirculatory tissue beds in human oral cavity in vivo with a field of view at 10 mm × 10 mm. Three-dimensional (3D) structural and vascular images of labial mucosa tissue are obtained at a single 3D acquisition. Pathologic mucosal sites with mouth ulcers are examined using the OCT tomograms and angiograms, upon which to monitor the lesion healing process over a period of 2 weeks. Quantitative metrics of the capillary loop density within the lamina propria layer are evaluated, providing statistically significant difference between healthy and diseased conditions over time. Furthermore, tissue anatomy and vessel morphology of other susceptible sites to ulcer, such as tongue, alveolar mucosa, and labial frenulum, are also imaged to demonstrate the promise of the proposed method as a clinically useful tool for the diagnosis and monitoring of therapeutic treatment of oral tissue abnormalities.

Tail artifact removal in OCT angiography images of rodent cortex.

Optical coherence tomography angiography (OCTA) is a surging non-invasive, label-free, in vivo volumetric imaging method, currently being translated to clinical ophthalmology and becoming popular in neuroscience. Despite its attractiveness, there is an inherent issue of using OCT angiograms for quantitative cerebrovascular studies: The dynamic scattering of moving erythrocytes within pial vasculature creates tail-like artifacts that shadow the capillary vessels in the deeper layers of cortex. This false flow effect is relatively benign for qualitative visualization purposes, but it might have a significant impact on quantitative interpretation of angiographic results. In this work, we propose a simple image processing method to remove these tail artifacts in depth-resolved OCTA images using an adaptive enface mask generated with OCT structural images. We demonstrate the effectiveness of our method by comparing vessel densities and vessel similarities of depth-resolved OCT angiograms in a stroke study in a rodent model, in vivo. Thanks to the ability of seeing through the tails of pial vessels, capillary vessels beneath these vessels could be recovered to some extend in the deeper layers of mouse cerebral cortex, leading to a more accurate quantification. Tail artifact removed enface OCT angiogram of deeper layer in vivo mouse cortex.

Cerebral capillary velocimetry based on temporal OCT speckle contrast.

We propose a new optical coherence tomography (OCT) based method to measure red blood cell (RBC) velocities of single capillaries in the cortex of rodent brain. This OCT capillary velocimetry exploits quantitative laser speckle contrast analysis to estimate speckle decorrelation rate from the measured temporal OCT speckle signals, which is related to microcirculatory flow velocity. We hypothesize that OCT signal due to sub-surface capillary flow can be treated as the speckle signal in the single scattering regime and thus its time scale of speckle fluctuations can be subjected to single scattering laser speckle contrast analysis to derive characteristic decorrelation time. To validate this hypothesis, OCT measurements are conducted on a single capillary flow phantom operating at preset velocities, in which M-mode B-frames are acquired using a high-speed OCT system. Analysis is then performed on the time-varying OCT signals extracted at the capillary flow, exhibiting a typical inverse relationship between the estimated decorrelation time and absolute RBC velocity, which is then used to deduce the capillary velocities. We apply the method to in vivo measurements of mouse brain, demonstrating that the proposed approach provides additional useful information in the quantitative assessment of capillary hemodynamics, complementary to that of OCT angiography.

Optical coherence tomography based microangiography provides an ability to longitudinally image arteriogenesis in vivo.

BACKGROUND: Arteriogenesis describes the active growth of the pre-existing collateral arterioles, which is a crucial tissue-saving process in occlusive vascular diseases. NEW METHOD: We propose to use optical coherence tomography (OCT)-based microangiography (OMAG) to monitor arteriogenesis following artery transection in mouse ear and focal stroke in mouse brain. RESULTS: Our longitudinal mouse ear study shows that the growth phase of arteriogenesis, indicated by changes in collateral vessel diameter and velocity, occurs between 12 and 24h after vessel transection. Additionally, the magnitude of local inflammation is consistent with the time course of arteriogenesis, judging by the tissue thickness measurement and lymphatic vessel signals in OCT. In the mouse brain study, collateral vessel morphology, blood flow velocity and directionality are identified, and an activation of the collateral flow at the arteriolo-arteriolar anastomoses (AAA) is observed during stroke. COMPARISON WITH EXISTING METHODS: In comparison with histology and fluorescence imaging, OCT/OMAG is completely non-invasive and capable of producing consistent results of longitudinal changes in collateral vessel morphology and vasodynamics. CONCLUSION: OCT/OMAG is a promising imaging tool for longitudinal study of collateral vessel remodeling in small animals. This technique can be applied in guiding the in vivo experiments of arteriogenesis stimulation to treat occlusive vascular diseases, including stroke.