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Objective To assess the repeatability of blood flow velocity index (BFVi) metrics obtained with a recently FDA-cleared laser speckle contrast imaging device, the XyCAM RI, and characterize differences in these metrics between control, glaucoma suspect, and glaucoma subjects. Design Prospective observational study Participants 46 subjects (20 control, 16 glaucoma suspect, and 10 glaucoma; one eye per subject) Methods Key dynamic BFVi metrics–mean, peak, dip, volumetric rise index (VRI), volumetric fall index (VFI), time to rise (TtR), time to fall (TtF), blow out time (BOT), skew, acceleration time index (ATI)–were measured in the optic disc, optic disc vessels, optic disc perfusion region, and macula in four imaging sessions on the same day. Intrasession and intersession variability were calculated using the coefficient of variation (CV) for each metric in each region of interest (ROI). Values for each dynamic BFVi variable were compared between glaucoma subjects, glaucoma suspects, and controls using bivariate and multivariable analysis. Pearson correlation coefficients were used to correlate each variable in each ROI with age, intraocular pressure, cup to disc ratio, mean deviation, pattern standard deviation, retinal nerve fiber layer thickness, and minimum rim width. Main outcome measures CV for the intrasession and intersession variability for each dynamic BFVi metric in each ROI, and differences in each metric in each ROI between each diagnostic group. Results The intersession CV for mean, peak, dip, as well as VRI, VFI, TtR, and TtF ranged from 3.2 ± 2.5% to 11.0 ± 3.8%. Age, cup-to-disc ratio, optical coherence tomography metrics, and visual field metrics showed significant correlations with dynamic BFVi variables. Peak, mean, dip, VRI, and VFI, were significantly lower in glaucoma subjects than in control subjects in all ROI except the fovea. These metrics were also significantly lower in glaucoma subjects than suspects in the disc vessels. Conclusions Dynamic blood flow metrics measured with the XyCAM RI are reliable, associated with structural and functional glaucoma metrics, and significantly different between glaucoma subjects, glaucoma suspects, and controls. The XyCAM RI may serve as an important tool in glaucoma management in the future.

Retinal ischemia characterizes the underlying pathology in a multitude of retinal diseases that can ultimately lead to vision loss. A variety of novel imaging modalities have been developed to characterize retinal ischemia by measuring retinal oxygenation and blood flow in-vivo. These technologies offer valuable insight into the earliest pathophysiologic changes within the retina and provide physicians and researchers with new diagnostic and monitoring capabilities. Future retinal imaging technologies with the capability to provide affordable, noninvasive, and comprehensive data on oxygen saturation, vasculature, and blood flow mechanics are needed. This review will highlight current and future trends in multimodal imaging to assess retinal blood flow and oxygenation.摘要: 视网膜缺血是多种视网膜疾病的基本病理特征, 最终可导致视力丧失。目前已有多种新的影像学成像技术通过测量体内视网膜氧合水平以及血流来诊断视网膜缺血。这些技术为监测视网膜最早的病理生理变化提供了有价值的信息, 并为医生和研究人员提供了新的诊断和监测疾病的能力。未来的视网膜成像技术在氧饱和度以及血管系统和血流力学方面不仅使患者可以负担得起、无创并且可以提供更加全面的数据。本文将重点强调多模态成像技术平台评估视网膜血流以及氧合水平的目前状态以及未来的趋势。.

INTRODUCTION Ocular blood flow plays a critical role in eye health by nourishing the retinal and ocular tissues with oxygen and nutrients and removal of ocular metabolic waste. Imaging of retinal and optic blood flow may provide insights for early and more specific diagnoses of ocular vascular disorder and facilitate eye-based biomarkers applicable to neurological health assessment and research. AREAS COVERED The ability of the XyCAM RI (Vasoptic Medical Inc., MD, USA) to visualize and to analyze ocular blood flow dynamics XyCAM RI using laser speckle contrast imaging is reviewed and compared with concurrent clinical ophthalmic imaging technologies like optical coherence tomography - angiography (OCT-A), fundus imaging, fluorescein angiography (FA), indocyanine green angiography (ICGA), laser Doppler flowmetry (LDF), and laser speckle flowgraphy (LSFG). EXPERT OPINION XyCAM RI, with its unprecedented imaging capabilities to assess blood flow dynamics provides a powerful tool to ophthalmic researchers and doctors to obtain greater clinical insights into the physiological status of the posterior segment and treatment approaches for various diseases in a very patient-friendly, noninvasive manner, unlike dye-based angiographic techniques such as FA or ICG. XyCAM RI is well suited as a modality that could close the gap between current screening and comprehensive eye exams.

Cerebrovascular surgery can benefit from an intraoperative system that conducts continuous monitoring of cerebral blood flow (CBF). Such a system must be handy, non-invasive, and directly integrated into the surgical workflow. None of the currently available techniques, considered alone, meets all these criteria. Here, we introduce the SurgeON™ system: a newly developed non-invasive modular tool which transmits high-resolution Laser Speckle Contrast Imaging (LSCI) directly onto the eyepiece of the surgical microscope. In preclinical rodent and rabbit models, we show that this system enabled the detection of acute perfusion changes as well as the recording of temporal response patterns and degrees of flow changes in various microvascular settings, such as middle cerebral artery occlusion, femoral artery clipping, and complete or incomplete cortical vessel cautery. During these procedures, a real-time visualization of vasculature and CBF was available in high spatial resolution through the eyepiece as a direct overlay on the live morphological view of the surgical field. Upon comparison with indocyanine green angiography videoangiography (ICG-VA) imaging, also operable via SurgeON, we found that direct-LSCI can produce greater information than ICG-VA and that continuous display of data is advantageous for performing immediate LSCI-guided adjustments in real time.

Laser speckle contrast imaging (LSCI) is a full field optical imaging technique, capable of imaging blood flow without the introduction of any exogenous dyes. Spatial and temporal resolution in LSCI images depend on how pixels are chosen from the raw image stack for contrast processing. However, all processing schemes are based on isotropic treatment of the spatial neighborhood about each pixel, restricting further improvement in spatiotemporal resolution and image quality. We present a novel spatiotemporal processing scheme for LSCI where the spatial neighborhood is anisotropic, that is, restricted along a specific direction that matches direction of blood flow. The technique allows for a significant increase in temporal resolution, from conventionally used 40 or 80 frames to just three frames; while simultaneously achieving 23% and 47% higher signal-to-noise ratios over concurrent spatiotemporal schemes, when imaging rapid and slow functional changes in blood flow, respectively. We present the concept, justification, and performance evaluation of the novel scheme and demonstrate its suitability for imaging rapid changes in blood flow. Anisotropic LSCI was able to monitor the heart rate associated fluctuations in intravascular blood flow and showed them to be as high as 28% of the mean.

Laser speckle contrast imaging (LSCI) is a high-resolution and high contrast optical imaging technique often used to characterize hemodynamic changes in short-term physiological experiments. In this study, we demonstrate the utility of LSCI for characterizing microvascular remodeling and hemodynamic changes during wound healing angiogenesis in vivo. A 2 mm diameter hole was made in the mouse ear and the periphery of the wound imaged in vivo using LSCI over 12 days. We were able to visualize and quantify the vascular and perfusion changes that accompanied wound healing in the microenvironment proximal to the wound, and validated these changes with histology. We found that consistent with the stages of wound healing, microvessel density increased during the initial inflammatory phase (i.e., day 0–3), stayed elevated through the tissue formation phase (i.e., until day 7) and returned to baseline during the tissue remodeling phase (i.e., by day 12). Concomitant ‘‘wide area mapping’’ of blood flow revealed that tissue perfusion in the wound periphery initially decreased, gradually increased from day 3–7, and subsided as healing completed. Interestingly, some regions exhibited a reestablishment of tissue perfusion approximately 6 days earlier than the ∼ 18 days usually reported for the long term remodeling phase. The results from this study demonstrate that LSCI is an ideal platform for elucidating in vivo changes in microvascular hemodynamics and angiogenesis, and has the potential to offer invaluable insights in a range of disease models involving abnormal hemodynamics, such as diabetes and tumors.

Purpose We assessed the image quality and reproducibility of blood flow measurements from a novel handheld laser speckle imager in handheld and stabilized use cases. Methods Eleven dilated human subjects were imaged with the XyCAM Handheld Retinal Imager investigational device (XyCAM HRI) in the handheld and stabilized use case in nine consecutive imaging sessions. Subjects then underwent standard color fundus photography using a Topcon TRC 50DX. The vessel-to-background contrast of the XyCAM HRI red-free photo was compared to the fundus photograph, while the coefficient of variation of blood flow measurements in specific arteries and veins also was determined. Results Vessel-to-background contrast was statistically greater in the handheld use case when compared to the standard color fundus photographs (P = 0.01). Estimates of mean blood flow velocity (BFV) were highly correlated between the stabilized and handheld use case (r2 = 0.96). Peak velocity estimates in arteries were significantly higher than those in veins (P < 0.05). Conclusions The XyCAM HRI prototype can acquire fundus photographs with the same or better level of clarity as color fundus photographs, and reproducibly acquire functional blood flow information in the handheld use case. Translational Relevance To our knowledge, this is the first human study of a handheld laser speckle retinal imaging device. Determination of retinal blood flow has applications to ophthalmic and systemic disease and a portable handheld retinal imager that determines blood flow may be widely adopted at the point of care.

In this paper, a model-based reconstruction technique is proposed to simultaneously measure the relative deoxyhemoglobin concentration and the relative blood flow velocity in cerebral cortex. With the help of this model-based reconstruction technique, artifacts due to nonuniform laser illumination and curvature of cortex are efficiently corrected. The results of relative deoxy-hemoglobin concentration and relative blood flow velocity are then used to detect and distinguish cerebral arteries and veins. In an experimental study on rat, cerebral blood vessels are segmented from the reconstructed blood flow image by Otsu multiple threshold method. Afterwards, arteries and veins are distinguished by a simple fuzzy criterion based on the information of relative deoxyhemoglobin concentration.

A 16-channel current-measuring very large-scale integration (VLSI) sensor array system for highly sensitive electrochemical detection of electroactive neurotransmiters like dopamine and nitric-oxide is presented. Each channel embeds a current integrating potentiostat within a switched-capacitor first-order single-bit delta-sigma modulator implementing an incremental analog-to-digital converter. The duty-cycle modulation of current feedback in the delta-sigma loop together with variable oversampling ratio provide a programmable digital range selection of the input current spanning over six orders of magnitude from picoamperes to microamperes. The array offers 100-fA input current sensitivity at 3.4-muW power consumption per channel. The operation of the 3 mm times3 mm chip fabricated in 0.5-mum CMOS technology is demonstrated with real-time multichannel acquisition of neurotransmitter concentration.

Diabetes care is currently undergoing a transformation as a result of the rapid adoption of mobile technology. In addition to a variety of traditional diagnostic and therapeutic devices, innovative mobile health or “mHealth” solutions are being designed to empower patients and providers to better manage and prevent the disease through increased access to educational information, patient health data, novel sensors, and powerful analytics. While the adoption of mHealth technologies has the potential to dramatically change pre-diabetes and diabetes care, insufficient data of safety and effectiveness exist to support their integration into standard clinical practice. Poor reimbursement and an unclear regulatory framework further challenge the adoption of mHealth technologies. Nonetheless, the opportunity that mHealth technologies present to increase patient access to affordable, quality healthcare demands that these challenges be quickly overcome.

Laser Speckle Contrast Imaging (LSCI) is a wide field of view, non scanning optical technique for observing blood flow. Speckles are produced when coherent light scattered back from biological tissue is diffracted through the limiting aperture of focusing optics. Mobile scatterers cause the speckle pattern to blur; a model can be constructed by inversely relating the degree of blur, termed speckle contrast to the scatterer speed. In tissue, red blood cells are the main source of moving scatterers. Therefore, blood flow acts as a virtual contrast agent, outlining blood vessels. The spatial resolution ( ~ 10 μm) and temporal resolution (10 ms to 10 s) of LSCI can be tailored to the application. Restricted by the penetration depth of light, LSCI can only visualize superficial blood flow. Additionally, due to its non scanning nature, LSCI is unable to provide depth resolved images. The simple setup and non-dependence on exogenous contrast agents have made LSCI a popular tool for studying vascular structure and blood flow dynamics. We discuss the theory and practice of LSCI and critically analyze its merit in major areas of application such as retinal imaging, imaging of skin perfusion as well as imaging of neurophysiology.

Laser speckle contrast imaging (LSCI) is a contrast agent free imaging technique suited for longitudinal assessment of vascular remodeling that accompanies brain tumor growth. We report the use of LSCI to monitor vascular changes in a rodent glioma model. Ten rats are inoculated with 9L gliosarcoma cells, and the angiogenic response is monitored five times over two weeks through a thinned skull imaging window. We are able to visualize neovascularization and measure the number of vessels per unit area to assess quantitatively the microvessel density (MVD). Spatial spread of MVD reveals regions of high MVD that may correspond to tumor location. Whole-field average MVD values increase with time in the tumor group but are fairly stable in the control groups. Statistical analysis shows significant differences in MVD values between the tumor group and both saline-receiving and unperturbed control groups over the two-week period (p

We report the novel use of laser speckle contrast imaging (LSCI) at multiple exposure times (meLSCI) for enhanced in vivo imaging of the microvascular changes that accompany angiogenesis. LSCI is an optical imaging technique that can monitor blood vessels and the flow therein at a high spatial resolution without requiring the administration of an exogenous contrast agent. LSCI images are obtained under red (632 nm) laser illumination at seven exposure times (1-7 ms) and combined using a curve-fitting approach to obtain high-resolution meLSCI images of the rat brain vasculature. To evaluate enhancement in in vivo imaging performance, meLSCI images are statistically compared to individual LSCI images obtained at a single exposure time. We find that meLSCI reduced the observed variability in the LSCI-based blood-flow estimates by 30% and improved the contrast-to-noise ratio in regions with high microvessel density by 41%. The ability to better distinguish microvessels, makes meLSCI uniquely suited to longitudinal imaging of changes in the vascular microenvironment induced by pathological angiogenesis. We demonstrate this utility of meLSCI by sequentially monitoring, over days, the microvascular changes that accompany wound healing in a mouse ear model.

Laser speckle contrast imaging (LSCI) has classically been used to image regional blood flow changes in animal models. In this paper, we demonstrate the use of LSCI for elucidating blood flow characteristics in individual microvessels with diameters as small as 24µm. We extracted profiles of speckle contrast values within individual vessels, both along their diameters and along their lengths and inferred that they could be attributed to the flow within the vessel. Profiles along the diameter of vessels revealed maxima at the center of vessels, consistent with fluid dynamics. These observed profiles could be fitted with parabolic curves with a mean coefficient of determination of 0.92. Similarly, analysis of speckle contrast values in the axial direction revealed profiles that progressively decreased in discreet quanta at branch points indicating blood flow bifurcations. Flow estimates obtained from speckle contrast values within branches of vessels obeyed the law of mass conservation with a mean error of only 3.5%. This allowed us to elucidate the percentage distribution of blood flow into each of the downstream branches. This ability of LSCI to resolve blood flow distribution in branching microvessel trees in a minimally invasive and dye free environment over a wide field of view promises to find application in both the neuroscience laboratory as well as intraoperative neurosurgery.

Laser speckle imaging (LSI) and optical intrinsic signal (OIS) imaging are shown to produce high resolution information of cerebral blood flow(CBF) and de-oxygen hemoglobin(dHb) respectively. However, the cortex curvature and non-uniform illumination always result in the inhomo-geneous impact and thus distort the CBF and dHb results. In this paper, we propose to extract both CBF and dHb images from raw speckle images. A parametric model for such inhomogeneity is estimated by adaptive window median-mean filtering and curve fitting technique to reconstruct the CBF and dHb image.

A laser speckle imaging (LSI) technique, with high spatio-temporal resolution, is presented for studying cerebrovascular response to stimulation. LSI is evaluated in a rodent model of cerebrovascular activity, in a model of migraine, by eliciting functional response to brain trigeminal nerve stimulation. The specific haemodynamic response, including deoxy-hemoglobin saturation and blood flow responses in cortical vessels to the abnormal activation of the trigeminal system, are obtained from the processed LSI images. The simultaneous optical imaging methods for imaging blood flow and deoxygenation saturation changes could be of great use in basic investigation of functional brain responses in conditions such as migraine and for evaluating investigational therapeutic solutions.

High-resolution cerebral vasculature imaging has applications ranging from intraoperative procedures to basic neuroscience research. Laser speckle, with spatial contrast processing, has recently been used to map cerebral blood flow. We present an application of the technique using temporal contrast processing to image cerebral vascular structures with a field of view a few millimeters across and approximately 20 microm resolution through a thinned skull. We validate the images using fluorescent imaging and demonstrate a factor of 2-4 enhancement in contrast-to-noise ratios over reflectance imaging using white or spectrally filtered green light. The contrast enhancement enables the perception of approximately 10%-30% more vascular structures without the introduction of any contrast agent.

Nitric oxide (NO) serves as an important intercellular messenger in the human body, and is mechanistically involved in vascular disease, stroke, chronic hear failure, and epilepsy. We present a multi-electrode NO measurement sensor with integrated microfluidics. An array of carbon-based electrodes detect the spatial and temporal diffusion profile of NO in a PDMS laminar fluidic channel. The array interfaces to a multichannel potentiostatic VLSI system recording the amperometric output in real time, with five orders of magnitude in dynamic range over four scales down to hundreds of picoamperes. The integrated sensor-fluidic-VLSI system is expected to serve as a powerful tool to study the diffusion mechanism of NO under different fluid flow paradigms.