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PURPOSE: To assess global, zonal, and local correlations between vessel density changes measured by optical coherence tomography angiography (OCTA) and retinal sensitivity measured by microperimetry across diabetic retinopathy severity. METHODS: Diabetic patients with and without retinopathy, and age matched non-diabetic controls, underwent OCTA imaging and microperimetry testing. Skeletonized vessel density (SVD) was computed from 3 mm x 3 mm OCTA images of the superficial capillary plexus, deep capillary plexus, and full retinal layer, excluding larger retinal vessels and the foveal avascular zone (FAZ). Pearson’s correlation was used to assess associations between average sensitivity and vessel density globally and in four parafoveal zones; centrally, average sensitivity was correlated with the FAZ area. Linear mixed effects modeling was used to assess relationships between local SVD measurements and their spatially corresponding retinal sensitivity measurements. RESULTS: Thirty-nine eyes from 39 participants were imaged. In all slabs, there was a statistically significant positive correlation between retinal sensitivities and SVDs on both global and zonal scales. No statistically significant correlation was found between central retinal sensitivities and the FAZ areas. Assessment of 1,136 spatially paired retinal sensitivity and SVD measurements revealed a statistically significant local relationship; this appeared to be driven by eyes with proliferative diabetic retinopathy that had reduced retinal sensitivities. CONCLUSIONS: Data from this study supports positive correlations between SVD and retinal sensitivity at global and zonal spatial scales in the parafovea of diabetic eyes. However, our analysis did not find evidence of statistically significant correlations between retinal sensitivity and SVD on a local scale until advanced diabetic retinopathy.

A panel of imaging experts was assembled to review neovascular age-related macular degeneration optical coherence tomography angiography descriptors published to date, and test agreement on use of these terms, which was found to be low. Optical coherence tomography angiography (OCTA) has been used to identify and characterize macular neovascularization (MNV) secondary to age-related macular degeneration (AMD). 1 , 2 , 3 , 4 Many studies have explored OCTA morphological features of MNV that might serve as biomarkers to assess disease activity and response to treatment. 1 , 2 , 3 , 4 , 5 , 6 The proliferation of studies however has resulted in an OCTA terminology that has been variable and inconsistent. To address inconsistency of nomenclature and allow harmonization, a multidisciplinary panel of retinal imaging experts with a history of relevant research contributions to the field was assembled with the purpose of reviewing published terminology and to recommend a reduced list of key terms pertinent to OCTA. The group was called UNICORN, because of its ultimate goal of generating a UNIfied COmmentary of the committee of inteRnational experts on the nomenclature for Neovascular AMD in OCTA. In this report we describe the first steps, which included a review of OCTA descriptors of neovascular AMD (nAMD) published to date, and an exercise that tested agreement of these terms among retinal imaging experts. Prior to the first UNICORN meeting, a non-systematic review of the literature was performed, using the search terms “optical coherence tomography angiography” or “OCT angiography” or “OCT-A”, AND “neovascular macular degeneration” or “neovascular age-related macular degeneration” or “neovascular AMD” or “nAMD” or “wet age-related macular degeneration” or “wet AMD” or “wet ARMD”. A dictionary of OCTA descriptors relating to the features of MNV in AMD was generated and circulated to the panel.

Purpose To identify optical coherence tomography angiography (OCTA) derived vessel metrics of the macula and optic nerve head (ONH) that predict diabetic retinopathy (DR) disease progression. Design Secondary analysis of clinical trial data Methods This was a sub-analysis of prospectively collected data from 73 subjects that participated in the TIME-2b Study (Aerpio Pharmaceuticals), a multi-center clinical trial for patients with moderate to severe DR treated with AKB-9778 and followed over a 12-month period. Eligible subjects were tested every 3 months with color fundus photography, spectral domain OCT and slit-lamp biomicroscopy. OCTA of the macula and ONH was obtained for a subset of patients enrolled at participating sites. En-face, full-depth retinal projections centered at the macula were analyzed for multiple metrics including foveal avascular zone (FAZ) area and perimeter, non-perfusion area, vessel density (VD) and presence of intraretinal microvascular abnormalities (IRMA). VD of the radial peripapillary capillaries was evaluated in four quadrants surrounding the optic disc for ONH images. Progression was defined as a ≥ 2-step increase in DR severity scale score or development of diabetic macular edema. Results Over a follow-up period of 12 months, 15 of 73 (20.5%) subjects progressed. At pre-treatment baseline, larger FAZ area, presence of IRMA, and reduced peripapillary VD in the superior temporal and inferior temporal regions were significantly associated with increased odds of progression. Conclusions FAZ area and temporal peripapillary VD are predictors of DR progression. OCTA metrics may improve progression risk assessment in DR when compared to established risk factors alone.

Purpose To develop a multiscale analysis framework for investigating the relationships between geographic atrophy (GA) growth rate and choriocapillaris (CC) blood flow impairment using optical coherence tomography (OCT) and OCT angiography (OCTA). Design Retrospective case series. Methods We developed an OCT/OCTA analysis framework that quantitatively measures GA growth rates at global and local scales and CC impairment at global, zonal, and local scales. A geometric GA growth model was used to measure local GA growth rates. The utility of the framework was demonstrated on 7 eyes with GA imaged at 2 time points using a prototype 400-kHz, 1050-nm swept-source OCTA system. Results Qualitatively, there was a trend of increasing GA growth rate with increasing CC impairment. The local analysis model enabled growth rates to be estimated at each point on the GA boundary. However, there was no generally observed trend between local GA growth rates and local CC impairment. Conclusions The global, zonal, and local analysis framework may be useful for investigating relationships between GA growth and CC impairment at different spatial scales. The geometric GA growth model enables spatially resolved growth measurements that capture the anisotropy of GA growth and may improve the characterization of GA progression.

Purpose To establish a process to evaluate and standardize a state-of-the-art nomenclature for reporting neovascular age-related macular degeneration (AMD) data. Design Consensus meeting. Participants An international panel of retina specialists, imaging and image reading center experts, and ocular pathologists. Methods During several meetings organized under the auspices of the Macula Society, an international study group discussed and codified a set nomenclature framework for classifying the subtypes of neovascular AMD and associated lesion components. Main Outcome Measures A consensus classification of neovascular AMD. Results The study group created a standardized working definition of AMD. The components of neovascular AMD were defined and subclassified. Disease consequences of macular neovascularization were delineated. Conclusions The framework of a consensus nomenclature system, a definition of AMD, and a delineation of the subtypes of neovascular AMD were developed. Establishing a uniform set of definitions will facilitate comparison of diverse patient groups and different studies. The framework presented is modified and updated readily, processes that are anticipated to occur on a periodic basis. The study group suggests that the consensus standards outlined in this article be used in future reported studies of neovascular AMD and clinical practice.

Intraoperative evaluation of specimens during radical prostatectomy using frozen sections can be time and labor intensive. Nonlinear microscopy (NLM) is a fluorescence microscopy technique that can rapidly generate images that closely resemble H&E histology in freshly excised tissue, without requiring freezing or microtome sectioning. Specimens are stained with nuclear and cytoplasmic/stromal fluorophores, and nonlinear microscopy evaluation can begin within 3 minutes of grossing. Fluorescence signals can be displayed using an H&E color scale, facilitating pathologist interpretation. This study evaluates the accuracy of prostate cancer detection in blinded reading of nonlinear microscopy images compared to the gold-standard of formalin fixed, paraffin embedded H&E histology. A total of 122 freshly excised prostate specimens were obtained from 40 patients undergoing radical prostatectomy. The prostates were grossed, dissected into specimens of ~10×10 mm with 1–4 mm thickness, stained for 2 minutes for nuclear and cytoplasmic/stromal contrast, and then rinsed with saline for 30 seconds. Nonlinear microscopy images were acquired and multiple images were stitched together to generate large field of view, centimeter-scale digital images suitable for reading. Specimens were then processed for standard paraffin H&E. The study protocol consisted of training, pre-testing, and blinded reading phases. After a washout period, pathologists read corresponding paraffin H&E slides. Three pathologists achieved a 95% or greater sensitivity with 100% specificity for detecting cancer on nonlinear microscopy compared to paraffin H&E. Pooled sensitivity and specificity was 97.3% (93.7%−99.1%; 95% confidence interval) and 100.0% (97%−100%), respectively. Interobserver agreement for nonlinear microscopy reading had a Fleiss κ=0.95. The high cancer detection accuracy and rapid specimen preparation suggest that nonlinear microscopy may be useful for intraoperative evaluation in radical prostatectomy.

Background The purpose of this study was to investigate the association between diabetic retinopathy (DR) severity and macular choriocapillaris (CC) flow deficit percentage (FD %) in different macular regions using swept-source optical coherence tomography angiography (SS-OCTA). Methods Diabetic patients with SS-OCTA images were graded by severity and retrospectively assessed. CC FD % was calculated in four different regions of the OCTA image: inner, middle, outer, and full-field region. The generalized estimating equations (GEE) approach for clustered eye data was used to determine effect size and significance of age and disease severity on FD % for each region. Results 160 eyes from 90 total diabetic patients met inclusion criteria. Out of 90 patients, 33 had no DR, 17 had mild nonproliferative DR (NPDR), 8 had moderate NPDR, 10 had severe NPDR and 22 had proliferative DR. Age and DR severity had a significant positive association with FD % for each region studied with a greater effect in the two centermost regions. The increase in flow deficit percentage per year of age by region was: inner 0.12 (p Conclusions Topographic analysis of the CC FD % in diabetic eyes suggests that CC flow impairment corresponds to DR severity, with all studied regions of the CC significantly affected. There was greater regional impairment due to age and disease severity in the inner and middle regions.

Purpose To develop an optical coherence tomography angiography (OCTA)-based framework for quantitatively analyzing the spatial distribution of choriocapillaris (CC) impairment around choroidal neovascularization (CNV) secondary to age-related macular degeneration. Methods In a retrospective, cross-sectional study, 400-kHz swept-source OCTA images from 7 eyes of 6 patients with CNV secondary to age-related macular degeneration were quantitatively analyzed using custom software. A lesion-centered zonal OCTA analysis technique-which portioned the field-of-view into zones relative to CNV boundaries-was developed to quantify the spatial dependence of CC flow deficits. Results Quantitative, lesion-centered zonal analysis of CC OCTA images revealed highest flow-deficit percentages near CNV boundaries, decreasing in zones farther from the boundaries. Optical coherence tomography angiography using shorter (1.5 ms) interscan times revealed more severe flow deficits than OCTA using longer (3.0 ms) interscan times; however, spatial trends were similar for both interscan times. A detailed description of the OCTA processing steps and parameters was provided so as to elucidate their influence on quantitative measurements. Conclusion Impairment of the CC, assessed by flow-deficit percentages, was most prominent closest to CNV boundaries. The lesion-centered zonal analysis technique enabled quantitative CC measurements relative to focal lesions. Understanding how processing steps, imaging/processing parameters, and artifacts can affect quantitative CC measurements is important for longitudinal, OCTA-based studies of disease progression, and treatment response.

This study reports the development of prototype swept-source optical coherence tomography (SS-OCT) technology for imaging the anterior eye. Advances in vertical-cavity surface-emitting laser (VCSEL) light sources, signal processing, optics and mechanical designs, enable a unique combination of high speed, long range, and deep penetration that addresses the challenges of anterior eye imaging. We demonstrate SS-OCT with a 325 kHz A-scan rate, 12.2 µm axial resolution (in air), and 15.5 mm depth range (in air) at 1310 nm wavelength. The ultrahigh 325 kHz A-scan rate not only facilitates biometry measurements by minimizing acquisition time and thus reducing motion, but also enables volumetric OCT for comprehensive structural analysis and OCT angiography (OCTA) for visualizing vasculature. The 15.5 mm (~ 11.6 mm in tissue) depth range spans all optical surfaces from the anterior cornea to the posterior lens capsule. The 1310 nm wavelength range enables structural OCT and OCTA deep in the sclera and through the iris. Achieving high speed and long range requires linearizing the VCSEL wavenumber sweep to efficiently utilize analog-to-digital conversion bandwidth. Dual channel recording of the OCT and calibration interferometer fringe signals, as well as sweep to sweep wavenumber compensation, is used to achieve invariant 12.2 µm (~ 9.1 µm in tissue) axial resolution and optimum point spread function throughout the depth range. Dynamic focusing using a tunable liquid lens extends the effective depth of field while preserving the lateral resolution. Improved optical and mechanical design, including parallax “split view” iris cameras and stable, ergonomic patient interface, facilitates accurate instrument positioning, reduces patient motion, and leads to improved imaging data yield and measurement accuracy. We present structural and angiographic OCT images of the anterior eye, demonstrating the unique imaging capabilities using representative scanning protocols which may be relevant to future research and clinical applications.

Neovascular age-related macular degeneration (AMD) can lead to rapid, irreversible vision loss in untreated eyes. While the pathogenesis of neovascular AMD remains incompletely understood, the choriocapillaris has been hypothesized as the initial site of injury. Due to limitations of dye-based angiography, in vivo imaging of the choriocapillaris has been a longstanding challenge. However, the clinical introduction of optical coherence tomography angiography (OCTA) has enabled researchers and clinicians to noninvasively image the choriocapillaris vasculature, allowing the evaluation of the choriocapillaris in eyes with a variety of pathologies. In this perspective, we review important OCTA-based findings regarding choriocapillaris impairment in neovascular AMD and discuss limitations and future directions of OCTA technologies in the context of this disease.

A novel integration of retinal multispectral imaging (MSI), retinal oximetry and laser speckle contrast imaging (LSCI) is presented for functional imaging of retinal blood vessels that could potentially allow early detection or monitoring of functional changes. We designed and built a cost-effective, scalable, retinal imaging instrument that integrates structural and functional retinal imaging techniques, including MSI, retinal oximetry and LSCI. Color fundus imaging was performed with 470 nm, 550 nm and 600 nm wavelength light emitting diode (LED) illumination. Retinal oximetry was performed using 550 nm and 600 nm LED illumination. LSCI of blood flow was performed using 850 nm laser diode illumination at 82 frames per second. LSCI can visualize retinal and choroidal vasculature without requiring exogenous contrast agents and can provide time-resolved information on blood flow, generating a cardiac pulse waveform from retinal vasculature. The technology can rapidly acquire structural MSI images, retinal oximetry and LSCI blood flow information in a simplified clinical workflow without requiring patients to move between instruments. Results from multiple modalities can be combined and registered to provide structural as well as functional information on the retina. These advances can reduce barriers for clinical adoption, accelerating research using MSI, retinal oximetry and LSCI of blood flow for diagnosis, monitoring and elucidating disease pathogenesis.

Rapid histological assessment of large areas of prostate tissue is required for many intraoperative consultation scenarios such as margin evaluation. Nonlinear microscopy (NLM) enables imaging of large (whole mount) specimens without freezing or cryotoming. This study demonstrates rapid histological imaging of unsectioned prostate cancer surgical specimens using nonlinear microscopy and compares features of prostate pathology to standard paraffin embedded H&E histology. Fresh or formalin fixed specimens were stained in 2.5 min with fluorescent nuclear and stromal dyes. Nonlinear microscopy images of unsectioned tissues were generated by nonlinear (two-photon) excitation of the fluorophores, where fluorescence is only emitted from tissue at the microscope focus, avoiding the need for physical sectioning. The images were displayed in real time using a color scale similar to H&E, then tissues were processed for standard paraffin embedded H&E histology. Seventy nonlinear microscopy and corresponding paraffin H&E images of fresh and fixed prostate specimens (15 cancer, 55 benign) from 24 patients were read by genitourinary pathologists to assess if nonlinear microscopy could achieve an equivalent evaluation to paraffin embedded H&E histology. Differences between nonlinear microscopy images and paraffin H&E slides, including cytoplasmic color and stromal density, were observed, however nonlinear microscopy images could be interpreted with minimal training. Nonlinear microscopy enabled visualization of benign, atrophic and hyperplastic glands and stroma, ejaculatory ducts, vasculature and inflammatory changes. Nonlinear microscopy enabled identification of typical and variants of adenocarcinoma, as well as Gleason patterns. Perineural invasion and extraprostatic extension could also be assessed. Nonlinear microscopy images closely resemble paraffin H&E slides and enable rapid assessment of normal prostate architecture, benign conditions, and carcinoma in freshly excised and fixed specimens. Nonlinear microscopy can image large regions of tissue, equivalent to multiple frozen section tissue blocks, within minutes because cryotoming/microtoming are not required, making it a promising technique for intraoperative consultation.

BACKGROUND Chronic radiation proctopathy (CRP) occurs as a result of pelvic radiation therapy and is associated with formation of abnormal vasculature that may lead to persistent rectal bleeding. While incidence is declining due to refinement of radiation delivery techniques, CRP remains one of the major complications of pelvic radiation therapy and significantly affects patient quality of life. Radiofrequency ablation (RFA) is an emerging treatment modality for eradicating abnormal vasculature associated with CRP. However, questions remain regarding CRP pathophysiology and optimal disease management. AIM To study feasibility of optical coherence tomography angiography (OCTA) for investigating subsurface vascular alterations in CRP and response to RFA treatment. METHODS Two patients with normal rectum and 8 patients referred for, or undergoing endoscopic RFA treatment for CRP were imaged with a prototype ultrahigh-speed optical coherence tomography (OCT) system over 15 OCT/colonoscopy visits (2 normal patients, 5 RFA-naïve patients, 8 RFA-follow-up visits). OCT and OCTA was performed by placing the OCT catheter onto the dentate line and rectum without endoscopic guidance. OCTA enabled depth-resolved microvasculature imaging using motion contrast from flowing blood, without requiring injected dyes. OCTA features of normal and abnormal microvasculature were assessed in the mucosa and submucosa. Blinded reading of OCTA images was performed to assess the association of abnormal rectal microvasculature with CRP and RFA treatment, and rectal telangiectasia density endoscopic scoring. RESULTS OCTA/OCT images are intrinsically co-registered and enabled depth-resolved visualization of microvasculature in the mucosa and submucosa. OCTA visualized normal vascular patterns with regular honeycomb patterns vs abnormal vasculature with distorted honeycomb patterns and ectatic/tortuous microvasculature in the rectal mucosa. Normal arterioles and venules < 200 μm in diameter versus abnormal heterogenous enlarged arterioles and venules > 200 μm in diameter were visualized in the rectal submucosa. Abnormal mucosal vasculature occurred in 0 of 2 normal patients and 3 of 5 RFA-naïve patients, while abnormal submucosal vasculature occurred more often, in 1 of 2 normal patients and 5 of 5 RFA-naïve patients. After RFA treatment, vascular abnormalities decreased, with abnormal mucosal vasculature observed in 0 of 8 RFA-follow-up visits and abnormal submucosal vasculature observed in only and 2 of 8 RFA-follow-up visits. CONCLUSION OCTA visualizes depth-resolved microvascular abnormalities in CRP, allowing assessment of superficial features which are endoscopically visible as well as deeper vasculature which cannot be seen endoscopically. OCTA/OCT of the rectum can be performed in conjunction with, or independently from endoscopy. Further studies are warranted to investigate if OCTA/OCT can elucidate pathophysiology of CRP or improve management.

Rapid histologic assessment of fresh prostate biopsies may reduce patient anxiety, aid in biopsy sampling, and enable specimen triaging for molecular/genomic analyses and research that could benefit from fresh tissue analysis. Nonlinear microscopy (NLM) is a fluorescence microscopy technique that can produce high-resolution images of freshly excised tissue resembling formalin-fixed paraffin-embedded (FFPE) H&E. NLM enables evaluation of tissue up to ~100 µm below the surface, analogous to serial sectioning, but without requiring microtome sectioning. One hundred and seventy biopsies were collected from 63 patients who underwent in-bore MRI or MRI/ultrasound fusion biopsy procedures. Biopsies were stained in acridine orange and sulforhodamine 101, a nuclear and cytoplasmic/stromal fluorescent dye, for 45 s. Genitourinary pathologists evaluated the biopsies using NLM by translating the biopsies in real time to areas of interest and NLM images were recorded. After NLM evaluation, the biopsies were processed for standard FFPE H&E and similarities and differences between NLM and FFPE H&E were investigated. Accuracies of NLM diagnoses and Gleason scores were calculated using FFPE histology as the gold standard. Pathologists achieved a 92.4% sensitivity (85.0–96.9%, 95% confidence intervals) and 100.0% specificity (94.3–100.0%) for detecting carcinoma compared to FFPE histology. The agreement between the Grade Group determined by NLM versus FFPE histology had an unweighted Cohen’s Kappa of 0.588. The average NLM evaluation time was 2.10 min per biopsy (3.08 min for the first 20 patients, decreasing to 1.54 min in subsequent patients). Further studies with larger patient populations, larger number of pathologists, and multiple institutions are warranted. NLM is a promising method for future rapid evaluation of prostate needle core biopsies.

Purpose To demonstrate the applicability of a growth modeling framework for quantifying spatial variations in geographic atrophy (GA) lesion kinetics. Methods Thirty-eight eyes from 27 patients with GA secondary to age-related macular degeneration were imaged with a commercial swept source optical coherence tomography instrument at two visits separated by 1 year. Local GA growth rates were computed at 6-µm intervals along each lesion margin using a previously described growth model. Corresponding margin eccentricities, margin angles, and growth angles were also computed. The average GA growth rates conditioned on margin eccentricity, margin angle, growth angle, and fundus position were estimated via kernel regression. Results A total of 88,356 GA margin points were analyzed. The average GA growth rates exhibited a hill-shaped dependency on eccentricity, being highest in the 0.5 mm to 1.6 mm range and lower on either side of that range. Average growth rates were also found to be higher for growth trajectories oriented away from (smaller growth angle), rather than toward (larger growth angle), the foveal center. The dependency of average growth rate on margin angle was less pronounced, although lesion segments in the superior and nasal aspects tended to grow faster. Conclusions Our proposed growth modeling framework seems to be well-suited for generating accurate, spatially resolved GA growth rate atlases and should be confirmed on larger datasets. Translational Relevance Our proposed growth modeling framework may enable more accurate measurements of spatial variations in GA growth rates.

Purpose To develop geometric perfusion deficits (GPD), an optical coherence tomography angiography (OCTA) biomarker based on oxygen diffusion, and to evaluate its utility in a pilot study of healthy subjects and patients with diabetic retinopathy (DR). Design Retrospective cross-sectional study. Methods Commercial spectral-domain optical coherence tomography angiography (OCTA) instruments were used to acquire repeated 3 × 3-mm2 and 6 × 6-mm2 motion-corrected macular OCTA volumes. En face OCTA images corresponding to the superficial capillary plexus (SCP), deep capillary plexus (DCP), and full retinal projections were obtained using automatic segmentation. For each projection, the GPD percentage and the vessel density percentage, the control metric, were computed, and their values were compared between the normal and DR eyes. The repeated OCTA acquisitions were used to assess the test-retest repeatability of the GPD and vessel density percentages. Results Repeated OCTA scans of 15 normal eyes and 12 DR eyes were obtained. For all en face projections, GPD percentages were significantly higher in DR eyes than in normal eyes; vessel density percentages were significantly lower in all but 1 projection (DCP). Large GPD areas were used to identify focal perfusion deficits. Test-retest analysis showed that the GPD percentage had superior repeatability than the vessel density percentage in most cases. A strong negative correlation between the GPD percentage and the vessel density percentage was also found. Conclusions Geometric perfusion deficits, an OCTA biomarker based on oxygen diffusion, provides a quantitative metric of macular microvascular remodeling with a strong physiological underpinning. The GPD percentage may serve as a useful biomarker for detecting and monitoring DR.

Optical coherence tomography angiography (OCTA) is a clinically promising modality to image retinal vasculature. For this end, optical coherence tomography (OCT) volumes are repeatedly scanned and intensity changes over time are used to compute OCTA images. Because of patient movement and variations in blood ow, OCTA data are prone to noise.

We propose a novel method for non-rigid 3-D motion correction of orthogonally raster-scanned optical coherence tomography angiography volumes. This is the first approach that aligns predominantly axial structural features like retinal layers and transverse angiographic vascular features in a joint optimization. Combined with the use of orthogonal scans and favorization of kinematically more plausible displacements, the approach allows subpixel alignment and micrometer-scale distortion correction in all 3 dimensions. As no specific structures or layers are segmented, the approach is by design robust to pathologic changes. It is furthermore designed for highly parallel implementation and brief runtime, allowing its integration in clinical routine even for high density or wide-field scans. We evaluated the algorithm with metrics related to clinically relevant features in a large-scale quantitative evaluation based on 204 volumetric scans of 17 subjects including both a wide range of pathologies and healthy controls. Using this method, we achieve state-of-the-art axial performance and show significant advances in both transverse co-alignment and distortion correction, especially in the pathologic subgroup., 22 pages, 11 figures, 4 tables

Optical coherence tomography angiography (OCTA) is a novel and clinically promising imaging modality to image retinal and sub-retinal vasculature. Based on repeated optical coherence tomography (OCT) scans, intensity changes are observed over time and used to compute OCTA image data. OCTA data are prone to noise and artifacts caused by variations in flow speed and patient movement. We propose a novel iterative maximum a posteriori signal recovery algorithm in order to generate OCTA volumes with reduced noise and increased image quality. This algorithm is based on previous work on probabilistic OCTA signal models and maximum likelihood estimates. Reconstruction results using total variation minimization and wavelet shrinkage for regularization were compared against an OCTA ground truth volume, merged from six co-registered single OCTA volumes. The results show a significant improvement in peak signal-to-noise ratio and structural similarity. The presented algorithm brings together OCTA image generation and Bayesian statistics and can be developed into new OCTA image generation and denoising algorithms., Comment: 14 pages, 4 figures, to be published in Biomedical Optics Express

Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations.

ObjectiveBarrett’s oesophagus (BE) screening outside the endoscopy suite can identify patients for surveillance and reduce mortality. Tethered capsule optical coherence tomography (OCT) can volumetrically image oesophageal mucosa in unsedated patients and detect features of BE. We investigated ultrahigh-speed tethered capsule swept-source OCT (SS-OCT), improved device design, developed procedural techniques and measured capsule contact, longitudinal pullback non-uniformity and patient toleration.DesignOCT was performed in 16 patients prior to endoscopic surveillance/treatment. Unsedated patients swallowed the capsule with sips of water and the tether was pulled back to image the oesophagus. SS-OCT at 1 000 000 A-scans/s enabled imaging 10 cm oesophageal lengths in 10 s with 30 µm transverse and 8 µm axial resolution. Capsule contact, longitudinal image coverage and patient toleration were assessed.ResultsNine patients had non-dysplastic BE, three had ablative treatment-naïve neoplasia and four had prior ablation for dysplasia. Dry swallows facilitated capsule transit through the lower oesophageal sphincter (LES), and waiting 10 s before pullback reduced swallow induced LES relaxation. Slow nasal inhalation facilitated capsule retrieval and minimised gag reflex. The procedure was well tolerated. Ultrahigh-speed SS-OCT generated cross-sectional and subsurface en face images showing BE features, while subsurface en face images were required to assess the gastro-oesophageal junction. Candidate features of dysplasia were also identified which could inform follow-up endoscopy/biopsy. BE features were seen in all patients with histologically confirmed BE. Mean capsule contact over BE was 75%±27% for all patients and better in short segment BE. Mean longitudinal image coverage over BE was 59%±34% and better for long segment BE.ConclusionsUltrahigh-speed tethered capsule SS-OCT can image en face and cross-sectional mucosal features over wide areas. Device and procedure optimisation improved performance. BE features could be identified in all patients, but limited capsule contact and longitudinal coverage could cause sampling errors for focal pathologies.

Copyright 2019 The Authors PURPOSE. To evaluate whether retinal capillary nonperfusion is found predominantly adjacent to arteries or veins in eyes with diabetic retinopathy (DR). METHODS. Sixty-three eyes from 44 patients with proliferative DR (PDR) or non-PDR (NPDR) were included. Images (12 3 12-mm) foveal-centered optical coherence tomography (OCT) angiography (OCTA) images were taken using the Zeiss Plex Elite 9000. In 37 eyes, widefield montages with five fixation points were also obtained. A semiautomatic algorithm that detects nonperfusion in full-retina OCT slabs was developed, and the percentages of capillary nonperfusion within the total image area were calculated. Retinal arteries and veins were manually traced. Based on the shortest distance, nonperfusion pixels were labeled as either arterial-side or venous-side. Arterial-adjacent and venous-adjacent nonperfusion and the A/V ratio (arterial-adjacent nonperfusion divided by venous-adjacent nonperfusion) were quantified. RESULTS. Twenty-two eyes with moderate NPDR, 16 eyes with severe NPDR, and 25 eyes with PDR were scanned. Total nonperfusion area in PDR (median: 8.93%) was greater than in moderate NPDR (3.49%, P < 0.01). Arterial-adjacent nonperfusion was greater than venous-adjacent nonperfusion for all stages of DR (P < 0.001). The median A/V ratios were 1.93 in moderate NPDR, 1.84 in severe NPDR, and 1.78 in PDR. The A/V ratio was negatively correlated with the total nonperfusion area (r ¼ -0.600, P < 0.0001). The results from the widefield montages showed similar patterns. CONCLUSIONS. OCTA images with arteries and veins traced allowed us to estimate the nonperfusion distribution. In DR, smaller nonperfusion tends to be arterial-adjacent, while larger nonperfusion tends toward veins.

We demonstrate the first 1050nm MEMS-eVCSEL co-packaged with a wideband amplifier to achieve over 70nm wavelength tuning at over 30mW of output power and SMSR greater than 40dB. Ophthalmic Optical Coherence Tomography Angiography (OCTA) images acquired at 800kHz A-scan rates showcase the telecom grade 14pin butterfly co-package as a path to low cost swept source OCT engines. Device design employs a strain-compensated InGaAs/GaAsP gain region disposed on a wideband fully oxidized GaAs/AlxOy back mirror capable of tuning ranges beyond 100nm. It has been suggested the wideband fully oxidized GaAs/AlxOy back mirror may pose risk to device lifetime reliability. However, over 9000hrs of lifetime testing validates reliability and projects device lifetimes exceed 20,000hrs under continuous use.

This study aimed to evaluate the use of ultrahigh-speed volumetric en face and cross-sectional optical coherence tomography (OCT) with micromotor catheters for the in vivo assessment of Barrett's esophagus and dysplasia.74 OCT datasets with correlated biopsy/endoscopic mucosal resection histology (49 nondysplastic Barrett's esophagus [NDBE], 25 neoplasia) were obtained from 14 patients with Barrett's esophagus and a history of dysplasia and 30 with NDBE. The associations between irregular mucosal patterns on en face OCT, absence of mucosal layering, surface signal subsurface, and 5 atypical glands on cross-sectional OCT vs. histology and treatment history were assessed by three blinded readers.Atypical glands under irregular mucosal patterns occurred in 75 % of neoplasia (96 % of treatment-naïve neoplasia) vs. 30 % of NDBE datasets (43 % of short- and 18 % of long-segment NDBE). Mucosal layering was absent in 35 % of neoplasia and 50 % of NDBE datasets, and surface signal subsurface occurred in 29 % of neoplasia and 30 % of NDBE datasets.Atypical glands under irregular mucosal patterns are strongly associated with neoplasia, suggesting potential markers for dysplasia and a role in pathogenesis.This study aimed to evaluate the use of ultrahigh-speed volumetric en face and cross-sectional optical coherence tomography (OCT) with micromotor catheters for the in vivo assessment of Barrett’s esophagus and dysplasia.74 OCT datasets with correlated biopsy/endoscopic mucosal resection histology (49 nondysplastic Barrett’s esophagus [NDBE], 25 neoplasia) were obtained from 14 patients with Barrett’s esophagus and a history of dysplasia and 30 with NDBE. The associations between irregular mucosal patterns on en face OCT, absence of mucosal layering, surface signal subsurface, and 5 atypical glands on cross-sectional OCT vs. histology and treatment history were assessed by three blinded readers.Atypical glands under irregular mucosal patterns occurred in 75 % of neoplasia (96 % of treatment-naïve neoplasia) vs. 30 % of NDBE datasets (43 % of short- and 18 % of long-segment NDBE). Mucosal layering was absent in 35 % of neoplasia and 50 % of NDBE datasets, and surface signal subsurface occurred in 29 % of neoplasia and 30 % of NDBE datasets.Atypical glands under irregular mucosal patterns are strongly associated with neoplasia, suggesting potential markers for dysplasia and a role in pathogenesis.

Optical coherence tomography (OCT) was one of the biggest advances in ophthalmic imaging. Building on that platform, OCT angiography (OCTA) provides depth resolved images of blood flow in the retina and choroid with levels of detail far exceeding that obtained with older forms of imaging. This new modality is challenging because of the need for new equipment and processing techniques, current limitations of imaging capability, and rapid advancements in both imaging and in our understanding of the imaging and applicable pathophysiology of the retina and choroid. These factors lead to a steep learning curve, even for those with a working understanding dye-based ocular angiography. All for a method of imaging that is a little more than 10 years old. This review begins with a historical account of the development of OCTA, and the methods used in OCTA, including signal processing, image generation, and display techniques. This forms the basis to understand what OCTA images show as well as how image artifacts arise. The anatomy and imaging of specific vascular layers of the eye are reviewed. The integration of OCTA in multimodal imaging in the evaluation of retinal vascular occlusive diseases, diabetic retinopathy, uveitis, inherited diseases, age-related macular degeneration, and disorders of the optic nerve is presented. OCTA is an exciting, disruptive technology. Its use is rapidly expanding in clinical practice as well as for research into the pathophysiology of diseases of the posterior pole.

The lamina cribrosa is a primary site of damage in glaucoma. While mechanical distortion is hypothesized to cause reduction of axoplasmic flow, little is known about how the pores, which contains the retinal ganglion cell axons, traverse the lamina cribrosa. We investigated lamina cribrosa pore paths in vivo to quantify differences in tortuosity of pore paths between healthy and glaucomatous eyes. We imaged 16 healthy, 23 glaucoma suspect and 48 glaucomatous eyes from 70 subjects using a swept source optical coherence tomography system. The lamina cribrosa pores were automatically segmented using a previously described segmentation algorithm. Individual pore paths were automatically tracked through the depth of the lamina cribrosa using custom software. Pore path convergence to the optic nerve center and tortuosity was quantified for each eye. We found that lamina cribrosa pore pathways traverse the lamina cribrosa closer to the optic nerve center along the depth of the lamina cribrosa regardless of disease severity or diagnostic category. In addition, pores of glaucoma eyes take a more tortuous path through the lamina cribrosa compared to those of healthy eyes, suggesting a potential mechanism for reduction of axoplasmic flow in glaucoma.

Up to 40% of patients undergoing breast conserving surgery for breast cancer require repeat surgeries due to close to or positive margins. The lengthy processing required for evaluating surgical margins by standard paraffin-embedded histology precludes its use during surgery and therefore, technologies for rapid evaluation of surgical pathology could improve the treatment of breast cancer by reducing the number of surgeries required. We demonstrate real-time histological evaluation of breast cancer surgical specimens by staining specimens with acridine orange (AO) and sulforhodamine 101 (SR101) analogously to hematoxylin and eosin (H&E) and then imaging the specimens with fluorescence nonlinear microscopy (NLM) using a compact femtosecond fiber laser. A video-rate computational light absorption model was used to produce realistic virtual H&E images of tissue in real time and in three dimensions. NLM imaging could be performed to depths of 100 μm below the tissue surface, which is important since many surgical specimens require subsurface evaluation due to contamination artifacts on the tissue surface from electrocautery, surgical ink, or debris from specimen handling. We validate this method by expert review of NLM images compared to formalin-fixed, paraffin-embedded (FFPE) H&E histology. Diagnostically important features such as normal terminal ductal lobular units, fibrous and adipose stromal parenchyma, inflammation, invasive carcinoma, and in situ lobular and ductal carcinoma were present in NLM images associated with pathologies identified on standard FFPE H&E histology. We demonstrate that AO and SR101 were extracted to undetectable levels after FFPE processing and fluorescence in situ hybridization (FISH) HER2 amplification status was unaffected by the NLM imaging protocol. This method potentially enables cost-effective, real-time histological guidance of surgical resections.

Glaucoma is a leading cause of blindness that leads to characteristic changes in the optic nerve head (ONH) region, such as nasalization of vessels. It is unknown whether the spatial location of this vessel shift inside the ONH occurs within the lamina cribrosa (LC) or the prelaminar tissue. The purpose of this study was to compare the location of the central retinal vessel trunk (CRVT) in the LC and prelaminar tissue in living healthy and glaucomatous eyes. We acquired 3-dimensional ONH scans from 119 eyes (40 healthy, 29 glaucoma suspect, and 50 glaucoma) using optical coherence tomography (OCT). The CRVT location was manually delineated in separate projection images of the LC and prelamina. We found that the CRVT in glaucoma suspect and glaucomatous eyes was located significantly more nasally compared to healthy eyes at the level of the prelamina. There was no detectable difference found in the location of the CRVT at the level of the LC between diagnostic groups. While the nasal location of the CRVT in the prelamina has been associated with glaucomatous axonal death, our results suggest that the CRVT in the LC is anchored in the tissue with minimal variation in glaucomatous eyes.

Background Lipid-rich plaque (LRP) is thought to be a precursor to cardiac events. However, its clinical significance in coronary arteries has never been systematically investigated. Objectives This study investigated the prevalence and clinical significance of LRP in the nonculprit region of the target vessel in patients undergoing percutaneous coronary intervention (PCI). Methods The study included 1,474 patients from 20 sites across 6 countries undergoing PCI, who had optical coherence tomography (OCT) imaging of the target vessel. Major adverse cardiac events (MACE) were defined as a composite of cardiac death, acute myocardial infarction, and ischemia-driven revascularization. Patients were followed for up to 4 years (median of 2 years). Results Lipid-rich plaque was detected in nonculprit regions of the target vessel in 33.6% of patients. The cumulative rate of nonculprit lesion-related MACE (NC-MACE) over 48 months in patients with LRP was higher than in those without LRP (7.2% vs. 2.6%, respectively; p = 0.033). Acute coronary syndrome at index presentation (risk ratio: 2.538; 95% confidence interval [CI]: 1.246 to 5.173; p = 0.010), interruption of statin use ≥1 year (risk ratio: 4.517; 95% CI: 1.923 to 10.610; p = 0.001), and LRP in nonculprit regions (risk ratio: 2.061; 95% CI: 1.050 to 4.044; p = 0.036) were independently associated with increased NC-MACE. Optical coherence tomography findings revealed that LRP in patients with NC-MACE had longer lipid lengths (p Conclusions Presence of LRP in the nonculprit regions of the target vessel by OCT predicts increased risk for future NC-MACE, which is primarily driven by revascularization for recurrent ischemia. Lipid-rich plaque with longer lipid length, wider lipid arc, and higher degree of stenosis identified patients at higher risk of future cardiac events. (The Massachusetts General Hospital Optical Coherence Tomography Registry; NCT01110538 )

Purpose To evaluate tumor vasculature with optical coherence tomography angiography (OCTA) in malignant iris melanomas and benign iris lesions. Design Cross-sectional observational clinical study. Participants Patients with iris lesions and healthy volunteers. Methods Eyes were imaged using OCTA systems operating at 1050- and 840-nm wavelengths. Three-dimensional OCTA scans were acquired. Iris melanoma patients treated with radiation therapy were imaged again after I-125 plaque brachytherapy at 6 and 18 months. Main Outcome Measures OCT and OCTA images, qualitative evaluation of iris and tumor vasculature, and quantitative vessel density. Results One eye each of 8 normal volunteers and 9 patients with iris melanomas or benign iris lesions, including freckles, nevi, and an iris pigment epithelial (IPE) cyst, were imaged. The normal iris has radially oriented vessels within the stroma on OCTA. Penetration of flow signal in normal iris depended on iris color, with best penetration seen in light to moderately pigmented irides. Iris melanomas demonstrated tortuous and disorganized intratumoral vasculature. In 2 eyes with nevi there was no increased vascularity; in another, fine vascular loops were noted near an area of ectropion uveae. Iris freckles and the IPE cyst did not have intrinsic vascularity. The vessel density was significantly higher within iris melanomas (34.5%±9.8%, P < 0.05) than in benign iris nevi (8.0%±1.4%) or normal irides (8.0%±1.2%). Tumor regression after radiation therapy for melanomas was associated with decreased vessel density. OCTA at 1050 nm provided better visualization of tumor vasculature and penetration through thicker tumors than at 840 nm. But in very thick tumors and highly pigmented lesions even 1050-nm OCTA could not visualize their full thickness. Interpretable OCTA images were obtained in 82% of participants in whom imaging was attempted. Conclusions This is the first demonstration of OCTA in iris tumors. OCTA may provide a dye-free, no-injection, cost-effective method for monitoring a variety of tumors, including iris melanocytic lesions, for growth and vascularity. This could be helpful in evaluating tumors for malignant transformation and response to treatment. Penetration of the OCT beam remains a limitation for highly pigmented tumors, as does the inability to image the entire iris in a single field., National Institutes of Health (U.S.) (Grants R01 EY023285, R01 EY024544, R01 EY018184, DP3 DK104397, UL1TR000128, and P30 EY010572

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. Purpose:To map and measure the depths of corneal neovascularization (NV) using 3-dimensional optical coherence tomography angiography (OCTA) at 2 different wavelengths.Methods:Corneal NV of varying severity, distribution, and underlying etiology was examined. Average NV depth and vessel density were measured using 840-nm spectral-domain OCTA and 1050-nm swept-source OCTA. The OCTA results were compared with clinical slit-lamp estimation of NV depth.Results:Twelve eyes with corneal NV from 12 patients were imaged with OCTA. Clinically "superficial," "midstromal," and "deep" cases had an average vessel depth of 23%, 39%, and 66% on 1050-nm OCTA, respectively. Average vessel depth on OCTA followed a statistically significant ordinal trend according to the clinical classification of vessel depth (Jonckheere-Terpstra test, P < 0.001). In 8 cases where both 840-nm OCTA and 1050-nm OCTA were acquired, there was excellent agreement in the mean vessel depth between the 2 systems (concordance correlation coefficient = 0.94, P < 0.001). The average vessel density measured by 840-nm OCTA was higher (average 1.6-fold) than that measured by 1050-nm OCTA.Conclusions:Corneal OCTA was able to map corneal NV in 3 dimensions and measure vessel depth and density. The depth of corneal NV varied between different pathologies in a manner consistent with previous pathologic studies. The measured vessel density appeared to be affected by the interscan time, which affects blood flow velocity sensitivity, and the wavelength, which affects the ability to penetrate through opacity. These findings suggest possible clinical applications of OCTA for the diagnosis of corneal pathology and quantitative monitoring of therapeutic response in patients with corneal NV.

Optical coherence tomography angiography (OCTA) is an increasingly popular modality for imaging of the retinal vasculature. Repeated optical coherence tomography (OCT) scans of the retina allow the computation of motion contrast to display the retinal vasculature. To the best of our knowledge, we present the first application of compressed sensing for the generation of OCTA volumes. Using a probabilistic signal model for the computation of OCTA volumes and a 3D median filter, it is possible to perform compressed sensing reconstruction of OCTA volumes while suppressing noise. The presented approach was tested on a ground truth, averaged from ten individual OCTA volumes. Average reductions of the mean squared error of 9:67% were achieved when comparing reconstructed OCTA images to the stand-alone application of a 3D median filter.

Eye movements, blinking and other motion during the acquisition of optical coherence tomography (OCT) can lead to artifacts, when processed to OCT angiography (OCTA) images. Affected scans emerge as high intensity (white) or missing (black) regions, resulting in lost information. The aim of this research is to fill these gaps using a deep generative model for OCT to OCTA image translation relying on a single intact OCT scan. Therefore, a U-Net is trained to extract the angiographic information from OCT patches. At inference, a detection algorithm finds outlier OCTA scans based on their surroundings, which are then replaced by the trained network. We show that generative models can augment the missing scans. The augmented volumes could then be used for 3-D segmentation or increase the diagnostic value.

Point-wise scanning modalities like Optical Coherence Tomography (OCT) or Scanning Laser Ophthalmoscopy suffer from distortions due to the perpetual motion of the eye. While various motion correction approaches have been proposed, the absence of ground truth displacements or images entails a lack of accurate and comparable evaluations. The purpose of this paper is to close this gap by initiating an open source framework for the simulation of realistic eye motion and corresponding artificial distortion of scans, thereby for the first time enabling the community to a) create datasets with accessible ground truth and b) compare the correction of identical motion patterns in data acquired with different scanners or scan patterns. This paper extends previous work on simulation of fixational eye drift via a self-avoiding random walk in a potential to a continuous domain in time and space, allowing the derivation of smooth displacement fields. The model is demonstrated by presenting an examplary motion path, whose properties resemble reported properties of recordings in current literature on fixational eye motion. Furthermore, the artificial distortion of scans is demonstrated by showing a correspondingly distorted image of a virtual raster scan modeled according to the properties of an existing OCT scanner. All experiments can be reproduced and adapted to arbitrary scanner- and raster scan pattern-properties in the publicly available framework. Beyond that, the open source code provides a starting point for the community to integrate extensions like saccadic or axial eye motion.

Fundus photography and Optical Coherence Tomography Angiography (OCT-A) are two commonly used modalities in ophthalmic imaging. With the development of deep learning algorithms, fundus image processing, especially retinal vessel segmentation, has been extensively studied. Built upon the known operator theory, interpretable deep network pipelines with well-defined modules have been constructed on fundus images. In this work, we firstly train a modularized network pipeline for the task of retinal vessel segmentation on the fundus database DRIVE. The pretrained preprocessing module from the pipeline is then directly transferred onto OCT-A data for image quality enhancement without further fine-tuning. Output images show that the preprocessing net can balance the contrast, suppress noise and thereby produce vessel trees with improved connectivity in both image modalities. The visual impression is confirmed by an observer study with five OCT-A experts. Statistics of the grades by the experts indicate that the transferred module improves both the image quality and the diagnostic quality. Our work provides an example that modules within network pipelines that are built upon the known operator theory facilitate cross-modality reuse without additional training or transfer learning.

Optical coherence tomography (OCT) enables cross-sectional, volumetric, and functional imaging of internal microstructure and pathology in biological tissues. OCT can perform an “optical biopsy”, imaging pathology in situ and in real time without the need for excisional biopsy. OCT imaging has become a standard of care in ophthalmology and is an emerging imaging modality in cardiology, dermatology, gastroenterology and other specialties where it provides information that often cannot be obtained by any other means. This chapter reviews the early history of OCT development with an emphasis on basic concepts and the process of technology translation. Early OCT technology and catheter imaging devices as well as advances in imaging speed using swept source/Fourier domain detection are reviewed. The process of clinical translation, beginning with ex vivo imaging and histology, preclinical animal studies and progressing to clinical studies in patients is discussed. The history of commercial intravascular OCT development is also summarized.

This paper introduces an universal and structure-preserving regularization term, called quantile sparse image (QuaSI) prior. The prior is suitable for denoising images from various medical imaging modalities. We demonstrate its effectiveness on volumetric optical coherence tomography (OCT) and computed tomography (CT) data, which show different noise and image characteristics. OCT offers high-resolution scans of the human retina but is inherently impaired by speckle noise. CT on the other hand has a lower resolution and shows high-frequency noise. For the purpose of denoising, we propose a variational framework based on the QuaSI prior and a Huber data fidelity model that can handle 3-D and 3-D+t data. Efficient optimization is facilitated through the use of an alternating direction method of multipliers (ADMM) scheme and the linearization of the quantile filter. Experiments on multiple datasets emphasize the excellent performance of the proposed method., Accepted for MICCAI2017 special issue

Background Healed plaques, the signature of prior subclinical plaque destabilization, are frequently found in autopsy studies and have recently been described in patients with acute coronary syndromes (ACS). Objectives To compare the prevalence and features of plaque vulnerability of healed culprit lesions in stable angina pectoris (SAP) versus ACS patients by using Optical Coherence Tomography (OCT). Methods A total of 752 patients were included: 376 patients with SAP were selected using propensity score matching, comparable to 376 patients with ACS. Healed plaques were identified using established criteria, defined as layers of different optical density on OCT. Healed plaque prevalence along with angiographic and OCT findings were compared between the two groups. Results Healed plaques were more frequent in SAP than in ACS patients (42.0% vs 28.7%, p Conclusions Healed plaques, detected more frequently in SAP than in ACS patients, portend different atherosclerotic backgrounds. In SAP patients, plaque destabilization frequently does not lead to occlusive thrombosis, possibly due to low level of local vulnerability and systemic inflammation. In ACS patients, the presence of high level of local vulnerability and systemic inflammation may play an important role in occlusive thrombus formation, resulting in terminating the cycles of subclinical thrombosis and healing.

Purpose: To develop high-speed, extended-range, ultrahigh-resolution spectraldomain optical coherence tomography (UHR SD-OCT) and demonstrate scan protocols for clinical retinal imaging. Methods: A UHR SD-OCT operating at 840-nm with 150-nm bandwidths was developed. The axial imaging range was extended by dynamically matching reference arm length to the retinal contour during acquisition. Two scan protocols were demonstrated for imaging healthy participants and patients with dry age-related macular degeneration. A high-definition raster protocol with intra–B-scan reference arm length matching (ReALM) was used for high-quality cross-sectional imaging. A cube volume scan using horizontal and vertical rasters with inter–B-scan ReALM and software motion correction was used for en face and cross-sectional imaging. Linear OCT signal display enhanced visualization of outer retinal features. Results: UHR SD-OCT was demonstrated at 128-and 250-kHz A-scan rates with 2.7 μm axial resolution and a 1.2-mm, 6-dB imaging range in the eye. Dynamic ReALM was used to maintain the retina within the 6-dB imaging range over wider fields of view. Outer retinal features, including the rod and cone interdigitation zones, retinal pigment epithelium, and Bruch’s membrane were visualized and alterations observed in agerelated macular degeneration eyes. Conclusions: Technological advances and dynamic ReALM improve the imaging performance and clinical usability of UHR SD-OCT. Translational Relevance: These advances should simplify clinical imaging workflow, reduce imaging session times, and improve yield of high quality images. Improved visualization of photoreceptors, retinal pigment epithelium, and Bruch’s membrane may facilitate diagnosis and monitoring of age-related macular degeneration and other retinal diseases., National Institutes of Health (U.S.) (Grant 5-R01-EY011289-33), United States. Air Force. Office of Scientific Research (Grant FA9550-15-1-0473)