Visualization of Cataract Surgery Steps With 4D Microscope-Integrated Swept-Source Optical Coherence Tomography in Ex Vivo Porcine Eyes.

Purpose: To investigate the visualization capabilities of high-speed swept-source optical coherence tomography (SS-OCT) in cataract surgery. Methods: Cataract surgery was simulated in wet labs with ex vivo porcine eyes. Each phase of the surgery was visualized with a novel surgical microscope-integrated SS-OCT with a variable imaging speed of over 1 million A-scans per second. It was designed to provide four-dimensional (4D) live-volumetric videos, live B-scans, and volume capture scans. Results: Four-dimensional videos, B-scans, and volume capture scans of corneal incision, ophthalmic viscosurgical device injection, capsulorrhexis, phacoemulsification, intraocular lens (IOL) injection, and position of unfolded IOL in the capsular bag were recorded. The flexibility of the SS-OCT system allowed us to tailor the scanning parameters to meet the specific demands of dynamic surgical steps and static pauses. The entire length of the eye was recorded in a single scan, and unfolding of the IOL was visualized dynamically. Conclusions: The presented novel visualization method for fast ophthalmic surgical microscope-integrated intraoperative OCT imaging in cataract surgery allowed the visualization of all major steps of the procedure by achieving large imaging depths covering the entire eye and high acquisition speeds enabling live volumetric 4D-OCT imaging. This promising technology may become an integral part of routine and advanced robotic-assisted cataract surgery in the future. Translational Relevance: We demonstrate the visualization capabilities of a cutting edge swept-source OCT system integrated into an ophthalmic surgical microscope during cataract surgery.

Microaneurysm detection using high-speed megahertz optical coherence tomography angiography in advanced diabetic retinopathy.

PURPOSE: To compare detection rates of microaneurysms (MAs) on high-speed megahertz optical coherence tomography angiography (MHz-OCTA), fluorescein angiography (FA) and colour fundus photography (CF) in patients with diabetic retinopathy (DR). METHODS: For this exploratory cross-sectional study, MHz-OCTA data were acquired with a swept-source OCT prototype (A-scan rate: 1.7 MHz), and FA and CF imaging was performed using Optos® California. MA count was manually evaluated on en face MHz-OCTA/FA/CF images within an extended ETDRS grid. Detectability of MAs visible on FA images was evaluated on corresponding MHz-OCTA and CF images. MA distribution and leakage were correlated with detectability on OCTA and CF imaging. RESULTS: 47 eyes with severe DR (n = 12) and proliferative DR (n = 35) were included. MHz-OCTA and CF imaging detected on average 56% and 36% of MAs, respectively. MHz-OCTA detection rate was significantly higher than CF (p < 0.01). The combination of MHz-OCTA and CF leads to an increased detection rate of 70%. There was no statistically significant association between leakage and MA detectability on OCTA (p = 0.13). For CF, the odds of detecting leaking MAs were significantly lower than non-leaking MAs (p = 0.012). Using MHz-OCTA, detection of MAs outside the ETDRS grid was less likely than MAs located within the ETDRS grid (outer ring, p < 0.01; inner ring, p = 0.028). No statistically significant difference between rings was observed for CF measurements. CONCLUSIONS: More MAs were detected on MHz-OCTA than on CF imaging. Detection rate was lower for MAs located outside the macular region with MHz-OCTA and for leaking MAs with CF imaging. Combining both non-invasive modalities can improve MA detection.

Association of Diabetic Lesions and Retinal Nonperfusion Using Widefield Multimodal Imaging.

PURPOSE: To evaluate the association of microvascular lesions on ultrawidefield (UWF) color fundus (CF) images with retinal nonperfusion (RNP) up to the midperiphery on single-capture widefield (WF) OCT angiography (OCTA) in patients with diabetic retinopathy (DR). DESIGN: Cross-sectional study. SUBJECTS: Seventy-five eyes of 50 patients with mild to severe nonproliferative DR (NPDR) and proliferative DR (PDR) were included in this analysis. METHODS: ETDRS level and presence of predominantly peripheral lesions (PPLs) were assessed on UWF-CF images acquired with a Zeiss Clarus 700. Single-capture 65°-WF-OCTA was performed using a PlexElite prototype (Carl Zeiss Meditec, Inc.). A custom grid consisting of a central ETDRS grid extended by 2 rings reaching up to the midperiphery was overlaid to subdivide retinal areas visible on WF-OCTA en face images. Retinal nonperfusion was measured in each area and in total. Nonperfusion index (NPI) was calculated from total RNP. On UWF-CF images, the number of microaneurysms, hemorrhages, neovascularizations, and areas with intraretinal microvascular abnormalities (IRMAs) were evaluated using the same grid. MAIN OUTCOME MEASURES: Association of diabetic lesions with RNP was calculated using Spearman correlations (rs). RESULTS: Median RNP on WF-OCTA was 0 mm2 (0-0.9), 4.9 mm2 (1.9-5.4), 23.4 mm2 (17.8-37), and 68.4 mm2 (40.8-91.7) in mild, moderate, and severe NPDR and PDR, respectively. We found a statistically significant correlation (P < 0.01) of overall RNP (rs = 0.96,) and NPI (rs = 0.97) on WF-OCTA with ETDRS level. Number of grid-fields affected by IRMAs on CF images was highly associated with NPI (rs = 0.86, P < 0.01). Intraretinal microvascular abnormalities and RNPs had similar topographic distributions with high correlations in affected areas. Eyes with PPLs (n = 43 eyes, 57%) on CF images had a significantly higher NPI (P = 0.014) than eyes without PPLs. CONCLUSION: The combination of UWF-CF imaging and single-capture WF-OCTA allows precise and noninvasive analysis of the retinal vasculature up to the midperiphery in patients with DR. The presence and extent of IRMAs on CF images may serve as an indicator for underlying RNP, which is more pronounced in eyes with PPLs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Multiple instance learning based classification of diabetic retinopathy in weakly-labeled widefield OCTA en face images.

Diabetic retinopathy (DR), a pathologic change of the human retinal vasculature, is the leading cause of blindness in working-age adults with diabetes mellitus. Optical coherence tomography angiography (OCTA), a functional extension of optical coherence tomography, has shown potential as a tool for early diagnosis of DR through its ability to visualize the retinal vasculature in all spatial dimensions. Previously introduced deep learning-based classifiers were able to support the detection of DR in OCTA images, but require expert labeling at the pixel level, a labor-intensive and expensive process. We present a multiple instance learning-based network, MIL-ResNet,14 that is capable of detecting biomarkers in an OCTA dataset with high accuracy, without the need for annotations other than the information whether a scan is from a diabetic patient or not. The dataset we used for this study was acquired with a diagnostic ultra-widefield swept-source OCT device with a MHz A-scan rate. We were able to show that our proposed method outperforms previous state-of-the-art networks for this classification task, ResNet14 and VGG16. In addition, our network pays special attention to clinically relevant biomarkers and is robust against adversarial attacks. Therefore, we believe that it could serve as a powerful diagnostic decision support tool for clinical ophthalmic screening.

Live 4D-OCT denoising with self-supervised deep learning.

By providing three-dimensional visualization of tissues and instruments at high resolution, live volumetric optical coherence tomography (4D-OCT) has the potential to revolutionize ophthalmic surgery. However, the necessary imaging speed is accompanied by increased noise levels. A high data rate and the requirement for minimal latency impose major limitations for real-time noise reduction. In this work, we propose a low complexity neural network for denoising, directly incorporated into the image reconstruction pipeline of a microscope-integrated 4D-OCT prototype with an A-scan rate of 1.2 MHz. For this purpose, we trained a blind-spot network on unpaired OCT images using a self-supervised learning approach. With an optimized U-Net, only a few milliseconds of additional latency were introduced. Simultaneously, these architectural adaptations improved the numerical denoising performance compared to the basic setup, outperforming non-local filtering algorithms. Layers and edges of anatomical structures in B-scans were better preserved than with Gaussian filtering despite comparable processing time. By comparing scenes with and without denoising employed, we show that neural networks can be used to improve visual appearance of volumetric renderings in real time. Enhancing the rendering quality is an important step for the clinical acceptance and translation of 4D-OCT as an intra-surgical guidance tool.

Surgical microscope integrated MHz SS-OCT with live volumetric visualization.

Intraoperative optical coherence tomography is still not overly pervasive in routine ophthalmic surgery, despite evident clinical benefits. That is because today's spectral-domain optical coherence tomography systems lack flexibility, acquisition speed, and imaging depth. We present to the best of our knowledge the most flexible swept-source optical coherence tomography (SS-OCT) engine coupled to an ophthalmic surgical microscope that operates at MHz A-scan rates. We use a MEMS tunable VCSEL to implement application-specific imaging modes, enabling diagnostic and documentary capture scans, live B-scan visualizations, and real-time 4D-OCT renderings. The technical design and implementation of the SS-OCT engine, as well as the reconstruction and rendering platform, are presented. All imaging modes are evaluated in surgical mock maneuvers using ex vivo bovine and porcine eye models. The applicability and limitations of MHz SS-OCT as a visualization tool for ophthalmic surgery are discussed.

Detection of diabetic neovascularisation using single-capture 65°-widefield optical coherence tomography angiography.

AIM: To assess the detection rate of retinal neovascularisation (NV) in eyes with proliferative diabetic retinopathy (PDR) using widefield optical coherence tomography angiography (WF-OCTA) in comparison to ultrawidefield fluorescein angiography (UWF-FA). METHODS: Single-capture 65°-WF-OCTA-imaging was performed in patients with NV at the disc or elsewhere (NVE) detected on UWF-FA using a modified PlexElite system and B-scans were examined for blood flow signals breaching the internal limiting membrane. Sensitivity of WF-OCTA and UWF colour fundus (UWF-CF) photography for correct diagnosis of PDR was determined and interdevice agreement (Fleiss' κ) between WF-OCTA and UWF-FA for detection of NV in the total gradable area and each retinal quadrant was evaluated. RESULTS: Fifty-nine eyes of 41 patients with PDR detected on UWF-FA were included. Sensitivity of detecting PDR on WF-OCTA scans was 0.95 in contrast to 0.78 on UWF-CF images. Agreement in detecting NVE between WF-OCTA and UWF-FA was high in the superotemporal (κ=0.98) and inferotemporal (κ=0.94) and weak in the superonasal (κ=0.24) and inferonasal quadrants (κ=0.42). On UWF-FA, 63% of NVEs (n=153) were located in the temporal quadrants with 93% (n=142) of them being detected on WF-OCTA scans. CONCLUSION: The high reliability of non-invasive WF-OCTA imaging in detecting PDR can improve clinical examination with the potential to replace FA as a single diagnostic tool.

Enhanced medical diagnosis for dOCTors: a perspective of optical coherence tomography.

SIGNIFICANCE: After three decades, more than 75,000 publications, tens of companies being involved in its commercialization, and a global market perspective of about USD 1.5 billion in 2023, optical coherence tomography (OCT) has become one of the fastest successfully translated imaging techniques with substantial clinical and economic impacts and acceptance. AIM: Our perspective focuses on disruptive forward-looking innovations and key technologies to further boost OCT performance and therefore enable significantly enhanced medical diagnosis. APPROACH: A comprehensive review of state-of-the-art accomplishments in OCT has been performed. RESULTS: The most disruptive future OCT innovations include imaging resolution and speed (single-beam raster scanning versus parallelization) improvement, new implementations for dual modality or even multimodality systems, and using endogenous or exogenous contrast in these hybrid OCT systems targeting molecular and metabolic imaging. Aside from OCT angiography, no other functional or contrast enhancing OCT extension has accomplished comparable clinical and commercial impacts. Some more recently developed extensions, e.g., optical coherence elastography, dynamic contrast OCT, optoretinography, and artificial intelligence enhanced OCT are also considered with high potential for the future. In addition, OCT miniaturization for portable, compact, handheld, and/or cost-effective capsule-based OCT applications, home-OCT, and self-OCT systems based on micro-optic assemblies or photonic integrated circuits will revolutionize new applications and availability in the near future. Finally, clinical translation of OCT including medical device regulatory challenges will continue to be absolutely essential. CONCLUSIONS: With its exquisite non-invasive, micrometer resolution depth sectioning capability, OCT has especially revolutionized ophthalmic diagnosis and hence is the fastest adopted imaging technology in the history of ophthalmology. Nonetheless, OCT has not been completely exploited and has substantial growth potential-in academics as well as in industry. This applies not only to the ophthalmic application field, but also especially to the original motivation of OCT to enable optical biopsy, i.e., the in situ imaging of tissue microstructure with a resolution approaching that of histology but without the need for tissue excision.

Holographic line field en-face OCT with digital adaptive optics in the retina in vivo.

We demonstrate a high-resolution line field en-face time domain optical coherence tomography (OCT) system using an off-axis holography configuration. Line field en-face OCT produces high speed en-face images at rates of up to 100 Hz. The high frame rate favors good phase stability across the lateral field-of-view which is indispensable for digital adaptive optics (DAO). Human retinal structures are acquired in-vivo with a broadband light source at 840 nm, and line rates of 10 kHz to 100 kHz. Structures of different retinal layers, such as photoreceptors, capillaries, and nerve fibers are visualized with high resolution of 2.8 µm and 5.5 µm in lateral directions. Subaperture based DAO is successfully applied to increase the visibility of cone-photoreceptors and nerve fibers. Furthermore, en-face Doppler OCT maps are generated based on calculating the differential phase shifts between recorded lines.

Demonstration of Shot-noise-limited Swept Source OCT Without Balanced Detection.

Optical coherence tomography (OCT) has been utilized in a rapidly growing number of clinical and scientific applications. In particular, swept source OCT (SS-OCT) has attracted many attentions due to its excellent performance. So far however, the limitations of existing photon detectors have prevented achieving shot-noise-limited sensitivity without using balanced-detection scheme in SS-OCT, even when superconducting single-photon detectors were used. Unfortunately, balanced-detection increases OCT system size and cost, as it requires many additional components to boost the laser power and maintain near ideal balanced performance across the whole optical bandwidth. Here we show for the first time that a photon detector is capable of achieving shot noise limited performance without using the balanced-detection technique in SS-OCT. We built a system using a so-called electron-injection photodetector, with a cutoff-wavelength of 1700 nm. Our system achieves a shot-noise-limited sensitivity of about -105 dB at a reference laser power of ~350 nW, which is more than 30 times lower laser power compared with the best-reported results. The high sensitivity of the electron-injection detector allows utilization of micron-scale tunable laser sources (e.g. VCSEL) and eliminates the need for fiber amplifiers and highly precise couplers, which are an essential part of the conventional SS-OCT systems.

Line-field parallel swept source MHz OCT for structural and functional retinal imaging.

We demonstrate three-dimensional structural and functional retinal imaging with line-field parallel swept source imaging (LPSI) at acquisition speeds of up to 1 MHz equivalent A-scan rate with sensitivity better than 93.5 dB at a central wavelength of 840 nm. The results demonstrate competitive sensitivity, speed, image contrast and penetration depth when compared to conventional point scanning OCT. LPSI allows high-speed retinal imaging of function and morphology with commercially available components. We further demonstrate a method that mitigates the effect of the lateral Gaussian intensity distribution across the line focus and demonstrate and discuss the feasibility of high-speed optical angiography for visualization of the retinal microcirculation.

Line-field parallel swept source interferometric imaging at up to 1 MHz.

We present a novel medical imaging modality based on optical coherence tomography (OCT) that enables in vivo 3D tomography at acquisition rates up to 1 MHz. Line field parallel swept source interferometric imaging (LPSI) combines line-field swept source OCT with modulation of the interferometric signal in spatial direction for full range imaging. This method enables high speed imaging with cost-effective and commercially available technology. We explain the realization of the LPSI setup, acquisition, and postprocessing and finally demonstrate 3D in vivo imaging of human nail fold. To the best of our knowledge, sensitivity and depth penetration are competitive with respective point scanning OCT methods at a comparable wavelength. Measured maximum sensitivity is 98.5 dB for 100 kHz and 90 dB for 1 MHz. Together with the significantly relaxed technological requirements regarding detection and swept source technology, LPSI might be a promising concept for future diagnostic OCT imaging.

Measuring pulse-induced natural relative motions within human ocular tissue in vivo using phase-sensitive optical coherence tomography.

We use phase-sensitive optical coherence tomography to measure relative motions within the human eye. From a sequence of tomograms, the phase difference between successive tomograms reveals the local axial motion of the tissue at every location within the image. The pulsation of the retina and of the lamina cribrosa amounts to, at most, a few micrometers per second, while the bulk velocity of the eye, even with the head resting in an ophthalmic instrument, is a few orders of magnitude faster. The bulk velocity changes continuously as the tomograms are acquired, whereas localized motions appear at acquisition times determined by the repeated scan of the tomogram. This difference in timing allows the bulk motion to be separated from any localized motions within a temporal bandwidth below the tomogram frame rate. In the human eye, this reveals a map of relative motions with a precision of a few micrometers per second.

Measurement of tear film thickness using ultrahigh-resolution optical coherence tomography.

PURPOSE: To visualize the precorneal tear film with ultrahigh-resolution spectral domain optical coherence tomography, enabling quantification of tear film thickness in healthy subjects. METHODS: A custom-built spectral domain optical coherence tomography system comprising a broadband titanium:sapphire laser operating at 800 nm and a high-speed charge coupled device (CCD) camera with a read-out rate of 47 kHz was used for measurement of precorneal tear film thickness. The system provides a theoretical axial resolution of 1.2 µm in tissue. The signal-to-noise ratio close to the zero delay was measured with 94 dB. A total of 26 healthy subjects were included in this study. Measurement was started immediately after blinking and averaged over a period of 1 second. In a subset of eight healthy subjects, the reproducibility of the approach was studied by measuring the tear film thickness every 10 minutes over 1 hour. RESULTS: The average central tear film thickness of the measured population was 4.79 ± 0.88 µm. Reproducibility was very high, with an intraclass correlation coefficient of 0.97. A breakup of the tear film was observed in one subject after 14 seconds. CONCLUSIONS: Our data indicate that the human precorneal tear film can be measured with excellent reproducibility using ultrahigh-resolution optical coherence tomography. This technique may be a valuable tool in the management of dry eye syndrome.

Heart-beat-phase-coherent Doppler optical coherence tomography for measuring pulsatile ocular blood flow.

We introduce a Doppler OCT (DOCT) platform that is fully synchronized with the heart-beat via a pulse oximeter. The system allows reconstructing heart-beat-phase-coherent quantitative DOCT volumes. The method is to acquire a series of DOCT volumes and to record the pulse in parallel. The heartbeat data is used for triggering the start of each DOCT volume acquisition. The recorded volume series is registered to the level of capillaries using a cross-volume registration. The information of the pulse phase is used to rearrange the tomograms in time, to obtain a series of phase coherent DOCT volumes over a pulse. We present Doppler angle independent quantitative evaluation of the absolute pulsatile blood flow within individual retinal vessels as well as of the total retinal blood flow over a full heartbeat cycle.

Ultrahigh-speed non-invasive widefield angiography.

Retinal and choroidal vascular imaging is an important diagnostic benefit for ocular diseases such as age-related macular degeneration. The current gold standard for vessel visualization is fluorescence angiography. We present a potential non-invasive alternative to image blood vessels based on functional Fourier domain optical coherence tomography (OCT). For OCT to compete with the field of view and resolution of angiography while maintaining motion artifacts to a minimum, ultrahigh-speed imaging has to be introduced. We employ Fourier domain mode locking swept source technology that offers high quality imaging at an A-scan rate of up to 1.68 MHz. We present retinal angiogram over ∼48 deg acquired in a few seconds in a single recording without the need of image stitching. OCT at 1060 nm allows for high penetration in the choroid and efficient separate characterization of the retinal and choroidal vascularization.

In-line reference-delayed digital holography using a low-coherence light source.

We present a holographic imaging device with a low-coherence light source that uses the reflection of the objective lens as reference illumination. This results in a simple setup and allows applications to microscopy with only small modifications of the setup for aberration measurements. In addition, it opens the prospects to in vivo ophthalmic imaging. We present in vitro experiments using a resolution test target to quantify the system performance. We demonstrate that we can achieve diffraction-limited resolution and show the possibility of aberration correction. We also present preliminary results using a scattering sample.

Precise thickness measurements of Bowman's layer, epithelium, and tear film.

PURPOSE: To visualize corneal microstructure such as tear film, epithelium, and Bowman's layer in three dimensions with spectral domain optical coherence tomography (SDOCT) exhibiting 1.3 µm axial resolution at 100,000 A-scans/s. This enables measurement of epithelial and Bowman layer thickness across an area of 8.4 mm × 8.4 mm and measuring the tear film thickness at the central cornea. METHODS: We designed a high-performance SDOCT system, which uses a broad bandwidth TiSapph Laser and a high-speed complementary metal-oxide-semiconductor detector technology, providing a resolution in tissue of 1.3 µm and an acquisition speed of 100,000 A-scans/s. Such speed and resolution is a prerequisite if precise anatomy is to be determined. The high resolution gives access to corneal microstructure such as the epithelium layer as well as the boundaries of Bowman's layer and stroma. Even more interestingly, the tear film can be distinguished on the surface of the cornea. The Bowman's layer and epithelial thickness for both eyes of nine subjects have been measured out of which two subjects underwent photorefractive keratectomy treatment. RESULTS: Three-dimensional volumes of the human cornea have been recorded in vivo at an A-scan rate of 100,000 scans/s. Epithelial thickness was measured to be 55.8 ± 3.3 µm and Bowman's layer thickness 18.7 ± 2.5 µm in normal eyes. Epithelial thickness in the eyes after refractive surgery was measured to be 68.2 ± 5.0 µm. The Bowman layer was degenerated in these eyes. The average tear film thickness of four eyes was 5.1 ± 0.5 µm. CONCLUSIONS: Using a high-performance SDOCT system with high-imaging speed and ultrahigh resolution, we produced precise thickness maps of the epithelium and for the first time of the Bowman's layer. Such a system will give insight into high-fidelity three-dimensional corneal microstructure helping to precisely plan refractive surgery. It may furthermore yield new perspectives on studying and understanding tear film dynamics.

Speckle noise reduction in high speed polarization sensitive spectral domain optical coherence tomography.

We present a high speed polarization sensitive spectral domain optical coherence tomography system based on polarization maintaining fibers and two high speed CMOS line scan cameras capable of retinal imaging with up to 128 k A-lines/s. This high imaging speed strongly reduces motion artifacts and therefore averaging of several B-scans is possible, which strongly reduces speckle noise and improves image quality. We present several methods for averaging retardation and optic axis orientation, the best one providing a 5 fold noise reduction. Furthermore, a novel scheme of calculating images of degree of polarization uniformity is presented. We quantitatively compare the noise reduction depending on the number of averaged frames and discuss the limits of frame numbers that can usefully be averaged.

Imaging of the parafoveal capillary network and its integrity analysis using fractal dimension.

Using a spectral domain OCT system, equipped with a broadband Ti:sapphire laser, we imaged the human retina with 5 µm x 1.3 µm transverse and axial resolution at acquisition rate of 100 kHz. Such imaging speed significantly reduces motion artifacts. Combined with the ultra-high resolution, this allows observing microscopic retinal details with high axial definition without the help of adaptive optics. In this work we apply our system to image the parafoveal capillary network. We demonstrate how already on the intensity level the parafoveal capillaries can be segmented by a simple structural high pass filtering algorithm. This data is then used to quantitatively characterize the capillary network of healthy and diseased eyes. We propose to use the fractal dimension as index for capillary integrity of pathologic disorders.