Relative retinal flow velocity detection using optical coherence tomography angiography imaging.

Optical coherence tomography angiography (OCTA) imaging is a valuable tool for the visualization of retinal vasculature at an unprecedented level of details. However, due to relatively long time-interval between repeated scans in the conventional OCTA scanning protocol, the OCTA flow signal suffers from low dynamic range and loss of velocity-intensity correlation. The ability to distinguish fast and slow flow in the retina may provide a powerful tool for the assessment of early-stage retinal diseases such as vein occlusion. Here, we report a method to detect relative flow velocity in human retina using a 67.5 kHz spectral-domain OCTA device. By adapting the selection of A-scan time-intervals within a single OCTA acquisition and combining the resulting OCTA images, we expand the detectable velocity range. After a quantitative validation of this method performing microchannel flow experiments with varying flow velocities, we demonstrate this approach on human eyes using CIRRUS HD-OCT 5000 with AngioPlex (ZEISS, Dublin, CA) through a prototype scanning pattern.

Hybrid intravascular imaging: recent advances, technical considerations, and current applications in the study of plaque pathophysiology.

Cumulative evidence from histology-based studies demonstrate that the currently available intravascular imaging techniques have fundamental limitations that do not allow complete and detailed evaluation of plaque morphology and pathobiology, limiting the ability to accurately identify high-risk plaques. To overcome these drawbacks, new efforts are developing for data fusion methodologies and the design of hybrid, dual-probe catheters to enable accurate assessment of plaque characteristics, and reliable identification of high-risk lesions. Today several dual-probe catheters have been introduced including combined near infrared spectroscopy-intravascular ultrasound (NIRS-IVUS), that is already commercially available, IVUS-optical coherence tomography (OCT), the OCT-NIRS, the OCT-near infrared fluorescence (NIRF) molecular imaging, IVUS-NIRF, IVUS intravascular photoacoustic imaging and combined fluorescence lifetime-IVUS imaging. These multimodal approaches appear able to overcome limitations of standalone imaging and provide comprehensive visualization of plaque composition and plaque biology. The aim of this review article is to summarize the advances in hybrid intravascular imaging, discuss the technical challenges that should be addressed in order to have a use in the clinical arena, and present the evidence from their first applications aiming to highlight their potential value in the study of atherosclerosis.

Intravascular fibrin molecular imaging improves the detection of unhealed stents assessed by optical coherence tomography in vivo.

AIMS: Fibrin deposition and absent endothelium characterize unhealed stents that are at heightened risk of stent thrombosis. Optical coherence tomography (OCT) is increasingly used for assessing stent tissue coverage as a measure of healed stents, but cannot precisely identify whether overlying tissue represents physiological neointima. Here we assessed and compared fibrin deposition and persistence on bare metal stent (BMS) and drug-eluting stent (DES) using near-infrared fluorescence (NIRF) molecular imaging in vivo, in combination with simultaneous OCT stent coverage. METHODS AND RESULTS: Rabbits underwent implantation of one BMS and one DES without overlap in the infrarenal aorta (N = 20 3.5 × 12 mm). At Days 7 and/or 28, intravascular NIRF-OCT was performed following the injection of fibrin-targeted NIRF molecular imaging agent FTP11-CyAm7. Intravascular NIRF-OCT enabled high-resolution imaging of fibrin overlying stent struts in vivo, as validated by histopathology. Compared with BMS, DES showed greater fibrin deposition and fibrin persistence at Days 7 and 28 (P < 0.01 vs. BMS). Notably, for edge stent struts identified as covered by OCT on Day 7, 92.8 ± 9.5% of DES and 55.8 ± 23.6% of BMS struts were NIRF fibrin positive (P < 0.001). At Day 28, 18.6 ± 10.6% (DES) and 5.1 ± 8.7% (BMS) of OCT-covered struts remained fibrin positive (P < 0.001). CONCLUSION: Intravascular NIRF fibrin molecular imaging improves the detection of unhealed stents, using clinically translatable technology that complements OCT. A sizeable percentage of struts deemed covered by OCT are actually covered by fibrin, particularly in DES, and therefore such stents might remain prothrombotic. These findings have implications for the specificity of standalone clinical OCT assessments of stent healing.

Clinical Characterization of Coronary Atherosclerosis With Dual-Modality OCT and Near-Infrared Autofluorescence Imaging.

OBJECTIVES: The authors present the clinical imaging of human coronary arteries in vivo using a multimodality optical coherence tomography (OCT) and near-infrared autofluorescence (NIRAF) intravascular imaging system and catheter. BACKGROUND: Although intravascular OCT is capable of providing microstructural images of coronary atherosclerotic lesions, it is limited in its capability to ascertain the compositional/molecular features of plaque. A recent study in cadaver coronary plaque showed that endogenous NIRAF is elevated in necrotic core lesions. The combination of these 2 technologies in 1 device may therefore provide synergistic data to aid in the diagnosis of coronary pathology in vivo. METHODS: We developed a dual-modality intravascular imaging system and 2.6-F catheter that can simultaneously acquire OCT and NIRAF data from the same location on the artery wall. This technology was used to obtain volumetric OCT-NIRAF images from 12 patients with coronary artery disease undergoing percutaneous coronary intervention. Images were acquired during a brief, nonocclusive 3- to 4-ml/s contrast purge at a speed of 100 frames/s and a pullback rate of 20 or 40 mm/s. OCT-NIRAF data were analyzed to determine the distribution of the NIRAF signal with respect to OCT-delineated plaque morphological features. RESULTS: High-quality intracoronary OCT and NIRAF image data (>50-mm pullback length) were successfully acquired without complication in all patients (17 coronary arteries). The maximum NIRAF signal intensity of each plaque was compared with OCT-defined type, showing a statistically significant difference between plaque types (1-way analysis of variance, p < 0.0001). Interestingly, coronary arterial NIRAF intensity was elevated only focally in plaques with a high-risk morphological phenotype (p < 0.05), including OCT fibroatheroma, plaque rupture, and fibroatheroma associated with in-stent restenosis. CONCLUSIONS: This OCT-NIRAF study demonstrates that dual-modality microstructural and fluorescence intracoronary imaging can be safely and effectively conducted in human patients. Our findings show that NIRAF is associated with a high-risk morphological plaque phenotype. The focal distribution of NIRAF in these lesions furthermore suggests that this endogenous imaging biomarker may provide complementary information to that obtained by structural imaging alone.

Dual modality intravascular optical coherence tomography (OCT) and near-infrared fluorescence (NIRF) imaging: a fully automated algorithm for the distance-calibration of NIRF signal intensity for quantitative molecular imaging.

Intravascular optical coherence tomography (IVOCT) is a well-established method for the high-resolution investigation of atherosclerosis in vivo. Intravascular near-infrared fluorescence (NIRF) imaging is a novel technique for the assessment of molecular processes associated with coronary artery disease. Integration of NIRF and IVOCT technology in a single catheter provides the capability to simultaneously obtain co-localized anatomical and molecular information from the artery wall. Since NIRF signal intensity attenuates as a function of imaging catheter distance to the vessel wall, the generation of quantitative NIRF data requires an accurate measurement of the vessel wall in IVOCT images. Given that dual modality, intravascular OCT-NIRF systems acquire data at a very high frame-rate (>100 frames/s), a high number of images per pullback need to be analyzed, making manual processing of OCT-NIRF data extremely time consuming. To overcome this limitation, we developed an algorithm for the automatic distance-correction of dual-modality OCT-NIRF images. We validated this method by comparing automatic to manual segmentation results in 180 in vivo images from six New Zealand White rabbit atherosclerotic after indocyanine-green injection. A high Dice similarity coefficient was found (0.97 ± 0.03) together with an average individual A-line error of 22 µm (i.e., approximately twice the axial resolution of IVOCT) and a processing time of 44 ms per image. In a similar manner, the algorithm was validated using 120 IVOCT clinical images from eight different in vivo pullbacks in human coronary arteries. The results suggest that the proposed algorithm enables fully automatic visualization of dual modality OCT-NIRF pullbacks, and provides an accurate and efficient calibration of NIRF data for quantification of the molecular agent in the atherosclerotic vessel wall.

Digital broadband linearization of optical links.

We present a digital postprocessing linearization technique to efficiently suppress dynamic distortions added to a wideband signal in an analog optical link. Our technique achieves up to 35 dB suppression of intermodulation distortions over multiple octaves of signal bandwidth. In contrast to conventional linearization methods, it does not require excessive analog bandwidth for performing digital correction. This is made possible by regenerating undesired distortions from the captured output, and subtracting it from the distorted digitized signal. Moreover, we experimentally demonstrate a record spurious-free dynamic range of 120 dB·Hz(2/3) over a 6 GHz electrical signal bandwidth. While our digital broadband linearization technique advances state-of-the-art optical links, it can also be applied to other nonlinear dynamic systems.

Optical coherence tomography--near infrared spectroscopy system and catheter for intravascular imaging.

Owing to its superior resolution, intravascular optical coherence tomography (IVOCT) is a promising tool for imaging the microstructure of coronary artery walls. However, IVOCT does not identify chemicals and molecules in the tissue, which is required for a more complete understanding and accurate diagnosis of coronary disease. Here we present a dual-modality imaging system and catheter that uniquely combines IVOCT with diffuse near-infrared spectroscopy (NIRS) in a single dual-modality imaging device for simultaneous acquisition of microstructural and compositional information. As a proof-of-concept demonstration, the device has been used to visualize co-incident microstructural and spectroscopic information obtained from a diseased cadaver human coronary artery.

High-throughput single-microparticle imaging flow analyzer.

Optical microscopy is one of the most widely used diagnostic methods in scientific, industrial, and biomedical applications. However, while useful for detailed examination of a small number (< 10,000) of microscopic entities, conventional optical microscopy is incapable of statistically relevant screening of large populations (> 100,000,000) with high precision due to its low throughput and limited digital memory size. We present an automated flow-through single-particle optical microscope that overcomes this limitation by performing sensitive blur-free image acquisition and nonstop real-time image-recording and classification of microparticles during high-speed flow. This is made possible by integrating ultrafast optical imaging technology, self-focusing microfluidic technology, optoelectronic communication technology, and information technology. To show the system's utility, we demonstrate high-throughput image-based screening of budding yeast and rare breast cancer cells in blood with an unprecedented throughput of 100,000 particles/s and a record false positive rate of one in a million.

Nomarski serial time-encoded amplified microscopy for high-speed contrast-enhanced imaging of transparent media.

High-speed high-contrast imaging modalities that enable image acquisition of transparent media without the need for chemical staining are essential tools for a broad range of applications; from semiconductor process monitoring to blood screening. Here we introduce a method for contrast-enhanced imaging of unstained transparent objects that is capable of high-throughput imaging. This method combines the Nomarski phase contrast capability with the ultrahigh frame rate and shutter speed of serial time-encoded amplified microscopy. As a proof of concept, we show imaging of a transparent test structure and white blood cells in flow at a shutter speed of 33 ps and a frame rate of 36.1 MHz using a single-pixel photo-detector. This method is expected to be a valuable tool for high-throughput screening of unstained cells.