Wide-Field Three-Dimensional Depth-Invariant Cellular-Resolution Imaging of the Human Retina.

Three-dimensional (3D) cellular-resolution imaging of the living human retina over a large field of view will bring a great impact in clinical ophthalmology, potentially finding new biomarkers for early diagnosis and improving the pathophysiological understanding of ocular diseases. While hardware-based and computational adaptive optics (AO) optical coherence tomography (OCT) have been developed to achieve cellular-resolution retinal imaging, these approaches support limited 3D imaging fields, and their high cost and intrinsic hardware complexity limit their practical utility. Here, this work demonstrates 3D depth-invariant cellular-resolution imaging of the living human retina over a 3 × 3 mm field of view using the first intrinsically phase-stable multi-MHz retinal swept-source OCT and novel computational defocus and aberration correction methods. Single-acquisition imaging of photoreceptor cells, retinal nerve fiber layer, and retinal capillaries is presented across unprecedented imaging fields. By providing wide-field 3D cellular-resolution imaging in the human retina using a standard point-scan architecture routinely used in the clinic, this platform proposes a strategy for expanded utilization of high-resolution retinal imaging in both research and clinical settings.

Robust and easy-to-operate stretched-pulse mode-locked wavelength-swept laser with an all-polarization-maintaining fiber cavity for 10 MHz A-line rate optical coherence tomography.

We demonstrate robust and easy-to-operate stretched-pulse mode-locked laser (SPML) architectures using all-polarization-maintaining fiber laser cavities. Because of the polarization-maintaining construction, the laser performance is unaffected by mechanical perturbation on the cavity fibers. The lasers automatically initiate linear-in-wavenumber sweeps across 100 nm centered at 1290 nm with a 10 MHz repetition rate. OCT imaging with a sensitivity of 98 dB and a single-sided 6 dB coherence length of 2.5 mm is demonstrated. OCT angiography of a mouse brain that visualized three-dimensional cerebral microvasculature over a field of 1.5mm×1.5mm (398 A-lines × 380 B-scans) at a rate of 5.26 volumes per second is also presented. The robust all-PMF SPML lasers are a turnkey, high-performance source for ultrahigh-speed OCT imaging.

Intracoronary dual-modal optical coherence tomography-near-infrared fluorescence structural-molecular imaging with a clinical dose of indocyanine green for the assessment of high-risk plaques and stent-associated inflammation in a beating coronary artery.

AIMS: Inflammation plays essential role in development of plaque disruption and coronary stent-associated complications. This study aimed to examine whether intracoronary dual-modal optical coherence tomography (OCT)-near-infrared fluorescence (NIRF) structural-molecular imaging with indocyanine green (ICG) can estimate inflammation in swine coronary artery. METHODS AND RESULTS: After administration of clinically approved NIRF-enhancing ICG (2.0 mg/kg) or saline, rapid coronary imaging (20 mm/s pullback speed) using a fully integrated OCT-NIRF catheter was safely performed in 12 atheromatous Yucatan minipigs and in 7 drug-eluting stent (DES)-implanted Yorkshire pigs. Stronger NIRF activity was identified in OCT-proven high-risk plaque compared to normal or saline-injected controls (P = 0.0016), which was validated on ex vivo fluorescence reflectance imaging. In vivo plaque target-to-background ratio (pTBR) was much higher in inflamed lipid-rich plaque compared to fibrous plaque (P < 0.0001). In vivo and ex vivo peak pTBRs correlated significantly (P < 0.0022). In vitro cellular ICG uptake and histological validations corroborated the OCT-NIRF findings in vivo. Indocyanine green colocalization with macrophages and lipids of human plaques was confirmed with autopsy atheroma specimens. Two weeks after DES deployment, OCT-NIRF imaging detected strong NIRF signals along stent struts, which was significantly higher than baseline (P = 0.0156). Histologically, NIRF signals in peri-strut tissue co-localized well with macrophages. CONCLUSION: The OCT-NIRF imaging with a clinical dose of ICG was feasible to accurately assess plaque inflammation and DES-related inflammation in a beating coronary artery. This highly translatable dual-modal molecular-structural imaging strategy could be relevant for clinical intracoronary estimation of high-risk plaques and DES biology.

Dual-wavelength band spectroscopic optical frequency domain imaging using plasmon-resonant scattering in metallic nanoparticles.

We demonstrate a dual-wavelength band optical frequency domain imaging (OFDI) system that provides high-resolution spectroscopic imaging with metallic nanoparticles as exogenous contrast agents. The local increase of the OFDI signal by elastic scattering from two different custom-fabricated nonspherical nanoparticles resonant at each wavelength band of the system was successfully detected, and we were able to distinguish and visualize the location of each of the nanoparticles in a scattering sample and in biological tissue.

Stepped frequency comb generation based on electro-optic phase-code mode-locking for moderate-speed circular-ranging OCT.

Circular-ranging (CR) optical coherence tomography (OCT) uses frequency comb sources to improve long-range imaging. While the initial development of CR-OCT focused on extremely high-speed imaging (i.e., operation at A-line rates of several to tens of MHz), there are many applications and imaging strategies for which more moderate speeds are preferred. However, we lack suitable frequency comb sources to enable moderate speed CR-OCT imaging. Here, we describe a novel phase-code mode-locking (PCML) laser architecture that can be operated from the kilohertz to megahertz range, while also offering novel features such as dynamic re-configurability and simplified linear-in-time frequency stepping. We demonstrate a prototype CR-OCT system with a PCML laser and present imaging results at A-line rates from 176 kHz to 3.52 MHz with coherence-length limited imaging depths as high as 170 mm.

9.4 MHz A-line rate optical coherence tomography at 1300 nm using a wavelength-swept laser based on stretched-pulse active mode-locking.

In optical coherence tomography (OCT), high-speed systems based at 1300 nm are among the most broadly used. Here, we present 9.4 MHz A-line rate OCT system at 1300 nm. A wavelength-swept laser based on stretched-pulse active mode locking (SPML) provides a continuous and linear-in-wavenumber sweep from 1240 nm to 1340 nm, and the OCT system using this light source provides a sensitivity of 98 dB and a single-sided 6-dB roll-off depth of 2.5 mm. We present new capabilities of the 9.4 MHz SPML-OCT system in three microscopy applications. First, we demonstrate high quality OCTA imaging at a rate of 1.3 volumes/s. Second, by utilizing its inherent phase stable characteristics, we present wide dynamic range en face Doppler OCT imaging with multiple time intervals ranging from 0.25 ms to 2.0 ms at a rate of 0.53 volumes/s. Third, we demonstrate video-rate 4D microscopic imaging of a beating Xenopus embryo heart at a rate of 30 volumes/s. This high-speed and high-performance OCT system centered at 1300 nm suggests that it can be one of the most promising high-speed OCT platforms enabling a wide range of new scientific research, industrial, and clinical applications at speeds of 10 MHz.

Comprehensive intravascular imaging of atherosclerotic plaque in vivo using optical coherence tomography and fluorescence lifetime imaging.

Comprehensive imaging of both the structural and biochemical characteristics of atherosclerotic plaque is essential for the diagnosis and study of coronary artery disease because both a plaque's morphology and its biochemical composition affect the level of risk it poses. Optical coherence tomography (OCT) and fluorescence lifetime imaging (FLIm) are promising optical imaging methods for characterizing coronary artery plaques morphologically and biochemically, respectively. In this study, we present a hybrid intravascular imaging device, including a custom-built OCT/FLIm system, a hybrid optical rotary joint, and an imaging catheter, to visualize the structure and biochemical composition of the plaque in an atherosclerotic rabbit artery in vivo. Especially, the autofluorescence lifetime of the endogenous tissue molecules can be used to characterize the biochemical composition; thus no exogenous contrast agent is required. Also, the physical properties of the imaging catheter and the imaging procedures are similar to those already used clinically, facilitating rapid translation into clinical use. This new intravascular imaging catheter can open up new opportunities for clinicians and researchers to investigate and diagnose coronary artery disease by simultaneously providing tissue microstructure and biochemical composition data in vivo without the use of exogenous contrast agent.

The effect of long working hours on 10-year risk of coronary heart disease and stroke in the Korean population: the Korea National Health and Nutrition Examination Survey (KNHANES), 2007 to 2013.

BACKGROUND: Recently, the emergence of long working hours and the associated conditions such as coronary heart disease (CHD) and stroke have gained attention. The aim of this study was to investigate the association between long working hours and the 10-year-risk of CHD and stroke, estimated by Jee's health risk-appraisal model for ischemic heart disease. METHODS: We analyzed data from Koreans who randomly enrolled in Korean National Health and Nutrition Examination Survey 2008-2012 and finally included 13,799 participants. The participants were classified as per their working hours: 0-30 h/week, 31-39 h/week, 40 h/week, 41-50 h/week, 51-60 h/week, 61-70 h/week, 71-80 h/week, and >80 h/week. The risks for CHD and stroke were determined using Jee's health risk-appraisal model. Multiple logistic regression was used to analyze the association between working hours and 10-year risk for CHD. RESULTS: The 10-year risks for CHD and stroke were significantly and positively associated with working hours in both men and women. Furthermore, higher risks for CHD and stroke were associated with longer working hours in women. CONCLUSION: Long working hours are significantly associated with the risks of CHD and stroke, estimated by Jee's health risk-appraisal model. This study suggests the need for proper management of working hours to reduce CHD risk and stroke risk in the Korean population.

Single cardiac cycle three-dimensional intracoronary optical coherence tomography.

While high-speed intracoronary optical coherence tomography (OCT) provides three-dimensional (3D) visualization of coronary arteries in vivo, imaging speeds remain insufficient to avoid motion artifacts induced by heartbeat, limiting the clinical utility of OCT. In this paper, we demonstrate development of a high-speed intracoronary OCT system (frame rate: 500 frames/s, pullback speed: 100 mm/s) along with prospective electrocardiogram (ECG) triggering technology, which enabled volumetric imaging of long coronary segments within a single cardiac cycle (70 mm pullback in 0.7 s) with minimal cardiac motion artifact. This technology permitted detailed visualization of 3D architecture of the coronary arterial wall of a swine in vivo and fine structure of the implanted stent.

Intravascular optical imaging of high-risk plaques in vivo by targeting macrophage mannose receptors.

Macrophages mediate atheroma expansion and disruption, and denote high-risk arterial plaques. Therefore, they are substantially gaining importance as a diagnostic imaging target for the detection of rupture-prone plaques. Here, we developed an injectable near-infrared fluorescence (NIRF) probe by chemically conjugating thiolated glycol chitosan with cholesteryl chloroformate, NIRF dye (cyanine 5.5 or 7), and maleimide-polyethylene glycol-mannose as mannose receptor binding ligands to specifically target a subset of macrophages abundant in high-risk plaques. This probe showed high affinity to mannose receptors, low toxicity, and allowed the direct visualization of plaque macrophages in murine carotid atheroma. After the scale-up of the MMR-NIRF probe, the administration of the probe facilitated in vivo intravascular imaging of plaque inflammation in coronary-sized vessels of atheromatous rabbits using a custom-built dual-modal optical coherence tomography (OCT)-NIRF catheter-based imaging system. This novel imaging approach represents a potential imaging strategy enabling the identification of high-risk plaques in vivo and holds promise for future clinical implications.