Depth-resolved investigation of multiple optical properties and wrinkle morphology in eye-corner areas with multi-contrast Jones matrix optical coherence tomography.

BACKGROUND: Multi-contrast Jones matrix optical coherence tomography (JM-OCT) can provide quantitative depth-resolved local optical properties by improving the measurement algorithm. MATERIALS AND METHODS: We examined the relationship between depth-resolved local optical properties of eye-corner skin measured by JM-OCT and corresponding wrinkle morphology of aged women (n = 21; age range, 71.7 ± 1.7 years). Wrinkle morphology was analyzed by measuring the surface topography of three-dimensional replicas. The same regions were measured three-dimensionally by JM-OCT, and the local optical properties at each depth were computed. RESULTS: Birefringence (BR) and mean wrinkle depth correlated significantly at a depth of 88.2-138.6 µm from the skin surface, and attenuation coefficient (AC) and mean wrinkle depth correlated significantly at a depth of 12.6-18.9 µm and 189-459.9 µm from the skin surface, although a degree of polarization uniformity (DOPU) did not. Stepwise multiple regression analysis demonstrated that a significant regression equation (R2  = 0.649, P < .001) for predicting mean wrinkle depth was determined by BR at 107.1 µm depth (BR 107.1 µm ), DOPU at 170.1 µm (DOPU 170.1µm ), and AC at 252 µm (AC 252 µm ) as independent variables and that these standardized beta regression coefficients were -0.860, -0.593, and -0.440, respectively, suggesting that BR, DOPU, and AC sufficiently explained mean wrinkle depth. CONCLUSION: These results suggest that BR 107.1 µm , DOPU 170.1 µm, and AC 252 µm may indicate collagen-related structure in the papillary, upper-reticular dermis, and microstructure or tissue density in reticular dermis, respectively, and may be involved in wrinkle formation.

Compression optical coherence elastography with two-dimensional displacement measurement and local deformation visualization.

Current compression-based optical coherence elastography (OCE) only measures the axial displacement of a tissue, although the tissue also undergoes lateral displacement and microstructural alteration by the compression. In this Letter, we demonstrate a new compression-based OCE method that visualizes not only axial displacement, but also lateral displacement and microstructural decorrelation (MSD). This method employs complex correlation-based displacement and MSD measurements. It is implemented in a swept-source optical coherence tomography system with an active submicrometer compression. The performance of the method was demonstrated by measuring the porcine carotid artery and esophagus. The results showed significant axial and lateral displacements in the tissues by compression. An MSD map demonstrates high-contrast mechanical-property imaging.

Maximum a posteriori estimator for high-contrast image composition of optical coherence tomography.

A quantitative signal amplitude estimator for optical coherence tomography (OCT) is presented. It is based on a statistical model of OCT signal and noise, using a Bayesian maximum a posteriori (MAP) estimation framework. Multiple OCT images are used for estimation, similar to the widely utilized intensity averaging method. The estimator is less biased especially at low-intensity regions, where intensity averaging approaches the noise power and hence is biased. The estimator is applied to posterior ocular OCT images and provides high-contrast visualization of pathologies. In addition, histogram analysis objectively shows the superior performance of the estimator compared with intensity averaging.

In-plane and out-of-plane tissue micro-displacement measurement by correlation coefficients of optical coherence tomography.

We propose a method to measure the in-plane and out-of-plane displacements of tissue using the correlation coefficients of optical coherence tomography (OCT) signals. The displacements are determined by the local correlation coefficients between digitally shifted reference OCT images and a target image. The method achieves sub-micron displacement measurement with an accuracy better than 0.32 µm and repeatability better than 0.36 µm. The feasibility of the method was examined by measuring the displacement field of a laser irradiated porcine retina. This method successfully visualized the dynamic change of the displacement field during laser irradiation.

Noise statistics of phase-resolved optical coherence tomography imaging: single-and dual-beam-scan Doppler optical coherence tomography.

Noise statistics of phase-resolved optical coherence tomography (OCT) imaging are complicated and involve noises of OCT, correlation of signals, and speckles. In this paper, the statistical properties of phase shift between two OCT signals that contain additive random noises and speckle noises are presented. Experimental results obtained with a scattering tissue phantom are in good agreement with theoretical predictions. The performances of the dual-beam method and conventional single-beam method are compared. As expected, phase shift noise in the case of the dual-beam-scan method is less than that for the single-beam method when the transversal sampling step is large.

Bayesian maximum likelihood estimator of phase retardation for quantitative polarization-sensitive optical coherence tomography.

This paper presents the theory and numerical implementation of a maximum likelihood estimator for local phase retardation (i.e., birefringence) measured using Jones-matrix-based polarization sensitive optical coherence tomography. Previous studies have shown conventional mean estimations of phase retardation and birefringence are significantly biased in the presence of system noise. Our estimator design is based on a Bayes' rule that relates the distributions of the measured birefringence under a particular true birefringence and the true birefringence under a particular measured birefringence. We used a Monte-Carlo method to calculate the likelihood function that describes the relationship between the distributions and numerically implement the estimator. Our numerical and experimental results show that the proposed estimator was asymptotically unbiased even with low signal-to-noise ratio and/or for the true phase retardations close to the edge of the measurement range. The estimator revealed detailed clinical features when applied to the in vivo anterior human eye.

Degree of polarization uniformity with high noise immunity using polarization-sensitive optical coherence tomography.

A new metric representing polarization uniformity is presented. Noise corrected degree of polarization uniformity (DOPU) is computed from polarization-sensitive optical coherence tomography (OCT), and selectively visualizes tissue with the multiple scattering, such as highly pigmented tissues. The new metric is designed to be minimally sensitive to systematic additive noise. The performance of this new metric is analyzed by numerical simulation and in vivo human retinal imaging, using Jones matrix OCT. The new metric exhibited only a small dependency on the signal-to-noise ratio. Selective in vivo visualization of pigmented tissues in the human retina is demonstrated, with cross sectional and en-face images.

Label-free visualization and quantification of the drug-type-dependent response of tumor spheroids by dynamic optical coherence tomography.

We demonstrate label-free dynamic optical coherence tomography (D-OCT)-based visualization and quantitative assessment of patterns of tumor spheroid response to three anti-cancer drugs. The study involved treating human breast adenocarcinoma (MCF-7 cell-line) with paclitaxel (PTX), tamoxifen citrate (TAM), and doxorubicin (DOX) at concentrations of 0 (control), 0.1, 1, and 10 µM for 1, 3, and 6 days. In addition, fluorescence microscopy imaging was performed for reference. The D-OCT imaging was performed using a custom-built OCT device. Two algorithms, namely logarithmic intensity variance (LIV) and late OCT correlation decay speed (OCDS[Formula: see text]) were used to visualize the tissue dynamics. The spheroids treated with 0.1 and 1 µM TAM appeared similar to the control spheroid, whereas those treated with 10 µM TAM had significant structural corruption and decreasing LIV and OCDS[Formula: see text] over treatment time. The spheroids treated with PTX had decreasing volumes and decrease of LIV and OCDS[Formula: see text] signals over time at most PTX concentrations. The spheroids treated with DOX had decreasing and increasing volumes over time at DOX concentrations of 1 and 10 µM, respectively. Meanwhile, the LIV and OCDS[Formula: see text] signals decreased over treatment time at all DOX concentrations. The D-OCT, particularly OCDS[Formula: see text], patterns were consistent with the fluorescence microscopic patterns. The diversity in the structural and D-OCT results among the drug types and among the concentrations are explained by the mechanisms of the drugs. The presented results suggest that D-OCT is useful for evaluating the difference in the tumor spheroid response to different drugs and it can be a useful tool for anti-cancer drug testing.

Optical-coherence-tomography-based deep-learning scatterer-density estimator using physically accurate noise model.

We demonstrate a deep-learning-based scatterer density estimator (SDE) that processes local speckle patterns of optical coherence tomography (OCT) images and estimates the scatterer density behind each speckle pattern. The SDE is trained using large quantities of numerically simulated OCT images and their associated scatterer densities. The numerical simulation uses a noise model that incorporates the spatial properties of three types of noise, i.e., shot noise, relative-intensity noise, and non-optical noise. The SDE's performance was evaluated numerically and experimentally using two types of scattering phantom and in vitro tumor spheroids. The results confirmed that the SDE estimates scatterer densities accurately. The estimation accuracy improved significantly when compared with our previous deep-learning-based SDE, which was trained using numerical speckle patterns generated from a noise model that did not account for the spatial properties of noise.

Polarization-artifact reduction and accuracy improvement of Jones-matrix polarization-sensitive optical coherence tomography by multi-focus-averaging based multiple scattering reduction.

Polarization-sensitive optical coherence tomography (PS-OCT) is a promising biomedical imaging tool for the differentiation of various tissue properties. However, the presence of multiple-scattering (MS) signals can degrade the quantitative polarization measurement accuracy. We demonstrate a method to reduce MS signals and increase the measurement accuracy of Jones matrix PS-OCT. This method suppresses MS signals by averaging multiple Jones matrix volumes measured using different focal positions. The MS signals are decorrelated among the volumes by focus position modulation and are thus reduced by averaging. However, the single scattering signals are kept consistent among the focus-modulated volumes by computational refocusing. We validated the proposed method using a scattering phantom and a postmortem medaka fish. The results showed reduced artifacts in birefringence and degree-of-polarization uniformity measurements, particularly in deeper regions in the samples. This method offers a practical solution to mitigate MS-induced artifacts in PS-OCT imaging and improves quantitative polarization measurement accuracy.

Neural-network based high-speed volumetric dynamic optical coherence tomography.

We demonstrate deep-learning neural network (NN)-based dynamic optical coherence tomography (DOCT), which generates high-quality logarithmic-intensity-variance (LIV) DOCT images from only four OCT frames. The NN model is trained for tumor spheroid samples using a customized loss function: the weighted mean absolute error. This loss function enables highly accurate LIV image generation. The fidelity of the generated LIV images to the ground truth LIV images generated using 32 OCT frames is examined via subjective image observation and statistical analysis of image-based metrics. Fast volumetric DOCT imaging with an acquisition time of 6.55 s/volume is demonstrated using this NN-based method.

Erratum: Deep convolutional neural networks-based scatterer density and resolution estimators in optical coherence tomography: erratum.

[This corrects the article on p. 168 in vol. 13, PMID: 35154862.].

Advanced multi-contrast Jones matrix optical coherence tomography for Doppler and polarization sensitive imaging.

An advanced version of Jones matrix optical coherence tomography (JMT) is demonstrated for Doppler and polarization sensitive imaging of the posterior eye. JMT is capable of providing localized flow tomography by Doppler detection and investigating the birefringence property of tissue through a three-dimensional (3-D) Jones matrix measurement. Owing to an incident polarization multiplexing scheme based on passive optical components, this system is stable, safe in a clinical environment, and cost effective. Since the properties of this version of JMT provide intrinsic compensation for system imperfection, the system is easy to calibrate. Compared with the previous version of JMT, this advanced JMT achieves a sufficiently long depth measurement range for clinical cases of posterior eye disease. Furthermore, a fine spectral shift compensation method based on the cross-correlation of calibration signals was devised for stabilizing the phase of OCT, which enables a high sensitivity Doppler OCT measurement. In addition, a new theory of JMT which integrates the Jones matrix measurement, Doppler measurement, and scattering measurement is presented. This theory enables a sensitivity-enhanced scattering OCT and high-sensitivity Doppler OCT. These new features enable the application of this system to clinical cases. A healthy subject and a geographic atrophy patient were measured in vivo, and simultaneous imaging of choroidal vasculature and birefringence structures are demonstrated.

Thickness mapping of the inner retina by spectral-domain optical coherence tomography in an N-methyl-D-aspartate-induced retinal damage model.

Spectral-domain optical coherence tomography (SD-OCT) is an interferometric optical tomography technique and provides high resolution and noninvasive visualization of retinal morphology. The purpose of this study was to assess the utility of thickness maps and quantitative thickness measurements of the ganglion cell complex (GCC: retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer) obtained by SD-OCT of a mouse model of N-methyl-d-aspartate (NMDA)-induced retinal damage. SD-OCT imaging was performed in ddY mice at 1, 3, and 7 days and 1 month after intravitreal injection of NMDA. GCC thickness maps and circle cross-sectional OCT images were made from volumetric OCT images. The GCC thickness was measured on a cross-sectional OCT image on a circle with a radius 300 µm from the center of the optic nerve disc. Histological analysis was conducted by measuring the GCC thickness at the same time intervals. The thickness maps and the quantitative thickness values of GCC showed thickness changes at each time point in the NMDA-treated mice when compared with normal and vehicle-treated mice. Both the OCT sectional images and the histological images revealed increases in GCC thickness at 1 day, followed by decreases from 3 days to 1 month after NMDA injection. The GCC thickness measured using OCT sectional images correlated with the thickness measured using histological images. In conclusion, GCC thickness mapping is a useful method for evaluating NMDA-induced retinal degeneration in mice.

Synthesizing the degree of polarization uniformity from non-polarization-sensitive optical coherence tomography signals using a neural network.

Degree of polarization uniformity (DOPU) imaging obtained by polarization-sensitive optical coherence tomography (PS-OCT) has the potential to provide biomarkers for retinal diseases. It highlights abnormalities in the retinal pigment epithelium that are not always clear in the OCT intensity images. However, a PS-OCT system is more complicated than conventional OCT. We present a neural-network-based approach to estimate the DOPU from standard OCT images. DOPU images were used to train a neural network to synthesize the DOPU from single-polarization-component OCT intensity images. DOPU images were then synthesized by the neural network, and the clinical findings from ground truth DOPU and synthesized DOPU were compared. There is a good agreement in the findings for RPE abnormalities: recall was 0.869 and precision was 0.920 for 20 cases with retinal diseases. In five cases of healthy volunteers, no abnormalities were found in either the synthesized or ground truth DOPU images. The proposed neural-network-based DOPU synthesis method demonstrates the potential of extending the features of retinal non-PS OCT.

Multi-focus averaging for multiple scattering suppression in optical coherence tomography.

Multiple scattering is one of the main factors that limits the penetration depth of optical coherence tomography (OCT) in scattering samples. We propose a method termed multi-focus averaging (MFA) to suppress the multiple-scattering signals and improve the image contrast of OCT in deep regions. The MFA method captures multiple OCT volumes with various focal positions and averages them in complex form after correcting the varying defocus through computational refocusing. Because the multiple-scattering takes different trajectories among the different focal position configurations, this averaging suppresses the multiple-scattering signal. Meanwhile, the single-scattering takes a consistent trajectory regardless of the focal position configuration and is not suppressed. Hence, the MFA method improves the ratio between the single-scattering signal and multiple-scattering signal, resulting in an enhancement in the image contrast. A scattering phantom and a postmortem zebrafish were measured to validate the proposed method. The results showed that the contrast of intensity images of both the phantom and zebrafish were improved using the MFA method, such that they were better than the contrast provided by the standard single focus averaging method. The MFA method provides a cost-effective solution for contrast enhancement through multiple-scattering reduction in tissue imaging using OCT systems.

Birefringence-derived artifact in optical coherence tomography imaging of the lamina cribrosa in eyes with glaucoma.

We investigated birefringence-derived artifacts that potentially mimic focal defects of the lamina cribrosa (focal LC defects) in optical coherence tomography (OCT) imaging of eyes with glaucoma. This study included 74 eyes of 48 patients with glaucoma. Five horizontal line B-scan images of the optic disc were obtained using commercial swept-source OCT. From a dataset of prototype swept-source polarization-diversity OCT, we calculated the following types of OCT images: polarization-dependent, polarization-dependent attenuation-coefficient, polarization-independent, and polarization-independent attenuation-coefficient. We assessed the commercial OCT images for the presence of birefringence-derived artifacts by comparison with the polarization-diversity OCT images. Commercial OCT showed suggestive findings of focal LC defects in 17 of 74 eyes. Reevaluation using polarization-independent OCT revealed that the focal LC defects in one of 17 eyes (5.9%) were actually birefringence-derived artifacts. This study demonstrated the existence of birefringence-derived artifacts mimicking focal LC defects in commercial OCT imaging and indicated that polarization-diversity OCT is an effective tool to evaluate the presence of these artifacts.

Renal tubular function and morphology revealed in kidney without labeling using three-dimensional dynamic optical coherence tomography.

Renal tubule has distinct metabolic features and functional activity that may be altered during kidney disease. In this paper, we present label-free functional activity imaging of renal tubule in normal and obstructed mouse kidney models using three-dimensional (3D) dynamic optical coherence tomography (OCT) ex vivo. To create an obstructed kidney model, we ligated the ureter of the left kidney for either 7 or 14 days. Two different dynamic OCT (DOCT) methods were implemented to access the slow and fast activity of the renal tubules: a logarithmic intensity variance (LIV) method and a complex-correlation-based method. Three-dimensional DOCT data were acquired with a 1.3 [Formula: see text]m swept-source OCT system and repeating raster scan protocols. In the normal kidney, the renal tubule appeared as a convoluted pipe-like structure in the DOCT projection image. Such pipe-like structures were not observed in the kidneys subjected to obstruction of the ureter for several days. Instead of any anatomical structures, a superficial high dynamics appearance was observed in the perirenal cortex region of the obstructed kidneys. These findings suggest that volumetric LIV can be used as a tool to investigate kidney function during kidney diseases.

Label-free drug response evaluation of human derived tumor spheroids using three-dimensional dynamic optical coherence tomography.

This study aims at demonstrating label-free drug-response-patterns assessment of different tumor spheroids and drug types by dynamic optical coherence tomography (D-OCT). The study involved human breast cancer (MCF-7) and colon cancer (HT-29) spheroids. The MCF-7 and HT-29 spheroids were treated with paclitaxel (Taxol; PTX) and the active metabolite of irinotecan SN-38, respectively. The drugs were applied with 0 (control), 0.1, 1, and 10 µM concentrations and the treatment durations were 1, 3, and 6 days. A swept-source OCT microscope equipped with a repeated raster scanning protocol was used to scan the spheroids. Logarithmic intensity variance (LIV) and late OCT correlation decay speed (OCDS[Formula: see text]) algorithms were used to visualize the tumor spheroid dynamics. LIV and OCDS[Formula: see text] images visualized different response patterns of the two types of spheroids. In addition, spheroid morphology, LIV, and OCDS[Formula: see text] quantification showed different time-courses among the spheroid and drug types. These results may indicate different action mechanisms of the drugs. The results showed the feasibility of D-OCT for the evaluation of drug response patterns of different cell spheroids and drug types and suggest that D-OCT can perform anti-cancer drug testing.

Label-free intratissue activity imaging of alveolar organoids with dynamic optical coherence tomography.

An organoid is a three-dimensional (3D) in vitro cell culture emulating human organs. We applied 3D dynamic optical coherence tomography (DOCT) to visualize the intratissue and intracellular activities of human induced pluripotent stem cells (hiPSCs)-derived alveolar organoids in normal and fibrosis models. 3D DOCT data were acquired with an 840-nm spectral domain optical coherence tomography with axial and lateral resolutions of 3.8 µm (in tissue) and 4.9 µm, respectively. The DOCT images were obtained by the logarithmic-intensity-variance (LIV) algorithm, which is sensitive to the signal fluctuation magnitude. The LIV images revealed cystic structures surrounded by high-LIV borders and mesh-like structures with low LIV. The former may be alveoli with a highly dynamics epithelium, while the latter may be fibroblasts. The LIV images also demonstrated the abnormal repair of the alveolar epithelium.