Computational refocusing in phase-unstable polarization-sensitive optical coherence tomography.

We present computational refocusing in polarization-sensitive optical coherence tomography (PS-OCT) to improve spatial resolution in the calculated polarimetric parameters and extend the depth-of-field in phase-unstable, fiber-based PS-OCT systems. To achieve this, we successfully adapted short A-line range phase-stability adaptive optics (SHARP), a computational aberration correction technique compatible with phase-unstable systems, into a Stokes-based PS-OCT system with inter-A-line polarization modulation. Together with the spectral binning technique to mitigate system-induced chromatic polarization effects, we show that computational refocusing improves image quality in tissue polarimetry of swine eye anterior segment ex vivo with PS-OCT. The benefits, drawbacks, and potential applications of computational refocusing in anterior segment imaging are discussed.

Endoscopic imaging of white matter fiber tracts using polarization-sensitive optical coherence tomography.

Polarization sensitive optical coherence tomography (PSOCT) has been shown to image and delineate white matter fibers in a label-free manner by revealing optical birefringence within the myelin sheath using a microscope setup. In this proof-of-concept study, we adapt recent advancements in endoscopic PSOCT to perform depth-resolved imaging of white matter structures deep inside intact porcine brain tissue ex-vivo, through a small, rotational fiber probe. The probe geometry is comparable to microelectrodes currently used in neurosurgical interventions. The presented imaging system is mobile, robust, and uses biologically safe levels of optical radiation making it well suited for clinical translation. In neurosurgery, where accuracy is imperative, endoscopic PSOCT through a narrow-gauge fiber probe could provide intra-operative feedback on the location of critical white matter structures.

Polarimetric Signatures of Coronary Thrombus in Patients With Acute Coronary Syndrome.

BACKGROUND: Intravascular polarization-sensitive optical frequency domain imaging (PS-OFDI) offers a novel approach to measure tissue birefringence, which is elevated in collagen and smooth muscle cells, that in turn plays a critical role in healing coronary thrombus (HCT). This study aimed to quantitatively assess polarization properties of coronary fresh and organizing thrombus with PS-OFDI in patients with acute coronary syndrome (ACS).Methods and Results:The POLARIS-I prospective registry enrolled 32 patients with ACS. Pre-procedural PS-OFDI pullbacks using conventional imaging catheters revealed 26 thrombus-regions in 21 patients. Thrombus was manually delineated in conventional OFDI cross-sections separated by 0.5 mm and categorized into fresh thrombus caused by plaque rupture, stent thrombosis, or erosion in 18 thrombus-regions (182 frames) or into HCT for 8 thrombus-regions (141 frames). Birefringence of coronary thrombus was compared between the 2 categories. Birefringence in HCTs was significantly higher than in fresh thrombus (∆n=0.47 (0.37-0.72) vs. ∆n=0.25 (0.17-0.29), P=0.007). In a subgroup analysis, when only using thrombus-regions from culprit lesions, ischemic time was a significant predictor for birefringence (ß (∆n)=0.001 per hour, 95% CI [0.0002-0.002], P=0.023). CONCLUSIONS: Intravascular PS-OFDI offers the opportunity to quantitatively assess the polarimetric properties of fresh and organizing coronary thrombus, providing new insights into vascular healing and plaque stability.

Whole Murine Brain Imaging Based on Optical Elastic Scattering.

Imaging whole brains is one of the central efforts of biophotonics. While the established imaging modalities used in radiology, such as MRI and CT, have enabled in vivo investigations of various cognitive and affective processes, the prevailing resolution of one-cubic-millimeter has limited their use in studying the "ground-truth" of neuronal activities. On the other hand, electron microscopy (EM) visualizes the finest anatomic structures at a resolution of around 30 nm. However, the extensive tissue preparation process and the required large-scale morphological reconstruction restrict this method to small sample volumes. Light microscopy (LM) has the potential to bridge the above two spatial scales, with a resolution ranging from a few hundred nanometers to a few micrometers. Recent advances in tissue clearing have paved the way for optical investigation of large intact tissue volumes. However, most of these LM studies rely on fluorescence-a nonlinear optical process to provide contrast. This chapter introduces an alternative type of LM that is solely based on a linear optical process-elastic scattering, which has some unique advantages over conventional LM methods for the investigation of large-scale biological systems, such as intact murine brains. Here, we will first lay out the background and the motivation of developing this scattering-based method. Then, the basic principle of this approach will be introduced, including controlling tissue scattering and coherent imaging. Next, we explore current implementation and practical considerations. Up-to-date results and the utility of this method will also be demonstrated. Finally, we discuss current limitations and future directions in this promising field.

Retinal imaging in Alzheimer's and neurodegenerative diseases.

In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.

Linear-in-wavenumber actively-mode-locked wavelength-swept laser.

We report on an akinetic actively-mode-locked wavelength-swept laser (ASL) with a sweep that is highly linear in wavenumber. By tailoring the drive waveform of the intracavity modulator, the wavenumber sweep was further linearized to enable high fidelity frequency-domain interferometric ranging without resampling of the acquired data. Used for catheter-based optical coherence tomography, the ASL showed comparable imaging performance to a state-of-the-art polygon-based wavelength-swept source at a matching sweep rate of 103.6 kHz, a duty cycle of 95%, and a bandwidth of 100 nm, centered at 1330 nm.

Computational adaptive optics in phase-unstable optical coherence tomography.

We present a scheme for correction of x-y-separable aberrations in optical coherence tomography (OCT) designed to work with phase unstable systems with no hardware modifications. Our approach, termed SHARP, is based on computational adaptive optics and numerical phase correction and follows from the fact that local phase stability is sufficient for the deconvolution of optical aberrations. We demonstrate its applicability in a raster-scan polygon-laser OCT system with strong phase-jitter noise, achieving successful refocusing at depths up to 4 times the Rayleigh range. We also present in vivo endoscopic and ex vivo anterior segment OCT data, showing significant enhancement of image quality, particularly when combining SHARP results with a resolution-preserving despeckling technique like TNode.

Motorized capsule for shadow-free OCT imaging and synchronous beam control.

We demonstrate a tethered motorized capsule for unobstructed optical coherence tomography (OCT) imaging of the esophagus. By using a distal reflector design, we avoided the common shadow artifact induced by the motor wires. A synchronous driving technique features three types of beam-scanning modes of the capsule, i.e., circumferential beam scanning, localized beam scanning, and accurate beam positioning. We characterized these three modes and carried out ex vivo imaging experiments using the capsule. The results show that the capsule can potentially be a useful tool for diagnostic OCT imaging and OCT-guided biopsy and therapy of the esophagus.

Robust wavenumber and dispersion calibration for Fourier-domain optical coherence tomography.

Many Fourier-domain optical coherence tomography (FD-OCT) systems sample the interference fringes with a non-uniform wavenumber (k) interval, introducing a chirp to the signal that depends on the path length difference underlying each fringe. A dispersion imbalance between sample and reference arms also generates a chirp in the fringe signal which, in contrast, is independent of depth. Fringe interpolation to obtain a signal linear in k and compensate dispersion imbalance is critical to achieving bandwidth-limited axial resolution. In this work, we propose an optimization-based algorithm to perform robust and automated calibration of FD-OCT systems, recovering both the interpolation function and the dispersion imbalance. Our technique relies on the fact that the unique function that correctly linearizes the fringe data in k space produces a depth-independent chirp. The calibration procedure requires experimental data corresponding to a single reflector at various depth locations, which can easily be obtained by acquiring data while moving a sample mirror in depth. We have tested both spectral domain OCT and swept source OCT systems with various nonlinearities. Results indicate that the proposed calibration method has excellent performance on a wide range of data sets and enables nearly constant resolution at all imaging depths. An implementation of the algorithm is available online.

Radiometric model for coaxial single- and multimode optical emission from double-clad fiber.

Double-clad fibers (DCFs) are versatile waveguides supporting a single-mode core surrounded by a multimode inner cladding. DCFs are increasingly used for multimodal biomedical applications, such as imaging or therapy, for which the core is typically used for coherent illumination and the inner cladding, to support a concurrent modality. Proper optimization is, however, critical to ensure high optical performance and requires accurate modeling of coaxial single- and multimode output beams. In this paper, we present an approach based on geometrical optics and radiometry, which provides a simple and efficient modeling tool for designing and optimizing DCF-based systems. A radiometric definition of single- and multimode output beams in terms of irradiance and radiant intensity allows for the modeling of the energy distribution along the beams' propagation. We confirmed the validity of the model through comparison with experimental measurements and demonstrate the use of the model for optimizing a catheter for concurrent OCT and laser coagulation.

Extended bandwidth wavelength swept laser source for high resolution optical frequency domain imaging.

Improving the axial resolution by providing wider bandwidth wavelength swept lasers remains an important issue for optical frequency domain imaging (OFDI). Here, we demonstrate a wide tuning range, all-fiber wavelength swept laser at a center wavelength of 1250 nm by combining two ring cavities that share a single Fabry-Perot tunable filter. The two cavities contain semiconductor optical amplifiers with central wavelengths of 1190 nm and 1292 nm, respectively. To avoid disturbing interference effects in the overlapping spectral region, we modulated the amplifiers in order to obtain consecutive wavelength sweeps in the two spectral regions. The two sweeps were fused together in post-processing to achieve a total scanning range of 223 nm, corresponding to 3.3 µm axial resolution in air. We confirm improved image quality and reduced speckle size in tomograms of swine esophagus ex vivo, and human skin and nailbed in vivo.

Rotational distortion correction in endoscopic optical coherence tomography based on speckle decorrelation.

We present a new technique for the correction of nonuniform rotation distortion in catheter-based optical coherence tomography (OCT), based on the statistics of speckle between A-lines using intensity-based dynamic light scattering. This technique does not rely on tissue features and can be performed on single frames of data, thereby enabling real-time image correction. We demonstrate its suitability in a gastrointestinal (GI) balloon-catheter OCT system, determining the actual rotational speed with high temporal resolution, and present corrected cross-sectional and en face views showing significant enhancement of image quality.

Single input state, single-mode fiber-based polarization-sensitive optical frequency domain imaging by eigenpolarization referencing.

Fiber-based polarization-sensitive optical frequency domain imaging is more challenging than free-space implementations. Using multiple input states, fiber-based systems provide sample birefringence information with the benefit of a flexible sample arm but come at the cost of increased system and acquisition complexity, and either reduce acquisition speed or require increased acquisition bandwidth. Here we show that with the calibration of a single polarization state, fiber-based configurations can approach the conceptual simplicity of traditional free-space configurations. We remotely control the polarization state of the light incident at the sample using the eigenpolarization states of a wave plate as a reference, and determine the Jones matrix of the output fiber. We demonstrate this method for polarization-sensitive imaging of biological samples.

Degree of polarization (uniformity) and depolarization index: unambiguous depolarization contrast for optical coherence tomography.

The degree of polarization (uniformity) has attracted increased interest as a functional contrast in optical coherence tomography (OCT). However, its computation from a single polarization state suggests an ambiguity that is strongly dependent on a sample's orientation. We here propose an improved metric to present depolarization with respect to the optical system rather than the propagating field. Using numerical simulations and optical frequency domain imaging, we evaluate the conventional DOP(U) for different polarization states and compare its performance with the unambiguous depolarization index.

Quantitative technique for robust and noise-tolerant speed measurements based on speckle decorrelation in optical coherence tomography.

Intensity-based techniques in optical coherence tomography (OCT), such as those based on speckle decorrelation, have attracted great interest for biomedical and industrial applications requiring speed or flow information. In this work we present a rigorous analysis of the effects of noise on speckle decorrelation, demonstrate that these effects frustrate accurate speed quantitation, and propose new techniques that achieve quantitative and repeatable measurements. First, we derive the effect of background noise on the speckle autocorrelation function, finding two detrimental effects of noise. We propose a new autocorrelation function that is immune to the main effect of background noise and permits quantitative measurements at high and moderate signal-to-noise ratios. At the same time, this autocorrelation function is able to provide motion contrast information that accurately identifies areas with movement, similar to speckle variance techniques. In order to extend the SNR range, we quantify and model the second effect of background noise on the autocorrelation function through a calibration. By obtaining an explicit expression for the decorrelation time as a function of speed and diffusion, we show how to use our autocorrelation function and noise calibration to measure a flowing liquid. We obtain accurate results, which are validated by Doppler OCT, and demonstrate a very high dynamic range (> 600 mm/s) compared to that of Doppler OCT (±25 mm/s). We also derive the behavior for low flows, and show that there is an inherent non-linearity in speed measurements in the presence of diffusion due to statistical fluctuations of speckle. Our technique allows quantitative and robust measurements of speeds using OCT, and this work delimits precisely the conditions in which it is accurate.

High-energy pulsed Raman fiber laser for biological tissue coagulation.

We demonstrate a high-energy pulsed Raman fiber laser (RFL) with an emission wavelength of 1.44 µm, corresponding to an absorption peak of water. Microsecond pulses with >20 mJ/pulse and >40 W peak power were generated, well above the threshold for tissue coagulation and ablation. Here, we focus on the optical characterization and optimization of high-energy and high-power RFLs excited by an ytterbium fiber laser, comparing three configurations that use different Raman gain fibers, but all of which were prepared with a one-side opened, free-run mode without output mirrors. We show that the free-run configuration can generate sufficiently high energy without requiring a closed cavity design. Experimental RFL characteristics corresponded well with numerical simulations. We discuss the Stokes beam generation process in our system and loss mechanisms mainly associated with fiber Bragg gratings.

All-fiber wavelength swept ring laser based on Fabry-Perot filter for optical frequency domain imaging.

Innovations in laser engineering have yielded several novel configurations for high repetition rate, broad sweep range, and long coherence length wavelength swept lasers. Although these lasers have enabled high performance frequency-domain optical coherence tomography, they are typically complicated and costly and many require access to proprietary materials or devices. Here, we demonstrate a simplified ring resonator configuration that is straightforward to construct from readily available materials at a low total cost. It was enabled by an insight regarding the significance of isolation against bidirectional operation and by configuring the sweep range of the intracavity filter to exceed its free spectral range. The design can easily be optimized to meet a range of operating specifications while yielding robust and stable performance. As an example, we demonstrate 240 kHz operation with 125 nm sweep range and >70 mW of average output power and demonstrate high quality frequency domain OCT imaging. The complete component list and directions for assembly of the laser are posted on-line at www.octresearch.org.

Practical decomposition for physically admissible differential Mueller matrices.

The differential Mueller matrix expresses the local action of an optical medium on the evolution of a propagating electromagnetic field, including partially coherent and partially polarized waves. Here, we present a derivation of the differential Mueller matrix from the canonical form of Type I Mueller matrices without making use of the exponential generators of uniform media. We demonstrate how to practically obtain this parameterization numerically using an eigenvalue decomposition and find validity criteria to ensure that the matrix satisfies the constraints of a physical system. This provides a convenient tool-set to investigate depolarization effects and extends previous treatments of the differential Mueller matrix formalism.

Esophageal-guided biopsy with volumetric laser endomicroscopy and laser cautery marking: a pilot clinical study.

BACKGROUND: Biopsy surveillance protocols for the assessment of Barrett's esophagus can be subject to sampling errors, resulting in diagnostic uncertainty. Optical coherence tomography is a cross-sectional imaging technique that can be used to conduct volumetric laser endomicroscopy (VLE) of the entire distal esophagus. We have developed a biopsy guidance platform that places endoscopically visible marks at VLE-determined biopsy sites. OBJECTIVE: The objective of this study was to demonstrate in human participants the safety and feasibility of VLE-guided biopsy in vivo. DESIGN: A pilot feasibility study. SETTING: Massachusetts General Hospital. PATIENTS: A total of 22 participants were enrolled from January 2011 to June 2012 with a prior diagnosis of Barrett's esophagus. Twelve participants were used to optimize the laser marking parameters and the system platform. A total of 30 target sites were selected and marked in real-time by using the VLE-guided biopsy platform in the remaining 10 participants. INTERVENTION: Volumetric laser endomicroscopy. MAIN OUTCOME MEASUREMENTS: Endoscopic and VLE visibility, and accuracy of VLE diagnosis of the tissue between the laser cautery marks. RESULTS: There were no adverse events of VLE and laser marking. The optimal laser marking parameters were determined to be 2 seconds at 410 mW, with a mark separation of 6 mm. All marks made with these parameters were visible on endoscopy and VLE. The accuracies for diagnosing tissue in between the laser cautery marks by independent blinded readers for endoscopy were 67% (95% confidence interval [CI], 47%-83%), for VLE intent-to-biopsy images 93% (95% CI, 78%-99%), and for corrected VLE post-marking images 100% when compared with histopathology interpretations. LIMITATIONS: This is a single-center feasibility study with a limited number of patients. CONCLUSION: Our results demonstrate that VLE-guided biopsy of the esophagus is safe and can be used to guide biopsy site selection based on the acquired volumetric optical coherence tomography imaging data. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01439633.).

Aging of deep venous thrombosis in-vivo using polarization sensitive optical coherence tomography.

Deep venous thrombosis (DVT) is a medical condition with significant post-event morbidity and mortality coupled with limited treatment options. Treatment strategy and efficacy are highly dependent on the structural composition of the thrombus, which evolves over time from initial formation and is currently unevaluable with standard clinical testing. Here, we investigate the use of intravascular polarization-sensitive optical coherence tomography (PS-OCT) to assess thrombus morphology and composition in a rat DVT model in-vivo, including changes that occur over the thrombus aging process. PS-OCT measures tissue birefringence, which provides contrast for collagen and smooth muscle cells that are present in older, chronic clots. Thrombi in the inferior vena cava of two cohorts of rats were imaged in-vivo with intravascular PS-OCT at 24 hours (acute, nrats = 3, 73 cross-sections) or 28 days (chronic, nrats = 4, 41 cross-sections) after thrombus formation. Co-registered histology was labelled by an independent pathologist to establish ground-truth clot composition. Automated analysis of OCT cross-sectional images differentiated acute and chronic thrombi with 97.6% sensitivity and 98.6% specificity using a linear discriminant model comprised of both polarization and conventional OCT metrics. These results support PS-OCT as a highly sensitive imaging modality for the assessment of DVT composition to differentiate acute and chronic thrombi. Intravascular PS-OCT imaging could be integrated with advanced catheter-based treatment strategies and serve to guide therapeutic decision-making and deployment, by offering an accurate assessment of DVT patients in real time.