Multifunctional Ablative Gastrointestinal Imaging Capsule (MAGIC) for Esophagus Surveillance and Interventions.

Objective and Impact Statement: A clinically viable technology for comprehensive esophagus surveillance and potential treatment is lacking. Here, we report a novel multifunctional ablative gastrointestinal imaging capsule (MAGIC) technology platform to address this clinical need. The MAGIC technology could also facilitate the clinical translation and adoption of the tethered capsule endomicroscopy (TCE) technology. Introduction: Recently developed optical coherence tomography (OCT) TCE technologies have shown a promising potential for surveillance of Barrett's esophagus and esophageal cancer in awake patients without the need for sedation. However, it remains challenging with the current TCE technology for detecting early lesions and clinical adoption due to its suboptimal resolution, imaging contrast, and lack of visual guidance during imaging. Methods: Our technology reported here integrates dual-wavelength OCT imaging (operating at 800 and 1300 nm), an ultracompact endoscope camera, and an ablation laser, aiming to enable comprehensive surveillance, guidance, and potential ablative treatment of the esophagus. Results: The MAGIC has been successfully developed with its multimodality imaging and ablation capabilities demonstrated by imaging swine esophagus ex vivo and in vivo. The 800-nm OCT imaging offers exceptional resolution and contrast for the superficial layers, well suited for detecting subtle changes associated with early neoplasia. The 1300-nm OCT imaging provides deeper penetration, essential for assessing lesion invasion. The built-in miniature camera affords a conventional endoscopic view for assisting capsule deployment and laser ablation. Conclusion: By offering complementary and clinically viable functions in a single device, the reported technology represents an effective solution for endoscopic screening, diagnosis, and potential ablation treatment of the esophagus of a patient in an office setting.

Deep learning-based optical coherence tomography image analysis of human brain cancer.

Real-time intraoperative delineation of cancer and non-cancer brain tissues, especially in the eloquent cortex, is critical for thorough cancer resection, lengthening survival, and improving quality of life. Prior studies have established that thresholding optical attenuation values reveals cancer regions with high sensitivity and specificity. However, threshold of a single value disregards local information important to making more robust predictions. Hence, we propose deep convolutional neural networks (CNNs) trained on labeled OCT images and co-occurrence matrix features extracted from these images to synergize attenuation characteristics and texture features. Specifically, we adapt a deep ensemble model trained on 5,831 examples in a training dataset of 7 patients. We obtain 93.31% sensitivity and 97.04% specificity on a holdout set of 4 patients without the need for beam profile normalization using a reference phantom. The segmentation maps produced by parsing the OCT volume and tiling the outputs of our model are in excellent agreement with attenuation mapping-based methods. Our new approach for this important application has considerable implications for clinical translation.

Direct Visualization and Quantitative Imaging of Small Airway Anatomy In Vivo Using Deep Learning Assisted Diffractive OCT.

OBJECTIVE/BACKGROUND: In vivo imaging and quantification of the microstructures of small airways in three dimensions (3D) allows a better understanding and management of airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). At present, the resolution and contrast of the currently available conventional optical coherence tomography (OCT) imaging technologies operating at 1300 nm remain challenging to directly visualize the fine microstructures of small airways in vivo. METHODS: We developed an ultrahigh-resolution diffractive endoscopic OCT at 800 nm to afford a resolving power of 1.7 µm (in tissue) with an improved contrast and a custom deep residual learning based image segmentation framework to perform accurate and automated 3D quantification of airway anatomy. RESULTS: The 800-nm diffractive OCT enabled the direct delineation of the structural components in the small airway wall in vivo. We further first demonstrated the 3D anatomic quantification of critical tissue compartments of small airways in sheep using the automated segmentation method. CONCLUSION: The deep learning assisted diffractive OCT provides a unique ability to access the small airways, directly visualize and quantify the important tissue compartments, such as airway smooth muscle, in the airway wall in vivo in 3D. SIGNIFICANCE: These pilot results suggest a potential technology for calculating volumetric measurements of small airways in patients in vivo.

Deep-learning two-photon fiberscopy for video-rate brain imaging in freely-behaving mice.

Scanning two-photon (2P) fiberscopes (also termed endomicroscopes) have the potential to transform our understanding of how discrete neural activity patterns result in distinct behaviors, as they are capable of high resolution, sub cellular imaging yet small and light enough to allow free movement of mice. However, their acquisition speed is currently suboptimal, due to opto-mechanical size and weight constraints. Here we demonstrate significant advances in 2P fiberscopy that allow high resolution imaging at high speeds (26 fps) in freely-behaving mice. A high-speed scanner and a down-sampling scheme are developed to boost imaging speed, and a deep learning (DL) algorithm is introduced to recover image quality. For the DL algorithm, a two-stage learning transfer strategy is established to generate proper training datasets for enhancing the quality of in vivo images. Implementation enables video-rate imaging at ~26 fps, representing 10-fold improvement in imaging speed over the previous 2P fiberscopy technology while maintaining a high signal-to-noise ratio and imaging resolution. This DL-assisted 2P fiberscope is capable of imaging the arousal-induced activity changes in populations of layer2/3 pyramidal neurons in the primary motor cortex of freely-behaving mice, providing opportunities to define the neural basis of behavior.

Visualization and Validation of The Microstructures in The Airway Wall in vivo Using Diffractive Optical Coherence Tomography.

RATIONALE AND OBJECTIVES: At present, there is no available method to study the in vivo microstructures of the airway wall (epithelium, smooth muscle, adventitia, basement membrane, glands, cartilage). Currently, we rely on ex vivo histologic evaluation of airway biopsies. To overcome this obstacle, we have developed an endoscopic ultrahigh-resolution diffractive optical coherence tomography (OCT) system, operating at a wavelength of 800 nm, to non-invasively study the in vivo microstructures of the airway wall. Prior to human study, validation of diffractive OCT's ability to quantitate airway microstructural components is required. MATERIALS AND METHODS: To validate and demonstrate the accuracy of this OCT system, we used an ovine model to image small airways (∼ 2 mm in diameter). Histologic samples and correlated OCT images were matched. The cross-sectional area of the airway wall, lumen, and other microstructures were measured and compared. RESULTS: A total of 27 sheep were studied from which we identified 39 paired OCT-histology airway images. We found strong correlations between the OCT and the histology measurements of the airway wall area and the microstructural area measurements of the epithelium, basement membrane, airway smooth muscle, glands, cartilage, and adventitia. The correlations ranged from r=0.61 (p<0.001) for the epithelium to r=0.86 (p<0.001) for the adventitia with the correlation between the OCT and the histology measurements for the entire airway wall of r=0.76 (p<0.001). CONCLUSION: Given the high degree of correlation, these data validate the ability to acquire and quantify in vivo microscopic level imaging with this newly developed 800nm ultra-high resolution diffractive OCT system.

Minimizing OCT quantification error via a surface-tracking imaging probe.

OCT-based quantitative tissue optical properties imaging is a promising technique for intraoperative brain cancer assessment. The attenuation coefficient analysis relies on the depth-dependent OCT intensity profile, thus sensitive to tissue surface positions relative to the imaging beam focus. However, it is almost impossible to maintain a steady tissue surface during intraoperative imaging due to the patient's arterial pulsation and breathing, the operator's motion, and the complex tissue surface geometry of the surgical cavity. In this work, we developed an intraoperative OCT imaging probe with a surface-tracking function to minimize the quantification errors in optical attenuation due to the tissue surface position variations. A compact OCT imaging probe was designed and engineered to have a long working distance of ∼ 41 mm and a large field of view of 4 × 4 mm2 while keeping the probe diameter small (9 mm) to maximize clinical versatility. A piezo-based linear motor was integrated with the imaging probe and controlled based upon real-time feedback of tissue surface position inferred from OCT images. A GPU-assisted parallel processing algorithm was implemented, enabling detection and tracking of tissue surface in real-time and successfully suppressing more than 90% of the typical physiologically induced motion range. The surface-tracking intraoperative OCT imaging probe could maintain a steady beam focus inside the target tissue regardless of the surface geometry or physiological motions and enabled to obtain tissue optical attenuation reliably for assessing brain cancer margins in challenging intraoperative settings.

Label-free imaging of human brain tissue at subcellular resolution for potential rapid intra-operative assessment of glioma surgery.

Background: Frozen section and smear preparation are the current standard for intraoperative histopathology during cancer surgery. However, these methods are time-consuming and subject to limited sampling. Multiphoton microscopy (MPM) is a high-resolution non-destructive imaging technique capable of optical sectioning in real time with subcellular resolution. In this report, we systematically investigated the feasibility and translation potential of MPM for rapid histopathological assessment of label- and processing-free surgical specimens. Methods: We employed a customized MPM platform to capture architectural and cytological features of biological tissues based on two-photon excited NADH and FAD autofluorescence and second harmonic generation from collagen. Infiltrating glioma, an aggressive disease that requires subcellular resolution for definitive characterization during surgery, was chosen as an example for this validation study. MPM images were collected from resected brain specimens of 19 patients and correlated with histopathology. Deep learning was introduced to assist with image feature recognition. Results: MPM robustly captures diagnostic features of glioma including increased cellularity, cellular and nuclear pleomorphism, microvascular proliferation, necrosis, and collagen deposition. Preliminary application of deep learning to MPM images achieves high accuracy in distinguishing gray from white matter and cancer from non-cancer. We also demonstrate the ability to obtain such images from intact brain tissue with a multiphoton endomicroscope for intraoperative application. Conclusion: Multiphoton imaging correlates well with histopathology and is a promising tool for characterization of cancer and delineation of infiltration within seconds during brain surgery.

In vivo assessment of vascular-targeted photodynamic therapy effects on tumor microvasculature using ultrahigh-resolution functional optical coherence tomography.

Vascular-targeted photodynamic therapy (VTP) is an emerging treatment for tumors. The change of tumor vasculatures, including a newly-formed microvascular, in response to VTP, is a key assessment parameter for optimizing the treatment effect. However, an accurate assessment of vasculature, particularly the microvasculature's changes in vivo, remains challenging due to the limited resolution afforded by existing imaging modalities. In this study, we demonstrated the in vivo imaging of VTP effects on an A431 tumor-bearing window chamber model of a mouse with an 800-nm ultrahigh-resolution functional optical coherence tomography (UHR-FOCT). We further quantitatively demonstrated the effects of VTP on the size and density of tumor microvasculature before, during, and after the treatment. Our results suggest the promising potential of UHR-FOCT for assessing the tumor treatment with VTP in vivo and in real time to achieve an optimal outcome.

Throughput-Speed Product Augmentation for Scanning Fiber-Optic Two-Photon Endomicroscopy.

Compactness, among several others, is one unique and very attractive feature of a scanning fiber-optic two-photon endomicroscope. To increase the scanning area and the total number of resolvable pixels (i.e., the imaging throughput), it typically requires a longer cantilever which, however, leads to a much undesired, reduced scanning speed (and thus imaging frame rate). Herein we introduce a new design strategy for a fiber-optic scanning endomicroscope, where the overall numerical aperture (NA) or beam focusing power is distributed over two stages: 1) a mode-field focuser engineered at the tip of a double-clad fiber (DCF) cantilever to pre-amplify the single-mode core NA, and 2) a micro objective of a lower magnification (i.e.,  âˆ¼ 2× in this design) to achieve final tight beam focusing. This new design enables either an ~9-fold increase in imaging area (throughput) or an ~3-fold improvement in imaging frame rate when compared to traditional fiber-optic endomicroscope designs. The performance of an as-designed endomicroscope of an enhanced throughput-speed product was demonstrated by two representative applications: (1) high-resolution imaging of an internal organ (i.e., mouse kidney) in vivo over a large field of view without using any fluorescent contrast agents, and (2) real-time neural imaging by visualizing dendritic calcium dynamics in vivo with sub-second temporal resolution in GCaMP6m-expressing mouse brain. This cascaded NA amplification strategy is universal and can be readily adapted to other types of fiber-optic scanners in compact linear or nonlinear endomicroscopes.

High-speed fiber-optic scanning nonlinear endomicroscopy for imaging neuron dynamicsin vivo.

Fiber-optic-based two-photon fluorescence endomicroscopy is emerging as an enabling technology for in vivo histological imaging of internal organs and functional neuronal imaging on freely-behaving animals. However, high-speed imaging remains challenging due to the expense of miniaturization and lack of suited fast beam scanners. For many applications, a higher imaging speed is highly desired, especially for monitoring functional dynamics such as transient dendritic responses in neuroscience. This Letter reports the development of a fast fiber-optic scanning endo-microscope with an imaging speed higher than 26 frames/s. In vivo neural dynamics imaging with the high-speed endomicroscope was performed on a freely-behaving mouse over the primary motor cortex that expressed GCaMP6m. The results demonstrate its capability of real-time monitoring of transient neuronal dynamics with very fine temporal resolution.

Ultra-sensitive optical coherence elastography using a high-dynamic-range force loading scheme for cervical rigidity assessment.

An ultra-sensitive, wide-range force loading scheme is proposed for compression optical coherence elastography (OCE) that allows for the quantitative analysis of cervical tissue elasticity ex vivo. We designed a force loading apparatus featuring a water sink for minuscule incremental loading through a volume-controlled water droplet, from which the Young's modulus can be calculated by fitting the stress-strain curve. We validated the performance of the proposed OCE system on homogenous agar phantoms, showing the Young's modulus can be accurately estimated using this scheme. We then measured the Young's modulus of rodent cervical tissues acquired at different gestational ages, showing that the cervical rigidity of rodents was significantly dropped when entering the third trimester of pregnancy.

Ultralow-voltage electrothermal MEMS based fiber-optic scanning probe for forward-viewing endoscopic OCT.

We report an ultralow-voltage, electrothermal (ET) micro-electro-mechanical system (MEMS) based probe for forward-viewing endoscopic optical coherence tomography (OCT) imaging. The fully assembled probe has a diameter of 5.5 mm and a length of 55 mm, including the imaging optics and a 40 mm long fiber-optic cantilever attached on a micro-platform of the bimorph ET MEMS actuator. The ET MEMS actuator provides a sufficient mechanical actuation force as well as a large vertical displacement, achieving up to a 3 mm optical scanning range with only a 3 VACp-p drive voltage with a 1.5 VDC offset. The imaging probe was integrated with a swept-source OCT system of a 100 kHz A-scan rate, and its performance was successfully demonstrated with cross-sectional imaging of biological tissues ex vivo and in vivo at a speed up to 200 frames per second.

Parallel deep neural networks for endoscopic OCT image segmentation.

We report parallel-trained deep neural networks for automated endoscopic OCT image segmentation feasible even with a limited training data set. These U-Net-based deep neural networks were trained using a modified dice loss function and manual segmentations of ultrahigh-resolution cross-sectional images collected by an 800 nm OCT endoscopic system. The method was tested on in vivo guinea pig esophagus images. Results showed its robust layer segmentation capability with a boundary error of 1.4 µm insensitive to lay topology disorders. To further illustrate its clinical potential, the method was applied to differentiating in vivo OCT esophagus images from an eosinophilic esophagitis (EOE) model and its control group, and the results clearly demonstrated quantitative changes in the top esophageal layers' thickness in the EOE model.

Current Advances in COPD Imaging.

OBJECTIVE: To review the recent advances in available technologies for imaging COPD and present the novel optical coherence tomography (OCT) airway imaging technology. MATERIALS AND METHODS: This is an unstructured review of published evidence of available pulmonary imaging technologies along with a demonstration of state-of-the-art OCT imaging technology of in vivo human and animal airways. RESULTS: Advanced imaging techniques such as Magnetic Resonance (MR) imaging using hyperoloarized noble gases, micro-Computed Tomography (micro-CT), and OCT aim to further our understanding of COPD. Lung densitometry can aid in identifying an exacerbation prone phenotype which may have implications for targeting specific therapies to these individuals. MR ventilation scans have the ability to provide a functional and regional distribution of airflow obstruction offering insight into the airway and parenchymal changes induced by COPD. Micro-CT gives a near microscopic view of the terminal bronchioles and alveoli permitting study of the microarchitecture of the lung ex vivo. Optical coherence tomography can visualize the microstructure of the airway walls (epithelium, smooth muscle, blood vessels, cartilage) permitting real time in vivo as well as longitudinal evaluation of airway changes in patients with COPD. CONCLUSION: Advanced imaging techniques play a vital role in expanding our current understanding of COPD.

Low diffuse reflection of silver nanowire/ruthenium oxide nanosheet hybrid films for high-performance transparent flexible electrodes.

Transparent conducting electrodes (TCEs) based on silver nanowire (AgNW) networks possess high conductance, transmittance, and mechanical flexibility. However, due to the relatively high diffuse reflection of incident light on AgNWs, they cannot be practically implemented in displays requiring low pattern visibility. One promising strategy for solving this problem is to place an optical stack with high refractive index underneath the AgNW layer. In this work, AgNW-RuO2 nanosheet hybrid TCEs with low diffuse reflections are fabricated using metallic RuO2 nanosheets as undercoats. As predicted by theoretical simulations, RuO2 nanosheets with high refractive indices reduce the diffuse reflections of AgNWs by almost 8%. Moreover, after the partial etching of AgNWs, the difference in the diffuse reflections of their etched and non-etched regions becomes equal to about 0.003, leading to the formation of an invisible pattern. The film consisting of micro-sized RuO2 nanosheets is not damaged during etching, but instead forms a current path between different AgNWs broken by cyclic bending, resulting in a tenfold decrease in the resistance of the AgNW TCE after 170 000 cycles. Further, RuO2 nanosheets suppress the diffusion of humid air from the outside, thus improving the environmental stability of the AgNW-RuO2 nanosheet hybrid TCEs.

Super-achromatic optical coherence tomography capsule for ultrahigh-resolution imaging of esophagus.

Endoscopic optical coherence tomography (OCT) is a noninvasive technology allowing for imaging of tissue microanatomies of luminal organs in real time. Conventional endoscopic OCT operates at 1300 nm wavelength region with a suboptimal axial resolution limited to 8-20 µm. In this paper, we present the first ultrahigh-resolution tethered OCT capsule operating at 800 nm and offering about 3- to 4-fold improvement of axial resolution (plus enhanced imaging contrast). The capsule uses diffractive optics to manage chromatic aberration over a full ~200 nm spectral bandwidth centering around 830 nm, enabling to achieve super-achromaticity and an axial resolution of ~2.6 µm in air. The performance of the OCT capsule is demonstrated by volumetric imaging of swine esophagus ex vivo and sheep esophagus in vivo, where fine anatomic structures including the sub-epithelial layers are clearly identified. The ultrahigh resolution and excellent imaging contrast at 800 nm of the tethered capsule suggest the potential of the technology as an enabling tool for surveillance of early esophageal diseases on awake patients without the need for sedation.

Broadband rotary joint for high-speed ultrahigh-resolution endoscopic OCT imaging at 800 nm.

We report the development of a broadband rotary joint for high-speed ultrahigh-resolution endoscopic optical coherence tomography (OCT) imaging in the 800 nm spectral range. This rotary joint features a pair of achromatic doublets in order to achieve broadband operation for a 3 dB bandwidth over 150 nm. The measured one-way throughput of the rotary joint is greater than 80%, while the fluctuation of the double-pass coupling efficiency during 360 deg rotation is less than ±5% at a near video-rate speed of 20 revolutions/s (rps). The rotary joint is used in conjunction with a diffractive-optics-based endoscope and 800 nm spectral domain OCT system and achieved an ultrahigh axial resolution of ∼2.4 µm in air. The imaging performance is demonstrated by 3D circumferential imaging of a mouse colon in vivo.

Electrothermal MEMS parallel plate rotation for single-imager stereoscopic endoscopes.

This work reports electrothermal MEMS parallel plate-rotation (PPR) for a single-imager based stereoscopic endoscope. A thin optical plate was directly connected to an electrothermal MEMS microactuator with bimorph structures of thin silicon and aluminum layers. The fabricated MEMS PPR device precisely rotates an transparent optical plate up to 37° prior to an endoscopic camera and creates the binocular disparities, comparable to those from binocular cameras with a baseline distance over 100 µm. The anaglyph 3D images and disparity maps were successfully achieved by extracting the local binocular disparities from two optical images captured at the relative positions. The physical volume of MEMS PPR is well fit in 3.4 mm x 3.3 mm x 1 mm. This method provides a new direction for compact stereoscopic 3D endoscopic imaging systems.