Feasibility and Safety of Tethered Capsule Endomicroscopy in Patients With Barrett's Esophagus in a Multi-Center Study.

BACKGROUND & AIMS: Tethered capsule endomicroscopy (TCE) involves swallowing a small tethered pill that implements optical coherence tomography (OCT) imaging, procuring high resolution images of the whole esophagus. Here, we demonstrate and evaluate the feasibility and safety of TCE and a portable OCT imaging system in patients with Barrett's esophagus (BE) in a multi-center (5-site) clinical study. METHODS: Untreated patients with BE as per endoscopic biopsy diagnosis were eligible to participate in the study. TCE procedures were performed in unsedated patients by either doctors or nurses. After the capsule was swallowed, the device continuously obtained 10-µm-resolution cross-sectional images as it traversed the esophagus. Following imaging, the device was withdrawn through mouth, and disinfected for subsequent reuse. BE lengths were compared to endoscopy findings when available. OCT-TCE images were compared to volumetric laser endomicroscopy (VLE) images from a patient who had undergone VLE on the same day as TCE. RESULTS: 147 patients with BE were enrolled across all sites. 116 swallowed the capsule (79%), 95/114 (83.3%) men and 21/33 (63.6%) women (P = .01). High-quality OCT images were obtained in 104/111 swallowers (93.7%) who completed the procedure. The average imaging duration was 5.55 ± 1.92 minutes. The mean length of esophagus imaged per patient was 21.69 ± 5.90 cm. A blinded comparison of maximum extent of BE measured by OCT-TCE and EGD showed a strong correlation (r = 0.77-0.79). OCT-TCE images were of similar quality to those obtained by OCT-VLE. CONCLUSIONS: The capabilities of TCE to be used across multiple sites, be administered to unsedated patients by either physicians or nurses who are not expert in OCT-TCE, and to rapidly and safely evaluate the microscopic structure of the esophagus make it an emerging tool for screening and surveillance of BE patients. Clinical trial registry website and trial number: NCT02994693 and NCT03459339.

Optical coherence tomography-guided laser marking with tethered capsule endomicroscopy in unsedated patients.

Tethered capsule endomicroscopy (TCE) is an emerging screening technology that comprehensively obtains microstructural OCT images of the gastrointestinal (GI) tract in unsedated patients. To advance clinical adoption of this imaging technique, it will be important to validate TCE images with co-localized histology, the current diagnostic gold standard. One method for co-localizing OCT images with histology is image-targeted laser marking, which has previously been implemented using a driveshaft-based, balloon OCT catheter, deployed during endoscopy. In this paper, we present a TCE device that scans and targets the imaging beam using a low-cost stepper motor that is integrated inside the capsule. In combination with a 4-laser-diode, high power 1430/1450 nm marking laser system (800 mW on the sample and 1s pulse duration), this technology generated clearly visible marks, with a spatial targeting accuracy of better than 0.5 mm. A laser safety study was done on swine esophagus ex vivo, showing that these exposure parameters did not alter the submucosa, with a large, 4-5x safety margin. The technology was demonstrated in living human subjects and shown to be effective for co-localizing OCT TCE images to biopsies obtained during subsequent endoscopy.

Smart laser osteotomy: integrating a pulsed 1064nm fiber laser into the sample arm of a fiber optic 1310nm OCT system for ablation monitoring.

Real-time depth metrology during material removal via laser ablation is useful in many forms of laser machining. Until now, coaxial optical coherence tomography (OCT) metrology was achieved by the coupling of an OCT imaging beam and ablating beams using a dichroic filter. We present an alternative design with all fiber delivery that is more suitable for surgical laser ablation applications. The novel system design integrates a high peak-power pulsed Yb-doped fiber laser (1064nm) coupled directly into the sample arm of a swept-source OCT system (λc = 1310nm). We measured the OCT signal degradation due to dispersion and attenuation through the ablation fiber laser cavity. Ablation progression is measured in real-time using M-mode OCT. The mean depth targeting error was found to range from 10µm to 80µm in phantom ablation experiments and 21µm to 60µm in bone ablation. A number of issues have been solved, including point-spread function (PSF) peak broadening due to signal delay and dispersion, high bending loss due to dissimilar fiber used throughout the design, and problems due to the extremely high ablation power to swept-source power ratio (> 2×104 peak to average power). To our knowledge, this is the first demonstration of thermal-mediated laser ablation drilling integrated with coaxial OCT imaging through a single-mode, single-cladded output fiber, without using dichroic beam splitters or free-space optic filters anywhere in the optical path and with this high ablation laser power to OCT source power ratio. The removal of bulk optics compared to existing designs opens a new path for compact integration of the entire system. Also, since the ablation laser and OCT feedback system exist along the same fiber path, the need for maintenance and repair are greatly reduced since spatial beam alignment and the potential open-air contamination of optical surfaces are virtually eliminated. We believe that this integrated system is a great candidate for adoption in depth-controlled surgical ablation applications.

Measuring the optical characteristics of medulloblastoma with optical coherence tomography.

Medulloblastoma is the most common malignant pediatric brain tumor. Standard treatment consists of surgical resection, followed by radiation and high-dose chemotherapy. Despite these efforts, recurrence is common, leading to reduced patient survival. Even with successful treatment, there are often severe long-term neurologic impacts on the developing nervous system. We present two quantitative techniques that use a high-resolution optical imaging modality: optical coherence tomography (OCT) to measure refractive index, and the optical attenuation coefficient. To the best of our knowledge, this study is the first to demonstrate OCT analysis of medulloblastoma. Refractive index and optical attenuation coefficient were able to differentiate between normal brain tissue and medulloblastoma in mouse models. More specifically, optical attenuation coefficient imaging of normal cerebellum displayed layers of grey matter and white matter, which were indistinguishable in the structural OCT image. The morphology of the tumor was distinct in the optical attenuation coefficient imaging. These inherent properties may be useful during neurosurgical intervention to better delineate tumor boundaries and minimize resection of normal tissue.

High-resolution imaging of the central nervous system: how novel imaging methods combined with navigation strategies will advance patient care.

This narrative review captures a subset of recent advances in imaging of the central nervous system. First, we focus on improvements in the spatial and temporal profile afforded by optical coherence tomography, fluorescence-guided surgery, and Coherent Anti-Stokes Raman Scattering Microscopy. Next, we highlight advances in the generation and uses of imaging-based atlases and discuss how this will be applied to specific clinical situations. To conclude, we discuss how these and other imaging tools will be combined with neuronavigation techniques to guide surgeons in the operating room. Collectively, this work aims to highlight emerging biomedical imaging strategies that hold potential to be a valuable tool for both clinicians and researchers in the years to come.

Development of an integrated optical coherence tomography-gas nozzle system for surgical laser ablation applications: preliminary findings of in situ spinal cord deformation due to gas flow effects.

Gas assisted laser machining of materials is a common practice in the manufacturing industry. Advantages in using gas assistance include reducing the likelihood of flare-ups in flammable materials and clearing away ablated material in the cutting path. Current surgical procedures and research do not take advantage of this and in the case for resecting osseous tissue, gas assisted ablation can help minimize charring and clear away debris from the surgical site. In the context of neurosurgery, the objective is to cut through osseous tissue without damaging the underlying neural structures. Different inert gas flow rates used in laser machining could cause deformations in compliant materials. Complications may arise during surgical procedures if the dura and spinal cord are damaged by these deformations. We present preliminary spinal deformation findings for various gas flow rates by using optical coherence tomography to measure the depression depth at the site of gas delivery.

Histogram flow mapping with optical coherence tomography for in vivo skin angiography of hereditary hemorrhagic telangiectasia.

Speckle statistics of flowing scatterers have been well documented in the literature. Speckle variance optical coherence tomography exploits the large variance values of intensity changes in time caused mainly by the random backscattering of light resulting from translational activity of red blood cells to map out the microvascular networks. A method to map out the microvasculature malformation of skin based on the time-domain histograms of individual pixels is presented with results obtained from both normal skin and skin containing vascular malformation. Results demonstrated that this method can potentially map out deeper blood vessels and enhance the visualization of microvasculature in low signal regions, while being resistant against motion (e.g., patient tremor or internal reflex movements). The overall results are manifested as more uniform en face projection maps of microvessels. Potential applications include clinical imaging of skin vascular abnormalities and wide-field skin angiography for the study of complex vascular networks.

High speed, wide velocity dynamic range Doppler optical coherence tomography (Part IV): split spectrum processing in rotary catheter probes.

We report a technique for blood flow detection using split spectrum Doppler optical coherence tomography (ssDOCT) that shows improved sensitivity over existing Doppler OCT methods. In ssDOCT, the Doppler signal is averaged over multiple sub-bands of the interferogram, increasing the SNR of the Doppler signal. We explore the parameterization of this technique in terms of number of sub-band windows, width and overlap of the windows, and their effect on the Doppler signal to noise in a flow phantom. Compared to conventional DOCT, ssDOCT processing has increased flow sensitivity. We demonstrate the effectiveness of ssDOCT in-vivo for intravascular flow detection within a porcine carotid artery and for microvascular vessel detection in human pulmonary imaging, using rotary catheter probes. To our knowledge, this is the first report of visualizing in-vivo Doppler flow patterns adjacent to stent struts in the carotid artery.

Evaluation of flow velocities after carotid artery stenting through split spectrum Doppler optical coherence tomography and computational fluid dynamics modeling.

Hemodynamics plays a critical role in the development of atherosclerosis, specifically in regions of curved vasculature such as bifurcations exhibiting irregular blood flow profiles. Carotid atherosclerotic disease can be intervened by stent implantation, but this may result in greater alterations to local blood flow and consequently further complications. This study demonstrates the use of a variant of Doppler optical coherence tomography (DOCT) known as split spectrum DOCT (ssDOCT) to evaluate hemodynamic patterns both before and after stent implantation in the bifurcation junction in the internal carotid artery (ICA). Computational fluid dynamics (CFD) models were constructed to simulate blood velocity profiles and compared to the findings achieved through ssDOCT images. Both methods demonstrated noticeable alterations in hemodynamic patterns following stent implantation, with features such as slow velocity regions at the neck of the bifurcation and recirculation zones at the stent struts. Strong correlation between CFD models and ssDOCT images demonstrate the potential of ssDOCT imaging in the optimization of stent implantation in the clinical setting.

Digital image correlation-based optical coherence elastography.

Optical coherence elastography (OCE) provides deformation or material properties, mapping of soft tissue. We aim to develop a robust speckle tracking OCE technique with improved resolution and accuracy. A digital image correlation (DIC)-based OCE technique was developed by combining an advanced DIC algorithm with optical coherence tomography (OCT). System calibration and measurement error evaluation demonstrated that this DIC-based OCE technique had a resolution of ~0.6 µm displacement and <0.5% strain measurement in the axial scan direction. The measured displacement ranged from 0.6 to 150 µm, obtained via phantom imaging. The capability of the DIC-based OCE technique, for differentiation of stiffness, was evaluated by imaging a candle gel phantom with an irregularly shaped stiff inclusion. OCE imaging of a chicken breast sample differentiated the fat, membrane, and muscle layers. Strain elastograms of an aneurysm sample showed heterogeneity of the tissue and clear contrast between the adventitia and media. These promising results demonstrated the capability of the DIC-based OCE for the characterization of the various components of the tissue sample. Further improvement of the system will be conducted to make this OCE technique a practical tool for measuring and differentiating material properties of soft tissue.

Review of speckle and phase variance optical coherence tomography to visualize microvascular networks.

High-resolution mapping of microvasculature has been applied to diverse body systems, including the retinal and choroidal vasculature, cardiac vasculature, the central nervous system, and various tumor models. Many imaging techniques have been developed to address specific research questions, and each has its own merits and drawbacks. Understanding, optimization, and proper implementation of these imaging techniques can significantly improve the data obtained along the spectrum of unique research projects to obtain diagnostic clinical information. We describe the recently developed algorithms and applications of two general classes of microvascular imaging techniques: speckle-variance and phase-variance optical coherence tomography (OCT). We compare and contrast their performance with Doppler OCT and optical microangiography. In addition, we highlight ongoing work in the development of variance-based techniques to further refine the characterization of microvascular networks.

In vivo feasibility of endovascular Doppler optical coherence tomography.

Feasibility of detecting intravascular flow using a catheter based endovascular optical coherence tomography (OCT) system is demonstrated in a porcine carotid model in vivo. The effects of A-line density, radial distance, signal-to-noise ratio, non-uniform rotational distortion (NURD), phase stability of the swept wavelength laser and interferometer system on Doppler shift detection limit were investigated in stationary and flow phantoms. Techniques for NURD induced phase shift artifact removal were developed by tracking the catheter sheath. Detection of high flow velocity (~51 cm/s) present in the porcine carotid artery was obtained by phase unwrapping techniques and compared to numerical simulation, taking into consideration flow profile distortion by the eccentrically positioned imaging catheter. Using diluted blood in saline mixture as clearing agent, simultaneous Doppler OCT imaging of intravascular flow and structural OCT imaging of the carotid artery wall was feasible. To our knowledge, this is the first in vivo demonstration of Doppler imaging and absolute measurement of intravascular flow using a rotating fiber catheter in carotid artery.

Intraoperative handheld optical coherence tomography forward-viewing probe: physical performance and preliminary animal imaging.

A prototype intraoperative hand-held optical coherence tomography (OCT) imaging probe was developed to provide micron resolution cross-sectional images of subsurface tissue during open surgery. This new ergonomic probe was designed based on electrostatically driven optical fibers, and packaged into a catheter probe in the form factor of clinically accepted Bayonet shaped neurosurgical probes. Optical properties of the probe were measured to have a ~20 µm spot size, 5 mm working distance and 4 mm field of view. Feasibility of this probe for structural and Doppler shift imaging was tested on porcine femoral blood vessel imaging.

Endovascular optical coherence tomography intensity kurtosis: visualization of vasa vasorum in porcine carotid artery.

Application of speckle variance optical coherence tomography (OCT) to endovascular imaging faces difficulty of extensive motion artifacts inherently associated with arterial pulsations in addition to other physiological movements. In this study, we employed a technique involving a fourth order statistical method, kurtosis, operating on the endovascular OCT intensity images to visualize the vasa vasorum of carotid artery in vivo and identify its flow dynamic in a porcine model. The intensity kurtosis technique can distinguish vasa vasorum from the surrounding tissues in the presence of extensive time varying noises and dynamic motions of the arterial wall. Imaging of vasa vasorum and its proliferation, may compliment the growing knowledge of structural endovascular OCT in assessment and treatment of atherosclerosis in coronary and carotid arteries.

Dual-core ytterbium fiber amplifier for high-power 1060 nm swept source multichannel optical coherence tomography imaging.

A novel (to our knowledge) dual-core ytterbium (Yb(3+)) doped fiber, as an optically pumped amplifier, boosts the output power from a 1060 nm swept source laser beyond 250 mW, while providing a wavelength tuning range of 93 nm, for optical coherence tomography (OCT) imaging. The design of the dual-core Yb-doped fiber amplifier and its multiple wavelength optical pumping scheme to optimize output bandwidth are discussed. Use of the dual-core fiber amplifier showed no appreciable degradation to the coherence length of the seed laser. The signal intensity improvement of this amplifier is demonstrated on a multichannel in vivo OCT imaging system at 1060 nm.

23 kHz MEMS based swept source for optical coherence tomography imaging.

The transition from benchtop to clinical system often requires the medical technology to be robust, portable and accurate. This poses a challenge to current swept source optical coherence tomography imaging systems, as the bulk of the systems footprint is due to laser components. With the recent advancement of micromachining technology, we demonstrate the characterization of a microelectromechanical system (MEMS) swept source laser for optical coherence tomography imaging (OCT). This laser utilizes a 2 degree of freedom MEMS scanning mirror and a diffraction grating, which are arranged in a Littrow configuration. This resulted in a swept source laser that was capable of scanning at 23.165 kHz (bidirectional) or 11.582 kHz (unidirectional). The free spectral range of the laser was ≈ 100 nm with a central wavelength of ≈ 1330 nm. The 6 dB roll off depth was measured to be at 2.5 mm. Furthermore, the structural morphology of a human finger and tadpole (Xenopus laevis) were evaluated. The overall volumetric footprint of the laser source was measured to be 70 times less than non-MEMS swept sources. Continued work on the miniaturization of OCT system is on going. It is hypothesized that the overall laser size can be reduced for suitable OCT imaging for a point of care application.