Endoscopic Optical Coherence Tomography for Clinical Gastroenterology

Optical coherence tomography (OCT) is a real-time optical imaging technique that is similar in principle to ultrasonography, but employs light instead of sound waves and allows depth-resolved images with near-microscopic resolution. Endoscopic OCT allows the evaluation of broad-field and subsurface areas and can be used ancillary to standard endoscopy, narrow band imaging, chromoendoscopy, magnification endoscopy, and confocal endomicroscopy. This review article will provide an overview of the clinical utility of endoscopic OCT in the gastrointestinal tract and of recent achievements using state-of-the-art endoscopic 3D-OCT imaging systems. Keywords: optical coherence tomography; optical biopsy; endoscopic imaging; Barrett’s esophagus; inflammatory bowel diseaseNational Institutes of Health (U.S.) (Grant R01-CA75289-17)National Institutes of Health (U.S.) (Grant R44-CA101067-06)National Institutes of Health (U.S.) (Grant R01-CA178636-01)National Institutes of Health (U.S.) (Grant R44EY022864-01)National Institutes of Health (U.S.) (Grant R01-EY011289-27)National Institutes of Health (U.S.) (Grant R01-NS057476-05)United States. Air Force Office of Scientific Research (Grant FA9550-12-1-0499)United States. Air Force Office of Scientific Research (Grant FA9550-10-1-0551

Swept source optical coherence microscopy for pathological assessment of cancerous tissues

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2013.Cataloged from PDF version of thesis.Includes bibliographical references.Optical coherence microscopy (OCM) combines optical coherence tomography (OCT) with confocal microscopy and enables depth resolved visualization of biological specimens with cellular resolution. OCM offers a suitable alternative to confocal imaging by providing enhanced contrast due to the additional coherence gate to the inherent confocal gate, increasing the field of view and imaging depth, and eliminating the need of external contrast agents. In the past, development of OCT systems have been focused on time domain and spectral/Fourier domain methods which offer high axial resolution and imaging speeds. However, recent advances in the OCT technology have pushed the development into the direction of swept source OCT technologies, and development of the OCM technology is likely to follow this path. This thesis describes construction, characterization and preliminary imaging results of a swept source OCM (SS-OCM) system utilizing a novel light source, Vertical Cavity Surface-Emission Laser (VCSEL). This swept source laser can reach sweep rates exceeding 1 MHz and provide wide tuning ranges, which will enable both imaging speeds approaching to time domain OCM (TD-OCM) systems, and axial resolution approaching to spectral/Fourier domain OCM (SD-OCM) systems. Several other advantages of SS-OCM compared to TD-OCM and SD-OCM that make this technology a promising alternative to the latter imaging methods are presented. Furthermore, practical concepts in the system development and signal processing, such as compensation for the scan curvatures, methods for calibration of the spectrums, selection of suitable color maps for display, and other related topics are also discussed in the text. In addition to technical description of the OCM system development, an in depth analysis of several clinical applications that will be likely to benefit from this imaging modality is also presented. Real time intraoperative feedback is required in order to reduce the morbidity and the rate of additional operations for the surgical management of several forms of cancer, where a benchtop OCM system residing in the pathology laboratory can be immensely beneficial. Furthermore, with the novel scanning mechanisms that have been developed in the recent years it is possible to translate this imaging modality to an in vivo setting where an OCM probe can be inserted through the working channel of an endoscope and generate cellular resolution images in real time without the need of external contrast agents. Endoscopic management and clinical challenges for a spectrum of lower gastrointestinal (GI) diseases is discussed where an in vivo OCM imaging probe can play an important role in the diagnosis and evaluation of the extend of the particular disease. A review of alternative imaging modalities, such as chromoendoscopy, narrow band imaging (NBI) and confocal laser endomicroscopy (CLE) is also included which outlines the relative strengths and limitations of these imaging modalities for the clinical management of lower GI diseases.by Osman Oguz Ahsen.S.M

Endoscopic optical coherence tomography for clinical studies in the gastrointestinal tract

Thesis (Ph. D.)--Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2013.Cataloged from PDF version of thesis.Includes bibliographical references.Optical coherence tomography (OCT) performs micrometer-scale, cross-sectional and three dimensional imaging by measuring the echo time delay of backscattered light. OCT imaging is performed using low-coherence interferometry. With the development of Fourier domain detection techniques and fiber-optic based OCT endoscopes, high speed internal body imaging was enabled, which makes OCT suitable for clinical research in the human gastrointestinal (GI) tract. Endoscopic OCT imaging is challenging because fast and stable optical scanning must be implemented inside a small imaging probe to acquire useable volumetric information from internal human bodies. Although several studies have shown the use of endoscopic OCT in human gastrointestinal tracts as a real-time surveillance tool, the capability of OCT has not yet been fully explored in endoscopic applications and OCT is not well accepted as a standard imaging modality for GI clinics due to hardware limitations and lack of comprehensive clinical evidences. This thesis presents a number of clinical studies using endoscopic OCT that provide solutions to clinical problems in the GI tract supported by statistically significant results and the development of ultrahigh speed endoscopic OCT system that enables advanced OCT imaging applications. In collaboration with medical partners, the structural features in the diseased esophagus identified from OCT images are compared before and immediately after different ablative therapies, and features that predict the treatment response are investigated. Working in collaboration with industrial partners, an ultrahigh speed endoscopic OCT imaging system is constructed for clinical research in gastroenterology. Distally actuated imaging catheters are developed, enabling the visualization of the detailed three-dimensional (3D) structure in the gastrointestinal tract. Finally, clinical pilot studies are conducted and demonstrate the utility of the ultrahigh speed endoscopic OCT imaging for broader surveillance coverage, pathology detection, and dye-less contrast enhancement. The convergence of 3D spatial resolution, imaging speed, field of view, and minimally invasive access enabled by endoscopic OCT are unmatched by most other biomedical imaging techniques. Though still in its early stage of clinical validation, endoscopic OCT may have a profound impact on human healthcare and industrial inspection by enabling visualization and quantification of 3D microstructure in situ and in real time.by Tsung-Han Tsai.Ph.D

TOWARDS HIGH RESOLUTION ENDOSCOPIC OPTICAL COHERENCE TOMOGRAPHY FOR IMAGING INTERNAL ORGANS

Optical coherence tomography (OCT) is a light based interferometric imaging technique that can provide high resolution (5-20 µm at 1300 nm), depth resolved, images in real-time. With recent advances in portable low coherent light sources for OCT it is now possible to achieve ultrahigh axial resolutions (≤ 3 µm) by moving to shorter central wavelengths such as 800 nm while utilizing a broad spectral bandwidth. Our goal was to push ultrahigh resolution OCT technology to in vivo imaging of internal organs for endoscopic assessment of tissue microstructure. This dissertation is separated into technological developments and biomedical imaging studies. Technological developments in this dissertation included development of a high speed, ultrahigh resolution distal scanning catheter. This catheter was based upon a miniature DC micromotor capable of rotational velocities in excess of 100 rps, a diffractive compound lens design that minimized chromatic aberrations, and a mechanical assembly that limited field of view blockage to less than 7.5% and maintained an outer diameter of 1.78 mm (with plastic sheath). In conjunction with the algorithm described in chapter 4 to correct for non-uniform rotational distortion, the overall imaging system was capable of high quality endoscopic imaging of internal organs in vivo. Equipped with the ultrahigh resolution endoscopic OCT system, imaging was performed in small airways and colorectal cancer. Imaging results demonstrated the ability to directly visualization of microstructural details such as airway smooth muscle in the small airways representing a major step forward in pulmonary imaging. With the ability to visualize airway smooth muscle, morphological changes in COPD and related diseases can be further investigated. Additionally, longitudinal changes in an ETBF induced colon cancer model in APCMin mice were studied as well. Quantitative assessment of tissue microarchitecture was performed by measuring the attenuation coefficient to find a bimodal distribution separating normal healthy tissue from polyps. Finally, results from two additional projects were also demonstrated. Chapter 7 shows some results from vascular imaging in a tumor angiogenesis model and middle cerebral artery occlusion model. Chapter 8 describes an endoscopic multimodal OCT and fluorescence imaging platform with results in ex vivo rabbit esophagus

Ultrahigh resolution optical coherence tomography for the detection of early stage neoplastic pathologies

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2005.Includes bibliographical references (p. 105-118).Identification of changes associated with early stage disease remains a critical objective of clinical detection and treatment. Effective screening and detection is important for improving outcome because advanced disease, such as metastatic cancer, can be difficult to impossible to cure. Many existing diagnostic modalities, including x-ray imaging, magnetic resonance imaging, ultrasound, and endoscopy do not have sufficient resolution to detect changes in architectural morphology associated with early neoplasia and other pathologies. Diagnostic modalities capable of identifying pre-malignant tissue at an early stage could therefore significantly improve treatment outcome. Optical coherence tomography (OCT) is an emerging biomedical imaging technique that can potentially be used as an in vivo tool for identifying early stage neoplastic pathologies. Recent advances in solid-state laser and nonlinear fiber technology have enabled the development of ultrahigh resolution and spectroscopic OCT techniques which promise to improve tissue differentiation and image contrast. Previous ex vivo, benchtop ultrahigh resolution OCT imaging studies suggest that differentiation of architectural morphology associated with pathology is feasible. This thesis covers the development and investigation of ultrahigh resolution OCT for studies of early neoplastic pathologies.(cont.) A section of this thesis will focus on development and evaluation of a novel turn-key broadband source for OCT. Feasibility studies were performed using ultrahigh resolution OCT for imaging human tissues ex vivo in the clinical pathology laboratory setting. Imaging results will be presented examining a variety of normal and neoplastic lesions in preliminary studies of the thyroid gland, large and small intestine, and breast. These experiments elucidate the optimal imaging parameters, potential and limitations of the technique, and establish the microstructural markers visible in OCT images that are characteristic of pathologic tissues. These studies establish a baseline which should help interpret future in vivo ultrahigh resolution OCT imaging studies.by Pei-Lin Hsiung.Ph.D

Fast widefield techniques for fluorescence and phase endomicroscopy

Thesis (Ph.D.)--Boston UniversityEndomicroscopy is a recent development in biomedical optics which gives researchers and physicians microscope-resolution views of intact tissue to complement macroscopic visualization during endoscopy screening. This thesis presents HiLo endomicroscopy and oblique back-illumination endomicroscopy, fast widefield imaging techniques with fluorescence and phase contrast, respectively. Fluorescence imaging in thick tissue is often hampered by strong out-of-focus background signal. Laser scanning confocal endomicroscopy has been developed for optically-sectioned imaging free from background, but reliance on mechanical scanning fundamentally limits the frame rate and represents significant complexity and expense. HiLo is a fast, simple, widefield fluorescence imaging technique which rejects out-of-focus background signal without the need for scanning. It works by acquiring two images of the sample under uniform and structured illumination and synthesizing an optically sectioned result with real-time image processing. Oblique back-illumination microscopy (OBM) is a label-free technique which allows, for the first time, phase gradient imaging of sub-surface morphology in thick scattering tissue with a reflection geometry. OBM works by back-illuminating the sample with the oblique diffuse reflectance from light delivered via off-axis optical fibers. The use of two diametrically opposed illumination fibers allows simultaneous and independent measurement of phase gradients and absorption contrast. Video-rate single-exposure operation using wavelength multiplexing is demonstrated

An Investigation of the Diagnostic Potential of Autofluorescence Lifetime Spectroscopy and Imaging for Label-Free Contrast of Disease

The work presented in this thesis aimed to study the application of fluorescence lifetime spectroscopy (FLS) and fluorescence lifetime imaging microscopy (FLIM) to investigate their potential for diagnostic contrast of diseased tissue with a particular emphasis on autofluorescence (AF) measurements of gastrointestinal (GI) disease. Initially, an ex vivo study utilising confocal FLIM was undertaken with 420 nm excitation to characterise the fluorescence lifetime (FL) images obtained from 71 GI samples from 35 patients. A significant decrease in FL was observed between normal colon and polyps (p = 0.024), and normal colon and inflammatory bowel disease (IBD) (p = 0.015). Confocal FLIM was also performed on 23 bladder samples. A longer, although not significant, FL for cancer was observed, in paired specimens (n = 5) instilled with a photosensitizer. The first in vivo study was a clinical investigation of skin cancer using a fibre-optic FL spectrofluorometer and involved the interrogation of 27 lesions from 25 patients. A significant decrease in the FL of basal cell carcinomas compared to healthy tissue was observed (p = 0.002) with 445 nm excitation. A novel clinically viable FLS fibre-optic probe was then applied ex vivo to measure 60 samples collected from 23 patients. In a paired analysis of neoplastic polyps and normal colon obtained from the same region of the colon in the same patient (n = 12), a significant decrease in FL was observed (p = 0.021) with 435 nm excitation. In contrast, with 375 nm excitation, the mean FL of IBD specimens (n = 4) was found to be longer than that of normal tissue, although not statistically significant. Finally, the FLS system was applied in vivo in 17 patients, with initial data indicating that 435 nm excitation results in AF lifetimes that are broadly consistent with ex vivo studies, although no diagnostically significant differences were observed in the signals obtained in vivo.Open Acces

Optical Imaging Techniques for the Detection of Esophageal Neoplasia in Barrett’s Esophagus

The main objective of this research was to develop a two-stage optical imaging platform to improve detection of cancer in Barrett’s esophagus (BE). BE caused by chronic reflux and patients with BE are at a higher risk for developing esophageal adenocarcinoma (EAC). However, neoplasia in BE is often unidentifiable under standard endoscopy, and studies have shown nearly half of early cancers can go unidentified by this method. Widefield imaging (resolves ~100 microns) allows efficient surveillance of large BE segments. Two widefield imaging techniques were identified to improve contrast between benign and abnormal lesions during an ex vivo 15 patient feasibility study. Cross-polarized imaging (CPI) reduced specular reflection and improved vascular contrast. Vital-dye fluorescence imaging (VFI) using topically-applied proflavine improved visualization of glandular pattern. Moreover, relevant pathologic features visible during VFI were seen in corresponding histology slides as well as high resolution images of the same sites. Based on these results, a cap-based Multispectral Digital Endoscope (MDE) was designed and built. The MDE can image in three different imaging modes: white light imaging, CPI, and VFI. Modifications to a Pentax EPK-i video processor and a Pentax endoscope were made to incorporate these imaging modes into one system. A 21 patient in vivo pilot study with 65 pathologically correlated sites demonstrated the feasibility of using this system in vivo; image criteria were developed to classify neoplasia with a sensitivity and specificity of 100% and 76% respectively. High resolution imaging (resolves ~2-5 micron) may verify the disease presence in suspicious areas identified using widefield techniques. 2-NBDG, a fluorescent metabolic marker, was used as to identify neoplastic biopsies. In a study with 21 patients yielding 38 pathologically correlated biopsies and 158 image sites, 2-NBDG imaging allowed classification of cancerous biopsies with a sensitivity of 96% and specificity of 90%. The unique contributions of these results is the development of a multimodal cap-based endoscopic system to identify suspicious areas in BE, and using a metabolic marker to verify the presence of disease. This application extends beyond esophageal cancer detection and may be explored for cancer detection in other organ sites characterized by columnar epithelium