[Truncated] Biological tissue has intrinsic optical and mechanical properties that are linked to its structure and function, and are altered by pathologies such as cancer. Techniques for imaging these properties could, thus, aid in the detection, diagnosis, and understanding of disease. Birefringence is one such optical property, arising from structural and molecular anisotropies in tissue and, thus, a measure of the tissue microstructure. Similarly, many pathologies lead to a stiffening or softening of tissues, and, in principle, can be detected from changes in mechanical elasticity. Optical coherence tomography (OCT) is a minimally invasive optical imaging modality, with micrometre-scale resolution and millimetre-scale depth penetration, which can be extended to measure these tissue properties. This research combines three-dimensional OCT imaging with parametric modelling to develop signal processing methods for spatially resolved micro-scale measurements of tissue birefringence and elasticity, an approach referred to as parametric OCT.
Optical imaging offers unique advantages in medical diagnostics. In particular, high resolution, fast imaging speed, and strong depth penetration make optical coherence tomography (OCT) an attractive modality for non-perturbatively investigating structural changes in tissue that accompany disease progression on the microscale. Although clinical interpretation of OCT images is generally qualitative, the scattered light intensity signal underlying these images may be analyzed further to calculate sub-resolution sample properties, accessing additional functional information in tissue. Developing meaningful ways to compute and interpret these properties could enable earlier detection of structural disease-associated tissue changes, such as increases in sizes and densities of epithelial nuclei with the progression of esophageal dysplasia. In this thesis research, we investigate the application of novel signal processing methods and custom OCT hardware to uncover biomarkers of dysplasia based on these pathological changes in cell nuclei. Further, we apply our methods to evaluate patients during upper gastrointestinal endoscopy using a custom imaging device designed for enhanced sensitivity to these dysplastic changes, potentiating a more sensitive screening paradigm towards earlier detection of esophageal cancer.
Optical coherence tomography (OCT) is the optical analog of ultrasound imaging and is emerging as a powerful imaging technique that enables non-invasive, in vivo, high resolution, cross-sectional imaging in biological tissue. This book introduces OCT technology and applications not only from an optical and technological viewpoint, but also from biomedical and clinical perspectives. The chapters are written by leading research groups, in a style comprehensible to a broad audience.
Microcirculation refers to the functions of capillaries and the neighboring lymphatic vessels. It plays a vital role in the pathophysiology of disorders in many clinical areas including cardiology, dermatology, neurology and ophthalmology, and so forth. It is crucial to develop imaging technologies that can provide both qualitative and quantitative information as to how microcirculation responds to certain injury and/or disease, and its treatment. Optical coherence tomography (OCT) is a non-invasive optical imaging technique for high-resolution cross-sectional imaging of specimens, with many applications in clinical medicine. Current state-of-the-art OCT systems operate in the Fourier domain, using either a broadband light source with a spectrometer, known as spectral domain OCT (SDOCT), or a rapidly tunable laser, known as swept source OCT (SSOCT). The current Fourier domain OCT systems have dramatically improvement in sensitivity, resolution and speed compared to time domain OCT. In addition to the improvement in the OCT system hardware, different methods for functional measurements of tissue beds have been developed and demonstrated. This includes but not limited to, i) Phase-resolved Doppler OCT for quantifying the blood flow, ii) OCT angiography for visualization of microvasculature, iii) Polarization sensitive OCT for measuring the intrinsic optical property/ birefringence of tissue, iv) spectroscopic OCT for measuring blood oxygenation, etc. Functional OCT can provide important clinical information that is not available in the typical intensity based structural OCT images. Among these functional OCT modalities, Doppler OCT and OCT angiography attract great interests as they show high capability for in vivo study of microvascular pathology. By analyzing the Doppler effect of a flowing particle on light frequency, Doppler OCT allows the quantification of the blood flow speed and blood flow rate. The most popular approach for Doppler OCT is achieved through analysis of the phase term in complex OCT signal which termed as Phase-resolved Doppler OCT. However, as limited by the phase noise and motion, Phase-resolved Doppler OCT can only be applied for relative large blood vessels, such as arterioles and venules. On the other hand, in order to visualize the microcirculation network, a number of strategies to enable better contrast of microvasculature components, which we termed OCT angiography, have been introduced during recent years. As a variation of Fourier domain OCT, optical microangiography (OMAG) is one of earliest proposed OCT angiography technique which is capable of generating 3D images of dynamic blood perfusion distribution within microcirculatory tissue beds. The OMAG algorithm works by separating the static and moving elements by high pass filtering on complex valued interferometric data after Fourier transform. Based on the conventional OMAG algorithm, we further developed ultra-high sensitive OMAG (UHS-OMAG) by switching the high-pass filtering from fast scan direction (adjacent A-lines within one B-frame) to slow scan direction (adjacent B-frames), which has a dramatically improved performance for capillary network imaging and analysis. Apart from the microvascular study with current available functional OCT for, visualization of the lymphatic system (lymph nodes and lymphatic vessels) plays a significant role in assessing patients with various malignancies and lymphedema. However, there is a lack of label-free and noninvasive method for lymphangiography. Hence, a cutting edge research to investigate the capability of OCT as a tool for non-invasive and label-free lymphangiography would be highly desired. The objective of my thesis is to develop a multiple-functional SDOCT system to image the microcirculation and quantify the several important parameters of microcirculation within microcirculatory tissue beds, and further apply it for pre-clinical research applications. The multifunctional OCT system provides modalities including structural OCT, OCT angiography, Doppler OCT and Optical lymphangiography, for multi-parametric study of tissue microstructure, blood vessel morphology, blood flow and lymphatic vessel all together. The thesis mainly focus on two parts: first, development of multi-functional OCT/optical microangiography (OMAG) system and methods for volumetric imaging of microvasculature and quantitative measurement of blood flow, and its application for pathological research in ophthalmology on rodent eye models; second, development of ultra-high resolution OCT system and algorithm for simultaneous label free imaging of blood and lymphatic vessel, and its application in wound healing study on mouse ear flap model. Objectives of my research are achieved through the following specific aims: Aim 1: Improve the sensitivity of OMAG for microvasculature imaging; perform volumetric and quantitative imaging of vasculature with combined OMAG and Phase-resolved Doppler OCT for in vivo study of vascular physiology. Aim 2: Develop high speed high resolution OCT system and method for rodent eye imaging. Apply the combined OMAG and Phase-resolved Doppler OCT approach to investigate the impact of elevated intraocular pressure on retinal, choroidal and optic nerve head blood flow in rat eye model, which aids to the better understanding of the mechanism and development of glaucoma. Aim 3: Apply the developed OCT system and ultra-high sensitive OMAG algorithm for noninvasive imaging of retinal morphology and microvasculature in obese mice, which may play an important role in early diagnosis of Diabetic retinopathy. Aim 4: Developing an ultra-high resolution SDOCT system using broadband Supercontinuum light source to achieve ultra-high resolution microvasculature imaging of biological tissue. Aim 5: Develop methods for simultaneous label free optical imaging of blood and lymphatic vessel and demonstrate its capability by monitoring the blood and lymph response to wound healing on mouse ear pinna model.
Optical Coherence Elastography: Imaging Tissue Mechanics on the Micro-Scale provides a unique and practical overview of this important new fi eld, which has seen tremendous growth in the last decade. Using optical coherence tomography (OCT) to measure sample deformation, optical coherence elastography (OCE) provides visualization of the three-dimensional, micro-scale mechanical properties of tissues and biomaterials and has shown distinct promise for application across clinical medicine, biology, and tissue engineering. This timely book provides: -- Detailed coverage of the key elements required for the successful implementation of OCE techniques, particularly OCT imaging, mechanical deformation, and image processing -- Synthesis of theory, methodology, and applications in one resource -- Detailed discussion of the historical context within which OCE has evolved, particularly regarding ultrasound elastography and magnetic resonance elastography -- Perspectives on likely future developments in OCE This book is an invaluable resource for graduate students and researchers in biophotonics and tissue engineering and for professionals working with OCT and elastography.
Microvasculature can be found in almost every part of the human body, including the internal organs. Importantly, abnormal changes in microvasculature are usually related to pathological development of the tissue cells. Monitoring of changes in blood flow properties in microvasculature, therefore, provides useful diagnostic information about pathological conditions in biological tissues as exemplified in glaucoma, diabetes, age related macular degeneration, port wine stains, burn-depth, and potentially skin cancer. However, the capillary network is typically only one cell in wall thickness with 5 to 10 microns in diameter and located in the dermis region of skin. Therefore, a non-invasive flow imaging technique that is capable of depth sectioning at high resolution and high speed is demanded. Optical coherence tomography (OCT), particularly after its advancement in frequency domain OCT (FD-OCT), is a promising tool for non-invasive high speed, high resolution, and high sensitivity depth-resolved imaging of biological tissues. Over the last ten years, numerous efforts have been paid to develop OCT-based flow imaging techniques. An important effort is the development of phase-resolved Doppler OCT (PR-DOCT). Phase-resolved Doppler imaging using FD-OCT is particularly of interest because of the direct access to the phase information of the depth profile signal. Furthermore, the high speed capability of FD-OCT is promising for real time flow monitoring as well as 3D flow segmentation applications. However, several challenges need to be addressed; 1) Flow in biological samples exhibits a wide dynamic range of flow velocity caused by, for example, the variation in the flow angles, flow diameters, and functionalities. However, the improvement in imaging speed of FD-OCT comes at the expense of a reduction in sensitivity to slow flow information and hence a reduction in detectable velocity range; 2) A structural ambiguity so-called 'mirror image' in FD-OCT prohibits the use of maximum sensitivity and imaging depth range; 3) The requirement of high lateral resolution to resolve capillary vessels requires the use of an imaging optics with high numerical aperture (NA) that leads to a reduction in depth of focus (DOF) and hence the imaging depth range (i.e. less than 100 microns) unless dynamic focusing is performed. Nevertheless, intrinsic to the mechanism of FD-OCT, dynamic focusing is not possible. In this dissertation, the implementation of PR-DOCT in a high speed swept-source based FD-OCT is investigated and optimized. An acquisition scheme as well as a processing algorithm that effectively extends the detectable velocity dynamic range of the PR-DOCT is presented. The proposed technique increased the overall detectable velocity dynamic range of PR-DOCT by about five times of that achieved by the conventional method. Furthermore, a novel technique of mirror image removal called 'Dual-Detection FD-OCT' (DD-FD-OCT) is presented. One of the advantages of DD-FD-OCT to Doppler imaging is that the full-range signal is achieved without manipulation of the phase relation between consecutive axial lines. Hence the full-range DD-FD-OCT is fully applicable to phase-resolved Doppler detection without a reduction in detectable velocity dynamic range as normally encountered in other full-range techniques. In addition, PR- DOCT can utilize the maximum SNR ratio provided by the full-range capability. This capability is particularly useful for imaging of blood flow that locates deep below the sample surface, such as blood flow at deep posterior human eye and blood vessels network in the dermis region of human skin. Beside high speed and functional imaging capability, another key parameter that will open path for optical diagnostics using OCT technology is high resolution imaging (i.e. in a regime of a few microns or sub-micron). Even though the lateral resolution of OCT can be independently improved by opening the NA of the imaging optics, the high lateral resolution is maintained only over a short range as limited by the depth of focus that varies inversely and quadratically with NA. Recently developed by our group, 'Gabor-Domain Optical Coherence Microscopy' (GD-OCM) is a novel imaging technique capable for invariant resolution of about 2-3 [micrometers] over a 2 mm cubic field-of-view. This dissertation details the imaging protocol as well as the automatic data fusion method of GD-OCM developed to render an in-focus high-resolution image throughout the imaging depth of the sample in real time. For the application of absolute flow measurement as an example, the precise information about flow angle is required. GD-OCM provides more precise interpretation of the tissue structures over a large field-of-view, which is necessary for accurate mapping of the flow structure and hence is promising for diagnostic applications particularly when combined with Doppler imaging. Potentially, the ability to perform high resolution OCT imaging inside the human body is useful for many diagnostic applications, such as providing an accurate map for biopsy, guiding surgical and other treatments, monitoring the functional state and/or the post-operative recovery process of internal organs, plaque detection in arteries, and early detection of cancers in the gastrointestinal tract. Endoscopic OCT utilizes a special miniature probe in the sample arm to access tubular organs inside the human body, such as the cardiovascular system, the lung, the gastrointestinal tract, the urinary tract, and the breast duct. We present an optical design of a dynamic focus endoscopic probe that is capable of about 4 to 6 [micrometers] lateral resolution over a large working distance (i.e. up to 5 mm from the distal end of the probe). The dynamic focus capability allows integration of the endoscopic probe to GD-OCM imaging to achieve high resolution endoscopic tomograms. We envision the future of this developing technology as a solution to high resolution, minimally invasive, depth-resolved imaging of not only structure but also the microvasculature of in vivo biological tissues that will be useful for many clinical applications, such as dermatology, ophthalmology, endoscopy, and cardiology. The technology is also useful for animal study applications, such as the monitoring of an embryo's heart for the development of animal models and monitoring of changes in blood circulation in response to external stimulus in small animal brains.
This book covers the results of the creation of methods for ophthalmologists support in OCT images automated analysis. These methods, like the application developed on their basis, are used during routine examinations carried out in hospital. The monograph comprises proposals of new and also of known algorithms, modified by authors, for image analysis and processing, presented on the basis of example of Matlab environment with Image Processing tools. The results are not only obtained fully automatically, but also repeatable, providing doctors with quantitative information on the degree of pathology occurring in the patient. In this case the anterior and posterior eye segment is analysed, e.g. the measurement of the filtration angle or individual layers thickness. To introduce the Readers to subtleties related to the implementation of selected fragments of algorithms, the notation of some of them in the Matlab environment has been given. The presented source code is shown only in the form of example of implementable selected algorithm. In no way we impose here the method of resolution on the Reader and we only provide the confirmation of a possibility of its practical implementation.
