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Diagnostic and Therapeutic Devices and Applications of Endoscopic Diagnostic and Therapeutic Devices and Applications of Endoscopic Optical Coherence Tomography by Osman Oguz Ahsen B.S., Electrical and Electronics Engineering Bilkent University, 2010 S.M., Electrical Engineering and Computer Science Massachusetts Institute of Technology, 2013 Submitted to the DEPARTMENT OF ELECTRICAL ENGINEERING AND COMPUTER SCIENCE in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY June 2018 © Massachusetts Institute of Technology 2018 All rights reserved Signature of Author _____________________________________________________________ Department of Electrical Engineering and Computer Science May 18, 2018 Certified by ___________________________________________________________________ James G. Fujimoto Elihu Thomson Professor of Electrical Engineering and Computer Science Thesis Supervisor Accepted by ___________________________________________________________________ Leslie A. Kolodziejski Professor of Electrical Engineering and Computer Science Chair, Department Committee on Graduate Students Diagnostic and Therapeutic Devices and Applications of Endoscopic Optical Coherence Tomography by Osman Oguz Ahsen Submitted to the Department of Electrical Engineering and Computer Science on May 18, 2018 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Electrical Engineering and Computer Science Abstract There is an increased demand for developing transformative technologies to satisfy unmet needs in the clinical management of a number of gastrointestinal (GI) tract diseases. With the maturation of swept‐ source lasers, OCT technology has undergone major advancements over the last few years. Swept‐source laser sources based on Fourier domain mode locking (FDML), akinetic and vertical cavity surface emitting laser (VCSEL) technologies have shown to reach and exceed MHz OCT imaging speeds. Our group has harnessed these advances by developing an ultrahigh‐speed endoscopic OCT system that operated at and above 600 kHz A‐scan rates, > 10 times faster than commercial endoscopic OCT systems. Equipped with distal rotating micromotor catheters, this system allowed visualization of microstructures and functional processes that were not possible to observe with the older generation OCT systems. The overarching aim of this thesis was to showcase novel clinical and research applications that were enabled by this next generation ultrahigh‐speed endoscopic OCT system. Towards this aim, this thesis focused on two main projects, 1) Demonstrating clinical applications of volumetric en face and cross‐ sectional OCT, and OCT angiography (OCTA) and 2) Developing integrated OCT imaging and esophageal electrical muscle stimulation methods. For the first project, two gastrointestinal (GI) tact diseases were investigated: Barrett’s esophagus (BE) and associated dysplasia, and chronic radiation proctopathy (CRP). For the second project, esophageal electrical muscle stimulation methods were assessed to achieve circumferential esophageal tissue coverage for catheter imaging and therapeutic applications, with experiments performed in living swine. Furthermore, methods for improving scanning stability and robustness of the ultrahigh‐speed endoscopic OCT system, as well as for optimizing data acquisition and visualization were discussed. This thesis illustrated that ultrahigh‐speed endoscopic OCT technology powered by the next generation swept‐source light sources and precision scanning micromotor catheters opened new research directions ranging from diagnosis of early cancers to studying the pathophysiology of GI tract diseases and assessing efficacy of and response to therapeutic interventions. As the field of OCT continues to evolve, endoscopic OCT is one step closer to find its niche in solving prolonged clinical problems. Thesis Supervisor: James G. Fujimoto Title: Elihu Thomson Professor of Electrical Engineering 2 Acknowledgements I appreciate my thesis advisor Prof. James Fujimoto for giving me the opportunity to work in his research group and providing the facilities and guidance that enabled me to complete this thesis. I would like to thank many of the graduate students and postdoctoral associates that were immensely helpful during my graduate studies. Kenny Tao was instrumental in teaching me fundamental concepts of optics and OCT technology. Similarly, Chao Zhou, Ireneusz Grulkowski, Mike Giacomelli and Jonathan Liu were always reachable and did not hesitate to share their experience and wisdom. I am very glad to be working closely with the endoscopy team in our group including Tsung‐Han Tsai, Hsiang‐Chieh Lee, Kaicheng Liang and Zhao Wang. I got the opportunity to work with Tan Nguyen, Jason Zhang, Siyu Chen and Oscar Carrasco‐Zevallos towards the ends of my studies and found them to be highly skillful and pleasant to interact with, and wish them the best for their upcoming tenures at MIT. Members of the ophthalmic and microscopy groups including Chen Lu, Tadayuki Yoshitake, Lennart Husvogt, Lucas Cahill, Eric Moult, Patrick Yiu and Ben Lee were always available to complement our knowledge and cheer us up during stressful times. Ben Potsaid was very helpful especially in setting up and operating the VCSEL light sources, as well as bridging our collaboration with Thorlabs. I am very grateful for the comments and insights of Aaron Aguirre on various projects and his sincere advice on matters of graduate life. I am very thankful to Julia Schottenhamml, for not only helping me with her programming experience on different projects but also for accompanying me in various extracurricular adventures. I can not thank Dorothy Fleischer enough for not only her excellent job as our group’s administrative assistant but also for her wonderful personality and caring spirit. I also would like to acknowledge the clinical support of Veterans Affairs Boston Healthcare personnel. Dr. Hiroshi Mashimo was a great clinical collaborator, mentor and friend. Dr. Qin Huang was always available for interpreting the pathological data with his unique positive attitude. Marisa Figueiredo, Frances Achee, Lisa Jepeal, Rayhme Collins and Greg Daniels were instrumental in patient scheduling and other logistical arrangements, and maintaining our research credentials and protocols. The VA nursing staff including Annalee Murphy and Joanne Hill were immensely helpful in facilitating our studies at the VA hospital. I also would like to acknowledge the help of MIT E25 animal facility veterinary personnel and staff, including Dr. Alison Hayward, in facilitating our swine studies. I thank Prof. Giovanni Traverso for giving access to swine under his research protocols for OCT imaging and EMS experiments. Last but not least I would like to thank my family and friends for all their unconditional support over the years as I navigated through the rough paths of graduate life. My friends from the Turkish gang including Sukru Cinar, Burak Dura, Halil Tekin, Erman Timurdogan, Onur Ornek, Melih Okan, Mustafa Yalcinoz and Ahmet Demir were always right by my side whenever I needed their support. My friends from MIT Outing club including Katherine Rosenfeld, Shireen Warnock, Colie Pilling, Maike Sonnewald, Hariharan Rahul and Ben Thompson were always up for an adventure and showed me that it is possible to have fun while doing things that are physically extremely challenging. I look forward to continuing my endeavors in tackling clinical issues related to debilitating diseases and do my very best in the never‐ending struggle to improve the human condition. 3 “So many people live within unhappy circumstances and yet will not take the initiative to change their situation because they are conditioned to a life of security, conformity, and conservatism, all of which may appear to give one peace of mind, but in reality nothing is more dangerous to the adventurous spirit within a man than a secure future. The very basic core of a man’s living spirit is his passion for adventure. The joy of life comes from our encounters with new experiences, and hence there is no greater joy than to have an endlessly changing horizon, for each day to have a new and different sun.” Jon Krakauer This thesis is dedicated to the kind ones, to the compassionate ones, to the fair ones and to the ones who want to do good for this world. 4 Contents Abstract ........................................................................................................................................... 2 Acknowledgements ......................................................................................................................... 3 Introduction .......................................................................................... 7 1.1. Overview of Barrett’s esophagus and chronic radiation proctopathy ............... 7 1.2. Recent advances in endoscopic OCT technology ............................................... 9 1.3. Scope of the thesis ........................................................................................... 13 Improvements to the Ultrahigh-speed Endoscopic OCT System ........... 16 2.1. Motivation ........................................................................................................ 16 2.2. Optimization of pullback uniformity ................................................................ 24 2.3. Optimization of rotational scanning uniformity............................................... 27 2.4. Optimization of data acquisition and visualization
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