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Development of Peritoneal Microbubble Oxygenation As an Extrapulmonary Treatment for Hypoxia Nathan Legband University of Nebraska-Lincoln, [email protected]

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Development of Peritoneal Microbubble Oxygenation As an Extrapulmonary Treatment for Hypoxia Nathan Legband University of Nebraska-Lincoln, Ndlegband@Huskers.Unl.Edu University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Mechanical (and Materials) Engineering -- Mechanical & Materials Engineering, Department Dissertations, Theses, and Student Research of 5-2017 Development of Peritoneal Microbubble Oxygenation as an Extrapulmonary Treatment for Hypoxia Nathan Legband University of Nebraska-Lincoln, [email protected] Follow this and additional works at: http://digitalcommons.unl.edu/mechengdiss Part of the Biomedical Devices and Instrumentation Commons, and the Mechanical Engineering Commons Legband, Nathan, "Development of Peritoneal Microbubble Oxygenation as an Extrapulmonary Treatment for Hypoxia" (2017). Mechanical (and Materials) Engineering -- Dissertations, Theses, and Student Research. 115. http://digitalcommons.unl.edu/mechengdiss/115 This Article is brought to you for free and open access by the Mechanical & Materials Engineering, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Mechanical (and Materials) Engineering -- Dissertations, Theses, and Student Research by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. DEVELOPMENT OF PERITONEAL MICROBUBBLE OXYGENATION AS AN EXTRAPULMONARY TREATMENT FOR HYPOXIA by Nathan D. Legband A DISSERTATION Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Doctor of Philosophy Major: Mechanical Engineering and Applied Mechanics Under the Supervision of Professor Benjamin S. Terry Lincoln, Nebraska May, 2017 DEVELOPMENT OF PERITONEAL MICROBUBBLE OXYGENATION AS AN EXTRAPULMONARY TREATMENT FOR HYPOXIA Nathan David Legband, Ph.D. University of Nebraska, 2017 Advisor: Benjamin S. Terry Patients affected by a respiratory disease or injury experience a substantially impaired respiratory system and as a consequence are unable to obtain a sufficient amount of oxygen. Hypoxia can quickly result in developing permanent tissue damage or death. Currently, the medical methods of treating hypoxia are mechanical ventilation or extracorporeal membrane oxygenation. However, these treatments are ineffective in certain cases and possess significant additional risks including barotrauma, infection, hemorrhage, and thrombosis. The extrapulmonary method of peritoneal oxygenation has been investigated by other research groups as a potential alternative to providing supplemental oxygen in hypoxic animals. In peritoneal oxygenation, the peritoneum, the serous membrane that lines the abdominal cavity and organs, functions as an interface for gas exchange. However, previous attempts using artificial perfluorocarbons and hemoglobin based oxygen carriers have demonstrated limited increase in oxygenation and substantial health concerns. In this work, peritoneal microbubble oxygenation (PMO) therapy has been investigated as a viable method for delivering supplemental oxygen to hypoxic patients with critical lung injury. PMO therapy is accomplished with a custom infusion device designed to safely deliver oxygen microbubbles (OMBs), an innovative oxygen carrier, into the abdomen. Animal models of acute lung trauma and respiratory disease were used to validate PMO therapy. The first model was a small animal feasibility study where fatal hypoxia was induced by pneumothorax. The second model was asphyxia by tracheal occlusion to test PMO therapy in the most severe lung injury. When animals were infused with OMBs, the average survival times after the incidence of injury increased significantly. PMO treatment increased mean survival time in fatal pneumothorax by 650% and by 180% in asphyxia. Finally, a respiratory disease model was developed and characterized to replicate acute respiratory distress syndrome (ARDS) in rats. ARDS pathology was reproduced by aerosolizing an endotoxin, lipopolysaccharide, into the lungs to incite an antagonistic immune response. Additionally, delivering OMBs for prolonged PMO treatment to rats was facilitated by comparing the efficiencies of multiple catheters implanted into the peritoneal cavity. The ARDS and treatment model could then be used to evaluate PMO therapy and other new methods of supplemental oxygen delivery. iv Acknowledgments I would like to thank the Institutional Animal Care Program (IACP) staff at UNL for housing and caring for the animals used in my research. Special thanks to the facility manager, Vicky Samek, for assisting with ordering animals and supplies; and the director and attending veterinarian, Dr. Keely Heath, for a memorable first day of research and his support for me and the lab from the beginning. I also give thanks to MME department staff of accounting technician, Mary Ramsier, for completing numerous orders of supplies and always coming through with the businesses and rush orders; and graduate secretary, Kathie Hiatt, for answering questions about all the “minor” details of classes and graduate forms. I would not have come this far in the research without assistance from our collaborators. From University of Colorado-Boulder: associate professor, Dr. Mark Borden, for beginning this endeavor; Dr. Jameel Feshitan for providing assistance and knowledge when I began the project and making the largest of volume of OMBs ever used for our trials in rabbits; and PhD student, Alec Thomas, and professional research assistants, Connor Slage & Hunter Velds, for continuing the time consuming job of manufacturing microbubbles for our research. From the IACP at UNL: clinical veterinarian, Dr. Kreikemeier-Bower, for the many hours doing surgeries with me and fitting the surgeries into his busy schedule. I give my gratitude to my fellow members of the Terry Research Lab: Piotr Slawinski & Xiaojian Yang for building the foundations of the lab with me; fellow PhD students, Wanchuan Xie, Pengbo Li, & Hossein Dehghani, for 4 long years strengthening and establishing the lab; Liana Hatoum, for always being willing to help and dealing with v my faults while working together; and PhD student, Fariba Aghabaglou for continuing where I leave off and again dealing with my faults. I would not be able to thank the members of my committee enough for contributing their vast knowledge, experience, and time. Dr. Carl Nelson for being the calmest mind during committee meetings and straightening us out when getting off topic; Dr. Angie Pannier for her sharp mind/tongue, asking the hard questions, and striving to have her disciples be the best they can be; Dr. Doug Hostetler for his insight, surgical support, and providing handy solutions; Dr. Keely Buesing for her numerous ideas and contacts, promoting the project, and unwavering optimism. Finally, I thank my adviser and committee chairman, Dr. Benjamin Terry, for giving me the opportunity to work on this project, for believing in me as he was creating his lab here at UNL, for being the “devil’s advocate”, for understanding that things will not always go our way, and for inspiring and supporting the imagination and ideas of all his students. vi Preface Portions of Chapter 3.3.2 and Chapter 7.1-7.4 were published in Biomaterials (Feshitan, J. A., Legband, N. D., Borden, M. A., and Terry, B. S., 2014, “Systemic Oxygen Delivery by Peritoneal Perfusion of Oxygen Microbubbles,” Biomaterials, 35(9), pp. 2600–2606.) Chapter 8.1-8.4 has been published in IEEE Transactions on Biomedical Engineering. (Legband, N. D., Feshitan, J. A., Borden, M. A., and Terry, B. S., 2015, “Evaluation of Peritoneal Microbubble Oxygenation Therapy in a Rabbit Model of Hypoxemia,” IEEE Transactions on Biomedical Engineering, 62(5), pp. 1376–1382.) vii Table of Contents Chapter 1: Introduction ....................................................................................................... 1 1.1 Research objectives .................................................................................................. 2 Chapter 2: Background ....................................................................................................... 5 2.1 Physiological respiration .......................................................................................... 5 2.1.1 Interactions of blood and oxygen ...................................................................... 9 2.1.2 Impairment ...................................................................................................... 11 2.2 Measuring oxygen saturation in the body .............................................................. 13 2.2.1 Pulse oximetry ................................................................................................ 14 2.2.2 Blood gas analysis........................................................................................... 18 2.2.3 Hemoximetry .................................................................................................. 22 2.3 Current O2 delivery methods .................................................................................. 24 2.3.1 Mechanical ventilation .................................................................................... 24 2.3.2 Extracorporeal membrane oxygenation .......................................................... 30 Chapter 3: Peritoneal oxygenation .................................................................................... 38 3.1 Limitations .............................................................................................................. 40 3.2 Previous peritoneal oxygenation methods .............................................................
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