DEVELOPMENT AND MODELING OF A POLYMER CONSTRUCT FOR PERFUSION IMAGING AND TISSUE ENGINEERING by Auresa Thomas A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biomedical Engineering) in The University of Michigan 2014 Doctoral Committee: Professor Scott J. Hollister, Co-Chair Professor James M. Balter, Co-Chair Associate Professor Joseph L. Bull Professor Yue Cao The Road Not Taken Two roads diverged in a yellow wood, And sorry I could not travel both And be one traveler, long I stood And looked down one as far as I could To where it bent in the undergrowth; Then took the other, as just as fair, And having perhaps the better claim Because it was grassy and wanted wear, Though as for that the passing there Had worn them really about the same, And both that morning equally lay In leaves no step had trodden black. Oh, I marked the first for another day! Yet knowing how way leads on to way I doubted if I should ever come back. I shall be telling this with a sigh Somewhere ages and ages hence: Two roads diverged in a wood, and I, I took the one less traveled by, And that has made all the difference. - Robert Frost If you can't fly, then run. If you can't run, then walk. If you can't walk, then crawl. But whatever you do, you have to keep moving forward. - Dr. Martin Luther King, Jr. © Auresa Thomas 2014 ALL RIGHTS RESERVED DEDICATION To my parents for their sacrifices and timely words of support and encouragement throughout my education. ii ACKNOWLEDGEMENTS For the last six years, or should I say, for the last decade, I’ve dreamed of earning a PhD. Looking back, I realize that I had no idea what I was in for! The PhD process has taught me how to question, it has challenged my desire to succeed, and time and time again, it has pushed me beyond my comfort zone, both academically and personally. Dr. James Balter and Dr. Scott Hollister have been instrumental in my growth as a scientist through this process. Dr. Balter has provided me with invaluable guidance on setting goals and executing projects. Unfortunately, the conclusion of my PhD means we won’t have any more weekend scanning sessions nor gelatin experiments. I thank you for giving me the opportunity to be creative and to explore device development. As well, I am thankful that Dr. Hollister welcomed me into the world of bone tissue engineering. We lost several batches of cells and went through tons of polycaprolactone. I always knew that during a one-on-one meeting with Dr. Hollister we’d solve or work through any challenge I was facing. In my time working with Dr. Balter and Dr. Hollister, I’ve learned how to consider the big picture and how to anticipate problems. This experience allowed me to tap into so many areas of science and engineering; and for that I am a more well-rounded engineer. I would like to thank my other doctoral committee members: Dr. Yue Cao and Dr. Joe Bull. You both offered expertise in your respective fields that I just couldn’t find in any journal paper or Google search (and I made sure to extensively search before meeting with you all!). I’d like to thank Colleen Flanagan for always taking my calls on weekends and late nights, when I just wanted to know what shelf reagent X was on. Your patience and assistance was always appreciated. I would also like to acknowledge all of my lab mates (current and past) for lending your experiences and assistance when needed: Alisha Diggs, Annie Mitsak, Chanho Park, Eiji Saito, Frank Winterroth, Heesuk Kang, Huina Zhang, Janki Patel, Claire Jeong and Shelley Brown. I sincerely appreciated the iii opportunity to work in the Scaffold Tissue Engineering Group (STEG). Several members of the Radiation Physics group have been a great support: Rojano Kashani, Hesheng Wang, Dr. Kwok Lam, Shu-Hui Hsu and Dr. Peng Wang. Thank you! There are many people (undergraduates and visiting scholars) that I may be forgetting, but am appreciative of all the support I’ve received throughout my PhD journey. Thank you to all my ‘G-chat friends,’ because our daily rantings and venting session were very necessary! Thank you to the friends that randomly texted me to make sure I made it home safely after late nights alone in the lab. Thank you to my writing group for keeping me motivated through what might have otherwise been a lonely process. A special thank you to Dr. Carl S. McGill for sticking around for that PhD! Thank you for supporting me along the way with your optimistic spirit. Aside from the conferences, research talks and lab meetings, I’ve had the pleasure of being an active member of the University of Michigan community. SMES-G, AGEP, WISE and the CoE Office have been wonderful supports of any idea I ever wanted to execute. A special thank you to Dr. Debby Mitchell, Mr. Mike Nazareth, Dr. Alex Gallimore (especially for your guidance in the final year of this journey!) and Mrs. Debbie Taylor. Through these organizations and through the many one-on-one interactions, Michigan has broadened my perspective on learning and service. I came to Michigan because I wanted to be on campus that cared about me both as a student and as a citizen of this world. I chose well, ‘and that has made all the difference’. There was definitely a Michigan difference, and for that I am grateful. iv TABLE OF CONTENTS Dedication .......................................................................................................................... ii Acknowledgements .......................................................................................................... iii List Of Figures.................................................................................................................. xi List Of Tables ................................................................................................................. xix List Of Appendices ......................................................................................................... xxi List Of Abbreviations .................................................................................................. xxiii Abstract ......................................................................................................................... xxvi Chapter 1 Introduction..................................................................................................... 1 Introduction ................................................................................................................. 1 1.1 Problem Statement ................................................................................................ 1 1.1.1 Background .................................................................................................. 3 1.2 Research Objectives .............................................................................................. 5 1.2.1 Aim One ....................................................................................................... 6 1.2.2 Aim Two ....................................................................................................... 8 1.2.3 Aim Three ................................................................................................... 10 1.3 Overview of Dissertation ..................................................................................... 12 1.4 References ........................................................................................................... 14 CHAPTER 2 Engineering an In Vitro Distributed Flow System ............................... 27 2.1 Introduction ......................................................................................................... 27 2.2 Background ......................................................................................................... 27 2.2.1 Structure and Bio-fluid Mechanics of Blood and Blood Vessels ............... 27 2.3 Methodology ....................................................................................................... 30 v 2.3.1 Computer Generated Vascular Trees ......................................................... 30 2.3.2 Controllable Scaffold Architecture ............................................................ 39 2.3.3 Fabrication of a Polymer Construct ............................................................ 41 2.4 References ........................................................................................................... 45 CHAPTER 3 Development of a Dynamic Flow Phantom for Quantitative Assessment of Flow with Dynamic Contrast Enhanced – Computed Tomography Imaging ............................................................................................................................ 49 3.1 Introduction ......................................................................................................... 50 3.2 Methods and Materials ........................................................................................ 53 3.2.1 Design of Vascular Phantom ...................................................................... 53 3.2.2 Computerized Vascular Tree Design and Manufacturing .......................... 55 3.2.3 Solvent-Casted/Salt-Leached (SC/SL) PCL Scaffolds ............................... 57 3.2.4 SLS PCL Scaffolds ..................................................................................... 57 3.2.5 Inverted Colloidal Crystal (ICC) PCL Scaffolds ....................................... 58 3.3 Characterization of Phantom Components .......................................................... 59 3.3.1 Resolution,