ABSTRACT RICHARDS, ANDREW LATIMER. Experimental
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ABSTRACT RICHARDS, ANDREW LATIMER. Experimental Investigations into the Targeted Delivery of Microspheres in Radioembolization Therapy. (Under the direction of Gregory D. Buckner). The evolution of liver tumor treatment has enabled marked improvements in patient survivability and quality of life. In recent years, radioembolization (RE) procedures, in which radioactive microspheres are introduced directly into the hepatic vasculature, have provided promising results for the treatment of liver tumors. These procedures combine the efficacy of radiation therapy with the selective delivery of transarterial embolization. Despite the well documented advances, however, the lack of a direct tumor-targeting strategy has limited the widespread adoption of RE. Recent work employing computational fluid-particle modeling of the hepatic arteries has suggested that optimized release locations exist which maximize 90 Y microsphere delivery to targeted artery branches. Studies examining this strategy have been primarily computational in nature; no experimental validation has been presented demonstrating directed microsphere delivery in a hepatic artery model. Furthermore, limited data has been published regarding the physical properties of clinical 90 Y RE microspheres most relevant to the simulation model. This dissertation details experimental investigations examining the methods and materials used in this targeting strategy. First, a hepatic artery circulation model is constructed to match simulation-specified flow conditions. Controlled microsphere injections are performed at various locations within the model and the resulting branch distributions are compared with those predicated computationally. For the first time ever, selectable targeting is demonstrated in a physical hepatic model. Achieving predictable targeting in a controlled environment lays the groundwork for adapting this technique for eventual clinical application. Complete physical characterization of the treatment microspheres is required for accurate modeling and targeting in a clinical environment. For the first time in the more than 40 years of radioembolization therapy, independently measured data is reported for microsphere concentration, size distribution, and density values. The physical properties of the microspheres are characterized using multiple particle measurement techniques. Complete knowledge of the microsphere dose can only help to improve the treatment and analysis of patients receiving RE-based therapies. Current RE procedures do not easily permit physicians to determine the delivered dose of microspheres (i.e. number of delivered microspheres), a necessary step when evaluating a targeting methodology. A novel micro-fluidics device utilizing liquid metal electrodes is developed which provides accurate microsphere detection in an easily- fabricated, inexpensive package. This device demonstrates a proof-of-concept which could be further developed for clinical integration. © Copyright 2013 by Andrew Latimer Richards All Rights Reserved Experimental Investigations into the Targeted Delivery of Microspheres in Radioembolization Therapy by Andrew Latimer Richards A dissertation submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Mechanical Engineering Raleigh, North Carolina 2013 APPROVED BY: _______________________________ ________________________________ Gregory D. Buckner Michael Dickey Committee Chair _______________________________ ________________________________ Ola Harrysson Clement Kleinstreuer DEDICATION To my wife, Libby. ii BIOGRAPHY Andrew Richards was born and raised in Irmo, SC, a suburb of Columbia. A proud product of public education, Andrew graduated from Dutch Fork High School in 2000. He attended Clemson University from 2000-2004, graduating with a Bachelor of Science degree in Computer Engineering with a minor in International Engineering and Science. During his time at Clemson, Andrew participated in internships with Mettler-Toledo Inc. in Inman, SC, and with Sealevel Systems in Liberty, SC, and also studied abroad in Ulm, Germany. Following graduation, Andrew continued working with Sealevel Systems on a full-time basis, though his time there was short-lived. In 2005, dissatisfied with the direction his career was headed, Andrew moved to Raleigh, NC to pursue a Master of Science in Biomedical Engineering, offered as a joint program by North Carolina State University and University of North Carolina Chapel Hill. Under the direction of Dr. Gregory Buckner, Andrew completed his M.S. in 2008 and was encouraged to continue with doctoral studies further investigating engineering solutions to medical problems. iii ACKNOWLEDGMENTS I am grateful to all members, past and present, of the Electromechanics Research Lab, who offered assistance, guidance, and friendship throughout my time here. I would especially like to thank Shaphan Jernigan, who was there since the beginning and on whom I could always rely for assistance or brainstorming sessions. I’d like to thank Drs. Michael Dickey, Glenn Walker, and Thomas Ward for allowing me to conduct experiments in their labs. Their students, though already busy, never hesitated to offer assistance. I am especially grateful to my advisor, Dr. Buckner, for always challenging me to do more and for helping me to stay on track when I strayed too far. Most of all, I would like to thank my wife, Libby, and my parents, Varner and Lynne, for their unconditional support throughout this journey. iv TABLE OF CONTENTS LIST OF TABLES .......................................................................................... viii LIST OF FIGURES .......................................................................................... ix Chapter 1 Introduction ...................................................................................... 1 1.1 Background and motivation ....................................................................................... 1 1.1.1 Radioembolization .............................................................................................. 5 1.1.2 Model-based targeting ........................................................................................ 8 1.2 Specific aims ............................................................................................................ 10 1.3 Organization ............................................................................................................. 11 Chapter 2 Experimental targeting ..................................................................12 2.1 Introduction .............................................................................................................. 12 2.2 Methods and materials ............................................................................................. 14 2.2.1 Model construction ........................................................................................... 14 2.2.2 Experimental parameter determination ............................................................. 20 2.2.3 Simulation design.............................................................................................. 22 2.2.4 Experimental microsphere injection ................................................................. 24 2.3 Results ...................................................................................................................... 26 2.4 Discussion and limitations ....................................................................................... 30 2.5 Conclusion ................................................................................................................ 36 Chapter 3 Microsphere physical properties ...................................................37 3.1 Introduction .............................................................................................................. 37 3.2 Methods and materials ............................................................................................. 39 3.2.1 Concentration .................................................................................................... 39 3.2.2 Size distribution ................................................................................................ 40 3.2.3 Density .............................................................................................................. 41 3.3 Results ...................................................................................................................... 43 3.3.1 Concentration .................................................................................................... 43 3.3.2 Size distribution ................................................................................................ 45 3.3.3 Density .............................................................................................................. 49 3.4 Discussion ................................................................................................................ 50 3.5 Conclusion ................................................................................................................ 55 v Chapter 4 Micro-Coulter counter: Design and demonstration ....................56 4.1 Introduction .............................................................................................................. 56 4.2 Methods and materials ............................................................................................