ABSTRACT TAN, ZHUO. Analysis of An Antimicrobial Dual-metal Implant System Activated by Low Intensity Direct Current. (Under the direction of Dr. Rohan A. Shirwaiker). Orthopaedic implant infections pose serious threats to patients in terms of morbidity, mortality and medical costs. Because drug resistance can prevent systemic administration of antibiotics from providing effective treatment for the infections, new technologies are oriented towards the increasing needs of non-antibiotics. Silver-based system activated by electric current has raised the interest of many investigators because of its broad-spectrum antimicrobial activity. However, so far there has been limited research on the parameter characterization of the system in terms of antimicrobial efficacy and biocompatibility. Furthermore, the control mechanism of the system, which is the key issue for clinical applications, needs to be investigated. The goal of this dissertation was to understand, model and analyze the antimicrobial efficacy and the biocompatibility of the electrically-activated dual-metal implant system (DIS), and to incorporate the closed loop control mechanism into the system. The specific objectives of this research were as follows: 1. Analyzing and modeling the effects of primary system design parameters on the in vitro antimicrobial efficacy of the DIS in a simulated environment. 2. Evaluating the in vitro cytotoxic effects of the DIS with critical system design based on results from Objective 1. 3. Developing a closed loop control on the output current of the DIS, and evaluating the antimicrobial performance of the closed loop controlled DIS. This research provides a systematic understanding of the functionality of the proposed implant system. The testing models and mathematical analysis developed in this research give a generalized approach of quantitative assessment of antimicrobial efficacy and cytotoxicity of similar systems. In addition, the design of closed loop control mechanism serves as a foundation of future development of antimicrobial and biocompatible implant system. Overall the characterization of the system provides references for future standards and regulations of electrically-activated silver-based antimicrobial prophylaxis. Analysis of An Antimicrobial Dual-metal Implant System Activated by Low Intensity Direct Current by Zhuo Tan 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 Industrial Engineering Raleigh, North Carolina 2015 APPROVED BY: _______________________________ ______________________________ Rohan A. Shirwaiker Richard A. Wysk Committee Chair ________________________________ ________________________________ Ola L. A. Harrysson Paul E. Orndorff BIOGRAPHY Zhuo Tan, George, received his B.S. degree in Statistics from Communication University of China, Beijing, in 2009. He worked as an Assistant Systems Engineer at China Film Crest Digit Co.,Ltd., a China-US joint venture in Beijing, from 2009 to 2010. George joined the Ph.D. program in Industrial & Systems Engineering at North Carolina State University in Fall 2010. During his Ph.D. study, he married his wife Xiaomei and they had their first baby, Eliana. ii ACKNOWLEDGEMENTS I first want to give thanks and praise to my God who has been blessing me with strength, wisdom, health and endurance in Christ through these five years at North Carolina State University. He has also blessed me by placing many special and important people in my life to guide me along the way. I must thank my beloved wife Xiaomei. Without her love and support, I could never have completed this research and doctoral program. A special thanks to my parents who always espoused the virtues of education and supported me with all their hearts. I would like to graciously acknowledge Dr. Rohan Shirwaiker, my committee chair, for his guidance, support, patience and understanding to maintain the high standards of this research, and for his every moment devoted to mentoring me to be an interdisciplinary industrial engineer. It has been a privilege to be his first PhD student. I am thankful for the time and support given to me by Dr. Richard Wysk, who was my advisor in the first year of my graduate study. His insights and mentoring was extremely helpful in structuring and communicating my research ideas. I express my gratitude to Dr. Paul Orndorff for his assistance and guidance. I thoroughly enjoyed my interactions with him in conducting biological experiments. I also appreciate the support and feedback from Dr. Ola Harrysson. I am truly grateful for having such wonderful colleagues who made my journey to this achievement full of love, inspiration and courage. They are Dr. Edward Havell, Ms. Patty Spears, Ms. Mitsu Suyemoto and Dr. Meghan Samberg. I cherish every moment that they offered my selfless supports when I felt frustrated in my research. God has showed me His grace and love through these friends. iii I give my sincere thanks to Mr. Edward P. Fitts for his generous endowment. I am just one of the many students who have benefited from the Scholarship created by him. I would like to thank Dr. Paul Cohen and Ms. Cecilia Chen for their constant advice, counsel and help throughout my stay at NC State. Last but not least, I appreciate the friendship and assistance my research group gave me during my time here: Ms. Priyanka Sheshadri, Mr. Anirudh Ganapathy and Mr. Lokesh Karthik Narayanan. My best wishes to them all in their future pursuits. iv TABLE OF CONTENTS LIST OF TABLES .......................................................................................................................... viii LIST OF FIGURES ......................................................................................................................... ix CHAPTER 1 INTRODUCTION .................................................................................................. 1 1.1 Background .................................................................................................................... 1 1.2 Motivation ...................................................................................................................... 6 1.3 Research Objectives ...................................................................................................... 8 1.4 Research Contributions ................................................................................................ 8 1.5 Dissertation Outline ...................................................................................................... 9 1.6 Chapter Summary ....................................................................................................... 10 CHAPTER 2 LITERATURE REVIEW ................................................................................... 11 2.1 Overview of Orthopaedic Implant Infections ........................................................... 11 2.2 Causes of Orthopaedic Implant Infections ............................................................... 13 2.3 Conventional Treatment Options .............................................................................. 15 2.4 Silver-based Implants ................................................................................................. 19 2.5 Potential Side Effects of Silver ................................................................................... 22 2.6 Silver Oligodynamic Iontophoresis ............................................................................ 25 2.7 Chapter Summary ....................................................................................................... 31 CHAPTER 3 SYSTEM DESIGN AND IN VITRO EMPIRICAL MODELING OF ANTIMICROBIAL EFFICACY ................................................................................................. 33 3.1 Introduction ................................................................................................................. 33 3.2 System Design .............................................................................................................. 34 3.3 Antimicrobial Efficacy Study-1.................................................................................. 36 3.3.1 Materials and Methods ........................................................................................ 37 3.3.2 Results and Discussion ......................................................................................... 42 3.4 Antimicrobial Efficacy Study-2.................................................................................. 50 3.4.1 Materials and Methods ........................................................................................ 51 v 3.4.2 Results and Discussion ......................................................................................... 59 3.5 Antimicrobial Efficacy Study-3.................................................................................. 67 3.5.1 Model Development .............................................................................................. 68 3.5.2 Data Analysis......................................................................................................... 75 3.5.3 Results and Discussion ......................................................................................... 76 3.6 Chapter Summary ....................................................................................................... 95 CHAPTER 4 IN VITRO CYTOTOXICITY OF THE SYSTEM .......................................