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Point-Of-Care Diagnostics for Lung Transplantation

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Point-Of-Care Diagnostics for Lung Transplantation Point-of-Care Diagnostics for Lung Transplantation by Andrew Thomas Sage A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Pharmaceutical Sciences University of Toronto © Copyright by Andrew Thomas Sage 2015 Point-of-Care Diagnostics for Lung Transplantation Andrew Thomas Sage Doctor of Philosophy Graduate Department of Pharmaceutical Sciences University of Toronto 2015 Abstract Over the last few decades, lung transplantation (LTx) has become a well-established therapy for patients suffering from end-stage lung disease. Despite the many innovations that have occurred in recent years, the outcomes following LTx still lag behind those of other organ transplant procedures due to a lack of technologies that could monitor predictive biomarkers. Recently, several genomic and proteomic analytes have been identified that are prognostic of LTx outcome; however, traditional analytical methods are impractical for use in the transplant setting. Rapid analysis of molecular biomarkers reporting on the initial and long-term status of a donated organ would improve utilization rates and transplant outcomes. The work herein focuses on developing a novel class of chip-based sensors that would enable direct analysis of mRNAs and proteins that are correlated with the suitability of a lung for transplant. The biosensing approach utilized in these studies was performed using a simple and elegant electrochemical reporter system with metal electrodes of varying morphologies and sizes. ii By fabricating fractal circuit sensors (FraCS), we demonstrated the technological and biological validation required for a point-of-care (POC) diagnostic device to be used for gene quantitation in the transplant setting. This approach was applied to confirm the clinical validity of previously reported biomarkers (IL-6, IL-10, EGLN1, and ATP11B) and, importantly, was used to develop a FraCS prediction model (FPM), which was highly predictive (AUC 0.82) of primary graft dysfunction (PGD) in donor lungs. Using nanostructured microelectrodes (NMEs), a sensing platform was developed to detect two proteins implicated in chronic lung rejection: TGFβ1 and ET-1 – biomarkers involved in restrictive allograft syndrome (RAS) and bronchiolitis obliterans syndrome (BOS). We highlight novel strategies used for the electrochemical detection of small (< 50-kDa) proteins and demonstrate that this approach is compatible for use with lung perfusate – a biopsy-free approach to donor lung outcome prediction. This work reports the rapid detection of lung transplant specific biomarkers for the first time. It achieved this advance with the use of novel electrochemical biosensors. These diagnostic tools represent a significant development in the field of transplantation. In summary, this work further strengthens the role of POC devices in the transplant setting and will have broad implications for the transplant community. iii Acknowledgments This work is the culmination of the efforts of many people, whose contributions are truly appreciated. First and foremost, I would like to thank my Ph.D. supervisor, Dr. Shana Kelley. I am extremely grateful for the opportunities I have been given in your research lab and the independence in which you let me pursue this project with. Your guidance and support throughout this process has helped me become a better scientist. To my committee members, Dr. Shaf Keshavjee, Dr. Mingyao Liu, and Dr. Edward Sargent: I am so very thankful for your efforts in this project. Together, you helped push this work into something I am extremely proud of. Your advice and suggestions have taught me so much and has given me such a strong foundation in this field. There are so many people in both the Kelley Laboratory and Latner Thoracic Surgery Research Group that have had a hand in this work. For all of your contributions, I am sincerely grateful. Projects such as these would not be possible without the hard work and dedication of so many. I would like to thank my family for always being so supportive through every step of this process – your personal triumph in the face of adversity continues to inspire me. Finally, I would like to thank Holly for being there for me throughout this work. You have been there for the ups and downs of research and your love and support mean the world to me. Thank you for being the sounding board to my ideas, the voice of reason, and my best friend. iv Table of Contents Abstract .................................................................................................................. ii Acknowledgements ............................................................................................... iv List of Tables ....................................................................................................... viii List of Figures ....................................................................................................... ix List of Abbreviates ................................................................................................ xi CHAPTER 1 - Introduction 1.0 ........................................................................................................................ 1 1.1 The Challenges Facing Lung Transplantation ................................................ 2 1.2 Origins and Rationale for Lung Transplantation ............................................. 4 1.3 Lung Transplantation – A Donor Lung Shortage ............................................ 5 1.4 Novel Strategies for Organ Preservation ........................................................ 6 1.5 Patient Outcomes Following Lung Transplantation ........................................ 8 1.6 Prognostic Tools in Lung Transplantation - Biomarkers ............................... 10 1.7 The Challenges Surrounding Current Lung Transplantation Diagnostics ..... 17 1.8 The Current State of Diagnostics .................................................................. 18 1.9 Assays for Protein Detection ......................................................................... 19 1.10 Assays for Nucleic Acids Detection ............................................................ 22 1.11 The Emergence of Electrochemical Biosensors ......................................... 23 1.12 Meeting the Challenges of RNA Extraction ................................................. 25 1.13 Putting it all Together – Integrated Diagnostic Devices .............................. 26 1.14 The Future of Electrochemical Sensors–Nanostructured Microelectrodes . 27 1.15 Using the Nanostructured Microelectrode Platform for Superior Clinical Performance ....................................................................................................... 33 v 1.16 Meeting the Challenges of Lung Transplantation Diagnostics–Summary .. 36 1.17 Project Hypothesis and Goals ..................................................................... 37 1.18 Overview of Thesis Chapters ...................................................................... 39 CHAPTER 2 – The Development of a Quantitative Biosensing Platform 2.0 ....................................................................................................................... 41 2.1 Abstract ......................................................................................................... 42 2.2 Introduction ................................................................................................... 42 2.3 Results .......................................................................................................... 44 2.4 Discussion ..................................................................................................... 59 2.5 Conclusions .................................................................................................. 65 2.6 Materials and Methods .................................................................................. 66 CHAPTER 3 – Using the FraCS Platform to Predict Lung Transplantation Outcomes 3.0 ....................................................................................................................... 71 3.1 Abstract ......................................................................................................... 72 3.2 Introduction ................................................................................................... 72 3.3 Results .......................................................................................................... 75 3.4 Discussion ..................................................................................................... 84 3.5 Conclusions .................................................................................................. 87 3.6 Materials and Methods .................................................................................. 87 CHAPTER 4 – The Development of an Electrochemical Assay for Small Protein Targets Using TGFβ1 4.0 ....................................................................................................................... 92 4.1 Abstract ......................................................................................................... 93 vi 4.2 Introduction ................................................................................................... 93 4.3 Results .......................................................................................................... 96 4.4 Discussion ..................................................................................................
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