Development of Functionalized Paper-Based Sample Collection and Direct Mass Spectrometry Analysis Platforms Dissertation Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the Graduate School of The Ohio State University By Deidre Erin Damon Graduate Program in Chemistry The Ohio State University 2019 Dissertation Committee: Dr. Abraham K. Badu-Tawiah, Advisor Dr. Vicki H. Wysocki Dr. James V. Coe Copyrighted by Deidre Erin Damon 2019 Abstract The goal of this dissertation is to develop a paper-based mass spectrometry (MS) ionization method for detection of small molecules from biological fluids and water samples. In biofluids, highly sensitive analytical methods are required to monitor small biologically active molecules during treatment. When analyzing both biofluids and industrial water samples, rapid and inexpensive detection platforms streamline screening for harmful concentrations of chemicals. Paper spray ionization shortens analysis time to less than one minute. Current analytical detection methods for these molecules include gas chromatography (GC)-MS, which is useful for creating databases for small molecules. However, GC-MS often requires extensive sample preparation and analyte derivatization prior to analysis. Liquid chromatography (LC)-MS offers better sensitivity without the need for derivatization. However, LC-MS is also limited by additional sample preparation/handling procedures. In particular, matrix components must be removed prior to any chromatographic work, which can be time consuming. For these reasons, immunoassay screening is still the most commonly used detection method for these small molecules despite their well-recognized limitations with regards to sensitivity and selectivity. Alternatively, paper spray (PS) ionization MS is capable of direct analysis of small biological sample volumes. However, PS often suffers from low sensitivity due to inefficient extraction. The second chapter in this document utilizes treated hydrophobic paper substrates prepared by a gas-phase silanization reaction. Hydrophobic PS utilizes online liquid/liquid extraction from a drop of biological fluid without drying steps or sample pretreatment, which is applicable in point-of-care analyses. Preliminary experiments demonstrated high sensitivity in the analysis of drugs cocaine, benzoylecgonine, methamphetamine, and ii amphetamine in 4 μL of raw blood, serum, and urine. When the sample is dried, a 3- dimensional dried spheroid is formed, as opposed to a dried blood spot. This spheroid decreases interaction between the bulk of the blood sample and ambient air, decreasing oxidative stress, increasing the lifetime of the analyte in the sample. Experiments show that labile organic compounds diazepam and cocaine have increased stability up to 28 days, where sample signal decreases by 90% within a day when stored in dried blood spots. The third chapter discusses the use of wax printing on paper. Wax printing creates microfluidic channels in which the designer can control solvent flow. Through this solvent control, spray time was increased from 1.5 minutes to 10 minutes. Additionally, because the solvent acts as the charge carrier, manipulation of the electric field decreased the required voltage applied to the paper triangle from 3-5 kV to 0.5-1 kV. The fourth chapter outlines the detection of low concentration corrosion inhibitor Duomeen O and molluscicide metaldehyde in industrial and environmental water samples. On-site analysis of Duomeen O would facilitate the maintaining of appropriate levels to prevent corrosion in water tube boiler plants. Because metaldehyde is readily soluble in water, runoff during periods of heavy rainfall ultimately introduces metaldehyde into drinking water. Paper spray ionization has been demonstrated as a viable technique for rapid screening and quantification of these molecules without sample preconcentration with detection limits below the threshold set by the World Health Organization. iii Dedication This dissertation is dedicated to my father, Darrel Damon, for his advice in research and life. iv Acknowledgements I would like to thank my advisor, Dr. Abraham Badu-Tawiah, for his support and guidance, as well as the opportunities he gave me to develop my scientific potential. I also want to thank him for his unyielding optimism and ability to see much broader impacts that I was not capable of noticing. Additionally, I want to thank my group members, including Colbert Miller, Dmytro Kulyk, Qiongqiong Wan, and Suming Chen for joining me in the founding of the Badu group and giving me advice, support, and distraction necessary to survive graduate school while maintaining sanity. I also want to thank the undergraduate student researchers who worked with me, including Yosef Maher, Mengzhen Yin, Jill Baker, Christian Tanny, and Danyelle Baker for helping with research and persevering when experiments never seemed to work. Further, I would like to thank the rest of my group for giving me support and reprieve from daily research life, including Savithra Jayaraj, Sierra Jackson, Tatiana Velez, and Benji Frey. I want to also thank Fred Jjunju, Simon Maher, and Steven Taylor for their advice and partnership in research that is discussed in this document. Finally, I would like to thank my father and step mother, Darrel and Paula Damon, and my mother Cindy Damon for their unceasing support and advice through graduate school and beyond. v Vita 2009 ‒ 2014 ……………………………..… B.Sc. Chemistry, Biochemistry Concentration, Department of Chemistry, University of Wisconsin – Parkside 2014 ‒ 2019 …………………………..…… Graduate Associate, Department of Chemistry and Biochemistry, The Ohio State University Publications Deidre E. Damon, Mengzhen Yin, Christian J. Tanny, Yosef S. Maher, Stephanie Oyoloa- Reynoso, Barry L. Smith, Simon Maher, Martin M. Thuo, Abraham K. Badu-Tawiah, “Dried Blood Spheroids for Dry-state Room Temperature Stabilization of Microliter Blood Samples” Analytical Chemistry 2018, 90 (15), 9353-9358. Simon Maher, Fred P. M. Jjunju, Deidre E. Damon, Yosef S. Maher, Safaraz U. Syed, Ron M. A. Heeren, Stephen Taylor, Iain S. Young and Abraham K. Badu-Tawiah, “Direct Analysis and Quantification of Metaldehyde in Water using Reactive Paper Spray Mass Spectrometry” Scientific Reports 2016, 6, 35643. Deidre E. Damon, Yosef S. Maher, M. Yin, Fred P. M. Jjunju, Simon Maher, Stephen Taylor, and A. K. Badu-Tawiah, “2D wax-printed paper substrates with extended solvent supply capabilities allow enhanced ion signal in paper spray ionization” Analyst 2016,141, 3866-3873. Deidre E. Damon, Kathryn M. Davis, Camila R. Moreira, Patricia Capone, Riley Cruttenden, and Abraham K. Badu-Tawiah, “Direct Biofluid Analysis using Hydrophobic Paper Spray Mass Spectrometry” Analytical Chemistry 2016, 88 (3), 1878–1884. vi Fred P. M. Jjunju, Simon Maher, Deidre E. Damon, Dick. R. Barrett, S. U. Syed, R. M. A. Heere, Stephen Taylor, Abraham K. Badu-Tawiah, “Screening and Quantification of Aliphatic Primary Alkyl Corrosion Inhibitor Amines in Water Samples by Paper Spray Mass Spectrometry” Analytical Chemistry 2015, 88 (2), 1391–1400. Fields of Study Major Field: Chemistry Analytical Chemistry vii Table of Contents Abstract .............................................................................................................................. ii Dedication ......................................................................................................................... iv Acknowledgements ........................................................................................................... v Vita .................................................................................................................................... vi Table of Contents ........................................................................................................... viii List of Tables ................................................................................................................. xxv List of Equations .......................................................................................................... xxvi List of Abbreviations .................................................................................................. xxvii Chapter 1. Introduction and Background ................................................................... 1 1.1 Overview ........................................................................................................................1 1.2 Dried Blood Spots on Paper as a Biofluid Collection Platform.....................................2 1.3 Ionization Methods for Mass Spectrometry ...................................................................3 1.3.1 Electrospray Ionization ...............................................................................................4 1.3.2 Ambient Ionization .....................................................................................................6 1.3.2.1 Paper Spray ...................................................................................................... 7 1.4 Linear Ion Trap Mass Spectrometer Detection ..............................................................8 Chapter 2. Hydrophobic Paper Spray Ionization ..................................................... 11 viii 2.1 Introduction: Dried Blood Spots ..................................................................................11 2.1.1 Paper Spray Strategies for Biofluid Analysis ...........................................................12