Indiana University-Purdue University Indianapolis (IUPUI) / Suboptimal dosing of anti-microbial agents increases the likelihood of therapeutic failure and resistance. Dosing optimization, while an attractive approach to combat these issues, is difficult to implement due to the different pharmacokinetics of each individual. These limitations highlight the inadequacies of a “standardized” dosing strategy. Therapeutic drug monitoring (TDM) provides a tailored treatment for individuals while avoiding adverse side effects from compounds with a narrow therapeutic window where elevated concentrations of a drug cause organ toxicity. This strategy involves accurately measuring the concentration of the analyte and interpreting the results based on pharmacokinetic parameters. Clinicians then draw conclusions regarding dose adjustment for their patient. However, TDM is expensive and difficult to perform because measurements occur in biofluids. Rapid and robust methods are necessary to quantify antimicrobial agents at the institutional level to guide patient care toward improved outcomes in serious infection. Paper spray ionization (PS), an emerging ambient ionization technique for clinical settings, demonstrations a wide versatility both in analyte variety and applications. This technique offers a rapid, accurate method to analyze these compounds with low rates of false positives even when multiplexing. The work herein explains the method development of assays for TDM of various antimicrobial agents. Chapters two and three describe ways to improve the quantitative capability of paper spray through substrate pre-treatment, modification, and manipulation of key factors. Chapter four describes real-world applications for paper spray utility in clinical settings with the cross-validation of antifungal agents against a “gold standard” method. The final chapter, while not clinical based, describes the method development process for a LC-MS/MS assay to detect urobilinoids in fly guts.

Indiana University-Purdue University Indianapolis (IUPUI) / Paper spray is an ambient ionization technique for mass spectrometry that is well-known for its ability to accomplish rapid and sensitive analyses without any need for sample preparation. This work further develops the technique in two major areas: negative ionization and drug screening. Negative ionization has always been an obstacle to electrospray-based ion sources because of its vulnerability to corona discharge, but methods are presented here to both quantify and suppress this electrical phenomenon, thus preventing it from interfering with qualitative/quantitative analyses. The validity of the discharge-suppressing method is demonstrated for both a simple screen of barbiturates and other acidic drugs (Chapter 2) and the detection and quantitation of chemical warfare agent hydrolysis products (Chapter 3). Additionally, a positive ion drug screen is applied to the analysis of postmortem blood samples (Chapter 4), achieving rapid and effective screening of 137 different drugs ranging from pharmaceuticals to drugs of abuse. The performance of this screen is also evaluated by comparing the results of the postmortem samples to those obtained using a more established series of assays. The research contained herein presents strides toward forensic application of paper spray mass spectrometry, especially in disciplines related to forensic toxicology.

Indiana University-Purdue University Indianapolis (IUPUI) / Paper spray mass spectrometry (PS-MS) is an ambient ionization technique that has been proven useful in many types of investigative analyses. However, the use of this technique with regards to environmental samples has been largely unexplored since the technique’s development. In this work, paper spray mass spectrometry was utilized to detect and quantify compounds for environmental, forensic and chemical defense applications. Due to the sensitive nature of some projects, the work was split into two volumes. Volume 1 focuses on the detection of pharmaceuticals in soil using paper spray (Chapter 2) and the detection of chemical warfare agent (CWA) simulants and CWA hydrolysis products (Chapter 3). Volume 2 focuses on the detection and quantitation of fentanyl analogs in environmental matrices. Chapter 5 focuses on the rapid analysis of fentanyl analogs in soil matrices. The following chapter evaluates the ability of PS-MS to detect low concentrations of fentanyl analogs in water (Chapter 6). Throughout this work, paper spray has proven to be an effective, rapid alternative to chromatography for the analysis of environmental samples.

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<p dir="ltr">Paper spray mass spectrometry (PS-MS) offers advantages in simplicity and rapid analysis but faces challenges that have limited its widespread adoption. These include insufficient sensitivity for certain analytes, susceptibility to matrix effects in complex samples, and inconsistent quantitative performance. Such limitations have restricted the application of PS-MS in fields requiring high sensitivity in analysis of complex biological matrices. This dissertation explores approaches to enhance the capabilities and applications of PS-MS, with a particular focus on overcoming sensitivity limitations. </p><p dir="ltr">Chapter 2 demonstrates the potential of PS-MS in forensic toxicology through an automated high-throughput urine drug screening method. Chapter 3 investigates the negative impact of laser cutting paper spray substrates on sensitivity and provides practical remedies. The core of this work revolves around the development and application of electrokinetic stacking coupled to PS-MS. Chapter 4 describes the integration of field-amplified sample stacking and faradaic ion concentration polarization into paper-based MS ionization cartridges. Chapter 5 presents mathematical modeling to complement the experimental work, offering a theoretical framework for understanding system behavior. Chapter 6 demonstrates practical applications of the technique, utilizing stacking devices to detect low levels of per- and polyfluoroalkyl substances (PFAS) in tap water and drugs of abuse in urine. These applications demonstrate substantial enhancements in sensitivity over conventional PS-MS, while preserving the technique's advantage of minimal sample preparation. Moreover, this work also identifies a potential path towards incorporating electrokinetic separations in PS-MS, addressing a longstanding limitation of the technique and potentially broadening its applicability in complex sample analysis. </p><p dir="ltr"><br></p>

Different sampling devices for paper spray - mass spectrometry (PS - MS) were investigated to improve the assay’s simplicity and sensitivity over traditional approaches. In the first one, pressure-sensitive adhesive paper was used as both sampling tool to collect drug residues on surfaces and paper substrate in PS - MS analysis. This method showed a significant improvement in drug collection on surfaces leading to low nano-gram level detection limits. Other sampling device being investigated was snap-in solid-phase extraction column, which demonstrated the ability to detect trace amounts of drugs in plasma while allowed easy transportation and the use of PS - MS automated system.

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<p> Illicit drug abuse is a widespread issue in the United States and worldwide. Many methods  seek to ease the analytical workload required to collect, analyze, and identify these drugs. Paper  spray-mass spectrometry (PS-MS) is one response to this analytical workload as it offers a rapid,  affordable, and simple means for drug identification by mass spectrometry. This work centers on  the use of pressure-sensitive adhesive (PSA) lined paper as a PS-MS substrate for drug recovery  and detection. The use of PSA paper as a sampling and analysis substrate has been previously  established but is expanded herein with new capabilities and applications. Chapter 2 introduces  the combination of color tests followed by PS-MS for presumptive and confirmatory drug  identification. Three color tests (cobalt thiocyanate, Simon, or Marquis) were performed on the  PSA paper with subsequent drug confirmation occurring by PS-MS. Chapter 3 examines the use  of PSA paper and PS-MS for the recovery and detection of fentanyl, fentanyl precursors, and  analogs from shipping-related surfaces and in the presence of high amounts of cutting agents. The  use of a cartridge that accommodates a full-sized PSA paper ticket was also explored for drug  detection. Chapter 4 assesses PS-MS with PSA paper on portable MS instrumentation. Analyte  recovery and carryover as well as instrument robustness were evaluated. The color test and PS-MS protocol examined in Chapter 2 was also successfully applied to a portable MS instrument.  Application of PS-MS to the portable system highlights the potential fieldability of the technique. </p>

<p>Paper spray mass spectrometry (PS-MS) is an ambient ionization technique that has been proven useful in many types of investigative analyses. However, the use of this technique with regards to environmental samples has been largely unexplored since the technique’s development. In this work, paper spray mass spectrometry was utilized to detect and quantify compounds for environmental, forensic and chemical defense applications. Due to the sensitive nature of some projects, the work was split into two volumes. Volume 1 focuses on the detection of pharmaceuticals in soil using paper spray (Chapter 2) and the detection of chemical warfare agent (CWA) simulants and CWA hydrolysis products (Chapter 3). Volume 2 focuses on the detection and quantitation of fentanyl analogs in environmental matrices. Chapter 5 focuses on the rapid analysis of fentanyl analogs in soil matrices. The following chapter evaluates the ability of PS-MS to detect low concentrations of fentanyl analogs in water (Chapter 6). Throughout this work, paper spray has proven to be an effective, rapid alternative to chromatography for the analysis of environmental samples. </p>

Indiana University-Purdue University Indianapolis (IUPUI) / Paper spray - mass spectrometry (PS-MS) has been developed as a rapid and direct ionization method for qualitative and quantitative analysis of complex samples at trace levels. In this work, different sampling devices for PS-MS were investigated to improve the assay’s simplicity and sensitivity over traditional approaches. In particular, chapter two characterizes an alternate paper substrate to enhance drug detection on surfaces like asphalt, cloth, concrete, aluminum, and glass. Analysis occurs on a single spray ticket coated with pressure-sensitive adhesive (PSA), also known as Post-it notes to detect and quantify drug residues. A PS-MS method utilizing PSA paper was developed to detect a mixture of ten drugs off of various surfaces to evaluate the qualitative and quantitative capabilities of the aforementioned substrate. After the method development on a conventional linear ion trap mass spectrometer, the assay was translated for use on a portable mass spectrometer to evaluate the suitability of the pressure-sensitive adhesive paper substrate in the field in chapter three. Chapter four introduces a sampling device combined with a snap-in solid-phase extraction (SPE) column. The new cartridge design not only inherits the functions from the first iteration SPE cartridge, including extraction and preconcentration from complex samples, but also exhibits greater flexibility in volume control and ease of use for on-site sample collection.