Development of microdroplet calibration for the accurate quantification of particles by single-particle ICP-TOFMS

The quantification of discreet entities such as nanoparticles (NPs), sub-micron particles, and microparticles at the single-particle level presents a significant challenge in analytical chemistry. Single-particle inductively coupled plasma time-of-flight mass spectrometry (spICP-TOFMS) can provide highly time-resolved multi-elemental mass quantification of nanoparticles, sub-micron particles, microparticles, and cells. The primary objective of this research is to develop and validate a microdroplet calibration technique that improves the reliability and throughput of particle measurements in complex sample matrices. This work establishes the feasibility and effectiveness of microdroplet calibration in overcoming existing limitations associated with conventional calibration methods and sample introduction systems, particularly in complex matrices. The first chapter gives a general introduction to spICP-TOFMS and describes challenges associated with calibrating single-particle measurements. The final chapter discusses general conclusions from the work and future directions. The second chapter discusses the characterization of an ICP-TOFMS instrument for single-particle analysis. Microdroplets are used as tunable nanoparticle proxies to determine figures of merit for the instrument, demonstrating single-digit attogram detection limits for many elements. Accurate size distribution measurements for gold nanoparticles are made using online microdroplet calibration in addition to the quantification of carbon in polystyrene microparticles. Chapter three demonstrates the efficacy of online microdroplet calibration for the quantification of spICP-TOFMS measurements in organic matrices. Organic solvents pose unique challenges for ICP measurements; they cause intense signal attenuation while simultaneously increasing the plasma uptake. Online microdroplet calibration can effectively correct for both of these effects without the need for preparing matrix matched standards. Two different particle types were measured (100 nm monodisperse Au NPs and polydisperse TiO2 sub-micron particles) in three different organic matrices (ethanol, acetone, and acetonitrile). Microdroplet calibration was used to determine the particles' mass and particle number concentration (PNC, NPs mL-1) in varying concentrations of the organic matrices. The fourth chapter presents online microdroplet calibration as a method for the quantification of microplastics, nanoparticles, and sub-micron particles in seawater using spICP-TOFMS. Particles of interest in ocean environments, such as anthropogenic nanoparticles or microplastics, are very dilute, which makes them a challenge to measure with optical detection methods such as microscopy. The high-throughput nature of spICP-TOFMS makes it an ideal method of analysis for these sample types; however, the high salt content of seawater samples can cause pronounced matrix effects that must be accounted for with calibration. Online microdroplet calibration is demonstrated to be an effective method for calibrating spICP-TOFMS measurements of microplastics, nanoparticles, and sub-micron particles in a simulated seawater matrix. Chapter five explores calibration approaches for single-cell (sc)ICP-TOFMS measurements. scICP-TOFMS allows for high-throughput multi-elemental measurements of individual cells, which can reveal information about cell heterogeneity within populations. Efficient introduction of cells (i.e., as close to 100% sample transport as possible) into the ICP during scICP-TOFMS measurements is essential to ensure that the sample introduction does not lead to data artifacts. Specialized spray chambers have been created for high-efficiency cell sample introduction. However, while cells are much larger than nanoparticles or aerosolized droplets, many calibration approaches for both sc- and spICP-MS assume that particles, cells, and dissolved aerosolized standards behave identically in the spray chamber and ICP. The study uses a single-cell sample introduction system to evaluate various calibration approaches for single-cell and single-particle measurements, focusing on transport efficiency and mass calibration.