Annual Review of Analytical Chemistry - Volume 13, 2020

Most of my research directions were opportunistic. Having worked with lasers in the early stages of laser applications in analytical chemistry, attending conferences, workshops, and administrative meetings that were not exactly aligned with our own research, locating to a building or in a department that housed scientists with different backgrounds, having certain specialized equipment at the right time, and having funding agencies that were broad-minded clearly contributed to my ventures into diverse fields. Most of all, it had to be the many eager minds that I have had the fortune to work with. I have always tried to suggest research topics that might be interesting to the individual coworker rather than something straight out of my own research proposals. Only then did each person actually own the project rather than consider it a chore. After all, we work in the field of analytical chemistry, in which almost anything we do can fit in.

Acoustic microfluidic devices are powerful tools that use sound waves to manipulate micro- or nanoscale objects or fluids in analytical chemistry and biomedicine. Their simple device designs, biocompatible and contactless operation, and label-free nature are all characteristics that make acoustic microfluidic devices ideal platforms for fundamental research, diagnostics, and therapeutics. Herein, we summarize the physical principles underlying acoustic microfluidics and review their applications, with particular emphasis on the manipulation of macromolecules, cells, particles, model organisms, and fluidic flows. We also present future goals of this technology in analytical chemistry and biomedical research, as well as challenges and opportunities.

Traditional microfabrication techniques suffer from several disadvantages, including the inability to create truly three-dimensional (3D) architectures, expensive and time-consuming processes when changing device designs, and difficulty in transitioning from prototyping fabrication to bulk manufacturing. 3D printing is an emerging technique that could overcome these disadvantages. While most 3D printed fluidic devices and features to date have been on the millifluidic size scale, some truly microfluidic devices have been shown. Currently, stereolithography is the most promising approach for routine creation of microfluidic structures, but several approaches under development also have potential. Microfluidic 3D printing is still in an early stage, similar to where polydimethylsiloxane was two decades ago. With additional work to advance printer hardware and software control, expand and improve resin and printing material selections, and realize additional applications for 3D printed devices, we foresee 3D printing becoming the dominant microfluidic fabrication method.

Measurement of humoral factors secreted from cells has served as an indispensable method to monitor the states of a cell ensemble because humoral factors play crucial roles in cell–cell interaction and aptly reflect the states of individual cells. Although a cell ensemble consisting of a large number of cells has conventionally been the object of such measurements, recent advances in microfluidic technology together with highly sensitive immunoassays have enabled us to quantify secreted humoral factors even from individual cells in either a population or a temporal context. Many groups have reported various miniaturized platforms for immunoassays of proteins secreted from single cells. This review focuses on the current status of time-resolved assay platforms for protein secretion with single-cell resolution. We also discuss future perspectives of time-resolved immunoassays from the viewpoint of systems biology.

Microfluidic paper-based analytical devices (μPADs) are the newest generation of lab-on-a-chip devices and have made significant strides in both our understanding of fundamental behavior and performance characteristics and expansion of their applications. μPADs have become useful analytical techniques for environmental analysis in addition to their more common application as medical point-of-care devices. Although the most common method for device fabrication is wax printing, numerous other techniques exist and have helped address factors ranging from solvent compatibility to improved device function. This review highlights recent reports of fabrication and design, modes of detection, and broad applications of μPADs. Such advances have enabled μPADs to be used in field and laboratory studies to address critical needs in fast, cheaper measurement technologies.

Organs-on-chips (OOC) are widely seen as being the next generation in vitro models able to accurately recreate the biochemical-physical cues of the cellular microenvironment found in vivo. In addition, they make it possible to examine tissue-scale functional properties of multicellular systems dynamically and in a highly controlled manner. Here we summarize some of the most remarkable examples of OOC technology's ability to extract clinically relevant tissue-level information. The review is organized around the types of OOC outputs that can be measured from the cultured tissues and transferred to clinically meaningful information. First, the creation of functional tissues-on-chip is discussed, followed by the presentation of tissue-level readouts specific to OOC, such as morphological changes, vessel formation and function, tissue properties, and metabolic functions. In each case, the clinical relevance of the extracted information is highlighted.

Avoiding the growth of SiOx has been an enduring task for the use of silicon as an electrode material in dynamic electrochemistry. This is because electrochemical assays become unstable when the SiOx levels change during measurements. Moreover, the silicon electrode can be completely passivated for electron transfer if a thick layer of insulating SiOx grows on the surface. As such, the field of silicon electrochemistry was mainly developed by electron-transfer studies in nonaqueous electrolytes and by applications employing SiOx-passivated silicon-electrodes where no DC currents are required to cross the electrode/electrolyte interface. A solution to this challenge began by functionalizing Si–H electrodes with monolayers based on Si–O–Si linkages. These monolayers have proven very efficient to avoid SiOx formation but are not stable for a long-term operation in aqueous electrolytes due to hydrolysis. It was only with the development of self-assembled monolayers based on Si–C linkages that a reliable protection against SiOx formation was achieved, particularly with monolayers based on α,ω-dialkynes. This review discusses in detail how this surface chemistry achieves such protection, the electron-transfer behavior of these monolayer-modified silicon surfaces, and the new opportunities for electrochemical applications in aqueous solution.

Neuronal transmission relies on electrical signals and the transfer of chemical signals from one neuron to another. Chemical messages are transmitted from presynaptic neurons to neighboring neurons through the triggered fusion of neurotransmitter-filled vesicles with the cell plasma membrane. This process, known as exocytosis, involves the rapid release of neurotransmitter solutions that are detected with high affinity by the postsynaptic neuron. The type and number of neurotransmitters released and the frequency of vesicular events govern brain functions such as cognition, decision making, learning, and memory. Therefore, to understand neurotransmitters and neuronal function, analytical tools capable of quantitative and chemically selective detection of neurotransmitters with high spatiotemporal resolution are needed. Electrochemistry offers powerful techniques that are sufficiently rapid to allow for the detection of exocytosis activity and provides quantitative measurements of vesicle neurotransmitter content and neurotransmitter release from individual vesicle events. In this review, we provide an overview of the most commonly used electrochemical methods for monitoring single-vesicle events, including recent developments and what is needed for future research.

In seeking to develop and optimize reagentless electroanalytical assays, a consideration of the transducing interface features lies key to any subsequent sensitivity and selectivity. This review briefly summarizes some of the most commonly used receptive interfaces that have been employed within the development of impedimetric molecular sensors. We discuss the use of high surface area carbon, nanoparticles, and a range of bioreceptors that can subsequently be integrated. The review spans the most commonly utilized biorecognition elements, such as antibodies, antibody fragments, aptamers, and nucleic acids, and touches on some novel emerging alternatives such as nanofragments, molecularly imprinted polymers, and bacteriophages. Reference is made to the immobilization chemistries available along with a consideration of both optimal packing density and recognition probe orientation. We also discuss assay-relevant mechanistic details and applications in real sample analysis.

The electrochemical behavior of platinum single crystal surfaces can be taken as a model response for the interpretation of the activity of heterogeneous electrodes. The cyclic voltammogram of a given platinum electrode can be considered a fingerprint characteristic of the distribution of sites on its surface. We start this review by providing some simple mathematical descriptions of the voltammetric response in the presence of adsorption processes. We then describe the voltammogram of platinum basal planes, followed by the response of stepped surfaces. The voltammogram of polycrystalline materials can be understood as a composition of the response of the different basal contributions. Further resolution in the discrimination of different surface sites can be achieved with the aid of surface modification using adatoms such as bismuth or germanium. The application of these ideas is exemplified with the consideration of real catalysts composed of platinum nanoparticles with preferential shapes.

Transporters are key to understanding how an individual will respond to a particular dose of a drug. Two patients with similar systemic concentrations may have quite different local concentrations of a drug at the required site. The transporter profile of any individual depends upon a variety of genetic and environmental factors, including genotype, age, and diet status. Robust models (virtual patients) are therefore required and these models are data hungry. Necessary data include quantitative transporter profiles at the relevant organ. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is currently the most powerful method available for obtaining this information. Challenges include sourcing the tissue, isolating the hydrophobic membrane-embedded transporter proteins, preparing the samples for MS (including proteolytic digestion), choosing appropriate quantification methodology, and optimizing the LC-MS/MS conditions. Great progress has been made with all of these, especially within the last few years, and is discussed here.

Lipids are an important class of biomolecules with many roles within cells and tissue. As targets for study, they present several challenges. They are difficult to label, as many labels lack the specificity to the many different lipid species or the labels maybe larger than the lipids themselves, thus severely perturbing the natural chemical environment. Mass spectrometry provides exceptional specificity and is often used to examine lipid extracts from different samples. However, spatial information is lost during extraction. Of the different imaging mass spectrometry methods available, secondary ion mass spectrometry (SIMS) is unique in its ability to analyze very small features, with probe sizes <50 nm available. It also offers high surface sensitivity and 3D imaging capability on a subcellular scale. This article reviews the current capabilities and some remaining challenges associated with imaging the diverse lipids present in cell and tissue samples. We show how the technique has moved beyond show-and-tell, proof-of-principle analysis and is now being used to address real biological challenges. These include imaging the microenvironment of cancer tumors, probing the pathophysiology of traumatic brain injury, or tracking the lipid composition through bacterial membranes.

High-resolution SIMS analysis can be used to explore a wide range of problems in material science and engineering materials, especially when chemical imaging with good spatial resolution (50–100 nm) can be combined with efficient detection of light elements and precise separation of isotopes and isobaric species. Here, applications of the NanoSIMS instrument in the analysis of inorganic materials are reviewed, focusing on areas of current interest in the development of new materials and degradation mechanisms under service conditions. We have chosen examples illustrating NanoSIMS analysis of grain boundary segregation, chemical processes in cracking, and corrosion of nuclear components. An area where NanoSIMS analysis shows potential is in the localization of light elements, in particular, hydrogen and deuterium. Hydrogen embrittlement is a serious problem for industries where safety is critical, including aerospace, nuclear, and oil/gas, so it is imperative to know where in the microstructure hydrogen is located. By charging the metal with deuterium, to avoid uncertainty in the origin of the hydrogen, the microstructural features that can trap hydrogenic species, such as precipitates and grain and phase boundaries, can be determined by NanoSIMS analysis on a microstructurally relevant scale.

As the core component of cell metabolism, central carbon metabolism, consisting of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle converts nutrients into metabolic precursors for biomass and energy to sustain the life of virtually all extant species. The metabolite levels or distributions in central carbon metabolism often change dynamically with cell fates, development, and disease progression. However, traditional biochemical methods require cell lysis, making it challenging to obtain spatiotemporal information about metabolites in living cells and in vivo. Genetically encoded fluorescent sensors allow the rapid, sensitive, specific, and real-time readout of metabolite dynamics in living organisms, thereby offering the potential to fill the gap in current techniques. In this review, we introduce recent progress made in the development of genetically encoded fluorescent sensors for central carbon metabolism and discuss their advantages, disadvantages, and applications. Moreover, several future directions of metabolite sensors are also proposed.

Technological advances in mass spectrometry have enabled the extensive identification, characterization, and quantification of proteins in any biological system. In disease processes proteins are often altered in response to external stimuli; therefore, proteomics, the large-scale study of proteins and their functions, represents an invaluable tool for understanding the molecular basis of disease. This review highlights the use of mass spectrometry–based proteomics to study the pathogenesis, etiology, and pathology of several neglected tropical diseases (NTDs), a diverse group of disabling diseases primarily associated with poverty in tropical and subtropical regions of the world. While numerous NTDs have been the subject of proteomic studies, this review focuses on Buruli ulcer, dengue, leishmaniasis, and snakebite envenoming. The proteomic studies highlighted provide substantial information on the pathogenic mechanisms driving these diseases; they also identify molecular targets for drug discovery and development and uncover promising biomarkers that can assist in early diagnosis.

Live-cell single-molecule fluorescence imaging has become a powerful analytical tool to investigate cellular processes that are not accessible to conventional biochemical approaches. This has greatly enriched our understanding of the behaviors of single biomolecules in their native environments and their roles in cellular events. Here, we review recent advances in fluorescence-based single-molecule bioimaging of proteins in living cells. We begin with practical considerations of the design of single-molecule fluorescence imaging experiments such as the choice of imaging modalities, fluorescent probes, and labeling methods. We then describe analytical observables from single-molecule data and the associated molecular parameters along with examples of live-cell single-molecule studies. Lastly, we discuss computational algorithms developed for single-molecule data analysis.

Protein separations have gained increasing interest over the past two decades owing to the dramatic growth of proteins as therapeutics and the completion of the Human Genome Project. About every decade, the field of protein high-performance liquid chromatography (HPLC) seems to mature, having reached what appears to be a theoretical limit. But then scientists well versed in the basic principles of HPLC invented a way around the limit, generating another decade of exciting progress. There is still the need for higher resolution and better compatibility with mass spectrometry because it is an essential tool for identification of proteins and their modifications. To make advances, the fundamental principles need to be understood. This review covers recent advances and current needs in the context of the principles that underlie the many contributions to peak broadening.

Single particle tracking (SPT) has proven to be a powerful technique in studying molecular dynamics in complicated systems. We review its recent development, including three-dimensional (3D) SPT and its applications in probing nanostructures and molecule-surface interactions that are important to analytical chemical processes. Several frequently used 3D SPT techniques are introduced. Especially of interest are those based on point spread function engineering, which are simple in instrumentation and can be easily adapted and used in analytical labs. Corresponding data analysis methods are briefly discussed. We present several important case studies, with a focus on probing mass transport and molecule-surface interactions in confined environments. The presented studies demonstrate the great potential of 3D SPT for understanding fundamental phenomena in confined space, which will enable us to predict basic principles involved in chemical recognition, separation, and analysis, and to optimize mass transport and responses by structural design and optimization.

The detailed molecular characterization of petroleum-related samples by mass spectrometry, often referred to as petroleomics, continues to present significant analytical challenges. As a result, petroleomics continues to be a driving force for the development of new ultrahigh resolution instrumentation, experimental methods, and data analysis procedures. Recent advances in ionization, resolving power, mass accuracy, and the use of separation methods, have allowed for record levels of compositional detail to be obtained for petroleum-related samples. To address the growing size and complexity of the data generated, vital software tools for data processing, analysis, and visualization continue to be developed. The insights gained impact upon the fields of energy and environmental science and the petrochemical industry, among others. In addition to advancing the understanding of one of nature's most complex mixtures, advances in petroleomics methodologies are being adapted for the study of other sample types, resulting in direct benefits to other fields.

Development and application of nanotechnology-enabled medical products, including drugs, devices, and in vitro diagnostics, are rapidly expanding in the global marketplace. In this review, the focus is on providing the reader with an introduction to the landscape of commercially available nanotechnology-enabled medical products as well as an overview of the international documentary standards and reference materials that support and facilitate efficient regulatory evaluation and reliable manufacturing of this diverse group of medical products. We describe the materials, test methods, and standards development needs for emerging medical products. Scientific and measurement challenges involved in the development and application of innovative nanoenabled medical products motivate discussion throughout this review.

The National Institute of Standards and Technology (NIST), formerly the National Bureau of Standards, was established by the US Congress in 1901 and charged with establishing a measurement foundation to facilitate US and international commerce. This broad language provides NIST with the ability to establish and implement its programs in response to changes in national needs and priorities. This review traces some of the changes in NIST's reference material programs over time and presents the NIST Material Measurement Laboratory's current approach to promoting accuracy and metrological traceability of chemical measurements and validation of chemical measurement processes.

The current teaching and practice of analytical chemistry reflect the evolution of measurement science over time. Qualitative and quantitative measurements can be traced back to prebiblical times, have been important throughout human history, and today are key to the functioning of a modern society. This review is designed to provide a brief overview of the evolution of analytical science and a summary of the evolution, development, and growth of analytical chemistry in the United States, with emphasis on developments up to the mid-twentieth century. Some degree of emphasis is placed on early centers of analytical chemistry and contributions of pioneers of analytical chemistry within the United States. The evolution of journals, early textbooks, and reference books on analytical chemistry as well as developments in analytical chemistry curricula in the United States are traced.