Balaram Vysetti

The miniaturization of analytical instruments of various forms of spectroscopy has improved dramatically in recent years mainly because of the requirements in certain areas such as space, industrial, and environmental research. Research into miniaturization is primarily driven by the need to reduce the instrumental space and costs by reducing the consumption of expensive reagents and by increasing throughput and automation. Like other fields, analytical systems have also been affected by novel ideas and unprecedented advances in the microelectronics leading to miniaturization of different components in recent years. This article presents an overview of the current developments in the miniaturization of analytical instruments mainly for detecting metals at extremely low concentrations, with some important examples from areas such as space, mineral exploration, the environment, and pharmaceuticals, focusing primarily on advancements as well as the challenges that have impacted from some of the major international manufacturers.

	Elemental analysis is one of the most important fundamental measurements made for industrial quality control and research and development. The need for better productivity is driving the development of handheld or portable analytical devices. For example, pharmaceutical scientists want instrumentation companies to develop smaller, faster, and more precise analytical tools (1). Over the past few decades, analytical instruments have shrunk in size dramatically whereas previous generations of spectrometers were large enough to fill rooms. Today, the majority of instruments have moved to the benchtop and, in some cases, into the hand. Last year one firm made an award-winning micro-ultraviolet–visible (UV–vis) spectrometer that was about the size of a fingertip (2). Recently, IBM came out with the 7-nm Super-Chip with more than 20 billion tiny switches on a fingernail-size chip that can power everything from a smartphone to a spacecraft. It is not easy to achieve this level of miniaturization, and this particular breakthrough is a direct result of IBM’s $3 billion, five-year investment in chip research and development (R&D) in 2014 (3). Of course, the large footprints of previous generations of spectrometers were cumbersome to use in small workplaces, such as R&D laboratories and small manufacturing facilities. However, the miniaturization of analytical tools is more than a space saver. This trend encompasses various fields, from laboratories interested in creating novel microfabricated structures to application laboratories focused on specific uses. Many manufacturing industry observers believe that small instrumentation holds the key to generating information about product quality faster, which can result in significant savings in time and money. In fact, these developments in analytical, experimental, and modeling methods have largely facilitated the major advances in science and technology during the last ï¬ve decades. In addition, the encroaching limits of our planet’s resources and the continuing deterioration of the environment are adding urgency to the trend toward miniaturization of analytical instrumentation. This synergy of academia and industry led to a rapid expansion toward significant applications of these miniaturized gadgets in several areas, including cosmochemistry, geochemistry, exploration, and environmental sciences.

	Analytical Techniques for Inorganic Analyses

	Elemental analysis has been known as an important process for accurately determining the composition of elements in different materials for a variety of applications. Popular instrumental analytical techniques such as atomic absorption spectrometry (AAS), X-ray fluorescence (XRF) spectrometry, instrumental neutron activation analysis (INAA), inductively coupled plasma–atomic emission spectrometry (ICP-AES), inductively coupled plasma–mass spectrometry (ICP-MS), and high-resolution inductively coupled plasma–mass spectrometry (HR-ICP-MS) are being used today (4). Currently, these instruments have become relatively smaller in size compared to earlier models with higher performance characteristics. Even the recently introduced microwave plasma atomic emission spectrometry (MP-AES) is already performed using a compact instrument when compared to other such instrumentation (5). Recently, one firm released a portable AAS system that is ideal for fast field determination of important heavy metal elements such as Pb, Cd, and V in environmental water systems. It features a tungsten coil electrothermal atomizer and a miniature charge-coupled device (CCD) spectrometer, contains no moving parts with a much smaller size and weight, and consumes much lower energy than full-size laboratory-based instruments (6). There has even been significant progress on the miniaturization of mass spectrometers for a variety of field applications and these systems are becoming portable or transportable, which is the latest innovation. The world’s first handheld mass spectrometer was created in 2013 for trace-level chemical detection and identification and continuous incident monitoring directly in hand, at the point of action (7). Conventional mass spectrometers analyze samples that are specially prepared and placed in a vacuum chamber whereas these new handheld devices can be used in the field.

	Geological, Environmental, Industrial, and Space Applications

	The exploration of new prospects is challenging since the most accessible and obvious ore deposits have already been explored and mined. These circumstances reinforce the importance of identifying geochemical exploration keys and models that can be used to facilitate new discoveries. For example, one of the most popular techniques for elemental analysis is XRF, which has the capability of simultaneous, multielement, nondestructive analysis of both solids and liquids with sufficient sensitivity, and portable XRF devices have been available for many years. This instrument, which was built for the first time in 1948, has transformed itself from a floor model to the benchtop model and now into a field-portable instrument. This instrument has gained widespread acceptance by mineral exploration and environmental communities as a viable analytical tool for on-site analysis of a variety of samples. Such devices weigh only a couple of kilograms, can rapidly quantify most elements heavier than Al, and often provide limits of detection reaching the microgram-per-gram level and below. These instruments also help in reducing human error-related activities such as data transfer to laptop computers, global positioning system (GPS) coordinate merging, and geographic information system (GIS) integration for the generation of concentration anomaly maps in a given area for a particular element using BlueTooth devices in mineral prospecting studies (8–10). Such connectivity to the “Cloud” and other internet systems offers great potential for the application of data processing algorithms that can improve the analytical potential of these miniature devices. There is no doubt that these valuable instruments can play a significant role not only in grass-root exploration projects such as locating centers of hydrothermal activity and mineralization, for example, which are the prime targets for exploration and mining, but also in advanced mining programs and even daily routine grade control and ore processing. These instruments will help geologists make decisions on time and efficiently manage their mining projects, thereby saving time and money. Trace-level detection of metallic impurities in pharmaceutical materials in the pharmaceutical industry is another active area where portable analytical tools such as handheld XRF and Raman spectrometers are extensively used (1).

	Portable laser-induced breakdown spectroscopy (LIBS) is another important development in that direction. LIBS offers improved detection limits for light elements such as Mg, Al, and Si. A LIBS instrument traveled to Mars as part of ChemCam on the Mars Science Laboratory Rover. Measurements by such devices on spacecrafts have significantly advanced cosmochemistry and helped in understanding more about outer space. The experimental results showed that LIBS is sensitive to minor compositional variations with depth and can correctly identify rock type even if the series of laser pulses does not penetrate to unweathered material (11). Such developments have taken place not only with portable XRF and LIBS spectrometers, but also with Raman spectrometers, elemental mass spectrometers, and optical emission spectrometers, such as ICP spectrometers, for a variety of field applications (12,13).

	As already stated, since the late 1980s and early 1990s, MS instrumentation underwent an evolution from complex, room-sized instruments to more user-friendly, benchtop equipment. These developments further led to the development of smaller, more portable, and smarter systems. Micromachined instruments have opened the door for consideration of ion traps, quadrupoles, sector instruments, and many other types of mass analyzers. Some of these devices can become more powerful and simpler with fast data acquisition capability, making it possible to read detector-array chips even more rapidly and making it more straightforward to perform multielemental analysis on transient samples, such as those produced by laser ablation, flow injection, or chromatography. Anderson and colleagues (14) developed a miniaturized laser ablation resonance ionization mass spectrometry (LA-RIMS) system for measuring the ages of rocks encountered during space missions to the Moon or other planets. Spacecraft missions impose serious limitations on instrument volume, mass, and power. The new Mars Rover that is being developed for launch in 2020 by the National Aeronautics and Space Administration (NASA) will include a micro-XRF system called PIXL, which stands for planetary instrument for X-ray lithochemistry (15). PIXL will be mounted at the end of the rover’s robotic arm and is designed to provide fine-scale identification of the elemental composition of rocks and soils on Mars. It is one of seven instruments on the Mars 2020 Rover designed to seek evidence of past life on Mars (16).

	Even in environmental studies, for example, currently the restriction of hazardous substances (RoHS) directive requirements are better mitigated by these portable devices. Millions of workers are employed in manufacturing, mining, construction, and other industries where significant amounts of airborne toxic metals and metal compounds are generated. Depending on the nature of work practices, processes, techniques, and locations, exposure to some of these airborne toxic chemicals can cause occupational illnesses creating adverse health effects such as lung disease, anemia, cancer, asthma, skin allergies, and neurological damage. These portable analytical tools can be used on site in the field to understand and prevent such exposure to toxic chemicals in workplaces (17).

	Miniaturization continues to be an important consideration in the design and development of many probes, assays, and analyzers. Another challenge is designing instruments that can function in extreme environments of temperature, pressure, and radiation as required in space and deep marine conditions. The escalating interest in high-throughput screening of materials for industry, ocean, and environmental studies will continue to be major driving factors influencing miniaturization. Instrument companies are currently developing chips ranging in size from a match tip to a matchbox, leading to the 

-a miniature device for separating and identifying molecules and atoms of different materials. For lab-on-a-chip techniques, ever-increasing complexity of chip design allows for more sophisticated analyses to be performed wherever the analyst desires. This ability coupled with the ability to fabricate these chips in a relatively short period of time add to the attractiveness of these miniaturized devices. A lab-on-a-chip device, also known as a micro-total-analytical system (µTAS) or microfluidics device, is a device that can integrate miniaturized laboratory functions (such as separation and analysis of components of a mixture) on a single microprocessor chip using extremely small fluid volumes on the order of nanoliters to picoliters. Most lab-on-a-chip technologies, which can be tailored to detect any contaminant, are used mainly for detecting organic compounds in biomedical analysis applications. For example, this technology can be used to detect certain industrial chemicals in the breath and saliva of exposed workers, biomarkers of cancer and other chronic disease, and markers of explosives for airport screening applications. The core microfabricated silicon chips, when stacked, are roughly the size of a wristwatch. They require less power and can be made smaller and less expensive than traditionally manufactured counterparts. Currently these lab-on-a-chip devices are used in a diverse range of applications, such as detecting toxic gases, fabricating integrated circuits, and screening biological molecules (18).

	These and the upcoming nanotechnologies together have the advantages of a small size and limited reagent and power requirements, and have great potential for addressing future R&D as well as societal needs.

	The synergistic combination of the recent advances in microelectronics, bioelectronics, and bioengineering has led to the development of miniaturized metal detecting biosensors. Dedicated biosensors are being developed for off-line and on-line analysis, and their extent and diversity could be called a real “biosensor revolution.” Biosensors have the advantages of specificity, low cost, ease of use, portability, the ability to perform simultaneous detection of multiple metals, and the ability to furnish continuous real-time signals. For example, these sensors could be used to detect water contaminants, precious metals in mineral exploration, and critical metals such as gold in pharmaceutical and biological samples (19,20). Very recently Rebecca Lai at the University of Nebraska-Lincoln succeeded in the development of a DNA-based gold sensor, which is the latest in a series of metal-detecting biosensors (21). According to the author, other sensors for detecting metals such as mercury, silver, and platinum are at various stages of development. Similar technology could be used to detect other metals such as Cd, Pb, As, and metalloids. For example, serious lead contamination has been reported recently in drinking water from Flint, Michigan (22). A lead sensor can be very effective and conveniently utilized to understand the extent of lead contamination in water, and monitor decontamination methodologies.

	In addition to the miniaturization of analytical instruments, corresponding improvements in sample preparation techniques is also a challenge that has been fulfilled up to a certain point in many fields of analytical chemistry. As instrumentation gets smaller, so do fluid volumes used in the analyses, which subsequently offers scientists several ancillary advantages such as sample size reduction. By requiring less sample for each analysis, sample preparation time as well as sample handling efforts are reduced leading to faster overall analysis times and subsequent increased daily analysis capacity for each system. Particularly, the hyphenation of miniaturized techniques such as solid-phase microextraction (SPME) or liquid-phase microextraction (LPME) with advanced analytical techniques has allowed the monitoring of target analytes in a vast variety of environmental samples (23).

	The interdisciplinary nature of these systems relies on design, engineering, and manufacturing expertise from a wide and diverse range of technical areas including integrated circuit fabrication technology, mechanical engineering, material science, electrical engineering, physics, chemistry, and chemical engineering as well as optics, instrumentation, and packaging. The complexity of such devices is also seen in the extensive range of applications not only in earth and environmental sciences, but also in several other areas such as automotive, medical, and defense applications. These tools bring a miniature version of the laboratory to the field, with obvious limitations of course. As with any new technology or technological advances, in addition to the advantages, there are challenges and limitations, and miniaturization of analytical instrumentation is no exception. Dramatic and significant differences in the results can be obtained between standard-scale equipment and miniaturized equipment because of scale factors that can be more pronounced when more heterogeneous materials, such as geological samples, are analyzed leading to misinterpretation of results. Smaller sample sizes can lead to undesired variability with an ever-shrinking sample size commensurate with the reduced size of equipment, it is possible to get interferences from variables that are not present with larger-scale analyses. For example, in chromatographic applications, the scale factor differences can lead to substantial shifts in peak shapes, retention times, and so forth, that sometimes may lead to the generation of unacceptable results. There is also no true commercial standardization as exists currently with larger-scale equipment (24). In addition, different types of reference materials have to be developed for calibration as well as assessing the accuracy of the determinations. However, with the current pace of advances in this area, some of these challenges can be overcome in the near future.

	Current technologies in the miniaturization of analytical instruments have led to the continued development of smaller gadgets and the miniaturization of laboratory equipments are now allowing the rapid, low-cost determination of virtually all elements in the periodic table apart from gases in different types of materials at and below parts-per-million or parts-per-billion levels. This capability provides the scientists and technologists engaged in R&D work with unprecedented choices. These miniature devices that are quick, precise, and easy to use offer unique benefits that cannot be matched by more traditional larger-scale equipment. Miniaturization makes it possible to decrease demands in working equipment space, reagents, water, power, and so on. With current advances pushing the detection limits of several elements in the periodic table further down, there is no doubt that miniaturized chemical analysis systems have a tremendous potential in the future for addressing space, environment, and other research areas. For instance, it is foreseeable that such devices in biochemistry will allow the study and analysis of complex cellular processes, facilitate the development of new diagnostic abilities that could revolutionize medicine, and have applications in environmental monitoring, food analysis, and industry. The first generation of lab-on-a-chip devices are already working, and the future generation systems would look forward to integrate sample collection and sample preparation and detection to further improve the benefits of miniaturization in analytical chemistry. The use of field-portable methods and instrumentation for on-site monitoring of toxic chemicals is meant to alleviate such problems that may be brought on by delayed analytical results. These developments in addition to improving productivity for identification, confirmation, and quantification measurements, also contribute to substantial cuts to the instrument and operating costs. In the coming decades, handheld devices will rule the R&D studies in all areas including space, health, environmental safety, food safety, forensics, pharmaceuticals, surveillance, counterfeit detection, agriculture, exploration, mining, and metallurgy. Increased portability also allows for performing on-site tests during disaster relief efforts and chemical warfare threats. The lab-on-a-chip technology is a multibillion dollar industry today. Some of the systems are still at the development stage and numerous companies are in the race. For example, the DNA-based biosensors need more refinement before they can be made commercially available. Miniaturization can sometimes introduce technical challenges that are not present in the macro world. It is very difficult to predict how this technology will affect our future.

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Articles

Miniaturization of analytical instruments of various forms of spectroscopy has improved dramatically in recent years mainly because of the requirements in certain areas such as space, industrial, and environmental research. Research into miniaturization is primarily driven by the need to reduce the instrumental space and costs by reducing the consumption of expensive reagents and by increasing throughput and automation. Like other fields, analytical systems have also been affected by novel ideas and unprecedented advances in the microelectronics leading to miniaturization of different components in recent years. This article presents an overview of the current developments in the miniaturization of analytical instruments for mainly detecting metals at extremely low concentration levels, with some important examples from areas such as space, mineral exploration, the environment, and pharmaceuticals, focusing primarily on advancements as well as the challenges that have impacted from some of the major international manufacturers.

Current Advances in the Miniaturization of Analytical Instruments—Applications in Cosmochemistry, Geochemistry, Exploration, and Environmental Sciences