Growing Clinical Applications With Advancing MS Technologies

Advancements in MS technology continue to increase, both, speed and resolution factors, and with the discovery of new tools and software MS have the potential to stimulate its increased usage across several fields.

With a history that spans one hundred years, mass spectrometer (MS) is one of the most widely used analytical system in bioscience and medical research. Since the development of the first MS in 1918, the technology has advanced steadily over time and has found its’ way into a range of applications from forensic toxicology to cancer diagnostics. Although histopathology is still the gold standard for diagnosing cancer, molecular analysis using MS has gained traction in the recent years for detecting tumors, monitoring progression, and even predicting treatment response. Faster, more precise, and often more cost-effective MS-based workflows and laboratory-developed tests are enabling clinical researchers to obtain results with improved confidence using smaller sample volumes. Bulky, expensive equipment that defined historical MS are less common now, and have been replaced by faster, more sensitive, and cost-effective workflows. Newer spectrometers are also largely automated and user-friendly, making them more adaptable for clinical use.

The use of MS in the clinical laboratory really took off with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Its adoption over the last 15 years has been driven by the need for greater immunoassay accuracy, faster results, and a desire for cost reduction. The high specificity and sensitivity of LC-MS/MS overcomes many of the limitations associated with traditional immunoassays, such as nonspecific antibody binding and cross-reactivity, giving clinical scientists increased confidence in results. Affordability is another reason clinical laboratories are turning to LC-MS/MS. Conventional hospital diagnostic assays have largely been based on clinical chemistry and immunoassay techniques, which require analyte-specific reagents and antibodies. LC-MS/MS-based approaches are considered reagent-free, which means there is less waste and running costs are approximately one-fifth those of immunoassays. Combined with the expense associated with sending samples externally when specific immunoassays are unavailable in-house, the cost over equipment lifetime can be considerably less.

Global market
The global MS market is expected to grow at a CAGR of close to 7 percent from 2018–2022, owing to the rising focus on drug discovery and development along with increasing demand for MS in personalized medicine, estimates Technavio. With ongoing technological advances, application of mass spectroscopy is increasing in various fields, and thus, contributing to its market growth. Other factors increasing the market are growing concerns over food safety, increasing R&D expenditure by pharmaceutical industry and government research organizations.

High cost of instrument is a major challenge
Over the last few decades, a MS instrument has undergone revolutionary change. In 1990, the instrument cost hundreds of thousands of dollars, covered a lot of the lab’s floor space, could only be operated by experienced doctoral-level staff, and existed primarily within core facilities. Chemists would prepare pure samples in hopes to receive a simple spectrum several days later. Although the instrument has become compact, occupying a tenth of what it used to, and has become far more time efficient with an analysis taking less than a minute and automation decreasing the level of skill and experience required to operate, the cost arising from its high specificity yet poses a major restraint for its adoption.

Technology trends
Mass spectrometry has become the go-to technique to supply answers to a range of analytical questions, offering sensitivity, selectivity, and specificity. Over the past decade advances in MS are allowing more information on higher order structure and new imaging techniques are even providing in vivo insights.

LC-MS is the dominant technology for clinical research, ‘omics, and the discovery and targeted quantitation of protein-based and small-molecule biomarkers. Hybrid MS technology, such as quadrupole-Orbitrap systems, couple high-resolution ion-trap instruments with a front-end quadrupole component that allow analytes to be identified with high precision through analyte fragmentation in a more affordable benchtop design. These full-scan techniques enable clinical researchers to scan for highly mass-resolved structures more quickly. Advances in clinical multi-’omics show promise to enable noninvasive liquid biopsies for early detection of diseases such as cancer in patients who otherwise present no symptoms. Researchers are leveraging highly sensitive LC-MS/MS for targeted analysis of protein biomarkers in donor samples, providing oncologists with information in minutes. Future approaches may allow greater patient stratification, leading to more targeted treatment, while potentially facilitating improved patient monitoring.

Inductively coupled plasma/mass spectrometry (ICP/MS), has undergone intensive development in recent years. With detection limits for most elements about 100 times greater than those achieved by graphite furnace atomic analysis (GFAA) and its multi-element capability, ICP/MS has become the standard technique for trace elemental analysis of donor samples. For heavy-metal forensic toxicology, for instance, ICP/MS not only offers more precise quantification, but also the ability to perform isotopic tracer, dilution, and ratio measurements. Medical scientists are researching the application of this technique to understand an individual’s personal ability to absorb essential elements, as well as select therapeutics to enable more effective treatment programs in the future.

MasSpec Pen, a hand-held device that connects to a MS and identifies cancerous tissue during surgery hit the headlines last year, claiming to deliver results in 10 seconds. Termed MasSpec Pen, the device contains a probe that can soak up molecules from human tissue and send to a MS wheeled into the surgery room. Within a matter of seconds, molecular analysis by an ambient ionization MS technique indicates which areas of tissue are cancerous and should be removed by surgery. The device can also sample tissue non-destructively, displaying an advantage over a similar device called iKnife that causes tissue damage due to electrocauterization.

Triple quadrupole mass spectrometer (triple quad or TQMS or QqQ) is a tandem MS consisting of two quadrupole mass analyzers in series and in between the two mass analyzer quadrupoles is a third quadrupole which acts as a cell for collision-induced dissociation. Triple quads are extraordinarily sensitive and there are many places within the discovery and development pipeline where researchers need extreme sensitivity. This can be critical for pre-clinical and clinical studies. But, they do not provide deep MS information, which is what quadrupole time-of-flight (Q-TOF) MS offers. Q-ToF MS is another important high-resolution mass spectrometry method that allows detecting and characterizing proteins and peptides with extremely high accuracy and resolution. That is critically important for confidently distinguishing very small, yet important, differences in very big biotherapeutics.

Outlook
MS is one of the most powerful tools being used for the analyses of a wide range of chemical and biological entities. Advancements in MS technology continue to increase, both, speed and resolution factors. The discovery of new tools and software have the potential to stimulate the increased usage of MS across drug development, proteomics, pharmaceuticals, food safety testing, and many other fields. Moreover, with the advent of increasingly sensitive technologies, the range of MS technologies and clinical applications will continue to expand, such as, tissue imaging using MS techniques is a developing field that is set to enter the clinical mainstream.

Since improving sample-to-knowledge analysis time is critical for labs processing routine samples, continued progress toward simplified pushbutton MS processes is to be expected. While instruments can deliver results at exceptional speed, in some cases sample preparation steps are still tedious. Increased automation and seamless integration of sample preparation and analysis are helping to simplify processes and reduce times to results. Additionally, the development of transportable or handheld mass spectrometers could open up a range of possibilities for point-of-care applications.