“TTP has designed and built a very nice and easy to use IR-MALDESI system for high-throughput screening. Integrating key components, including a burst-mode mid-IR laser with fibre-opticfor safety and a translation stage, this system can speed up drug discovery efforts in BioPharma.”
David Muddiman, Professor of Chemistry at North Carolina State University
Mass spectrometers are found in an increasing number of applied industrial settings where there is a need for high quality analytical data. In pharma, mass spectrometry is used in almost every part of the drug discovery process. Historically, the exception has been in areas where sample numbers have necessitated really high throughput.
While the sensitive detectors operate in the milli-second range, and could support truly high-throughput applications, the sample delivery techniques used to load samples into mass spectrometry (MS) systems are often several orders of magnitude slower. This has long limited the throughput potential of mass spectrometry.
Laser-based approaches have the potential to vastly increase the sample acquisition rate. Recently, IR-MALDESI has emerged as a powerful sample acquisition technology, but a lack of implementation in commercial instrumentation has so far limited its adoption in pharma (and beyond).
Evolution to higher throughput
Traditionally, liquid chromatography (LC) has been used to deliver samples and separate and introduce the analytes into MS instruments. This enables high-sensitivity analysis, but throughput is limited by the travel time of analytes through the chromatography column, which can take at least 1 minute per sample.
At the turn of the 21st century, the development of RapidFire™ MS delivered a platform capable of processing samples in seconds rather than minutes. This was achieved by means of a faster separation process, but at the price of reduced sensitivity for some analytes. Still, it made it possible to test 1000’s of samples each day and opened up new applications for mass spectrometry in pharma and other industries.
Laser-based MS technologies take advantage of the speed of the laser illumination event to generate plumes for sample acquisition.
Matrix-assisted laser desorption/ionization (MALDI) can operate at 1 second per sample. However, the technique requires the addition of a matrix layer to absorb the laser energy to volatilize the sample under a vacuum. This can suppress the signal from small molecule analytes, however, and the sample preparation process for MALDI limits MS throughput and adds costs.
IR-MALDESI
A more recently invented technique, Infrared Matrix-Assisted Desorption Electrospray Ionization Mass Spectrometry (IR-MALDESI) offers label-free detection of a wide range of analytes with minimal sample preparation.
In this technique, the laser (2970 nm wavelength) selectively excites hydroxyl groups (OH) to generate droplet plumes directly from water-based samples and other common solvents under ambient conditions.
Analytical scientists at AbbVie have shown that IR-MALDESI can measure an impressive range of biologically relevant molecules not only from biochemical reactions but also from cellular assays, with demonstrated sample acquisition rates of over 20 samples per second.
In addition to its analytical power, IR-MALDESI requires only very small amounts of sample, meaning that it could also be used with high density arrays of samples on re-usable solid supports rather than single use plastics such as microtitre plates.
This takes the throughput potential of mass spectrometry to >100k samples per day, bringing its analytical power to truly high-throughput applications.
Fibre-based laser delivery
To make that a reality, we’ve joined forces with a major pharmaceutical company to develop an IR-MALDESI interface with optimized optical fibre-based laser delivery.
In our system, the critical laser light for volatilising samples is guided through an optical fibre, which improves beam quality. This implementation gives us better control over beam focus, which could, for example, facilitate sample acquisition from high density arrays. Better spot size also enables more efficient sample plume generation and reduces optical power requirements.
Naturally, the lenses and laser parameters, including power and pulse rate, in our technology demonstrator can be fine-tuned to suit specific applications.
Importantly, our system complies with Class 1 laser safety standards – critical for widespread deployment of mass spectrometry in pharma and other laboratory environments.
We’ve already shown that our system can interface and works with commercial MS instruments from two different manufacturers (see poster presentation), but further optimisation is needed for commercialisation.
High-throughput IR-MALDESI as a future product
“TTP has designed and built a very nice and easy to use IR-MALDESI system for high-throughput screening. Integrating key components, including a burst-mode mid-IR laser with fibre-optic for safety and a translation stage, this system can speed up drug discovery efforts in BioPharma,” told us David Muddiman, Jacob and Betty Belin distinguished professor of chemistry at North Carolina State University, who first developed the IR-MALDESI technique.
We take this as high praise for our system and are truly thrilled about the prospects of IR-MALDESI as a commercial tool in drug discovery.
Are you interested in the future of IR-MALDESI and mass spectrometry? We will be at The American Mass Spectrometry Society meeting in Baltimore sharing a poster on IR-MALDESI on Monday 2nd June. Please reach out to find out more.
