TIMS Triple Quadrupole MS for High-Precision Multiplexed Ion Detection
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Solution Overview
Problem
Current methods for quantifying high numbers of substance-characteristic fragment ion species from proteolytic digests or complex matrices using liquid-chromatography/mass-spectrometry are limited by precision and sensitivity, especially when dealing with large numbers of substances, due to the high cost and complexity of instruments like QqTOF mass spectrometers.
Innovation Solution
Coupling a triple-quadrupole mass spectrometer with a trapped ion mobility separator (TIMS) for parallel accumulation, which separates ions by mobility, concentrating ions and improving signal-to-noise ratio, allowing for the measurement of a higher number of ion species with increased sensitivity and precision.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If triple quadrupole mass spectrometry is used for quantification of multiple substances, then measurement precision is maintained, but the number of measurable substances is limited
Solution Approach 1:
The invention segments the complex mixture analysis by introducing ion mobility separation as an additional dimension. Ions are separated based on their mobility characteristics before mass analysis, creating distinct ion packets that can be sequentially measured. This segmentation allows the triple quadrupole to measure multiple substances with high precision without the measurements interfering with each other, effectively increasing the number of measurable substances while maintaining measurement precision.
Solution Approach 2:
The invention adds ion mobility separation as another dimension to the traditional mass spectrometry approach. By separating ions based on their mobility in addition to their mass-to-charge ratio, the system creates a two-dimensional separation space. This dimensional expansion allows significantly more substances to be measured simultaneously or sequentially without compromising the measurement precision that the triple quadrupole provides.
2Adaptability or versatility
If the number of substances measured by MRM is increased, then more substances are detected, but measurement precision decreases
Solution Approach 1:
Ion mobility separation segments the ion population into distinct mobility-based groups before they enter the triple quadrupole for MRM measurement. This segmentation allows the system to measure multiple substances in sequence based on their mobility characteristics, rather than attempting to measure all substances simultaneously. As a result, the number of measurable substances increases while each individual measurement maintains high precision because fewer ions are being measured at any given moment.
Solution Approach 2:
The ion mobility separator performs preliminary separation of ions based on their mobility characteristics before the ions reach the triple quadrupole mass spectrometer. This preliminary action organizes the complex mixture into mobility-ordered ion packets, allowing the MRM detector to systematically measure each substance with high precision. The preliminary separation ensures that when MRM measurement begins, the ions are already organized in a way that maximizes measurement precision while enabling detection of many substances.
3Measurement precision
If high-resolution mass analyzers are used, then mass measurement precision is improved, but instrument cost and size increase
Solution Approach 1:
The invention uses ion mobility separation to segment and pre-sort ions before they enter the triple quadrupole mass spectrometer. This segmentation allows the use of the relatively simple and cost-effective triple quadrupole analyzer instead of expensive high-resolution mass analyzers. By organizing ions into mobility-based groups beforehand, the system achieves effective separation and identification capability with lower-cost instrumentation.
Solution Approach 2:
The ion mobility separator acts as an intermediary device between the ion source and the triple quadrupole mass spectrometer. It performs the initial separation and organization of ions based on mobility characteristics, allowing the triple quadrupole to focus on its strength of precise mass measurement and quantification. This intermediary function reduces the burden on the mass analyzer, enabling the use of more affordable and compact triple quadrupole instruments while maintaining effective analytical performance.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach enables the measurement of fivefold to fiftyfold more ion species with improved signal-to-noise ratio and sensitivity, significantly enhancing the workload capacity of mass spectrometers, potentially reducing the need for upstream separators and shortening chromatographic run times.
Implementation Method 1
TIMS works with gas flow and electric counterfield and is thus more similar to the device of A. V. Loboda. In contrast to Loboda's device, an electric field profile with a ramped electric field barrier is used in a constant gas flow to hold back ions by their ion mobility
Implementation Method 2
an electric field profile with a ramped electric field barrier is used in a constant gas flow to hold back ions by their ion mobility; a decrease of the field barrier releases ions with increasing ion mobility
Data Source
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Figure 2
Figure 5~6
AI summary
The invention provides a method for acquiring fragment ion spectra of substances in complex substance mixtures wherein a trapped ion mobility spectrometer ("TIMS") is used as the ion mobility separation device coupled to a triple quadrupole mass filter assembly. The fragment ion spectra may be used for the identification of high numbers of proteins in complex mixtures, or for a safe quantification of some substances, by their fragment ion mass spectra in a mass spectrometer with upstream substance separator. TIMS, in particular equipped with parallel accumulation, provides the unique possibility to prolong the ion accumulation duration to find more detectable ion species without decreasing the measuring capacity for fragment ion mass spectra. The high measurement capacity for fragment ion mass spectra permits the repeated measurement of low abundance on species such as to improve the quality of the fragment ion spectra.