By a News Reporter-Staff News Editor at Life Science Weekly — From Alexandria, Virginia, NewsRx journalists report that a patent by the inventors Park, Melvin Andrew (Billerica, MA); Kaplan, Desmond Allen (Billerica, MA); Ridgeway, Mark (Bremen, DE), filed on April 26, 2011, was published online on July 1, 2014 (see also Bruker Daltonics, Inc.).
The patent’s assignee for patent number 8766176 is Bruker Daltonics, Inc. (Billerica, MA).
News editors obtained the following quote from the background information supplied by the inventors: “The invention relates to devices and methods for the acquisition of ion mobility spectra in ion mobility spectrometers which apply gas flows to push ions against and over DC electric field barriers. Mass spectrometers can only ever determine the ratio of the ion mass to the charge of the ion. Where the terms ‘mass of an ion’ or ‘ion mass’ are used below for simplification, they always refer to the ratio of the mass m to the dimensionless number of elementary charges z of the ion. This charge-related mass m/z has the physical dimension of a mass; it is often also called ‘mass-to-charge ratio’, although this is incorrect with regard to physical dimensions. ‘Ion species’ shall denote ions having the same elemental composition, the same charge and the same three-dimensional structure. Ion species generally comprise all the ions of an isotope group, which consist of ions of slightly different masses, but virtually the same mobilities.
“Different kinds of isomers are known for bioorganic molecules: isomers related to the primary structure (structural isomers) and isomers related to the secondary or tertiary structure (conformational isomers). Isomers have different geometrical forms but exactly the same mass. It is therefore impossible to differentiate between isomers on the basis of their mass. Some information as to the structure can be obtained from fragment ion mass spectra; however, an efficient and certain way to recognize and distinguish such isomers is to separate their ions according to their different mobilities.
“Nowadays, the mobility of ions is most often measured via their drift velocities in a stationary gas under the influence of an homogeneous electric field. A drift region is filled with an inert gas such as helium, nitrogen or argon. The ions of the substance under investigation are pulled through the gas by means of the electric field, which is produced by suitable DC potentials applied to ring electrodes arranged along the drift region. The friction with the gas results in a constant drift velocity v.sub.d for each ion species which is proportional to the electric field strength E: v.sub.d=.mu..times.E. The proportionality factor .mu. is called the ‘ion mobility’ of the ion species. The ion mobility .mu. is a function of gas temperature, gas pressure, type of gas, ion charge and, in particular, the collision cross-section of the ions.
“Isomeric ions with the same charge-related mass m/z but different collision cross-section have different ion mobilities in a gas of the same temperature, pressure and type. Isomers of the smallest geometric dimension possess the greatest mobility and therefore the highest drift velocity v.sub.d through the gas. Unfolded protein ions undergo more collisions than tightly folded proteins. Protein ions which are unfolded or partially folded therefore arrive at the end of the drift region later than strongly folded ions of the same mass. But structural isomers, for example proteins with glycosyl, lipid or phosphoryl groups at different sites, also have different collision cross-sections, which allow them to be distinguished by measuring their ion mobility.
“In chemical and biological research, it has become more and more important to have knowledge about the folding structures of ions, which can be identified via their mobility. Therefore devices to measure the mobility of ions have been incorporated into mass spectrometers, in particular, in order to combine the measurements of the charge-related mass of ions with the measurement of collision cross-sections. The folding structures determine the mechanism of action and thus the function of the molecules in the living organism; different foldings can signify normal or abnormal functioning of biopolymers in biosystems, and hence health or disease of tissue parts or even whole organisms.
“A number of academic research groups have coupled ion mobility spectrometers of the drift tube type with mass spectrometers. A pressure range of several hectopascals has been adopted almost universally for the mobility drift region. In this pressure range, the drifting ions appear to form hardly any complexes with other substances, so the mobilities of the ion species can be measured without interferences, unlike mobility measurements at atmospheric pressure where quite often complex ions are formed with impurity molecules in the gas. The drift region for higher mobility resolutions measures up to four meters and more, and electric field strengths of 2,000 volts per meter and more are applied. But in the long drift regions, the ions also diffuse radially over long distances, and therefore quite large diameters have to be chosen for these drift regions.
“The ions are usually introduced into the drift region in the form of temporally short ion pulses by a gating device, producing spatially small ion clouds, which are pulled through the drift region by the electric field. In the gas of the drift region, these ion clouds are subject to diffusion into all directions, caused by their Brownian motion (Boltzmann distribution). The diffusion acts equally in all directions; it takes place as well in forward and backward direction as at all angles to the drift direction. The gas in the drift region is sometimes kept at temperatures of between about 150 and 300 degrees Celsius, but can also be greatly cooled for special experiments.
“The mobility resolving power (‘mobility resolution’ for short) is defined as R.sub.mob=.mu./.DELTA..mu.=v.sub.d/.DELTA.v.sub.d, where .DELTA..mu. is the width of the ion signal of the mobility .mu. at half height, measured in units of ion mobility, and .DELTA.v.sub.d is the corresponding difference in speed. The mobility resolution R.sub.mob is influenced predominantly by the diffusion broadening of the ion clouds, especially for long drift regions and high electric field strengths; all other influences, such as the space charge, tend to be negligibly small. The part of the mobility resolution Rd determined by the diffusion broadening is given by the equation
“.times..times..times..times..times..times..times..times..times..times..ti- mes..times..times. ##EQU00001## where z is the number of elementary charges e, E the electric field strength, L.sub.d the length of the drift region, k the Boltzmann constant and T the temperature of the gas in the drift region. A high mobility resolution for an ion with a given number z of elementary charges e can thus only be achieved by means of a high field strength E, a long drift region L.sub.d, or a low temperature T. The part Rd of the mobility resolution that is given by the diffusion is not dependent on either the type or pressure of gas in the drift region; the mobility .mu. itself, however, does depend not only on the temperature, but also on the pressure and type of gas.
“Compared to the numerical values for mass resolutions in mass spectrometry, which can be up to several ten thousand, the mobility resolutions which can be achieved in practice are generally very low. The first commercial combination of an ion mobility spectrometer and a mass spectrometer for bioorganic ions has a maximum mobility resolution of only R.sub.mob=40. With a mobility resolution of R.sub.mob=40, two ion species whose collision cross-sections differ by only five percent can be separated very well.
“Only highly specialized groups of scientists have, as yet, been able to achieve significantly higher mobility resolutions than R.sub.mob=100, in rare individual cases up to R.sub.mob=200, with drift lengths roughly between two and six meters and field strengths between 2,000 and 4,000 volts per meter, making it possible to differentiate between ion species whose mobilities differ by only one to two percent. Ion mobility spectrometers with a resolution above R.sub.mob=100 shall be regarded as ‘highly resolving’ here.
“As mentioned above, in long mobility drift regions also a strong transverse diffusion occurs. Therefore, longer drift regions must also have a large diameter so that the ions do not touch the wall electrodes. A well-tried method is to guide the ions back to the axis of the drift region after they have passed through a part of the drift region, about two meters, for example. This is done using so-called ‘ion funnels’. These consist of a larger number of parallel ring diaphragms, a small distance in the order of millimeters apart, whose aperture diameters taper continuously from the diameter of the drift region, 30 to 40 centimeters, for example, down to around two to five millimeters and thus form a funnel-shaped enclosed volume. The two phases of an RF voltage, usually of several megahertz and between a few tens of volts and one hundred volts, are applied alternately to the apertured diaphragms, thus generating a pseudopotential which keeps the ions away from the funnel wall. A DC electric field is superimposed on the RF voltage by a DC voltage gradient, and this electric field pushes the ions slowly to the narrow exit of the funnel and through it. Such an ion funnel does not measurably reduce the mobility resolution of a long drift region.
“Ion funnels are not only used to guide the ions back to the axis of the drift regions in ion mobility spectrometers; they are also used in mass spectrometers in general to capture larger ion clouds and to thread these ion clouds into narrow ion guides. Such ion funnels are often found in mass spectrometers with electrospray ion sources; the ions generated outside the vacuum system are transferred, together with a curtain gas, through inlet capillaries and into the vacuum, where they are captured by ion funnels and freed of most of the curtain gas. Some mass spectrometers even contain two such ion funnels, placed in series, in order to move the ions quickly from regions with higher pressure of several hectopascals at the end of the inlet capillary to regions with lower pressure of around 10.sup.-2 to 10.sup.-6 pascal.
“High-resolution time-of-flight mass spectrometers with orthogonal injection of the ions (OTOF-MS), in particular, have proven successful for combinations of mobility spectrometers with mass spectrometers. For such combinations, the high-resolution ion mobility spectrometers of the current type have the disadvantage of being several meters long. Such a solution is unfavorable for instruments marketed commercially. Even ion mobility spectrometers with a straight drift region offering only moderate resolution are about one meter long. For the construction of small, high-resolution mobility analyzers, one therefore has to look for a solution which shortens the overall length but does not diminish the mobility resolution.
“In document U.S. Pat. No. 7,838,826 B1 (M. A. Park, 2008), an ion mobility spectrometer is presented, the size of which amounts to about ten centimeters only. It is based upon moving gases driving ions over an electric counter-field barrier in a modified ion funnel built into a time-of-flight mass spectrometer. Unlike many other trials to build small ion mobility spectrometers, the device by M. A. Park has already achieved ion mobility resolutions in excess of R.sub.mob=100.
“The apparatus of M. A. Park and its operation is schematically illustrated in FIGS. 1A to 1D. FIG. 1B shows, how the parts (10) and (12) of a quadrupolar funnel, open as usual to the flow of gas between the electrodes, are separated by a closed quadrupole device (11), vertically sliced into thin electrodes (17, 18 FIG. 1A) forming a circular tube arranged around the z-axis of the device. The electrode slices are separated by insulating material closing the gaps between the electrodes around the tube to make the tube gas-tight. FIG. 1A shows the shape perpendicular to the device axis (denoted as the z-axis) of the electrodes of the funnel (15, 16) and shapes perpendicular to the device axis of the quadrupole tube electrodes (17, 18), the latter with equipotential lines of the quadrupolar RF field inside the tube at a given time. The differential pumping system of a mass spectrometer (not shown), surrounding the ion mobility spectrometer, is dimensioned to cause a gas to flow through the tube (11) in a laminar way, thereby causing the flow to assume the usual parabolic velocity profile (14). Ions entering the first part (10) of the funnel together with the gas are collisionally focused onto the axis of the tube (11) and move, driven by the gas, along the axis of the tube towards its exit through the apertured diaphragm (13). Most of the gas escapes through gaps between the electrodes of the funnel part (12).
“A funnel (10) or (12) usually is operated with apertured diaphragms the openings of which taper to smaller diameters thus forming an inner volume in the shape of a funnel. The two phases of an RF voltage are applied alternately to the diaphragms to build up a pseudopotential which keeps the ions away from the funnel walls. The ion funnel entrance part (10) is here built from electrodes which are divided into four parts to allow a more complicated RF field to be applied, but this is not essential for the operation of this ion mobility spectrometer.
“FIGS. 1C and 1D show, in two diagrams, different DC potential profiles P (22 to 26) along the z-axis, and corresponding barriers of the electric counter field E.sub.z=dP/dz along the z-axis, respectively. The potential profiles are produced, as usual, by a network of resistors with exactly chosen values between the electrode slices, operating as voltage dividers. In this way, only a single voltage has to be applied and forms the complete profile; changing this voltage changes the potential profiles (22 to 26) as a whole.
“The operation of the ion mobility spectrometer will be described by the sequence in which the potential profiles are changed. The operation starts with a filling process. The steepest potential profile (22) is generated by a voltage in the order of 100 to 200 volt, producing the highest electric field barrier. The ions (27) are blown by the gas flow against the field barrier and are stopped there because they cannot surmount the field barrier. Ions with high mobility (small cross section) gather at the foot of the barrier, ions with low mobility gather (large cross section) near the summit, as symbolically indicated by the size of the dots for the ions (27). When a suitable number of ions are collected, further ions are prevented from entering the ion mobility spectrometer, for instance, by changing the voltage gradient in the ion funnel (10). Then, for a spectrum acquisition, the potential profile (22) is smoothly lowered by decreasing the voltage continuously in a procedure denominated as a ‘scan’ (28), passing through profile states (23) to (26). During the scan, ions of higher and higher mobilities can surmount the decreasing summit of the barrier and exit the ion mobility spectrometer. The exiting ions are measured by an ion detector, favorably a mass spectrometer. The measured ion current curve presents directly the ion mobility spectrum from low ion mobilities to high ion mobilities. This device is denominated a ‘TIMS’, or ‘trapped ion mobility spectrometer’.
“As shown in FIG. 1D, a characteristic feature of this instrument is the long increasing part of the electric field barrier until position (20), the start of the plateau. This long ascent between foot and top of the barrier collects the ions (27) in a rather large volume along the z-axis, reducing greatly any space charge effects.
“Another characteristic feature of this instrument is the flat plateau of the electric field barrier height between positions (20) and (21) on the z-axis. If the barrier is lowered slowly during an acquisition, ions have to dwell, for a few milliseconds while passing over the flat plateau, in a critical balance between the pushing force of the gas friction and the retarding force of the electric counter field, before they are finally blown from the end of the plateau into weaker field regions. In these few milliseconds, the high number of gas collisions causes a statistically equal selection of all ions of the same mobility, resulting in the high mobility resolution. The flat plateau of the electric barrier between positions (20) and (21) is generated by a number of resistors with exactly equal resistance in the resistor chain of the voltage divider.
“With this instrument, the ion mobility resolution R.sub.mob was found to increase with increasing pressure and with decreasing acquisition speed. Furthermore, the mobility resolution R.sub.mob was found to be a function of the mobility .mu. itself: with linearly decreasing voltage, the mobility resolution R.sub.mob decreases from lower to higher mobilities .mu.. It is to be expected that the mobility resolution R.sub.mob will depend also on gas velocity v.sub.g in connection with changes of the height of the electric barrier; the type of gas should also play a role. The rather small device turns out to be as good as long drift tubes with resting gas described above which also have to be operated in measuring phases started by pulses of ions which have to be collected first. Ion mobilities in excess of R.sub.mob=100 have been achieved with the small apparatus in first experiments.
“As operated hitherto, the device still shows a disadvantage. If during a scan (28) the voltage decreases linearly, the mobility spectrum is not linear in mobility or in resolution. Linearity in mobility, however, is advantageous for any calibration and the necessary interpolations.”
As a supplement to the background information on this patent, NewsRx correspondents also obtained the inventors’ summary information for this patent: “In accordance with the principles of the invention, the linear scan method of the ion mobility spectrometer as described in U.S. Pat. No. 7,838,826 is modified to be a non-linear function of time.
“A first embodiment generates a linear mobility spectrum by decreasing the field strength, E.sub.z, of the electric barrier as a function of time t in a hyperbolic scan function E.sub.z(t)=c/t, (c is a constant) while keeping the gas velocity, v.sub.g, constant. Surprisingly, not only a linear mobility scale is achieved, this acquisition mode also generates ion mobility spectra with much better constancy of the resolution than the acquisition modes with linear scans applied hitherto.
“A second embodiment scans the field strength of the electric barrier relatively slowly over a predetermined range of interest, but comparatively rapidly over ranges outside the range of interest. This increases the mobility resolution within the range of interest without sacrificing the speed of analysis.
“In a third embodiment, the field strength E.sub.z is scanned as an exponential function of time, E.sub.z(t)=c e.sup.-t/.tau. resulting in a spectrum having a fixed resolution versus mobility. These embodiments do not require any modification of the hardware, only the control software has to be changed to allow for the non-linear application of the DC voltage generating the electric barrier.
“Other embodiments change the gas flow conditions. In one embodiment the gas velocity, v.sub.g, is linearly increased while keeping the profile of the electric counter field constant, also resulting in an ion mobility spectrum with a linear spectrum scale. In another embodiment, the gas pressure p is increased. Both these latter spectrum acquisition embodiments require the introduction of new gas supply lines for the control of gas speed and gas pressure, and some modifications of the differential pumping system. These new gas supply lines also allow for the introduction of special gases in order to replace the primary ion transport gas by more favorable gases like helium or argon.”
For additional information on this patent, see: Park, Melvin Andrew; Kaplan, Desmond Allen; Ridgeway, Mark. Spectrum Acquisition Modes for Ion Mobility Spectrometers Using Trapped Ions. U.S. Patent Number 8766176, filed April 26, 2011, and published online on July 1, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8766176.PN.&OS=PN/8766176RS=PN/8766176
Keywords for this news article include: Bruker Daltonics Inc.
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