CN1585666A - Methods and apparatus for electrospray-augmented high field asymmetric ion mobility spectrometry - Google Patents

Abstract

Method and apparatus for the analysis of compounds using electrospray in hihg field asymmetric ion mobility spectrometry.

Description

The method and apparatus that is used for the asymmetric ionic mobility spectroscopic assay of the high electric field instrument of electron spray enhancing

Invention field

The present invention relates to the ionic mobility spectroscopic assay, it is used for asymmetric waveform ionic mobility spectroscopic assay instrument on the scene (field asymmetric waveform ion mobilityspectrometer) and transmits and use inside or outer locator being prepared, filtering and surveying gas and fluid sample by the electron spray sample.

Background technology

It is a kind of strong analysis tool that is widely used in biomolecular structure analysis (being protein, peptide and DNA) that electrospray ionization mass spectrum is measured.Referring to Richard B.Cole, " electrospray ionization mass spectrometry is measured basis, device and used " (Electrospray Ionization Mass Spectrometry Fundamental.Instrument and Applications) literary composition that JohnWiley and Sons delivered in 1997.This technology is being played the part of important role in the exploitation of most of medicine, and just is being used to carry out the mankind are exposed to the quantitative measurment of carcinogen.Because the size in pharmacy market and potential repayment, the instrumentation table that people measure based on electrospray ionization mass spectrum exploitation reveals interest, and has technically obtained reinforcement.

In recent years, total trend is to minimize analyzing required sample size, little electro-spray ionization (micro-ESI, micro-ES) and nanometer spraying (nanospray) be in these methods two kinds.These two kinds of methods have a lot of common ground, and they are usually exchanged use.Micro-ES is the small-sized electrospray ionization source that has with " tradition " electron spray identical systems element.These elements comprise the pumping liquid flowing source that comprises analytic sample, the sharp-pointed hollow needle of minor diameter that passes through its pumping liquid, and the high-voltage power supply that produces spraying.Nanometer spraying depends on liquid in the pin and the electrostatic attraction of attractor reverse electrode is produced mobile, rather than relies on pumping.This characteristic makes nanometer spraying make the sample minimum method of waste and very attractive as a kind of.Because electron spray, micro-ES and nanometer spraying all are the kinds (species) that is collectively referred to as the electron spray classification, they will be called electron spray interchangeably in this patent.

The character of electro-spray ionization process makes sample preparation become main consideration item.The solvent that exists with sample, the complexity that buffer salt has increased spectrum have significantly reduced detection limit.The electro-spray ionization process has produced a large amount of lyate ions, and these lyate ions have produced strong mass spectrum background, and this has seriously limited the identification to the chemical compound lot of trace level in the solution.Even without the competition of these lyate ions, many application also need to work with complex mixture, the feasible separation that must carry out before quality analysis to a certain degree of these mixtures.Referring to J.Lee, J.F.Kelly, I.Chernushevich, " using the little manufacturing device of combination Capillary Electrophoresis/nanometer electrospray ionization mass spectrum from the memebrane protein that colloid is isolated, to separate and identification polypeptide " (Separation and Identification of Peptides fromGel-Isolated Membrane Proteins Using a Microfabricated Device forCombined Capillary Electrophoresis/Nanoelectrospray MassSpectrometry that D.J.Harrison and P.Thibalut deliver, Anal.Chem.2000,72, a 599-609) literary composition.Therefore, need better method to remove unwanted solvent and sample separation ion from background.

Electrospray ionization mass spectrum is measured (ES-MS) and is provided strong tool for the structure of determining peptide, protein.Because the long-range structure has been determined the function of protein, so this is very important.Structural information about protein is generally determined from its amino acid sequence.In order to discern this sequence, protein uses enzyme to decompose (digest) usually, and fragments of peptides sorts by series connection (tandem) mass spectroscopy.Another method that may obtain sequence is decomposing protein and the molecular wt of measuring fragments of peptides.These are the data that are input to computer program, and this computer program decomposes the protein that all can find in database in theory, and these theoretical fragment and measured molecular wt are compared.

Recently, have been noted that the ionic mobility spectroscopic assay can provide Useful Information for electron spray/mass-spectrometer measurement.The ionic mobility spectroscopic assay is normally a kind of to molecular size and the very sensitive normal pressure measuring technique of profile.By can reducing proteolytic needs, and simplified sample preparation in conjunction with IMS and mass spectral protein identification.

Commercial adaptable IMS system is based on the flight time, and (time-of-flight, TOF), promptly their are measured and make ion reach the needed time of detector from shutter by internal atmosphere (1 to 760 holds in the palm).Depend on the mobility (that is, size, quality and electric charge) of ion this drift time, and be feature with the ionic species of being surveyed.TOF-IMS is a kind of for the chemical compound lot detection useful technology that comprises arcotic, explosive and chemical warfare preparation.Referring to PCT application No.PCT/CA99/00715 and U.S. Patent No. 5,420,424, by these documents being incorporated in this paper in this citation.In the ionic mobility spectroscopic assay, use battery drift tube to determine the gaseous ion mobility with constant low field intensity electric field.Opening the sluices makes ion enter drift tube, and based on the difference of drift speed they is separated successively.Ion drift speed and electric field strength under these conditions are proportional, and is irrelevant with the electric field that is applied from testing definite ionic mobility.Present spectroscopic assay instrument uses the conventional machine-processed drift tube (minimal size is 40cm3) that is used for ion identification.

In traditional flight time ionic mobility spectroscopic assay instrument (TOF-IMS), in low strengh electric field, carry out ion identification (being lower than 100V/cm), this moment every kind of ion coefficient of mobility in fact with irrelevant (the W.Mcdaniel and Edward A.Mason of field intensity, Themobility and diffusion of ions in gases, John Wiley ﹠amp; Sons, 1973).

In high electric field, ionic mobility becomes and depends on the electric field strength that is applied, and the ion migration rate may be no longer along with the field intensity linear change.In theme of the present disclosure, utilized this principle.

Field asymmetric waveform ionic mobility spectroscopic assay instrument (FAIMS is also referred to as RF-IMS) utilizes these obviously higher electric fields, and discerns ionic species based on the difference of ion mobility in high strength and low intensive electric field.

FAIMS spectroscopic assay instrument uses such as the ion source of ultraviolet light induced ionization lamp gaseous sample is converted into the mixture of ionic species, and every kind of ionic type is corresponding to chemical substance concrete in the gaseous sample.Ionic species applies specific electric field here and selects to allow by this filter ionic type by ion filter between electrode then.In case passed through filter, ionic type collision detector electrode, and produce the signal of telecommunication.In order to survey the mixture of sample intermediate ion kind, put on the spectrum that the electric field between the filter electrodes can scan gamut and be produced.This ion filter obtains by two electric fields that produced between the combined ionic filter electrodes, and one is asymmetric, periodicity radio frequency (RF) electric field, and one is the DC compensation electric field.Asymmetrical rf electric field has significant difference between its maximum positive field intensity and negative field intensity.Asymmetrical rf electric field disperses ion and makes them deflect into the ion filter electrode, and here they are neutralized, and compensating electric field stops specific ion to disperse so that it is by arriving detector.On the basis of the mobility of ion in high electric field, in device, ion is filtered with respect to the difference of its mobility in low electric field.That is, because the compound dependent behavior of the mobility of their high electric fields relative with the mobility of low electric field, ion is separated.

The FAIMS method is to be based upon [.W.McDaniel and Edward A.Mason, The mobility and diffusion ofions in gases, John Wiley ﹠amp on the basis that Mason and McDaniel observe; Sons, 1973], they find that the mobility of ion is subjected to the electric field strength influence that is applied.(E＞10 under atmospheric pressure, in the time of 700V/cm), coefficient of mobility K (E) has the non-linear dependence to electric field to electric field greater than 40Td with respect to the ratio (E/V) of gas density.It is specific that this dependence is considered to for each ionic species.Be some examples that provide by Mason and McDaniel [.W.McDaniel and Edward A.Mason, The mobility and diffusion ofions in gases, John Wiley ﹠amp below; Sons, 1973].Ion cluster CO ⁺The mobility of CO increases along with the increase of field intensity (with reference to [.W.McDaniel and Edward A.Mason, The mobility and diffusion of ions in gases, John Wiley ﹠amp; Sons, 1973] Fig. 7-1-K-1).For some molecules and atomic ion, coefficient of mobility can change in more complicated mode.For example, for atomic ion K ⁺Coefficient of mobility in CO (carbon monoxide converter) gas increases along with electric field and increases with 20%, but at E/N during greater than～200Td, coefficient begins to reduce (with reference to [.W.McDaniel and Edward A.Mason, Themobility and diffusion of ions in gases, John Wiley ﹠amp; Sons, 1973] Fig. 7-1-K-3).For other ion, for example N ⁺, N ₃ ⁺And N ₄ ⁺, mobility changes very little (with reference to [.W.McDaniel and Edward A.Mason, The mobility anddiffusion of ions in gases, John Wiley ﹠amp; Sons, 1973] Fig. 7-1-H-1/2).Figure 1A illustrates ionic mobility to three kinds of electric field possible dependences.For the sake of simplicity, we will suppose that (E is approximately 10 at weak electric field ²-10 ³V/cm) the mobility K (E in _Min) low electric field value is identical for all three kinds of ionic types.But, at E _MaxCoefficient of mobility K (E _Max) value is inequality for every kind of ionic type.

The electric field dependence of coefficient of mobility K (E) can enough E/N[18] even number time power sequential deployment represent:

K(E)＝K(0)[1+α ₁(E/N) ²+α ₂(E/N) ⁴+...] (1)

Wherein, K (0) is the coefficient of mobility of weak electric field intermediate ion, and α 1 and α 2 are expansion coefficients.This equation can use effective α shown in Equation 2 (E) to simplify [T.W.Carr, Plasma Chromatography, Plenum Press, New York and London, 1984],

K(E)≈K(0)[1+α(E)] (2)

According to this expansion, when α (E)＞0, coefficient of mobility K (E) increases and increases along with field intensity, and when α (E)～0, coefficient of mobility K (E) does not change, and when α (E)＜0, coefficient of mobility K (E) increases and reduces along with field intensity.Consider that from momentum and energy balance aspect also can deriving appears on the scene relies on the expansion of coefficient of mobility.Ion energy ε=3/2kT wherein _EffCan be expressed as the function [18-20] of its effective temperature.

$K\left(E\right)=\frac{V}{E}=\frac{q}{N}{\left(\frac{1}{3\mathrm{\μk}{T}_{\mathrm{eff}}}\right)}^{1/2}\frac{1}{\mathrm{\Ω}\left(T_{\mathrm{eff}}\right)}--\left(3\right)$

Wherein the situation of α (E)＜0 can make an explanation on the expressed model based of equation 3, if neutral cross section (ion neutral cross-section) the Ω T of hypothesis ion _EffCan not change [T.W.Carr significantly for firm ball interaction, PlasmaChromatography, Plenum Press, New York and London, 1984, E.A.Mason and E.W.McDaniel, Transport Properties of Ions inGases, Wiley, New York, 1988], and reduced mass μ constant.Under these conditions, it is found that mobility K (E) will increase if the effective temperature of ion or energy increase.Physically, this effect there is simple explanation.When electric field strength increased, ion is driven more strongly passed neutral gas.This has increased the neutral collision frequency of ion, and it causes average ion speed and ionic mobility coefficient to reduce.

But rigid sphere model can not explain that those show that some ionic mobility is along with electric field (α (E)＞0) increases and the experimental result of increase.When high electric-field strength, allow ion to separate bunch (de-clustering) and take place, can provide a kind of the possible explanation of mobility increase when the high E/N value.Ion in the weak electric field environmental condition does not generally exist with free state.They normally have n for example polar molecule cluster form (for example, the MH of hydrone ⁺(H ₂O) _n).When electric field strength increased, because the energy delivery between the collision, kinetic energy increased, thus the effective temperature (T of ion _Eff) also increase.This can cause reduce (n reduces) of ion cluster rank, thereby causes littler ion cross section Ω T _EffLittler ion reduced mass.According to equation 3, if separate bunch, and cross section and reduced mass are with adequate remedy T _EffThe mode that increases reduces, and the situation of α (E)＞0 just can access explanation so.

The third situation when α (E)～0 can be interpreted as: reduce owing to separate bunch ion cross section that causes, be compensated by the increase of ion effective temperature.This causes the coefficient of mobility of ion not have net change.

Mechanism to the operation of the FAIMS that is used for ion filter describes below.Consideration has three kinds of ions (that is, α (E)＞0, the α (E)＜0 of different coefficient of mobility dependences to electric field, α (E)～0), they are owing to the neutral molecule partial ionization, and are formed on two same positions in the narrow gap between the electrode, shown in Figure 1B.Between the slit, carrier gas stream longitudinally transports these ions along drift tube.If at this moment on electrode, apply asymmetric RF electric field, ion response RF electric field, along with carrier gas stream when drift tube moves, vibrate on the vertical direction flowing with carrier gas.Here, use maximum field strength to be | E _Max|＞10,000V, minimum field strength | E _Min|＜＜| E _Max| the asymmetric RF electric field of simplification waveform (Fig. 1 C) operating principle of RF-IMS is described.Design asymmetric RF electric field waveform and make that the time average of electric field is 0, and

|E _max|t ₁＝|E _min|t ₂＝β (1)

t ₁Be the part that applies high electric field in the cycle, t ₂It is the time that applies low electric field.β is the constant corresponding to high electric field in the cycle and the area below the low electric field curve.Ion is provided by following formula in the speed of y direction:

V _y＝K(E)E(t) (2)

Here in this case, K be ionic species fully at the ionic mobility coefficient of y direction, E is fully in the electric field strength of y direction.If the anodal amplitude (t of RF potential pulse ₁During this time) electric field strength that is produced is greater than 10,000V/cm, and the speed towards top electrode is so:

V _up＝K _up|E _max| (3)

Because the coefficient of mobility K of each ion under high current field condition _UpBe different, shown in Fig. 1 A, so also be different (Figure 1B) to this velocity amplitude of each ionic species.The ion of α (E)＞0 will move sooner, the ion velocity minimum of α (E)＜0, and therefore the slope of every kind of ion trajectory also is different.Next part (t in the cycle ₂), in case the polarity of RF electric field is switched, all these three kinds of ionic types will begin to move towards bottom crown downwards with identical speed:

V _down＝K(E _min)|E _min| (4)

(see Figure 1A) under the condition of this low field intensity, all these three kinds of ionic types will have identical ionic mobility COEFFICIENT K _DownTherefore, in this part in cycle, all these three kinds of ion trajectories will have identical speed (Figure 1B).

Ion is the speed V of ion in the y direction with respect to the displacement of its original position on the y direction _yMultiply by the time span Δ t that applies electric field:

Δt＝VyΔt (5)

In the one-period of the RF electric field that is applied, ion moves on positive and negative y direction.Bring equation 2 into equation 5, the average displacement amount of ion in RF electric field one-period can be written as:

Δy _RF＝K _up|E _max|t ₁-K _down|E _min|t ₂ (6)

Use equation 1, expansion can be rewritten as:

Δy _RF＝β(K _up-K _down)＝βΔK (7)

Because β is by the determined constant of RF electric field that is applied, ion is at each RF electric field period T=t ₁+ t ₂The y displacement depend on the variation of ionic mobility between high electric field and low electric field.Suppose that carrier gas only transports ion in the z direction.Between the ion filter pole plate, at ion time of staying t _ResDuring this time, (because electric field) can be expressed as from the total ion displacement amount Y (y direction) of its original position:

$Y=\frac{\mathrm{\&Delta;}{y}_{\mathrm{RF}}}{({\mathrm{<figure-callout\; id="1"\; label="t"\; filenames="A0281213000641.png,A0281213000681.png"\; state="\{\{state\}\}">t</figure-callout>}}_1+t_2)}{t}_{\mathrm{res}}=\frac{\mathrm{\&beta;\&Delta;K}}{T}{t}_{\mathrm{res}}---\left(8\right)$

The average ion time of staying in the ion filter zone provides in equation 9.A is the cross-sectional area of filter area, and L is the ion filter electrode length, and V is the volume in ion filter zone, V=AL, and Q is the volume flow rate of carrier gas.

$t_{\mathrm{res}}=\frac{\mathrm{AL}}{Q}=\frac{V}{Q}--\left(9\right)$

Bring equation 9 into equation 8, note from equation 1 have β=| E _Max| t ₁, and definition RF duty of ratio is D=t ₁/ T.Therefore the equation 8 of ionic species displacement can be rewritten as:

$Y=\frac{\mathrm{\&Delta;}{\mathrm{KE}}_{\max }\mathrm{VD}}{Q}--\left(10\right)$

Wherein, Y is now based on the ion of the average ion time of staying in the ion filter zone total displacement on the y direction.From equation 10, clearly intermediate ion displacement in vertical direction in slit is directly proportional with ionic mobility difference between low field intensity condition and the high electric-field strength condition.Different types of ion with different Δ K values is for given t _ResThe Y value that displacement is different.The every other parameter that comprises maximum field strength value, ion filter zone volume, duty ratio and flow velocity comes down to identical for all ionic speciess at single order.

When causing with average RF on (the y orientation) ion motion rightabout, except that the RF electric field, also apply low-intensity DC electric field (| E _c|＜| E _Min|＜＜| E _Max|), the track of specific ionic species can be seen Fig. 1 D (1), 1D (2), 1D (3) by " stretching ".This allows the ion of specific kind to pass through between the ion filter electrode without hindrance, and the ion of every other kind is partial to the filter electrode.Dc voltage " tuning " filter also produces the electric field that compensation RF causes motion, it is characterized in that ionic species, and is called as bucking voltage.The spectrum complete at the gaseous sample intermediate ion can be by streaking (ramping) or the inswept DC bucking voltage acquisition that puts on filter.The relation of ionic current intensity and scanning voltage has formed RF-IMS spectrum.If not an ion filter electrode is applied scanning voltage, and apply fixing dc voltage (bucking voltage), this spectroscopic assay instrument will be worked as the continuous ionic filter that only allows a kind of ion to pass through.

In PCT application No.PCT/CA99/00715, electro-spray ionization chamber or electrospray ionization source are used to produce ion, and these ions are transported to analyzed area at last, and high frequency voltage asymmetric waveform and DC bucking voltage act on this zone.

Therefore, the purpose of this invention is to provide a kind of method and apparatus that makes the ionic mobility of use asymmetric waveform improve the compound detection.

Summary of the invention

Reached purpose of the present invention in the practice of asymmetric ionic mobility analyzer on the scene and the new improvement, specifically aspect three: 1) sample preparation and introducing, 2) ion filter, 3) output and signal collection.

Embodiments of the invention are illustrated the combination of many aspects, comprise and use the FAIMS ion filter to come ion is filtered, wherein, except that high electric field asymmetric waveform radiofrequency signal, by variable DC compensating signal is controlled, or use the FAIMS filter, obtain the control which kind of ion is filtered, at the FAIMS filter, acquisition such as the wavelength of the control which kind of ion is filtered by the high electric field asymmetric waveform of conversion radiofrequency signal, frequency, amplitude, cycle, duty ratio; Use plane FAIMS filter, its use dielectric substrate very accurately controls the slit between the ion filter electrode, and guarantee that the ion filter electrode is parallel, this allows to obtain complete renewable, it has caused more high-resolution spectroscopic assay instrument, use plane FAIMS filter, wherein, the coincident of insulation partition and filter electrodes, this causes having the more high-resolution FAIMS to the more accurate identification of compound, because all samples all are forced to pass through between the ion filter electrode, do not have ion to walk around filter electrodes and still arrive filter electrodes.

In by use such as the spraying source of electron spray head, obtained desolvation, wherein for obtain reliably, spectrum repeatably, extremely important to the desolvation of ion.The desolvation electrode can be comprised helping desolvation, and the desolvation of enhancing can obtain by the desolvation electrode being applied symmetrical RF signal.The RF signal provides energy for ion, and the effective temperature of this ion that raise and help strengthen the desolvation process.

The desolvation electrode also can be used to control the ion reunion degree from the gaseous sample of electron spray and other electrospray ionization sources.Reunion is controlled and can be allowed more repeatably measurements to ion, and the extra information about the ion that just is being detected also can be provided.

New embodiment of the present invention and sample preparation part correlation.This embodiment comprises using of electron spray head and the use of the attraction electrode opened from the ion filter electrode separation.The advantage that attracts electrode to open from the ion filter electrode separation is this allows relative ion filter electrode freely the attraction electrode to be applied different electromotive forces, and this permission is optimized electron spray condition among the FAIMS and ion introducing condition.Separating also of ion filter and attraction electrode can realize in cylindrical FAIMS structure.

In addition, can provide leading electrode, ion filter is optimized also to allow to inject into to ion.In another embodiment, electrospray assembly can be connected on the FAIMS substrate, leading electrode is used to guide ion to enter ionisation region.Leading electrode can be freestanding additional structure, perhaps can be connected to, or near a FAIMS substrate.Assembly can have back draught and strengthen desolvation.

The present invention has also illustrated the realization to this notion: flight time measurement and FAIMS method can be made up, by the extra information that is provided by flight time measurement, use electron spray that improved identification to ionic species is provided.Can measure the traveling time of ion from the FAIMS mouth of pipe to detector.This can be by controlling acquisition to attraction electrode and leading electrode electromotive force independently.For example, initial do not have ion to make it enter drift tube to attracting electrode potential to regulate, making, but be collected in leading electrode.Then, apply pulse voltage, make some ions make it enter ionisation region and enter ion filter attracting electrode.Since can measure from the time that ionisation region advances to detector ion, this provides the extra differentiation information about ion identification.

The new aspect of the present invention is the notion that forms electrode on insulation or insulated substrate, and wherein dielectric substrate can form shell.This method is obtaining obvious improvement aspect device configuration is simplified.This make low-cost, the worker artistic skill is used in enormous quantities, for example little processing, can cause multi-chip module, microsensor cheaply.

For output, the embodiment of the FAIMS that is recommended at first has simultaneously the output to the ability of for example surveying with a plurality of ions of the ion of positive and negative electric charge.

Since the sample analysis among the FAIMS carries out in gas phase usually, fluid sample need be converted to gas phase from liquid phase.In a preferred embodiment, method of electrospraying (" traditional ", miniature and/or nanometer spraying have been contained in our definition) is used to fluid sample is converted to gaseous ion.The ion flow that comes from the electron spray needle point is preferably by plane FAIMS effect.In preferred embodiment of the present invention, all sample preparations, ionization, filtration and detecting function all carry out on single " chip ".

In another embodiment, electron spray FAIMS is used as the filter of mass spectroscopy instrument.The FAIMS that is coupled to the mass spectroscopy instrument provides enhanced resolution, better detection limit, can extract the shape and the structural information of just analyzed molecule better.The FAIMS technology is based on ionic mobility, and wherein, ion filter and identification highly depend on the size and the shape of ion.Because the character of protein has been determined its function to a great extent, so this information is very interested in genome and proteome research (that is, pharmaceuticals industry), so FAIMS can be as low-cost, jumbo protein characterizing method.A certain embodiments comprises replaceable FAIMS filter chip, and it is inserted into the carrier that is installed on mass spectroscopy instrument inlet.FAIMS electron spray device also can provide structure (structure) information about just analyzed molecule, and the information that can not simply obtain by the electrospray ionization mass spectrum analyzer.In addition, FAIMS allows to distinguish between isomers (have equal in quality, but variform molecule), and this can not obtain by the electrospray ionization mass spectrum analyzer separately.

In a certain embodiments, electron spray FAIMS forms filter and detection system in independent shell.Electron spray FAIMS of the present invention structure can be used as the separate detectors that is used for fluid sample analysis, or as the front end of mass spectroscopy instrument.The present invention also has other for example liquid separation technologies of liquid chromatogram, high pressure liquid chromatography and Capillary Electrophoresis.The preferred embodiment of the invention comprises plane FAIMS device, and in one embodiment, this device and electro-spray ionization source are integrated on the public shell or substrate, and are coupled to the mass spectroscopy instrument.

An alternative embodiment of the invention can comprise cylindrical or coaxial FAIMS device.Embodiments of the invention can be filtered molecule after spraying from the source of for example electron spray needle point or Capillary Electrophoresis outlet, and are ionized before the filtration via the FAIMS filter, and via internal electrode, or mass spectroscopy instrument or other detectors are detected.In one embodiment of the invention, little processing (MEMS) handle make the electron spray needle point can and the FAIMS filter be integrated into simple device, and cause accurately but be used for closely accurately, highly repeatably, the analytical system of fluid sample evaluation.In another embodiment of the present invention, can be used for that biologic product surveys portable, miniature, biology sensor cheaply, it uses integrated electron spray FAIMS chip.Preferably, they are to use little processing and manufacturing technology preparation.In one embodiment, the FAIMS filter of the prefilter by being used as the mass spectroscopy instrument has obtained atmospheric pressure chemical ionization (APCI).

Before the present invention, traditional processing causes high manufacturing cost, and the repeatability that differs between the FAIMS device.In addition, the cylindrical FAIMS geometry of prior art or when being connected, limited collection efficiency with mass spectroscopy instrument interface, or allow sample neutral substance and sample ions all to enter the mass spectroscopy instrument, caused complicated more spectrum.At embodiments of the invention, advantageously after sample ionsization, carry out ion filter, therefore the inevitable buffer salt that produces is separated from interested biomolecule with lyate ion in the electron spray process.This provides obvious much simple mass spectrum and has improved detection limit and to Recognition of Biomolecular.

Electron spray and the combination of FAIMS filter means are made that analyzing sensitive detection parts has susceptibility and the resolution that strengthens greatly.In some situations, this ability is provided to the compound that can not discern under the situation that does not have FAIMS to exist is decomposed.When electron spray and FAIMS filter means are combined in the sample of the device operation low concentration by being used for high flux, low-cost sample analysis, cause the pollution problems between the sample, but these have obtained overcoming in practice of the present invention.

The new FAIMS of the present invention be cheaply, can make in batches, little and closely, based on the spectroscopic assay instrument of ionic mobility difference.The existing relatively device of the present invention provides several extra benefits, and especially those use the invention such as the batch manufacturing technology structure of the MEMS manufacturing technology that includes ceramic packaging, PC plate manufacturing technology or plastic process.Manufacturing technology causes cheaply, is made the device that can replace in batches, has therefore avoided the problem of sample cross pollution.These chips will be available as the laboratory that the FAIMS interface filter is used for biomolecule identification for any use mass spectroscopy instrument.Such filter comprises the FAIMS interface chip that can be inserted into interface fixing apparatus, and this interface fixing apparatus comprises filtering electronic equipment.Electron spray needle point or electrophoresis chip can with FAIMS chip integrated (being fabricated to a part).The MEMS technology is not needed but preferred, and has given reliability and repeatability in the FAIMS chip of making in batches; This has reduced their cost, and makes replaceable device be called possibility.This substitutability has been avoided the pollution from a sample to next sample, and this is for obeying, be used for and/or to regulate the test that preparation carries out be priceless by being similar to EPA and FDA, and their are polluted is a main problem of paying close attention to.

In one embodiment of the present of invention, made plane MEMS FAIMS chip, wherein, ion is focused in the mass spectroscopy instrument, and collection efficiency is near 100%.In this embodiment, there is not ion need be injected in the FAIMS ion filter zone.This device is micro-machined on plane surface.It can be easily carries out integrated with micro-machined or traditional electron spray needle point and/or micro-machined electrophoresis chip.This is the design of a simplification, has the manufacturing requirement of minimizing, and can be configured to only use single gas channel.

Little processing provides good manufacturing repeatability and filter capability.This is very crucial, thus the result from a device to next device, from a laboratory to consistent the next laboratory.Little processing make the FAIMS filter chip that can not otherwise make new be constructed to possibility.These new structures are comparatively simple, and have higher efficient when transmitting ion to mass spectroscopy instrument and the unwanted ion of filtration.

Successfully made and characterized MEMS FAIMS drift tube.Verified high spectroscopic assay instrument sensitivity and decompose the ability that in traditional TOF-IMS, does not have separated chemical substance.That MEMS FAIMS make to realize is microminiaturized, the detector of low cost, high sensitivity, high reliability becomes possibility.FAIMS spectroscopic assay instrument of the present invention also has been proved to be the prefilter of mass spectroscopy instrument.New FAIMS/MS combination allows complex mixture is better resolved.

By using such as micro-machined little manufacture method, be used for that biologic product is surveyed, use integrated electron spray FAIMS chip portable, miniature, biology sensor is possible cheaply, this be since these technology and institute can product make size reduce that reduction becomes possibility with cost.These instruments have many purposes, comprise high-quality bioanalysis useful in this area.For example, the people who is exposed to biologic product under a cloud can be instrument one liquid of bleeding is provided.Blood mixes pre-buffer salt, handle, and is introduced in FAIMS by the electron spray nozzle, at this ion is analyzed.If detect concrete biomolecule, will give a warning.Equally, little processing make otherwise unavailable FAIMS filter chip new be constructed to possibility.For example, disclosed plane FAIMS in this patent.These new structures are simpler, and have higher efficient when transmitting ion to mass spectroscopy instrument and the unwanted ion of filtration.In a preferred embodiment, electron spray and FAIMS have formed atmospheric pressure chemical ionization (APCI) prefilter, analysis and filter device and the detection system in single shell.New FAIMS-APCI provides high-performance, low cost, can make in batches, little and ionic mobility analyzer closely.

In one embodiment of the invention, its breakthrough can be given the credit to provides multiduty shell/substrates/packages, and they have simplified the formation and the consequent assembling of element.Supplementary features comprise such possibility, with substrate as setting up the physical platform of filter thereon and coming to give structure for entire device; As insulated platform or scope, it has defined the flow path by device with substrate; And/or use substrate that the insulation system that can improve performance is provided.In device, can be incorporated into spacer, the right possibility of silicon electrode that it provides definition structure and has been used for further bias voltage control.Can utilize arranging of multi-electrode formation and function spacer, this has improved performance and capacity.Filtration has been used with control element and has been applied to FAIMS asymmetrical period voltage on the filter, and this element can be bias voltage signal or voltage, perhaps can otherwise provide simply, for example pass through control, and this needs to the DC compensating circuit have been removed to the duty ratio of identical asymmetrical signals.This is arranged closely and makes it possible to get rid of the heater that is used to clean ion, and even can use the existing electrode of filter for example or detector electrodes to heat/temperature control.

Embodiment of the present invention comprise an asymmetric ionic mobility analyzer device, and some preferred embodiments comprise sample preparation part, ion filter part, output and control section, and filter comprises the FAIMS filter that is used for ion filter.Embodiments of the invention can also diversely comprise: plane FAIMS filters, its use dielectric substrate controls very exactly the slit between the ion filter electrode, and guarantee that the ion filter electrode is parallel, this makes it possible to obtain cause the reproducible electric field of the spectroscopic assay instrument of high-resolution; FAIMS filter, the wherein coincident of insulating spacer and filter electrodes.Owing to make all samples all pass through between the ion filter, and do not have ion can walk around filter electrodes, and still arrive detector electrodes, so this has obtained more high-resolution FAIMS, and had the more accurate identification of compound; The electron spray head provides desolvation to ion by the desolvation electrode; By applying the desolvation that symmetrical RF signal can obtain to strengthen to the electrode that desolvates; The RF signal provides energy for ion, this their effective temperature that raise, and help to strengthen the desolvation process; Wherein, in practice of the present invention, provide the electrode that desolvates, it is used for degree that control gaseous sample intermediate ion reunites, manyly repeatably measures and provide extra information for just measured ion.

New aspect is included on substrate insulation or insulated and forms electrode, wherein, dielectric substrate can form shell, and in simplification, provide tangible progress to device configuration, because low cost, such as little processing, can cause multi-chip module cheaply and use the technology of batch manufacturing of the microsensor of FAIMS structure to obtain use; In output, has the ability that for example to survey simultaneously with the ionic species of positive and negative electric charge; Also combine the use of electron spray head and the use that attracts electrode, this attraction electrode by from the ion filter electrode separation so that apply different electromotive forces with respect to the ion filter electrode, and this makes and can be optimized to the electron spray condition with the condition that ion is introduced the FAIMS device.The FAIMS device can be cylindrical shape type, plane type or other forms.Leading electrode allows further to optimize ion is injected in the ion filter.

Also may form the flight time measurement device that combines with the FAIMS device, it is by by the extraneous information that flight time measurement provided, and uses electron spray that identification to improved ionic species is provided; Can measure from the time that the FAIMS mouth of pipe advances to detector ion, this can be by controlling acquisition to attraction electrode and leading electrode electromotive force independently; Wherein, electrospray assembly can be affixed to the substrate of FAIMS, and leading electrode is used to guide ion to enter ionisation region; Back draught has strengthened desolvation; Wherein, leading electrode can be to be affixed to, to be connected to or near the stand-alone configuration of the substrate of FAIMS.Wherein, except that high electric field asymmetric waveform radiofrequency signal, by controlling variable DC compensating signal, can obtain control which kind of ion is filtered, perhaps the control which kind of ion is filtered by the acquisitions such as frequency that change such as duty ratio, amplitude or high electric field asymmetric waveform radiofrequency signal.

All sample preparations, ionization, filtration and detecting function can carry out on independent chip of the present invention or workpiece; Wherein, electron spray FAIMS is used as filter, the chip carrier of mass spectroscopy instrument and is inserted into replaceable FAIMS filter chip in the carrier, and this carrier can be installed in the inlet of mass spectroscopy instrument; Wherein, electron spray FAIMS forms filter and detection system in independent shell; Wherein, electron spray FAIMS of the present invention structure can be used as the separate detectors of fluid sample or as the front end of mass spectroscopy instrument; Wherein, the present invention also has the application such as other liquid separation technologies of liquid chromatogram, high pressure liquid chromatography and Capillary Electrophoresis; Wherein, the preferred embodiments of the present invention comprise the FAIMS device, and wherein in one embodiment, the FAIMS device carries out integratedly with electric spray ion source on public shell or substrate, and is coupled to the mass spectroscopy instrument; Wherein, embodiments of the invention can be at molecule after injected such as the source of electron spray needle point or Capillary Electrophoresis outlet, they are filtered, before filtering, carried out ionization by the FAIMS filter, through inner detector, mass spectroscopy instrument or other detectors are detected, and in practice of the present invention, little processing (MEMS) makes the electron spray needle point to be integrated into simple cells/devices with plane electric fields asymmetric waveform ionic mobility analyzer filter, and still produce and be used for accurately, highly repeatably, the accurate analytical system of fluid sample assessment, perhaps in other practices of the present invention, be used to use the biologic product of integrated electron spray FAIMS chip to survey, portable, miniature, biology sensor is possible cheaply, and can use little processing and manufacturing technology to be prepared; Wherein, the FAIMS parts are planes, and are mass spectroscopy instrument formation atmospheric pressure chemical ionization (APCI) prefilter; Wherein, ion filter carries out after sample ionsization, thereby inevitable buffer salt that produces and lyate ion are from interested bio-molecular separation in the electron spray process, and this provides much obviously simple mass spectrum, and have improved detection limit and to Recognition of Biomolecular; Wherein, the combination of electron spray and FAIMS filter means is made to have highly reinforcing sensitivity and the Analysis of Resolution sensitive detection parts become possibility, wherein in some situations, the ability that can decompose the compound that can not be identified when not having FAIMS to exist is provided, and when the FAIMS filter means of electron spray and prior art is combined in the sample of the device operation low concentration by being used for high flux, low-cost sample analysis, caused the pollution problems of sample room, but these have obtained overcoming in practice of the present invention.

In practice of the present invention, the mass spectroscopy instrument is directly coupled to the discharge port at drift tube one end, wherein, can place baffle plate and adjust drift about the relatively speed of air-flow of exhaust flow.No matter can use several samples to prepare part, be the port of simply drawing the sample in the air atmosphere, or electron spray, gas-chromatography, liquid chromatogram etc., can use branch air guide stream to stop to reunite and allow the ionic species better recognition.

To given ionic species, the relation between monomer and reunion amount of ions depends on the concentration of sample and concrete experiment condition (for example, humidity, temperature, low speed, the intensity of RF electric field).In practice of the present invention, monomer or aggregating state all are detected with the useful information to providing chemical substance to discern.In an example, plane binary channels FAIMS is used to obtain this result, wherein, the sample neutral substance is applied an act air-flow, stops them to enter second channel " II ", and the ion of free state can be detected.In another embodiment, lethargy stream can flow and is discharged from the mouth of pipe with identical direction, perhaps comprised and in the opposite direction being flowed when ion guides entered second channel " II " in leading electrode, attract electrode also to be used to attract ion admission passage " II ", thereby owing to use pump, sample neutral substance and sample ions can be sucked into passage " II " now, so when lethargy was closed, the ion of aggregating state can be observed.

Method of the present invention comprises that coupling FAIMS device is to the mass spectroscopy instrument, to pass through enhanced resolution, better detection limit, extract the shape of just analyzed molecule and the ability of structural information, molecule can comprise the biomolecule such as protein and peptide, the FAIMS technology is based upon on the basis of ionic mobility, wherein, to the filtration of ion and the size that depends on ion and the shape of identification height, FAIMS electron spray device provides structure (structure) information of just analyzed molecule, and can not use electron spray one mass spectroscopy instrument simply with regard to obtainable sequence information, and allow to distinguish between isomers (having the quality that is equal to and variform molecule), this can not use electron spray-mass spectroscopy instrument just can discern separately.

Embodiment of the present invention are illustrated the multifunctional usage of FAIMS substrate.Substrate is to be used for accurately determining and the component parts of positioning devices or the platform (or physical support mechanism) of part.Substrate forms shell, and by filter, may be that detector and other elements are around flow path.This multi-functional design has reduced number of components, accurately locatees simultaneously component parts and makes obtain quality and consistency in making in batches.Littler device also has beyond thought improvement in performance, may be because littler drift tube also may be because substrate also has the electrical isolation function.Since be insulation or insulator (for example, glass, pottery, plastics), substrate can be have improvement performance characteristic, form such as the direct platform of the element of electrode.

Embodiment of the present invention can be cylindrical or plane etc.In the disclosed embodiment, substrate not being discharged other " shell " parts or other structures as support/shell is built into around the device.For example, placing the humidity barrier on device perhaps is suitable.Equally, extra can be installed in the outside of substrate/shell such as the element of battery, for example, in battery case.But inventive embodiment required for protection here can provide insulated substrate function, support function, multi-functional shell function and other functions.

Insulate or insulated substrate/flow path invention has obtained excellent performance aspect simplified structure.Insulated flow path makes the asymmetrical period voltage that is applied can isolate (for example, from the electrode of detector) from output block on the use electricity in the FAIMS device, surveys herein.Because insulated substrate in flow path filter and detector between insulated zone is provided, so can finish this minimizing, what this separation was favourable again separates the filter electric field from detector.The acquisition environment of less noise means sensitiveer FAIMS device.

In addition, by form electrode on the insulating properties substrate, it is more approaching that ion filter electrode and detector electrodes can be placed, and this has unexpectedly strengthened ion collection efficient and has advantageously reduced the quality that the needs of device are adjusted, heated and control.This also reduces the demand to electric power.In addition, use little electrode to reduce electric capacity, this has reduced the consumption of electric power again.Equally, because the insulating surface of substrate is the fabulous platform that is used to form such electrode, therefore closely separated electrode itself has caused the technology of large-scale production.

Embodiment required for protection has caused obtaining such FAIMS device: have high-resolution, operation fast and high sensitivity, but low number of components is arranged and be in can by in large quantities, in the structure making effectively and assemble on the cost.Be apparent that very for so competent FAIMS device, encapsulation is very closely, and have per 1,000,000,000 or the scope of part per trillion in sensitivity.In addition, the hardware of the minimizing of the device that this is littler (real estate) has caused electric power needs that reduce, no matter is discerning ion or in the heater element surface, this makes it possible to use littler battery.Few as 1 second (even still less) time produces the complete spectrum of given sample according to the general needs of benefit of simplification of the present invention and the instrument of FAIMS spectroscopic assay closely.The FAIMS system that does not also have to obtain so useful result is instructed in the prior art or is open.

Description of drawings

As depicted in the figures, according to the more specific description of following the preferred embodiments of the present invention, aforesaid and other purpose, the feature and advantage of the present invention will become clear, in all different views, in the accompanying drawing similarly mark refer to identical parts.Needn't be pro rata for accompanying drawing, and should emphasize illustrating to principle of the present invention.

Figure 1A shows the dependence of the mobility of three kinds of different ions kinds to electric field;

Figure 1B shows in the slit between the upper and lower parallel-plate electrode of ion filter, the track of ion under carrier gas stream and asymmetric rf electric field waveform act on simultaneously;

Fig. 1 C shows the asymmetrical RF electric field waveform that is used for ion filter of simplification;

Fig. 1 D1 shows to be applied in and compensates for unique bucking voltage that the RF electric field produces;

Fig. 1 D2 shows under the situation that only has the RF electric field that is applied ion from the track of origin position, and under the situation that only has the compensation that is applied the track of ion;

Fig. 1 D3 shows the track of ion under the situation of the RF that applies having and compensating electric field;

Fig. 2 is the schematic diagram of the chemical sensor during the present invention puts into practice;

Fig. 3 A shows the chemical sensor system with liquid sample preparation part, and this preparation partly comprises the electron spray of the present invention in putting into practice;

Fig. 3 B shows the chemical sensor system with liquid sample preparation part, and this preparation partly comprises the electron spray of the present invention in putting into practice;

Fig. 3 B1 shows the mach electron spray head in the present invention's practice;

Fig. 3 C shows the coil in the present invention's practice;

Fig. 3 D shows the substrate of the formation shell in the present invention's practice;

Fig. 4 A shows the separated FAIMS spectroscopic assay instrument that is insulated substrate that has in the present invention's practice;

Fig. 4 B shows the embodiment of another the structural electrode in the present invention's practice;

Fig. 4 C shows the side viewgraph of cross-section with the filter of the overlapping insulation partition of electrode edge of having in the present invention practice;

Fig. 4 D shows the electron spray head in the present invention's practice, and this electron spray head has the sample container to the split tunnel charging of leading to the needle point of spraying;

Fig. 5 A shows the desolvated symmetrical AC rf electric field that is used in the present invention's practice;

Fig. 6 shows the cylindrical FAIMS of the prior art that is connected to the mass spectroscopy instrument;

Fig. 7 A, 7B show the improved cylindrical FAIMS in the present invention's practice;

Fig. 8 shows the electron spray erection tower in the present invention's practice;

Fig. 9 A shows in the present invention practice and the electron spray head leading electrode cooperation;

Fig. 9 B shows in the present invention practice and the electron spray head leading electrode cooperation;

Figure 10 A shows the control system in the present invention's practice;

Figure 10 B shows the control signal in the present invention's practice;

Figure 11 A shows the chip carrier socket in the present invention's practice;

Figure 11 B shows the chip carrier socket that joins with the mass spectroscopy instrument in the present invention practice;

Figure 12 A, 12B show the plane FAIMS in the present invention's practice;

Figure 12 C, 12D show the cylindrical FAIMS device of prior art;

Figure 13 A, 13B show in the present invention practice otherwise from the mouth of pipe by last substrate from the top or inject the electron spray needle point in ion zone from the side;

Figure 14 A, 14B show the embodiment by the longitudinal electric field driving in the present invention's practice;

Figure 15 A, 15B show the branch air guide stream embodiment in the present invention's practice;

Figure 16 shows the binary channels embodiment in the present invention's practice;

Figure 17 show in the present invention practice for the ketone in different ions source and the dependence of bucking voltage;

Figure 18 shows the binary channels embodiment in the present invention's practice;

Figure 19 shows the detecting light spectrum in the present invention's practice.

Embodiment

Below the preferred embodiments of the invention are described.

The invention provides preferably method and apparatus by high electric field asymmetric waveform ionic mobility spectroscopic assay instrument compound that realize, that be used for analyzing liquid sample.

In the illustrative embodiment of the present invention as shown in Figure 2, chemical sensor system 10 comprises sample preparation part 10A, filter part 10B and output 10C.In practice, with fluid sample S ionization, the ion that is produced is transferred to filter part 10B then and is filtered at sample preparation part 10A, and the ion by the filter part is sent to output 10C to survey then.Liquid sample preparation part 10A, filter part 10B and output 10C work under the control of controller part 10D and indication.The preferably operation of control system 10 of controller part 10D, and estimate and report detection data D.

In a preferred embodiment of the invention, liquid sample preparation part 10A comprises the electron spray head, its reception, adjusting and ionization fluid sample S.These ions are transported to the high electric field in preferred plane asymmetric ionic mobility spectroscopic assay instrument (PFAIMS) filter among the part 10B, and the latter filters the ion transmitted and interested ionic species is delivered to output 10C.In a plurality of embodiment of the present invention, by using read-out device, the function of output 10C can comprise to the instant detection of ionic species or with ion-transfer to such as another parts of mass spectrum (MS) ionic species being surveyed at this, this read-out device can utilize the data D of the ionic species that indication is detected.

As skilled in the art to understand, the FAIMS filter that has flat surfaces in an embodiment of the present invention is preferred, but be to use a plurality of non-planar parts and surface, embodiments of the invention also are manipulable, and these parts comprise filter, detector, flow path, electrode etc.Here the explanation to PFAIMS is descriptive, and nonrestrictive.

In the embodiment of Fig. 3 A, 3B, liquid sample preparation part 10A comprises electron spray sample ions source with the chamber 14 that is used to receive fluid sample S or 12.In the invention process, fluid sample S can comprise biologic artifact in solvent X, for example compd A and B.The present invention is devoted to discern one or more compounds in the fluid sample.

In the enforcement to the electron spray device of part 10A, high voltage 18 is put on by controller 10D on the fluid sample S in the chamber 14 of electron spray head 12.Drive by controller 10D, in ion zone 23, make compd A and B ionization among the solvent X of sample S in the fluid sample S of electron spray needle point 20 and electrical potential difference between the attraction part 22.This has produced the ion 24 and 26 and solvent molecule 28 of representation compound A and B.In a preferred embodiment, ion and solvent are driven or are drawn to the filter part 10B between the filter electrodes parallel in the PFAIMS ion filter 40 44,46 downwards along flow path 30.

Filtration in PFAIMS ion filter device 40 is the difference based on ionic mobility, and this difference is subjected to the influence of projects such as ionic size and shape.This makes and can separate ionic species based on the feature of ion.In one embodiment of the invention, apply high-intensity asymmetric waveform radio frequency (RF) signal 48 and DC compensating signal 50 to filter electrode 44,46 by the RF/DC generator circuit in the controller 10D.This asymmetric electric field is checker between high electric field strength condition and low electric field strength condition, and this makes ion move according to their mobility response electric field.Usually, the mobility in the high electric field is different with mobility in the low electric field.The mobility difference produces the clean lateral displacement of ion when ion vertically moves by filter between filter electrodes.In the situation that does not have the compensating offset signal, these ions will clash into a filter electrodes and be neutralized.If there is the compensation bias voltage signal 50 (or other compensation) through selecting, specific ionic species will turn back to the central authorities of flow path, and will pass through filter.Therefore, when having the asymmetric RF signal 48 compensated, can ion be separated from each other out according to the kind of ion.Non-selected kind will be clashed into electrode and will be neutralized, and interested kind will be passed through filter.In order to select which ionic species by filter, data and system controller 10D regulate the signal 48,50 that is applied on the filter electrodes 44,46.

It should be understood that isolate ion 24 and 26 with obtain to compd A and B or wherein any realizing identification leave nothing to be desired, this just as 40 of use PFAIMS filters obtainable.PFAIMS filter 40 is distinguished between them based on the mobility of ion A and B, thereby according to the compensation that is applied by controller 10D, only takes out one or another is to survey at output 10C in principle.For example, in Fig. 3 A, 3B, ion 24 is shown as the ion 24 ' by filter 40.

Refer again to Fig. 3 A, 3B, output 10C comprises the detector 69 with exploring electrode 70,72.Electric current on the controller 10D measurement electrode 70,72 is with as to 24 indications of the ion by filter 40.These electrodes maintain certain electromotive force by the bias voltage signal 71,73 of controller 10D.Under the control of controller 10D, depend on the polarity and the control signal on the exploring electrode 71,73 of electrode, the ion 24 ' by filter 40 with their charge deposition on exploring electrode 70,72.In addition, by scan compensation (that is, bias voltage), can detect the complete spectrum of sample S intermediate ion kind.

By the Based Intelligent Control of controller 10D, can select different opereating specifications, can will filter as target thus interested ionic species.In the practice of one embodiment of the present of invention, in conjunction with compensation bias voltage 50, apply Asymmetric Electric signal 48, consequently under the control of electric controller 10D, filter transmits desired ionic species.Equally, by at predetermined voltage range interscan bias voltage 50, can obtain the complete spectrum of sample S intermediate ion kind.

In another embodiment, still under the detection of the control signal that electric controller provided, for compensation is Asymmetric Electric signal form with change in duty cycle, and does not need to compensate the situation of bias voltage, makes the desired ionic species of Asymmetric Electric signal by becoming possibility.Utilize these features, device is tunable, that is, it can be come the filter ions kind by tuning, only have desired and the kind selected by arriving detector.

Additional benefit of the present invention is: filter can make has similar mobility and the different different kinds of ions of polarity is passed through, and these ionic speciess can be detected simultaneously.If each exploring electrode 70,72 is maintained at different polarity, the different kinds of ions by filter (having similar mobility and the polarity difference) just can be detected simultaneously so.The ion that is detected is associated with control signal that is applied 48,50 and potential bias signal 71,73, to determine the indicated ionic species that is detected of data D of Fig. 2.

As shown in Figure 3A, this is multi-functional can further understand with reference to output 10C, and wherein top electrode 70 is maintained at predetermined voltage, and identical with interested ion polarity by filter 40, and bottom electrode 72 is maintained at other voltage, and this may be a ground connection.Top electrode 70 is deflected downwards to bottom electrode 72 to survey with ion 24 '.But the signal that arbitrary electrode all can be dependent on electric charge, the polarity of ion and puts on electrode comes ion is surveyed.Therefore, use top electrode 70 as a detector, bottom electrode 72 is as second detector, and in controller 10D, use two different detector circuits, and therefore send the different output of two-way, by filter, have similar mobility and the different different kinds of ions of polarity can be detected simultaneously.So detector 69 can be surveyed a plurality of kinds by PFAIMS filter 40 simultaneously, for example comprises the gaseous sample of sulphur in the hydrocarbon gas background.

Electronic controller 10D provides the control electronic signal for system 10.Have the situation of the control section of the lead-in wire that is connected to control circuit 10D shown in Fig. 4 A and connection pads at least at the PFAIMS device, control circuit can be onboard, or not onboard.Come the signal of self-controller to be applied to filter electrodes via these connections.

In the embodiment shown in Fig. 4 A, PFAIMS system 10 comprises spectroscopic assay instrument chip 100, the dielectric substrate 52,54 (for example, Pyrex  glass, pottery, plastics etc.) of filter electrodes 44,46 such as (gold) that this chip 100 has is separated, form thereon.Substrate 52,54 has been determined drift tube 29 and flow path 30 between them, thereby has had the function of shell.Substrate preferably insulate, and perhaps has the surface 60,62 of the electrode that is used to be insulated installation.Electrode 44,46 forms ion filter 40, and filter electrodes is installed in insulating surface 60,62, and they are relative in flow path 30 both sides.

Shown in Fig. 4 A, 4B, 4C, substrate 52,54 is separated by spacer 53,55, for example, these spacers can be insulation and form by pottery, plastics, Teflon  etc., perhaps form, perhaps produce the prolongation of substrate 52,54 and form by etching or cutting silicon.The thickness of spacer has determined to have the distance " D " between the face of substrate 52,54 of electrode 44,46.In the embodiment of Fig. 4 A, the silicon spacer can be used as electrode 53 ', 55 ', and by controller 10D deboost is applied on the silicon wafer electrode with the ion limit that will the be filtered center built in flow path.This restriction will cause more ionic bombardment detector, also strengthen detection.

In Fig. 4 B an alternative embodiment of the invention, another kind of structure electrode 44x, 46x have substituted substrate 52,54, and are installed on the insulating spacer 53,55 and by them and separate, and form flow path 30 therebetween.At an end of flow path, sample preparation part 10A is input to filter part 10B with ion, and at the other end, the ion that process is filtered is by entering into output 10C.The mode that plays structure function and formation shell with substrate is identical, and structure electrode 44x, 46x also play the function of shell, also are electrodes simultaneously.Owing to have a substrate, the outer surface of these electrodes is can yes or no smooth, and can be insulated 61 coverings in surface.

In the embodiment of Fig. 4 C, shown in the side cross section, edge 44f, the 46f of insulating spacer 53,55 and filter electrodes 44,46 are overlapping.This has guaranteed to be limited in the zone of uniform transverse electric field between the filter electrodes 44,46 at the ion that flows in the flow path (that is, drift tube) 29, and away from the electrode edge 44f, the 46f that have non-homogeneous fringe field " f ".Another benefit is that all ions are forced to pass through between the filter electrodes, and is acted on by this uniform electric field.

Get back to Fig. 3 A, in operation, ion 24,26 inflow filters 40.Some ions are neutralized when they clash into mutually with filter electrodes 44,46.These ions that are neutralized are generally cleaned by carrier gas.For example, by flow path 30 is heated also and can clean, such as filter electrodes (for example, the coiled pipe shown in Fig. 3 D 44 ', 46 ') that can be by electric current being applied to suitable configuration or be applied to resistive spacer electrode and heat.The spacer electrode 53,55 of Fig. 4 A can use resistive material to form, and therefore can be used as heating electrode 53r, 55r.

Ion 24 is transferred to the output 10C shown in Fig. 3 A.Be provided with and discharge the ion 24 discharge molecules 28 of port 42 being transmitted.Ion 24 separated making detecting function simple, and make chemical analysis more accurate.Even but used this precautionary measures, still there are some solvent molecules to depend on interested ion 24.Accordingly, in a preferred embodiment, provide and before for example 24 and 26 ion filters, they are being carried out the device of desolvation (desolvate).Desolvation can obtain by heating.For example, any electrode 44,46,53r and 55r can have the heater signal that is applied thereto by controller 10D.In another embodiment, the air-flow that enters can be by heating element 89 heating, shown in Fig. 3 B.

What will be understood by those skilled in the art that is, the electron spray ion is carried out desolvation or " drying " is part crucial in the electron spray process.At first when ion when the electron spray needle point ejects, the form that it is in drop has a large amount of solvents to be wrapped in drop.When drop arrived reverse electrode by air, the solvent final evaporation was fallen, and stays the desolvated ion that then can analyze.Non-desolvation completely may make the analysis distortion before analyzing.Therefore,, may need long ion stroke, to allow the abundant desolvation of ion there not being other auxiliary situation.Therefore, it should be understood that desolvation is useful in the embodiment of this invention.

In another embodiment of the invention, use symmetrical RF electric field to strengthen desolvation to the ion that is produced in the electron spray before analyzing.Shown in Fig. 5 A, 5B, the ion that the symmetrical rf electric field that is applied perpendicular to carrier gas stream causes being produced in the electron spray process vibrates symmetrically, and be heated, owing to these ions move along drift tube, thereby ion is not having from the clean situation that is offset of this signal by desolvation.

More particularly, raise their effective temperature of the interaction between ion and the neutral molecule has strengthened their desolvation.In their durations of oscillation, ion will influence neutral air molecule, and their internal temperature will rise.The ion internal temperature rises and has strengthened the evaporation of solvent, has shortened and has realized by the time of desolvated charged ion.This action makes desolvation to carry out in the drift tube of relative shorter length.Desolvation causes detection data more accurately, and said method can combine with PFAIMS filter of the present invention easily.

By have the space betwixt, be parallel to each other the configuration two electrodes between apply voltage, can produce the desolvation electric field.For example, under the control of controller 10D, any electrode pair 44,46 and 53,55 can be used to this function.The separated electrode 77,79 that desolvates shown in Fig. 3 B preferably can be used to this function.

In another embodiment of the invention, shown in Fig. 3 B and 3B1, micro-machined electron spray head 80 is installed on the substrate 52.Electrode 82,84,86,88 is formed on a relative side of substrate 52, and guiding electron spray ion 24,26 enters the ion zone 23 of the flow path 30 in the drift tube 29.Attraction electrode 22 has the electromotive force that is applied thereto and enters ion zone 23 to attract ion 24,26.Carrier gas stream 90 is set at desired flow velocity catching ion 24,26, and carries them and arrive the filtering function of filters 40 to have illustrated.Gas releaser 91 comprises carrier gas 90, and with nonionic change into branch and through the neutralization ion take away.

Put on electrode 22,82,84,86,88, or even the energy of position of the electrode 77,79 that desolvates is set up, and they each other and and electrode 44,46 between can be independently controlled.For example, this advantageously make attractor electrode 22 by with drive such as the different signal of any other electrode of contiguous filter electrodes 46.Especially make this become convenient by the insulated surface that substrate is provided, and spaced electrodes allow the ion introducing that is independent of filter driving demand is optimized.

This structure also makes leading electrode 82,84,86,88 and attractor electrode 22 can be operated (for example, switching on or off) separately in pulse mode.In this pattern, select a certain amount of ion to be incorporated in the ion zone 23." flight time " that can be used in operation such as these ions run duration of 72 from the mouth of pipe to the detector be the FAIMS pattern (TOF).In this pattern, the flight time is associated with ionic species, therefore need be used for the additional information that kind is distinguished.This has caused the improvement to cylindric FAIMS device.

As understanding at the those of ordinary skill of IMS technical field, this TOF is the simulation to the flight time of being put into practice in the IMS device, but but obtains practice in the FAIMS structure now.Therefore, the present invention can provide IMS and FAIMS detection data in an operated device; The combination of IMS and FAIMS data can produce better result of detection.

In preferred embodiments, shown in Fig. 3 A-3B, 4A-4B, shell 64 is made up of substrate 52,54, and has from importation 10A and extend to output 10C and definite internal flow path 30 by ion filter 10B.More particularly, substrate 52,54 has provided working surface 60,62, and it is partial to form electrode there.These surfaces 60,62 can curved surface or the plane, and preferably Jue Yuan (or insulated) for example used glass or ceramic substrate when forming.This makes it can adopt the present extensive manufacturing technology such as microelectromechanical systems (MEMS), multi-chip module (MCM) or other technologies, and obtains encapsulating very closely the result with the small electrode size.Like this, the filter electrodes 44,46 that the veneer of flow path 30 is arranged by the centre, ion filter preferably is defined on these insulated surfaces, separate the control signal 48,50 of filter electrodes again on the insulated surface of substrate from detector electrodes 70,72, to obtain the lower noise and the performance of improvement.This is unlike in the extension conductive region of exterior circular column of the FAIMS device of prior art traditional in (United States Patent (USP)) 5,420,424, and this patent is by being incorporated in this paper in full in this citation.

What will be further understood that is, for how much with physically consideration, the ion in the cylinder design of prior art will distribute on the cross section of drift tube, and therefore only some ion in region R, can utilize near mass spectroscopy instrument inlet 96.Columniform FAIMS structure (referring to PCT/CA99/00715, quotes in full with for referencial use) as shown in Figure 6 here in the prior art, makes great efforts by making extra ion be sent to mass spectrum inlet 96, to overcome this restriction.But neutral sample molecule also may enter mass spectroscopy instrument inlet 96, because do not separate between neutral molecule that injects solvent molecule 28 and sample ions 24.This causes obvious more complicated spectrum in the mass spectrum, and resolution descends.

For example, in the structure of Fig. 3 B, the present invention has overcome these shortcomings.In practice of the present invention, nearly all ion 24 that enters detector region 69 all is focused mass spectroscopy instrument inlet 96.This causes detection efficient sharply to rise, and the raising of system sensitivity, especially compares with cylindrical FAIMS device, and in cylindrical FAIMS device, ion is along the circumferential distribution of entire flow path, rather than enters the mouth at the mass spectroscopy instrument.

In addition, the new cylinder design of reference the present invention shown in Fig. 7 A, under the attraction of attractor electrode 22 ', electron spray needle point 20 sprays the moving pipeline 30 ' of influent stream by the mouth of pipe 31 ' among the external electrode 44C with sample, sample by the fluxion strap of gas G to filter part 10B '.Attractor electrode forms near interior electrode 46C, separates but but be insulated on bar In1, the In2 electricity.Therefore, attractor electrode can separate with the adjacent electrode of for example 46C and by bias voltage independently.This embodiment has also made up function and structural detail, thereby has reduced number of components, can be combined together by the adhesive function of insulating barrier In1, In2 such as the inner cylinder element.

In another embodiment shown in Fig. 7 B, attractor electrode 22 " form near exterior loop electrode 44C ', and be insulated at this by insulated coil In3.Sample is in attractor electrode 22 " attraction and be filtered device part 10B " flow duct 30 " in gas G when carrying; electron spray needle point 20 is incorporated into coil 46C with sample S from this side " inside, coil 46C " can be the electrode that separates or the extension of interior electrode 46C '.Similarly, electrode 22 " be insulated device In3 and separate from electrode 44C ', so electrode is by drive.

In another embodiment of the invention shown in Figure 8, be installed on the electrospray assembly 80 of substrate 52 " comprise electron spray head 12.Ion is carried to the mouth of pipe 31 by leading electrode " F " (having 3 in the present embodiment), and also is attracted device electrode 22 and is drawn into ion zone 23 such as 82,84 and/or 86,88 leading electrode.

Preferably, on each leading electrode, apply separation DC bias voltage " DC " to produce the potential gradient that the guiding ion enters ion zone 23.Strengthen desolvation by also applying symmetrical RF signal " DS ", leading electrode can be used to other function, as previously mentioned.

Introduce Purge gas G at port P1 and further strengthen desolvation.The ion counter current that is guided in this gas and the chamber 93, and discharge at port P2, P3.This preferably operation when not having barometric gradient to stride across the mouth of pipe 31.

In order to improve spray condition, the interval 20S between needle point 20 and the last leading electrode F1 can be conditioned in practice of the present invention.In one embodiment, the position of shell 12a can be regulated with respect to substrate B, and this has regulated 20S at interval conversely.In another embodiment, 12 height can be regulated with respect to electrode F1.

In another embodiment shown in Fig. 9 A and 9B, isolated leading electrode F (Fig. 9 A) or F1, F2, F3 (Fig. 9 B) embathe in certain air-flow CG.This air-flow can not be limited, and perhaps is comprised among the shell H1.Electron spray head 12 is installed among the fixed mount M1 by adjustable ground, and wherein its transmission angle can be regulated with respect to substrate 52.In addition, its height can be regulated with respect to substrate.

With reference to figure 4A, sample container 92 receives fluid sample S, and then this sample is carried out ionization and filtration as previously mentioned like that.In such embodiments, single spectroscopic assay instrument chip 100 combines the high electric field asymmetric waveform of ion source and the plane ionic mobility filter 40 such as miniflow electron spray module 80 '.Can also comprise interior detector, or ion is output to survey.Have multiple micro-machined microfiuidic elements or their combination can be used as ion source, this comprises electron spray, nanometer electron spray, liquid chromatograph, electrophoretic separation.

In another embodiment, the electron spray head 80 ' of Fig. 4 A can be installed in substrate 52 (preferably by anode welding or brazing).Do not need leading electrode 82 and 84 in this embodiment.

In the embodiment of Fig. 4 D, miniflow electron spray module 80 ' comprises the separating pipe 92a feed that crawls of 92 pairs of lengthenings of sample container, and leads to the mouth of pipe 20 ' and arrive needle point 20 then.Pipeline 92a can be liquid chromatograph or electrophoretic separation etc., before needle point 20 carries out ionization the composition in the sample regulated or to be separated.

For have or do not have the motivation of the such chip of Microflow module 100 is reduce sample preparation and analyze in variation, this can by reduce people influence each other and provide can all are important combination of elements obtain to the device in the single structure.These chips 100 make them self have low manufacturing cost, from but replaceable.For using new chip, each sample analysis reduced the cross pollution of sample room.In addition, by reducing people's interference, reduced the sample preparation time.In tradition was arranged, the position of electron spray needle point or microfiuidic elements must be regulated with respect to any filter or mass spectrum inlet at every turn again.This has increased time and cost.Use integrated micro flow chip of the present invention/PFAIMS device, the fixed relative position of microfiuidic elements and PFAIMS inlet is got off.In case finished analysis, only entire chip is abandoned, be loaded with the new chip that will analyze and be installed on the sample of mass spectroscopy instrument possibly.This allows the throughput of obvious analysis times faster and Geng Gao.

Shown in Figure 10 A, in an illustrative embodiment of the present invention, controller 10D comprises several subsystems, this comprises electron spray control 10D1, be used to filter electrodes 44,46 to apply waveform generator (synthesizer) 10D2 asymmetric drive signal of RF and DC control bias voltage, that cooperate with high pressure RF waveform and DC generator 10D3, and the detection electronics 10D4 that is used to survey the ion on the detector electrodes.Computer 10D5 hand is collected signal and control system.In one embodiment, produce the RF electric field by soft switch Semi-resonance circuit in generator 10D3, this Semi-resonance circuit combines kickback transformer and produces high-voltage pulse apace.This circuit provides near for 100KHz-4MHz voltage to be at least peak to the peak RF voltage that 1400 volts, duty ratio are about 10-70% in frequency.The RF waveform example that is used to drive filter electrodes is shown in Figure 10 B, though it can also change in practice of the present invention.

Chip 100 preferably is inserted into chip receiver assembly 220.Assembly 220 comprises the socket 222 that is used for receiving chip.This socket is electrically connected controller 10D.A preferred embodiment of chip receiver 220 also plays the function that chemical sensor system 10 is coupled to mass spectroscopy instrument MS98, shown in Figure 11 B.Receiver assembly 220 is fixed in the face 224 of mass spectroscopy instrument, thereby the outlet mouth of pipe 99 of system 10 aligns with MS mouth of pipe import 96 by mouth of pipe 99x, guides ion 24 ' to enter MS to survey and to analyze thus.

In conjunction with the detector electrodes 70,72 of Fig. 3 A, can carry out aforesaid detection to ion by filter 40.In another embodiment shown in Fig. 3 B, electrode 70 is used as the inlet 96 that the steering gear electrode deflects into ion 24 ' in mass spectroscopy instrument 98 this moment.Ion is directed or by focusing electrode 72a, 72b it is focused on, by the mouth of pipe in the substrate 54 ' 99, and via mounting adapter 102 by plenum chamber 101.The low flow velocity inflation of supposing inlet chamber 101 has stoped the sample ions of neutralization or solvent molecule to enter mass spectroscopy instrument inlet 96.The ion that is focused on mass spectroscopy instrument inlet then is detected according to the mass spectrum program standard.It it should be understood that plenum chamber 101 is not illustrated among Figure 11 B, although can advantageously be used in this embodiment.

Assembly of the present invention can complied with mass spectroscopy instrument inlet 96 (have or do not have plenum chamber) assembling easily and got on, for example, and shown in Fig. 3 B, 11B and 12A-12B.(among Fig. 3 B or the 12A-12B side dress) steering gear electrode almost allows 100% ion to be deflected mass spectrum.

The cylinder design that is installed in mass spectral inlet 96 among this high efficiency and Figure 12 C-12D in the prior art has formed contrast, wherein, only there is a very little part to be pushed them in whole ions in the drift tube and enters inlet 96 electric field and influence, and cause that only some is detected in the utilizable in the prior art ion.

It should be understood that now in practice of the present invention, can use several ion detectors to carry out chemical analysis.In the embodiment of Fig. 3 A and 4A, detector is fully in the inside of assembly 10.In the embodiment of Fig. 3 B, assembly 10 closely cooperates by adapter 102 and mass spectroscopy instrument 98, just just as detector.In the embodiment of Fig. 3 B, if the electric current on focusing electrode 72a, 72b is monitored, so extra detector information is utilizable for the detection information of handling mass spectroscopy instrument 98.Even without focusing electrode 72a, 72b, FAIMS spectrum of the present invention also can be rebuild by total ionic current in the monitoring mass spectroscopy instrument.

Another embodiment of the invention is shown in Figure 13 A, 13B, and wherein electron spray needle point 20 has been inserted into into ion zone 23, this otherwise from the top by the mouth of pipe 31 (Figure 13 A) the last substrate 52 ', or from side (Figure 13 B).When the ion in flow path 30 moved in air-flow 90, attractor electrode 104,106 attracted them and guides.In Figure 13 A, to assemble in container 54a from the drop of electron spray needle point 20, this also can use tap 54b to provide.

After ion is by ion filter and before they enter output 10C, it is suitable that ion is assembled.This has improved signal to noise ratio at detector, and has improved sensitivity.Ion trap or ion trap be collection of ions by this way, and they are concentrated, and will be sent to output through the ion of concentrating at once then.Neutral material can not be collected in the ion trap, and is removed continuously from the air-flow of ion trap T.

For example in Fig. 3 A, B, C, in many embodiments of the present invention, can use ion trap.In the illustrative embodiment as shown in FIG. 13A, wherein ion trap T forms by the electrode pair of several suitable bias voltages.In an example, for cation, electrode is carried out bias voltage to form the electromotive force minimum value in the zone of electrode pair 76b, the electromotive force on electrode pair 76a and 76c is higher.Ion is allowed to build up in gatherer, after the time quantum of one section expectation, causes collecting the ion of desired number, can open this gatherer by the voltage that is applied to electrode 76a, 76b and 76c is regulated.When opening gatherer, collected ion 24 ' flows into output 10C.

In aforesaid embodiment, ion filter 40 comprises isolated electrode 44,46, and they are driven when ion is promoted by air-flow in drift tube 29 by RF and DC generator 10D3.In the embodiment of Figure 14 A, 14B, show the embodiment that drives by longitudinal electric field of the present invention, a kind of method that transports the ion in the drift tube 29 of novelty.

In the embodiment of Figure 14 A, 14B, use by electrode 110 and 112 longitudinal electric fields that produce, promote ion and arrive output 10C.These embodiment have illustrated the air flow structure that is simplified in design very closely, and air-flow is continuously optionally.

In one embodiment, in fact ion moves on the direction opposite with air-flow 122, and is promoted by electric field intensity 120.The air-flow opposite with the ion motion direction increased the desolvation of sample ions.This has also kept an ion filter 40 that does not have the cleaning of neutral sample molecule.Therefore, this has reduced the level that ion cluster forms, and has caused the more accurate detection of ionic species.In addition, back draught is removed and has been reduced in ionisation region 23 memory effect to previous sample.This embodiment can comprise integrated electron spray needle point 20, its from the top or the side insert into ion zone 23, as shown in the figure.

In the embodiment that is driven by longitudinal electric field of Figure 14 A, 14B, ion 24,26 is not by air-flow 122 but transported with the effect of the longitudinal electric fields of 110,112 groups of generations of cooperating electrode of DC generator 10D3 ' in vertical RF.As the example of the operation of the PFAIMS in the concrete electrode skew scheme, when stepping DC electromotive force drives ion to detector to form vertical potential gradient, electrode pair 110a-h, several among the 112a-h or all have the RF voltage that is applied.This embodiment can not operate when having air-flow, or can comprise exhaust airstream 122 alternatively, and it can discharge neutral substance and solvent molecule at exhaust port 124.

In an example, electrode 110,112a can have the 10VDC that is applied thereto, and electrode 110h, the 112h 100V DC that can apply to some extent.Anion in regional 10A is attracted by electrode pair 110a-112a now, and is attracted by electrode pair 110h, 112h, transmits if be filtered device then, and their momentum carries them and enters regional 10C.

This RF and compensation can be applied to a plurality of electrode 110a-h, 112a-h, and will operate in the top mode of being set forth.

In another embodiment of Figure 14 A, the electron spray needle point can be in the outside of 23 (not shown) of the ionisation region above the mouth of pipe 31, and electrode 112j plays a part to attract electrode in ionisation region 23.Among the embodiment that is driven by longitudinal electric field in Figure 14 B, ion filter comprises spaced apart, the resistive layer 144,146 from electrode 134,136 insulation, for example by dielectric 140,142---a kind of low temperature oxide carries out.Substrate preferably insulate.Resistive layer 144,146 preferably is deposited on the ceramic material on the insulating barrier 140,142.Terminal electrode is connected with resistive layer 150,152,154,156, and makes the voltage drop of passing each resistive layer produce the longitudinal electric field vector.Electrode 150 and 154 carries out bias voltage according to application, and for example they can be set at 1000 volts, and electrode 152 and 156 can be at 0 volt.

When implementing the embodiment of Figure 14 B in cylinder design, electrode 150 and 154 forms a ring electrode, and electrode 152 and 156 forms an electrode, and resistive layer 144,146 forms cylinder.

Of the present inventionly can also carry out flight time ionic mobility spectroscopic assay function.For example, in the embodiment of Figure 14 A, electrode 104,106 carries out pulse to spur ionizable sample from needle point 20, the time started circulation.Electrode 110a-h, 112a-h relatively their neighbour carry out bias voltage, thereby ion is driven by the longitudinal electric field gradient of the sensing that is produced output 10C.Back draught 122 can be used to removes the sample neutral substance.The combination of these electrodes can be used to form aforesaid ion trap T (referring to Figure 13 A).

In the branch air guide stream embodiment of Figure 15 A, electron spray pin 12 is inserted in the ion zone 23 by substrate 52, but it can be installed in the outside of drift tube as shown in Figure 3A like that.Ion airflow generator in this design comprises that in a relative side of flow path 30 a plurality of segmented electrodes 160,162 are to produce longitudinal electric field E.In a preferred embodiment, the electrode 160 of one or more separation ', 162 ' be placed in the downstream of gas access 170 and longitudinal electric field E extended to outside the split flow of gas, guaranteed ion inflow filter 40 when being carried thus by carrier gas stream 172.

In the embodiment of Figure 15 B, mass spectroscopy instrument 98 is directly coupled to the end of drift tube 30.The advantage of this design is that owing to divide conductive gas stream, ion filter 40 avoids the influence of sample neutral substance.This has stoped the reunion of neutral sample molecule and ion, and has caused higher detection accuracy.The ventilation device 103 that is used for neutral substance N ventilation is discharged to neutral substance outside the MS inlet.

As shown in the figure, can place baffle plate 174 and regulate the speed of exhaust flow 176 with respect to drift air-flow 172.Usually, the speed of drift air-flow 172 is greater than exhaust flow 176.But other modes that are used to that exhaust flow velocity is different from and drift about air velocity fall within the scope of the invention.

In the embodiment of Figure 15 A, Figure 15 B, can use a plurality of sample preparation parts, no matter be the port of simply drawing the air atmosphere sample, perhaps electron spray, gas-chromatography, liquid chromatogram etc.No matter what uses, branch air guide stream embodiment as shown in the figure can both prevent to reunite, and allows to discern better ionic species.

Usually, sample ions trends towards being found at monomer or aggregating state.For given ionic species, the relation between monomer and reunion amount of ions depends on the concentration of sample and concrete experiment condition (for example, the intensity of humidity, temperature, flow velocity, RF electric field).Monomer and aggregating state all provide for chemistry identification Useful Information.To being in the condition of promote reuniting and promoting to have only the investigation that identical sample carries out separating in the environment that the monomer ion forms will be useful.The plane binary channels PFAIMS of embodiment can be used to obtain this effect as shown in figure 16.

In the binary channels embodiment of Figure 16, first passage as shown in the figure " I " is used for being received in the ion 24 and the molecule 28 of the drift air-flow 190 in ion zone 194.Also include PFAIMS filter electrodes 44,46 and detector electrodes 70,72.

In order to investigate the sample ions that is in free state, ion is extracted out from air-flow (by the effect of electric field between electrode 198 and 200), and they upwards flow into upward chamber " II ".Normally the neutral molecule 28 of solvent continues to flow by passage " I ", flows out at drift gas discharger 192.Electrical potential difference between electron spray needle point 20 and the attraction electrode 191 is accumulated to ion zone 194 by the mouth of pipe in the substrate 56 196 with ion.Second air-flow 202 stops sample neutral substance inlet chamber " II ", and carry ion 24 and arrive PFAIMS filter 40 ( electrodes 44,46 among the II of chamber), then the ion that is transmitted is surveyed, for example this is by the detector electrodes 70,72 among Fig. 3 A, perhaps by the mass spectroscopy instrument among Fig. 3 B.Second air-flow 202 is used as air-flow 204 and discharges.When surveying and attractor electrode 198,200 is not energized, can in chamber " I ", observe the sample ions that be in aggregating state so by partial detection device electrode 72 and 70.By electrode 198 and 200 is carried out alternate energisation and outage, can obtain obvious more information chemical example is discerned better.

Figure 17 shows the homologue of the ketone sample that obtains in one embodiment of the invention, and scope is from the butanone to the decanone.From figure, be apparent that for same chemical substance comparing reunion ion (top area) with monomer ion (bottom section) needs very different compensating signal.So by observing the difference of monomer and position, reunion peak, can be significantly improved to the identification of chemical compound.For example, for butanone, the position at the peak of free state appears at approaching-9 volts position, and the reunion peak appears near 0.For example, for decanone, the monomer peak is near 0, and the reunion peak is near 4 volts.

The motivation of embodiment shown in Figure 180 is identical with embodiment 16.In this system, the switching between free state and aggregating state operating condition can obtain by control curtain air-flow 190a and 192a.By applying an act air-flow, sample neutral substance 28 is prevented from admission passage " II ", and the ion in the free state can be investigated.For example, curtain air- flow 190a and 192a can flow in the same direction, and discharge at the mouth of pipe 196.When gas flows into, passage " II " remain with Figure 16 in system's identical construction.Comprise that leading electrode 206 and 208 guides ion admission passage " II ".Also use and attract electrode 200 to attract ion admission passage " II ".When closing closing gas, because this moment by using pump 204a with sample neutral substance and sample ions suction passage " II ", so can observe the ion of aggregating state.Also can use air-flow 202 and 204.Output can be connected to the mass spectroscopy instrument.

In an application of the invention, the asymmetric ionic mobility filtering technique of high electric field uses the high-frequency and high-voltage waveform.Apply electric field perpendicular to ion transport, planar configuration is preferred.This preferred planar configuration allows drift tube by small size, manufacturing cheaply, and is preferably micro-machined.Equally, can be to the electronic equipment microminiaturization, estimated gross power can be low to moderate 4 watts (heating) or lower, promptly is applicable to the level of field apparatus.

We have illustrated the novel apparatus that comprises electron spray and filter element.We also disclose micro-machined PFAIMS electrospray interface chip.Compare with all existing biomolecule filter methods that are used for electrospray ionization mass spectrum, this PFAIMS electrospray interface chip provides unique benefit.Simultaneously, this method can be used in combination such as isolation technics in the liquid of Capillary Electrophoresis with many.

In the practice of one embodiment of the invention, tri-n-butylamine is entered PFAIMS filter and detector by electron spray.Figure 19 shows that the spectrum and the independent spectrum of solvent elutriant of amine in the resulting solvent.In fact do not have for the independent response of elutriant, and amine is had tangible response.This has proved practical value of the present invention and function.

The present invention closely and is cheaply providing improved chemical analysis in the encapsulation.With closely, in (fieldable) encapsulation that can on-the-spotly use based on the new method and the device of the identification chemical classes of ionic mobility, the present invention has overcome the TOF-IMS of prior art and the restriction of FAIMS device cost, size or performance.Consequently, novel plane, the asymmetric ionic mobility spectroscopic assay of high electric field device spare can closely be coupled with the electron spray needle point and obtain the new chemical sensor of a class,, or are independently (standalone) or be coupled to the device of MS that is.Can provide a kind of can on-the-spot PFAIMS chemical sensor that use, integrated, it can produce accurately fast, (or being close in real time), scene, quadrature (orthogonal) data come the chemical compound of wide scope is discerned in real time.These transducers also have the ability that the kind of wide region is surveyed simultaneously, and the ability that the positive and negative ion in the sample is surveyed simultaneously.Still very it is shocking, these can by expense effectively, closely, the encapsulation that can make in batches obtains, this encapsulation can be operated in the lower powered scene of needs, but it can produce the orthogonal data that can discern the multiple kind that is detected fully.

Another advantage that PFAIMS designs the cylinder design of relative prior art is that PFAIMS can filter all types of ions with different electric field strength dependence α and work (the more details of relevant α sees also the background technology part).This fact makes the complexity of measuring in the complex sample mixture of the unknown obviously reduce.

Present technique field those of ordinary skill it should be understood that in the cylinder design of the prior art shown in Figure 12 C-D, radial Electric Field Distribution is heterogeneous.Simultaneously, in practice of the present invention, the PFAIMS shown in Fig. 3 A, 3B for example, the Electric Field Distribution in the PFAIMS design between ion filter electrode (ignoring fringe field) is that electric field is uniform uniformly.

Have been found that when arriving the condition of ion focusing, the time of in plane P FAIMS design, ion being separated significantly less than (about 10 times) prior art in cylindrical FAIMS design.

But embodiment of the present invention can be implemented in the method and apparatus that uses cylindrical, plane and other structures, and still are within the spirit and scope of the present invention.Example application of the present invention is included in the application in biological and chemical transducer etc.A plurality of modifications of the top particular that proposes also are within the spirit and scope of the present invention.Example disclosed herein illustrates by the method that illustrates, rather than limits.The scope of these and other embodiments only has following claim to limit.

Although the present invention has carried out concrete diagram and explanation with reference to its preferred embodiment, but what will be understood by those skilled in the art that is, under the situation that does not deviate from the scope of the present invention that claims contain, can carry out many changes to form and details.

Claims (99)

1. the asymmetric ionic mobility spectroscopic assay in field instrument apparatus comprises:

Sample preparation and introduce part, comprise be used for from fluid sample transmit ion head and

The ion filter part, output element and electronic component,

Described filtration fraction comprises the insulating surface of determining flow path, also is included in the opposed facing ion filter electrode in described flow path top, and described flow path is used for the ion flow between the described electrode, and described ion is from described fluid sample,

Described electronic component is configured to described electrode is applied control signal, described electronic component applies the high and low current field condition that the asymmetrical period signal produces checker on described electrode, with condition ion flow described in the described flow path is filtered according to described checker, described filter electric field compensated transmit desired ionic species outside the described filter, the described desired kind that is transmitted arrives described output element along described flow path.

2. device as claimed in claim 1, wherein, described insulating surface forms the plane dielectric substrate of described filter, and wherein, described dielectric substrate is controlled the slit between filter electrodes.

3. device as claimed in claim 1 also comprises the plate filter with insulation partition, the coincident of wherein said insulation partition and filter electrodes.

4. device as claimed in claim 1, wherein, described head comprises the electron spray head.

5. device as claimed in claim 4 also comprises described ion is carried out the desolvated electrode that desolvates.

6. device as claimed in claim 4, wherein, described electronic component applies symmetrical RF signal to the described electrode that desolvates, and wherein, described RF signal provides energy with the rising ion temperature and strengthen described desolvation to ion.

7. device as claimed in claim 1 also comprises the substrate with insulated substrate surface, and described substrate forms shell.

8. device as claimed in claim 7, wherein, described hull shape becomes the microelectronic chip encapsulation.

9. device as claimed in claim 1 also comprises output, and it has a plurality of electrodes that are used for surveying simultaneously the different kinds of ions kind.

10. device as claimed in claim 9, wherein, described output is surveyed the ion with positive and negative electric charge simultaneously.

11. device as claimed in claim 1 also comprises the electron spray head and attracts electrode that described attraction electrode is separated from ion filter by described substrate, to allow attracting electrode to apply the electromotive force different with respect to ion filter.

12. device as claimed in claim 11 also comprises the cylindrical spectroscopic assay instrument encapsulation in conjunction with the FAIMS on described surface.

13. device as claimed in claim 11, described surface also comprise the FAIMS spectroscopic assay instrument of determining plane surface.

14. device as claimed in claim 11 also comprises the leading electrode of the ion that is used for guiding described flow path.

15. device as claimed in claim 1, comprise the device that is used to produce the FAIMS detection data, also comprise the flight time measurement device that produces the TOF detection data, described TOF device and described FAIMS combination of devices, described head is used for discerning ionic species by described TOF and FAIMS detection data are made up in described filter.

16. device as claimed in claim 15, comprise that also the ion that is used for the transmission of described filter surveys, also comprise attraction and the leading electrode independently controlled, use at least one described electrode pair ion to measure to the run duration of described detector from described head.

17. device as claimed in claim 16, wherein, electrospray assembly can be affixed to a substrate, and leading electrode is used to guide ion to enter ionisation region.

18. device as claimed in claim 17 comprises that also the back draught source strengthens desolvation in described flow path.

19. device as claimed in claim 1 wherein, is controlled acquisition by described electronic component to described variable backoff feature and high electric field asymmetric waveform radiofrequency signal to the control that in the described ion which is filtered.

20. device as claimed in claim 1, wherein, the control that in the described ion which is filtered is controlled acquisition by described electronic component to the described electronic section and the high electric field asymmetric waveform radiofrequency signal of described variable backoff feature, wherein, described compensation is controlled by the feature that changes high electric field asymmetric waveform radiofrequency signal.

21. device as claimed in claim 20, wherein, transform characteristics comprises the control to the cycle of character, duty ratio, amplitude, frequency or high electric field asymmetric waveform radiofrequency signal.

22. device as claimed in claim 1 also comprises spectroscopic assay instrument chip and erecting device, wherein, described chip can be installed to the mass spectroscopy instrument via erecting device.

23. device as claimed in claim 22 also comprises chip carrier, described chip is installed in the described carrier, and this carrier can be installed in the inlet of detector.

24. device as claimed in claim 1 also comprises detector and shell, described filter and detector are comprised in the described shell.

25. device as claimed in claim 1, wherein, embodiments of the invention make and are carried out molecular filtration at molecule after spraying such as the source of electron spray needle point or electrocapillary phoresis outlet injection, before filtering, carry out ionization by the FAIMS filter, and by inner detector, mass spectroscopy instrument or other detectors filter it after surveying.

26. device as claimed in claim 1 is also determined a little processing electron spray needle point in plane electric fields asymmetric waveform ionic mobility spectroscopic assay instrument filter.

27. device as claimed in claim 26, also be included in the device that is used for ion filter after the sample ionsization, wherein, the buffer salt that produces in the electron spray process and lyate ion are separated from the interested biomolecule of institute, with provide described biomolecule through the detection limit of the mass spectrum simplified and raising with to described Recognition of Biomolecular.

28. device as claimed in claim 1 has the size of miniaturization, and is formed on the chip.

29. device as claimed in claim 28, wherein, described chip forms with MEMS technology.

30. device as claimed in claim 1 also is included in the fixing mass spectroscopy instrument installation component of described output.

31. an ionic mobility spectroscopic assay device comprises:

The asymmetric ionic mobility spectroscopic assay of high electric field instrument, it has the ion filter part, the liquid sample preparation part, it comprises the electron spray head, and output, described reception, adjusting and ionization fluid sample, wherein, described filter part is filtered the ion from described liquid sample preparation part, and interested ionic species is delivered to described output, to allow kind to survey and analyze, described part is coupled by public flow path.

32. device as claimed in claim 31, wherein, liquid sample preparation partly comprises electron spray sample ions source, and it has the chamber that is used to receive fluid sample, and the gatherer that is used to catch ion that forms after filtering.

33. device as claimed in claim 31, wherein, described spectroscopic assay instrument comprises separates insulated planar substrate, and forms filter electrodes thereon, described substrate between they self around described flow path.

34. device as claimed in claim 33, wherein, described substrate preferably insulate, or has the surface that is used for the insulating mounting of opposed facing electrode on flow path.

35. device as claimed in claim 34, wherein, described substrate is separated by separator, and this separator can insulate, and wherein, the thickness of separator has been determined between the substrate and distance between electrodes.

36. device as claimed in claim 31 also comprises separator as electrode, is used for described separator electrode is applied the device that voltage is limited in the electronics of filter at the flow path center.

37. device as claimed in claim 36, wherein, ion by filter drops on the detector electrodes under the control of controller, this depends on the polarity of detector electrodes and the control signal on the detector electrodes, wherein, if each detector electrodes is maintained at different polarity, so multiple ionic species can be detected simultaneously, wherein, the ion that is detected is associated definite ionic species of being surveyed with control signal that is applied and compensating signal.

38. device as claimed in claim 31, also comprise and the insulating spacer of the imbricate of filter electrodes guarantees that the ion that flows is limited in the even transverse electric field zone between the filter electrodes in drift tube, and away from the electrode edge that has non-homogeneous fringe field, all ions are forced to pass through between the filter electrodes, and are subjected to the effect of this uniform electric field.

39. device as claimed in claim 38, wherein, some ions are neutralized when the collision of they and filter electrodes, described ion through neutralization is removed by carrier gas, perhaps remove by heating, for example this can apply electric current and comes flow path is heated by the filter electrodes to suitable configuration.

40. device as claimed in claim 39, wherein, described flow path is by filter electrodes or the resistive spacer heated by electrodes of crawling.

41. device as claimed in claim 31, also comprise a kind of device, it carries out desolvation to them before ion is filtered, for example by heater electrode is applied heater signal, or by using heating element that input gas is heated, or strengthen desolvation to the ion that produces in the electron spray by the RF-electric field that applies common symmetry, preferably such as applying perpendicular to carrier gas stream so that the symmetrical rf electric field of the ion symmetric oscillations that produces in the electron spray process, thereby and when they move downward ion and do not having under the situation of clean skew desolvation along drift tube, it is heated.

42. device as claimed in claim 31, also comprise the plane working surface that is used to form electrode, this surface can be insulating properties or insulated, just as use glass or ceramic substrate when in the situation that encapsulates and use little electrode size very closely, being formed, ion filter is formed on these insulated surfaces by veneer (facing) filter electrodes, has flow path therebetween, this insulated surface separates the control signal of filter electrodes again from detector electrodes, to reduce noise and to improve performance.

43. device as claimed in claim 31, wherein, structural electrode is separated by insulating spacer, and flow path is formed on wherein.

44. device as claimed in claim 31, wherein, structural electrode is separated by insulating spacer, and flow path is formed on wherein, and described structural electrode plays the function of shell.

45. device as claimed in claim 44, wherein, described output has top electrode, this top electrode is maintained at predetermined voltage, and it is identical with the polarity of the interested ion that passes through filter, and hearth electrode is maintained at another level, and this may be a ground connection, and top electrode is deflected downwards to hearth electrode to test with ion.

46. device as claimed in claim 45, wherein, the signal that top electrode or hearth electrode depend on ionic charge, polarity and put on electrode can be surveyed ion, thereby by using top electrode as a detector, hearth electrode is as second detector, and use two different detector circuits, and therefore may with the time the different output of two-way, can survey simultaneously the different kinds of ions kind, so this detector can be surveyed the different kinds of ions that is almost transmitted by FAIMS simultaneously.

47. device as claimed in claim 31, wherein, electronic controller provides the control electronic signal for system, control circuit can be onboard, or not onboard, at least have lead-in wire and the connection pads that is connected to control circuit at this FAIMS device, and come the signal of self-controller to be applied to filter electrodes via these electrical leads.

48. device as claimed in claim 31 also is included on the insulating properties substrate and forms electrode, places ion filter electrode and detector electrodes more approaching to strengthen ion collection efficient and to reduce the quality that need adjust, heat and control.

49. device as claimed in claim 31, also comprise the structure that reduces power demand, comprise the small electrode that uses electric capacity to reduce, this has reduced power consumption again, and wherein, since the insulating surface of substrate is the ideal platform that is used to form such electrode, the closely spaced electrode of opening can allow production process in enormous quantities.

50. device as claimed in claim 31, also comprise the little processing electron spray head that is installed on the substrate, with be formed on the electrode that guides the electron spray ion to enter the ion zone in the drift tube flow path on the substrate, attract ion to enter the ion zone by attraction electrode with the electromotive force that is applied thereto, carrier gas stream be set at a desired flow velocity catch ion and carry they to filter filtering, and gas exhausting device comprises current-carrying gas and has taken away do not have Ionized composition and through the ion of neutralization.

51. device as claimed in claim 50, wherein, the electromotive force that puts on electrode can be set up and control each other independently, makes attractor electrode can use the signal different with other any electrodes to drive, and makes the optimization of ion input not rely on filter driving demand.

52. device as claimed in claim 51, wherein, leading electrode and attractor electrode can be operated in pulse mode, the ion of selected amount can be introduced into the ion zone, and the traveling time such as these ions from the mouth of pipe to the detector can use in the TOF-FAIMS pattern of operation, wherein, the flight time is associated with ionic species, thereby provides extra information for the identification of kind.

53. device as claimed in claim 1 wherein, by attractor electrode is separated from filter electrodes, and can carry out total control to attractor electrode to the main improvement of cylindrical FAIMS device.

54. device as claimed in claim 1, wherein, electrospray assembly is affixed to substrate, and comprises the electron spray head, and wherein, ion drives the mouth of pipe by leading electrode, and is attracted device electrode and leading electrode and is drawn into ion zone in the drift tube.

55. device as claimed in claim 54, wherein, preferably applying independently to each leading electrode, the DC bias voltage produces potential gradient, this potential gradient guiding ion is to the ion zone, and strengthen desolvation by applying symmetrical RF signal, leading electrode can be used to further function, and gas be introduced into further enhancing with guided, flow from discharging the opposite desolvation of ion that port discharges, discharge ion and preferably under the situation that does not have barometric gradient on the mouth of pipe, operate.

56. device as claimed in claim 55, in order to improve spray condition, interval between electron spray needle point and last leading electrode can be adjusted, for example this can reach by the position of adjusting shell with respect to substrate/substrate, this has regulated this separation again, perhaps, the electron spray head can be conditioned with respect to the height of electrode.

57. device as claimed in claim 1, wherein, separated leading electrode is embathed in the curtain air-flow, this act air-flow or be not limited to or be included in the local shell, electron spray head adjustable ground is installed in the erecting device, wherein its transmission angle can be conditioned with respect to substrate surface, and its height can be conditioned with respect to substrate.

58. device as claimed in claim 1, also comprise microchip with the sample container that can receive fluid sample, this fluid sample then is ionized and filters, and chip is integrated such as the high electric field asymmetric waveform of ionization source and the plane ionic mobility filter of Microflow module.

59. device as claimed in claim 58, wherein, the Microflow module element or their combination of multiple micro production can be used as ion source, and this comprises, and electron spray, nanometer electron spray, liquid chromatography separate, electrophoretic separation.

60. device as claimed in claim 58, wherein, the electron spray head is included as the split tunnel feed, leads to the sample container of the needle point of spraying, and this passage can be liquid chromatography or electrophoretic separation device etc., be used for before needle point is in ionization regulating or sample separation in composition.

61. device as claimed in claim 57 also comprises the chip receiver assembly, and this chip is inserted into the socket that is used for receiving chip of receiver, this socket is electrically connected controller.

62. device as claimed in claim 57, wherein, described chip receiver comprises the coupler that is used to be coupled to the spectroscopic assay instrument, thereby the output mouth of pipe of output aligns with mass spectroscopy instrument mouth of pipe inlet, ion is introduced into mass spectroscopy instrument inlet thus, to survey and to analyze.

63. device as claimed in claim 62, wherein, detector electrodes is used as the deviator electrode now ion is displaced to mass spectroscopy instrument inlet, and this ion is guided or focused on by focusing electrode, and passes through plenum chamber by the mouth of pipe in the substrate with via mounting adapter.

64. device as claimed in claim 62, also provide low flow velocity inflation to enter and prevented from the chamber to enter mass spectroscopy instrument inlet through the sample ions or the solvent molecule of neutralization, wherein, then survey being focused the ion that enters mass spectroscopy instrument inlet according to the mass spectroscopy instrument process of standard.

65. as the described device of claim 64, wherein, the ion that enters detector region is focused and enters mass spectroscopy instrument inlet, this causes the rapid rising of detection efficient and system sensitivity to improve.

66. device as claimed in claim 1, the controller that also comprises several subsystems, it comprises the electron spray control device, waveform generator or synthesizer, be used for high pressure RF waveform and the cooperation of DC generator filter electrodes being applied asymmetric drive signal of RF and control bias voltage signal, and detecting electronic component is used for the ion on the detector electrodes is surveyed, wherein, computer can be collected data and this system of control.

67. as the described device of claim 66, wherein, chemical analysis is undertaken by using assembly, this assembly via adapter with closely cooperate as the mass spectroscopy instrument of detector, and the electric current on the focusing electrode is monitored, obtain to be used to handle the extra detector information of the detection information of mass spectroscopy instrument then, and FAIMS spectroscopic assay instrument of the present invention can be rebuild by total ionic current in the monitoring mass spectroscopy instrument.

68. device as claimed in claim 1, wherein, the electron spray needle point from the top by the mouth of pipe of last substrate or be inserted into the ion zone from the side, when the ion of attractor electrode in flow path moves in flowing to the air-flow of filter electrodes they are attracted and guide, drop from the electron spray needle point is collected in the container, and this container also can be provided with tap.

69. device as claimed in claim 1 also comprises ion trap, comes after ion is by ion filter, enters concentrated ion before the output, to improve the signal to noise ratio of institute's detectable signal.

70. as the described device of claim 69, wherein, neutral substance is not collected in the ion trap, and is removed continuously from ion trap by air-flow.

71. device as claimed in claim 1, also comprise the embodiment that longitudinal electric field of the present invention drives, be used for the ion of drift tube is transmitted, and the longitudinal electric field of using electrode to provide promotes ion and arrives output, can use back draught to remove or reduces in the ion zone memory effect to previous sample.

72. as the described device of claim 71, ion is not that the effect of the longitudinal electric field that produced by air-flow but by the cooperating electrode group with vertical RF and DC generator transmits.

73. as the described device of claim 72, wherein, the electron spray needle point can be on the mouth of pipe, the outside in ion zone, here electrode plays the effect that attracts electrode, in the embodiment that longitudinal electric field drives, ion filter comprises separated resistive layer, it is by dielectric and electrode insulation, this is preferably formed as on the Pyrex substrate, and for example, dielectric can be a low temperature oxide material, resistive layer is preferably such as the ceramic material that is deposited on the insulating barrier, terminal electrode is connected with each resistive layer respectively to apply voltage drop on each resistive layer, to produce the longitudinal electric field vector, is driven between high potential and low potential.

74. as the described device of claim 73, wherein, in cylinder design, electrode forms ring electrode, resistive layer forms cylinder.

75. device as claimed in claim 1, be used to carry out flight time ionic mobility spectroscopic assay, wherein, electrode is applied in pulse voltage to draw sample from needle point, in cycle time started, relative their adjacent electrodes of electrode are carried out bias voltage, thereby the longitudinal electric field gradient that is produced drives ion to output, can apply back draught the sample neutral substance is removed, have the possibility that is combined to form ion trap of using these electrodes.

76. device as claimed in claim 1, has branch air guide stream, wherein, the electron spray pin is inserted into and passes substrate, and enter the ion zone, but, it can be installed in the outside of drift tube, ion flow generator in this design comprises the electrode of a plurality of segmentations on the opposite side of flow path, to produce longitudinal electric field E, in a preferred embodiment, one or more separate mesh electrodes are placed in the downstream of gas access longitudinal electric field E is extended to outside the branch air guide stream, guarantee the ion inflow filter thus when being driven by carrier gas stream.

77. as the described device of claim 76, wherein, the mass spectroscopy instrument is directly coupled to the discharge port of drift tube end, wherein, can place baffle plate and regulate drift about the relatively speed of speed of air-flow of exhaust flow.

78. device as claimed in claim 1, wherein, can use several samples to prepare part, no matter be a simple port of drawing the sample in the air atmosphere, or electron spray, gas-chromatography, liquid chromatogram etc., divide the air guide flow resistance to end and reunite, and make and to discern ionic species better.

79. device as claimed in claim 1, wherein, for given ionic species, relation between monomer and the aggregate quantity depends on the concentration of sample and concrete experiment condition, this can comprise the intensity of humidity, temperature, flow velocity, RF electric field, monomer and aggregate state are surveyed to chemical substance identification provides Useful Information, in the plane binary channels FAIMS that uses, can be obtained these effects.

80. as the described device of claim 79, have first passage " I " and second channel " II ", wherein, the sample neutral substance is applied curtain gas, they are prevented from entering passage II, can investigate the ion of free state, wherein, lethargy can flow and discharges at the mouth of pipe in identical direction or in opposite direction, and comprises that leading electrode guides ion admission passage II, attracts electrode also to be used to attract ion admission passage II, thereby when lethargy is closed, because sample neutral substance and sample ions are used pump inspiration passage II now, so the ion of aggregating state can be observed, output can be connected to the mass spectroscopy instrument.

81. the asymmetric ionic mobility spectroscopic assay in a field instrument apparatus comprises: the sample ions source and

The ion filter part, output element and electronic component,

Described filtration fraction comprises the insulating surface of determining flow path, also is included in the opposed facing ion filter electrode in described flow path top, and described flow path is used for the ion flow between the described electrode, and described ion is from described sample source,

Described electronic component is configured to described electrode is applied control signal and generation (generating); Described electronic component applies the asymmetrical period signal at described electrode and produces the height of checker and low current field condition; With the condition according to described checker ion current described in the described flow path is filtered; Described filter electric field is compensated to transmit desired ionic species outside described filter; The described desired kind that is transmitted arrives described output element along described flow path

Also determined a plurality of integrated miniflow heads with filter element in shell, described shell has been determined the position between miniflow head and the filter element.

82., also comprise the described replaceable array in the shell with integrated miniflow head of filter element as the described device of claim 81.

83. as the described device of claim 81, wherein, described filter partly is plane or curved surface.

84. the asymmetric ionic mobility spectroscopic assay in a field instrument apparatus comprises:

Ion source, output equipment, the stream of between described source and output equipment, determining

Moving path,

A plurality of ring electrodes and insulator ring, first group of electrode and ring have formed and

First cylinder of two cylinder cooperations, described flow path is determined at described cylinder

Between the body,

Ion filter is determined at least two described electrode cooperations, described mobile road

The footpath is used for the ion flow between the described electrode, from described source to described output equipment,

Electronic component is configured to described electrode is applied control signal, described resistance

Element applies control signal, with according to described signal to the institute in the described flow path

Stating ion flow filters.

85. as the described device of claim 84, electronic component is configured to apply control signal for described electrode, described electronic component applies the asymmetrical period signal and produces the height of checker and low current field condition on described electrode, with condition ion flow described in the described flow path is filtered according to described checker, described filter electric field compensated transmit desired ionic species outside the described filter, the described desired kind that is transmitted arrives described output element along described flow path.

86. as the described device of claim 85, also determined sample preparation and introduced part that it comprises and be used for fluid sample is carried out Ionized head that described sample is ionized at described ion source.

87. as the described device of claim 86, wherein, described head comprises the electron spray head.

88. as the described device of claim 87, also comprise separator, described separator is separated described electrode and is held it in the fixed relationship.

89. as the described device of claim 85, also comprise vertical driving electric field electrode group, described driving electric field electrode is driven the vertical driving gradient that produces along described flow path, arrives described output equipment with the ion that drives in the described filter.

90. as the described device of claim 89, wherein, described output equipment also comprises at least one detector electrodes, so that the ion that is transmitted by described filter is surveyed.

91. a method that is used for sample separation comprises the steps: to provide via head to send from the sample preparation of the ion of fluid sample and introduce part,

Via the ion filter part described ion is filtered,

Provide the filter part of insulating surface, ion with definite flow path

Filter electrodes is faced above described flow path mutually, and described flow path is used

In the described ion flow between described electrode, described ion is from described liquid-like

Product,

Provide the electronic component that is configured to described electrode is applied control signal, institute

Stating electronic component applies the asymmetrical period signal and produces alternately on described electrode

Height and low current field condition, with according to the condition of described checker to described stream

Ion flow filters described in the moving path, and described filter electric field is compensated

Transmit desired ionic species outside described filter, the described institute that is transmitted

The kind of expectation arrives described output element along described flow path.

92. as the method for claim 91, also comprise step: described insulating surface is formed the plane dielectric substrate, and the described substrate of use is controlled the slit between the described filter electrodes in cooperation.

93. as the method for claim 92, also comprise step: provide plate filter with insulation partition.

94. as the method for claim 91, wherein, described head comprises the electron spray head.

95., also comprise step: the desolvation electrode is provided, and uses the described ion of described desolvation electrode pair to carry out desolvation as the method for claim 91.

96., also comprise step: described desolvation electrode is applied symmetrical RF signal to strengthen described desolvation as the method for claim 95.

97. a method that is used for an asymmetric ionic mobility spectroscopic assay instrument comprises the steps:

Sampling ion source, ion filter part, output element,

Be provided at the insulating surface of determining flow path in the described filter part, its

Have opposed facing ion filter electrode above described flow path, described

Flow path is used for the described ion flow between described electrode, described ion from

Described sample source,

The electronics unit that is configured to described electrode is applied control signal and generation is provided

Part, described electronic component apply the asymmetrical period signal and produce on described electrode

The height of checker and low current field condition are with the condition according to described checker

Ion flow described in the described flow path is filtered, to described filter electric field

Compensate and transmit desired ionic species outside described filter, described quilt

The desired kind of transmission arrives described output element along described flow path,

Determine a plurality of integrated miniflow heads with filter element in shell, described shell is solid

Decide the relative position of miniflow head and filter element.

98. method that is used for an asymmetric ionic mobility spectroscopic assay device, this device has sample preparation and introduces part, the ion filter part, output and control section, the method comprising the steps of: insulating surface is provided, formation is included in the described filter part of opposed facing ion filter electrode on the described insulating surface, after sample ionsization, carry out ion filter, in by the height that compensated-low asymmetric RF electric field that changes, separate interested biomolecule, based on described biomolecule at height, the difference of the low compensation RF electric field intermediate ion mobility that changes is discerned them.

99. a method that is used for an asymmetric ionic mobility spectroscopic assay instrument comprises the steps:

Sampling preparation and introducing part, it comprises and is used to send from liquid-like

The head of the ion of product,

Ion filter part and output element are provided,

Provide the filter part of insulating surface, ion with definite flow path

Filter electrodes is faced above described flow path mutually, and described flow path is used

In the described ion flow between described electrode, described ion is from described liquid-like

Product,

Provide the electronic component that is configured to described electrode is applied control signal, institute

Stating electronic component applies the asymmetrical period signal and produces alternately on described electrode

The height of conversion and low current field condition, with according to the condition of described checker to institute

State that ion flow filters described in the flow path, described filter electric field is carried out

Compensation is transmitted desired ionic species outside described filter, described being transmitted

Desired kind along described flow path arrive described output element and

Afford redress control input, the feature that is used to control described electric field provides institute

State compensation.

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