CN103499628A - Ion sensor for liquid and manufacturing method of ion sensor - Google Patents
Ion sensor for liquid and manufacturing method of ion sensor Download PDFInfo
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- CN103499628A CN103499628A CN201310424762.XA CN201310424762A CN103499628A CN 103499628 A CN103499628 A CN 103499628A CN 201310424762 A CN201310424762 A CN 201310424762A CN 103499628 A CN103499628 A CN 103499628A
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Abstract
The invention provides a method for detecting the concentration of charged species in a sample. The sample is provided with various types of charged species and at least one insoluble component. The method comprises the steps of arranging the sample on the surface of a partially penetrable layer (30); enabling the components of the sample to enter a channel (12) through the partially penetrable layer (30); separating the components into parts, so that each base body of at least one part comprises a single type of the various types of charged species; determining the charge concentration in at least one part.
Description
Technical field
The present invention relates to the sensor of charged species in biology, chemistry, industry or environmental sample.Especially, the present invention relates to for measuring sample as the charged species concentration, particularly ion concentration of blood method and the sensor as lithium concentration.The present invention also relates to the method for the manufacture of this sensor.
Background technology
Inorganic ions is the primary demand of life, and finds that it is present in potable water, blood and organic each cell and in environment in a large number.For example, many ions of cell interior and outside are absolutely necessary concerning any living organism as the concentration of sodium, potassium, magnesium and calcium.Therefore, the blood of animals and humans and the ion concentration in haemocyte are also very important to a large amount of body functions.
Usually, lithium is the trace element existed in blood plasma, but it can be treated to bipolarity phrenoblabia disease as medicine.According to estimates, the whole world surpasses 1,000,000 people absorb lithium in daily medication.Using the shortcoming of lithium is extremely low therapeutic index, i.e. ratio between toxic concentration and treatment concentration.Most patients is fine to the blood plasma reaction of 0.4～1.2mmol/L lithium concentration, and the lithium concentration generation toxic action more than 1.6mmol/L.The horizontal blood of long high lithium even can cause neural permanent damage, and even dead.Therefore, in treatment, the monitoring lithium concentration is necessary, within every two months, is made regular check on that lithium quantity is remained on to aspiration level.
The a large amount of manual handle for fear of the operator, used ion-selective electrode (ISEs) automatically to measure blood parameters usually.These ion-selective electrode are also can provide large dynamic range fast, and still, their response is logarithmic form and is also a problem to the needed high selectivity of lithium.In addition, in the situation that lithium is poisoning, need a kind of fast method of blood analysis.At present, the venous blood sample must extract and be transported to centralab from patient by the personnel of special training, needs to remove haemocyte before being measured.This method will spend 45 minutes.In order to reduce the sample preparation time and to measure on the spot, use the midget plant of the field effect transistor of ion-sensitive to can be used to measure potassium concn and na concn in whole blood, as hold analyzer.Yet this analyzer also is not used in lithium measurement, because compare with the lithium ion than small concentration, there are other charged species, particularly sodion of high base concentration.
In whole blood in the direct mensuration of lithium and blood plasma the mensuration of inorganic cation described and be presented at the Electrophoresis2004 such as E.Vrouwe, 25,1660-1667 and Electrophoresis2005, in 26,3032-3042.Use the microchip capillary electrophoresis (CE) of determining sample load and apply the column coupling principle, measuring the alkaline metal in whole blood.Refer to that the blood that thorn (finger stick) is collected is sent on chip, without leaching or remove component.Without sample pretreatment, just can measure from the lithium concentration in lithium treatment patient's blood plasma.Use has the microchip that conductance detects, and in the sodium matrix of 140mmol/L, has obtained the lithium detection limit of 0.1mmol/L.
In these disclosures, the component of blood sample is in the inside microchannels electrophoretic separation.Double-T shaped injection geometry is used for ion component that select to be concerned about by they guiding detecting electrodes.
In these systems, sample load is had to clear restriction to guarantee that plasma component correctly is separated in the double T geometry.In addition, the double T geometry applications complexity of getting up is not well suited for easily using these application.
Summary of the invention
The invention provides a kind of measuring method for sample charged species concentration, described sample has polytype charged species and at least one indissolvable component.The method comprises: sampling is on the surface of partly permeable layer; Make the component of sample through this partly permeable layer admission passage; And component is separated into to part, each that makes at least one part comprises the single kind in described polytype charged species basically; And determine the concentration of electric charges in described at least one part.
Therefore, the invention provides a kind of method, for by sample particularly biological sample become part as separating plasma, every part comprises a kind of or one group of charged species basically, and determines subsequently the concentration of charged species in this part.
The present invention also provides the measurement mechanism of charged species concentration in a kind of sample, described sample comprises polytype charged species and at least one indissolvable component, this device comprises at least one passage with at least one opening, cover the partly permeable layer of described at least one opening, along at least two iontophoretic electrodes arranging at least one passage of the every side of opening, and for measuring at least one sensor of at least one charged species at least one passage.
The method and device are specially adapted to measure the ion concentration of biological sample as blood plasma.The ion of measuring includes, but are not limited to sodium, potassium, magnesium, calcium etc.In an application of the present invention, sample also can comprise lithium.In this case, preferred ion to be measured is lithium, but can be also other ions that exist in sample.The present invention is equally applicable to other charged species, and for example lipid, DNA or other polyelectrolytes or electric charge transmit polymkeric substance.
With respect to the polytype charged species of the second, the concentration of the polytype charged species of the first can be determined.Therefore the first charged species can be lithium ion, and the second charged species can be sodion, can determine the ratio between lithium and sodion in sample.
At least one passage can have the single opening covered by partly permeable layer.Use the single opening applied for sample, can effectively avoid the electron-osmosis pressure of channel interior or fluid pressure and any hydrodynamic force to flow.Like this, be diffused as main or unique transfer mechanism.
In one embodiment, at least one passage can have two openings in other local sealed channel system.Use fluid pressure, by the convection current from an opening to another, realized the sample injection.Under this particular case, opening be coated with sample and another opening not.
Partly permeable layer can be film, and sample and at least one channel separation are opened.This film can be permeable to ion or other charged species, and this film can be impervious to larger component simultaneously.Especially, this film is impermeable described indissolvable component.This film can be also the ventilated membrane of liquid impermeable.Partly permeable layer can be arranged on the independent stratum of at least one open top of the first overlayer or below.
Membrane support can be used on the first overlayer to place the first supratectal film.Membrane support can adhere to, i.e. bonding the first overlayer or be formed directly in the first overlayer.
Permeable layer can be also to be made into first a partly permeable tectal zone.Permeable layer can comprise that at least one has the zone of hydrophilic surface.In addition, permeable layer or the first overlayer can comprise that at least one has the zone of hydrophobic surface.
Permeable layer also can be comprised of one or more holes in passage.Sample thereby can directly contact with the solution in passage.
Sample also comprises at least one indissolvable component, such as in the situation that biological sample as the blood that exists in common blood, red blood cell, white blood cell, blood platelet etc.Therefore, the present invention is without in the situation of formerly purifying or processing, just measuring easily the ion concentration in whole blood, thereby avoided any laboratory pre-service of sample.Therefore the present invention is particularly suitable for not needing in patient's surgery systems of the doctor of special training or healthcare.
At least one sensor comprises one or more pairs of conductance electrodes, and for determining the charged species in described at least one part, this at least one part comprises the single kind of described polytype charged species basically.For example, the first pair of conductance electrode is arranged in passage with the certain distance at a distance of at least one opening or measures the charged species concentration of the first polarity near it.Second pair of conductance electrode can be arranged in the concentration of the opposite end of passage with the second charged species of measurement and the first polarity relative polarity.
The present invention also provides a kind of manufacture method for the device of measuring sample charged species concentration, described method comprises provides a substrate, formation enters into intrabasement passage, the first overlayer is set in substrate, make the first overlayer cover passage, the first overlayer comprises that at least one leads to the opening of passage thus, and the permeable layer of part is set at least one opening.
Manufacture this device by the method, can be before the first overlayer be arranged on to substrate, afterwards or simultaneously the first overlayer is arranged at least one opening.
Before device is used, at least one passage can be full of electrolyte.In one embodiment, filling channel comprises and finds time and suck electrolyte in passage.Before the second overlayer covers passage, electrolyte is packed at least one passage.
The accompanying drawing explanation
Consult the detailed description of accompanying drawing and preferred implementation and can understand better the present invention, this is only exemplary, is not used for limiting the present invention, wherein:
Fig. 1 a-1d has shown the primary clustering vertical view of apparatus of the present invention, and Fig. 1 e has shown the side view of the assembly of Fig. 1 a-1d that assembles apparatus of the present invention.
Fig. 2 shows the sectional view of Fig. 1 e in greater detail.
Fig. 3 a-3f shown provide sample to be measured to Fig. 2 amplify and the microchannel of detailed view in key step.
Fig. 4 a and 4b have shown respectively vertical view and the side view of apparatus of the present invention embodiment.Fig. 4 c and Fig. 4 d have shown the electrode structure detected for conductivity, and contactless (Fig. 4 c) is attainable with contacting conductivity detection (Fig. 4 c and Fig. 4 d) two kinds.Fig. 4 e has shown for example two kinds of possible substrate measurement signals at two kinds of different measurement temperature.
Fig. 5 a and 5b have shown another embodiment of the present invention, and Fig. 5 c has shown the embodiment of corresponding measuring-signal.
Fig. 6 a has shown another embodiment with the device that is essentially the U-shaped passage.
Fig. 6 b has shown the another embodiment that has two openings in the single channel.
Fig. 7 has shown the another embodiment of the invention with membrane support.
Fig. 8 a and 8b have shown the one embodiment of the present invention with additional electrode.
Fig. 9 a-9d is exemplified with method of the present invention, and wherein, liquid vacuum is inserted in passage.
Figure 10 has shown another embodiment of the invention, and wherein, liquid utilizes the second opening of passage to insert in passage.
In the accompanying drawings, identical reference number has been described same or analogous object.
Embodiment
Fig. 1 a-1d has shown the assembly plan view of apparatus of the present invention.
This device comprises the substrate 10 that wherein is formed with passage 12, as shown in Figure 1a.Substrate 10 can be made by glass or plastic material.Can use any other material that can manufacture passage 12.In the situation that glass is as base material, during passage 12 etches into substrate between the first storage appts (reservoir) 14 and the second storage appts 16, and the sidewall of passage 12 is coated with polymkeric substance.Passage 12 has the size of inferior centimetre, and particularly the width of passage 12 is less than 1cm, and the degree of depth is less than 100 μ m.The size of the first reservoir 14 and the second reservoir 16 is greater than the width (for example 100 μ m-1cm) of passage 12 significantly, but can have the substantially the same degree of depth.Passage 12 and the first reservoir 14 and the second reservoir 16 can be filled with electrolyte before use.For example this can pass through emptying passage 12, the first reservoir 14 and the second reservoir 16, then makes electrolyte be inhaled in passage 12, the first reservoir 14 and the second reservoir 16 and carries out.It is poor to guarantee that passage 12 always is full of electrolyte that the first reservoir 14 and the second reservoir for example can be used in equalized pressure.
This device further comprises and being presented in Fig. 1 b as tectal ground floor 20, for cover with any liquid of using passage 12 inside of substrate 10 and preventing for closing passage 12 as electrolyte and sample evaporation or leak out passage 12.The name that ground floor 20 can be provided as Pall company by for example glass, polypropylene film or hydrophobic film be called Supor Membrane Disk Fillers (hydrophilic polyethersulfone) or Millipore Durapor (polyvinylidene-PVDE) those make, and can there is the thickness that is less than 1mm, particularly be less than 1 μ m.Ground floor 20 is impermeable.Ground floor 20 provides the first opening 22 be arranged on passage 12 tops, with by offering sample in passage 12.
Enter opening 22 and can there is circular shape, be applicable to liquid is inserted into to any shape in passage but also can use.
In addition, according to the invention provides film 30, as shown in Figure 3 c.In the embodiment shown, film 30 in use is arranged on top or the bottom of the opening 22 of ground floor 20.Film 30 can by the permeable hydrophilic polymer of 1-100 μ m thickness and/or semipermeable bioavailable polymer for example nitrocellulose make.Before ground floor 20, film 30 can be arranged on passage 12.Therefore, film 30 also can be arranged between ground floor 20 and substrate 10.Film 30 also can be attached in ground floor 20.Under any circumstance, film 30 is hydrophilic, and for example can be made by nitrocellulose.
The size of film 30 and performance will be applicable to making the diffusion of grain kind or the sample of designated volume to transfer to passage 12 inside from the sample side, to carry out comparable measurement.
According to an aspect of the present invention, its component in the permeable blood plasma of film 30 and sample, but filter out larger indissolvable component as cellular material in sample etc.Like this, cellular material is filtered off and only has blood plasma admission passage 12 further to check as red blood cell, white blood cell, blood platelet etc.Other components also can filter out.
According to a further aspect in the invention, the charged species in the permeable blood plasma of film 30, the film 30 that covers the first opening 22 is unique openings of admission passage.It is also unique opening that can make convective flow admission passage 12.Like this, convective flow is suppressed, and prevents it being at least the cellular material admission passage of blood plasma and all kinds, only has charged species, particularly ion to diffuse into passage 12 further to check simultaneously.
In another embodiment of the invention, film 30 and ground floor 20 may be that a step is made, and wherein ground floor 20 is that to make local polymer film or ground floor 20 as film are polymer films, and wherein whole polymer film is the film that hydrophobicity changes.In the situation that back, the hydrophobicity of film changes, make will the eject position place at sample film be hydrophilic.
Can manufacture the more than one opening 22 that enters in ground floor 20.This for example can be used for making sample at place, a plurality of entrance admission passage 12.This can take multiple measurements and averaging.More than one another advantage that enters opening 22 is the convective flow allowed from an opening to another opening, thereby provides by another connecting gear of opening 22 admission passages 12.
The second polymer film 40 shown in Fig. 1 d is provided for covering ground floor 20 and semipermeable partition 30 so that protection ground floor 20 and semipermeable partition 30 are contaminated, aseptic and/or clean and prevent that liquid from revealing from passage to keep before use them.If semipermeable partition 30 has probe, these microcosmic probes also can be protected by the second polymer film 40.The second polymer film 40 is for example made by polypropylene.Remove immediately the second polymer film 40 before use, can be by blood sample in use, namely the whole blood drop is arranged on the top of semipermeable partition 30.The second polymer film 40 can have soft end, so that it can easily be caught, before operative installations 2, is removed.
Fig. 1 e has shown the side view of Fig. 1 a-1d assembly that is assembled into device 2 of the present invention.Ground floor 20 is arranged on the top of substrate 10, thereby covers the top of passage 12.Ground floor 20 has the opening 22 be arranged on passage 12 tops.Opening 22 is covered by film 30.In the situation that shown in Fig. 1 d, the second polymer layer 40 that installs 2 surfaces all or in part by cladding system 2 covers, thereby 2 damages of anti-locking apparatus, dust, evaporation etc.
Fig. 2 shows the exploded view in the zone of circles mark in Fig. 1 e in greater detail.Film 30 is arranged on the top of the opening 22 in ground floor 20.Ground floor 20 covers the interior passage 12 of substrate 10, stays the entrance of passage 12 by opening 22.Opening 22 is covered by film 30.Therefore, in use, only can spread or otherwise the component by film 30 can reach passage 12.In order to protect and to stop undesired lead to film 30 or its pollution, film 30 is covered by the second polymeric membrane 40.Film can be gluing or be fixed under ground floor 20 or among.It will will be also possible in the opening 22 of this support insertion ground floor 20 that film 30 is arranged in support.The embodiment of support has hereinafter been described with reference to Fig. 7.
Fig. 3 a-3f has shown for the key step of sample to be measured to the passage 12 of Fig. 2 amplification and detailed view is provided.
Fig. 3 a is exemplified with the detail view of the device of Fig. 2.Wherein passage 12, opening 22 and film 30 are equipped with background solution (as the gray area in figure).In order to detect lithium, background solution can be the 2-(N-morpholino that for example comprises 50mmol/L) pH of ethyl sulfonic acid and 50mmol/L histidine back-ground electolyte (BGE) solution that is 6.1.Can add glucose, for example about 200mmol/L adjusts the osmotic strength of background solution.According to charged species, ion to be measured can be used other background solution.The second polymer film 40 protective device 2 and solution, and prevent that solution is contaminated before use.Fig. 3 a example the shape that device 2 can be transported to the user.
Fig. 3 b had shown before device 2 is used and has removed the second polymer film 40.The second polymer film 40 is used as protective seam with diaphragm 30 and the first polymeric layer 20 during transportation and save set 2.As shown in Fig. 3 b, the second polymer film 40 from install 2 remove in case for offering sample by the import of film 30.The second polymer film 40 has quick-release mechanism as draw ring, can easily remove at least a portion of the second polymer film 40.
Before sample being placed on the film shown in Fig. 3 c, can measure one or more device parameters as electrolytical conductance or temperature is calibrated or as system check.
Whether whether pure electrolytical conductivity measurement also can be used as system check, that is to say in the verification passage and exist electrolyte and measuring system correctly to work to carry out.Be preferably in to implement to measure before passage 12 electric power are rinsed.This will remove the first diffusion part of sample in passage 12.Conductivity measurement can be for temperature survey.Conductivity measurement also can be used as the built-in check of the condition of device 2.The latter can with in device 2 or the other thermometry that implement in somewhere on every side realize.
Heating element can be arranged on passage 12 inner or on every side or around device to change the fluid temperature in passage 12.Change as the conductance of temperature funtion can be used for controlling or calibration.
In Fig. 3 c, sample 50, untreated whole blood sample, be arranged on the upper surface of film 30.Film 30 is hydrophilic and is permeable.Therefore, sample 50 will be absorbed and pass through film 30, and as shown in Figure 3 d, wherein cellular material is filtered off as red blood cell, white blood cell etc.This can be along with cellular material completes in the concentration of the interior partial solution of passage 12 and change passage 12 inside.For example lipid or other larger components also can be adjusted to leach in the aperture of film 30, only to make in electrolyte admission passage 12.Diffuse through film 30, the sample 50 of filtration contacts with ground floor 20 and enters in opening 22.
As shown in Fig. 3 d and 3e, the sample 50 of filtration diffuses through the passage 12 that opening 22 enters substrate 10.Arriving the electrolyte that the quantity of the filtered sample 50 of passage 12 exists in the performance of the performance of the size of opening 22, film 30, sample 50 and passage 12 determines.
Fig. 3 f is exemplified with when applying electric field along passage 12, and how a part of filtered sample 50 electrophoresis that diffuse in passage are separated in passage 12.Electric field all charged species charged species is shifted to the reservoir 14 and 16 of passage 12 ends in will the separating and filtering sample.
Along passage 12 but the electrode embedding of electric field is provided or be inserted in the first reservoir 14 and the second reservoir 16 in.It is also possible along passage 12, a plurality of electrodes being set, and with those places needing isolating ions, by electric field is transformed into to another zone from a zone, produces strong especially field.As explained above, the hydrophobic membrane of gas-permeable can be used in device preventing the waste gas superpressure.This superpressure is because electrolysis occurs in the electrode place.
Measurement can repeat.
Fig. 4 a and 4b have shown respectively vertical view and the side view of device 2 embodiment of the present invention, and wherein the first reservoir 14 comprises that the first iontophoretic electrode 64, the second reservoirs 16 comprise the second iontophoretic electrode 66.By to iontophoretic electrode 64,66, applying voltage, the charged particle of passage 12 inside can separate or move along passage 12.Iontophoretic electrode 64,66 can be made by any conductive material.The titanium electrode that the electrode embodiment used includes, but are not limited to have chromium layer or silver/silver chloride electrode.Iontophoretic electrode 64,66 can be combined in substrate 10 otherwise be set in reservoir 14 and 16 or passage 12 in Anywhere.
In another embodiment, iontophoretic electrode 64,66 and/or conductance electrode 72,74 can be set on measurement mechanism, on it, can measure by setting device 2.
Electrode 72,74 is not restricted to independent bipolar electrode and arranges, and also can have a plurality of electrode spread.
Apply voltage by power supply or any device as known in the art to iontophoretic electrode 64,66.
Fig. 4 c has shown that circles mark Region Decomposition vertical view in Fig. 4 a and Fig. 4 d have shown the decomposition side view of the same area side surface direction of same circles mark in Fig. 4 b.In this zone, two conductance electrodes 72 and 74 next-door neighbours arrange or are arranged in passage 12 to measure the liquid conduction rate of passing through passage 12 of conductance electrode 72,74 positions.Conductance electrode 72 and 74 can be combined in substrate 10 and extend at least in part in passage 12.As shown in Fig. 4 d, conductance electrode 72,74 can be arranged on the bottom of passage 12, but any other position of passage 12 is possible.Conductivity electrode 72,74 can be connected on conductivity measuring apparatus well known in the prior art.
In one embodiment of the present invention, two pairs of conductance electrodes 72 and 74 have been used.Positive ion in pair of conductive rate electrode measurement passage 12, another is to conductance electrode measurement negative ion.The two pairs of conductance electrodes 72 and 74 are arranged on the both sides of opening 22, and sample is by this opening admission passage 12.
In device 2 manufacture or can carry out afterwards conductance electrode 72 and 74 and the placement of electrolysis electrode 64,66.For example, conductance electrode 72 and 74 and electrolysis electrode 64,66 can pass through surface or substrate 10 admission passages 12 of polymeric layer 20, thereby can avoid conductance electrode 72 in chip and 74 and the expensive installation of electrolysis electrode 64,66.
Conductance in passage 12 between conductance electrode 72 and 74 can be monitored in time.For example, if do not have the electric charge component or exist the charged particle of equivalent to distribute in passage, BGE solution, the conductance that will go out constant or change more slowly as measurement and monitoring as shown in Fig. 4 e.
In the situation that use relates to method that Fig. 3 describes, charged species is inserted to passage 12 as ion etc., by the electric field be applied between iontophoretic electrode 64 and 66, along passage 12, move charged species.Charged species will electrolytic separation when moving along passage 12.Faster than the Li ionic transfer also existed in blood sample 50 of the Na ion of blood sample 50 for example.Therefore, will be continuous by conductance electrode 72 and 74 measure two peaks.First peak means the mobile Na ion sooner by conductance electrode 72 and 74, and the second peak means the more mobile Li ion by conductance electrode 72 and 74.It is evident that to those skilled in the art the ion that can measure more than two types, and any electric charge component of separating by electrolysis mode can be monitored by that way.
The present invention can be used for measuring absolute ion concentration or for measuring relative ion concentration, namely for measuring the Na/Li concentration ratio.
The sensor of other potential electrode or other types, optical sensor as known in the art fluorescent optical sensor can be added measure the concentration of other kinds in sample in identical measurement or exist.Also can use capacitive transducer.
Before measurement of concetration at charged species as ion, the electrolytical electric conductivity of the temperature survey of coupling apparatus is effectively, with assurance device, correctly moves.
Fig. 5 a and 5b have shown replacement embodiment of the present invention.These embodiments for example can be used for alignment purpose.
Fig. 5 a has shown apparatus of the present invention 102 device based on foregoing description 2.In this embodiment of the present invention, passage 112 branches between the first reservoir 114 and the second reservoir 116 become first passage branch road 111 and second channel branch road 113.The first passage branch road 111 of passage 112 and second channel branch road 113 both before the second reservoir 116 again can with.First passage branch road 111 significantly is longer than second channel branch road 113.First passage branch road 111 and second channel branch road 113 have respectively opening 122 and 123.Opening 122 and 123 each be coated with respectively film 130 and 131.
If two different samples 150 and 151 each be arranged on those films 130 and 131 separately and while along passage 112, applying electric field, the ion of each sample will be separated and move along passage 112.Because it is that at first ion will arrive passage 112 that first passage branch road 111 is longer than the charged species of second channel branch road 113, the second samples 151, and the charged species of the first sample 150 need to be grown the some time a little.Therefore, both can be measured charged species by enough identical right conductance electrode (not shown) in succession independently, produce the signal as shown in Fig. 5 c top line.
By providing known sample 150 to produce the first signal for calibrating accordingly to film 130, this embodiment also can be used for calibration.From the secondary signal of the unknown sample 151 that offers film 131 due to the more late arrival in time of longer passage branch road 111.The intensity of secondary signal can compare with the first calibrating signal, and the charged concentration of component in unknown sample can be determined according to well known in the prior art.
This embodiment also may be used the same sample that offers film 130 and film 131 for example by averaging, to realize higher degree of accuracy.
Fig. 5 b has shown another embodiment of the present invention, and wherein two passages 212 and 213 are arranged in parallel.Each passage 212 is basically identical with the embodiment of Fig. 1-4 with 213, and advantage is that two samples 250 and 251 are set in parallel in respectively film 230 and 231, makes two sample horizontal surveies.Because two passages 212 and 213 are identical, can compare and measure.Embodiment is presented in rolling off the production line of Fig. 5 c.
For alignment purpose, sample for example the first sample 250 can be the known sample with known ion concentration.Therefore, the signal of the first sample 250 can be used for calibration and compares with the signal of the second sample 251 from second channel 213, and the concentration of charged particle can mode well known in the prior art be determined.
Obviously, a plurality of passages that can be arranged in parallel, for example carry out a plurality of measurements and measure statistical figure to accelerate treatment capacity or to increase.
Fig. 6 a has shown the another embodiment for the device of sample intermediate ion measurement of concetration, wherein passage 312 is essentially curve, comprises that the first reservoir 314 of the first electrolysis electrode 364 is arranged on the substrate side identical with the second reservoir 316 that comprises the second electrolysis electrode 366.But electrolysis electrode 364 and 366 both sides of contact guide piece are with the side of contact device easily.In addition, conductance electrode 372 and 374 arranges near the to measure the conductance of the electric charge component in this position passage 312 of the second reservoir 366.Conductance electrode 372 can be connected by contact with 374, on the device that contact arrangement is identical in the contact with the conductance electrode or the side of substrate.A part that like this, only has the device of contact need to be contacted with measuring equipment and can guarantee freely to enter in the film 330 be arranged in opening 322.Utilize this device, for example with fingertip, can easily pass in and out film 330, make device insert or contact measurement equipment and/or opertaing device simultaneously.Passage 312 is further straight between opening 322 and conductance electrode 372,374, makes the unnecessary bending of passage 312 that comprises sample, and this may affect measuring accuracy or be difficult to carry out other measurements.
Fig. 6 b has shown the modification of the embodiment shown in Fig. 6 a.Further in passage 412, be provided with the second opening 423, this opening is covered by the same film 430 as the first opening 422.Therefore, the sample on film 430 will spread two openings 422 and 423 in passage 412 with the substantially the same time.Applying electric field to iontophoretic electrode 464 and 466 for example will make according to the symbol of voltage positive charged species or ionic transfer in the first passage part 411 of leading to the second electrolysis electrode 466.In the same manner, negative charging grain kind moves in the channel part 412 that leads to the first electrolysis electrode 464.Conductance electrode 472,474 and 471,473 can be measured positive charged species and negative charging grain kind.Therefore, the charged species of two kinds of electric charges can horizontal survey.
Fig. 7 has shown the modification of the apparatus of the present invention shown in Fig. 2.Membrane support 32 is arranged on the top of the second layer 20.Film 30 is arranged on, and for example is glued to or is adhesive in membrane support 32.Therefore, before being arranged on device by membrane support, film can be assemblied on membrane support.
In the embodiment shown, membrane support 32 forms " cup-shaped " or loop configuration, for film 30 provides holding portion.The upper face of film is flat basically, has the coboundary of " cup-shaped " structure of membrane support.Membrane support thereby offer the well-defined film surface area of framework one of film 30, this area remains with sample and contacts.Like this, can be simply and effectively control the quantity of the sample contacted with film, even when sample is more much larger than film.
The wall of membrane support also can be higher than the thickness of film, thereby be the cup-shaped or loop configuration (not shown) of offering sample, and the bottom of " cup " has film.Cup can be for the sample on collection membrane.
For example by ratchet (click) and fixing means can further make membrane support 32 easily fixedly film 30 on the first overlayer.
Fig. 8 a and Fig. 8 b have shown one embodiment of the present invention, have other anti-tailing electrode 65 in case sample or the component tailing in stop-pass road 12.Anti-tailing electrode 65 is presented between the first overlayer 20 and film 30.Yet anti-tailing electrode 65 also can differently be arranged on opening 22 upsides or the opening part of the first overlayer 20.Fig. 8 a has shown the device with anti-tailing electrode 65 under the device equal state that shows with Fig. 3 e and describe.Correspondingly use the apparatus and method of Fig. 1-3 description and the sample filtered as mentioned above thereby can pass through diffusely film 30 and the first opening 22 admission passages 12.
Along passage 12 apply electric field with before the filtered sample of electrolytic separation Fig. 3 f illustration and description part or in, apply voltage to anti-tailing electrode 65 in addition.Thereby a part of sample component is also by rear drive, by leading to the first opening 22 of film 30, as shown in the arrow 800 in Fig. 8 b.Charged species in the electric field separates filtered sample and charged species is shifted to the reservoir 14 and 16 and shift to film 30 of passage 12 ends.Therefore, starting there is no the sample component admission passage after separation.This result has increased measuring accuracy.
Fig. 9 a-9d has shown that the unique opening 22 that how to use in passage 12 is inserted into liquid in the passage 12 of the device that Fig. 1-3 describes as background electrolyte (BGE) or any other solution.Fig. 9 a is exemplified with the device of the Fig. 2 before inserting any liquid.As Fig. 9 b example one drop of liquid 14 is placed on film 30.Then liquid 14 flows in film 30, until it covers the opening 22 of passage 12.Here, as shown in Fig. 9 c, liquid itself is due to the air of passage 12 inside or other and further in admission passage 12.The single opening 22 that air in passage 12 or gas only can cover by liquid 14 is discharged from passage 12.Fig. 9 d shows, by using vacuum (shown in arrow 900), can, from air or the gas of passage sucking-off passage 12 inside, make liquid 14 enter into passage 12.
Figure 10 has shown for liquid is sampled to the another method of microchannel 12 as blood or any other sample.The second opening 23 also can be arranged on a distance of the first opening 22.Opening 22 with 23 both by passage 12, be connected.Preferably, passage 12 does not have other opening except described opening 22 and 23, and passage is sealed in other place.Yet the second opening 23 also be can't help film and is covered.In the time of on sample being applied to the first opening 22, the liquid in passage 12 can be discharged by the second opening 23.
After liquid has been filled to passage 12, the second opening 23 can be closed by polymeric layer covering or other modes.Have to be communicated on air by any way at sampling the second opening 23, and may can't help sample and directly cover.
The web member of electrode also can be arranged in a side of device.Can be easy to additional and be connected on measuring equipment.When device is can disposable chip form the time, can disposable chip can be inserted in measuring equipment and carry out one-shot measurement, easily turnover is particular importance, wherein said measuring equipment can be operated by patient.
Device 2 can be packaged in packing, has suitable can be connected to interface, communication interface and display interface device for measuring and control electron device and for the interface of power electronic device.
Device 2 also can easily be used to measure the ion concentration in blood by patient.For example, for those patients that suffer from bipolarity phrenoblabia disease, patient can measure the concentration of lithium ion in blood termly.If concentration for example, lower than critical level (0.4mmol/L), patient can take extra lithium so.If concentration surpasses critical level (1.0mmol/L), patient can stop or reducing administration so, is in hospital in case of necessity.
The purposes of device 2 has been described the measurement that relates to lithium ion.Device 2 also can be for measuring potassium and/or phosphate ion to observe renal function or measurement sodium and/or potassium to measure dehydration.
Device of the present invention has the outer application of medical domain.For example wish to use this device in environment and other field, in order to can within a period of time, use this device.In this case, this device can have a plurality of openings 22, and each opening has its oneself lid.The lid of self will periodically remove repeatedly to measure from those different a plurality of openings 22.
The present invention is described with regard to a plurality of embodiments.But those skilled in the art be it is evident that to the present invention is not restricted to this.On the contrary, scope of the present invention should make an explanation in conjunction with following claim.
Claims (20)
1. the method that a use can disposable device be measured sample, the method comprises the steps:
Remove overlayer (40) from partly permeable layer (30), described partly permeable layer (30) is included as one or more holes that at least one passage (12) provides fluid inlet, and described at least one passage is equipped with background solution and sealed;
Provide sample on the surface of partly permeable layer (30);
Make the component of sample enter at least one passage (12) through partly permeable layer (30);
Determine at least one attribute of the component of sample.
2. method claimed in claim 1, wherein provide sample to comprise from human body and obtain sample and do not carry out pre-service.
3. the described method of claim 1 or 2, wherein the component of sample comprises polytype charged species.
4. method claimed in claim 3, also be included in after the component that makes sample enters at least one passage through partly permeable layer (30) existence of the component of sample for reference at least one passage (12).
5. the described method of claim 1 or 2, wherein determine that at least one attribute of component comprises conductivity measurement.
6. method claimed in claim 3, also comprise polytype charged species be separated into to part.
7. method claimed in claim 6, wherein be separated into part according to Capillary Electrophoresis by polytype charged species.
8. the described method of claim 1 or 2, wherein determine that at least one attribute of the component of sample comprises the concentration of determining at least one charged species in polytype charged species.
9. the described method of claim 1 or 2, at least one attribute of wherein determining the component of sample comprises the attribute with respect to the second charged species in polytype charged species, determine the attribute of the first charged species in polytype charged species, to determine the concentration of arbitrary charged species in polytype charged species.
10. method claimed in claim 3, wherein said polytype charged species comprises lithium cation.
11. one kind can disposablely be installed (2) for what carry out measurement, described can disposablely install (2) comprising:
At least one passage (12), it is applicable to, before using, background solution is housed, and other place that this at least one passage (12) comprises at least one the first opening (22) and this at least one passage is sealed;
Partly permeable layer (30), it is positioned at least one the first opening (22) top, this partly permeable layer (30) comprises one or more holes, and these one or more holes are permeable to the component of sample, and these one or more holes are applicable to place sample thereon; And
Overlayer (40), it is placed on this one or more openings top, and this overlayer is applicable to make described at least one passage (12) with respect to the environmental exposure sealing, and can remove from described one or more openings.
Can disposablely install (2) 12. claim 11 is described, wherein said partly permeable layer (30) is impervious at least part of component of cellular material.
Can disposablely install (2) 13. claim 11 or 12 is described, wherein said partly permeable layer (30) is the ground floor (20) that comprises at least one the first opening (22).
Can disposablely install (2) 14. claim 11 or 12 is described, also comprise at least one first conductance electrode (72) and at least one the second conductance electrode (74), at least one first conductance electrode (72) and at least one the second conductance electrode (74) are arranged on distance the first opening (22) a distance, and are arranged in described at least one passage or near described at least one passage.
Can disposablely install (2) 15. claim 11 or 12 is described, wherein said at least one passage (12) comprises the first reservoir (14) that is positioned at least one passage (12) first end and is positioned at second reservoir (16) of at least one passage (12) second end.
Can disposablely install (2) 16. claim 11 or 12 is described, also comprise be arranged at least one passage (12) or at least one passage (12) near at least one first iontophoretic electrode (72) and at least one the second iontophoretic electrode (74).
Can disposablely install (2) 17. claim 11 or 12 is described, wherein said at least one passage (12) comprises at least one second opening (23), and wherein said at least one passage is sealed in other place.
Can disposablely install (2) 18. claim 11 or 12 is described, wherein said partly permeable layer (30) is film.
Can disposablely install (2) 19. claim 11 or 12 is described, also comprise heating element, this heating element is arranged on inner or at least one passage (12) of at least one passage (12) on every side or can disposablely installs (2) on every side.
Can disposablely install (2) 20. claim 11 or 12 is described, wherein at least one passage (12) was equipped with background solution before shipment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310424762.XA CN103499628A (en) | 2006-11-21 | 2006-11-21 | Ion sensor for liquid and manufacturing method of ion sensor |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310424762.XA CN103499628A (en) | 2006-11-21 | 2006-11-21 | Ion sensor for liquid and manufacturing method of ion sensor |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2006800567434A Division CN101568828B (en) | 2006-11-21 | 2006-11-21 | Ion sensor for fluid and method for its manufacture |
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| CN103499628A true CN103499628A (en) | 2014-01-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201310424762.XA Pending CN103499628A (en) | 2006-11-21 | 2006-11-21 | Ion sensor for liquid and manufacturing method of ion sensor |
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| CN109844491A (en) * | 2016-09-28 | 2019-06-04 | 光云大学校产学协力团 | Specimen separation device based on paper folding |
| CN113616204A (en) * | 2020-05-06 | 2021-11-09 | 上海交通大学医学院附属第九人民医院 | Device for monitoring dynamic change of blood ionized calcium in real time on line and applicable to CRRT (continuous room temperature recovery) |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107532994A (en) * | 2015-03-05 | 2018-01-02 | 韩国标准科学研究院 | Include the measurement apparatus of the high sensitivity light absorption units for micro-example |
| CN109844491A (en) * | 2016-09-28 | 2019-06-04 | 光云大学校产学协力团 | Specimen separation device based on paper folding |
| CN109844491B (en) * | 2016-09-28 | 2022-04-15 | 卡尔斯股份有限公司 | Sample separator based on folded paper |
| CN113616204A (en) * | 2020-05-06 | 2021-11-09 | 上海交通大学医学院附属第九人民医院 | Device for monitoring dynamic change of blood ionized calcium in real time on line and applicable to CRRT (continuous room temperature recovery) |
| CN113616204B (en) * | 2020-05-06 | 2024-06-11 | 上海交通大学医学院附属第九人民医院 | Device capable of being used for CRRT (continuous variable rate) on-line real-time monitoring of dynamic change of blood ionized calcium |
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