WO1989012226A1 - Disposable ion activity analyzer - Google Patents
Disposable ion activity analyzer Download PDFInfo
- Publication number
- WO1989012226A1 WO1989012226A1 PCT/US1989/002381 US8902381W WO8912226A1 WO 1989012226 A1 WO1989012226 A1 WO 1989012226A1 US 8902381 W US8902381 W US 8902381W WO 8912226 A1 WO8912226 A1 WO 8912226A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- membrane
- electrometer
- analyzer
- electrode
- sample
- Prior art date
Links
- 230000000694 effects Effects 0.000 title description 11
- 239000012528 membrane Substances 0.000 claims abstract description 37
- 239000012472 biological sample Substances 0.000 claims abstract description 8
- 239000000523 sample Substances 0.000 claims description 17
- 239000003792 electrolyte Substances 0.000 claims description 16
- 239000002555 ionophore Substances 0.000 claims description 4
- 230000000236 ionophoric effect Effects 0.000 claims description 4
- 241000894007 species Species 0.000 claims description 4
- 241000100287 Membras Species 0.000 claims 1
- 235000015250 liver sausages Nutrition 0.000 claims 1
- 150000002500 ions Chemical class 0.000 abstract description 30
- 239000012482 calibration solution Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000011049 filling Methods 0.000 description 8
- 238000005259 measurement Methods 0.000 description 6
- 229920000915 polyvinyl chloride Polymers 0.000 description 6
- 239000004800 polyvinyl chloride Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004014 plasticizer Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 235000003325 Ilex Nutrition 0.000 description 2
- 241000209035 Ilex Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108700021638 Neuro-Oncological Ventral Antigen Proteins 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- 102000018361 Contactin Human genes 0.000 description 1
- 108060003955 Contactin Proteins 0.000 description 1
- 235000009300 Ehretia acuminata Nutrition 0.000 description 1
- 244000046038 Ehretia acuminata Species 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005048 flame photometry Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/403—Cells and electrode assemblies
Definitions
- This invention relates, to potentiometric systems for selectively measuring ion activity in solution, and in particular potentiometric systems utilizing single use ion selective membranes to measure ion activity in biological fluids.
- analyzers examples include the Nova 1, 2, 5, 6, 11, 13 manufactured by Nova Biomedical Corp., of Newton, MA, the AVL 982 sodium/potassium analyzer manufactured by AVL, Gratz, Austria, the Corning 614 Na/K analyzer manufactured by Ciba-Corning of Medfield, MA. , and the Orion 1020 Na/K Analyzer manufactured by Orion Research Inc., of Boston, MA.
- Other analyzers utilize single use card type electrodes such as the Ilex Prompt, manufactured by Ilex Corporation, formerly of oburn, MA and described in U.S.
- Patent #4,713,165 the Chem Pro -sensor card manufactured by Johnson & Johnson of Minneapolis, MN; and the slide electrodes utilized in the Model DT-60 analyzer with electrolyte module manufactured by Eastman Kodak of Rochester, NY, and described in U.S. Patents 4,214,968, 4,053,281 and 4,302,313.
- RT/f is the Nernst factor or electrode slope (normally, 59. 1 6mV at 25°C)
- As is the activity of the ion in the sample
- E 0 is the sum of all other potentials in the cell.
- the flow through analyzers referred to above all utilize two calibrating solutions to determine the slope of the electrodes.
- one of the calibrators is utilized to make a comparative measurement with the biological sample. In this case: r
- csample the concentration of the measured ion in the sample.
- cstandard The concentration of the measured ions in the standard.
- the measurement of the standard solution generally takes place after the measurement on the biological sample to correct for any drift in the E 0 value of the cell as is set forth more particularly below.
- E Q In use, frequent recalibration of E Q is necessary as the voltage interval corresponding to activity changes over the physiological signal range of the ion to be sensed is small in comparison to the drift in E 0 which arises when the ion selective electrode is brought in contact with biological samples containing proteins.
- a standard solution is usually run after a sample is measured to correct for the drift in E 0 .
- a standard or calibrating solution is utilized to calibrate the ion selective electrode with each measurement. They also include a bar code. The host analyzer reads the bar code to know what test to perform, and makes the appropriat measurements by reading the voltages generated by the io selective electrode mounted on the card.
- the present invention is directed to an electrolyte analyzer tha utilizes a single use ion selective membrane that gives quick an precise results without the use of any calibrating solutions
- Another object of the invention is an electrolyte analyzer tha uses a disposable ion selective membrane which is inexpensive t manufacture.
- Other objects of the invention will in part b obvious and will in part appear hereinafter.
- the inventio accordingly comprises the apparatus possessing the construction, combination of elements and arrangements of parts, and th processes involving the several steps and the relation and orde of one or more steps with respect to the others, all of which ar exemplified in the following disclosure, and the scope of th application of which will be indicated in the claims.
- FIG. 1 Graph of asymmetrical electrode potential in a conventional flow through ion selective electrode.
- Fig. 2 Schematic drawing of electrolyte analyzer when not in use.
- Fig. 3 Schematic drawing of electrolyte analyzer with disposable symmetrical membrane in place.
- Fig. 4 Schematic drawing of electrolyte analyzer with sample in place on symmetrical membrane.
- Fig. 5 Schematic drawing of electrolyte analyzer in measuring position.
- Fig. 6 Cross sectional view of electrolyte analyzer and single use disposable membrane cartridge.
- the present invention generally involves a novel analyzer fo measuring ionic species in biological samples. It is comprise of a first reference electrode, a disposable symmetrical io selective membrane containing an ionophore selective to the io to be measured, a second reference electrode, means for contactin the first reference electrode and one side of the symmetrica membrane, means for contacting the second reference electrode t the sample which is in contact with the other side of th membrane, an electrometer for measuring the cell EMF, and mean for zeroing the electrometer.
- symmetrical membrane it is meant an ion selective membrane in which there i substantially no E 0 shift when the membrane is contacted by biological sample containing proteins. For such memebranes, se Wilhelm Simon, Swiss Application 05 030/87 (Jan. 6, 1988) and 03 403/87-3 (Sept. 16, 1987) , Incorporated by reference herein.
- the standard cell potential 1 of a conventional flow through ion selective electrode in contact with an aqueous solution is compared before and after being exposed to a seru sample.
- the difference in potential 2 is the asymmetry potential E as . It is not reproducible.
- the ion selective membrane used in the electrolyte analyzer described herein be symmetrical i.e., the asymmetry potential E as is sufficiently small compared to the change in potential corresponding to the physiological value of the sample being measured.
- FIGs 2-5 illustrates a schematic of the present invention.
- reference electrodes 10 and 12 are connected to electrometer 14.
- the reference electrodes 10, 12 should be highly stable such as the commonly used Ag/AgCl or Hg/Hg Cl reference electrodes.
- the internal filling solution 11, 13 is an electrolyte comprising a concentrated solution containing the chloride salt of the ion to be sensed. For instance, if the electrolyte analyzer were being utilized to measure potassium ions, a 3 M KC1 internal filling solution would be appropriate.
- the reference electrodes 10, 12 are linked together by glass capillaries, 16, 18, and pad 20.
- the glass capillaries 16, 18 contain bridge electrolytes which contain the ion to be sensed at a concentration similar to what exists in the physiological range, for example 140 mM Na+, 4.25 mM K+, 1.1 mM Ca++.
- the capillaries 16, 18 are joined electrically at pad 20. In this position, the electrometer 14 is zeroed.
- the reference electrodes 10, 12 are not linked by their glass capillaries 16, 18, at pad 20. Since this is a schematic of the invention, the means to mechanically separate electrode 10, from pad 20 is not illustrated. Such means, however, will be readily obvious to one skilled in the art.
- a symmetrical ion selective membrane 22 is mounted on pad 20.
- a drop of whole blood 24, about 10 ul, is placed on symmetrical membrane 22. The means for doing so are not illustrated.
- reference electrode 10 and glass capillary 16 are lowered such that capillary 16 makes electrical contact with the blood sample 24 on membrane 22. The lowering means are not illustrated. Again, such means will be obvious to one be skilled in the art.
- the electrometer 14 is then read, the EMF being logarthimically proportional to the concentration of the ion to be sensed in accordance with -the well known Nernst equation.
- An example of a symmetrical membrane would be one prepared b using a vinyl chloride copolymer rather than conventional PVC.
- the preparation of a vinyl chloride/vinyl alcohol (OH PVC) would be as follows.
- the educt is a copolymer of 81% vinyl chloride, 17% vinyl acetate, and 2% maleic acid.
- the poly (vinyl chloride) copolymer (5 gr.) was dissolved in 100 L tetrahydrofuran, and during a period of 10 minutes, added drop wise to a solution of 1% NaOH is 30 mL of methanol at 50-60 C. The solution is stirred during 1.5 hours at 63°C, reduced to half of the volume and then passed through a filter paper into 1.5L of water (25 C) under stirring. After 10 minutes the precipitate was filtered off, suspended in 300 mL MeOH and filtered again. The residue is suspended once more in 200 mL MeOH and poured into .8L of water (25°C) . After filtering and drying (60°C, vacuum), 1.2 g of product were obtained.
- Membranes are prepared from this polymer by dissolving 1% (by weight) of the desired ionophore, 33% OH PVC, and 66% plasticizer in tetrahydraofuran (THF) by using an ultrasonic bath.
- THF tetrahydraofuran
- Various ionophores and plasticizers and combinations thereof can be used to control the selectivity and specificity of the sensor as is known to those skilled in the art.
- the resulting solution is poured into a support ring made of glass or other material not affected by the solvent or plasticizer. Beneath the ring, a plate of a fluorocarbon or similar material is required to prevent adhesion of the membrane.
- the solvent is evaporated slowly from the membrane into an air chamber saturated with THF vapor over several days, resulting in a flat membrane in a support ring.
- the membranes are conditioned by soaking for 24 hours in electrolyte solution in which the concentration of the ion to be sensed is in the physiological range.
- FIG. 6 An example of an analyzer embodying the present invention is illustrated in Fig. 6.
- the analyzer has a measuring block 37 containing reference electrodes 32, ' 34, having the same internal filling solution 36, contained in chambers 38 and 40.
- the concentration of the internal filling solution should be chosen
- Membrane cartridge 46 is the single use disposable portion of the system. It is made of plastic. It has a PVC/PVA symmetrical membrane 48 on support ring 44. The membrane 48 is in contact with wick 50. When membrane cartridge 46 is installed on measuring block 37 by sliding it over the groves 43, 45, and 47 in the measuring block, the wick 50 makes contact with the internal filling solution 36 in chamber 40.
- the membrane cartridge 46 also has filter paper wick 52 which connects the sample 53 with wick 54.
- the wick 54 makes contact with filling solution 36 in chamber 38. Further, passageway 42 is closed so that there is no electrical connection between the filling solution 36 in chambers 38 and 40.
- the membrane cartridge 46 also has a chamber 56 in which the sample to be tested is placed, and a foil heat " seal cover 58 which covers the chamber 56 and membrane 48 when the cartridge 46 is being stored.
- a cover (not shown) is installed on measuring block 37. Passageway 42 remains open so that filling solution 36 can communicate between chambers 38 and 40. In this manner, the electrometer 14 may be continuously zeroed.
- the cover is removed and disposable cartridge 46 slides on to measuring block 37.
- passageway 42 is closed off by its mating with groove 45 so that there is no electrical contact between chambers 38 and 40.
- Foil cover 58 is removed, and a sample 53 is placed in chamber 56 on membrane 48.
- the electrometer 14 can be read. Using the conventional Nernstian plot of E vs. log As, the activity of the ion is readily ascertainable from the electrometer reading. Conversion from activity to concentration units is readily apparent to those skilled in the art.
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Electrochemistry (AREA)
- Molecular Biology (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
An electrode analyzer for measuring ions in biological samples having two reference electrodes (32, 34) and a disposable single-use symmetrical ion selective membrane (48). The analyzer provides quick and precise results without any calibration solutions.
Description
DISPOSABLE ION ACTIVITY ANALYZER BACKGROUND OF INVENTION
This invention relates, to potentiometric systems for selectively measuring ion activity in solution, and in particular potentiometric systems utilizing single use ion selective membranes to measure ion activity in biological fluids.
Historically, flame photometry has been the accepted method for measuring the activity of electrolytes such as Na+, K+, and Li-t¬ in blood serum. Ion selective electrodes were first utilized in automated analyzers to measure Na+ and K+ in whole blood in 1976. Since this time, there has been a proliferation of analyzers utilizing ion selective electrodes to measure blood electrolytes. Some of these analyzers utilize dipping type electrodes, such as the sodium/potassium analyzer manufactured by Applied Medical Technology Inc., formerly of Mountain View, California and described in U.S. patent 4,350,579. Other analyzers utilized flow through type ion selective electrodes. Examples of such analyzers would include the Nova 1, 2, 5, 6, 11, 13 manufactured by Nova Biomedical Corp., of Newton, MA, the AVL 982 sodium/potassium analyzer manufactured by AVL, Gratz, Austria, the Corning 614 Na/K analyzer manufactured by Ciba-Corning of Medfield, MA. , and the Orion 1020 Na/K Analyzer manufactured by Orion Research Inc., of Boston, MA. Other analyzers utilize single use card type electrodes such as the Ilex Prompt, manufactured by Ilex Corporation, formerly of oburn, MA and described in U.S. Patent #4,713,165; the Chem Pro -sensor card manufactured by Johnson & Johnson of Minneapolis, MN; and the slide electrodes utilized in the Model DT-60 analyzer with electrolyte module manufactured by Eastman Kodak of Rochester, NY, and described in U.S. Patents 4,214,968, 4,053,281 and 4,302,313.
The ion selective electrodes measuring the activity of blood electrolytes in these analyzers generate a potential which is proportion to the logarithm of the activity of the ion being sensed in accordance with the well known Nernst Equation:
E = Eo + RT/f log (As)
where "RT/f" is the Nernst factor or electrode slope (normally, 59.16mV at 25°C) , "As" is the activity of the ion in the sample, and "E0" is the sum of all other potentials in the cell.
The flow through analyzers referred to above all utilize two calibrating solutions to determine the slope of the electrodes. The slope changes with time and usage, and as such electrodes must be calibrated periodically to insure accurate results. In addition, one of the calibrators is utilized to make a comparative measurement with the biological sample. In this case: r
E Sample - E Standard = R-T/ fLog Sample cStandard
Where csample = the concentration of the measured ion in the sample.
cstandard = The concentration of the measured ions in the standard.
The measurement of the standard solution generally takes place after the measurement on the biological sample to correct for any drift in the E0 value of the cell as is set forth more particularly below.
In use, frequent recalibration of EQ is necessary as the voltage interval corresponding to activity changes over the physiological signal range of the ion to be sensed is small in comparison to the drift in E0 which arises when the ion selective electrode is brought in contact with biological samples containing proteins. As such, a standard solution is usually run after a sample is measured to correct for the drift in E0. In the case of the card type electrodes, a standard or calibrating solution is utilized to calibrate the ion selective electrode with each measurement. They also include a bar code. The host analyzer reads the bar
code to know what test to perform, and makes the appropriat measurements by reading the voltages generated by the io selective electrode mounted on the card. In the case of the Koda slide electrodes, a comparative measurement is made utilizing tw identical ion selective electrodes. These slide electrodes ar further limited in that only serum or plasma may be utilized Precise amounts of sample and calibrating solution must b pipetted onto the slide electrode.
The present invention is directed to an electrolyte analyzer tha utilizes a single use ion selective membrane that gives quick an precise results without the use of any calibrating solutions Another object of the invention is an electrolyte analyzer tha uses a disposable ion selective membrane which is inexpensive t manufacture. Other objects of the invention will in part b obvious and will in part appear hereinafter. The inventio accordingly comprises the apparatus possessing the construction, combination of elements and arrangements of parts, and th processes involving the several steps and the relation and orde of one or more steps with respect to the others, all of which ar exemplified in the following disclosure, and the scope of th application of which will be indicated in the claims.
BRIEF DESCRIPTION OF THE DRAWINGS The invention will be better understood and the objects other those set forth above will become apparent when consideration is given to the following detailed description thereof. Such description makes reference to the annexed drawings wherein:
Fig. 1 Graph of asymmetrical electrode potential in a conventional flow through ion selective electrode. Fig. 2 Schematic drawing of electrolyte analyzer when not in use. Fig. 3 Schematic drawing of electrolyte analyzer with disposable symmetrical membrane in place. Fig. 4 Schematic drawing of electrolyte analyzer with sample in place on symmetrical membrane. Fig. 5 Schematic drawing of electrolyte analyzer in measuring position. Fig. 6 Cross sectional view of electrolyte analyzer and single use disposable membrane cartridge.
DETAILED DESCRIPTION OF THE INVENTION For the purposes of promoting and understanding the principles o the invention, reference will now be made to the embodimen illustrated in the drawings and specific language will be used t describe the same. It will nevertheless be understood that n limitation of the scope of the invention is thereby intended. Suc alterations and modifications in the illustrated device, and suc further applications of the principles of the invention a illustrated therein being contemplated as would normally occur t one skilled in the art to which the invention relates.
The present invention generally involves a novel analyzer fo measuring ionic species in biological samples. It is comprise of a first reference electrode, a disposable symmetrical io selective membrane containing an ionophore selective to the io to be measured, a second reference electrode, means for contactin the first reference electrode and one side of the symmetrica membrane, means for contacting the second reference electrode t the sample which is in contact with the other side of th membrane, an electrometer for measuring the cell EMF, and mean for zeroing the electrometer. By the term symmetrical membrane, it is meant an ion selective membrane in which there i substantially no E0 shift when the membrane is contacted by biological sample containing proteins. For such memebranes, se Wilhelm Simon, Swiss Application 05 030/87 (Jan. 6, 1988) and 03 403/87-3 (Sept. 16, 1987) , Incorporated by reference herein.
When conventional solvent polymeric PVC membranes are used, a non reproducible shift in the standard cell potential EQ results whe proteins from biological samples contact the membrane surface. The protein layer may induce a membrane asymmetrical potential, E-._. In Figure 1, the standard cell potential 1 of a conventional flow through ion selective electrode in contact with an aqueous solution is compared before and after being exposed to a seru sample. The difference in potential 2 is the asymmetry potential Eas . It is not reproducible. It is essential to the present invention that the ion selective membrane used in the electrolyte analyzer described herein be symmetrical i.e., the asymmetry
potential Eas is sufficiently small compared to the change in potential corresponding to the physiological value of the sample being measured.
Figures 2-5 illustrates a schematic of the present invention. In Figure 2, reference electrodes 10 and 12 are connected to electrometer 14. The reference electrodes 10, 12 should be highly stable such as the commonly used Ag/AgCl or Hg/Hg Cl reference electrodes. The internal filling solution 11, 13 is an electrolyte comprising a concentrated solution containing the chloride salt of the ion to be sensed. For instance, if the electrolyte analyzer were being utilized to measure potassium ions, a 3 M KC1 internal filling solution would be appropriate.
The reference electrodes 10, 12 are linked together by glass capillaries, 16, 18, and pad 20. The glass capillaries 16, 18 contain bridge electrolytes which contain the ion to be sensed at a concentration similar to what exists in the physiological range, for example 140 mM Na+, 4.25 mM K+, 1.1 mM Ca++. The capillaries 16, 18 are joined electrically at pad 20. In this position, the electrometer 14 is zeroed.
In Figure 3, the reference electrodes 10, 12 are not linked by their glass capillaries 16, 18, at pad 20. Since this is a schematic of the invention, the means to mechanically separate electrode 10, from pad 20 is not illustrated. Such means, however, will be readily obvious to one skilled in the art. A symmetrical ion selective membrane 22 is mounted on pad 20. In Figure 4, a drop of whole blood 24, about 10 ul, is placed on symmetrical membrane 22. The means for doing so are not illustrated. In Figure 5, reference electrode 10 and glass capillary 16 are lowered such that capillary 16 makes electrical contact with the blood sample 24 on membrane 22. The lowering means are not illustrated. Again, such means will be obvious to one be skilled in the art. The electrometer 14 is then read, the EMF being logarthimically proportional to the concentration of the ion to be sensed in accordance with -the well known Nernst equation.
An example of a symmetrical membrane would be one prepared b using a vinyl chloride copolymer rather than conventional PVC. The preparation of a vinyl chloride/vinyl alcohol (OH PVC) would be as follows. The educt is a copolymer of 81% vinyl chloride, 17% vinyl acetate, and 2% maleic acid. The poly (vinyl chloride) copolymer (5 gr.) was dissolved in 100 L tetrahydrofuran, and during a period of 10 minutes, added drop wise to a solution of 1% NaOH is 30 mL of methanol at 50-60 C. The solution is stirred during 1.5 hours at 63°C, reduced to half of the volume and then passed through a filter paper into 1.5L of water (25 C) under stirring. After 10 minutes the precipitate was filtered off, suspended in 300 mL MeOH and filtered again. The residue is suspended once more in 200 mL MeOH and poured into .8L of water (25°C) . After filtering and drying (60°C, vacuum), 1.2 g of product were obtained.
Membranes are prepared from this polymer by dissolving 1% (by weight) of the desired ionophore, 33% OH PVC, and 66% plasticizer in tetrahydraofuran (THF) by using an ultrasonic bath. Various ionophores and plasticizers and combinations thereof can be used to control the selectivity and specificity of the sensor as is known to those skilled in the art. The resulting solution is poured into a support ring made of glass or other material not affected by the solvent or plasticizer. Beneath the ring, a plate of a fluorocarbon or similar material is required to prevent adhesion of the membrane. The solvent is evaporated slowly from the membrane into an air chamber saturated with THF vapor over several days, resulting in a flat membrane in a support ring. The membranes are conditioned by soaking for 24 hours in electrolyte solution in which the concentration of the ion to be sensed is in the physiological range.
An example of an analyzer embodying the present invention is illustrated in Fig. 6. The analyzer has a measuring block 37 containing reference electrodes 32,' 34, having the same internal filling solution 36, contained in chambers 38 and 40. The concentration of the internal filling solution should be chosen
SUBSTITUTESHUT
to minimize the junction potential with the sample interface and secondly to be as close to the physiological range as possible. The chambers 38, 40 are connected by passageway 42. Membrane cartridge 46 is the single use disposable portion of the system. It is made of plastic. It has a PVC/PVA symmetrical membrane 48 on support ring 44. The membrane 48 is in contact with wick 50. When membrane cartridge 46 is installed on measuring block 37 by sliding it over the groves 43, 45, and 47 in the measuring block, the wick 50 makes contact with the internal filling solution 36 in chamber 40.
The membrane cartridge 46 also has filter paper wick 52 which connects the sample 53 with wick 54. When the membrane cartridge 46 is installed on the measuring block 37, the wick 54 makes contact with filling solution 36 in chamber 38. Further, passageway 42 is closed so that there is no electrical connection between the filling solution 36 in chambers 38 and 40. The membrane cartridge 46 also has a chamber 56 in which the sample to be tested is placed, and a foil heat "seal cover 58 which covers the chamber 56 and membrane 48 when the cartridge 46 is being stored.
When the analyzer is not being used, a cover (not shown) is installed on measuring block 37. Passageway 42 remains open so that filling solution 36 can communicate between chambers 38 and 40. In this manner, the electrometer 14 may be continuously zeroed. When a sample 53 is to be tested, the cover is removed and disposable cartridge 46 slides on to measuring block 37. When the disposable cartridge 46 is in place, passageway 42 is closed off by its mating with groove 45 so that there is no electrical contact between chambers 38 and 40. Foil cover 58 is removed, and a sample 53 is placed in chamber 56 on membrane 48. After a short time for equilibration, the electrometer 14 can be read. Using the conventional Nernstian plot of E vs. log As, the activity of the ion is readily ascertainable from the electrometer reading. Conversion from activity to concentration units is readily apparent to those skilled in the art.
SUBSTITUTESHEET
The present invention has been described with reference to one or more particular embodiments thereof, and it is intended that all matters contained in the above description or shown in the accompanying drawings shall be interpreted in an illustrative and not in a limiting sense since it should be understood that those skilled in the art may make many other modifications and embodiments, thereof which will fall within the spirit and scope of the principles of this invention.
SUBSTITUTE SHEET
Claims
1. An electrolyte analyzer for measuring the concentration ionic species in a biological sample comprising: a. A first reference electrode; b. a second reference electrode; c. an electrometer; d. means for joining the first and second referen electrodes and electrometer in series to form potentiometric cell; e. means to zero the electrometer; f. a disposable single use disc type symmetrical membra having an ionophore selective to the ionic species to measured; g. means for an electrically contacting the first referen electrode to a first side of the symmetrical membrane; h. means for electrically contacting the second referen electrode to a sample placed upon the second side of t symmetrical membrane; and i. means for reading the electrometer and determining t concentration of the ionic species.
SUBSTITUTE SHEET
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US20246488A | 1988-06-07 | 1988-06-07 | |
US202,464 | 1988-06-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1989012226A1 true WO1989012226A1 (en) | 1989-12-14 |
Family
ID=22749967
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1989/002381 WO1989012226A1 (en) | 1988-06-07 | 1989-06-06 | Disposable ion activity analyzer |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO1989012226A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0366645A3 (en) * | 1988-10-27 | 1990-09-12 | Avl Medical Instruments Ag | Measuring apparatus for determining a chemical parameter in an aqueous sample |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3351544A (en) * | 1964-03-23 | 1967-11-07 | Honeywell Inc | Gas detecting cell with detachable unit |
US3399667A (en) * | 1965-10-18 | 1968-09-03 | Matsushita Electric Ind Co Ltd | Composite glass electrode |
US3445369A (en) * | 1966-10-31 | 1969-05-20 | Beckman Instruments Inc | Electrolytic sensor with improved membrane support |
US3591464A (en) * | 1968-09-06 | 1971-07-06 | Orion Research | Method and apparatus for detecting ionic activity |
US3707455A (en) * | 1968-07-15 | 1972-12-26 | Ibm | Measuring system |
US3806440A (en) * | 1973-04-02 | 1974-04-23 | Owens Illinois Inc | Electrode with replaceable ion selective glass sensor |
US3843490A (en) * | 1970-06-26 | 1974-10-22 | Interx Research Corp | Method of measuring hydrophobic organic ions |
US3926765A (en) * | 1973-04-13 | 1975-12-16 | Instrumentation Labor Inc | Electrochemical electrode structure |
US3926764A (en) * | 1971-05-19 | 1975-12-16 | Radiometer As | Electrode for potentiometric measurements |
US4276141A (en) * | 1978-02-24 | 1981-06-30 | Beckman Instruments, Inc. | Solid state ion selective electrodes |
US4287042A (en) * | 1979-03-09 | 1981-09-01 | National Research Development, Corp. | Ion-selective electrode and method of making said electrode |
US4608149A (en) * | 1983-06-20 | 1986-08-26 | Eastman Kodak Company | Potassium ion-selective compositions and electrodes containing same |
-
1989
- 1989-06-06 WO PCT/US1989/002381 patent/WO1989012226A1/en unknown
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3351544A (en) * | 1964-03-23 | 1967-11-07 | Honeywell Inc | Gas detecting cell with detachable unit |
US3399667A (en) * | 1965-10-18 | 1968-09-03 | Matsushita Electric Ind Co Ltd | Composite glass electrode |
US3445369A (en) * | 1966-10-31 | 1969-05-20 | Beckman Instruments Inc | Electrolytic sensor with improved membrane support |
US3707455A (en) * | 1968-07-15 | 1972-12-26 | Ibm | Measuring system |
US3591464A (en) * | 1968-09-06 | 1971-07-06 | Orion Research | Method and apparatus for detecting ionic activity |
US3843490A (en) * | 1970-06-26 | 1974-10-22 | Interx Research Corp | Method of measuring hydrophobic organic ions |
US3926764A (en) * | 1971-05-19 | 1975-12-16 | Radiometer As | Electrode for potentiometric measurements |
US3806440A (en) * | 1973-04-02 | 1974-04-23 | Owens Illinois Inc | Electrode with replaceable ion selective glass sensor |
US3926765A (en) * | 1973-04-13 | 1975-12-16 | Instrumentation Labor Inc | Electrochemical electrode structure |
US4276141A (en) * | 1978-02-24 | 1981-06-30 | Beckman Instruments, Inc. | Solid state ion selective electrodes |
US4287042A (en) * | 1979-03-09 | 1981-09-01 | National Research Development, Corp. | Ion-selective electrode and method of making said electrode |
US4608149A (en) * | 1983-06-20 | 1986-08-26 | Eastman Kodak Company | Potassium ion-selective compositions and electrodes containing same |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0366645A3 (en) * | 1988-10-27 | 1990-09-12 | Avl Medical Instruments Ag | Measuring apparatus for determining a chemical parameter in an aqueous sample |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5286365A (en) | Graphite-based solid state polymeric membrane ion-selective electrodes | |
US5312590A (en) | Amperometric sensor for single and multicomponent analysis | |
CA2087720C (en) | Method for analytically utilizing microfabricated sensors during wet-up | |
KR100342165B1 (en) | Solid-State Type Micro Reference Electrode with Self-Diagnostic Function | |
EP2176652B1 (en) | System and methods for determination of analyte concentration using time resolved amperometry | |
US6663756B2 (en) | Microchip-type oxygen gas sensor based on differential potentiometry | |
EP1164372B1 (en) | Microchip-based differential carbon dioxide gas sensor | |
CA2173672A1 (en) | Planar bicarbonate sensor | |
Errachid et al. | FET‐based chemical sensor systems fabricated with standard technologies | |
US6197172B1 (en) | Electrochemical sensor with gelled membrane and method of making | |
AU2001247614A1 (en) | Lithium ion-selective electrode for clinical applications | |
WO2001073425A2 (en) | Lithium ion-selective electrode for clinical applications | |
US5958201A (en) | Sodium ion-selective-electrode membrane having extended uselife | |
Anker et al. | Potentiometry of Na+ in undiluted serum and urine with use of an improved neutral carrier-based solvent polymeric membrane electrode. | |
US4487679A (en) | Potassium ion-selective electrode | |
US20220170880A1 (en) | Method of conditioning an ion-selective electrode | |
Uhlig et al. | Miniaturised ion-selective sensor chip for potassium measurement in a biomedical application | |
WO1989012226A1 (en) | Disposable ion activity analyzer | |
EP0288724B1 (en) | Ion-selective electrode for measuring carbonate concentration | |
Lemke et al. | Multisensor array for pH, K+, Na+ and Ca2+ measurements based on coated-film electrodes | |
Lewenstam | Clinical analysis of blood gases and electrolytes by ion-selective sensors | |
Rumenjak et al. | The study of some possible measurement errors in clinical blood electrolyte potentiometric (ISE) analysers | |
Lemke et al. | Coated film electrodes | |
Smith et al. | An evaluation of the ICA1 ionized calcium analyzer in a clinical chemistry laboratory | |
RU2731411C1 (en) | Biosensor with high sensitivity factor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): JP |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LU NL SE |