WO2001069227A2

WO2001069227A2 - Ion-sensitive microelectrodes

Info

Publication number: WO2001069227A2
Application number: PCT/IL2001/000230
Authority: WO
Inventors: Ronnie Klein; Leonid Rabinovich; Leonid Perlin
Original assignee: Phuture Sense Ltd.
Priority date: 2000-03-16
Filing date: 2001-03-11
Publication date: 2001-09-20
Also published as: WO2001069227A3

Abstract

The present invention discloses an ion-sensitive solid state microelectrode for the determination of the activity of a specific ion in a solution. The microelectrode comprises a membrane and a core encapsulated therein. The membrane is selectively penetrable to said specific ion and contains a first metal, while the core comprises an electrically conducting microwire, made of an alloy of said first metal with at least one other metal.

Description

ION-SENSITIVE MICROELECTRODES

FIELD OF THE INVENTION

This invention relates to glass encapsulated microwires of electrical conductors that serve as ion-sensitive solid state electrodes.

BACKGROUND OF THE INVENTION Publications that may be helpful in carrying out the invention are:

1) W. Donald, Journal of Materials Science 22 (1987) pp. 2661-2679.

2) M.E. Dril and L.L. Zusman, Metallurgia, Moscow, 1988 p.222. 3) R.N. Khuri in "Glass Electrodes for hydrogen and other cations" (G. Eisenman, Ed.), M.Decker, NY, 1967

4) The glass electrodes (M. Dole, Ed.), John Wiley&Sons, NY,

1947

5) Ion-Selective Electrodes (R.A. Durst, Ed.), Proceedings of Symposium held at the NBS Gaithersburg, Maryland, 1969

Publications that may be considered relevant prior art are:

6) EP 0 382 486 7) A.N. Balashov et al Microprovod v priborostroenii (Russ.),

1974, pp. 154-158. 8) GB 2,284,267 9) SU 1,425,531

10) US 5,948,236

11) US 5,122,254

Microwires made of glass-encapsulated electric conductors are known for about 80 years. Methods for their production are to be found, for instance, in references 1 of the above list. In summary, there are three principal methods by which such microwires may be produced . In the Taylor-wire method, one puts a peace of metal in a glass tube casing, heats the metal by induction, lets the heated metal soften the glass, and draws fine wires made of the glass encapsulating the metal. According to the Taylor method the melting point of the metal should be at least 50°C lower than the working temperature of the glass.

The working temperature of a glass is a temperature at which the glass viscosity is in the range from 10² to 10⁴ Pa*s. At this temperature the glass is soft enough for drawing and other similar processing operations.

In a second method one puts a peace of metal in a glass tube casing, softens the glass by heating it with a regular heat source (as, for example, a ribbon heater), lets the hot glass heat the metal to its melting point, and again, draws fine wires made of the soft glass encapsulating the melted metal. According to this method also, the melting point of the metal should be at least 50°C lower than the working temperature of the glass. In the third method, one first prepares a fine wire of the desired metal (by methods known per se, like extrusion or rolling). Glass is being melted in a small pot of a suitable material (typically platinum) having a small hole in its bottom. The metal wire is then drawn through the hole and thus being encapsulated with the molten glass, which is then cooled to solidify. According to this method the metal melting point should be at least 200°C higher than the working temperature of the glass.

Ion selective electrodes are devices for the measurement of the activity of a specific ion in solution and they typically include a casing, a portion of which is made of a so-called ion selective membrane, i.e. a material that is penetrable in preference to the specific ion to be measured. The casing holds in its interior a body of an ion acquiring material, which is in contact with an electric conductor.

The ion selective electrode membrane is usually a special kind of glass that contains labile ions of some alkali metal, usually in the form of oxides, and is capable of conducting these ions. This kind of glass is also referred to as ion conducting glass. The glass used for measuring pH in solutions is called "pH glass " and typically contains labile alkali metal ions. Some useful ion specific membranes and the labile metal ions they contain are summarized in the table 1.

Table 1

In operation, surface functional groups of the ion-selective glass membrane are partly dissociated so that negatively charged groups remain attached to the glass surface and positively charged cations leave the surface towards the test solution so that a potential drop between the solution and the membrane is created. The ions, whose activity in the solution has to be determined, selectively associate with the functional groups of the membrane, and the equilibrium of this dissociation-association process determines the potential drop between the solution and the membrane. This potential depends upon the activity of the measured ion in the solution, and it is measured as e.m.f. vis-a-vis a reference electrode. The ion activity is then calculated from this measured potential. The most widely used ion specific electrodes are so called "ionic contact" electrodes, which are of the solid/liquid type in which the body of ion acquiring material (present in the surface layer of the glass membrane) is a liquid, usually an aqueous electrolytic solution. The presence of a liquid limits the use of the ionic contact electrodes to situations in which the electrode can be placed essentially vertically since otherwise, the liquid might not maintain good contact with the electric conductor. In addition, use of a liquid ion acquiring body imposes a need for frequent replacement of the liquid and as a result also for frequent calibration. There are also known ion selective electrodes, which have a solid ion-acquiring core instead of a liquid body, and they are accordingly referred to as "solid contact" or "solid state " electrodes. In solid state electrodes the core is usually metallic and have the advantages over ionic contact electrodes in several aspects: for one, they may be used for a wider temperature range; furthermore, they may be positioned in space as required; and still further, they lend themselves to miniaturization, which is of particular significance for various diagnostic applications.

EP 0 382 486 describes solid state pH electrodes that use a metallic core, which comprises a metal identical to that contained in the pH glass membrane alloyed together with tin or indium. This patent application specifically states that it is impractical to use Cd, Pb, Tl and Ga in glass electrodes, since these compounds cannot stand the required voltages. The findings, on which the present application is based are contradictory to this teaching.

Microelectrodes for the measurements of pH were described by Balashov '. These electrodes comprised a core made solely of silver metal (not alloyed with any other metal) and have been of rather poor quality: electrode potential of +950mN at pH=7.0 and slope of 50 mV/pH unit. The electrode potential was reported to be tested against T1/T1C1 in KC1 (sat) reference electrode.

The measured potential should linearly depend upon the logarithm of the measured ion activity. This linear relationship may be graphically described as a straight line with a slope having the units of mV/log[ai_on]. Principally, the greater the slope the more accurately the activity can be measured. However, the upper limit of the potential slope is restricted from theoretical considerations to be 59.16 mV/log[ajon], for monovalent ions at 25°C. Slopes that are much lower or higher are sometimes obtained, but these are severely affected from factors that are not well controlled, and, therefore, are not constant and reliable. Positive electrode potentials in the case of alkali ion conducting glass are disadvantageous because they usually stem from side electrochemical reactions on the glass - metal interface. In such a case, the potential will definitely suffer from considerable drift. Baring this in mind there is no wonder that the Balashov reference has not been followed in the 50 years and more that passed since its publication.

Other publications that may be considered relevant to the understanding of the state of the art are:

GB 2,284,267, which describes a microelectrode for measuring oxygen in blood and comprises a microwire of noble metal such as gold, encapsulated in inert material such as borosilicate glass;

SU 1,425,531, which describes a microelectrode for measuring the pH of a solution, and comprises an active element of cubic mono crystalline sodium-tungsten bronze carrying an active connector in the shape of a needle placed on the upper face of the cube and a current lead in an insulator attached below the cube;

US 5,948,236, which describes microelectrodes that exhibit catalytic properties towards chlorate ion electroreduction and electrooxidation, and are suitable to measure high concentrations of chlorate ions; and

US 5,122,254, which discloses a sensor for the determination of sodium ion in solution that includes a mechanically strong solid state electrode. The electrode is prepared by screen-printing, and comprises a sodium sensitive membrane and a reference electrode applied to it. The reference electrode is preferably made of a sodium alloy having a stable sodium ion activity. SUMMARY OF THE INVENTION

The present invention provides an ion-sensitive, solid state microelectrode for the determination of the activity of a specific ion in a solution, comprising a glass membrane and a metallic core encapsulated therein, said glass membrane contains a first metal and being selectively penetrable to said specific ion, and said core contains an alloy of said first metal together with at least one other metal.

Preferably the core should be electrically engaged with a conducting microwire for the connection to an electric potential measuring device.

Small membrane surface areas of the glass membrane might result in fast poisoning of the electrode, therefore, large surface area of the glass membrane per electrode-volume (hereinafter A to V ratio) is of great importance.

Preferably the A to V ratio is 8 mm^" or more, more preferably it is 25 mm^" or more and most preferable A to V ratios are between 30 and 60 mm^" .

The term "microwire " is used for any wire with the cross-section peφendicular to its main axis having an area of 0.25 mm or less. Preferable microwires are those having a cross-section of 0.01 mm or less.

The term "microelectrode " is used similarly for any electrode with the cross-section peφendicular to its main axis having an area of 0.25 mm or less. Preferable microelectrodes are those having a cross-section of 0.01 mm or less. The term "encapsulates " means that the core is coated by the glass membrane from all its sides, with the exception of those portions that have to take part in an electrical engagement with the microwire. Those portions will typically be in the region of the electrode, which is not intended to be immersed in the test solution. Thus, practically all the surface area of the microelectrode according to the invention is active in determining the ion activity in the solution. The small diameter of the electrodes according to the invention makes their active surface area per electrode volume particularly large: from 8 mm^" in case the diameter is 0.5 mm to 40 mm^" for electrodes having a diameter of 0.1 mm. Naturally, electrodes with smaller diameters have even larger active surface area per volume. The glass membrane is made of ion selective glass, of the kind usually used for potentiometric measurements of ion activities, as well known in the art. Some non-limiting examples to such glasses can be found in table 1 above.

Specific ions, which activities are to be determined according to the present invention, are hydrogen, sodium, lithium, potassium, ammonium, silver, calcium, and lactate.

The determination of the activity of a specific ion is achieved by measuring the potential difference between the metallic core of the microelectrode according to the invention and a reference electrode. The reference electrode is to be similar to those used conventionally in potentiometric measurements of ionic activities, as well known in the art. A non-limiting example for a suitable reference electrode is Ag/AgCl in KC1 3M.

The potential thus measured is converted into ion activity according to the following formula: E = A + B log[a_ion]

Wherein A and B are constants, ai_0n is the activity of the ion to be measured, and E is the potential difference between the electrode according to the invention and the reference electrode. A and B are determined empirically by measuring the potential E in solutions having known ion activities and plotting a calibration curve. The obtained conversion from potential to activity can be more accurate as the value of B goes higher. The upper limit of B is theoretically determined by the well-known Nernst equation, and for a monovalent ion at 25°C it is 59.16 mV/log[a_i0n].

The term "alloy" is to be construed as encompassing any solid that is obtainable by mixing two or more liquid metals to obtain a homogenous product and cooling this product to obtain a homogenous solid. This definition includes solid solutions, compounds, mixtures thereof or any other form of matter obtained in this way.

The 'other metal' participating with the first metal in the alloy is to be selected according to the following considerations: (i) It should be able to alloy with the first metal;

(ii) The melting temperature of its alloy with the first metal should comply with the demands imposed by the method of manufacture of the electrode. Although the melting temperature of the alloy with the first metal is a major consideration in selecting the other metal, one should bear in mind that this melting temperature may be manipulated by adding to the alloy another metal. For example, the melting temperature of lead-lithium or lead-sodium alloy may be manipulated by adding to it silver to obtain lead-lithium-silver or lead-sodium-silver alloy. The melting temperature of gold-sodium alloy may be manipulated by adding to it copper.

Another consideration that has to be taken into account when selecting the "other metal" is that during the preparation of the electrode, the alloy components might react with atmospheric oxygen. The first metal is usually an alkali metal that reacts with oxygen quite violently and should usually be processed in an oxygen free atmosphere. However, it is preferable that the other metal does not react with oxygen, so the difficulty of obtaining the alloy will not be even greater. Therefore, metals that their reactivity to oxygen may be neglected in planning the manufacture conditions of the alloy, without causing a commercially meaningful decrease in the quality of the electrode are preferable.

Thus, the 'other metal' according to the present invention is preferably selected from the group consisting of lead, tin, silver, gold, platinum, palladium, bismuth, gallium, thallium and cadmium. More preferably it is selected from the group consisting of lead, silver, gold, platinum, palladium, bismuth, gallium, thallium and cadmium, and most preferably it is selected from the group consisting of lead, gallium, thallium and cadmium.

According to the invention, the molar ratio between the first metal and the other metal is to be determined according to the agreement between the melting temperature of the resultant alloy and the melting temperature that is desirable in the encapsulation method chosen for the microelectrode manufacture. As the demands set by the manufacture methods are to the difference between the melting point of the alloy and the working temperature of the encapsulating glass, the specific glass to be used may also have an effect on the exact desirable composition. Another consideration in determining the molar ratio between the first metal and the at least one other metal is that compositions of the eutectic point are preferable. This is so, because the melt alloy is cooled and solidifies during electrode manufacture and drawing. Thus, alloys with non-eutectic compositions might result in electrodes having a composition that varies from one part thereof to the other.

According to these criteria, alloy compositions that are especially advantageous for the manufacture of microelectrodes according to the invention may be deduced from phase diagrams of the alloys. Such phase diagrams may be found, for example, in reference (Tl . Preferred microelectrodes according to the invention are those characterized by an electrode potential of between -200 and -3000 mV (Ag/AgCl in 3M KC1), a slope of between 50 and 60 mN/log[ai_on] (at 25°C), and a potential drift smaller than 15mV/hour.

An important consideration that has to be taken into account when designing the thickness of the electrode is its flexibility. For many applications especially flexible electrodes are needed. The flexibility of the electrode is usually expressed in the smallest radius that the electrode can be folded into without braking. From the art of fibers handling it is known that this radius is proportional to the fiber diameter. The proportion coefficient depends upon the specific fiber, and in the case of the microelectrodes of the invention it depends upon the specific alloy and glass used. In the case of an electrode made of Corning 0150 glass encapsulating a lead-sodium alloy it was found that the proportionality coefficient is around 200, which means that an electrode of 50 μm diameter, for instance, can be folded to have a curvature radius as small as 10 mm without breaking. The diameter of the electrical conductor according to the invention is to be determined according to the desirable electrical conductivity of the electrode. However, in the methods of manufacture described above, it is not independent of the thickness of the electrode as a whole. Generally, it was found that diameters between 5 and 300μm are suitable, and that diameters of between 10 and 100 μm are preferable and most preferable are conductors having a diameter between 20 and 30 μm. The exact preferable diameter depends also on the specific alloy used, and its electrical conductivity.

The thickness of the encapsulating glass to be used according to the invention is determined as follows:

The minimal thickness of the encapsulating glass membrane is determined by the minimal thickness that prevents penetration of the test solution through the glass, which is typically around 20μm.

The maximal thickness is determined by the maximal thickness that allows a suitable electrode response. Corning 0150 glass of thickness smaller than 120μm,

(3 for example, gives excellent electrode response in pH measurements . This quality of electrode response decreases when the glass thickness goes above 120μm. Thus, when Corning 0150 glass is used, the glass encapsulation according to the invention should have a thickness of between 20 and 120μ. Preferable glass thickness of Corning 0150 glass for pH-measurements was found to be between 30 to 50μm.

According to another aspect the present invention concerns an array for the determination of the activity of a specific ion in a solution, said array comprising at least two ion-sensitive solid state microelectrodes according to the invention, said at least two microelectrodes being electrically connected to the same point. The same point in this context is not necessarily the same physical point but includes also any two points that are connected by a conductor and that in operation have the same electric potential. This arrangement allows to connect all the microelectrodes in the array in parallel. Such an array of microelectrodes connected in parallel has an effective surface area equal to the sum of the surface areas of the microelectrodes constituting it, while having an electric conductivity equal to the reciprocal of the sum of the electric resistances of these microelectrodes. (This last relation is based on the identity between the resistance and the reciprocal of conductivity). Such an array of microelectrodes allows increasing the effective surface area in respect of a single electrode without adding to its length and without decreasing its flexibility.

By yet another aspect the present invention concerns a system for the determination of the activity of a specific ion in a solution. The system comprises at least one microelectrode of the invention, wherein the metallic core of the microelectrode is connected to a potentiometric device such as a voltmeter. The potential measured by the system can then be calibrated to give the activity of the specific ion in the solution, according to the formula mentioned above.

The invention also concerns a variant of this last system, wherein the electrode of the invention is replaced by an array of the invention and the other components are replaced or adapted accordingly. In particular, it is the same point that all the cores of the electrodes in the array are connected to, as described above, that is connected in this system to the potentiometric device.

The invention also concerns a system for the simultaneous determination of the activity of several specific ions in a solution, said system comprises several microelectrodes according to the invention, wherein the metallic core of the microelectrodes are connected to a potentiometric device, and the potentials measured by the system are capable of being calibrated to give the activity of said several specific ions in the solution. Also provided by the invention is a system for the determination of the activity of several specific ions in a solution, said system comprises several arrays according to the invention, wherein said same point in each of the arrays is connected to a potentiometric device, and the potentials measured by the system are capable of being calibrated to give the activity of said several specific ions. According to another aspect of the invention there is provided a method for determining the activity of a specific ion in a living tissue, the method comprises inserting into the tissue a microelectrode or an array of microelectrodes according to the invention, measuring the electric potential of the electrode or the array vis-a-vis a reference electrode, and converting the measured potential into the ion activity as explained above.

Inserting an array of microelectrodes into a tissue may be eased by mechanically supporting the array, for instance, by inserting it into a hypodermic needle, having pores that allow the solution to reach each individual microelectrodes.

Such a method may be especially useful when the specified ion is hydrogen and the tissue is the scalp of a fetal. The measurement of pH in fetal scalp during the birth is considered a Gold Standard to the determination of fetal distress and lack of oxygen. The invention also concerns a method for determining the activity of a specific ion in body fluids, the method comprises inserting into the body a microelectrode or an array according to the invention as to bring the microelectrode or array in contact with said body fluid, measuring the potential of the electrode or the array by potentiometric equipment, and converting the potential so measured into the activity of said specific ion.

A possible use of this method is to determine pH values in the blood of patients (including grown-ups) that suffer from trauma.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS As mentioned in the background section, Balashov suggested to manufacture microelectrodes for pH measurements. In an attempt to repeat his work, the inventors have produced a microwire, which is not in accordance to the present invention but rather in accordance to the teaching of Balashov. Five 120 μm thick silver microwires encapsulated in a 40 ± 10 μm thick Corning 0150 glass were prepared and tested. They had an electrode potential of 100 ±100 mN that drifted in about 36 to 40 mN per hour at pH=7. The slope was measured to be 40 ± 3mN/pH. The measurements were taken against a reference electrode of Ag/AgCl in KC1 3M at 36.5°C. Microelectrodes in accordance with the invention were prepared using a lead-sodium alloy having 1% by weight sodium and a metal core having a

150±50 μm diameter encapsulated in a 40±10 μm Corning 0150 glass. These electrodes were found to have an electrode potential of -2100±100 mV at pH=7.0 (vs. Ag/AgCl in 3M KC1) and were characterized by a slope of 58±2 mV/pH and a drift of 3±2 mN/hour.

Other pH electrodes that were prepared according to the present invention and their characteristics are given in table 2 below. All these electrodes have been prepared with Corning 0150 glass as the ion selective membrane.

Table 2

Claims

CLAIMS:

1. An ion-sensitive, solid state microelectrode for the determination of the activity of a specific ion in a solution, comprising a glass membrane and a metallic core

5 encapsulated therein, said glass membrane contains a first metal and being selectively penetrable to said specific ion, and said core contains an alloy of said first metal together with at least one other metal.

2. A microelectrode according to claim 1 wherein the core is electrically engaged with a conducting microwire for the connection to an electric potential measuring ιo device.

3. An ion-sensitive, solid state microelectrode according to claim 1, having a ratio of at least 8 mm^" between the surface area of said glass membrane and the volume of said electrode.

4. A microelectrode according to claim 2 wherein the ratio being between 30 and 15 60 mm^" .

5. A microelectrode according to claim 1 with a cross-section peφendicular to its main axis having an area of 0.25mm or less.

6. A microelectrode according to claim 1 with a cross-section peφendicular to its main axis having an area of 0.01mm or less. 0

7. A microelectrode according to claim 1 wherein said specific ion is hydrogen.

8. A microelectrode according to Claim 1, wherein said specific ion is selected from the group consisting of sodium, lithium, potassium, ammonium, silver, and calcium.

9. A microelectrode according to Claim 1, wherein said at least one other metal is 5 selected from the group consisting of lead, tin, silver, gold, platinum, palladium, bismuth, gallium, thallium and cadmium.

10. A microelectrode according to Claim 1 , wherein said at least one other metal is selected from the group consisting of lead, silver, gold, platinum, palladium, bismuth, gallium, thallium and cadmium.

11. A microelectrode according to Claim 1 wherein said at least one other metal 5 is selected from the group consisting of lead, gallium, thallium and cadmium.

12. A microelectrode according to Claim 1 wherein the diameter of said core is between 5 and 300 μm.

13. A microelectrode according to Claim 12 wherein the diameter of said core is between 10 and 100 μm.

10 14. A microelectrode according to Claim 13 wherein the diameter of said core is between 20 and 30 μm.

15. A microelectrode according to Claim 1 wherein the thickness of said glass membrane is between 20 and 120 μm.

16. A microelectrode according to Claim 15 wherein the thickness of said glass 15 membrane is between 30 and 50 μm.

17. A microelectrode according to Claim 1 that the smallest radius it can be folded into without breaking is a radius of 100 mm or less.

18. A microelectrode according to Claim 17 wherein said radius is 20 mm or less.

20 19. A microelectrode according to Claim 18 wherein said radius is 10 mm or less.

20. An array for the determination of the activity of a specific ion in a solution comprising at least two ion-sensitive solid state microelectrodes according to claim 1, said at least two microelectrodes being electrically connected to the same point.

25 21. An array according to claim 20 wherein said at least two electrodes are mechanically supported.

22. An array according to claim 21 wherein said support is provided by a pored hypodermic needle, into which the electrodes of said array are inserted.

23. A system for the determination of the activity of a specific ion in a solution, 30 said system comprises a microelectrode according to claim 1, wherein the metallic core of the microelectrode is connected to a potentiometric device, and the potential measured by the system is capable of being calibrated to give the active concentration of the specific ion in the solution.

24. A system for the determination of the activity of a specific ion in a solution, said system comprises an array according to claim 20, wherein the metallic cores of each individual microelectrode in the array are connected through said same point to a potentiometric device, and the potential measured by the system is capable of being calibrated to give the activity of said specific ion.

25. A system for the simultaneous determination of the activity of several specific ions in a solution, said system comprises several microelectrodes according to claim 1 , wherein the metallic core of the microelectrodes are connected to a potentiometric device, and the potentials measured by the system are capable of being calibrated to give the activity of said several specific ions in the solution.

26. A system for the determination of the activity of several specific ions in a solution, said system comprises several arrays according to claim 20, wherein said same point in each of the arrays is connected to a potentiometric device, and the potentials measured by the system are capable of being calibrated to give the activity of said several specific ions.

27. A method for determining the activity of a specific ion in a living tissue, the method comprises

(i) inserting into the tissue a microelectrode according to claim 1 or an array according to claim 20, (ii) measuring the potential of the electrode or the array by potentiometric equipment, and (iϋ) converting the potential measured in (ii) into the activity of said specific ion.

28. A method according to claim 27 for measuring pH in the scalp of a fetus.

29. A method for determining the activity of a specific ion in body fluids, the method comprises (i) inserting into said body a microelectrode according to claim 1 or an array according to claim 20 so as to bring said microelectrode or array in contact with said body fluid, (ii) measuring the potential of the electrode or the array by potentiometric equipment, and

(iii) converting the potential measured in (ii) into the activity of said specific ion.

30. A method according to claim 29, for measuring the pH in blood of patients that suffer from trauma.