Electrode array for measuring pH of animal tissue, probe comprising such array, and assembly comprising said probe

Abstract

The invention relates to an electrode array (1) for measuring the pH value of animal tissue, comprising an indicator electrode (2) and a reference electrode (3). The reference electrode (3) is in an all-solid state and comprises a steel wire (3a) having an applied layer of an electrically conductive polymer (3b) and a film (3c) containing an ionic liquid and a polyurethane. Furthermore, the invention relates to a probe (11) for continuously measuring the pH value of animal tissue in real time, comprising a main body (12) in the form of a mounting capsule in which the electrode array (1) according to the invention, a vacuum system (13) and a temperature sensor (14) are housed. The vacuum system (13) is designed for attaching the probe (11) to a tissue surface and comprises a vacuum tube (13a) and a vacuum surface (13b), where the temperature sensor (14) is a contact sensor designed for application to the tissue surface. Furthermore, the invention relates to an assembly (111) for measuring pH values, comprising a probe (11) according to the invention, a display device (17) and a calibration solution (24).

Description

[0001] The present invention relates to an electrode array for measuring the pH value of animal tissue.

[0002] More specifically, the present invention relates to a probe for real-time continuous measurement of pH value of animal tissue and a component comprising the probe, the probe comprising the electrode array. Technical Field

[0003] Monitoring tissue pH enables appropriate treatment decisions in many medical procedures. This is particularly true during cardiac surgery, vascular surgery or transplantation.

[0004] During such surgery, tissue acidemia, i.e., a drop in pH below physiological values ​​(eg, below about 6.8 for the myocardium) may occur due to tissue ischemia. Due to this ischemia, irreversible damage and necrosis may occur.

[0005] Tissue acidemia is a parameter that indicates the dominance of dangerous anaerobic metabolism in cells, since the product of this process is mainly lactic acid, whose concentration in tissues leads to a decrease in pH. This acidemia is a strong marker for an increased risk of perioperative mortality and dangerous complications in patients undergoing medical procedures.

[0006] Cardiac surgery can cause myocardial acidosis.

[0007] Most cardiac surgeries require cardioplegia. Only in this way is it possible to open the heart and perform the planned surgical procedure, such as heart valve replacement. In addition, cardioplegia ensures the stability of the surgical field, which is necessary for some manipulations on the heart surface. Temporarily isolating the heart from the patient's natural circulation also leads to the cessation of coronary blood flow, which activates anaerobic metabolism and causes local acidification of the myocardium. This acidification can be monitored by the pH value of the myocardial tissue. In the surgical situation, in order to avoid the activation of pathological anaerobic metabolism, cardioplegia solutions are injected directly into the coronary arteries, which cools the heart, stops its electrical and mechanical activity, and greatly slows down the metabolism of the heart cells, thus temporarily preventing the death of the heart cells. During cardiac surgery, situations in which cardioplegia solutions are ineffective for cardioprotection lead to the restoration of heart cell metabolism in the absence of oxygen supply. Inadequate cardioprotection leading to acidemia and intraoperative heart damage are one of the main causes of mortality and complications after cardiac surgery.

[0008] Monitoring pH is also important for other tissues, primarily muscles. For example, in the case of acute aortic dissection, monitoring the pH of muscle tissue in patients with acute ischemia of the lower or upper limbs allows the identification of acidification of the ischemic tissue and a decision on treatment (reoperation, other surgery, or, in irreversible cases, the need for amputation). Thus, monitoring pH allows an immediate assessment of whether the blood supply to the tissue has improved and whether a new blood supply has been created surgically to the tissue group or body part in question, or whether the acidemia has been eliminated by reimplantation surgery (re-suturing the amputated body part).

[0009] Monitoring pH levels is also important in transplantation. The success of organ transplantation depends on proper protection of the organ during transport (adequate cessation of metabolism). Ineffective protection can lead to premature failure of the transplanted organ, manifested by organ acidemia. Background Art

[0010] Electrode arrays for measuring the pH of animal tissue are known.

[0011] EP1503661 discloses a pH tissue monitoring system. The system comprises a first electrode arranged in the anterior wall of the ventricle and a second electrode arranged in the posterior wall of the ventricle. Known and commercially available silver chloride electrodes are used. The system is arranged in a probe that can be delivered to a certain part of the human body using a catheter and / or an endoscope. The electrodes are sutured to the inside of the tissue.

[0012] FR2744804 discloses a probe for measuring the potential difference between two measurement positions corresponding to the tissue of a human or animal organ. The probe comprises two electrodes. One of the two electrodes is in the form of a needle and is pressed into the tissue. The other electrode (reference electrode) is covered with an elastically deformable porous material and is in the form of a plate and is attached to the surface of the tissue using a wire.

[0013] US10321861 discloses a diagnostic method for estimating the condition of soft tissue in vivo using a pH sensor, such as muscle, fat, composite cells, and tissue cultures (explants) and cell cultures grown in vitro. In addition, the pH sensor can be used for medical diagnosis of organs such as the heart, lungs, and kidneys. The sensor uses a well-known commercial silver chloride electrode as a measuring / reference electrode.

[0014] US8095196 discloses a sensor probe for measuring pH in situ in a human tissue (e.g., cardiovascular) environment. The probe comprises an optical cable and a needle disposed in the tissue environment. The pH measurement result is based on the measurement of light-excited changes, which are transmitted through optical fibers. Summary of the invention

[0015] Therefore, there is a need to provide an electrode array that will allow real-time monitoring of the pH of animal tissue using electromotive force measurements, while meeting the requirements of biocompatibility and mechanical resistance and being independent of the chloride concentration of the tissue being monitored.

[0016] Furthermore, there is a need to provide a probe for real-time monitoring of pH in animal tissue, wherein the pH of a precisely defined area is measured and the probe itself is attached to the tissue surface in a non-invasive manner, i.e. without causing additional disturbances to the consistency of the tissue.

[0017] In addition, there is a need to provide a component comprising a probe, a monitor and a calibration solution for real-time monitoring of the pH value of animal tissue, which component can indicate the absolute pH value of the monitored tissue.

[0018] This object is achieved by an electrode array according to claim 1, a probe according to claim 16 and an assembly according to claim 25. Preferred embodiments are the subject of the dependent claims.

[0019] The object of the present invention is an electrode array for measuring the pH value of animal tissue, the electrode array comprising an indicator electrode and a reference electrode, the reference electrode being all solid and comprising a steel wire with an applied layer of a conductive polymer and a membrane comprising an ionic liquid and polyurethane.

[0020] Preferably, an electrode array according to the invention is intended, characterized in that the indicator electrode is an antimony electrode, a ruthenium(IV) oxide electrode or an electrode having a conductive polymer and a polymer film.

[0021] Preferably, an electrode array according to the invention is intended, characterized in that the indicator electrode is an antimony electrode deposited on a steel wire using a galvanostatic technique.

[0022] Preferably, the object is an electrode array according to the present invention, characterized in that the indicator electrode is an electrode having a deposited conductive polymer and a polymer film layer containing pH-sensitive ion carriers, wherein the conductive polymer is deposited on the steel wire using a constant current technique and the polymer film is deposited using a dip coating technique.

[0023] Preferably, an electrode array according to the invention is intended, characterized in that the conducting polymer in the reference electrode can be selected from PEDOT:PSS [poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid)], polypyrrole or polyaniline.

[0024] Preferably, an electrode array according to the invention is provided, characterized in that the conducting polymer in the reference electrode is PEDOT:PSS [poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid)].

[0025] Preferably, an electrode array according to the invention is intended, characterized in that the conductive polymer in the reference electrode is applied to the steel wire by electropolymerization or a ready-made suspension with the conductive polymer.

[0026] Preferably, an electrode array according to the invention is provided, characterized in that the reference electrode membrane contains 1% to 5% of ionic liquid in polyurethane.

[0027] Preferably, an electrode array according to the invention is provided, characterized in that the reference electrode membrane contains 2% of ionic liquid in polyurethane.

[0028] Preferably, the object is an electrode array according to the present invention, characterized in that the ionic liquid in the reference electrode membrane is selected from 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, 1-butyl-3-methylimidazolinium hexafluorophosphate, 1-butyl-3-methylimidazolinium acetate, 1-butyl-3-methylimidazolinium chloride, acetic acid choline and / or phosphorylcholine.

[0029] Preferably, an electrode array according to the invention is provided, characterized in that the ionic liquid in the reference electrode membrane is 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide.

[0030] Preferably, an electrode array according to the invention is intended, characterized in that the reference electrode film comprises 4 mg of 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide and 196 mg of polyurethane.

[0031] Preferably, an electrode array according to the invention is provided, characterized in that the reference electrode membrane comprises plasticized polyurethane or unplasticized polyurethane.

[0032] Preferably, an electrode array according to the invention is intended, characterized in that the reference electrode and the indicator electrode are in the form of wires or needles.

[0033] Preferably, an electrode array according to the invention is intended, characterized in that the diameter of the reference electrode and the indicator electrode is in the range of 0.2 mm to 1.5 mm.

[0034] Preferably, an electrode array according to the invention is intended, characterized in that the reference electrode and the indicator electrode have a diameter of 0.5 mm.

[0035] The object of the present invention is also a probe for real-time continuous measurement of the pH value of animal tissue, which comprises a body in the form of a capsule, in which an electrode array according to the present invention, a vacuum system, and a temperature sensor are housed. The vacuum system is designed to attach the probe to the tissue surface and comprises a vacuum tube and a vacuum surface. The temperature sensor is a contact sensor designed to be applied to the tissue surface.

[0036] Preferably, a probe according to the invention is intended, characterized in that the temperature sensor is applied to the outer surface of the tissue.

[0037] Preferably, a probe according to the invention is intended, characterized in that the probe comprises a suction cup envelope at the periphery of its point of attachment to the tissue.

[0038] Preferably, a probe according to the invention is intended, characterized in that the probe comprises a signal cable connecting the indicator electrode, the reference electrode and the temperature sensor and the display device for the pH measurement result.

[0039] A preferred object is a probe according to the invention, characterized in that said display device is a monitor.

[0040] Preferably, the object is a probe according to the invention, characterized in that the probe body is made of a material selected from the group consisting of medical silicone, acrylonitrile-butadiene-styrene terpolymer (ABS), HDPE, LDPE, polypropylene, PETG, polycarbonate, polyester, Kydex, POM, acetal copolymer, PET-P, Polybutylene terephthalate-polyester (PBT-P), polyvinylidene fluoride, modified polyphenylene ether, polyamide fiber, PEEK, polyethylene (including LDPE, HDPE and UHMW), polypropylene homopolymer, PPSU, PSU, A. R, Rulon 641, composite materials and their blends.

[0041] Preferably, a probe according to the invention is intended, characterized in that the body of the probe is made of an acrylonitrile-butadiene-styrene terpolymer.

[0042] Preferably, the object is a probe according to the present invention, characterized in that the probe has a lower main body and an upper main body, the lower main body comprising a channel and cable path for a temperature sensor, a channel and cable path for an indicator electrode, a channel and cable path for a reference electrode, a lead and a latch plate for a signal cable, the upper part of the main body comprising a clamp and a latch groove for the signal cable, the lower latch plate and the upper latch groove being a latch mechanism.

[0043] Preferably, a probe according to the invention is intended, characterized in that the probe has a cylindrical shape.

[0044] The subject of the invention is also an assembly for measuring the pH value, comprising a probe according to the invention, a display device and a calibration solution.

[0045] According to the present invention, the pH value of a specific area of ​​an animal tissue can be accurately monitored in real time, while taking into account the influence of temperature, and the measurement result is independent of the chloride concentration in the controlled area. Many prior art solutions use glass electrodes as indicator electrodes, but their low mechanical resistance increases the risk of electrode damage during the measurement process. On the other hand, silver chloride electrodes without electrolytes (so-called pseudo-reference electrodes) are usually used as reference electrodes and are sensitive to chloride ions, the concentration of which changes during the measurement process (for example, KCl is contained in the cardioplegia solution). The disadvantage of the previously used silver chloride electrodes is that chloride ions are present in the tissue and constantly change their local concentration, so chloride ions have an interfering effect on pH measurement. The present invention also enables the probe to be attached to the tissue non-invasively, i.e., no additional damage is caused to the tissue, thereby eliminating mechanical attachment means (such as using a wire). Therefore, it is possible to easily and quickly place the probe (on the tissue) and accurately measure the pH value, and eliminate the risk of bleeding. According to the present invention, pH measurement is performed at a predetermined tissue depth each time. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] The present invention will now be described with reference to the accompanying drawings, in which:

[0047] Figure 1

[0048] [Figure 1] shows the results of mechanical resistance testing of indicator electrodes made of antimony-coated surgical steel; [ Figure 1a ] shows the dynamic response of the electrode before insertion into the tissue sample, [ Figure 1b ] shows the dynamic response of the electrode after insertion into the tissue sample, [ Figure 1c ] shows the electrode calibration curve before the electrode is inserted into the tissue sample, [ Figure 1d ] shows the electrode calibration curve after the electrode is inserted into the tissue sample.

[0049] Figure 2

[0050] [ Figure 2 ] shows the potential variation of an electrode array according to the invention, wherein the successive stages of acid diffusion in a gelatin block are illustrated graphically.

[0051] Figure 3

[0052] [ Figure 3 ] shows the potential variation trend recorded for a cell consisting of an antimony indicator electrode and a reference electrode having a polymer film containing the ionic liquid bis(trifluoromethylsulfonyl)imide 1-ethyl-3-methylimidazolium.

[0053] Figure 4

[0054] [ Figure 4 ] schematically shows an electrode array according to the present invention.

[0055] Figure 5

[0056] [ Figure 5 ] schematically shows a pH probe according to the present invention.

[0057] Figure 6

[0058] [ Figure 6 ] A pH probe according to the present invention is schematically shown in the form of a "top view".

[0059] Figure 7

[0060] [ Figure 7 ] shows a pH probe in an unfolded state according to the present invention, which is divided into a lower main body part and an upper main body part.

[0061] Figure 8

[0062] [ Figure 8 ] shows a pH probe in a folded state according to the present invention.

[0063] Fig. 9

[0064] [ Fig. 9 ] shows a schematic diagram of a method for protecting and subsequently detecting acidification of human myocardium.

[0065] Fig.10

[0066] [ Fig.10 ] schematically shows a pH probe according to the present invention attached to the surface of the heart. DETAILED DESCRIPTION

[0067] Only the details necessary for understanding the invention are shown in the drawings. In order to emphasize only the features of the invention, structures and details that are not necessary for understanding the invention but are obvious to those skilled in the art are omitted in the drawings.

[0068] Electrode array

[0069] The electrode array for measuring the pH value of animal tissue according to the present invention comprises:

[0070] indicator electrode, and

[0071] Reference electrode.

[0072] Indicator electrode

[0073] The indicator electrode is a stainless steel wire with deposited antimony, ruthenium (IV) oxide or a conductive polymer and a polymer film layer. Preferably, the indicator electrode is an electrode made of stainless steel, such as SS 316L surgical steel, with deposited antimony or deposited conductive polymer and a polymer film layer. The polymer film layer in the electrode with deposited conductive polymer and polymer film layer includes a pH-sensitive ion carrier.

[0074] The deposition of antimony, ruthenium (IV) oxide or conductive polymer on the indicator electrode can be carried out by constant current technique or galvanodynamic polarization technique. Preferably, the deposition is carried out by constant current technique. The polymer film layer of the electrode having the conductive polymer and the polymer film layer is deposited using a dip coating technique.

[0075] The diameter of the steel wire in the indicator electrode may range from 0.2 mm to 1.5 mm. Preferably, the diameter is 0.5 mm, which provides a good compromise between mechanical resistance and low invasiveness when placed in tissue.

[0076] The indicator electrode is in the form of a wire or a needle.

[0077] The length of the indicator electrode (i.e., its active portion - the portion that performs the measurement) is in the range of 0.1 cm to 0.9 cm. Preferably, the length is in the range of 0.5 cm to 0.6 cm. This is related to the depth of insertion of the electrode into tissue, such as myocardial tissue. By inserting the electrode to such a depth, optimal pH measurements, particularly of the myocardium, can be obtained. The length of the electrode is related to the expected depth of insertion into the tissue and can vary depending on the tissue being tested.

[0078] Production of indicator electrodes

[0079] Prepare the antimony indicating electrode according to the following steps.

[0080] The antimony deposition solution is prepared so as to contain:

[0081] Potassium antimony tartrate K2Sb2(C4H2O6)2·3H2O (1.002 g);

[0082] KCI (0.134 g);

[0083] HCl concentration - add dropwise with stirring until the precipitate dissolves (about 5 ml);

[0084] H2O(20ml).

[0085] A stainless steel wire (0.5 mm in diameter and 6 cm in length) (SS 316L surgical steel) was degreased with acetone. Prior to antimony deposition, the steel was prepared by electrochemical etching in a 38 g / L NaOH solution (galvanostatic process with an anodic current of 0.0216 A for a duration of 120 seconds) and etching in a 10% H2SO4 solution (15 minutes). The antimony layer was deposited on this substrate. The following electrochemical deposition parameters were used: Galvanostatic deposition: cathodic current of 0.00152 A, deposition time of 120 seconds or 240 seconds.

[0086] Deposition of 120 seconds produced a well-adherent antimony layer, whereas deposition times longer resulted in a thicker antimony layer with poor adhesion to the steel. The slopes of the calibration curves for all electrodes in the pH range of 4-8 were in the range of 45-47 mV / pH. The repeatability of the electrode potentials generated under the same conditions was observed in the range of 5 mV. Potential oscillations were evident in the range below 1 mV.

[0087] The ruthenium(IV) oxide indicator electrode was prepared as follows.

[0088] A wire of stainless steel (SS 316L surgical steel) (0.5 mm diameter, 6 cm length) was degreased with acetone. Before ruthenium deposition, the steel was prepared by electrochemical etching in a 38 g / L NaOH solution (galvanostatic process, anodic current of 0.0216 A, duration of 120 seconds) and etching in a 10% H2SO4 solution (15 minutes). A RuO2 layer was deposited on this substrate. The following deposition method was used:

[0089] Cyclic voltammetry (CV): potential from -0.7 V to 0.5 V, 0.05 V / s, 15 cycles;

[0090] Constant potential deposition: potential -0.6 V, 180 seconds;

[0091] Constant current deposition: cathodic current of 0.01 A for 300 seconds.

[0092] In addition, before ruthenium deposition, a nickel coating was prepared on part of the electrode: 4.8 g NiCl2·6H2O solution, 1.66 ml hydrochloric acid, 20 ml water. Constant current deposition was used (cathode current was 0.016 or 0.01 A, 300 seconds).

[0093] Deposition using the CV technique did not provide the expected results, whereas electrostatic and galvanostatic deposition gave positive results. The electrode was characterized by a slope of the calibration curve in the range of 52-56 mV / pH in the pH range of 4-8. For the electrode with the galvanostatically deposited layer, a better potential convergence was observed between the individual specimens (potential spread of about 8 mV).

[0094] The electrode with the nickel adhesion layer showed a potential drift after about 4-5 minutes of immersion in the solution. The electrode without this layer was characterized by a stable potential.

[0095] The electrodes with the conductive polymer and the polymer film were prepared according to the following steps.

[0096] Wires of SS 316L surgical steel (0.5 mm diameter, 6 cm length) were degreased with acetone and electrochemically deposited with a PEDOT:PSS conductive polymer layer. Electropolymerization was carried out in an aqueous solution containing 0.1 M NaPSS and 0.01 M PEDOT. Galvanostatic deposition was carried out with an anodic current of 0.0785 mA for a duration of 714 seconds. Subsequently, a membrane of the following components was applied to the electrode by dip coating in two portions (15 min interval): H+I ionophore (Hydrogen Ionophore I, Merck catalog number 95292), 198 mg PU dissolved in 1.5 ml THF and 0.5 mg ion additive, potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. As the other components of the membrane, a polyether-based thermoplastic polyurethane (e.g. Tecoflex EG-80A from Lubrizol) was used. After drying, the electrode was conditioned for 8 h in a PBS solution at a pH of 7.4.

[0097] The electrodes with the conductive polymer and polymer membrane were calibrated using conventional solutions such as PBS.Testing confirmed that the electrodes prepared in this manner provided pH measurement sensitivity suitable for use in the present invention.

[0098] Testing the mechanical resistance of antimony electrodes

[0099] The four electrodes were calibrated to pH values ​​between 7.4 and 6.4 using PBS solution (in 0.2 pH increments). Each electrode was then inserted five times into an animal tissue sample (chicken breast) to a depth of approximately 5 mm. The electrodes were rinsed with distilled water from a water jet and recalibrated in the same manner. These figures show the pH electrodes made of antimony-coated steel wire before the electrodes were inserted five times into a chicken breast tissue sample ([ Figure 1a ]、[ Figure 1c ]) and after ([ Figure 1b ]、[ Figure 1d ])'s dynamic response ([ Figure 1a ]and[ Figure 1b ]) and calibration curve ([ Figure 1c ]]and[ Figure 1d ]). Neither the sensitivity nor the reversibility of the pH measurements changed significantly. Comparison of the results showed that the electrodes tested were not damaged when inserted into meat, which simulates their insertion into, for example, cardiac tissue ([ Figure 1a -d]).

[0100] Optimal adhesion properties of antimony layers and their mechanical wear resistance

[0101] In order to improve the adhesion of the antimony layer to the steel wire, deposition at lower current density was tested. For this purpose, wire sections of SS 316L surgical steel (0.5 mm diameter, 6 cm length) were degreased and prepared by electrochemical etching according to the above disclosed procedure. The electrochemical deposition parameters used were selected to keep the charge used in the previously described deposition process at a lower current density. Electrochemical parameters: Constant current deposition: cathodic current was 0.00076 A, deposition time was 240 seconds.

[0102] The electrode obtained is characterized by a slope of the calibration curve in the range of 46-47 mV / pH and pH values ​​in the range of 7.4-6.4, but some hysteresis of the response is observed depending on the direction of the pH variation. In addition, the adhesion of the antimony layer is weaker than that of the electrodes obtained at higher current densities. Therefore, the antimony deposition parameters obtained previously should be considered optimal.

[0103] Optimized structure of antimony indicator electrode

[0104] SS 316 surgical steel wire, 5 mm long and 0.5 mm in diameter (active part), was degreased by cleaning with acetone and electrochemically etching in 38 g / L NaOH solution (galvanostatic process, anodic current 0.00432 A, duration 120 s). Antimony deposition from solution:

[0105] Potassium antimony tartrate K2Sb2(C4H2O6)2·3H2O (1.002 g);

[0106] KCl (0.134 g);

[0107] HCl concentration (about 5 ml);

[0108] H2O(20ml).

[0109] The electrochemical parameters of the deposition process were as follows: cathode current 0.000304 A, deposition time 120 s.

[0110] in conclusion

[0111] During testing, it was found that the ruthenium oxide indicator electrode had good pH sensitivity; however, the adhesion of the RuO2 layer to stainless steel was poor. An attempt was made to improve the adhesion by using an adhesion layer in the form of electroplated nickel. This did not produce the expected results. In addition, further attempts to optimize the deposition process, i.e., changing the deposition technique used (constant current and galvanic deposition), the current density, and the composition of the plating solution, did not produce the expected results.

[0112] Antimony indicating electrodes do not cause adhesion problems of the pH sensitive layer to stainless steel. Antimony deposition is performed using both constant current and galvanodynamic techniques; however, electrodes prepared constant current are characterized by preferred electrochemical parameters. Therefore, as indicating electrodes, electrodes made of steel wire on which antimony is deposited using the constant current technique are optimal.

[0113] Reference electrodes with conductive polymers and polymer films exhibit high mechanical resistance and good adhesion to stainless steel wires. The deposition of conductive polymers is carried out using constant current and galvanodynamic techniques. Electrodes produced by electroplating are preferred from the point of view of electrochemical performance. Therefore, as indicator electrodes with conductive polymers and polymer films, electrodes made of steel wires, on which the conductive polymers are deposited using constant current techniques and the polymer films are deposited using dip coating, are optimal. Such electrodes include pH-sensitive ion carriers and conductive polymer layers. Depending on the structure, electrodes with conductive polymers and polymer films may also contain plasticizers, such as dioctyl sebacate.

[0114] Reference electrode

[0115] The reference electrode is a fully solid-state electrode. The reference electrode is a stainless steel wire, e.g. surgical steel SS 316L, with an applied layer of a conductive polymer and a membrane containing an ionic liquid and polyurethane.

[0116] The conductive polymer in the reference electrode may be selected from PEDOT:PSS [poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid)], polypyrrole or polyaniline. Preferably, the conductive polymer in the reference electrode is PEDOT:PSS [poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid)].

[0117] Preferably, the conductive polymer in the reference electrode is applied to the steel wire using electropolymerization or a ready-made suspension with the conductive polymer. More preferably, the conductive polymer in the reference electrode is applied to the steel wire by electropolymerization.

[0118] Preferably, the reference electrode membrane contains 1% to 5% ionic liquid in polyurethane. More preferably, the reference electrode membrane contains 2% ionic liquid in polyurethane.

[0119] Preferably, the ionic liquid in the reference electrode film is selected from the group consisting of 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, 1-butyl-3-methylimidazolinium hexafluorophosphate, 1-butyl-3-methylimidazolinium acetate, 1-butyl-3-methylimidazolinium chloride, acetic acid choline and / or phosphoryl choline. More preferably, the ionic liquid in the reference electrode film is 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide.

[0120] Preferably, the reference electrode membrane comprises 4 mg of 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide and 196 mg of polyurethane dissolved in 1.5 ml THF.

[0121] The reference electrode film comprises plasticized polyurethane or unplasticized polyurethane. Preferably, the polyurethane is unplasticized.

[0122] The reference electrode may be in the form of a wire or a needle.

[0123] The length of the reference electrode is in the range of 0.1 cm to 0.9 cm (its active part). Preferably, the length is in the range of 0.5 cm to 0.6 cm. This is related to the depth of insertion of the electrode into the tissue (such as myocardial tissue). By inserting the electrode to such a depth, the best pH measurement results, especially pH measurements of the myocardium, can be obtained. The length of the electrode is related to the expected depth of insertion into the tissue and can be adjusted accordingly depending on the tissue being tested.

[0124] Production of reference electrodes

[0125] The reference electrode with PEDOT:PSS was prepared according to the following steps. A wire section of SS 316L surgical steel (0.5 mm in diameter and 6 cm in length) was degreased with acetone and coated with a layer of the conductive polymer PEDOT:PSS in the form of a commercial suspension (2.8% by weight dispersed in water, Sigma-Aldrich, USA, product number: 560596). After drying (30 minutes), a film consisting of 15 mg of ionic liquid, 92.5 mg of PU and 92.5 mg of o-nitrophenyl octyl ether (plasticizer) was dissolved in 1.5 ml of THF. After drying, the electrode was conditioned in a 10-3 M NaCl solution for 16 hours. The electrode thus prepared had an average potential drift of about 1 mV / hour in a 12-hour measurement.

[0126] Optimal membrane adhesion and mechanical wear resistance are achieved, i.e. the risk of the membrane being retained in the cardiac tissue is reduced.

[0127] Removal of plasticizers:

[0128] To increase the mechanical resistance of the reference electrode, the membrane is made of a polyurethane matrix without plasticizers. Previously, a PU / plasticizer (o-nitrophenyl octyl ether) matrix with a 1:1 mass ratio was used, but such membranes tended to fall off the steel wires and stick together during storage.

[0129] Furthermore, to obtain better adhesion, the steel wire was degreased with acetone and electrochemically cleaned—electrochemically etched in 38 g / L NaOH solution with an anodic current of 0.0216 A for 120 s, and etched in 10% H2SO4 solution for 15 min.

[0130] A conductive polymer PEDOT:PSS layer in the form of a suspension was applied to the substrate and prepared thereby. After drying (30 minutes), a film containing 4 mg of ionic liquid and 196 mg of PU was dissolved in 1.5 ml of T1F. After drying, the electrode was conditioned in a PBS solution with a pH value of 7.4 for 16 hours.

[0131] The adhesion of the membrane to the steel substrate and the mechanical properties of such electrodes were significantly improved. No peeling of the membrane from the wire (which would have prevented the electrode from working) or adhesion of the electrodes to each other during storage (which would have caused damage to the membrane when trying to separate them) was observed.

[0132] Thicker film layers:

[0133] The reference electrode is coated with a polymer film by immersing the conductor of the applied layer of the conductive polymer into a solution of the membrane components (dip coating technique). During the testing of this electrode, it was found that damage to this film was common, resulting in high potential drifts. In order to increase the mechanical resistance of the reference electrode, an electrode with a thicker film was prepared. The steel conductor was degreased with acetone and electrochemically cleaned in a NaOH solution. The conductive polymer layer PEDOT:PSS was electrochemically applied to the substrate and prepared thereby. Subsequently, a film containing 4 mg of ionic liquid and 196 mg of PU was dissolved in 1.5 ml of T1F and applied to the electrode four times (15 minutes apart). After drying, the electrode was placed in a PBS solution with a pH value of 7.4 for adjustment for 16 hours. The potential stability of these electrodes was then tested in the same solution for 8 hours.

[0134] For the electrode thus prepared, the average drift at this time is 0.64 mV / h. Considering the theoretical value of the slope of the calibration curve for pH (59.2 mV / pH unit) and the expected maximum application time of the device (about 2-4 hours), it should be considered that the drift of the measured reference electrode potential is very small and therefore will not affect the pH measurement result.

[0135] Potentials between arrays remain convergent for repeatable production performance.

[0136] This feature was achieved by changing the application technique of the conductive polymer. The conductive polymer layer (PEDOT / PSS) was applied using an electropolymerization technique (previously, the conductive polymer layer was applied from a suspension, which was an obstacle to ensuring reproducibility).

[0137] The purified stainless steel wire was electropolymerized in an aqueous solution containing 0.1 M NaPSS and 0.01 M EDOT. The deposition was carried out with a constant current, an anodic current of 0.0785 mA, and a duration of 714 seconds. The electrode thus prepared was placed in PBS with a pH value of 7.4 for 8 hours.

[0138] The electrode was tested for potential stability of the reference electrode in PBS solutions with a pH range of 7.4 to 6.4 and back to 7.4 (every 0.2 pH unit change). The electrode potential converged better between samples when it was within 15 mV. Importantly, the electrode potential remained in the same range when inserted into a chicken breast tissue sample, which simulates the intended use of the device.

[0139] A potential stability of the potential drift of up to 1.5 mV / h was achieved within 8 hours.

[0140] The potential stability of the electrode prepared in the above manner was tested. The buffer was tested for 2 hours and 8 hours. When measured over 8 hours, the average potential drift of the prepared electrode was about 1.5 mV / h.

[0141] Despite membrane damage, the measuring capability is maintained.

[0142] The potential was then measured in PBS solutions at pH 7.4 and 6.4 before and after mechanical damage to the membrane. The membrane was damaged in two ways: first by firmly squeezing the electrode (about 3 mm from the end) with slotted tweezers and then by scraping the membrane three times with a razor blade.

[0143] The electrode arrays tested maintained significantly better potential stability than previously tested electrodes with a conductive polymer layer applied from a suspension. Because the conductive polymer layer applied by electroporation adheres better to the substrate, these electrodes have a stronger mechanical resistance.

[0144] The minimum effective amount of ionic liquid is used to ensure greater biocompatibility and reduce toxic effects on cardiac cells.

[0145] The influence of the amount of ionic liquid in the polymer membrane was tested. For this purpose, membranes were prepared containing 1%, 2%, 3% or 5% of ionic liquid in a matrix with the remainder being polyurethane. These tests were carried out in a classic microelectrode (Electrode Body ISE, Merck, catalog number 45137), which makes the results more reproducible. The test results showed slight differences in the potential stability of the electrodes tested, since the compound with the least ionic liquid content - 2% - had the lowest cost and the highest biocompatibility and the least risk of negative effects on heart cells, it was decided that this compound was considered the best choice.

[0146] Biocompatibility is achieved through the choice of ionic liquids while maintaining measurement capabilities.

[0147] The acute cytotoxicity of the reference electrode assembly was evaluated. The results obtained showed that the electrode containing the ionic liquid selected from 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, 1-butyl-3-methylimidazolinium hexafluorophosphate, 1-butyl-3-methylimidazolinium acetate, 1-butyl-3-methylimidazolinium chloride, acetic acid choline, phosphorylcholine did not show significant toxicity.

[0148] 1-Ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide was designated as the ionic liquid for the reference electrode due to its best potentiometric performance (good potentiometric stability in PBS test solutions with pH values ​​ranging from 7.4 to 6.4 and then constant at pH 7.4 for 8 h) and lowest cytotoxicity.

[0149] Cytotoxicity-based biocompatibility testing was performed according to the procedures of ISO 10993-5:2009(E) and ISO 10993-12:2021(E) standards.

[0150] Optimal reference electrode structure

[0151] SS 316 surgical steel wire, 5 mm long and 0.5 mm in diameter (active part), was cleaned with acetone and electrochemically etched for degreasing in 38 g / L NaOH solution (galvanostatic process, anodic current of 0.00432 A for 120 seconds). A PEDOT:PSS transition layer was deposited, containing an aqueous solution of 0.1 M NaPSS and 0.01 M EDOT. Galvanostatic deposition was performed with an anodic current of 0.0157 mA for 700 seconds. Subsequently, a film containing 4 mg of ionic liquid (1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) and 196 mg of PU dissolved in 1.5 ml of THF was applied to the electrode in four times (by immersion). After drying of the THF, the electrode was conditioned in a PBS solution with a pH of 7.4 for 16 hours.

[0152] in conclusion

[0153] During testing, it was found that the most convenient option was a reference electrode comprising a polymer membrane containing an ionic liquid that forms a homogeneous solution with the polymer matrix.

[0154] Polyurethane was identified as the polymer matrix. Polyurethane has better adhesion to solid substrates and better biocompatibility than previously known matrices such as plasticized polyvinyl chloride.

[0155] The possibility of using films without added plasticizers was also tested. Surprisingly, it was found that the potential stability is satisfactory for films without plasticizers, and therefore a preferred variant of the invention involves the use of unplasticized films made of polyurethane.

[0156] The possibility of using an intermediate layer in the form of a conducting polymer layer between the membrane and the transducer (steel wire) in the reference electrode was also tested. Unexpectedly, it was found that inserting a PEDOT:PSS conducting polymer layer between the membrane containing the ionic liquid and the steel wire provided excellent electrode performance.

[0157] Electropolymerization of polymers and application of commercially available polymer suspensions were used. It was observed that electrodes to which the transition layer of conducting polymers was applied by electropolymerization had better potential stability.

[0158] It was also found that the amount of ionic liquid introduced into the polymer membrane of the reference electrode is an important parameter. Higher amounts of this compound improve the stability of the electrode potential, but this reduces the biocompatibility. Membranes containing 1%, 2%, 3% or 5% ionic liquid in the polyurethane membrane were tested. It was found that a 2% ionic liquid content in the membrane was sufficient to stabilize the electrode potential, so this amount was determined to be the optimal value.

[0159] In order to improve the biocompatibility of the electrode, membranes containing 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, 1-butyl-3-methylimidazolium hexafluorophosphate, 1-butyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium chloride, acetic acid choline or phosphorylcholine were prepared. Among them, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide and 1-butyl-3-methylimidazolium acetate are the best choices for stabilizing the reference electrode potential. Biocompatibility tests concluded that 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide would be the best choice.

[0160] Electrode array structure

[0161] In order to demonstrate the effect of the electrode array according to the present invention, a test was conducted with a gelatin block. A gelatin solution was prepared to measure the potential change: 5 g of gelatin, 0.9 g of NaCl, 5 cm3 of saturated bromothymol blue solution and 100 cm3 of water. The pH value of the solution was adjusted to 7.2 using NaOH. The entire solution was heated in a water bath to dissolve the gelatin. The solution was poured into a glass ring with a diameter of 24 mm and placed in a refrigerator for concentration.

[0162] The measurement was performed using an antimony electrode or an electrode with a polymer film obtained at a deposition time of 120 seconds and a reference electrode composed of a film with 15 mg of ionic liquid and 92.5 mg of PU. The electrode was placed into the block from the top to a depth of about 5 mm. The block was placed on a petri dish into which a 0.1 M H3PO4 solution was poured.

[0163] The diffusion of the acid in the block was observed by the color change of bromothymol blue from green to yellow (in [ Figure 2 ], you can see that the blocks gradually become darker).

[0164] The potential change process is as follows [ Figure 3 The increase in electromotive force recorded by a cell consisting of an antimony indicator electrode and a reference electrode having a polymer membrane containing the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide demonstrated the correct operation of the electrode array.

[0165] Similar results of potential change were obtained when a polymer film electrode was used as the indicator electrode instead of the antimony electrode.

[0166] Experiments have confirmed that the electrode array according to the present invention has the characteristics of measuring the electromotive force of a sample and thus determining the pH value.

[0167] like[ Figure 4 ] as shown in FIG. 1 , an electrode array 1 for measuring the pH value of animal tissue according to a variant embodiment of the present invention includes an indicator electrode 2 and a reference electrode 3.

[0168] The reference electrode 3 is all solid and comprises a steel wire 3a with an applied layer of a conductive polymer 3b and a membrane 3c comprising an ionic liquid and polyurethane.

[0169] In a preferred variant embodiment, the electrode array 1 includes an indicator electrode 2 and a reference electrode 3. The indicator electrode 2 is a wire of SS 316L surgical steel with a deposited antimony layer. The indicator electrode 2 has a diameter of 0.5 mm and is needle-shaped. The antimony layer is deposited using a constant current technique. The reference electrode 3 is a wire 3a of SS 316L surgical steel, which has a layer of deposited conductive polymer 3b, which is PEDOT:PSS [poly (3,4-ethylenedioxythiophene) -poly (styrenesulfonic acid)], and has a film 3c containing ionic liquid bis (trifluoromethylsulfonyl) imide 1-ethyl-3-methylimidazolium (4 mg) and polyurethane (196 mg). The polyurethane is unplasticized polyurethane. The reference electrode 3 has a diameter of 0.5 mm and is needle-shaped. The layer of conductive polymer 3b and the ionic liquid film 3c are deposited using an electropolymerization technique.

[0170] Other possible example embodiments of the present invention are described below.

[0171] In an exemplary embodiment, indicator electrode 2 may be a ruthenium (IV) oxide electrode.

[0172] In an exemplary embodiment, the indicator electrode 2 may be an electrode having a conductive polymer and a polymer film. Such a polymer film electrode includes a pH-sensitive ion carrier in the polymer film.

[0173] In an exemplary embodiment, the conductive polymer 3b in the reference electrode 3 is applied to the steel wire 3a using a ready-made suspension with the conductive polymer 3b.

[0174] In an exemplary embodiment, the indicator electrode 2 and the reference electrode 3 may be coated with a substance that prevents platelets from adhering to the electrodes. Preferably, the substance may be

[0175] In the exemplary embodiment, the polyurethane of the membrane 3 c of the reference electrode 3 contains 1% to 5% of the ionic liquid.

[0176] In the exemplary embodiment, the polyurethane of the membrane 3 c of the reference electrode 3 contains 2% of the ionic liquid.

[0177] In an exemplary embodiment, the ionic liquid in the membrane 3c of the reference electrode 3 is selected from the group including: 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, 1-butyl-3-methylimidazolinium hexafluorophosphate, 1-butyl-3-methylimidazolinium acetate, 1-butyl-3-methylimidazolinium chloride, acetic acid choline and / or phosphorylcholine.

[0178] In the exemplary embodiment, the membrane 3 c of the reference electrode 3 comprises unplasticized polyurethane.

[0179] In the exemplary embodiment, the reference electrode 3 and the indicator electrode 2 are in the form of wires, which means that the tips of the electrodes to be inserted into the tissue are blunt, rather than sharp.

[0180] In another exemplary embodiment, the reference electrode 3 and the indicator electrode 2 are in the form of needles, which means that the tips of the electrodes to be inserted into the tissue are pointed.

[0181] [ Figure 5 ] shows a probe 11 for real-time continuous measurement of the pH value of animal tissue according to the present invention. The probe 11 includes a body 12 in the form of a mounting capsule, which accommodates an electrode array 1, a vacuum system 13, a temperature sensor 14 and a signal cable 16. The electrode array 1 includes an indicator electrode 2 and a reference electrode 3, the reference electrode 3 is fully solid and includes a steel wire 3a having an applied layer of a conductive polymer 3b and a membrane 3c containing an ionic liquid and polyurethane. The vacuum system 13 is designed to attach the probe 11 to the tissue surface and includes a vacuum tube 13a and a vacuum surface 13b. The temperature sensor 14 is a contact sensor designed for application to the outer surface of the tissue.

[0182] In an exemplary embodiment, the electrode array 1 included in the probe 11 according to the present invention includes an indicator electrode 2 and a reference electrode 3. The indicator electrode 2 is a wire of SS 316L surgical steel with a deposited antimony layer. In another exemplary embodiment, the indicator electrode 2 is a wire of SS 316L surgical steel with a deposited polymer film layer, which includes a pH-sensitive ion carrier on a conductive polymer layer. The diameter of the indicator electrode 2 is 0.5 mm and is needle-shaped. According to a variant embodiment, the antimony layer or the polymer film layer is deposited using a constant current technique. The reference electrode 3 is a wire 3a of SS 316L surgical steel, which has a layer of a deposited conductive polymer 3b, which is PEDOT:PSS [poly (3,4-ethylenedioxythiophene) -poly (styrenesulfonic acid)], and it also has a film 3c containing an ionic liquid bis (trifluoromethylsulfonyl) imide 1-ethyl-3-methylimidazolium (4 mg) and polyurethane (196 mg). The polyurethane is unplasticized polyurethane. The reference electrode 3 has a diameter of 0.5 mm and is needle-shaped. The layer of conductive polymer 3b and the ionic liquid film 3c are deposited using electropolymerization techniques.

[0183] In an example embodiment, the temperature sensor 14 is a PT-1000 temperature sensor.

[0184] In an exemplary embodiment, probe 11 includes a suction cup cuff 15 at the periphery of its point of attachment to the tissue.

[0185] In an exemplary embodiment, the body 12 of the probe 11 is made of a medical biocompatible material selected from the following: medical silicone, acrylonitrile-butadiene-styrene terpolymer (ABS), HDPE, LDPE, polypropylene, PETG, polycarbonate, polyester, Kydex, POM, acetal copolymer, PET-P, Polybutylene terephthalate-polyester (PBT-P), polyvinylidene fluoride, modified polyphenylene ether, polyamide fiber, PEEK, polyethylene (including LDPE, HDPE and UHMW), polypropylene homopolymer, PPSU, PSU, A. R, Rulon 641, composite materials and their blends.

[0186] In an exemplary embodiment, the probe 11 has a cylindrical shape. The cylindrical shape of the probe ensures the safety of the tissue being measured for pH as well as the surrounding tissue. The absence of sharp edges makes it impossible to accidentally cut into the tissue, break the surface or otherwise damage the tissue.

[0187] In an exemplary embodiment, the height of the probe 11 is 6 mm. This height is understood to be the distance between the edge defining the suction surface (the bottom surface of the lower part of the body 12) and the edge defining the top surface of the upper part of the body 12. The reason for such a size of the probe (in the case of cardiac surgery) is that the best place to apply the probe in cardiac surgery is the bottom wall of the heart, at the confluence of the arterial vascular systems of the right and left coronary arteries. During surgery, this area of ​​the heart rests on the pericardial sac from the posterior or diaphragmatic side. Therefore, the probe can be said to be pressed by the weight of the heart itself. Too high a probe height can cause the heart to shrink, making it impossible to manipulate the heart during surgery and increasing the risk of perforation of the heart or surrounding tissues. When the probe rests on the pericardial sac on the diaphragmatic side, a probe of 6 mm (or about 6 mm) height does not cause a noticeable depression of the arrested heart (treated with cardioplegia). When the probe rests on the free posterior wall of the pericardial sac, such a probe height allows the pericardial sac to deform freely and safely.

[0188] [ Figure 6 ] shows a probe 11 for real-time continuous measurement of pH value of animal tissue according to the present invention. Figure 6 ], the signal cable 16 and the vacuum line 13a are visualized. The signal cable 16 connects the indicator electrode 2 and the reference electrode 3 to a display device 17 of the measurement results, such as a heart monitor. The display device 17 simultaneously serves as a converter for converting the potential difference values ​​measured by the electrode array according to the present invention into pH scale values. The signal cable 16 is further connected to the temperature sensor 14 ([ Figure 6 ]). Preferably, the signal cable 16 is a four-wire cable. The connection of the electrical components is carried out in a manner known in the art, i.e., using pins, terminals, connectors, etc. The indicator electrode 2, the reference electrode 3 and the PT-1000 temperature sensor 14 are connected in a manner known in the art.

[0189] [ Figure 7 ] shows that the probe 11 according to the present invention is divided into a lower body part 2a and an upper body part 12b in an unfolded state. In an exemplary embodiment, the lower body part 12a includes a channel 18a and a cable path 19a for the temperature sensor 14, a channel 18b and a cable path 19b for the indicator electrode 2, a channel 18c and a cable path 19c for the reference electrode 3, a lead 20 of the signal cable, and a latching piece 21. The upper body part 12b includes a cable clamp 22 and a latching groove 23. The latching piece 21 of the lower part 12a and the latching groove 23 of the upper part 12b form a latching mechanism. Therefore, the latching mechanism works in such a way that when the lower part 12a and the upper part 12b are folded and the two parts are pressed together, the latching piece 21 of the lower part 12a and the latching groove 23 of the upper part 12b are interlocked. The latching mechanism allows the lower body part 12a and the upper body part 12b to be folded together without the need for additional bonding.

[0190] [ Figure 8 ] shows a probe 11 according to the present invention in an assembled state. [ Figure 8 ] shows the lower main body 12a, the upper main body 12b, the signal tube 16 and the vacuum tube 13a.

[0191] [ Fig. 9 ] shows a schematic diagram of a method for protecting and subsequently detecting acidification of human myocardium.

[0192] During cardiac surgery using the probe, a cardioplegic solution is injected into the coronary arteries to stop the heart. During the stage of injecting the cardioplegic solution into the coronary arteries, the electrical and mechanical functions of the heart will stop. At this stage, the probe 11 is applied to the inferior wall of the heart, which is in the area representing the termination of the left and right coronary artery basins. While the surgical part of the method is performed according to the surgical plan, the probe 11 begins to measure the pH value of the heart tissue. If the pH value drops below the alarm value (pH=6.8) or drops sharply, the surgical team will take measures to eliminate the risk of myocardial acidosis. These measures include, for example, the use of additional cardioplegic solution, achieving complete cessation of coronary blood flow, lowering the heart temperature, or using a cardioplegic agent through an alternative route. At the stage of completing the surgical measures that require stopping the heart condition, the probe is removed from the heart just before the surgery to restore coronary blood flow and the expected restoration of the electrical and mechanical functions of the heart.

[0193] [ Fig.10 ] shows a schematic diagram of the probe 11 according to the present invention attached to the surface of the heart while monitoring the pH value of the tissue.

[0194] In an exemplary embodiment, the probe 11 is attached to the inferior wall of the heart, in the region of the posterior descending branch where the blood supply of the right and left coronary arteries meet. The pH probe is connected to the surface of the heart by a vacuum mechanism at between -100 mmHg and -400 mmHg. The vacuum is generated by electrical suction and delivered through a vacuum tube 13a. The pH measurement is transmitted to a display device 17, such as a heart monitor, via a signal cable 16.

[0195] The probe 11 according to the present invention can be used to monitor the occurrence of acidemia in muscle, connective tissue, solid organ tissue, skin (also in monitoring wound healing processes), and body parts or organs that have undergone replantation or transplantation.

[0196] The calibration of the probe 11 is carried out in such a way that the probe 11 is connected to a display device 17 of the measurement results, such as a cardiopulmonary monitor, via a signal cable. The probe 11 is then immersed (after removing the cover protecting the electrode array) in a tank of a calibration solution 24 as an electrolyte, preferably in a phosphate buffer with a pH value close to the physiological pH of the tissue, i.e. pH = 7. The calibration is performed automatically by the patient monitor. The duration of the calibration, i.e. the conditioning time of the electrodes, can be adjusted as required, preferably 1 hour. The probe 11 is then removed from the electrolyte reservoir and the device can be applied to the tissue. The electrolyte reservoir is removed.

[0197] Industrial Applicability

[0198] Therefore, the probe 11 according to the present invention can be used in many medical procedures, in particular surgical procedures. For example, the probe 11 can be used in cardiac surgery (e.g. monitoring the pH value of cardiac tissue), vascular surgery (e.g. monitoring the pH value of muscle tissue in patients with acute ischemia of the lower or upper limbs in the case of acute aortic dissection) or transplantation (e.g. monitoring the pH value of organs for transplantation, in particular the heart, in order to properly protect them, i.e., to fully stop metabolism during transportation).

[0199] All exemplary embodiments of the electrode array 1 and the probe 11 also refer to the pH measurement assembly 111 described in the above specification, which includes the probe 11 as well as the electrode array 1 , the display device 17 and the calibration solution 24 .

[0200] The probe 11 according to the present invention can be used to monitor the pH value of mammalian tissue, especially primate tissue. One example is human. Therefore, the probe 11 according to the present invention can be used to measure the pH value of animal tissue, especially human tissue. Human tissue is a preferred embodiment.

[0201] The electrode array 1 according to the invention is thus used to measure electromotive force and therefore, among other things, it can also be used to measure the pH value of all samples characterized by a small volume / size. In particular, food samples or liquid samples, such as tap water, can be measured.

[0202] In addition, it should be understood that the application of the present invention indicated and described above is given as an example only. All example embodiments and modifications thereof given here are only non-limiting indications of the present invention and shall not limit the scope of protection defined by the claims in any way. It should be understood that any technical solution used in the electrode array according to the present invention and / or the probe according to the present invention can be implemented using equivalent technology without exceeding the scope of protection.

[0203] Furthermore, unless the context indicates otherwise, use of the singular form when referring to various elements of the present invention also includes the plural form and vice versa.

Claims

1. An electrode array (1) for measuring the pH value of animal tissue, comprising an indicator electrode (2) and a reference electrode (3), wherein the reference electrode (3) is fully solid and comprises a steel wire (3a), wherein the steel wire (3a) has an applied layer of a conductive polymer (3b) and a membrane (3c) containing an ionic liquid and polyurethane.

2. The electrode array according to claim 1, wherein: The indicator electrode (2) is an antimony electrode, a ruthenium (IV) oxide electrode or an electrode having a conductive polymer and a polymer film.

3. The electrode array according to claim 1 or 2, wherein: The indicator electrode (2) is an antimony electrode deposited on a steel wire (3a) using the constant current technique.

4. The electrode array according to claim 1 or 2, wherein: The indicator electrode (2) is an electrode having a deposited conductive polymer and a polymer film layer, the polymer film layer containing a pH-sensitive ion carrier, wherein the conductive polymer is deposited on a steel wire (3a) using a constant current technique and the polymer film is deposited using a dip coating technique.

5. An electrode array according to any one of the preceding claims, wherein: The conductive polymer in the reference electrode (3) may be selected from PEDOT:PSS [poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid)], polypyrrole or polyaniline.

6. The electrode array according to claim 5, wherein: The conductive polymer in the reference electrode (3) is PEDOT:PSS [poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid)].

7. An electrode array according to any one of the preceding claims, wherein: The conductive polymer in the reference electrode (3) is applied to the steel wire (3a) by electropolymerization or a ready-made suspension with the conductive polymer.

8. An electrode array according to any one of the preceding claims, wherein: The polyurethane of the membrane of the reference electrode (3) contains 1% to 5% of ionic liquid.

9. The electrode array according to claim 8, wherein: The polyurethane of the reference electrode membrane (3) contains 2% of ionic liquid.

10. An electrode array according to any one of the preceding claims, wherein: The ionic liquid in the reference electrode membrane (3) is selected from the group consisting of: 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, 1-butyl-3-methylimidazolium hexafluorophosphate, 1-butyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium chloride, acetic acid choline and / or phosphoryl choline.

11. The electrode array according to claim 10, wherein: The ionic liquid in the reference electrode film (3) is 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide.

12. The electrode array according to claim 10 or 11, wherein: The reference electrode film (3) contained 4 mg of 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide and 196 mg of polyurethane.

13. An electrode array according to any one of the preceding claims, wherein: The reference electrode film (3) comprises plasticized polyurethane or unplasticized polyurethane.

14. An electrode array according to any one of the preceding claims, wherein: The reference electrode (3) and the indicator electrode (2) are in the form of wires or needles.

15. An electrode array according to any one of the preceding claims, wherein: The diameters of the reference electrode (3) and the indicator electrode (2) are in the range of 0.2 mm to 1.5 mm.

16. The electrode array according to claim 15, wherein: The diameters of the reference electrode (3) and the indicator electrode (2) are 0.5 mm.

17. A probe (11) for real-time continuous measurement of pH value of animal tissue, comprising: a body (12) in the form of a mounting capsule, in which an electrode array (1) according to any one of the preceding claims, a vacuum system (13), a temperature sensor (14) is housed, the vacuum system (14) being designed to attach the probe (11) to a tissue surface and comprising a vacuum tube (13a) and a vacuum surface (13b), The temperature sensor (14) is a contact sensor designed to be applied to the surface of the tissue.

18. The probe (11) according to claim 17, wherein: The temperature sensor (14) is applied to the outer surface of the tissue.

19. The probe (11) according to claim 17 or 18, wherein: The probe (11) includes a suction cuff (15) at its periphery at the point of attachment to the tissue.

20. The probe (11) according to any one of claims 17 to 19, wherein: The probe (11) comprises a signal cable (16) and a display device (17), wherein the signal cable (16) connects the indicator electrode (2), the reference electrode (3) and the temperature sensor (14) to the display device (17) of the pH measurement result.

21. The probe (11) according to claim 20, wherein: The display device (17) is a monitor.

22. The probe (11) according to any one of claims 17 to 21, wherein: The body (12) of the probe (11) is made of a material selected from the following: medical silicone, acrylonitrile-butadiene-styrene terpolymer (ABS), HDPE, LDPE, polypropylene, PETG, polycarbonate, polyester, Kydex, POM, acetal copolymer, PET-P, Polybutylene terephthalate-polyester (PBT-P), polyvinylidene fluoride, modified polyphenylene ether, polyamide fiber, PEEK, polyethylene (including LDPE, HDPE and UHMW), polypropylene homopolymer, PPSU, PSU, Rulon 641, composite materials and blends thereof.

23. The probe (11) according to claim 22, wherein: The body (12) of the probe (11) is made of acrylonitrile-butadiene-styrene terpolymer.

24. The probe (11) according to any one of claims 17 to 23, wherein: The probe (11) has a lower body part (12a) and an upper body part (12b), the lower body part (12a) includes a channel (18a) and a cable path (19a) for the temperature sensor (14), a channel (18b) and a cable path (19b) for the indicator electrode (2), a channel (18c) and a cable path (19c) for the reference electrode (3), a lead (20) for the signal cable (16) and a latch plate (21), and the upper body part (12b) includes a clamp (22) and a locking groove (23) for the signal cable (16), the latch plate (21) of the lower part (12a) and the locking groove (23) of the upper part (12b) are the locking mechanism.

25. The probe (11) according to any one of claims 17 to 24, wherein The probe (11) has a cylindrical shape.

26. An assembly (111) for measuring pH values, comprising a probe (11) according to any one of claims 16 to 24, a display device (17) and a calibration solution (24).

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