KR20030047970A - Composition of electrodes for transdermal glucose monitoring bio-sensor - Google Patents

Abstract

Extracting body fluid through skin tissue using reverse ion osmosis, stabilizing glucose concentration in the extracted substance, and implementing a technique that can infer glucose concentration in the body, that is, blood glucose level, measurement of glucose including glucose oxidase The performance of the electrode in direct contact with hydrogen peroxide, the final chemical product generated in the hydrogel of the device, is an important factor in determining the performance of the entire device. Accordingly, in the present invention, the component materials of the electrode are set to platinum (Pt) and carbon (C), and the performance change according to the composition of these materials is observed to find an optimal composition to maximize the performance of the electrode material for glucose measurement.

Description

Composition of Electrodes for Transdermal Glucose Measurement {Composition of Electrodes for Transdermal Glucose Monitoring Bio-Sensor}

The present invention extracts a certain biochemical component from the body fluids present near the epidermis of the human body, and works electrode (WE), relative to generate an electrical signal among the components of the transdermal extraction biosensor used to monitor its concentration. The present invention relates to a counter electrode (CE) and a reference electrode (RE). An important application of the present invention is a non-invasive transdermal blood glucose monitoring system.

Diabetes can cause glucose (glucose), which is obtained by digesting foods due to insufficient insulin secretion or decreased cellular reactivity to insulin, to accumulate in the blood, cardiovascular diseases such as arteriosclerosis, hypertension, cerebrovascular infarction, kidney diseases such as diabetic nephropathy, It is a refractory disease that causes complications such as diabetic retinopathy, eye diseases such as cataracts, skin diseases such as pyoderma and necrosis, and oral diseases such as periodontal pylori. As socio-economic development has progressed, the diabetic population has increased significantly due to overeating, lack of exercise, and increased stress. In advanced countries, 5-10% of the total population is estimated to be diabetic. About% do not realize that they are diabetic. Diabetes patients are recommended to manage their blood glucose levels by periodically monitoring fasting (maximum tolerance 140 mg / dL) and 2 hours postprandial (maximum tolerance 200 mg / dL) blood glucose levels. In addition, blood sugar fluctuates during the day due to many conditions such as general condition, type and quantity of foods eaten, age, presence of complications, stress, and other accompanying diseases. Is a very important factor in maintaining health and preventing complications.

Conventional methods of monitoring glucose in blood, ie blood glucose, have relied primarily on blood sampling. In other words, only a single test can be performed by using a needle to collect blood from a fingertip or other part of the body. In addition, the blood glucose monitoring system is inconvenient to measure blood glucose at short intervals due to pain or discomfort during blood collection. In order to eliminate this inconvenience and to attempt continuous blood glucose measurement, various methods of continuous measurement blood glucose measurement system are under development. There are two products, microneedle type blood glucose sensor (MiniMed, USA) and skin patch type (Cygnus company) using reverse ion osmosis, which are inserted into the subcutaneous tissue. There is no situation. In addition, the research and development of the method of extracting interstitial fluid continuously by making a micro hole in the stratum corneum using the microneedle produced using compressed gas, LASER, MEMS technology, etc. have.

Therefore, the invention and application of a simple non-invasive type of self blood glucose measurement system is required in the art, and the extent to which the invention of the analytical electrode, which can be said to be a key element thereof, is very large.

It is well known that the cathodic components such as Na ⁺ and K ⁺ and neutral glucose molecules are extracted by applying a small amount of direct current to skin tissue. This action is called reverse ion osmosis, and these extracted glucose molecule components change in correlation with changes in glucose concentration in the blood. Therefore, it is possible to estimate reliable blood glucose levels by measuring the extracted glucose concentration.

When extracting a biochemical such as glucose by applying a current to the electrode, between the electrode and the skin is a hydrogel in which the final product is an enzyme, such as glucose oxidase (hydrogen peroxide) is fixed inside. The hydrogel consists of a polymer such as polyethylene oxide, polyacrylic acid, polyvinyl alcohol, polyacrylamidomethylpropanesulfonic acid or a copolymer thereof. When the polymer hydrogel is not excessively exposed to air, the polymer hydrogel can maintain a water content for several hours (about 12 to 24 hours) and maintain a constant internal environment. In the presence of a neutral physiological buffer (Phosphate Buffer Saline) in the hydrogel, it is possible to maintain the activity of glucose oxidase irrespective of the concentration of slightly generated acid or reactant. Therefore, effective estimated blood glucose can be measured several times (about 70 times / day or more).

Among the components extracted out of the body through the electroosmotic pressure and transferred to the hydrogel, glucose was made into hydrogen peroxide (H ₂ O ₂ ) using the reactive oxidase (Glucose oxidase) as shown below. ), Electrochemical analysis (2) can estimate glucose in the body.

Glucose + O ₂ + GOD → H ₂ O ₂ + Gluconic Acid (1)

H ₂ O ₂ → 2e- + O ₂ + 2H ⁺ (2)

When this method is applied, the minimum amount to analyze glucose extracted from the living body can be from tens to hundreds of nanometers. At this time, there are many factors that determine system performance such as sensitivity, resolution, minimum detection limit, and signal-to-noise ratio (S / N), but among them, the chemical composition of the electrode that decomposes the generated hydrogen peroxide to generate electrons Is very large. In order to complete the reaction of (2), a three-phase electrode system including a working electrode, a reference electrode, and a counter electrode is used. Of these three types of electrodes, the position where reaction (2) occurs directly is the surface of the working electrode. A platinum electrode may be used as the working electrode, but adding carbon may bring physical and chemical advantages over using the platinum electrode alone.

In the present invention, a working electrode having various platinum-to-carbon composition ratios is printed and manufactured by a screen method, and an object thereof is to obtain an optimum composition for quantitative analysis of glucose by confirming each performance. In other words, it is intended to apply the working electrode having the optimum composition obtained in the biosensor system for measuring the amount of glucose extracted by the reverse osmosis pressure from the body fluid through the skin.

1 is an electrode system mounted on a reverse ion osmotic transdermal extraction glucose monitor

A is the extraction electrode

B is the working electrode

C is the counter electrode

D is a reference electrode.

2 is a measurement charge function curve according to the composition of the working electrode.

The electrode is as shown in Figure 1, where A is the extraction electrode, B is the working electrode, C is the reference electrode, and D is the counter electrode. A and D are screen prints of ink in which a silver / silver chloride (Ag / AgCl) mixture is dispersed in an organic solvent. The thickness is about 100 μm, and B and C are platinum / carbon mixtures mixed in an appropriate ratio. It is an electrode which printed the ink disperse | distributed to this organic solvent so that the thickness might be about 100 micrometers by the screen printing method. These electrodes are printed on a substrate made of a ceramic or polymer material, which is a dielectric material, and manufactured by heat treatment at a temperature at which all the solvents can be volatilized.

The ratio of platinum and carbon was determined as shown in Table 1 below to produce C and D electrodes.

The working electrode manufactured as described above requires electrochemically limited properties to be used as an electrode for glucose analysis biosensors.

First, under a conventional three-phase electrode system constant potential condition, when a medium such as a hydrogel or PBS solution is on the electrode, the smaller the oxidation current value that is saturated and stabilized during initial operation is preferable. This is because the glucose molecules extracted through the skin tissue have a low electric signal detected at low concentration, so that the stabilization current value is smaller in order to efficiently distinguish the current value from the background signal.

In addition, it is a good electrode to generate a relatively high current signal for the same concentration of glucose or hydrogen peroxide amount. This is because in addition to the influence of the stabilization values mentioned above, it is important to distinguish the current signal due to glucose from the noise.

Finally, there should be a small amount of noise for the same concentration of glucose or hydrogen peroxide. Typically, the signal value of transdermal extracted glucose using the same or similar electrode structure and hydrogel is usually only a few to several hundred nA, so a few nA noise may seriously affect the result analysis. Therefore, the greater the magnitude of noise or the signal-to-noise ratio (SNR), the better the electrode. The signal-to-noise ratio is given by the following equation (3).

SNR = 10 X log ₁₀ (S / N) (3)

Where S is the magnitude of the signal and N is the magnitude of noise.

<Example 1>

Evaluation of glucose oxidation current performance according to electrode composition ratio in the biosensor for glucose The evaluation device was configured by using the same batch hydrogel having the same thickness on the electrode having the structure as shown in FIG. 1. A potentiostat was used to induce an electrochemical reaction and to measure the flow of electrons, ie, the current generated through the above reaction. That is, the glucose concentration was measured by the current change by hydrogen peroxide generated by the reaction of 100 μM glucose with Glucose Oxidase (GOD) through the reaction of (1) and (2).

At this time, the stabilization current value was obtained after stabilization after sufficient time, and the value is shown in Table 2 below.

After the negative stabilization current was sufficiently stable, a certain amount of 100 μM glucose solution was applied onto the hydrogel. Then, when descending after reaching the stabilization value, the curve under the stabilization value was integrated to measure the amount of charge generated by glucose. This charge generation amount has a linear functional relationship with the concentration of glucose injected into the same electrode.

The results are shown in FIG.

When the current signal nearly reached the stabilization value, the noise width reached the maximum at all electrodes, and the values are shown in Table 3 below.

The signal-to-noise ratio was the best when platinum was 50% and 70% compared to carbon, and increased as the platinum content increased. Considering the noise width and the signal-to-noise ratio, it can be seen that the optimum performance is achieved when the platinum content is 50% to 70%.

When the electrode of the present invention is applied to a three-phase electrode-based glucose extraction biosensor, optimal blood glucose concentration analysis can be performed.

Claims (6)

It is a working electrode where the final product reacts directly as a core part of the reverse ion osmotic transdermal biosensor. When 3 μL of 100 μM glucose solution is added with HPMA hydrogel containing glucose oxidase, the stabilization current is 35 nA or less. Is 4nA, the working electrode for the reverse osmosis transdermal biosensor, characterized in that the signal-to-noise ratio is 9 or more. The working electrode according to claim 1, wherein the component is a mixture of platinum and carbon. The working electrode of claim 2, wherein the working electrode exhibits excellent performance when the composition ratio of platinum and carbon is 50 to 90% based on the weight ratio of platinum. The working electrode according to claim 1, wherein the working electrode is printed on a non-conductive medium. The method of claim 1, wherein the working electrode is used in combination with a polymer made of a polymer such as polyethylene oxide, polyacrylic acid, polyvinyl alcohol, polyacrylamidomethylpropanesulfonic acid or copolymers thereof, and used in the transdermal biosensor of reverse ion osmotic pressure method. Working electrode, characterized in that The working electrode according to claim 5, wherein the working electrode is used in a transdermal biosensor by being attached to and used with a polymer, wherein the polymer is polymerized with glucose oxidase.