TWI571238B - Noninvasive metabolites sensor - Google Patents

Description

Non-invasive metabolite detection device

The invention relates to a non-invasive metabolite detection device, in particular to a potential difference generated by an electrode patch, which allows a metabolite to be reversely penetrated and extracted from the surface of the skin, and then subjected to subsequent detection of the metabolite to achieve non- The purpose of intrusive detection.

Biochemical tests are important in clinical disease prevention and in medical science research. With the development of medical science, the indicators of biochemical tests are increasing, and the quality and cost issues are getting more and more attention. In the biotechnology industry, the market value of in vitro test reagents is only lower than that of the pharmaceutical industry, but there is no high risk and long-term investment in the pharmaceutical industry. At present, the global market for test reagents is maintained at about 30 billion US dollars per year. It is known that research and development in vitro testing is worth developing.

In order to accurately detect human metabolites, blood is often taken in an invasive manner, and then the blood is introduced and reacted with the enzyme to obtain a signal of the corresponding metabolite, which is then detected electrochemically or optically. However, the intrusive (needle-needle) process causes pain problems, often causing fear to the patient, which in turn creates a resistance, and the resulting wound may also cause infection.

At present, there are also non-invasive detection methods on the market, such as metabolic thermal integration, photonic crystal technology and GlucoWatch® G2 Biographer. However, non-invasive detection means It is not directly a metabolite to be detected, so it is necessary to consider whether the detection method is representative. Therefore, it is necessary to develop a non-invasive metabolite detection device to solve the problems caused by the invasive method of blood collection and improve the accuracy of the detection method.

In view of the above problems of the prior art, the object of the present invention is to provide a non-invasive metabolite detection device and to improve the accuracy of detection.

Based on the above objects, the present invention provides a non-invasive metabolite detection device, which can include a sampling module and a detection module. The sampling module can include a hydrogel patch, an electrode set, and a power supply unit. A hydrogel patch that attaches to the skin of the subject. One end of the electrode set can contact the hydrogel patch to transfer current. The power supply unit can electrically connect the other end of the electrode group and control the current wave pattern flowing through the electrode group, so that the metabolites in the subcutaneous tissue fluid attached to the skin site are attracted by the electrode group, thereby extracting metabolites from the subcutaneous tissue fluid, and Stay in the hydrogel patch. The detection module may comprise at least one reaction unit and at least one reaction unit, and at least one reaction unit is disposed around the hydrogel patch and reacts with the metabolite to produce a reaction result. The sensing unit is disposed correspondingly around the at least one reaction unit to sense the reaction result and generate a corresponding physiological value.

Preferably, at least one of the reaction units may be an immobilized enzyme reaction unit.

Preferably, the at least one sensing unit may be an optical sensing unit or an electrochemical sensing unit.

Preferably, the metabolite comprises glucose, lactose, urea or a combination thereof.

Preferably, the current density provided by the power supply unit to the electrode group is between 0.1 mA/cm ² and 0.5 mA/cm ² .

Preferably, the current waveform includes a direct current, a pulse current, a two-pole current, and a pulse two. Extreme current or a combination thereof.

Preferably, the detecting module comprises a wireless transmission component electrically connected to the at least one sensing unit to transmit the physiological value to the monitoring module to monitor the physiological value.

Preferably, the non-invasive metabolite detection device of the present invention further comprises a portable wearing module for attaching the hydrogel patch to the skin.

As described above, the non-invasive metabolite detection device of the present invention has the following advantages:

(1) The non-invasive metabolite detection device of the present invention, although non-invasive sampling, can still extract metabolites (tissue fluid), thereby improving the accuracy of the test.

(2) Using the non-invasive detection product of the metabolite of the present invention, the physiological value of hypoglycemia and hyperglycemia can be reliably detected.

In order to make the above-mentioned objects, technical features, and gains after actual implementation more obvious, a more detailed description will be given below with reference to the corresponding drawings in the preferred embodiments.

100‧‧‧ Non-invasive metabolite detection device

10‧‧‧Sampling module

11‧‧‧Hydrogel patch

12‧‧‧Electrode group

121‧‧‧Metal conductor

122‧‧‧Insulator

123‧‧‧Reverse penetration power supply electrode

124‧‧‧ reference electrode

125‧‧‧Working electrode

126‧‧‧Auxiliary electrode

13‧‧‧Power supply unit

20‧‧‧Detection module

21‧‧‧Reaction unit

25‧‧‧Sensing unit

50‧‧‧Wireless transmission components

60‧‧‧Monitoring module

200‧‧‧ skin

110‧‧‧Subcutaneous tissue fluid

120‧‧‧ Metabolites

Figure 1 is a schematic representation of the reverse osmosis sampling of the non-invasive metabolites of the present invention.

Figure 2 is a block diagram of the non-invasive metabolite detection device of the present invention.

Figure 3 is a schematic diagram of the detection wafer of the non-invasive metabolite detection device of the present invention.

Figure 4 is a graph showing the time versus current of the glucose signal detected by the non-invasive metabolite detection device of the present invention.

Figure 5 is a graph showing the current response of the non-invasive metabolite detection device of the present invention for detecting glucose concentration.

Figure 6 is a graph showing the current response of the non-invasive metabolite detection device of the present invention for detecting the glucose concentration in the permeator.

The present invention will be described in conjunction with the accompanying drawings in the accompanying drawings, and the drawings The subject matter is only for the purpose of illustration and description. It is not intended to be a true proportion and precise configuration after the implementation of the present invention. Therefore, the scope of the present invention should not be construed as limiting the scope of the present invention.

The advantages and features of the present invention, as well as the technical methods of the present invention, are described in more detail with reference to the exemplary embodiments and the accompanying drawings, and the present invention may be implemented in various forms and should not be construed as limited thereby. The embodiments of the present invention, and the embodiments of the present invention are intended to provide a more complete and complete and complete disclosure of the scope of the present invention, and The scope of the patent application is defined.

Please refer to Fig. 1, which is a schematic diagram of the reverse osmosis sampling method of the non-invasive metabolite of the present invention. The reverse penetration method is an electrode patch formed by the hydrogel patch 11 and the electrode group 12, and the low current is generated by the power supply unit 13 through the skin 200, and the metabolite 120 of the skin 200 is directed to the positive or negative electrode. The principle is According to the same electric repellent, different electric attraction. When the metabolite 120 is negatively charged (eg, urea), it is attracted to the positively charged electrode patch, while the uncharged (eg, glucose) is carried by the electroosmotic flow to the negatively charged The electrode patch is further used to extract the metabolite 120 in the subcutaneous tissue fluid 110 from the bottom of the skin 200, and then react with the enzyme to obtain a corresponding physiological value.

Please refer to both FIG. 1 and FIG. 2, which are schematic diagrams of the reverse penetration method of the non-invasive metabolite of the present invention and a block diagram of the non-invasive metabolite detection device. In the figure, a non-invasive metabolite detection device 100 includes a sampling module 10 and a detection module 20. The sampling module 10 can include a hydrogel patch 11 , an electrode group 12 , and a power supply unit 13 . The detection module 20 can include a reaction unit 21 and a sensing unit 25 .

The hydrogel patch 11 and the electrode group 12 described above may be combined to form an electrode patch, and the electrode group 12 is carried by the hydrogel patch 11 and attached to the skin 200 of the subject, and the both ends of the electrode group 12 are provided. The contact hydrogel patch 11 forms an electrical path with the power supply unit 13. The power supply unit 13 is for controlling the current wave pattern flowing through the electrode patch, and the metabolite 120 in the subcutaneous tissue attached to the skin 200 is attracted by the electrode group 12, thereby extracting the metabolite 120 from the skin 200 and staying in the water. In the gel patch 11.

Furthermore, the current waveform provided by the power supply unit 13 may include a direct current, a pulse current, a two-pole current, a pulsed two-pole current, and a corresponding electrochemical analysis method.

The reaction unit 21 in the detecting module 20 is disposed around the hydrogel patch 11 and reacts with the metabolite 120 staying in the hydrogel patch 11 to generate a reaction result, and the sensing unit 25 is correspondingly disposed on The periphery of the reaction unit 21 is used to sense the reaction result and generate corresponding physiological value values.

In practice, the reaction unit 21 can be an immobilized enzyme reaction unit, which increases its stability and its service life. A plurality of reaction units 21 and corresponding sensing units 25 may be disposed around the electrode patch to simultaneously detect different types of metabolites 120. And the sensing unit 25 can use the optical sensing unit or the electrochemical sensing unit to correspond to the reaction unit 21 to detect the coloring method or detect the electron transfer to obtain the physiological value.

In practice, the non-invasive metabolite detection device 100 of the present invention may further comprise a liquid guiding solution. And contacting the hydrogel patch 11 and the reaction unit 21 with the liquid guiding unit, so that the metabolite 120 staying in the hydrogel patch 11 is transported to the reaction unit 21 by capillary action to act on the electrode The sheet becomes a disposable consumable that is convenient, hygienic and prevents cross-contamination.

In an implementation, the detection module 20 can include a wireless transmission component 50 electrically connected to the sensing unit 25 to transmit physiological values to the monitoring module 60. The monitoring module 60 can be a personal computer, a portable electronic device, or a medical device. Monitor physiological values.

In practice, the non-invasive metabolite detection device 100 of the present invention can form the sampling module 10 in the form of a wafer, and the carrier-type carrier can be used to fix the hydrogel patch 11 to the skin 200. A portable detection type physiological detecting device is formed.

Please also refer to FIG. 3, FIG. 4 and FIG. 5 as a schematic diagram of the detection of the non-invasive metabolite detection device of the present invention, a time-to-current curve for detecting the glucose signal, and a glucose concentration detection. Current response diagram. In the present embodiment, the glucose is extracted by the principle of reverse penetration, and the electron flow generated by the oxidation of glucose is sequentially transmitted by glucose oxidase (GOD) and ferrocene, and electrochemically. The way to detect to get physiological values. All electrochemical detection methods were analysis of variance (ANOVA), all data were analyzed by SPSS (v.11.5 software SPSS Inc., Chicago, Illinois, USA) statistical software, and 0.05 was set as the significant level standard. .

Please refer to FIG. 1 and FIG. 3 simultaneously for the process of detecting the wafer of the present invention by using a printing coating method, and part (a) of FIG. 3 is a hydrogel patch 11 for providing an electrode. Part (b) of Fig. 3 is to apply four metal conductors 121 on the electrodes to form electrical paths, and one end of the four metal conductors 121 is connected to the power supply unit 13 or the electrochemical sensing unit to provide a potential difference of reverse penetration extraction or Electrochemical detection analysis is carried out, one of which is a central dot, and the other three are circumferential lines surrounded by a central dot, and the four metal conductors 121 are not in contact.

Part (c) of Figure 3 is a layer of insulator 122 coated on the metal conductor 121 and bare a portion of the metal conductor 121 is exposed, and a silver/silver chloride (Ag/AgCl) electrode is applied to the central metal wire in the portion (d) of FIG. 3 as a reverse penetration power supply electrode 123, and one of the metals A circumferential line of the end of the conductor 121 is coated with a silver/silver chloride electrode as the reference electrode 124, and part (d) of the third figure is a graphite electrode as the working electrode 125 and the auxiliary electrode 126 at the end of the last two metal conductors 121. And the reaction unit 21 is disposed at the working electrode 125.

Please refer to Fig. 3 and Fig. 4, in which 12.5 mg/mL glucose oxidase and 0.1 M ferrocene are used as the reaction unit 21, and flow through the reverse penetration power supply electrode 123, when 4 mM glucose solution is mixed. In 0.01 M phosphate buffer (pH 7.4), the reduction current increased and reached a steady current at 10 seconds. The key factor that can achieve such a short detection time is that the positions of glucose oxidase, ferrocene and reverse penetration power supply electrode 123 are very close, thus reducing the energy barrier of diffusion, and the reduction current can be stabilized when measured. Current.

Please refer to Fig. 3 and Fig. 5, in which 8.5 mg/mL glucose oxidase and 0.05 M ferrocene are used as reaction unit 21, and three repeated experiments are performed, and the experimental results are plotted on the abscissa as glucose concentration (mM). The ordinate is the magnitude of the measured response current (μA) of the test wafer. The sensitivity of the test wafer to the glucose concentration is determined by the slope of the regression line of the current response and the glucose concentration profile. As shown, when the glucose concentration is from 0.5 mM to 4 mM, the regression line slope of the detected response current (μA) magnitude is 0.9913, indicating that the detection wafer of the present invention has good accuracy for glucose.

Please also refer to FIG. 1 , FIG. 3 and FIG. 6 , which are schematic diagrams of the detection wafer of the non-invasive metabolite detection device of the present invention and a current response diagram for detecting glucose in the permeator. In the figure, the detection wafer is placed on a diffusion cell, and a phosphate buffer (pH 7.4, 0.1 M) and a glucose solution of different concentrations are placed in the permeator, and the glucose concentration is 3 mM, 5 mM, The 15 mM system simulates hypoglycemia, normal, and hyperglycemia, and performs five repeated experiments. The power supply unit 13 provides a bipolar current for 30 minutes on the electrode group 12, and is performed at a normal temperature (22 to 24 ° C). 90 minutes of reverse penetration, and the current density flowing through the electrode was 0.3 mA/cm ² to extract the glucose in the permeator, and the reaction unit 21 on the detection wafer was 12.5 mg/mL glucose oxidase and 0.1 M dioxin. iron.

As shown, when the glucose concentration is in the range of 3 mM to 15 mM, the regression line slope of the detected response current (μA) magnitude is 0.99, indicating that the detection wafer of the present invention has good accuracy for glucose. Compared with the currently commercialized GlucoWatch, the detection wafer of the present invention can reliably detect hypoglycemia and hyperglycemia.

The embodiments described above are merely illustrative of the technical spirit and the features of the present invention, and the objects of the present invention can be understood by those skilled in the art, and the scope of the present invention cannot be limited thereto. That is, the equivalent variations or modifications made by the spirit of the present invention should still be included in the scope of the present invention.

100‧‧‧ Non-invasive metabolite detection device

10‧‧‧Sampling module

11‧‧‧Hydrogel patch

12‧‧‧Electrode group

13‧‧‧Power supply unit

20‧‧‧Detection module

21‧‧‧Reaction unit

25‧‧‧Sensing unit

50‧‧‧Wireless transmission components

60‧‧‧Monitoring module

Claims (8)

A non-invasive metabolite detection device comprises: a sampling module comprising: a hydrogel patch attached to a skin of a subject; an electrode group, one of the electrode groups respectively Contacting the hydrogel patch to transfer current; and a power supply unit electrically connecting the other end of the electrode group and controlling a current wave pattern flowing through the electrode group to adhere to one of the skin portions a metabolite in the subcutaneous tissue fluid is attracted by the electrode group, and the metabolite is extracted from the subcutaneous tissue fluid and stays in the hydrogel patch; and a detection module comprises: at least one reaction unit, the system is configured Surrounding the hydrogel patch and reacting with the metabolite to produce a reaction result; and at least one sensing unit correspondingly disposed around the at least one reaction unit to sense the reaction result and generate a physiological condition Value. The non-invasive metabolite detection device according to claim 1, wherein the at least one reaction unit is an immobilized enzyme reaction unit. The non-invasive metabolite detection device of claim 1, wherein the at least one sensing unit is an optical sensing unit or an electrochemical sensing unit. The non-invasive metabolite detection device of claim 1, wherein the metabolite comprises glucose, lactose, urea or a combination thereof. The non-invasive metabolite detection device according to claim 1, wherein the power supply unit supplies the electrode group with a current density of 0.1 mA/cm ² to 0.5 mA/cm ² . The non-invasive metabolite detection device of claim 1, wherein the current waveform comprises a direct current, a pulse current, a two-pole current, a pulsed two-pole current, or a combination thereof. The non-invasive metabolite detection device of claim 1, wherein the detection module comprises a wireless transmission component electrically connected to the at least one sensing unit to transmit the physiological value to a monitoring module. To monitor the physiological value. The non-invasive metabolite detection device of claim 1, further comprising a portable wearing module for attaching the hydrogel patch to the skin.