CN114557694A - Noninvasive subcutaneous tissue fluid extraction-detection device and extraction-detection method - Google Patents
Noninvasive subcutaneous tissue fluid extraction-detection device and extraction-detection method Download PDFInfo
- Publication number
- CN114557694A CN114557694A CN202210455230.1A CN202210455230A CN114557694A CN 114557694 A CN114557694 A CN 114557694A CN 202210455230 A CN202210455230 A CN 202210455230A CN 114557694 A CN114557694 A CN 114557694A
- Authority
- CN
- China
- Prior art keywords
- extraction
- electrode
- detection
- electrode layer
- tissue fluid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
- A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
- A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
- A61B5/1477—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means non-invasive
Abstract
The invention belongs to the technical field of medical diagnostic instruments, and particularly relates to a noninvasive subcutaneous tissue fluid extraction-detection device and an extraction-detection method, wherein the extraction-detection device comprises: an adherable substrate, a first electrode assembly and a second electrode assembly, the first electrode assembly including an extraction/detection electrode layer, the extraction/detection electrode layer including a double electrode; the second electrode assembly includes an extraction electrode positive electrode for cooperating with one of the two electrodes to extract subcutaneous tissue fluid transdermally by reverse iontophoresis; the extraction electrode anode covers the extraction/detection electrode layer, and the extraction electrode anode extends along the covered edge of the extraction/detection electrode layer. The extraction-detection device can provide an electrode system with a more uniform electric field, can extract a tissue fluid sample with a detection amount under the working current as low as 0.1mA, and reduces discomfort such as skin irritation and injury; the electrode has compact structure and high measurement accuracy.
Description
Technical Field
The invention belongs to the technical field of medical diagnostic instruments, and particularly relates to a noninvasive subcutaneous tissue fluid extraction-detection device and an extraction-detection method.
Background
At present, invasive detectors are still widely used for tissue fluid extraction-detection, but patients still escape the invasive detection as far as possible due to wound and pain. Thus, minimally invasive and non-invasive testers have become the prospect of patients.
Non-invasive tissue fluid extraction-detection, as the name implies, refers to the extraction and detection of subcutaneous tissue fluid without causing damage to human skin tissue. The existing methods for researching non-invasive tissue fluid detection are many and can be roughly divided into an optical method and an electrochemical method. The optical methods mainly include near infrared spectroscopy, polarized light rotation method, Raman spectroscopy, fluorescence method, optical coherence tomography and the like. The electrochemical method mainly utilizes the coherent relationship between other body fluids of a human body and the value of an object to be measured, for example, the blood sugar value is measured, the glucose content in body fluids such as saliva, tears, sweat, ISF and the like can be measured, and a data model is established after the glucose content is calibrated with the standard blood sugar value, so that the blood sugar value is obtained.
The inventor of the invention discloses an early patent CN105954331B for a paper-based electrode detection platform for biochemical analysis and a preparation method thereof, the paper-based electrode detection platform for biochemical analysis takes degradable paper as a substrate material, a carbon electrode is printed on the substrate material, and an electron transfer medium and an identification molecular layer are fixed on the surface of the carbon electrode, so that a completely degradable brand new paper-based electrode detection platform is obtained. Electrochemical tests show that the prepared degradable paper-based electrode detection platform has the same good electrochemical performance as the plastic substrate electrode. However, how to construct a non-invasive extraction device and method based on the detection platform still needs further research.
Meanwhile, in the counter ion permeation process, the extraction rate of the interstitial fluid (ISF) to-be-detected substance in the human skin is generally related to the current intensity, and the detection accuracy can be effectively improved by improving the extraction rate of the ISF to-be-detected substance. At present, the ISF extraction current is generally 0.3-0.5mA, and accurate detection can be realized; prolonged extraction at this current can cause irritation and damage to the skin.
CN110455887B provides a detection micro-sensor comprising: at least one detection unit and an NFC module; the detection unit comprises an extraction electrode, a micro-channel and a three-electrode array; the extraction electrode transmits sweat containing the substance to be detected to the three-electrode array through the micro-channel for detection to obtain a response current corresponding to the substance to be detected; and the NFC module is used for converting the response current into a modulation signal. Based on the detection micro-sensor, the concentration of physiological parameters such as glucose, lactic acid, uric acid and the like in blood can be detected noninvasively. The micro-sensor needs two detection electrodes and a plurality of three electrodes to be matched for use, has a complex structure, and needs higher extraction current due to larger difference between extraction and detection positions. Therefore, how to construct a more efficient ISF extraction and detection, reduce the detection limit, and avoid skin damage is an important point of current research.
Disclosure of Invention
The invention aims to overcome the defects of skin irritation and damage, blood sampling pain and susceptibility to infection in the existing tissue fluid detection technology and provide a noninvasive subcutaneous tissue fluid extraction-detection device and an extraction-detection method, wherein an electrode system of the extraction-detection device can provide a more uniform electric field, and can extract tissue fluid samples with enough detection quantity under the working current as low as 0.1mA, so that the discomfort of skin irritation, damage and the like is greatly reduced, and the problems of blood sampling pain, susceptibility to infection and blood coagulation disorder are solved; and, a more simplified electrode system is provided while obtaining high accuracy measurement results.
In order to achieve the above object, in a first aspect, the present invention provides a noninvasive subcutaneous tissue fluid extraction-detection apparatus comprising:
an adherable substrate;
a first electrode assembly disposed on the adherable substrate and including an extraction/detection electrode layer including a double electrode for electrochemically detecting a content of an analyte in the extracted subcutaneous tissue fluid;
a second electrode assembly disposed on the adherable substrate and including an extraction electrode positive electrode for cooperating with one of the two electrodes to transcutaneously extract subcutaneous tissue fluid by a reverse iontophoresis technique; and the extraction electrode anode covers the extraction/detection electrode layer, and the extraction electrode anode is arranged along the covered edge of the extraction/detection electrode layer in an extending manner.
In some preferred embodiments, the extraction electrode positive electrode has a rectangular or arc shape to perform the coating.
In some preferred embodiments, the extraction electrode anode is in the shape of "Contraband".
In some preferred embodiments, the shortest distance between the extraction electrode positive electrode and the extraction/detection electrode layer is between 2 and 3 mm.
In some preferred embodiments, the area of the positive electrode of the extraction electrode on the plane of the attached side is 0.5-10 cm2Preferably in the range of 0.5-4 cm2More preferably in the range of 1-2 cm2。
In some preferred embodiments, the extraction/detection electrode layer has an area of 0.5 to 5 cm2Preferably in the range of 0.5-2 cm2More preferably 0.5 to 1 cm2。
In some preferred embodiments, the extraction/detection electrode layer is rectangular or arc-shaped as a whole.
In some preferred embodiments, the electrode in the extraction/detection electrode layer is a glassy carbon electrode or a carbon electrode.
In some preferred embodiments, the double electrodes are arranged in a ridge, serpentine, concentric circular or comb-like interdigitated arrangement.
In some preferred embodiments, the bipolar electrodes are arranged as comb-like fingers.
In some preferred embodiments, the plane of the comb-like interdigital part of the double electrode satisfies: the area is 40-60mm2。
In some preferred embodiments, the plane of the comb-like interdigital part of the double electrode satisfies: the length is 9-12mm, the width is 3-6mm, and the interval between the fingers is 0.1-0.5 mm.
In some preferred embodiments, the first electrode assembly further comprises:
a base layer disposed on the adherable substrate and located below the extraction/detection electrode layer;
the modification coating is arranged above the extraction/detection electrode layer and close to the skin and comprises an electron transfer medium and recognition molecules, and the electron transfer medium and the recognition molecules are matched with the substance to be detected.
In some preferred embodiments, the extraction-detection apparatus further comprises: a gel layer disposed over the finish coating and proximate to the skin.
In a second aspect, the present invention further provides a noninvasive subcutaneous tissue fluid extraction-detection method, which uses the extraction-detection device of the first aspect for detection, and comprises the following steps:
the detection area of the extraction-detection device faces the skin of a subject, and the first electrode assembly and the second electrode assembly are attached to the skin area to be detected of the subject through an adhesive substrate;
one electrode in the double electrodes is used as a negative electrode and is combined with an extraction electrode positive electrode to carry out reverse iontophoresis extraction, so that the substance to be detected in the subcutaneous tissue fluid is extracted to the surface of the skin and is enriched in the extraction/detection electrode layer area;
and after the electroosmosis extraction is finished, one electrode of the double electrodes is used as a working electrode, the other electrode is used as a counter electrode, and the extract obtained by the electroosmosis extraction is subjected to electrochemical detection.
The inventor of the invention researches and discovers that two mechanisms exist in the counter-ion electroosmosis: firstly, active migration, direct interaction of charged ions and an external electric field and direct conduction to an electrode area on the surface of the skin through a skin accessory passage are realized; and the second is passive migration, namely the charge ion carriers carry neutral molecules to flow directionally. Sodium ions are the majority carriers in interstitial fluid, and the qualitative migration of these sodium ions creates a solvent flow that entrains neutral molecules such as glucose, which is conducted indirectly via the skin appendage pathway to the electrode area on the skin surface, so that the electric field distribution is particularly important, especially how to concentrate the penetration enhancing fluid to the detection electrode.
According to the technical scheme, the extraction/detection electrode layer comprising the double electrodes and the extraction electrode anode coating the extraction/detection electrode layer are particularly arranged to form an in-situ extraction and detection permeation-promoting electric field, and the permeation-promoting electric field is distributed on the extraction/detection electrode layer to ensure that a permeation-promoting liquid (namely a tissue liquid containing an object to be detected) is concentrated on the extraction/detection electrode layer, so that the method has the following advantages:
(1) the coating structure provided by the invention can realize extraction and detection at the same position, the extraction function and the electrochemical detection function are not interfered with each other, high-efficiency permeation promotion under the condition of extremely low current (as low as 0.1mA) is realized, and discomfort such as skin irritation and injury is greatly reduced. Meanwhile, the permeation promoting liquid is enriched on the extraction/detection electrode layer, so that a high-accuracy detection result can be obtained.
(2) Compared with the traditional detection device (two electrodes are generally adopted as extraction electrodes, and three electrodes are combined as detection electrodes), the detection device has a simple structure, and can realize high-accuracy detection of the object to be detected by using two electrodes under the condition of omitting a reference electrode. Specifically, one of the double electrodes is used as the negative electrode of the extraction electrode during extraction, and a human body is used as an equipotential potential which is basically unchanged in the process of detecting the content of the substance to be detected in the extracted tissue fluid, so that the potential of the counter electrode does not drift in the whole detection process, a reference electrode can be omitted, and a complex result of double-electrode measurement and quantitative analysis electrochemical reaction can be carried out to obtain a high-accuracy measurement result.
(3) The application range is wide, the kit can be used for real-time detection of human body noninvasive biochemical indexes (blood sugar, sodium, ammonia or other metal ions, lactic acid, picolinol and the like) in tissue fluid, and the defects of blood sampling pain, susceptibility to infection and the like are overcome; the device is suitable for self, real-time and in-situ detection of healthy human bodies and patients, and has the advantages of no wound, no pain, safety, portability, accuracy, stability, low price and the like.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and those skilled in the art can also obtain other related drawings based on the drawings without inventive efforts.
FIG. 1 is a schematic structural diagram of an embodiment of the non-invasive subcutaneous tissue fluid extraction-detection apparatus of the present invention.
Fig. 2 is a view showing a state of use of fig. 1 attached to the skin.
Fig. 3 is a schematic structural view of an embodiment of the extraction electrode of fig. 1 in which a positive electrode and a bipolar electrode are combined.
Fig. 4 is a graph of an electric field distribution simulation of the structure of fig. 3.
Fig. 5 is a schematic structural view of the double electrodes arranged in a ridge shape.
FIG. 6 is a schematic diagram of a serpentine arrangement of two electrodes.
Fig. 7 is a schematic structural view of the dual electrodes in a concentric circular arrangement.
FIG. 8 is a schematic representation of the dimensions of the comb-like interdigitated portions of the structure of FIG. 3; wherein a refers to comb-like interdigitated portions.
FIG. 9 is a graph showing the open circuit potential response of the extraction-detection apparatus of the present invention to NaCl solutions of different concentrations.
Description of the reference numerals
101-extraction electrode positive electrode lead, 102-extraction electrode positive electrode, 103-adherable substrate, 104-extraction/detection electrode layer, 105-clamping fixture, 106-first electrode lead, 107-second electrode lead, 108-finish coating, 109-double electrode, 200-skin.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
In a first aspect, the present invention provides a non-invasive subcutaneous tissue fluid extraction-detection apparatus, as shown in fig. 1, comprising: an adherable substrate 103, a first electrode assembly and a second electrode assembly, the first electrode assembly and the second electrode assembly being disposed on the adherable substrate, respectively.
Wherein, the first electrode assembly comprises an extraction/detection electrode layer 104, and the extraction/detection electrode layer 104 comprises a double electrode 109 for detecting the content of the substance to be detected in the extracted subcutaneous tissue fluid by an electrochemical method.
The extraction/detection electrode layer 104 according to the present invention may be used as both an extraction electrode layer and a detection electrode layer.
Wherein the second electrode assembly comprises an extraction electrode anode 102 for cooperating with one of the two electrodes 109 to transcutaneously extract subcutaneous tissue fluid by a reverse iontophoresis technique; the extraction electrode anode 102 covers the extraction/detection electrode layer 104, and the extraction electrode anode 102 extends along the covered edge of the extraction/detection electrode layer 104.
It should be understood that "the extraction/detection electrode layer 104 includes the dual electrode 109" means that the extraction/detection electrode layer 104 includes at least two electrodes (i.e., the dual electrode 109), and may include more than two electrodes.
The extraction-detection device of the invention can provide a more uniform electric field, can extract enough tissue fluid samples under the working current as low as 0.1mA, and can realize the high-accuracy electrochemical detection of the object to be detected under the condition of only the double electrodes 109.
The phrase "the extraction electrode positive electrode 102 covers the extraction/detection electrode layer 104" means that the extraction electrode positive electrode 102 may cover the entire extraction/detection electrode layer 104 or may cover a part of the extraction/detection electrode layer 104.
The phrase "the extraction electrode positive electrode 102 extends along the edge of the extraction/detection electrode layer 104, means that the coating portion of the extraction electrode positive electrode 102 is continuous and uninterrupted in the direction along the edge of the extraction/detection electrode layer 104, as shown in fig. 1 as an" Contraband "type structure.
It should be understood that when the extraction-detection device is used, the first electrode assembly and the second electrode assembly are both attached to the skin 200 to be tested on the surface of the human body, as shown in fig. 2, and are fixed by the adhesive substrate 103.
The adhesive substrate 103 of the present invention may be a flexible polymer tape, such as PET or other plastic or resin material, as long as the first electrode assembly and the second electrode assembly can be fixedly attached to the surface of the skin 200, such as the exposed epidermis to be tested, such as the arm and the back of the hand.
In the present invention, the extraction electrode positive electrode 102 may be a flexible patch electrode.
In some preferred embodiments, the extraction electrode anode 102 is rectangular or arcuate for the cladding. The extraction electrode anode 102 may be formed by a rectangular or arc structure, or may be formed by arranging a plurality of rectangular or arc structures in a matrix manner, or may be formed in other extending forms. The rectangle comprises a square, a rectangle, a model Contraband or a rectangle or a square with a notch on one side; the arc shape comprises a sealed edge or unsealed edge round shape and a sealed edge or unsealed edge oval structure.
In some embodiments, the extraction electrode positive electrode 102 encapsulates the extraction/detection electrode layer 104 in an "Contraband" shaped outer envelope (as shown in fig. 1).
In the present invention, the size of the cladding region between the extraction electrode positive electrode 102 and the extraction/detection electrode layer 104 can be optimized according to the detection effect (e.g., detection accuracy, low cost of operating current or voltage, etc.). In some preferred embodiments, the shortest distance between the extraction electrode positive electrode 102 and the extraction/detection electrode layer 104 is between 2-3 mm. Under the preferable scheme, the size of the coating structure of the extraction electrode anode 102 and the extraction/detection electrode layer 104 is more beneficial to the enrichment and electrochemical detection of the permeation promoting liquid.
The "shortest distance between the extraction electrode positive electrode 102 and the extraction/detection electrode layer 104" refers to the shortest distance between the coated edge of the extraction electrode positive electrode 102 and the coated edge of the extraction/detection electrode layer 104, and includes the shortest distance in the longitudinal direction, the shortest distance in the width direction (as shown in fig. 3, the distances in the longitudinal direction and the width direction are both 2.5 mm), or the shortest distance in the arc extending direction, in short, the minimum value in each direction.
In the present invention, the area of the extraction electrode positive electrode 102 is determined according to the area of the subject detection region. In some preferred embodiments, the area of the extraction electrode anode 102 is 0.5-10 cm on the plane of the attached side2Preferably in the range of 0.5-4 cm2More preferably 1-2 cm2. Under the preferred scheme, the method is more beneficial to the enrichment and electrochemical detection of the penetration-promoting liquid, and can avoid skin damage.
The "area of the extraction electrode positive electrode 102 on the plane of the attachment side" refers to the surface area of the region where the extraction electrode positive electrode 102 is attached to the skin 200.
The area of the extraction/detection electrode layer 104 is determined according to the area of the detection region of the subject and is limited by the area of the extraction electrode anode 102. In some preferred embodiments, the extraction/detection electrode layer 104 has an area of 0.5 to 5 cm2Preferably in the range of 0.5-2 cm2More preferably 0.5 to 1 cm2. Under the preferable scheme, the enrichment and electrochemical detection of the penetration-promoting liquid are facilitated.
The "area of the extraction/detection electrode layer 104" refers to an effective area of the extraction/detection electrode layer 104, and the effective area refers to an electrode area in the extraction/detection electrode layer 104, which is in contact with the skin, where a subcutaneous electric field is generated after a current is applied. For example, for the extraction/detection electrode layer 104 having a comb-like interdigital structure, the effective area of the extraction/detection electrode layer 104 refers to the area of comb-like interdigital portions that can generate a subcutaneous electric field, and the non-interdigital portions only function as conductive.
The overall morphology of the extraction/detection electrode layer 104 of the present invention matches the extraction electrode anode 102 to form the coating. In some preferred embodiments, the extraction/detection electrode layer 104 is rectangular or arc-shaped as a whole. The rectangle may be, for example, a square or a rectangle. The arc may be, for example, elliptical, circular, semi-circular, or the like.
The electrode material in the extraction/detection electrode layer 104 includes, but is not limited to, carbon, metal electrode, or polymer conductive material. In some preferred embodiments, the electrode in the extraction/detection electrode layer 104 is a glassy carbon electrode or a carbon electrode.
The skilled person can select the preparation method of the extraction/detection electrode layer 104 according to the requirement, and preferably the extraction/detection electrode layer 104 is prepared by screen printing. The application of screen printing to print the extraction/detection electrode layer 104 has the advantages of flexible design, low cost and batch fabrication.
In some preferred embodiments, the dual electrodes 109 are arranged in a ridge, serpentine, concentric circular, or comb-like interdigitated arrangement. The ridge shape means that the dual electrode 109 is arranged at least partially in a contour similar to a ridge, as shown in fig. 5, for example. Serpentine means that the dual electrode 109 is arranged at least partially in a serpentine-like configuration, as may be seen, for example, in fig. 6. The concentric circles refer to the concentric circles of two electrodes 109, one of which covers the other, as shown in fig. 7, for example. The comb-like interdigital arrangement refers to a double electrode 109 including comb-like structures of two electrodes, and the comb-like structures are engaged with each other to form an interdigital shape, as shown in fig. 3 and 8, for example.
In some preferred embodiments, the two electrodes 109 are arranged as comb-like fingers. According to the preferred scheme, the comb-shaped interdigital structure design is adopted, so that the effective area of the double electrode 109 can be ensured to the greatest extent, the double electrode 109 has good enough electrochemical properties, and the enrichment and electrochemical detection of the penetration promoting liquid are facilitated.
In some preferred embodiments, the extraction electrode positive electrode 102 wraps the double electrode 109 in the shape of "Contraband", and the double electrode 109 is arranged in a comb-like interdigital arrangement. In this preferred embodiment, the simulation diagram of the electric field distribution of the extraction-detection device is shown in fig. 4 when reverse iontophoresis is performed, and it can be seen that it can obtain the optimal permeation-promoting electric field and concentrate on the double electrode 109, and the electric field is more uniform and stable.
In some preferred embodiments, the plane of the comb-like interdigital portion of the dual electrode 109 satisfies: the area is 40-60mm2。
The "plane where comb-like interdigital portions of the two electrodes 109 are located" refers to a portion a as shown in fig. 8.
In some preferred embodiments, the plane of the comb-like interdigital portion of the dual electrode 109 satisfies: the length is 9-12mm, the width is 3-6mm, and the interval between the fingers is 0.1-0.5 mm.
The "length and width of the plane where comb-shaped interdigital parts of the dual electrode 109 are located and the interval between the interdigital parts" refers to the length and width of the part a and the interval between the interdigital parts as shown in fig. 8, and in one embodiment of fig. 8, the length is 10.50mm, the width is 4.8mm, and the interval between the interdigital parts is 0.3 mm.
Those skilled in the art can arrange corresponding parts or specific layers in the first electrode assembly according to the requirements of support, fixation or connection of the first electrode assembly, and the like, and the requirements of extraction, detection and identification. The detection and identification requires, for example, an electron transfer and recognition molecule corresponding to the analyte in the subcutaneous tissue fluid for electrochemical detection.
In some preferred embodiments, as shown in fig. 1, the first electrode assembly further comprises:
a base layer disposed on the adherable substrate 103 and located below the extraction/detection electrode layer 104;
a modifying coating 108 disposed over the extraction/detection electrode layer 104 and adjacent to the skin 200, comprising an electron transfer medium and recognition molecules, the electron transfer medium and recognition molecules being compatible with the analyte.
The substrate layer is preferably made of flexible material, more preferably made of material with porous structure, and may be degradable polymer or non-degradable polymer, such as cellulose paper, PET, nano gold and carbon nanotube material. Preferably, the base layer is a paper substrate, and its hydrophilic and hydrophobic properties ensure adhesion between the substrate and the extraction/detection electrode layer 104.
In some embodiments, the electron transport medium and the recognition molecule in the modified coating 108 can be separated into two layers, namely an electron transport medium layer and a recognition molecule layer. More preferably, the electron transfer medium layer is located between the extraction/detection electrode layer 104 and the recognition molecule layer. The electron transfer medium layer and the recognition molecule layer can be prepared by the existing method by those skilled in the art, and can be obtained by spraying and drying the corresponding solution. In some embodiments, for glucose as the analyte, the electron transfer medium layer can be formed by spraying and drying a potassium ferricyanide solution, and the glucose oxidase layer can be formed by spraying and drying a glucose oxidase solution with the activity of 1000U/mL to 1,000,000U/mL.
In other embodiments, the electron transport medium and the recognition molecule in the modified coating 108 are not layered, and may be mixed layers, or perform their corresponding functions. When not layered, for example, the electron transport medium and the recognition molecule may be combined with a conductive paste and then coated on the extraction/detection electrode layer 104.
The skilled person can select the corresponding electron transfer medium and recognition molecule according to the tissue fluid analyte to realize electrochemical detection. For example, in electrochemical detection of glucose, the electron transport mediator and the recognition molecule can be potassium ferricyanide and glucose oxidase (GOx), respectively.
In some preferred embodiments of the present invention, the first electrode assembly is a cellulose paper-based flexible electrode, and is located inside the skin 200, and sequentially comprises a waterproof layer, a cellulose paper-based flexible electrode, a carbon material extraction/detection electrode layer 104, potassium ferricyanide, glucose oxidase (GOx), and a hydrogel from outside to inside, wherein the hydrogel is located close to the skin 200.
Preferably, the paper-based carbon electrode is printed by screen printing, and the electron transfer medium and the recognition molecule are fixed in the working area of the carbon electrode by the liquid-jet printing method of a dispenser. In one embodiment, the paper electrode has an electron transfer rate constant ks=1.78×10-3cm/s, which shows that the compound has good electron transfer capability.
In the present invention, one skilled in the art can also choose to use some accessories in the extraction-detection device according to the fixing requirement, the reverse iontophoresis requirement, the electrochemical detection requirement, the requirement of increasing the comfort and the like. For example, as shown in fig. 1 and 2, the extraction-detection device further includes a clamp fixing portion 105 and an electrode lead; the clamping fixing part 105 is used for clamping and fixing the first electrode assembly and is connected with the adherable substrate 103, and a person skilled in the art can select a specific structure according to needs, for example, a clamping structure shown in fig. 1, which includes a metal joint for connecting the double electrode 109 and the double electrode 109 by a lead wire, can be adopted; the electrode lead is used for forming a loop and conducting current signals and comprises an extraction electrode positive lead 101 and a double-electrode 109 lead, wherein the extraction electrode positive lead 101 is connected with an extraction electrode positive electrode 102, and the double-electrode 109 lead comprises a first electrode lead 106 and a second electrode lead 107 so as to be correspondingly connected with each electrode in the double-electrode 109. For another example, a layer of glue is placed on the first electrode assembly for added comfort. The material of the water gel can be selected by the person skilled in the art according to the requirements.
In some preferred embodiments, the extraction-detection apparatus further comprises: a gel layer disposed over the decorative coating 108 and proximate the skin 200. The gel layer is preferably a hydrogel.
The extraction-detection device of the invention also comprises a current source and an electrochemical detection mechanism to realize the reverse iontophoresis and electrochemical detection. In the case of reverse iontophoresis, the extraction electrode positive electrode lead 101 is connected to the positive electrode of the current source, and any one of the double-electrode 109 leads is connected to the negative electrode of the current source to perform extraction, and analyte molecules in the interstitial fluid are concentrated in the region of the extraction/detection electrode layer 104 of the first electrode assembly with the ion flow (see fig. 4). During electrochemical detection, the current source is disconnected, and the leads of the double electrodes 109 are respectively externally connected with an electrochemical analyzer.
The extraction-detection device provided by the invention can be used for real-time detection of human body noninvasive biochemical indexes (blood sugar, sodium, ammonia or other metal ions, lactic acid, picolinic alcohol and the like) in subcutaneous tissue fluid, enough detection amount can be obtained at low working current, and the detection result is equivalent to or even better than the accuracy of a traditional necessary three-electrode system. In addition, the invention can be converted into different ISF biochemical index noninvasive sensors only by replacing different modified coatings 108; the defects of blood sampling pain, susceptibility to infection and the like are overcome; the kit is suitable for self, real-time and in-situ detection of healthy human bodies and diabetic patients, and has the advantages of no wound, no pain, safety, portability, accuracy, stability, low price and the like.
The extraction-detection device provided by the invention is used as an electrode device for extraction and detection, has good biocompatibility on materials, and does not cause adverse reactions such as skin allergy; the structure has good flexibility and is compact in fit with the skin; the electrochemical detection device has stable electrochemical characteristics in function, high sensitivity and low detection limit; the manufacturing is simple, and the cost can be greatly reduced; can realize disposable detection and use, is safer and avoids cross infection.
In a second aspect, the present invention further provides a noninvasive subcutaneous tissue fluid extraction-detection method, which uses the extraction-detection device of the first aspect for detection, and comprises the following steps:
the detection area of the extraction-detection device faces the skin 200 of the subject, and the first electrode assembly and the second electrode assembly are attached to the skin 200 area to be detected of the subject through the adhesive substrate 103;
one electrode in the double electrodes 109 is used as a negative electrode and is combined with the extraction electrode positive electrode 102 to carry out reverse iontophoresis extraction, so that the object to be detected in the subcutaneous tissue fluid is extracted to the surface of the skin 200 and is enriched in the extraction/detection electrode layer 104 area;
after the electroosmotic extraction is completed, one electrode of the two electrodes 109 is used as a working electrode, and the other electrode is used as a counter electrode, and the extract obtained by the electroosmotic extraction is subjected to electrochemical detection.
In the extraction process, a person skilled in the art can observe the changes of extraction current, extraction voltage and water content on the surface of the electrode in the extraction process, ensure that the extraction process operates in a safe range, and store detection data.
After the electrochemical detection, a person skilled in the art can calculate the concentration of the analyte according to the existing method by reading the electrochemical current signal according to the output detection signal.
The invention is further illustrated below with reference to specific examples.
Example 1
A non-invasive subcutaneous tissue fluid extraction-detection device is shown in figure 1, and comprises an adhesive substrate 103, a first electrode assembly, a second electrode assembly, a current source (not shown in the figure) and an electrochemical detection analysis device (not shown in the figure), wherein the second electrode assembly comprises an extraction electrode anode 102 in an 'Contraband' shape and an extraction electrode anode lead 101, the first electrode assembly comprises a fiber paper, a carbon electrode layer, a potassium ferricyanide layer, a glucose oxidase layer and a paper-based flexible bioelectrode of a gel layer which are sequentially arranged, and the gel layer is close to skin 200. The carbon electrode layers are arranged in a comb-like interdigital arrangement, as shown in fig. 8. The comb-shaped interdigital carbon electrode layer is favorable for the homogenization of the extraction electric field. The electrode of the embodiment adopts the fiber paper as the substrate, and the high-conductivity carbon electrode is prepared by a screen printing method, so as to reduce the resistance of electrons entering the electrode. And secondly, the cellulose has good biocompatibility and does not cause adverse reactions such as skin allergy and the like. The fiber paper has smooth surface, good adhesion with carbon paste, and loose holes of fiber specific to the paper, so that the thick film electrode printed on the paper base is more stable.
Connecting the positive electrode lead 101 of the extraction electrode with the positive electrode of a current source, connecting one electrode of the double electrodes 109 with the negative electrode of the current source, and carrying out reverse iontophoresis extraction to extract subcutaneous tissue fluid to the surface of the skin 200 and enrich the subcutaneous tissue fluid in the extraction/detection electrode layer 104 area, wherein the extraction current is 0.1 mA.
After extraction is finished, the current source is disconnected, one electrode in the double electrodes 109 is used as a working electrode, the other electrode is used as a counter electrode, the first electrode lead 106 and the second electrode lead 107 are respectively used as the connection wires of the working electrode and the counter electrode, an electrochemical analyzer is externally connected, and the open-circuit potential of sodium ions in subcutaneous tissue fluid is measured. The open circuit potential response curve of the extraction-detection device of this example for different concentrations of NaCl solution is shown in FIG. 9. As can be seen from fig. 9, the extraction-detection apparatus of the present embodiment is capable of having stable and highly sensitive response to sodium ions of different concentrations depending on the extraction time, indicating that the apparatus has superior detection performance.
And glucose in subcutaneous tissue fluid was detected by the extraction-detection apparatus of this example, and the results showed that the sensitivity was 1.057. mu.A/mM in the range of 1-8mM glucose concentration and 0.292. mu.A/mM in the range of 8-18 mM glucose concentration under the condition that the extraction current was 0.1 mA. The detection limit was 0.39mM (S/N = 3).
It can be seen from the above examples that the extraction-detection device of the present invention can generate a more uniform magnetic field at a lower extraction current, thereby performing efficient extraction and achieving extraction of a sufficient amount of the extraction solution.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (13)
1. A non-invasive subcutaneous tissue fluid extraction-detection apparatus, comprising:
an adherable substrate;
a first electrode assembly disposed on the adherable substrate and including an extraction/detection electrode layer including a double electrode for electrochemically detecting a content of an analyte in the extracted subcutaneous tissue fluid;
a second electrode assembly disposed on the adherable substrate and including an extraction electrode positive electrode for cooperating with one of the two electrodes to transcutaneously extract subcutaneous tissue fluid by a reverse iontophoresis technique; and the extraction electrode anode covers the extraction/detection electrode layer, and the extraction electrode anode is arranged along the covered edge of the extraction/detection electrode layer in an extending manner.
2. The extraction-detection apparatus according to claim 1, wherein the extraction electrode positive electrode has a rectangular or arc shape for the coating.
3. The extraction-detection apparatus according to claim 1, wherein the extraction electrode positive electrode is in the shape of "Contraband".
4. The extraction-detection apparatus according to claim 1, wherein the shortest distance between the extraction electrode positive electrode and the extraction/detection electrode layer is 2 to 3 mm.
5. The extraction-detection apparatus according to claim 1, wherein the area of the extraction electrode positive electrode on the plane of the attachment side is 0.5 to 10 cm2。
6. The extraction-detection apparatus according to claim 5, wherein the area of the extraction electrode positive electrode on the plane of the attachment side is 0.5 to 4 cm2。
7. The extraction-detection apparatus according to claim 1,
the area of the extraction/detection electrode layer is 0.5-5 cm2；
And/or the whole extraction/detection electrode layer is rectangular or arc-shaped;
and/or the electrode in the extraction/detection electrode layer is a glassy carbon electrode or a carbon electrode.
8. The extraction-detection apparatus according to claim 7, wherein the extraction/detection electrode layer has an area of 0.5 to 2 cm2。
9. The extraction-detection apparatus according to claim 1, wherein the dual electrodes are arranged in a ridge-like, serpentine, concentric circular or comb-like interdigital arrangement.
10. The extraction-detection apparatus according to claim 9, wherein the double electrodes are arranged in a comb-like interdigital arrangement, and a plane where comb-like interdigital portions of the double electrodes are located satisfies: the area is 40-60mm2(ii) a And/or the length is 9-12mm, the width is 3-6mm, and the interval between the fingers is 0.1-0.5 mm.
11. The extraction-detection apparatus according to claim 1, wherein the first electrode assembly further comprises:
a base layer disposed on the adherable substrate and located below the extraction/detection electrode layer;
the modification coating is arranged above the extraction/detection electrode layer and close to the skin and comprises an electron transfer medium and recognition molecules, and the electron transfer medium and the recognition molecules are matched with the substance to be detected.
12. The extraction-detection apparatus according to claim 11, further comprising: a gel layer disposed over the finish coating and proximate to the skin.
13. A non-invasive subcutaneous tissue fluid extraction-detection method, characterized in that the extraction-detection device of any one of claims 1-12 is used for detection, comprising the following steps:
the detection area of the extraction-detection device faces the skin of a subject, and the first electrode assembly and the second electrode assembly are attached to the skin area to be detected of the subject through an adhesive substrate;
one electrode in the double electrodes is used as a negative electrode and is combined with an extraction electrode positive electrode to carry out reverse iontophoresis extraction, so that the substance to be detected in the subcutaneous tissue fluid is extracted to the surface of the skin and is enriched in the extraction/detection electrode layer area;
and after the electroosmosis extraction is finished, one electrode of the double electrodes is used as a working electrode, the other electrode is used as a counter electrode, and the extract obtained by the electroosmosis extraction is subjected to electrochemical detection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210455230.1A CN114557694B (en) | 2022-04-28 | 2022-04-28 | Noninvasive subcutaneous tissue fluid extraction-detection device and extraction-detection method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210455230.1A CN114557694B (en) | 2022-04-28 | 2022-04-28 | Noninvasive subcutaneous tissue fluid extraction-detection device and extraction-detection method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114557694A true CN114557694A (en) | 2022-05-31 |
| CN114557694B CN114557694B (en) | 2022-09-23 |
Family
ID=81721469
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210455230.1A Active CN114557694B (en) | 2022-04-28 | 2022-04-28 | Noninvasive subcutaneous tissue fluid extraction-detection device and extraction-detection method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114557694B (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5954685A (en) * | 1996-05-24 | 1999-09-21 | Cygnus, Inc. | Electrochemical sensor with dual purpose electrode |
| CN201767968U (en) * | 2010-08-12 | 2011-03-23 | 长庚医学科技股份有限公司 | Noninvasive blood glucose meter electrode structure |
| CN105954331A (en) * | 2016-05-04 | 2016-09-21 | 中国科学院大学 | Paper-based electrode detection platform for biochemical analysis, and preparation method thereof |
| CN207336426U (en) * | 2017-06-07 | 2018-05-08 | 杭州暖芯迦电子科技有限公司 | A kind of biology sensor |
| CN108209942A (en) * | 2017-12-20 | 2018-06-29 | 清华大学 | A kind of non-invasive continuous blood sugar measuring system |
| CN109199400A (en) * | 2018-09-10 | 2019-01-15 | 中山大学 | Blood glucose electrochemical sensor based on microneedle array |
| CN109298048A (en) * | 2018-11-13 | 2019-02-01 | 海南大学 | A kind of copper-based sensor chip and preparation method thereof and detection method |
| CN109414227A (en) * | 2016-04-26 | 2019-03-01 | 巴斯大学 | Multiplexing for non-invasive monitoring substance is percutaneously extracted and detection device and its application method |
-
2022
- 2022-04-28 CN CN202210455230.1A patent/CN114557694B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5954685A (en) * | 1996-05-24 | 1999-09-21 | Cygnus, Inc. | Electrochemical sensor with dual purpose electrode |
| CN201767968U (en) * | 2010-08-12 | 2011-03-23 | 长庚医学科技股份有限公司 | Noninvasive blood glucose meter electrode structure |
| CN109414227A (en) * | 2016-04-26 | 2019-03-01 | 巴斯大学 | Multiplexing for non-invasive monitoring substance is percutaneously extracted and detection device and its application method |
| CN105954331A (en) * | 2016-05-04 | 2016-09-21 | 中国科学院大学 | Paper-based electrode detection platform for biochemical analysis, and preparation method thereof |
| CN207336426U (en) * | 2017-06-07 | 2018-05-08 | 杭州暖芯迦电子科技有限公司 | A kind of biology sensor |
| CN108209942A (en) * | 2017-12-20 | 2018-06-29 | 清华大学 | A kind of non-invasive continuous blood sugar measuring system |
| CN109199400A (en) * | 2018-09-10 | 2019-01-15 | 中山大学 | Blood glucose electrochemical sensor based on microneedle array |
| CN109298048A (en) * | 2018-11-13 | 2019-02-01 | 海南大学 | A kind of copper-based sensor chip and preparation method thereof and detection method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114557694B (en) | 2022-09-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| García-Guzmán et al. | Microneedle based electrochemical (Bio) Sensing: Towards decentralized and continuous health status monitoring | |
| US5954685A (en) | Electrochemical sensor with dual purpose electrode | |
| JP3155523B2 (en) | Biosensor, ion permeation sampling system and method of using the same | |
| US6391643B1 (en) | Kit and method for quality control testing of an iontophoretic sampling system | |
| ES2371766T3 (en) | IMPLANTABLE NEEDLE BIOSENSOR WITHOUT CATHETER. | |
| US20210204878A1 (en) | Percutaneous microneedle monitoring system | |
| JP6953431B2 (en) | Multiple transdermal extraction and detection devices for non-invasive monitoring of substances and usage | |
| JP2006167428A (en) | Analyte extraction device, analyzer, analyte extraction method, and analysis method | |
| CN1606423A (en) | A minimally-invasive system and method for monitoring analyte levels | |
| US20120252046A1 (en) | Transdermal systems, devices, and methods for biological analysis | |
| Chen et al. | Recent advances of tissue-interfaced chemical biosensors | |
| CN106725470B (en) | Continuous or discontinuous physiological parameter analysis system | |
| CN112617749A (en) | Physiological and biochemical monitoring device | |
| Zhang et al. | Current technological trends in transdermal biosensing | |
| Lyu et al. | Soft, disruptive and wearable electrochemical biosensors | |
| CN207202871U (en) | A kind of physiologic parameter analysis system continuously or discontinuously | |
| CN114557694B (en) | Noninvasive subcutaneous tissue fluid extraction-detection device and extraction-detection method | |
| Huang et al. | Microarrow sensor array with enhanced skin adhesion for transdermal continuous monitoring of glucose and reactive oxygen species | |
| CN114748064A (en) | Hollow microneedle vertical graphene sensor and preparation method thereof | |
| US20170188898A1 (en) | Devices and methods for enhanced skin perforation for continuous glucose monitoring | |
| KR100692783B1 (en) | Patch for extracting glucose | |
| Ausri et al. | Recent advances and challenges: Translational research of minimally invasive wearable biochemical sensors | |
| EP3928697A1 (en) | Analyte sensor and a method for producing an analyte sensor | |
| He et al. | Helical Microfilament‐Electrode‐Based Semi‐Implantable Biosensors for In Vivo Electrochemical Detection | |
| JPS63135131A (en) | Percataneous sensor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |