CN115590508A

CN115590508A - Miniature analyte sensor

Info

Publication number: CN115590508A
Application number: CN202110773283.3A
Authority: CN
Inventors: 杨翠军
Original assignee: Medtrum Technologies Inc
Current assignee: Medtrum Technologies Inc
Priority date: 2021-07-08
Filing date: 2021-07-08
Publication date: 2023-01-13

Abstract

The invention discloses a miniature analyte sensor, comprising: a substrate comprising an in vivo portion and an in vitro portion; at least one set of electrodes located on a surface of the intracorporeal portion, each set of electrodes including at least one working electrode and at least one additional electrode; PAD (pins) corresponding to the electrodes are arranged at the external part of the body, and the PAD is respectively and electrically connected with the working electrode and the additional electrode through leads; at least one surface of the electronic conducting layer of the working electrode and/or the additional electrode is provided with a microstructure, so that the surface area and the roughness of the electronic conducting layer are increased, the adhesion force of the electrode is enhanced, and the detection reliability of the sensor is improved.

Description

Miniature analyte sensor

Technical Field

The invention mainly relates to the field of medical instruments, in particular to a miniature analyte sensor.

Background

The pancreas in a normal human body can automatically monitor the glucose content in the blood of the human body and secrete the required insulin/glucagon automatically. The function of pancreas of diabetics is abnormal, and insulin required by human bodies cannot be normally secreted. Therefore, diabetes is a metabolic disease caused by abnormal pancreatic functions of a human body, and diabetes is a lifelong disease. At present, the medical technology can not cure the diabetes radically, and only can control the occurrence and the development of the diabetes and the complications thereof by stabilizing the blood sugar.

Diabetics need to test their blood glucose before injecting insulin into their bodies. At present, most detection methods can continuously detect blood sugar and transmit blood sugar data to remote equipment in real time, so that a user can conveniently check the blood sugar data. The method needs the detection device to be attached to the surface of the skin, and the probe carried by the detection device is penetrated into subcutaneous tissue fluid to finish detection. However, most of the electronic conducting layers of the existing sensor electrodes are smooth structures, the adhesion among the electronic conducting layers, the substrate and the film layer is small, the electrodes are easy to fall off in the using process, the film layer is easy to shift, and the use reliability and the service life of the sensor are influenced. In some improved technical schemes, in order to increase the adhesion between the electron conduction layer and the film layer, a layer of platinum black is processed on the electron conduction layer, but the adhesion between the platinum black and the substrate is still small, and the processing technology of the platinum black is complex and the cost is high.

Thus, there is a need in the art for a miniature analyte sensor with electrodes that have strong adhesion.

Disclosure of Invention

In view of the above disadvantages of the prior art, a first aspect of the embodiments of the present invention discloses a micro analyte sensor, which includes at least one electrode set, where the electrode set includes at least one working electrode and at least one additional electrode, and at least one surface of an electron conducting layer of the working electrode and/or the additional electrode is provided with a micro structure, so that the adhesion between the electron conducting layer and a substrate or a film layer can be improved, and the manufacturing cost is low.

The invention discloses a miniature analyte sensor, comprising: a substrate comprising an in vivo portion and an in vitro portion; at least one electrode set positioned on a surface of the intracorporeal portion, the electrode set including at least one working electrode and at least one additional electrode; pins (PAD) corresponding to the electrodes are arranged at the external part of the body, and the pins are respectively and electrically connected with the working electrode and the additional electrode through leads; at least one surface of the working electrode and/or the additional electrode is provided with a microstructure.

According to one aspect of the invention, the additional electrode comprises a counter electrode.

According to one aspect of the invention, the additional electrode further comprises a reference electrode.

According to one aspect of the invention, the working electrode, the reference electrode, and the counter electrode comprise at least an electron conducting layer, a tamper resistant layer, an enzyme layer, a conditioning layer, and a biocompatible layer.

According to one aspect of the invention, the electron conducting layers of the working electrode and the counter electrode are one of graphite, glassy carbon, or noble metals.

According to one aspect of the invention, the electron conducting layers of the working and counter electrodes are platinum.

According to one aspect of the invention, the electron conducting layer of the reference electrode is one of Ag/AgCl or calomel.

According to one aspect of the invention, a microstructure is disposed on the electron conducting layer.

According to one aspect of the invention, the microstructure comprises micro-grooves or micro-protrusions.

According to one aspect of the invention, the micro-grooves comprise one or more of micro-through holes or micro-blind holes or micro-scores.

According to one aspect of the invention, the diameter of the microstructures is between 0.01 and 100um.

According to one aspect of the invention, the density of the microstructures is 1 x 10 ² ～1*10 ¹⁰ /cm ² 。

According to one aspect of the invention, the material of the substrate is selected from the group consisting of polytetrafluoroethylene, polyethylene, polyvinyl chloride, acrylonitrile-butadiene-styrene copolymer, polymethyl methacrylate, polycarbonate, polyimide, and combinations of one or more thereof.

Compared with the prior art, the technical scheme of the invention has the following advantages:

the invention discloses a miniature analyte sensor, wherein a working electrode and an additional electrode are arranged at the internal part on a substrate, and all the electrodes are electrically connected with a PAD (PAD application) corresponding to the external part through leads. At least one surface of the working electrode and/or the additional electrode electronic conduction layer is provided with a microstructure, the surface area of the electronic conduction layer is increased, and meanwhile, the roughness of the surface is also increased, so that the adhesion force between the electronic conduction layer and the substrate and between the electronic conduction layer and the film layer can be increased, the possibility that the electrode and the film layer shift or fall off in the use process is reduced, and the reliability of the sensor is improved.

Further, the miniature analyte sensors disclosed herein can be divided into three-electrode systems, a counter electrode, a reference electrode and at least one working electrode, and two-electrode systems, a counter electrode and at least one working electrode. In addition, the present invention can be divided into two cases according to the number of working electrodes: 1) Single working electrode: only one working electrode is provided; 2) Double working electrodes: the working electrode has two, one of which undergoes an electro-redox reaction with the analyte to produce an electrical signal, and the other of which is generally responsible for detecting the interferent or the response signal of the background solution, and is referred to as the "auxiliary electrode". The three-electrode system can effectively control the detection potential because one more reference electrode is added, thereby preventing the potential from drifting and improving the reliability of detecting the parameter information of the analyte; the two-electrode system has simple structure and lower manufacturing cost.

Further, the electron conducting layer of each electrode employs a material having good electrical conductivity and strong chemical inertness as an electrode material. The preferred working electrode and counter electrode are one of graphite, glassy carbon or noble metals, and the reference electrode is one of Ag/AgCl or calomel. Noble metal materials such as gold, platinum, silver, etc. are preferred in view of the requirements of good ductility and surface structural stability. More preferably, the working electrode and the counter electrode are both platinum electrodes.

Furthermore, the microstructure on the surface of the electronic conduction layer can be a micro groove or a micro protrusion, and when the microstructure is a micro groove, the microstructure can be one or more of a micro through hole, a micro blind hole or a micro nick, namely the microstructure is not limited to the specific shape of the microstructure, the surface area and the roughness of the electrode can be increased, and the requirement on the processing technology and the processing cost are reduced.

Furthermore, the material of the sensor substrate is selected from one or more of polytetrafluoroethylene (Teflon), polyethylene (PE), polyvinyl chloride (PVC), acrylonitrile-butadiene-styrene copolymer (ABS), polymethyl methacrylate (PMMA), polycarbonate (PC), polyimide (PI) and the like, and the materials all have excellent insulating property, water impermeability and high mechanical strength, so that the service life of the sensor can be prolonged.

A second aspect of an embodiment of the present invention discloses a continuous analyte monitoring device, comprising: a bottom shell for mounting on a skin surface of a host; a sensor unit comprising a base and at least one miniature analyte sensor as described hereinbefore, the miniature analyte sensor being secured to the base, the sensor unit being mounted on the base via the base for detecting analyte parameter information in the host; the emitter is electrically connected with the sensor unit and used for sending the analyte parameter information to the outside; the battery is used for providing electric energy; and a receiver for receiving the analyte parameter information and indicating to a user.

The reliability of the sensor is often a key factor limiting the reliability of the continuous analyte monitoring device, and the adhesion between the electronic conduction layer and the substrate and between the electronic conduction layer and the film layer is enhanced by arranging the microstructure on the surface of the electronic conduction layer of the electrode, so that the reliability of the sensor is improved, and the reliability of the continuous analyte monitoring device is also improved.

Drawings

FIG. 1 is a schematic diagram of a sensor according to an embodiment of the present invention;

FIG. 2 is a side view of the sensor of the embodiment of FIG. 1;

FIG. 3 is a cross-sectional view of an electrode;

FIG. 4 is a schematic view of a microstructure on a surface of an electron-conducting layer according to an embodiment of the invention;

FIG. 5 is a cross-sectional view taken along line V-V' of FIG. 4;

FIG. 6 is a schematic view of a continuous analyte monitoring device according to an embodiment of the present invention.

Detailed Description

As mentioned above, the adhesion between the electron conducting layer of the analyte sensor electrode and the substrate or membrane layer is weak, and the electrode and the membrane layer are easy to shift or fall off during the use process, which affects the use reliability of the sensor.

To solve this problem, the present invention provides a miniature analyte sensor having at least one electrode set disposed on a surface of an in vivo portion on a substrate, the electrode set comprising at least one working electrode and at least one additional electrode, all of which are electrically connected by wires to corresponding PADs disposed on the in vitro portion. The surfaces of the working electrode and the additional electrode electron conduction layer are both provided with the microstructures, so that the surface area of the electron conduction layer is increased, and simultaneously, the surface roughness is increased, so that the adhesion force between the electron conduction layer and the substrate and between the electron conduction layer and the film layer can be increased, the possibility that the electrode and the film layer shift or fall off in the use process is reduced, and the reliability of the sensor is improved.

Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be understood that the relative arrangement of parts and steps, numerical expressions, and numerical values set forth in these embodiments should not be construed as limiting the scope of the present invention unless it is specifically stated otherwise.

Further, it should be understood that the dimensions of the various elements shown in the figures are not necessarily drawn to scale, for example, the thickness, width, length or distance of some elements may be exaggerated relative to other structures for ease of illustration.

The following description of the exemplary embodiment(s) is merely illustrative and is not intended to limit the invention or its application or uses in any way. Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail herein, but are intended to be part of the present description where applicable.

It should be noted that like reference numerals and letters refer to like items in the following figures, and thus, once an item is defined or illustrated in one figure, further discussion thereof will not be required in the subsequent figure description.

Furthermore, it is to be understood that one or more method steps mentioned in the present invention does not exclude that other method steps may also be present before or after the combined steps or that other method steps may also be inserted between these explicitly mentioned steps, unless otherwise indicated; it should also be understood that a combinational connection relationship between one or more devices/apparatuses mentioned in the present invention does not exclude that other devices/apparatuses may also be present before or after the combinational device/apparatus or that other devices/apparatuses may also be interposed between the two devices/apparatuses explicitly mentioned, unless otherwise stated. Moreover, unless otherwise indicated, the numbering of the various method steps is merely a convenient tool for identifying the various method steps, and is not intended to limit the order in which the method steps are arranged or the scope of the invention in which the invention may be practiced, and changes or modifications in the relative relationship may be made without substantially changing the technical content.

FIG. 1 is a schematic diagram of a sensor according to an embodiment of the present invention; fig. 2 is a side view of the sensor of the embodiment of fig. 1.

The sensor 11 includes a substrate 111, and the substrate 111 is divided into an external portion X and an internal portion Y by using a dotted line shown in fig. 1 as a boundary line. Electrodes are laid on the internal part Y and comprise at least one working electrode 1131 and at least one additional electrode, and obviously, in the present embodiment, the additional electrode comprises a counter electrode 1231 and a reference electrode 1331, so as to form a three-electrode system, the counter electrode 1231 is the other electrode opposite to the working electrode 1131 and forms a closed loop with the working electrode 1131, so that the current on the electrodes can be normally conducted, and the reference electrode 1331 is used for providing a reference potential for the working electrode 1131, so that the detection potential can be effectively controlled. In another embodiment of the present invention, the additional electrode may include only the counter electrode 1231 to form a two-electrode system, and the effective areas of the working electrode 1131 and the counter electrode 1231 may be increased in a limited area of the internal portion Y as compared to a three-electrode system, thereby extending the lifespan of the electrodes, and the manufacturing process is simpler because one electrode is reduced, but the reliability of the information detected by the analyte may be reduced because the working electrode 1131 does not have the detection potential of the reference electrode as a reference. In yet another embodiment of the present invention, there are at least two working electrodes 1131, one of which is used to generate an electrical signal by performing an electro-redox reaction with the analyte to be detected, and the other of which is used to detect the response signal of the interferent or background solution in the body fluid of the host, and this electrode is the auxiliary electrode.

With continued reference to fig. 1 and fig. 2, PADs (pins) are laid on the extracorporeal portion X, and the PADs correspond to the electrodes one by one and are electrically connected through wires, that is, the first PAD1111 corresponding to the working electrode 1131 is electrically connected through a wire 1121; a second PAD1211 electrically connected through a wire 1221 corresponding to the counter electrode 1231; and a third PAD1311 corresponding to reference electrode 1331, electrically connected by wire 1321. The different PADs, the conducting wires and the electrodes are insulated from one another, so that the electric signals are prevented from being subjected to crosstalk.

Since the sensor 11 has a planar structure, there are two opposite surfaces, i.e., a surface and a B surface. The working electrode 1131, the counter electrode 1231 and the reference electrode 1331 are laid on the a surface of the sensor as one electrode group, and the other electrode group is laid on the B surface of the sensor, wherein the electrode group can be a two-electrode system, a three-electrode system or a two-working electrode system, preferably, the electrode group is consistent with the a surface, i.e. the electrode group comprises a working electrode 1132, a counter electrode 1232 and a reference electrode 1332, and similarly, the B surface is also laid with PADs, the PADs are in one-to-one correspondence with the electrodes on the B surface and are electrically connected through a lead, i.e. the fourth PAD1112 corresponding to the working electrode 1132 is electrically connected through the lead 1122; a fifth PAD1212 corresponding to the counter electrode 1232, electrically connected through a wire 1222; and a sixth PAD1312, corresponding to the reference electrode 1332, electrically connected by a lead 1322. Therefore, under the condition that any electrode on the surface A is at the end of life or fails in advance, the like electrode on the surface B can be switched into a working state, the reliability of parameter data of the detected analyte is improved, and the service life of the sensor is prolonged.

It should be understood by those skilled in the art that the order and location of the PADs, leads and electrodes laid on the a-side and B-side of the sensor are not limited. The PAD, wires and electrodes on both sides may be arranged symmetrically or asymmetrically. Corresponding PAD, wire and electrode are laid on the same face, also can lay on different faces, and preferably, corresponding PAD, wire and electrode are laid on the same face, the wire of being convenient for is walked. For example, working electrode 1131 on side a can be replaced with counter electrode 1231, or counter electrode 1231 on side a can be replaced with reference electrode 1332 on side B, regardless of the order and position of the PAD, lead and electrode on side a and side B, so long as the PAD, lead and electrode are in a one-to-one, insulated relationship.

In other embodiments of the present invention, although the planar structure sensor has only a surface a and a surface B opposite to each other, the number of electrode groups can be increased by increasing the area of the sensor or decreasing the area of the electrodes, thereby further increasing the service life of the sensor. However, an excessively large sensor area may increase rejection response of the host, causing discomfort to the host; too small an electrode area can reduce the sensitivity of the electrode and reduce the reliability of the detected parameters. An excessive number of electrode sets also increases the complexity of the manufacturing process, for example, the wires can become very densely routed. Therefore, it is preferable that the number of the electrode groups is two.

In other embodiments of the present invention, the electrode groups may also be distributed on the same surface of the sensor, such as the a surface or the B surface, which is not limited herein.

In the embodiment of the present invention, the substrate 111 is a material with excellent insulating properties, mainly derived from inorganic non-metallic ceramics, silica glass, organic polymer, and the like, and the substrate material is also required to have high water impermeability and mechanical strength in consideration of the application environment of the implanted electrode. Preferably, the material of the substrate is selected from one or more of polytetrafluoroethylene (Teflon), polyethylene (PE), polyvinyl chloride (PVC), acrylonitrile-butadiene-styrene copolymer (ABS), polymethyl methacrylate (PMMA), polycarbonate (PC), polyimide (PI), and the like.

Fig. 3 is a cross-sectional view of an electrode. In one embodiment of the invention, the working electrode (auxiliary electrode), the counter electrode and the reference electrode at least comprise an electron conducting layer a, an interference-resistant layer b, an enzyme layer c, a regulating layer d and a biocompatible layer e, which are collectively referred to as membrane layers.

Electron conductive layer:

the electron-conducting layer a is made of a material having good electrical conductivity and strong chemical inertness. Preferably, the working electrode and the counter electrode are selected from one of graphite electrode, glassy carbon electrode, noble metal and the like, and the reference electrode is selected from one of Ag/AgCl or calomel. In view of the requirements of good ductility and stability of the surface structure, noble metal electrodes such as gold electrodes, platinum electrodes, silver electrodes, etc. are preferred, and it is further preferred that both the working electrode and the counter electrode are platinum electrodes.

In the technical solution of the present patent, the microstructure is disposed on the electron conduction layer a.

An anti-interference layer:

the interference rejection layer b is located between the enzyme layer and the electron-conducting layer. Interferents are molecules or substances that electrochemically reduce or electrochemically oxidize at the electrode surface, either directly or indirectly through an electron transfer agent, to produce a false signal that interferes with analyte detection. For example, for the determination of glucose as the analyte, common interferents in the body are urea, ascorbic acid, acetaminophen, and the like.

In a preferred embodiment, the interference rejection layer b may prevent the penetration of one or more interferents into the electrolyte surrounding the electrodes. For example, the interference rejection layer b may allow passage of an analyte (e.g., hydrogen peroxide) to be measured at the electrode while preventing passage of other species (e.g., potentially interfering species). In a preferred embodiment, the tamper resistant layer b may be a very thin film intended to limit the diffusion of those substances with a molecular weight greater than 34 Da.

In another preferred embodiment, the interference rejection layer b may be an organic polymer, which may be prepared from an organosilane and a hydrophilic copolymer. Hydrophilic copolymers, more preferably polyethylene glycol (PEG), poly (2-hydroxyethyl methacrylate) and polylysine. In preferred embodiments, the thickness of the tamper resistant layer b may range from 0.1 microns or less to 10 microns or more. A more preferred thickness range is 0.5 to 5 microns.

Enzyme layer:

the enzyme layer c is coated with active enzymes, and the corresponding active enzymes are coated according to the type of the analyte to be detected. The active enzyme can enable the analyte to be detected to generate certain chemical reactions to generate electrons, the quantity of the generated electrons is different according to the concentration of the analyte to be detected, and the electrons are collected by the electron conducting layer, so that different current intensities are formed, and therefore, the current intensity information can be used for representing the parameter information of the analyte.

Preferably, the enzyme layer c is coated with glucose oxidase (GOx).

A regulating layer:

the regulating layer d is positioned above the enzyme layer. In the embodiment of the present invention, when glucose oxidase is coated on the enzyme layer, the regulating layer d is mainly used to regulate the permeability of oxygen and glucose transferred to the enzyme layer. The glucose content (molarity) of the body fluid is an order of magnitude higher than the oxygen content. However, for enzyme-based sensors that require oxygen to participate, an excess of oxygen needs to be supplied to ensure that oxygen does not become a limiting species, so that the sensor can respond linearly to changes in glucose concentration without being affected by the oxygen partial pressure. That is, the linear range of the glucose oxygen monitoring reaction does not reach the expected concentration range when oxygen content becomes the limiting factor. Without a semi-permeable membrane over the enzyme layer to regulate oxygen and glucose permeation, the upper limit of the linear response of the sensor to glucose can only reach about 40mg/dL. However, in the clinical setting, the upper limit of the linear response of blood glucose levels needs to reach about 500mg/dL.

The regulating layer d mainly functions as a semipermeable membrane for regulating the permeation amount of oxygen and glucose delivered to the enzyme layer, more specifically, making the oxygen excess a non-limiting factor. The upper limit of the linear response to glucose of the sensor comprising the modulating layer can be reached at a higher level than without the modulating layer. In a preferred embodiment, the oxygen-glucose permeability of the regulating layer d can be up to a ratio of 200, so that it is ensured that there is sufficient oxygen for the enzyme-based reaction to proceed for the various glucose and oxygen concentrations that may occur subcutaneously.

In a preferred embodiment, the conditioning layer d may be an organic polymer, which may be prepared from an organosilane and a hydrophilic copolymer. Hydrophilic copolymers, more preferably, copolymerized or grafted polyethylene glycol (PEG). Other hydrophilic copolymers that may be used include, but are not limited to, other glycols such as propylene glycol, esters, amides, carbonates, and polypropylene glycol. By using the organic silicon polymer, the transmission of oxygen can be obviously improved, and the permeation of glucose can be effectively controlled. In a preferred embodiment, the thickness of the adjustment layer d may range from 1 micron or less to 50 microns or more, with a more preferred thickness range being from 1 micron to 10 microns.

A biocompatible layer:

the biocompatible layer e is located on the outermost surface of the electrode and is intended to eliminate the body's rejection of foreign bodies and to reduce the formation of a layer of shielding cells around the implanted electrode.

In a preferred embodiment, the biocompatible layer e can be prepared from an organosilane and a hydrophilic copolymer. Hydrophilic copolymers, more preferably, copolymerized or grafted polyethylene glycol (PEG). Other hydrophilic copolymers that may be used include, but are not limited to, other glycols such as propylene glycol, esters, amides, carbonates, and polypropylene glycol.

In a preferred embodiment, the thickness of the biocompatible layer e may range from 1 micron or less to 100 microns or more. A more preferred thickness range is 10 to 30 microns.

In the embodiment of the present invention, the thickness of the substrate 111 is 0.01 to 0.8mm, each electrode is rectangular, the width of each electrode is 0.01 to 1mm, and the area is 0.1 to 2mm ² 。

FIG. 4 is a schematic diagram of the electrode surface microstructure according to the embodiment of the invention, and FIG. 5 is a cross-sectional view of V-V' of FIG. 4.

In the embodiment of the present invention, taking the working electrode 1131 as an example, the electronic conducting layer a of the electrode is divided into an a surface and a B surface, one surface is attached to the sensor substrate 11, and the other surface is attached to the film layer (B \ c \ d \ e), and both surfaces have microstructures, which can increase the surface area of the electronic conducting layer on one hand, thereby increasing the current density, and can increase the roughness of the surface on the other hand, so as to enhance the adhesion force between the electronic conducting layer a and the substrate 11 and between the film layers (B \ c \ d \ e), prevent the electrode from shifting or falling off on the substrate or between the film layers when in use, and simultaneously enhance the bonding force between the electrode and a polymer, such as glucose in vivo, and improve the reliability and stability of the sensor detection.

The micro-structures protruding to the outside of the surface of the electron conducting layer a form micro-protrusions, such as

micro-protrusions

11311a, 11311b, 11311c, etc., the micro-protrusions are not limited to a specific shape, and may be triangular prism-like, spherical-like, rectangular parallelepiped-like, or irregular, and have a diameter of 0.001 to 100um, preferably 10 to 50um.

Accordingly, the micro-structures recessed into the surface of the electron conducting layer a form micro-grooves, such as micro-grooves 11311d, 11311e, and 11311f, and the micro-protrusions have no specific shape limitation, and may be in the shape of a triangular prism, a sphere, a rectangular parallelepiped, or a random shape, such as a long-stripe notch (not shown). The diameter of the micro groove is 0.001-100 um, and the height of the micro protrusion or the depth of the micro groove is 0.001-50 um. Preferably, the diameter is 10-50 um, and the height of the micro-protrusion or the depth of the micro-groove is 10-30 um.

In the embodiment of the present invention, no matter the micro-protrusions or the micro-grooves are formed, the micro-protrusions or the micro-grooves may be uniformly arranged on any surface of the electron conducting layer a at equal intervals or at equal intervals, or may be randomly arranged, which is not limited herein. But its density needs to be limited to a certain range or the like, e.g. 1 x 10 ² ～1*10 ¹⁰ /cm ² Either too high or too low microstructure density does not provide the desired adhesion enhancement.

In the embodiment of the present invention, the micro protrusions or micro grooves may be obtained by a chemical etching method. For example by means of a cleaning-chemical liquid (HCl/C) ₂ H ₂ O ₂ /NH ₄ Cl/FeCl ₃ ) The process steps of corrosion-cleaning-brightening treatment-cleaning-drying treatment can obtain the product with diameter of about 1-50 um and density of 5 x 10 ² ～3*10 ³ /cm ² And a micro-protrusion or a micro-groove with the thickness of 1-10 um. For another example, the laser etching process may also be used to control the stroke and energy of the laser, so as to obtain the micro-protrusions or micro-grooves with the above parameters. Compared with the method for processing the platinum black, the method for processing the micro groove or the micro protrusion is simpler, and the cost is saved。

The microstructure obtained by the chemical corrosion method is in an irregular shape, through holes or blind holes or nicks can be respectively obtained according to the using amount of chemical liquid and a corresponding treatment process, the aperture size is changed within a certain range, the diameter of each hole is also changed in different directions, and the holes in the irregular shape are more favorable for improving the adhesion force between the electron conduction layer and the substrate as well as between the electron conduction layer and the membrane layer.

It will be understood by those skilled in the art that the process for obtaining the micro-grooves or micro-protrusions is not limited to the above-mentioned process flow, and any process for obtaining the micro-grooves or micro-protrusions by micro-machining can be used.

In other embodiments of the present invention, the surface of the electron conducting layer a is further provided with a carbon nanotube modification layer (not shown). The carbon nano tube is modified on the surface of the electronic conduction layer a by physical adsorption, embedding or covalent bond and the like on the surface of the formed electronic conduction layer a by utilizing the specific mechanical strength, high specific surface area, rapid electronic transfer effect and chemical stability of the carbon nano tube so as to improve the electronic transfer speed, and the carbon nano tube can be used as an excellent catalyst (enzyme) carrier due to the large specific surface area. The carbon nanotube layer modification layer can be fixed on the surface of the electronic conducting layer a by a Nafion solution dispersion method, a covalent fixation method and the like.

FIG. 6 is a schematic diagram of continuous analyte monitoring device 100 according to an embodiment of the present invention. Continuous analyte monitoring device 100 includes a bottom housing 101 for mounting to a host skin surface; a sensor unit 102, the sensor unit 102 comprising a base 1021 on which the micro analyte sensor 11 is fixed and the micro analyte sensor 11 as described above, the sensor unit 102 being mounted on the bottom case 101 via the base; a transmitter unit 103, the transmitter unit 103 comprising an internal circuit 1031, a transmitter 1032 and an electrical connection region 1033, the electrical connection region 1033 being electrically connected to the sensor unit 102, the internal circuit 1031 storing the predetermined conditions for switching the electrodes as described above, the transmitter 1032 being configured to transmit analyte parameter information to the outside; a battery 104, the battery 104 being for providing electrical energy; a receiver 105, the receiver 105 being configured to receive analyte parameter information and indicate to a user.

In summary, the present invention discloses a miniature analyte sensor, wherein at least one electrode set is disposed on the surface of an in vivo portion on a substrate, the electrode set comprises at least one working electrode and at least one additional electrode, and all the electrodes are electrically connected to corresponding PADs disposed on the in vitro portion through wires. The surfaces of the electronic conduction layers of the working electrode and the additional electrode are both provided with the microstructures, so that the surface area of the electronic conduction layer is increased, and meanwhile, the roughness of the surface is also increased, so that the adhesion force between the electronic conduction layer and the substrate and between the electronic conduction layer and the film layer can be increased, the possibility that the electrode and the film layer shift or fall off in the use process is reduced, and the use reliability of the sensor is improved.

Although some specific embodiments of the present invention have been described in detail by way of example, it should be understood by those skilled in the art that the above examples are for illustration only and are not intended to limit the scope of the invention. It will be appreciated by those skilled in the art that modifications may be made to the above embodiments without departing from the scope and spirit of the invention. The scope of the invention is defined by the appended claims.

Claims

1. A miniature analyte sensor, comprising:

a substrate comprising an in vivo portion and an in vitro portion;

at least one electrode set located on a surface of the internal body portion, the electrode set including at least one working electrode and at least one additional electrode;

pins corresponding to the electrodes are arranged on the external part of the body, and the pins are respectively and electrically connected with the working electrode and the additional electrode through leads;

at least one surface of the working electrode and/or the additional electrode is provided with a microstructure.

2. The miniature analyte sensor of claim 1 wherein the additional electrode comprises a counter electrode.

3. The miniature analyte sensor of claim 2 wherein the additional electrode further comprises a reference electrode.

4. The miniature analyte sensor of claim 2 or 3 wherein the working electrode, the reference electrode, and the counter electrode comprise at least an electronically conductive layer, a tamper resistant layer, an enzyme layer, a conditioning layer, and a biocompatible layer.

5. The miniature analyte sensor of claim 4 wherein the electron conducting layer of the working electrode and the counter electrode is one of graphite, glassy carbon, or a noble metal.

6. The miniature analyte sensor of claim 5 wherein the electronically conductive layers of the working electrode and the counter electrode are platinum.

7. The miniature analyte sensor of claim 4 wherein the electronically conductive layer of the reference electrode is one of Ag/AgCl or calomel.

8. The miniature analyte sensor of claim 4 wherein the microstructures are disposed on the electron conducting layer.

9. The miniature analyte sensor of claim 8 wherein the microstructures comprise micro-grooves or micro-protrusions.

10. The miniature analyte sensor of claim 9 wherein the miniature groove comprises one or more of a miniature through hole or a miniature blind hole or a miniature score.

11. The miniature analyte sensor of claim 1 wherein the microstructures have a diameter of 0.01 to 100um.

12. The miniature analyte sensor of claim 1 wherein the density of microstructures is 1 x 10 ² ～1*10 ¹⁰ /cm ² 。

13. The miniature analyte sensor of claim 1 wherein the substrate is a material selected from the group consisting of polytetrafluoroethylene, polyethylene, polyvinyl chloride, acrylonitrile butadiene styrene, polymethyl methacrylate, polycarbonate, polyimide, and combinations thereof.

14. A continuous analyte monitoring device, comprising:

a bottom housing for mounting to a host skin surface;

a sensor unit comprising a base and at least one miniature analyte sensor of claim 1, said miniature analyte sensor being affixed to said base, said sensor unit being mounted to said bottom housing via said base for detecting analyte parameter information in a host;

a transmitter electrically connected to the sensor unit for transmitting the analyte parameter information to the outside;

a battery for providing electrical energy; and

a receiver for receiving the analyte parameter information and indicating to a user.