AN ANALYTE SENSOR WITH ELECTRODE ARRAYTECHNICAL FIELDThe invention mainly relates to the field of medical devices, in particular to an analyte sensor with electrode array.
BACKGROUNDThe pancreas in a normal human body can automatically monitor the layer of glucose in the human blood and automatically secrete the required insulin/glucagon. In diabetics, the pancreas does not function properly and cannot produce the insulin the body needs. Therefore, diabetes is a metabolic disease caused by abnormal pancreatic function, and diabetes is a lifelong disease. At present, there is no cure for diabetes with medical technology. The occurrence and development of diabetes and its complications can only be controlled by stabilizing blood glucose.
Diabetics need to have their blood glucose measured before they inject insulin into the body. At present, most of the testing methods can continuously measure blood glucose and send the data to a remote device in real time for the user to view. This method is called Continuous Glucose Monitoring (CGM) . The method requires the device to be attached to the skin and the probe it carries is penetrated into the tissue fluid beneath the skin.
However, during use, the electrode of the sensor may break as the substrate repeatedly bends, affecting the service life of the sensor and reducing its detection reliability.
Therefore, there is an urgent need for an analyte sensor with a longer lifespan and higher detection reliability in existing technology.
BRIEF SUMMARY OF THE INVENTION
In view of the shortcomings of the existing technologies mentioned above, the embodiment of the invention discloses an analyte sensor with electrode array. The entire electrode is made into an electrode unit with a smaller area. When the substrate is repeatedly bent, the possibility of electrode breakage is reduced, the service life of the sensor is extended, and the detection reliability of the sensor is improved.
The invention discloses an analyte sensor, which comprises: at least one layer of substrate, the substrate comprises an in vivo part and an in vitro part. At least two electrodes are arranged on the surface of the in vivo part for penetrating into the subcutaneous to obtain analyte parameter information. And PADs, which are arranged on the surface of the in vitro part and are electrically connected with the corresponding electrodes through wires. Wherein, the electrode is an array composed of electrode units.
According to one aspect of the invention, each electrode unit includes an independent electron conduction layer, anti-interference layer, enzyme layer, adjustment layer, and biocompatible layer.
According to one aspect of the invention, the electrode unit shares the anti-interference layer, the enzyme layer, the adjustment layer, and the biocompatible layer.
According to one aspect of the invention, the electrode unit is a three-dimensional structure with a length of 10-100um, a width of 1-50um, and a thickness of 0.05-10um.
According to one aspect of the invention, the electrode units are arranged at intervals of 1-20μm.
According to one aspect of the invention, the electrode comprises 10 to 500 electrode units.
According to one aspect of the invention, the substrate comprises at least two layers of secondary-substrate, with at least two electrodes arranged on secondary-substrates of different layers.
According to one aspect of the invention, each layer of secondary-substrate is prefabricated and pasted into a whole.
According to one aspect of the invention, at least one electrode is disposed on the reverse side of the substrate.
According to one aspect of the invention, at least one PAD is provided on the reverse side of the substrate.
According to one aspect of the invention, a secondary-PAD corresponding to the PAD is also provided on the obverse side of the substrate.
According to one aspect of the invention, the PADs are electrically connected to the secondary-PADs through the side of the substrate.
According to one aspect of the invention, the obverse side and reverse side of the substrate are prefabricated and pasted as a whole.
According to one aspect of the invention, the obverse side and/or reverse side of the substrate further comprises at least two layers of secondary-substrate, with at least two electrodes arranged on different layers of secondary-substrates.
According to one aspect of the invention, each layer of secondary-substrate is prefabricated and pasted into a whole.
According to one aspect of the invention, electrodes are distributed on the substrate surface in a predetermined manner to avoid areas where the substrate is easy to bend.
According to one aspect of the invention, the electrode comprises at least one group of electrodes with the same name.
According to one aspect of the invention, electrodes with the same name are arranged on the same side of the substrate.
According to one aspect of the invention, electrodes with the same name are respectively arranged on opposite sides of the substrate.
According to one aspect of the invention, the PADs corresponding to electrodes of the same name are set on the same side of the substrate.
According to one aspect of the invention, the PADs corresponding to the electrodes of the same name are respectively set on opposite sides of the substrate.
According to one aspect of the invention, the PADs arranged on the opposite side of the substrate are electrically connected from the side of the substrate.
According to one aspect of the invention, electrodes with the same name share corresponding PADs.
According to one aspect of the invention, the electrode of the same name shares the wire.
According to one aspect of the invention, the electrode includes a working electrode and a counter electrode.
According to one aspect of the invention, the electrode further includes a reference electrode.
According to one aspect of the invention, the wire is laid on the surface of the substrate.
According to one aspect of the invention, the wire is buried in the inner layer of the substrate.
Compared with the prior art, the technical scheme of the invention has the following advantages:
The analyte sensor disclosed in the invention involves making a whole electrode into electrode units with a smaller area. When the substrate is repeatedly bent, the possibility of electrode breakage is reduced, the service life of the sensor is extended, and the detection reliability of the sensor is improved.
Further, the substrate includes at least two layers of secondary-substrates. At least two electrodes are arranged on the secondary-substrates of different layers. The electrodes are located on the secondary-substrates of different layers, which can avoid the wire routing. The electrodes can be made larger, increase the contact area with analytes, enhance the electrode reaction sensitivity, and improve the detection reliability of the sensor.
Further, the secondary-substrates of different layers can be prefabricated first, that is, the electrodes, wires and PADs are prefabricated on each layer of substrate, and then pasted and combined into a whole to form a complete sensor. Different from the conventional layer by layer coating process, it can avoid insulation failure due to insufficient consolidation of the substrate material, resulting in embrittlement, further causing crosstalk between the electrical signals of the wires or electrodes, and noise in the detection signal, the detection reliability of the sensor is improved.
Further, at least one of the multiple electrodes is located on the reverse side of the substrate, and the area of the electrode can be set on the single-sided substrate is limited. Setting one or more electrodes on the reverse side of the substrate can make full use of the two sides of the substrate, so the electrode on each side can be set to a larger area, increasing the contact area with the analyte, improving the electrode reaction sensitivity and improving the detection reliability of the sensor.
Further, the area of one side of the PAD-area on the substrate is limited. At least one PAD is set on the reverse side of the substrate to facilitate the electrical connection with the electrode on the reverse side of the substrate through the wire. At the same time, the PAD on the single side of the substrate can be larger, and the PAD with larger area can be better electrically connected with the circuit, making the current conduction more stable and improving the detection reliability of the sensor.
Further, when the PAD is located on the reverse side of the substrate, the secondary-PAD corresponding to the PAD can also be set on the obverse side of the substrate. The secondary-PAD can be connected to the circuit together with the PAD on the obverse side of the substrate, without additional circuit design for the PAD on the reverse side of the substrate, simplifying the complexity of the circuit. At the same time, the PAD on the reverse side of the substrate and the secondary-PAD corresponding to the obverse side of the substrate are connected by conductive materials on the side of the substrate, the PADs on the opposite side and the secondary-PADs can be electrically connected. Different from the conventional process, the scheme of punching holes on the substrate to electrically connect the PADs on the opposite side. The PADs on the opposite side are electrically connected on the side of the substrate without aligning the PADs on the opposite side on the substrate, which simplifies the difficulty of the manufacturing process and improves the yield of the sensor.
Further, the opposite side of the substrate, i.e. the obverse side and reverse side of the substrate, can be prefabricated with electrodes, wires and PADs respectively, and then pasted and combined into a whole to form a complete sensor. Unlike the conventional layer by layer coating process, it can avoid insulation failure due to insufficient curing of the substrate material, resulting in embrittlement, further causing crosstalk between the electrical signals of wires or electrodes, and noise in the detection signal, the detection reliability of the sensor is improved.
Further, a multi-layer secondary-substrate can also be set on the opposite side of the substrate. The multi-layer secondary-substrate can also be prefabricated with electrodes, wires and PADs, and then pasted and combined into a whole to form the obverse side or reverse side of the substrate. Different from the conventional layer by layer coating process, it can avoid insulation failure due to insufficient curing of the substrate material, resulting in embrittlement, and further causing crosstalk between the electrical signals of wires or electrodes, the detection signal is noisy, which improves the detection reliability of the sensor.
Further, the penetration depth of the sensor into the subcutaneous skin is fixed. The base is fixed in the area of repeated bending with muscle peristalsis. The electrode is distributed on the substrate of sensor in a predetermined way. The electrode can avoid the area on the substrate of sensor that is easy to bend, avoid the electrode breaking or damage caused by repeated bending with the substrate, extend the service life of the electrode and improve the detection reliability of the sensor.
Further, the sensor can be equipped with multiple electrodes with the same name, such as two or more working electrodes, two or more counter electrodes, and two or more reference electrodes, to achieve different functions, such as multiple analyte detection, redundant detection, electrode relay use, enhancing electrode detection signal, reducing detection signal noise, and improving the detection reliability of the sensor.
Further, electrodes with the same name share the corresponding PADs, that is, electrodes with the same name share the same PAD. The wire connects two or more electrodes with the same name to the same PAD, and the detection signal of the electrode is transmitted to the same PAD, which can enhance the signal strength of the electrode and improve the detection reliability of the sensor.
Further, electrodes with the same name share the wire, which can reduce the number of wires on the substrate and avoid laying too many wires on the substrate, resulting in short circuits between each other and affecting detection, thereby improving the detection reliability of the sensor.
BRIEF DESCRIPTION OF THE DRAWINGSFig. 1 is a top view of a planar structure of the sensor according to the embodiment of the invention.
Fig. 2 is side A view of the planar structure of the sensor as an embodiment of Fig. 1.
Fig. 3 is a sectional view of an electrode according to an embodiment of the invention.
Fig. 4 is a schematic diagram of function realization according to the embodiment of the invention.
Fig. 5 is a top view of the sensor with a stepped structure according to the embodiment of the invention.
Fig. 6 is side A view of the sensor with a stepped structure as an embodiment of Fig. 5.
Fig. 7 is a schematic diagram of the sensor having a cylindrical structure according to the embodiment of the invention.
Fig. 8 shows a V-V’ section view of the transducer with a cylindrical structure as an embodiment of Fig. 7.
Fig. 9 is a schematic diagram of a continuous analyte monitoring device according to an embodiment of the invention.
Fig. 10a-Fig. 10l are schematic diagrams of different sensors according to the embodiment of the invention.
DETAILED DESCRIPTIONAs mentioned above, the electrodes of analyte sensors in existing technologies may break during use as the substrate repeatedly bends, affecting the service life of the sensor and reducing its detection reliability.
In order to solve this problem, the invention provides an analyte sensor with electrode array, which makes the entire electrode into smaller electrode units. When the substrate is repeatedly bent, the possibility of electrode breakage is reduced, the service life of the sensor is extended, and the detection reliability of the sensor is improved.
Various exemplary embodiments of the invention will now be described in detail with reference to the attached drawings. It is understood that, unless otherwise specified, the relative arrangement of parts and steps, numerical expressions and values described in these embodiments shall not be construed as limitations on the scope of the invention.
In addition, it should be understood that the dimensions of the various components shown in the attached drawings are not necessarily drawn to actual proportions for ease of description, e.g. the thickness, width, length or distance of some elements may be enlarged relative to other structures.
The following descriptions of exemplary embodiments are illustrative only and do not in any sense limit the invention, its application or use. Techniques, methods and devices known to ordinary technicians in the relevant field may not be discussed in detail here, but to the extent applicable, they shall be considered as part of this Manual.
It should be noted that similar labels and letters indicate similar items in the appending drawings below, so that once an item is defined or described in one of the appending drawings, there is no need to discuss it further in the subsequent appending drawings.
In addition, it should be understood that one or more method steps referred to in the invention do not exclude the possibility that other method steps may exist before and after the combined steps or that other method steps may be penetrated between such explicitly mentioned steps, unless otherwise stated. It should also be understood that the combination connection between one or more devices/devices referred to in the invention does not preclude the existence of other devices/devices before and after the said combination devices/devices or the insertion of other devices/devices between the two specifically mentioned devices/devices, unless otherwise stated. And, unless otherwise specified, the serial number of the steps just a convenient tool for identifying the steps, rather than to limit the steps of the order or limit the scope of the invention can be implemented, the relationship of the relative change or adjust, in the case of no substantial changes to technical content, when as well as the category of the invention can be implemented.
Implementation example 1
Planar structure sensor
Fig. 1 is a top view of a planar structure of the sensor according to the embodiment of the invention. Fig. 2 is side A view of the planar structure of the sensor as an embodiment of Fig. 1.
The sensor 11 comprises a substrate 111, which is divided into an in vitro part X and an in vivo part Y by the dotted line shown in Fig. 1. The in vivo part Y is paved with electrodes, comprising at least one working electrode 1131 and at least one additional electrode. Obviously, in this embodiment, the additional electrode comprises a counter electrode 1231 and a reference electrode 1331, thus forming a three-electrode system. The counter electrode 1231 is the other electrode relative to the working electrode 1131, forming a closed loop with the working electrode 1131, so that the current on the electrode can be normally conducted, the reference electrode 1331 is used to provide the reference potential of the working electrode 1131, so the detection potential can be effectively controlled. In another embodiment of the invention, the additional electrode can also only comprise the counter electrode 1231, thus forming a two-electrode system. Compared with the three-electrode system, the effective area of the working electrode 1131 and the counter electrode 1231 can be increased on the limited area of the in vivo part Y, thereby extending the service life of the electrode. Moreover, because one electrode is reduced, the manufacturing process is simpler, however, the working electrode 1131 does not have the detection potential of the reference electrode as a reference, and the reliability of the analyte detection information will be reduced. In another embodiment of the invention, there are two working electrodes 1131, one of which is used to detect the response signal of the interferents or background solution in the host body fluid through the electro redox reaction with the analyte to be detected, and the other is the auxiliary electrode.
Continuing to refer to Figs. 1 and 2, the in vitro part X is paved with PADs, which correspond to the electrode one-by-one and are electrically connected through wires, that is, the working PAD 1111 corresponding to the working electrode 1131 is electrically connected through wire 1121. The counter PAD 1211 corresponding to the counter electrode 1231 is electrically connected through wire 1221. And reference PAD 1311 corresponding to reference electrode 1331, which is electrically connected through wire 1321. Different PADs, wires and electrodes are insulated from each other to prevent electrical signals from interfering.
Because the sensor 11 is the planar structure, there are two opposite sides, obverse side A and reverse side B. The working electrode 1131, counter electrode 1231 and reference electrode 1331 are laid as one electrode-group on the obverse side A of the sensor. On the other hand, another electrode-group is laid on the reverse side B of the sensor. The electrode-group can be a two-electrode system, a three-electrode system or a double working electrode. Preferably, it is consistent with the electrode-group on the obverse side A, comprising working electrode 1132, counter electrode 1232 and reference electrode 1332. Similarly, PADs are also laid on the side B. In this way, when the service life of any electrode on side A terminates or fails in advance, the electrode with the same name on side B can take over and enter the working state, improving the reliability of the parameter data of the detected analyte and extending the service life of the sensor.
Those skilled in the art should understand that there is no restriction on the sequence and position of the PADs, wires and electrodes laid on the side A And side B of the sensor. The PADs, wires and electrodes on the two sides can be symmetrically or asymmetrically arranged. The corresponding PADs, wires and electrodes are laid on the same side or on different sides. Preferably, the corresponding PADs, wires and electrodes are laid on the same side for the convenience of wire routing. For example, the working electrode 1131 on the side A can be replaced with the counter electrode 1231, or the counter electrode 1231 on the side A can be replaced with the reference electrode 1332 on the side B. No matter how the order and position of the PADs, wires and electrodes on the A and side Bs change, just make the PADs, wires and electrodes have a one-to-one correspondence and insulation relationship with each other.
In other embodiments of the invention, although the planar structure sensor only has the side A And side B, it can also increase the number of electrode-groups by increasing the sensor area or reducing the electrode-area, so as to further increase the service life of the sensor. However, too large sensor area may increase the host’s rejection response and cause host discomfort. Too small electrode-area will reduce the sensitivity of electrode and reduce the reliability of detection parameters. Too many electrode-groups will also increase the complexity of the manufacturing process, such as the wiring of the wire will become very dense. Therefore, it is preferred that the number of electrode-groups is two.
In other embodiments of the invention, each electrode-group can also be distributed on the same side of the sensor, such as side A or side B, which is not limited here.
In the embodiment of the invention, the substrate 111 is a material with excellent insulation performance, mainly from inorganic non-metallic ceramics, silica glass, organic Polymers, etc. at the same time, considering the application environment of the implanted electrode, the substrate material is also required to have high impermeability and mechanical strength. Preferably, the substrate material is selected from one or more combinations of Teflon, PE, PVC, aBS, PMMA, PC, PI, etc.
Fig. 3 is a sectional view of the electrode. In an embodiment of the invention, the working electrode (auxiliary electrode) , counter electrode and reference electrode comprise at least an electron conduction layer a, an anti-interference layer b, an enzyme layer c, an adjustment layer d and a biocompatible layer e.
Electron conduction layer
The electron conduction layer a adopts a material with good conductivity and hardening inertia. Preferably, the working electrode and counter electrode are selected from one of graphite electrode, glassy carbon electrode, noble metal and other materials, and the reference electrode is selected from one of Ag/AgCl or calomel. Considering the requirements of good ductility and stability of surface structure, noble metal electrodes such as gold electrode, platinum electrode and silver electrode have become better choices. Further preferred, both working electrode and counter electrode are platinum electrodes.
Anti-interference layer
The anti-interference layer b is located between the enzyme layer and the electron conduction layer. Interferents are molecules or substances that will undergo electrochemical reduction or electrochemical oxidation directly or indirectly through electron transfer agents on the electrode surface, thus generating an error signal that interferes with the detection of analytes. For example, for the determination of glucose as the analyte, common interferents in the body comprise urea, ascorbic acid, paracetamol, and so on.
In a preferred example, the anti-interference layer b can prevent one or more interferents from penetrating into the electrolyte around the electrode. For example, the anti-interference layer b will allow the analytes (e.g., hydrogen peroxide) to be measured on the electrode to pass, while at the same time preventing the passage of other substances (e.g., potential interfering substances) . In a preferred scheme, the anti-interference layer b can be a very thin film designed to limit the diffusion of substances with molecular weight greater than 34Da.
In another preferred example, the anti-interference layer b may be an organic Polymer, which may be made from organosilane and a hydrophilic copolymer. The hydrophilic copolymers, more preferably Poly-ethylene glycol (PEG) , Poly-methacrylic acid, 2-hydroxyethyl ester and Poly-lysine. In a preferred embodiment, the thickness range of the anti-interference layer b may be 0.1um or less to 10um or more. The more preferred thickness range is 0.5um to 5um.
Enzyme layer
The enzyme layer c is coated with active enzyme, and the corresponding active enzyme is coated according to the type of analyte to be detected. The active enzyme can make the analyte to be detected produce some chemical reactions and generate electrons. According to different concentrations of analyte to be detected, the number of electrons generated is different, and the electrons are collected by the electron conduction layer, thus forming different current intensities. Therefore, the current intensity information can be used to characterize the analyte parameter information.
Preferably, the enzyme layer c is coated with glucose oxidase (Gox) .
Adjustment layer
The adjustment layer d is located above the enzyme layer. In the embodiment of the invention, when glucose oxidase is coated on the enzyme layer, the regulating layer d is mainly used to regulate the transmittance of oxygen and glucose transmitted to the enzyme layer. The glucose content (molar concentration) in body fluid is one order of magnitude higher than that of oxygen. However, for enzyme-based sensor that require oxygen participation, excess oxygen needs to be supplied to ensure that oxygen does not become a limiting substance, so that the sensor can respond linearly to changes in glucose concentration without being affected by oxygen partial pressure. In other words, when oxygen content becomes a limiting factor, the linear range of glucose oxygen monitoring reaction cannot reach the expected concentration range. When there is no semi permeable membrane on the enzyme layer to regulate the permeation of oxygen and glucose, the upper limit of the linear response of the sensor to glucose can only reach about 40mg/dL. However, in clinical situations, the upper limit of linear response of blood glucose layer needs to reach about 500mg/dL.
The regulating layer d mainly functions as a semipermeable membrane to regulate the amount of oxygen and glucose transmitted to the enzyme layer. More specifically, excess oxygen becomes a non-restrictive factor. The upper limit of the linear response to glucose of the sensor with an adjustment layer can reach a higher layer than that without an adjustment layer. In a preferred example, the ratio of oxygen glucose transmittance of the regulating layer d can reach 200: 1, which can ensure that there is enough oxygen for the enzymatic reaction for various glucose and oxygen concentrations that may occur under the skin.
In a preferred example, the adjustment layer d may be an organic Polymer, which may be manufactured from organosilane and a hydrophilic copolymer. Hydrophilic copolymers, more preferably copolymerized or grafted Poly-ethylene glycol (PEG) . Other hydrophilic copolymers that may be used comprise but are not limited to other diols, such as propylene glycol, esters, amides, carbonates, and Polypropylene glycol. The use of silicone Polymers can significantly improve oxygen transport and effectively control glucose permeation. In the preferred embodiment, the thickness range of the adjustment layer d can be 1um or less to 50um or more, and the more preferred thickness range is 1um to 10um.
Biocompatible layer
The biocompatible layer e is located at the outermost part of the electrode, aiming to eliminate the body’s rejection of foreign bodies and reduce the formation of a shielding cell layer around the implanted electrode.
In a preferred example, the biocompatible layer e can be manufactured from organosilane and a hydrophilic copolymer. Hydrophilic copolymers, more preferably copolymerized or grafted Poly-ethylene glycol (PEG) . Other hydrophilic copolymers that may be used, comprising but not limited: diols, such as propylene glycol, esters, amides, carbonates, and Polypropylene glycol.
In a preferred embodiment, the thickness range of the biocompatible layer e may be 1um or less to 100um or more. The more preferred thickness range is 10um to 30um.
In the embodiment of the invention, the thickness of the substrate 11 is 0.01～0.8mm, the electrodes are rectangular, the width of each electrode is 0.01～1mm, and the area is 0.1～2mm2.
In other embodiments of the invention, the surface of each electrode is also provided with a carbon nanotube layer modification layer. Taking advantage of the unique mechanical strength, high specific obverse side Area, rapid electron transfer effect and chemical stability of carbon nanotubes, carbon nanotubes are modified to the electrode surface by physical adsorption, embedding or covalent bonding on the formed electrode surface to improve the electron transfer speed. At the same time, due to its large specific obverse side Area, carbon nanotubes can be used as an excellent catalyst (enzyme) carrier. The carbon nanotube layer modified layer can be fixed on the electrode surface by Nafion solution dispersion method, covalent fixation method, etc.
Fig. 4 is the schematic diagram of the function realization of the embodiment of the invention.
After the sensor penetrates the host, the in vivo circuit applies voltage to the PAD, and the electrode corresponding to the PAD is activated to enter the working state. Generally speaking, the effective working time of the electrode after being activated is 1-14 days. After 14 days, the enzyme activity on the electrode decreases and enters the failure state. At the same time, there may be reasons such as electrode damage or manufacturing errors, and the activated electrode will enter the failure state in advance. If a single group of electrodes is set on the sensor, once a certain electrode enters the failure state, the sensor will fail, and the user needs to replace the sensor, which reduces the user experience and increases the user’s use cost. If multiple groups of electrodes are set on the sensor, such as two groups of electrodes, once one electrode enters the failure state, the in vivo circuit will apply voltage to the PAD corresponding to the electrode with the same name of other electrode-groups, activate the electrode with the same name, make it enter the working state, replace the failed electrode, and make the sensor continue to work normally.
For details, refer to Fig. 1 and Fig. 2. After the sensor penetrates the host, the working PAD 1111, the counter PAD 1211 and the reference PAD 1311 on side A are preferentially applied with voltage by the in vivo circuit. The working electrode 1131, the counter electrode 1231 and the reference electrode 1331 on side A enter the working state. Once any one of the working electrode 1131, the counter electrode 1231 and the reference electrode 1331 fails in advance or ends its life, the in vivo circuit switches the PAD object to which the voltage is applied, for example, when the working electrode 1131 fails in advance, the in vivo circuit switches to apply voltage to the fourth PAD 1112 on the side B, activates the working electrode 1132 on the side B, and combines it with the counter electrode 1231 and the reference electrode 1331 that have not yet failed to form a new electrode-group to detect the analyte to be tested, thus avoiding the early failure of the sensor 11. The user does not need to replace the sensor because of the early failure of the working electrode 1131, which enhances the user experience, it also reduces the cost of replacing sensors.
Those skilled in the art should understand that the above embodiment is not limited to the failure of the working electrode, other electrodes such as the counter electrode and the reference electrode fail, or two or three-electrodes fail at the same time. The method of using the same name electrode to replace the failed electrode in the above embodiment can be adopted.
In addition, it can also be switched before the electrode fails or the service life ends, and the preset condition at this time is the preset time t. For example, the electrode fails after 14 days in the normal working state, and the preset time t is 2 days. When the first electrode-group is energized and activated, after working for 2 days, switch to the second electrode-group, the second electrode-group is activated, and the first electrode-group is no longer energized and enters the sleep state. After the second electrode-group works for 2 days, other electrode-groups can be activated or the first electrode-group can be activated again. This cycle is activated until the service life of all electrode-groups ends and all electrode-groups enter the failure state. In this mode, the service life of multiple electrode-groups is superimposed, thus extending the service life of the sensor.
Those skilled in the art should understand that the preset time t can be any day within 14 days. If the service life of the electrode is extended to n (n>14) days due to process improvement or other reasons, the preset time t can be any day within n days.
Implementation example 2
Step structure sensor
Fig. 5 is a top view of the sensor with a stepped structure in the embodiment of the invention. Fig. 6 is side A view of the step structure of the sensor in the embodiment of Fig. 5.
The sensor 21 of the step structure comprises side A and side B, and each side is divided into the in vitro part X and the in vivo part Y with the dotted line as the dividing line. The in vivo part Y comprises a first substrate 211, a second substrate 221 and a third substrate 231, forming a step structure with each other. The number and layers of the substrate are consistent with the number of electrodes on the surface. For example, when there is a three-electrode system on the substrate, the substrate is a three-layer step structure. When the side A is a two-electrode system, the substrate is a two-layer step structure.
In the embodiment of the invention, different layers of substrates are insulated from each other, and each electrode is electrically connected with the corresponding PAD through the wires distributed on one substrate (such as the third substrate) , that is, a part of the wire is in contact with the electrode, and the main part of the wire is located under the substrate, which can effectively protect the wire. At the same time, the electrodes are distributed on different layers of substrates. On the one hand, the spacing of electrodes is enlarged, which reduces the influence of the microenvironment on the electrode surface. At the same time, the electrode distribution of the step structure can effectively inhibit the interference of human response on the electrode response. On the other hand, if the electrodes are distributed on different planes, the width of the whole sensor can be further reduced on the premise that the effective area of each electrode is unchanged. The width of step structure sensor can be reduced by about half on the basis of plane structure sensor.
Correspondingly, side B and side A are symmetrical step structures. The in vitro part X is paved with PADs, which correspond to the electrode one-by-one and are electrically connected through the wire, that is, the working PAD 2111 corresponding to the working electrode 2131 is electrically connected through the wire 2121. The counter PAD 2211 corresponding to the counter electrode 2231 is electrically connected through wire 2221. And the reference PAD 2311 corresponding to the reference electrode 2331, which is electrically connected through wire 2321. Different PADs, wires and electrodes are insulated from each other to prevent electrical signals from interfering.
The working electrode 2131, counter electrode 2231 and reference electrode 2331 are laid as an electrode-group on the obverse side A of the sensor. On the other hand, another electrode-group is laid on the reverse side B of the sensor. The electrode-group can be a two-electrode system, a three-electrode system or a double working electrode. Preferably, it is consistent with the electrode-group on the obverse side A, comprising the working electrode 2132, counter electrode 2232 and reference electrode 2332. Similarly, PADs are also laid on the side B. The PADs correspond to the electrodes on the side B one-by-one and are electrically connected through wires, that is, the fourth PAD 2112 corresponding to the working electrode 2132 is electrically connected through wires 2122. The fifth PAD 2212 corresponding to the counter electrode 2232 is electrically connected through wire 2222. And the sixth PAD 2312 corresponding to the reference electrode 2332, which is electrically connected through wire 2322. In this way, when the service life of any electrode on side A terminates or fails in advance, the electrode with the same name on side B can take over to enter the working state, improve the reliability of the parameter data of the detected analyte, and extend the service life of the sensor.
Those skilled in the art should understand that there is no restriction on the sequence and position of the PADs, wires and electrodes laid on the side A And side B of the sensor. The PADs, wires and electrodes on the two sides can be symmetrically or asymmetrically arranged. The corresponding PADs, wires and electrodes are laid on the same side or on different sides. Preferably, the corresponding PADs, wires and electrodes are laid on the same side for the convenience of wire routing. For example, the working electrode 2131 on the side A can be replaced with the counter electrode 2231, or the counter electrode 2231 on the side A can be replaced with the reference electrode 2332 on the side B. No matter how the order and position of the PADs, wires and electrodes on the side A And side B change, just make the PADs, wires and electrodes have a one-to-one correspondence and insulation relationship with each other.
In other embodiments of the invention, although the step structure sensor only has the opposite side A and side B, it can also increase the number of electrode-groups by increasing the sensor area or reducing the electrode-area, so as to further increase the service life of the sensor. However, too large sensor area may increase the host’s rejection response and cause host discomfort. Too small electrode-area will reduce the sensitivity of electrode and reduce the reliability of detection parameters. Too many electrode-groups will also increase the complexity of the manufacturing process, such as the wiring of the wire will become very dense. Therefore, it is preferred that the number of electrode-groups is two.
In other embodiments of the invention, each electrode-group can also be distributed on the same side of the sensor, such as side A or side B, which is not limited here.
In the embodiment of the invention, the first substrate 211, the second substrate 221 and the third substrate 231 are materials with excellent insulation properties, mainly from inorganic non-metallic ceramics, silica glass and organic Polymers. At the same time, considering the application environment of the implanted electrode, the substrate material is also required to have high water permeability and mechanical strength. Preferably, the material of the substrate is selected from one or more combinations of Poly-tetrafluoroethylene (Teflon) , Poly-ethylene (PE) , Poly-vinyl chloride (PVC) , acrylonitrile butadiene styrene copolymer (ABS) , Poly-methyl methacrylate (PMMA) , Poly-carbonate (PC) , Poly-imide (PI) , etc.
In an embodiment of the invention, the working electrode (auxiliary electrode) , counter electrode and reference electrode at least comprise an electron conduction layer a’, an anti-interference layer b’, an enzyme layer c’, an adjustment layer d’ and a biocompatible layer e’, the properties of each layer and their related descriptions can be seen in embodiment 1, and will not be repeated here.
Implementation example 3
Cylindrical structure sensor
Fig. 7 is a schematic diagram of the cylindrical structure of the sensor in the embodiment of the invention. Fig. 8 is the V-V’ sectional view of the cylindrical structure of the sensor in the embodiment of Fig. 7.
The columnar sensor 31 is divided by the dotted line on the figure, and its substrate 311 is divided into the in vitro part X and the in vivo part Y. The in vitro part X is planar or cylindrical, preferably planar. The in vivo part Y comprises the substrate 311, which is cylindrical, and each electrode is surrounded on the surface of the substrate. Compared with the planar electrode, the electrode with ring structure does not have sharp edges, which reduces the irritation to human tissues and human rejection reaction, which is conducive to achieving implantable long-term detection and improving the service life of the sensor.
The in vivo part Y comprises at least one working electrode 3131 and at least one additional electrode. Obviously, in this embodiment, the additional electrode comprises a counter electrode 3231 and a reference electrode 3331, thereby forming a three-electrode system. The counter electrode 3231 is the other electrode relative to the working electrode 3131, forming a closed loop with the working electrode 3131, so that the current on the electrode can be normally conducted. The reference electrode 3331 is used to provide the reference potential of the working electrode 3131, therefore, the detection potential can be effectively controlled. In another embodiment of the invention, the additional electrode can also only comprise the counter electrode 3231, thus forming a two-electrode system. Compared with the three-electrode system, the effective area of the working electrode 3131 and the counter electrode 3231 can be increased on the limited area of the in vivo part Y, thereby extending the service life of the electrode. Moreover, because there is less one electrode, the manufacturing process is simpler, however, the working electrode 3131 does not have the detection potential of the reference electrode as a reference, and the reliability of the analyte detection information will be reduced. In another embodiment of the invention, there are two working electrodes 3131, one of which is used to detect the response signal of the interferents or background solution in the host body fluid by electro redox reaction with the analyte to be detected, and the other electrode is the auxiliary electrode.
Continuing to refer to Fig. 7, the in vitro part X is paved with PADs, which correspond to the electrode one-by-one and are electrically connected through wires, that is, the working PAD 3111 corresponding to the working electrode 3131 is electrically connected through wire 3121. The counter PAD 3211 corresponding to the counter electrode 3231 is electrically connected through wire 3221. And the reference PAD 3311 corresponding to the reference electrode 3331 are electrically connected through the wire 3321. The working electrode 3131, the counter electrode 3231 and the reference electrode 3331 form an electrode-group. Different PADs, wires and electrodes are insulated from each other to prevent electrical signals from being disturbed.
Each electrode is laid on the in vivo part Y in a semi surrounded manner, so there can be two electrodes at the same place to form an enclosure for the in vivo part Y. Specifically, with reference to Fig. 8, at the V-V’ of the in vivo part Y, the reference electrodes 3331 and 3332 are semicircular rings, respectively, whose inner diameter is equal to the outer diameter of the in vivo part Y, and are in insulated contact with each other, maximizing the obverse side Area of the in vivo part Y.
In other embodiments of the invention, the working electrode 3131 or counter electrode 3231 of the same electrode-group, or the working electrode (not shown in the figure) or counter electrode (not shown in the figure) of other electrode-groups can form an enclosure with the reference electrode 3331, so that in the case of termination or early failure of any electrode, its corresponding electrode of the same name can take over and enter the working state, improve the reliability of the parameter data of the detected analytes and extend the service life of the sensor.
Those skilled in the art should understand that the sequence and position of the PADs, wires and electrodes laid on the substrate 311 are not limited. The PADs, wires and electrodes can be symmetrically or asymmetrically arranged. No matter how the order and position of the PADs, wires and electrodes change, it is only necessary to make the PADs, wires and electrodes have a one-to-one correspondence and insulation relationship with each other.
In other embodiments of the invention, the number of electrode-groups can also be increased by increasing the sensor area or reducing the electrode-area, thereby further increasing the service life of the sensor. However, too large sensor area may increase the host’s rejection response and cause host discomfort. Too small electrode-area will reduce the sensitivity of electrode and reduce the reliability of detection parameters. Too many electrode-groups will also increase the complexity of the manufacturing process, such as the wiring of the wire will become very dense. Therefore, it is preferred that the number of electrode-groups is two.
In the embodiment of the invention, the substrate 311 is a material with excellent insulation performance, mainly from inorganic non-metallic ceramics, silica glass, organic Polymers, etc. at the same time, considering the application environment of the implanted electrode, the substrate material is also required to have high impermeability and mechanical strength. Preferably, the material of the substrate is selected from one or more combinations of Poly-tetrafluoroethylene (Teflon) , Poly-ethylene (PE) , Poly-vinyl chloride (PVC) , acrylonitrile butadiene styrene copolymer (ABS) , Poly-methyl methacrylate (PMMA) , Poly-carbonate (PC) , Poly-imide (PI) , etc.
In the embodiment of the invention, the outer diameter of the in vivo part Y of the substrate 311 and the inner diameter of the electrode are 0.01～100um, preferably 10～50um. The electrode can be a half ring, a 1/3 ring, a 1/4 ring or other proportion of the ring.
In an embodiment of the invention, the working electrode (auxiliary electrode) , counter electrode and reference electrode at least comprise an electron conduction layer a” , an anti-interference layer b” , an enzyme layer c” , an adjustment layer d” , and a biocompatible layer e” , the properties of each layer and their related descriptions can be seen in embodiment 1, and will not be repeated here.
Those skilled in the art can understand that the in vivo part Y of the sensor is not necessarily limited to the shape of the above three embodiments. For example, in other embodiments, it can be circular, semi-circular, conical, spiral and other shapes, and the shape of the electrode arranged on it also changes based on the shape of the in vivo part Y. As long as the electrode can be easily laid on the in vivo part Y, there is no limitation here.
Fig. 9 is a schematic diagram of a continuous analyte detection device 100 according to an embodiment of the invention. The continuous analyte detection device 100 comprises a bottom shell 101 for mounting on the surface of the host skin. The sensor unit 102 comprises a substrate 1021 and a micro analyte sensor 11 (21/31) as previously described. The micro analyte sensor 11 (21/31) is fixed on the substrate, and the sensor unit 102 is installed on the bottom shell 101 through the substrate. The transmitter unit 103 comprises an in vivo circuit 1031, a transmitter 1032, and an electrical connection area 1033. The electrical connection area 1033 is electrically connected with the sensor unit 102. The in vivo circuit 1031 stores the predetermined conditions for switching electrodes described above. The transmitter 1032 is used to send analyte parameter information to the outside world. The battery 104 is used to provide electric energy. The receiver 105, which is used to receive analyte parameter information and indicate to the user.
Fig. 10a to Fig. 10l are the schematic diagrams of different schemes of the sensor in the embodiment of the invention.
Referring to Fig. 10a, in order to easily and clearly show the structural characteristics of the sensor 41, the length, width, thickness and curve characteristics of the sensor are expressed in exaggerated form in Fig. 10a. The actual length, width, thickness and curve characteristics of the sensor may be different from those shown in the figure.
In other illustrations in this invention, the length, width, thickness and curve characteristics of the sensor are expressed in the same exaggerated form. The actual length, width, thickness and curve characteristics of the sensor may be different from those in the illustration, and will not be repeated below.
Similarly, the wires, PADs and electrodes described above and later are also expressed in the figure in exaggerated form. The wires, PADs and electrodes in the figure are only used as auxiliary examples to express the scheme of the invention, and are not completely equivalent to the wires, PADs and wires in the actual sensor. For example, the wire in the actual sensor is a flat wire with a certain width, which is shown in the form of lines in the illustration.
In some embodiments of the invention, the substrate 411 of the sensor 41 is generally a flexible material, such as one or more combinations selected from Poly-tetrafluoroethylene, Poly-ethylene, Poly-vinyl chloride, acrylonitrile butadiene styrene copolymer, Poly-methyl-methacrylate, Poly-carbonate, Poly-imide, which has good electrical insulation characteristics, and the electrode and electrode, wire and wire set on it can be insulated from each other. In the preferred embodiment of the invention, the substrate 411 is made of Poly-imide, which has good adaptability to human physiology and will not suffer from excessive rejection due to penetration into the subcutaneous skin.
In some embodiments of the invention, after the sensor 41 is inserted subcutaneously, in order to adapt to the repeated peristalsis of muscles, the substrate 411 is generally soft, and the soft base is repeatedly bent during the process of muscle peristalsis. The electrode fixed on the substrate 411 is repeatedly bent along with the substrate 411, which may cause the electrode to be broken, affecting the detection reliability of the sensor 41. In order to improve the detection reliability of sensor 41, it is necessary to avoid electrode damage as much as possible.
Referring to Fig. 10a, in some embodiments of the invention, replacing the entire electrode with an array of smaller electrode units can prevent the entire electrode from being damaged and improve the detection reliability of sensor 41. For example, cutting the original working electrode 4131 into smaller working electrode units 4131a, and then assembling the working electrode units 4131a into an array to form a working electrode array. The various units in the working electrode array work together to achieve the detection function of the working electrode 4131, and its function is almost identical to the original working electrode 4131.
In some embodiments of the invention, although the wires 4121/4221/4321 in the diagram are represented by lines, in actual sensor 41, each wire 4121/4221/4321 is a conductive strip with a certain width. All working electrode units 4131a are laid on wire 4121, and the current of each working electrode unit 4131a during the detection of analytes is transmitted through wire 4121. After making the entire electrode into an electrode unit array, even if the substrate 411 is repeatedly bent with the user’s muscles, the array composed of electrode units can be bent to a certain extent, without being broken and losing detection performance, improving detection reliability. In Fig. 10a, only the schematic content of this technical solution is expressed, and the relative size and relative position relationship of the structure are not actually expressed.
In some embodiments of the invention, due to the fact that the electron conduction layer is a hard layer and other structural layers are soft layers, when the working electrode 4131 is damaged due to bending, it is likely that the electron conduction layer is bent and broken. Therefore, the working electrode unit 4131a can make the original entire electron conduction layer into smaller electron conduction layer units, which share the anti-interference layer, enzyme layer, regulatory layer, and biocompatible layer.
In other embodiments of the invention, each working electrode unit 4131a can independently achieve detection functions, that is, each working electrode unit 4131a includes an independent electron conduction layer, anti-interference layer, enzyme layer, regulatory layer, and biocompatible layer.
In some embodiments of the invention, the electrode unit is a cubic structure as shown in Fig. 10a, which has dimensions of approximately 10-100um in length (L) , 1-50um in width (K) , and 0.05-10um in thickness (H) , with adjacent electrode units arranged at intervals of 1-20um.
In some embodiments of the invention, each electrode may contain 10-500 electrode units, depending on the area of the electrode, the area of a single electrode unit, and the spacing between the electrode units. The specific number of electrode units in each electrode is not specifically limited here.
In some embodiments of the invention, the area of each electrode in sensor 41 is different, and there are different number of electrode units in the working electrode array, counter electrode array, and reference electrode array. For example, there can be 25-120 working electrode units 4131a in the working electrode array, 50-150 counter electrode units 4231a in the counter electrode array, and 15-75 reference electrode units 4331a in the reference electrode array.
In other embodiments of the invention, the electrode unit may be other three-dimensional structures, such as cylindrical structures, prism structures, conical structures, etc.
In the preferred embodiment of the invention, the length*width*thickness of the electrode unit is 50um*30um*0.2um. There are 75 working electrode units 4131 in the working electrode array, 110 counter electrode units 4231 in the counter electrode array, and 35 reference electrode units 4331 in the reference electrode array. The spacing between each electrode unit is 10um. If more advanced laser etching technology is adopted, the area of electrode units and the spacing between electrode units can be made smaller, which reduces the possibility of electrode unit damage and improves detection performance.
In some embodiments of the invention, after assembling each electrode unit into an electrode array, the approximate dimensions of each electrode array are: the length*width*thickness of the working electrode array is 1.08mm*0.18mm*0.2um, the length*width*thickness of the counter electrode array is 1.52mm*0.18mm*0.2um, and the length*width*thickness of the reference electrode array is 0.51mm*0.18mm*0.2um.
In some embodiments of the invention, the electrode unit array can be shown in Fig. 10b, and the substrate 411 can include a multi-level substrate, with the electrode unit array arranged on different layers of secondary-substrates. In some embodiments of the invention, when the electrode unit array is set on different layers of secondary-substrates, it can also refer to Fig. 10c, where each layer of substrate can be prefabricated first and then combined into a whole. In some embodiments of the invention, the electrode unit array can be arranged on the obverse side A and reverse side B of the substrate 411, as shown in Fig. 10d. In other embodiments of the invention, when the electrode unit array is arranged on the obverse side A and reverse side B of the substrate 411, the front substrate 411a and back substrate 411b can also be prefabricated as shown in Fig. 10e, and then combined into a whole.
In some embodiments of the invention, sensor 41 adopts a three-electrode system, including working electrode 4141, counter electrode 4241, and reference electrode 4341, corresponding to working PAD 4111, counter PAD, and reference PAD 4311, as well as wires 4121/4221/4321 connecting each PAD and electrode. In other embodiments of the invention, sensor 41 may also adopt a two-electrode system, which does not include reference electrode 4341 and corresponding PADs and wires. This is a common knowledge in the art and will not be described here.
In some embodiments of the invention, wires 4121/4221/4321 can be set on the surface or inner layer of substrate 411 through processes such as etching, laser welding, etc. When wires 4121/4221/4321 are installed on the inner layer of substrate 411, substrate 411 can provide insulation protection for each wire to avoid signal loss or instability caused by short circuits between wires, but the manufacturing process is relatively complex. In some embodiments of the invention, the substrate 411 is a single-layer plane as shown in Fig. 10a.
In other embodiments of the invention, the substrate 411 may also be a multi-layer plane as shown in Fig. 10b. The substrate 411 can be composed of multiple layers of secondary-substrates, such as the first substrate 411d, the second substrate 411e, and/or the third substrate 411f. Each layer of substrate 411d/411e/411f can be equipped with at least one electrode and at least one wire. Setting electrodes 4131/4231/4331 on different layers of secondary-substrates 411d/411e/411f can increase the distance between electrodes, reduce signal interference between electrodes, and improve detection reliability. On the second hand, the electrodes on each layer of substrate can be set with a larger area, which allows for fuller contact with body fluids, more stable signals, and improved detection reliability. On the third hand, due to the electrodes being placed on different layers of secondary-substrates, the wires 4121/4221/4321 electrically connected to the electrodes can also be run on different secondary-substrates. Therefore, the secondary-substrate can also electrically insulate the wires 4121/4221/4321. Based on this, the wires 4121/4221/4321 can be run on the surface of each layer of substrate 411d/411e/411f, simplifying the wire manufacturing process. On the fourth hand, although wires 4121/4221/4321 can run on the surface of different layers of secondary-substrates 411d/411e/411f, if a certain layer of substrate is damaged, adjacent two layers of wires may come into contact and short-circuit. Therefore, when laying wires 4121/4221/4321 on the secondary-substrate 411d/411e/411f, wires 4121/4221/4321 can be staggered and arranged as shown in the top view of Fig. 10b, forming a stepped distribution of wires, even if a certain layer of substrate is damaged, the adjacent two layers of wires do not come into contact and short-circuit, improving detection reliability. The fifth aspect is that the substrate composed of multi-level substrates has higher mechanical strength compared to single-layer substrates, is not easily broken or damaged, and extends and improves detection reliability.
The setting of each electrode on the secondary-substrate is not fixed. In some embodiments of the invention, as shown in Fig. 10b, the reference electrode 4331 can be set on the secondary-substrate 411f of the top layer. The cost of the reference electrode 4331 is higher than that of the working electrode 4131 and the counter electrode 4231. The reference electrode 4331 located on the secondary-substrate 411f of the top layer is manufactured in the final process, which can protect the reference electrode 4331 from damage. In other embodiments of the invention, the reference electrode 4331 can also be set on the secondary-substrate 411d of the bottom layer. Compared to the working electrode 4131 and the counter electrode 4231, the thickness of the reference electrode 4331 is thicker, and it is located on the secondary-substrate 411d of the bottom layer, which can improve the thickness consistency of sensor 41 and avoid excessive thickness difference, facilitating the storage and use of sensor 41. In Fig. 10b, the thickness of the secondary-substrates 411d/411e/411f and electrodes 4131/4231/4331 of each layer is expressed in an exaggerated form. It can be understood that this does not affect the description of this scheme.
In some embodiments of the invention, the secondary-substrates 411d/411e/411f of each layer can be manufactured layer by layer, that is, after manufacturing the bottom layer substrate 411d, the middle layer substrate 411e can be manufactured on top of the bottom layer substrate 411d. Similarly, after manufacturing the middle layer substrate 411e, the top layer substrate 411f can be manufactured. In the usual preparation process, each layer of substrate is manufactured by coating the substrate material, such as poly-imide, layer by layer on the mold after heating, and curing to form a complete secondary-substrate. However, during the curing process, there may be insufficient curing of the material in some areas, or different degrees of curing of the substrate materials in various parts of the secondary-substrate, or different degrees of curing of the substrate materials on different layers of secondary-substrates, causing brittle cracking of the substrate during subsequent use can lead to short circuits or even damage to the electrodes, wires, and PADs installed on the substrate, affecting the detection reliability of the sensor.
Referring to Fig. 10c, based on the existing problem of possible brittle fracture failure of the substrate, in other embodiments of the invention, the secondary-substrate 411d/411e/411f of each layer can be prefabricated first. Prefabrication completion here refers to fully curing the substrate material of each layer of substrate 411d/411e/411f, and then manufacturing electrodes, wires, or PADs on the substrate. According to the design requirements of sensor 41, electrodes, wires, and PADs are set on each layer of substrate The wires or PADs may be the same or different. After prefabrication, the secondary-substrates 411d/411e/411f of each layer are assembled into a whole by pasting. For example, when the secondary-substrate 411d/411e/411f material is selected as poly-imide, the precursor of poly-imide can be used to paste the substrate 411d/411e/411f of each layer, ultimately obtaining a complete sensor substrate. Due to the fact that each layer of substrate 411d/411e/411f is fully cured and then pasted as a whole, it can avoid the problem of brittle cracking caused by insufficient material curing in the same layer of substrate, as well as the problem of brittle cracking caused by insufficient material curing between different layers of secondary-substrates, improving the detection reliability of the sensor 41. In addition, due to the fact that each layer of substrate 411d/411e/411f can be independently prefabricated and then assembled into a whole, the production efficiency of sensor 41 can also be increased during the production process.
It is worth pointing out that in some embodiments of the invention, PADs 4111/4211/4311 corresponding to each electrode 4131/4231/4331 need to be prefabricated on the top layer of the secondary-substrate 411f to ensure the functional integrity of sensor 41. After the secondary-substrate 411d/411e/411f of each layer is pasted, the wires on the secondary-substrate 411d/411e are led to the secondary-substrate 411f of the top layer through drilling to establish an electrical connection with the PADs located on the secondary-substrate 411f.
In some embodiments of the invention, the thickness of each layer of substrate 411d/411e/411f can be from 0.1 to 200um. Unlike the single-layer substrate scheme shown in Fig. 10a, each layer of substrate 411d/411e/411f may need to be made thinner. Otherwise, the layers of substrates are stacked together to be too thick, without sufficient softness, which increases discomfort when punctured under the user’s skin. Therefore, it is preferred that the thickness of each layer of substrate 411d/411e/411f is 0.1-20um. Furthermore, the thickness of each layer of substrate 411d/411e/411f is about 10um, and the overall thickness is about 25-35um. This thickness will not be easily damaged or broken due to being too thin, nor will it increase user discomfort due to being too thick. Technicians in this field can understand that due to manufacturing errors, there may be deviations in the actual thickness of the secondary-substrate 411d/411e/411f of each layer.
In some embodiments of the invention, the material of the substrate 411d/411e/411f at each level is preferably poly-imide. In order to bond the substrate 411d/411e/411f at each level as a whole, the bonding material can be preferably poly-imide precursor. After curing, the poly-imide precursor can maintain consistency in physical properties with the poly-imide. This bonding method can avoid peeling or even shedding of the substrate 411d/411e/411f at each level due to stress concentration or uneven stress.
In some embodiments of the invention, the electrode set on the reverse side B of the substrate 411 may be the counter electrode 4231. Setting the counter electrode 4231 on the reverse side B of the substrate 411 can increase the relative distance between the counter electrode 4231 and the working electrode 4131, reduce current crosstalk between the counter electrode 4231 and the working electrode 4131, and reduce noise. On the other hand, maximizing the area of electrode 4231 can reduce electrochemical polarization and improve the accuracy and sensitivity of detection signals.
In other embodiments of the invention, the electrode set on the reverse side B of the substrate 411 can be a reference electrode 4331. Setting the reference electrode 4331 on the reverse side B of the substrate 411, on the one hand, during the manufacturing process, the reference electrode 4331 can be manufactured separately without affecting the working electrode 4131 and the counter electrode 4231, thereby improving the yield of the finished product. On the other hand, it can reduce the circuit risk caused by the migration of Ag/Cl substances in the reference electrode 4331 and improve detection reliability.
In other embodiments of the invention, the electrode set on the reverse side B of the substrate 411 may be the working electrode 4131. Set the working electrode 4131 on the reverse side B of the substrate 411. If there is a short circuit between the control electrode 4231 and the reference electrode 4331, the three-electrode system will become a two-electrode system, which will not affect the detection current and will not cause sudden changes in the detection signal, thus improving the detection stability.
Referring to Figs. 10d and 10e, in some embodiments of the invention, as the electrodes are respectively arranged on the reverse side and obverse side of the substrate 411, both the reverse side and obverse side of the substrate 411 need to be machined to set the electrodes, wires, etc., which inevitably causes damage to the other side during the machining process. Based on this, the reverse side and obverse side of the substrate 411 can be processed separately, that is, the obverse side A and reverse side B of the substrate 411 can be processed separately, and then the obverse side A and reverse side B of the substrate 411 can be assembled into a whole, forming a complete sensor can improve the integrity of the double-sided substrate.
In some embodiments of the invention, electrodes, wires, and PADs are processed on the substrate 411a of obverse side A, while electrodes and wires are processed on the substrate 411b of reverse side B. The positions of the electrodes, wires, and PADs on the substrates 411a and 411b are not limited.
In some embodiments of the invention, substrates 411a and 411b can be combined into a whole by pasting, for example, the materials of substrates 411a and 411b are both poly-imide, and the precursor materials of poly-imide are used to paste substrates 411a and 411b together. Relevant technical details can be referred to Fig. 10c and its description.
In practical use, due to increased user activity and other reasons, the degree and frequency of repeated bending of substrate 411 may exceed expectations, and the electrode may still be damaged due to this. Therefore, necessary measures can also be taken to prevent the electrode from being damaged.
Referring to Fig. 10f, in some embodiments of the invention, due to the fixed depth of penetration of the substrate 411 into the user’s subcutaneous area, the area where the substrate 411 repeatedly bends with muscle peristalsis is also fixed, or the area on the substrate 411 with larger bending amplitude and frequency is fixed, such as the easy-bending-area 412 in Fig. 10f. Generally, the easy-bending-area 412 on the substrate 411 will first reach the limit fatigue and be damaged compared to other areas. Therefore, the electrodes located on the substrate 411 can be distributed in a predetermined manner to avoid the easy-bending-area 412 and prevent electrode damage.
In some embodiments of the invention, the easy-bending-area 412 is not only limited to one easy-bending-area 412 shown in Fig. 10f, but may also have multiple easy-bending-areas, which are mainly determined by the material of the substrate 411 and the depth of penetration into the subcutaneous tissue. Furthermore, it is also related to the location of the substrate penetration into the user’s subcutaneous tissue, the user’s movement mode, the thickness of the substrate, and other reasons. Overall, for the same substrate material and penetration depth, the areas with large bending amplitude on substrate 411 are fixed, so avoid these easy-bending-areas when setting electrodes.
In some embodiments of the invention, the easy-bending-area 412 is the middle section area of the in vivo part Y. For example, when the depth of penetration of the in vivo part Y into the subcutaneous area is 5mm, the easy-bending-area 412 is about 2.5mm away from the end of the substrate 411. In some embodiments of the invention, the easy-bending-area 412 may be an area 2.1-2.8mm away from the Y-end of the in vivo part. The above values are for illustrative purposes only.
In some embodiments of the invention, when the substrate 411 includes a multi-level substrate or a double-sided substrate, there may also be some easy-bending-areas, which should be avoided when setting electrodes. In some embodiments of the invention, when at least one electrode is set on the opposite side of the substrate 411, the electrode set on the reverse side B of the substrate 411 also avoids these easy-bending-areas.
Referring to Fig. 10g, in some embodiments of the invention, PADs 4111/4211/4311 corresponding to electrodes 4131/4231/4331 may be set on the reverse side B of substrate 411, while electrodes 4131/4231/4331 are still set on the obverse side A of substrate 411, or PADs 4111/4211/4311 are set on the obverse side A of substrate 411, while electrodes 4131/4231/4331 are set on the reverse side B of substrate 411, the electrodes 4131/4231/4331 and PADs 4111/4211/4311 are respectively set on the opposite side of the substrate 411. Compared to the electrodes 4131/4231/4331 and PADs 4111/4211/4311 being set on the same side of the substrate 411, the in vitro part X of sensor 41 may have different bending directions relative to the in vivo part Y. For example, when PADs 4111/4211/4311 are set on the reverse side B of substrate 411, the in vitro part X is bent clockwise relative to the in vivo part Y, which requires sensor 41 to be installed in an analyte detection device in an inverted manner. The technical solution and application of sensor 41 inversion can be found in public patent PCT/CN2022/080845, and will not be further described here.
Referring to Fig. 10h, in some embodiments of the invention, not all PADs are located on the obverse side A or reverse side B of the substrate 411, but some PADs are located on the obverse side A of the substrate 411, while the remaining PADs are located on the reverse side B of the substrate 411. On the one hand, it can reduce the number of PADs on a single side of the substrate 411, thereby increasing the area of a single PAD, and the larger PADs have better electrical connection to the circuit, improved the detection reliability of sensors. On the other hand, if an electrode is set on the reverse side B of substrate 411, the corresponding PAD should also be set on the reverse side B of substrate 411, so that the wire can run on the reverse side B of substrate 411.
In some embodiments of the invention, if the PADs are located on opposite sides of the substrate 411, for the circuit, it is necessary to design electrical connection areas for the PADs on both sides of the substrate 411, which will increase the complexity of the circuit. Based on this, although some PADs are set on the reverse side B (obverse side A) of the substrate 411, the PADs of the reverse side B (obverse side A) can still be guided to the obverse side A (reverse side B) of the substrate 411, connect the circuit with other PADs located on the obverse side A (reverse side B) to simplify the complexity of the circuit.
In some embodiments of the invention, taking Fig. 10h as an example, the counter PAD 4211 corresponding to the counter electrode 4231 and the reference PAD 4311 corresponding to the reference electrode 4331 are set on the obverse side A of the substrate 411, while the working PAD 4111 corresponding to the working electrode 4131 is set on the reverse side B of the substrate 411. In addition, the first secondary-PAD 4111’ corresponding to the working PAD 4111 is also set on the obverse side A of the substrate 411, the first secondary-PAD 4111’ replaces the working PAD 4111 in the circuit to simplify the complexity of the circuit, or the working PAD 4111 and the first secondary-PAD 4111’ are simultaneously connected to the circuit to improve the electrical connection reliability between the PADs and the circuit.
In some embodiments of the invention, when the first secondary-PAD 4111’ is electrically connected to the circuit, the working PAD 4111 needs to establish an electrical connection with the first secondary-PAD 4111’ to connect the working electrode 4131 to the circuit. In a general solution, drilling holes (not shown in the figure) in the area covered by both the first secondary-PAD 4111’ and the working PAD 4111 on the substrate 411, and coating or spraying conductive materials in the holes, can establish an electrical connection between the first secondary-PAD 4111’ and the working PAD 4111. However, this process requires aligning the first secondary-PAD 4111’ and the working PAD 4111 on the substrate 411, at least a portion of the first secondary-PAD 4111’ and working PAD 4111 overlap on the substrate 411, otherwise the conductive material in the hole cannot simultaneously contact the first secondary-PAD 4111’ and working PAD 4111, resulting in the failure of sensor 41 production. This is common in the production process of sensor 41.
In some embodiments of the invention, conductive material 4111” is arranged on the surface of the substrate 411 to establish an electrical connection between the first secondary-PAD 4111’ and the working PAD 4111, without the need for drilling holes on the substrate 411. Specifically, the conductive material 4111” is set on the obverse side A and reverse side B of the substrate 411 through coating, spraying, and other processes, and the conductive material 4111” on the obverse side A and reverse side B is connected through the side edges of the substrate 411. The conductive material 4111” located on the obverse side A is electrically connected to the first secondary-PAD 4111’, and the conductive material 4111” on the reverse side B is electrically connected to the working PAD 4111, this establishes an electrical connection between PAD 4111’ and working PAD 4111 for the first time. In this scheme, there is no need to align the first secondary-PAD 4111’ and the working PAD 4111 when machining, which simplifies the production difficulty of sensor 41 and improves the production yield of sensor 41.
In some embodiments of the invention, the conductive material 4111” located on the obverse side A of the substrate 411 and the conductive material 4111” located on the reverse side B are connected through the "side edge" of the substrate 411, where the "side edge" refers to any edge of the substrate 411.
In some embodiments of the invention, conductive material 4111” can be some common solder, such as solder, or some conductive metal or alloy, such as copper zinc alloy, platinum, etc.
Referring to Fig. 10i, in some embodiments of the invention, when the PADs are located on opposite sides of the substrate 411, the obverse side A and reverse side B of the substrate 411 can be prefabricated first and then combined into a whole. Specifically, on the obverse side A of substrate 411, the specific production plan has been described in detail above and will not be repeated here.
Referring to Fig. 10j, in some embodiments of the invention, one or more of the working electrode 4131, counter electrode 4231, and reference electrode 4331 may have additional electrodes of the same name, for example, the working electrode 4131 includes the first working electrode 4131α and the second working electrode 4131β. For example, the working electrode 4131 includes the first working electrode 4131α and the second working electrode 4131β at the same time, the counter electrode 4231 also includes the first counter electrode 4231α and the second counter electrode 4231β.
In some embodiments of the invention, each electrode may have multiple electrodes with the same name, which can enrich and improve the functions of the sensor 41. For example, the first working electrode 4131α and the second working electrode 4131β can be used relay when the first working electrode 4131α the second working electrode 4131β as a redundant electrode, it can replace the first working electrode 4131α by connecting the circuit and continuing the detection function, the service life of the sensor 41 is extended and the detection reliability is improved. For another example, the first working electrode 4131α and the second working electrode 4131β can be different enzyme layers to detect different analytes in the user’s body, such as blood glucose and blood ketone. For another example, the first working electrode 4131α and the second working electrode 4131β can be connected to the circuit at the same time, and its detection data are calibrated with each other, which improves the detection reliability. For another example, the first working electrode 4131α and the second working electrode 4131β can be used alternately, reducing the consumption of each electrode enzyme layer during use, and can extend the first working electrode 4131α and the second working electrode 4131β and further, the service life of sensor 41 is extended. For another example, the first working electrode 4131α and the second working electrode 4131β be connected to the circuit at the same time, and the analyte parameter signal is detected at the same time. After the detection signals of the two electrodes are superimposed, a stronger signal can be obtained, which enhances the anti-interference of the signal and improves the detection reliability.
In some embodiments of the invention, each electrode has at least one electrode with the same name. The first working electrode, the first counter electrode, and the first reference electrode form the first electrode-group, and the second working electrode, the second counter electrode, and the second reference electrode form the second electrode-group. With this push, each electrode-group can complete the blood glucose or other analyte detection function completely and independently. When using the sensor 41, each electrode-group can be used simultaneously or separately.
In some embodiments of the invention, the electrode with the same name is added on the substrate 411, which means that the corresponding PAD is also added. As shown in Fig. 10j, the first working PAD 4111α、the second working PAD 4111β、the counter PAD 4211 and the reference PAD 4311 are set on the PAD-area a. The area of PAD-area a is limited, and the larger the number of PADs means the smaller the area of each PAD, which will affect the reliability of the electrical connection between the PAD and the circuit. Based on this, with reference to Fig. 10h, part of the PADs are set on the reverse side B of the substrate 411, effectively using the limited area of the obverse side A and the reverse side B of the PAD-area a.
In some embodiments of the invention, when the first working electrode 4131α and the second working electrode 4131β stack the detection signal, the first working PAD 4111α and the second working PAD 4111βare simultaneously connected to the circuit. At this time, if it set electrical connection area the first working PAD 4111α and the second working PAD 4111β on the circuit, which will increase the complexity of the circuit, so the first working PAD 4111α and the second working PAD 4111β can establish electrical connection on the sensor 41 directly, and the circuit only needs to connect with one of the first working PAD 4111α and the second working PAD 4111β to achieve the function of the sensor 41, which will reduce the complexity of the circuit. The electrical connection between the first working PAD 4111α and the second working PAD 4111βshould refer to Fig. 10i and its corresponding description, and will not be repeated here.
Referring to Fig. 10k, in some embodiments of the invention, the first working electrode 4131α and the second working electrode 4131β share the PAD. Specifically, the first working electrode 4131α and the second working electrode 4131β electrically connect with the working PAD 4111 through wire 4121α and wire 4121βrespectively, and the detection signals of the first working electrode 4131α and the second working electrode 4131β are transmitted through the working PAD 4111, which can realize the function of signal enhancement.
Referring to Fig. 10l, in some embodiments of the invention, the first working electrode 4131α and the second working electrode 4131β share the wire. Specifically, the first working electrode 4131α and the second working electrode 4131β are electrically connected with the working PAD 4111 through the wire 4121, and the detection signals of the first working electrode 4131α and the second working electrode 4131β are transmitted through wire 4121 and PAD 4111, which can realize the function of signal enhancement. The first working electrode 4131α shares the wire 4121 with the second working electrode 4131β can reduce the number of wires set on the substrate 411, reduce the possibility of short circuit between wires, and improve the detection reliability.
In some embodiments of the invention, electrodes with the same name can be placed on the same side of the substrate 411, which can reduce the manufacturing process steps and complexity.
In other embodiments of the invention, electrodes with the same name can be set on the opposite surface of substrate 411 to reduce signal interference between electrodes with the same name.
In some embodiments of the invention, due to the increase in the number of electrodes, the limited area of the obverse side A of the substrate 411 limits the area of the electrodes. Therefore, it is also necessary to set some of the electrodes on the reverse side B of the substrate 411. For example, setting the first working electrode 4131α and the counter electrode 4231 on the reverse side B not only achieves detection function, but also reduces the possibility of short circuit between the counter electrode 4231 and the reference electrode 4331.
Technicians in this field can understand that the above scheme is only for illustrative description, and the number and position of electrodes, PADs, and wires can be set differently according to different sensor functions and requirements, without any limitations.
As mentioned above, "avoiding" the area where PADs and electrodes are located can refer to avoiding structural areas that require electrical conductivity such as PADs and electrodes, or to the surface area where PADs and electrodes are set on the substrate in some embodiments of the invention.
In some embodiments of the invention, the schemes involved in different illustrations may be applicable to each other, and there is no limitation here.
In summary, the invention provides an analyte sensor with electrode array, which makes a whole electrode into smaller electrode units. When the substrate is repeatedly bent, the possibility of electrode breakage is reduced, the service life of the sensor is extended, and the detection reliability of the sensor is improved.
Although some specific embodiments of the invention have been detailed through examples, technicians in the field should understand that the above examples are for illustrative purposes only and are not intended to limit the scope of the invention. Persons skilled in the field should understand that the above embodiments may be modified without departing from the scope and spirit of the invention. The scope of the invention is limited by the attached claims.