Use of SEBS as an implantable bioelectrode substrate and an implantable bioelectrode

Abstract

The application provides application of SEBS in implanting a biological electrode base. The biological electrode based on the SEBS base can be implanted in biological tissues, and is used for continuously or discontinuously analyzing physiological parameters of the biological body. Compared with other flexible bases, the SEBS base has the characteristics of being thinner and more flexible, can reduce the interference of body movement on the electrical signal, reduce the volume range of the implanted tissue and reduce the inflammatory reaction, thereby improving the measurement accuracy and long-term stability, is expected to meet more implantation site requirements when used for implanting a sensor, and has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of biosensor technology, specifically relating to the application of SEBS as a substrate for implantable bioelectrodes and an implantable bioelectrode. Background Technology

[0002] Biosensors utilize biologically sensitive materials, such as enzymes, nucleic acids, antibodies, antigens, microorganisms, and tissues, as recognition units to convert chemical substances within a living organism into detectable signals, such as light, heat, and electrical signals. Currently, the most commercially successful biosensor is the current-type enzyme glucose sensor, which holds nearly 85% of the global market share. However, due to the body's rejection response, the stability of implantable current biosensors is closely related to the electrode substrate. For example, patent CN101530327A discloses a needle-shaped current-measuring glucose sensor for real-time monitoring of subcutaneous tissue and its manufacturing method. It includes at least one needle-shaped reference electrode and one needle-shaped working electrode. The working electrode consists of, from the inside out, a conductive layer, a polymer inner membrane layer, an enzyme membrane layer, and a polymer controlled diffusion layer. Although this sensor can be directly implanted into subcutaneous tissue via the needle-shaped electrode, the inclusion of at least one needle-shaped reference electrode and a needle-shaped working electrode results in a relatively large wound area during implantation, requiring a longer stabilization period before acquiring valuable electrical signals. In addition, the conductive layer of the device is composed of a metal substrate, a metal transition layer and a noble metal layer from the inside out, which is costly to manufacture and involves a complex processing technology.

[0003] With advancements in technology, implantable sensors have evolved to utilize flexible polymer films as substrates. Commonly used materials include polyimide (PI) resin and polyethylene terephthalate (PET) for glucose monitoring electrodes. Compared to rigid electrodes, flexible electrodes offer better biocompatibility, lower inflammatory responses, and can mitigate signal fluctuations caused by bodily movement. Currently, commercially available blood glucose microneedles are 300–500 μm thick, implanted primarily on the outer side of the arm, and effective for only 7–15 days. Developing smaller, more biocompatible sensors with wider implantation sites, while still meeting sensor performance requirements, is crucial for the screening and treatment of diabetes. Summary of the Invention

[0004] In view of this, the technical problem to be solved by the present invention is to provide an application of SEBS as a substrate for implanted bioelectrodes. The electrode provided by the present invention uses SEBS, which is thinner and more flexible, can reduce the volume range of the implanted tissue, reduce the inflammatory response, improve the accuracy and long-term stability of the measurement, reduce the interference of body movement on the electrical signal, and meet the needs of more implantation sites when used for implanted sensing, and has good application prospects.

[0005] This invention provides the application of SEBS as a substrate for implanted bioelectrodes.

[0006] The present invention also provides an implantable bioelectrode based on an SEBS substrate, comprising a sensing probe (7) and a connection structure (16), wherein the implantable bioelectrode includes:

[0007] The substrate is composed of a first SEBS electrode carrier (13) and a second SEBS electrode carrier (2) stacked together; the substrate includes a sensing probe portion and a connection portion;

[0008] A first conductive layer (8) and a working electrode contact (5) connected to the first conductive layer are disposed on the surface of the first SEBS electrode carrier (13); a sensing area (9) is disposed on the surface of the first conductive layer (8) at the sensing probe location and near the implantation end.

[0009] A second conductive layer (10) and a reference electrode contact (4) connected to the second conductive layer (10) are disposed on the surface of the second SEBS electrode carrier (2); a reference material layer (11) is disposed on the surface of the second conductive layer (10) at the sensing probe location and near the implantation end;

[0010] A first insulating layer (14) is disposed on the surface of the second conductive layer (10);

[0011] A third conductive layer (12) disposed on the surface of the first insulating layer (14) and a counter electrode contact (3) connected to the third conductive layer (12) and disposed on the surface of the second SEBS electrode carrier (2); or, the third conductive layer (12) and the counter electrode contact (3) are disposed on the other surface of the first SEBS electrode carrier (13);

[0012] The second insulating layer (6) is disposed on the surface of the third conductive layer (12).

[0013] Preferably, the length of the first SEBS electrode carrier (13) is greater than the length of the second SEBS electrode carrier (2);

[0014] The first conductive layer (8) is disposed at the sensing probe portion of the first SEBS electrode carrier (13), and the working electrode contact (5) is disposed at the connection portion of the first SEBS electrode carrier (13).

[0015] The first SEBS electrode carrier (13) and the second SEBS electrode carrier (2) of the substrate are aligned at one end, and the first SEBS electrode carrier (13) extends beyond the second SEBS electrode carrier (2) at the other end. The working electrode contact (5) is disposed on the surface of the part of the first SEBS electrode carrier (13) that extends beyond the second SEBS electrode carrier (2). The direction from one end to the other end is from the connection part to the sensing probe part.

[0016] Preferably, at the implantation end of the sensing probe (7), the first SEBS electrode carrier (13), the first conductive layer (8), the second SEBS electrode carrier (2), the second conductive layer (10), the first insulating layer (14), the third conductive layer (12), and the second insulating layer (6) are stacked in a stepped structure.

[0017] Preferably, a polymer hydrogel layer is coated on the surface of the implantable bioelectrode, and the thickness of the polymer hydrogel layer is 10-50 μm.

[0018] Preferably, an enzyme biochemical sensing layer is provided on the sensing area (9), and preferably, the thickness of the enzyme biochemical sensing layer is 10 to 300 μm.

[0019] Preferably, the SEBS is a styrene-ethylene-butene-styrene block copolymer, and the thickness of the substrate is 10-500 μm;

[0020] The conductive materials of the first conductive layer (8), the second conductive layer (10) and the third conductive layer (12) are gold, silver or carbon, with a thickness of 1μm to 20μm and a length of 0.05 to 5mm.

[0021] The reference material layer (11) on the second conductive layer (10) is silver and / or silver chloride, with a thickness of 1 to 20 μm.

[0022] The present invention also provides a method for preparing the above-mentioned implantable bioelectrode, comprising the following steps:

[0023] A) Disperse SEBS resin particles in a solvent to obtain an SEBS solution;

[0024] After the SEBS solution is coated onto a substrate and dried, the SEBS film is separated from the substrate.

[0025] B) Conductive carbon paste is printed onto the surfaces of two SEBS films to obtain a first conductive layer and a corresponding working electrode contact, and a second conductive layer and a corresponding working electrode contact.

[0026] Then, insulating ink is printed on the surface of the second conductive layer to form the first insulating layer;

[0027] Conductive carbon paste and insulating ink are sequentially printed on the surface of the first insulating layer, and a third conductive layer and a corresponding working electrode contact, as well as a second insulating layer, are sequentially formed on the surface of the first insulating layer; or, conductive carbon paste and insulating ink are sequentially printed on the other side surface of the SEBS film composited with the first conductive layer, and a third conductive layer and a corresponding working electrode contact, as well as a second insulating layer, are sequentially formed on the surface of the SEBS film.

[0028] C) Cut and bond the SEBS films with conductive layers obtained in step B) to form a shape.

[0029] D) Composite a catalyst layer with the sensing region of the first conductive layer, and then composite an enzyme biochemical sensing layer.

[0030] A reference material layer is laminated in the corresponding region of the second conductive layer;

[0031] E) Place the electrode obtained in step D) in a polymer hydrogel, and after drying, obtain the implanted bioelectrode.

[0032] Preferably, in step A), the mass ratio of the SEBS resin particles to the solvent is 1:2 to 4;

[0033] The solvent is selected from toluene or tetrahydrofuran.

[0034] Compared with existing technologies, this invention provides an application of SEBS as a substrate for implantable bioelectrodes. The SEBS-based bioelectrode of this invention can be implanted into biological tissues for continuous or discontinuous analysis of physiological parameters. Compared to other flexible substrates, the SEBS substrate is thinner and more flexible, reducing interference from body movement on electrical signals, minimizing the volume of implanted tissue and reducing inflammatory responses, thereby improving measurement accuracy and long-term stability. It is expected to meet the needs of more implantation sites when used for implantable sensing, showing promising application prospects. Attached Figure Description

[0035] Figure 1 A top view of the SEBS-based implantable bioelectrode provided by the present invention;

[0036] Figure 2 Right view of the SEBS-based implantable bioelectrode provided by the present invention;

[0037] Figure 3 yes Figure 1 Enlarged cross-sectional side view of sensor probe 7;

[0038] Figure 4 yes Figure 3 Left view section;

[0039] Figure 5A flowchart illustrating the fabrication process of the SEBS implantable bioelectrode provided by this invention;

[0040] Figure 6 These are the first SEBS electrode carrier size parameters;

[0041] Figure 7 These are the dimensions of the second SEBS electrode carrier;

[0042] Figure 8 The example shows the test response curve of the implanted bioelectrode prepared for measuring glucose solution under a concentration gradient.

[0043] Figure 9 It represents the linear relationship between the tested glucose concentration and the response current. Detailed Implementation

[0044] This invention provides an application of SEBS as a substrate for implanted bioelectrodes.

[0045] In this invention, styrene-ethylene-butene-styrene block copolymer (SEBS) has excellent flexibility and elasticity at room temperature. SEBS of the same thickness has higher flexural recovery performance than PI-type materials. Under the premise of meeting the sensing performance requirements, using SEBS as a substrate for implantable electrodes can further reduce the probe volume, or achieve multi-layer multifunctional assembly in the same volume. Furthermore, SEBS itself has excellent advantages such as high transparency, high biocompatibility, oxidation resistance, UV resistance, and wear resistance, making it highly promising in the field of implantable sensing.

[0046] The present invention also provides an implantable bioelectrode based on an SEBS substrate, comprising a sensing probe (7) and a connection structure (16), wherein the implantable bioelectrode includes:

[0047] The substrate is composed of a first SEBS electrode carrier (13) and a second SEBS electrode carrier (2) stacked together; the substrate includes a sensing probe portion and a connection portion;

[0048] A first conductive layer (8) and a working electrode contact (5) connected to the first conductive layer are disposed on the surface of the first SEBS electrode carrier (13); a sensing area (9) is disposed on the first conductive layer (8) at the location of the sensing probe and near the implantation end.

[0049] A second conductive layer (10) and a reference electrode contact (4) connected to the second conductive layer (10) are disposed on the surface of the second SEBS electrode carrier (2); a reference material layer (11) is disposed on the second conductive layer (10) at the location of the sensing probe and near the implantation end;

[0050] A first insulating layer (14) is disposed on the surface of the second conductive layer (10);

[0051] A third conductive layer (12) disposed on the surface of the first insulating layer (14) and a counter electrode contact (3) connected to the third conductive layer (12) and disposed on the surface of the second SEBS electrode carrier (2); or, the third conductive layer (12) and the counter electrode contact (3) are disposed on the other surface of the first SEBS electrode carrier (13);

[0052] The second insulating layer (6) is disposed on the surface of the third conductive layer (12).

[0053] See Figure 1 and Figure 2 , Figure 1 This is a top view of the SEBS-based implantable bioelectrode provided by the present invention. Figure 2 The right view of the SEBS-based implantable bioelectrode provided by the present invention.

[0054] Wherein, 2 is the second SEBS electrode carrier, 13 is the first SEBS electrode carrier, 3 is the counter electrode contact (connected to the third conductive layer), 4 is the reference electrode contact (connected to the second conductive layer), 5 is the working electrode contact (connected to the first conductive layer), 6 is the second insulating layer, 7 is the sensing probe, 8 is the first conductive layer, 9 is the enzyme biochemical sensing layer, 10 is the second conductive layer, 11 is the reference material layer, 12 is the third conductive layer, 14 is the first insulating layer, and 16 is the connection structure.

[0055] In this invention, the substrate is composed of a first SEBS electrode carrier (13) and a second SEBS electrode carrier (2) stacked together; the substrate includes a sensing probe portion and a connection portion.

[0056] The SEBS is a styrene-ethylene-butene-styrene block copolymer, and the thickness of the substrate is 10 to 500 μm, preferably 10, 50, 100, 200, 300, 400, 500, or any value between 10 and 500 μm.

[0057] The first conductive layer (8) is disposed at the sensing probe portion of the first SEBS electrode carrier (13), and the working electrode contact (5) is disposed at the connection portion of the first SEBS electrode carrier (13).

[0058] In some specific embodiments of the present invention, the length of the first SEBS electrode carrier (13) is greater than the length of the second SEBS electrode carrier (2); the first SEBS electrode carrier (13) and the second SEBS electrode carrier (2) of the substrate are aligned at one end, and the first SEBS electrode carrier (13) extends beyond the second SEBS electrode carrier (2) at the other end. The working electrode contact (5) is disposed on the surface of the first SEBS electrode carrier (13) extending beyond the second SEBS electrode carrier (2). The direction from one end to the other end is from the connection part to the sensing probe part.

[0059] In some specific embodiments of the present invention, the second SEBS electrode carrier (2) is provided with a notch at the location of the sensing probe and near the implantation end. When it is bonded to the first SEBS substrate which is composited with the first conductive layer (8), a recessed area is formed. The recessed area is convenient for loading enzyme biochemical materials.

[0060] In this invention, the implanted bioelectrode further includes a first conductive layer (8) disposed on the surface of the first SEBS electrode carrier (13) and a working electrode contact (5) connected to the first conductive layer; a sensing area (9) is disposed on the first conductive layer (8) at the location of the sensing probe and near the implantation end.

[0061] A second conductive layer (10) and a reference electrode contact (4) connected to the second conductive layer (10) are disposed on the surface of the second SEBS electrode carrier (2); a reference material layer (11) is disposed on the second conductive layer (10) at the location of the sensing probe and near the implantation end;

[0062] A first insulating layer (14) is disposed on the surface of the second conductive layer (10);

[0063] A third conductive layer (12) disposed on the surface of the first insulating layer (14) and a counter electrode contact (3) connected to the third conductive layer (12) and disposed on the surface of the second SEBS electrode carrier (2); or, the third conductive layer (12) and the counter electrode contact (3) are disposed on the other surface of the first SEBS electrode carrier (13);

[0064] The second insulating layer (6) is disposed on the surface of the third conductive layer (12).

[0065] In this invention, the shape of the counter electrode contact (3), reference electrode contact (4), and working electrode contact (5) is not particularly limited, and they can be square, rectangular, circular, elliptical, or other irregular shapes. In some specific embodiments of this invention, the counter electrode contact (3), reference electrode contact (4), and working electrode contact (5) are rectangular.

[0066] The working electrode contact (5) is located on the surface of the first SEBS electrode carrier.

[0067] The reference electrode contact (4) is located on the surface of the second SEBS electrode carrier.

[0068] The counter electrode contact (3) can be located on the surface of the second SEBS electrode carrier or on the surface of the first SEBS electrode carrier and is on the other side of the working electrode contact (5).

[0069] In this invention, there are no special restrictions on the positions of the counter electrode contact (3), the reference electrode contact (4), and the working electrode contact (5); any arrangement method known to those skilled in the art is acceptable. Preferably, the counter electrode contact (3), the reference electrode contact (4), and the working electrode contact (5) are arranged on the same straight line, and the three contacts can be located on either the left or right side of the extension line of the sensing probe connecting the structure, or they can be evenly distributed with the extension line as the axis of symmetry, either longitudinally or laterally.

[0070] In this invention, the first conductive layer (8), the second conductive layer (10), and the third conductive layer (12) are independently selected from gold, silver, or carbon, and their thicknesses are independently 1 μm to 20 μm, preferably 1, 3, 5, 8, 10, 11, 13, 15, 18, 20, or any value between 1 μm and 20 μm. Their lengths are independently 0.05 to 5 mm, preferably 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, or any value between 0.05 and 5 mm.

[0071] In some specific embodiments of the present invention, at the implantation end of the sensing probe (7), the first SEBS electrode carrier (13), the first conductive layer (8), the second SEBS electrode carrier (2), the second conductive layer (10), the first insulating layer (14), the third conductive layer (12), and the second insulating layer (6) are stacked in a stepped structure.

[0072] A sensing area (9) is provided on the surface of the first conductive layer (8) at the sensing probe location and near the implantation end; an enzyme biochemical sensing layer is provided on the sensing area (9). Preferably, the thickness of the enzyme biochemical sensing layer is 10-300 μm, preferably 10, 30, 50, 100, 150, 200, 250, 300 μm, or any value between 10 and 300 μm. The enzyme biochemical sensing layer includes a catalytic layer and a glucose enzyme sensing layer. The catalytic layer can use palladium, iridium, gold, titanium nanoparticles, or alloys of two or more of these materials instead of platinum nanoparticles.

[0073] Implanted bioelectrodes can be used to obtain the glucose concentration in tissue fluid or blood. However, this embodiment is not limited to this. For example, by changing the sensing layer on the sensing area (9), data on other body fluid components besides glucose can also be obtained. These body fluid components may include, for example, uric acid, lactic acid, acetylcholine, amylase, bilirubin, cholesterol, human chorionic gonadotropin, creatine kinase, creatine, creatine anhydride, DNA, fructosamine, glucose, glutamine, growth hormone, hormones, ketone bodies, lactate, oxygen, peroxides, prostate-specific antigen, prothrombin, RNA, thyroid-stimulating hormone, and troponin.

[0074] In some specific embodiments of the present invention, implanted bioelectrodes can also monitor the concentration of drugs in body fluids, such as antibiotics (e.g., gentamicin, vancomycin, midecamycin, etc.), digitoxin, digoxin, theophylline, and warfarin.

[0075] In this invention, a reference material layer (11) is disposed on the surface of the second conductive layer (10) at the location of the sensing probe and near the implantation end. The reference material (11) is silver and / or silver chloride, with a thickness of 1 to 20 μm, preferably 1, 3, 5, 8, 10, 12, 15, 18, 20, or any value between 1 and 20 μm.

[0076] A polymer hydrogel layer is coated on the surface of the implantable bioelectrode. The thickness of the polymer hydrogel layer is 10–50 μm, preferably 10, 20, 30, 40, or 50 μm, or any value between 10 and 50 μm. See also Figure 3 and Figure 4 , Figure 3 yes Figure 1 A magnified cross-sectional side view of the sensing probe 7, where 14 is the first insulating layer and 15 is the polymer hydrogel layer. Figure 4 yes Figure 3 Left view cross section.

[0077] The present invention also provides a method for preparing the above-mentioned implantable bioelectrode, comprising the following steps:

[0078] A) Disperse SEBS resin particles in a solvent to obtain an SEBS solution;

[0079] After the SEBS solution is coated onto a substrate and dried, the SEBS film is separated from the substrate.

[0080] B) Conductive carbon paste is printed onto the surfaces of two SEBS films to obtain a first conductive layer and a corresponding working electrode contact, and a second conductive layer and a corresponding working electrode contact.

[0081] Then, insulating ink is printed on the surface of the second conductive layer to form the first insulating layer;

[0082] Conductive carbon paste and insulating ink are sequentially printed on the surface of the first insulating layer, and a third conductive layer and a corresponding working electrode contact, as well as a second insulating layer, are sequentially formed on the surface of the first insulating layer; or, conductive carbon paste and insulating ink are sequentially printed on the other side surface of the SEBS film composited with the first conductive layer, and a third conductive layer and a corresponding working electrode contact, as well as a second insulating layer, are sequentially formed on the surface of the SEBS film.

[0083] C) Cut and bond the SEBS films with conductive layers obtained in step B) to form a shape.

[0084] D) Composite a catalyst layer with the sensing region of the first conductive layer, and then composite an enzyme biochemical sensing layer.

[0085] A reference material layer is laminated in the corresponding region of the second conductive layer;

[0086] E) Place the electrode obtained in step D) in a polymer hydrogel, and after drying, obtain the implanted bioelectrode.

[0087] See Figure 5 , Figure 5 This is a flowchart illustrating the preparation process of the SEBS implantable bioelectrode provided by the present invention.

[0088] Specifically, the present invention first prepares the SEBS substrate, the method of which is as follows:

[0089] The first step is to disperse the SEBS resin particles in a solvent and treat them on a linear shaker for 6 to 12 hours until they become transparent.

[0090] The second step is to apply SEBS resin particles to the substrate with a thick blade and let it dry at room temperature for 0.5h to 2h, and then transfer it to an oven to dry for 1h to 2h to remove residual solvent.

[0091] The third step is to peel the SEBS film off the substrate to obtain the SEBS substrate.

[0092] The mass ratio of the SEBS resin particles to the solvent is 1:2 to 4, preferably 1:2, 1:3, 1:4, or any value between 1:2 and 4.

[0093] The solvent is selected from toluene or tetrahydrofuran.

[0094] The substrate is made of PET, PU, ​​glass, or flat plastic film.

[0095] In some specific embodiments of the present invention, the film-forming tool used is a 1 mm thick blade. In some examples, other instruments can be used instead of resin transfer film forming, or the resin can be poured into a container of a customized height to obtain a SEBS film with a more accurate thickness. The SEBS film can be as thin as 10 μm while maintaining high flexibility. In some examples, its thickness can be in the range of 10 to 500 μm.

[0096] Next, conductive carbon paste is printed onto the surfaces of the two SEBS films to obtain the first conductive layer and the corresponding working electrode contact, as well as the second conductive layer and the corresponding working electrode contact.

[0097] Then, insulating ink is printed on the surface of the second conductive layer to form the first insulating layer;

[0098] Conductive carbon paste and insulating ink are sequentially printed on the surface of the first insulating layer, and a third conductive layer and a corresponding working electrode contact, as well as a second insulating layer, are sequentially formed on the surface of the first insulating layer; or, conductive carbon paste and insulating ink are sequentially printed on the other side surface of the SEBS film composited with the first conductive layer, and a third conductive layer and a corresponding working electrode contact, as well as a second insulating layer, are sequentially formed on the surface of the SEBS film.

[0099] The conductive layer can be gold, silver, or carbon, and the conductive layer can be formed by one of the following methods: vapor deposition, electroplating, electroless plating, dip coating, spraying, or printing.

[0100] Then, the two SEBS films with conductive layers obtained above are cut and bonded together. In this invention, it is preferable to use an ultraviolet laser cutting machine to cut the sheet into filamentous electrodes.

[0101] In this invention, the bonding molding method can be achieved by adhesive bonding or organic solvent welding, wherein the adhesive can be tape or adhesive.

[0102] The organic solvent is selected from toluene or tetrahydrofuran. The organic solvent is used to soften the contact surface of the first and second substrates, so as to achieve the purpose of re-bonding and molding the upper and lower substrates. After the organic solvent evaporates, the first SEBS substrate and the second SEBS substrate can be bonded together well.

[0103] Next, a catalyst layer is composited in the sensing region of the first conductive layer, and then an enzyme biochemical sensing layer is composited.

[0104] A reference material layer is laminated in the corresponding region of the second conductive layer;

[0105] Specifically, in some embodiments of the present invention, the catalyst layer is a platinum layer, that is, platinum nanoparticles 9 for catalyzing the glucose oxidation reaction are deposited on the conductive substrate layer 8. The locally protected electrode (only the effective working area of ​​the working electrode is exposed) is placed in a platinum plating solution (3wt% chloroplatinic acid, 0.25wt% lead acetate), with a platinum wire as the counter electrode. Using a constant voltage method, the working potential is set to -2.5V, and the deposition time is 60s to 180s to deposit a dense platinum black layer on the electrode. Then, a glucose enzyme sensing layer that can react with glucose is printed on the nanoparticle layer. The electrode is placed in a glutaraldehyde atmosphere container and reacted in an oven at 30-40°C for 60min. Then it is stored in a refrigerator at 4°C for 2h.

[0106] In some specific embodiments of the present invention, the catalyst layer may use palladium, iridium, gold, titanium nanoparticles or alloys of two or more of them to replace platinum nanoparticles, and the catalyst layer may be prepared by one or more of the following methods: electroplating, evaporation, printing or extrusion.

[0107] The reference material layer (11) on the second conductive layer (10) is silver and / or silver chloride. The reference material layer is formed by one of vapor deposition, electroplating, electroless plating, dip coating, spraying or printing, and has a thickness of 1 to 20 μm. The mass ratio of silver to silver chloride is 1:1 to 4:1, preferably 1:1, 2:1, 3:1, 4:1, or any value between 1:1 and 4:1.

[0108] Finally, the electrode prepared above is placed in a polymer hydrogel and dried to obtain an implanted bioelectrode.

[0109] The thickness of the polymer hydrogel layer 15 is 10–50 μm. In some specific embodiments, the polymer hydrogel layer is a hydrophilic membrane prepared by solution evaporation technology from materials known to those skilled in the art, such as Nafion, polytetrafluoroethylene, polyolefins, polyamides, polycarbonates, polydimethylsiloxane, polyurethane, chitosan, polyurea cellulose acetate, and polyester sulfonic acid. The preparation technology of the hydrophilic membrane is familiar to those skilled in the art, employing various sensor inner and outer membrane preparation techniques, such as coating, spraying, spin coating, impregnation, and casting. This method involves evaporating a polymer solution formed on the sensor electrode using a volatile liquid, such as water or an organic solvent, leaving a polymer membrane. Evaporation can be achieved through heat, high-energy radiation, ultraviolet light, or negative pressure. When the sensor is implanted into biological tissue, the hydrophilic membrane gradually expands under the influence of tissue fluid, forming a polymer hydrogel layer that improves biocompatibility.

[0110] In some specific embodiments of the present invention, the polymer hydrogel layer 15 is prepared by dissolving 4 wt% polyurethane in a mixed solution of 98% tetrahydrofuran and 2% dimethylformamide to form a polyurethane solution, forming a polyurethane hydrogel layer on the entire electrode surface by dip coating, drying, and storing.

[0111] In this embodiment, the biocompatible membrane layer 15 covers the entire implanted electrode probe 7, which reduces the precision requirements of the manufacturing process. In this invention, the biocompatible membrane layer only covers the electrode probe 7 and does not cover the connection structure.

[0112] In this invention, the SEBS electrode is small in size (the electrode thickness in this embodiment is only 200 μm), thus reducing inflammatory response and improving the accuracy and stability of the sensor. Furthermore, traditional implantation sites are mostly located in the arm because the possibility of electrode deformation due to physical movement at that site is small. However, the SEBS substrate itself has excellent bending and bending recovery properties and strong impact resistance. Therefore, SEBS is expected to solve the problem of ensuring the stability of the sensing signal even with deformation, thereby potentially extending the implantation site to the waist, abdomen, and other areas.

[0113] This invention provides a flexible implantable bioelectrode based on an SEBS substrate. Its purpose is to reduce the volume of implanted tissue by using thinner and more flexible SEBS as a substrate, thereby reducing inflammatory response, improving measurement accuracy and long-term stability, reducing interference of body movement on electrical signals, and meeting the needs of more implantation sites when used for implantable sensing. It has good application prospects.

[0114] To further understand the present invention, the application of SEBS provided by the present invention as a substrate for implantable bioelectrodes and an implantable bioelectrode are described below with reference to embodiments. The scope of protection of the present invention is not limited to the following embodiments.

[0115] Example 1

[0116] SEBS resin particles were dispersed in toluene at a mass ratio of 1:2 and treated on a linear shaker for 12 hours until they became transparent. They were then coated onto a PET substrate with a 1 mm thick blade (100 μm thick) and dried at room temperature for 1 hour. After that, they were dried in an 80 °C oven for 2 hours. Finally, the SEBS was peeled off from the PET substrate to obtain the SEBS flexible substrate.

[0117] Conductive carbon paste (ACHESON ED 423SS conductive carbon paste) is screen-printed (300 mesh screen, the same below) onto the SEBS surface (two independent SEBS substrates 13, 2) to form the first and second conductive layers 8, 10 and corresponding conductive contacts 5, 4. After drying in the shade or oven, photocurable insulating ink (ACHESON ED 452SS) is printed onto the surface of the second conductive layer 10 and cured with ultraviolet light to form the first insulating layer 14. The first insulating layer is 1 mm shorter than the second conductive layer to meet the requirements of the reference layer 11. Conductive carbon paste is then screen-printed onto the surface of 14 to form the third conductive layer 12 and conductive contacts 3. After drying in the shade or oven, photocurable insulating ink is then printed onto the surface of the third conductive layer to form the second insulating ink layer 6. The second insulating layer is 1 mm shorter than the third conductive layer.

[0118] The reference electrode region 11 was formed by screen printing with silver / silver chloride paste (Shanghai Julong Electronics Technology Co., Ltd., JL12) and dried in an 80℃ oven. The first and second SEBS substrates were then cut into specific shapes using a UV laser cutter; specific parameters are detailed in [link to relevant documentation]. Figure 6 , Figure 7 The second SEBS substrate 2 is soldered to the surface of the first SEBS substrate 13 using toluene solvent, exposing a 1mm first conductive layer for load sensing layer, and then placed in an 80°C oven until the toluene evaporates.

[0119] The first conductive layer 8 was placed in a platinum plating solution (3wt% chloroplatinic acid, 0.25wt% lead acetate). Using a platinum wire as the counter electrode, a constant voltage method was adopted, with the working potential set to -2.5V and the deposition time set to 120s, to deposit a dense platinum black layer on the electrode. Next, 1μL of 500U / mL glucose oxidase solution was drop-coated onto the nanoparticle layer using a pipette. The electrode was placed in a glutaraldehyde atmosphere container and reacted in an oven at 30-40℃ for 60min. Finally, it was stored in a refrigerator at 4℃ for 2h. At this point, the sensing layer 9 was completed.

[0120] 4 wt% polyurethane was dissolved in a mixed solution of 98 V% tetrahydrofuran and 2 V% dimethylformamide to form a polyurethane solution. A polyurethane hydrogel layer 15 was formed on the entire surface of the flexible electrode by dip coating. After drying, an implantable bioelectrode based on the SEBS substrate was obtained and stored.

[0121] See Figure 8 and Figure 9 , Figure 8 This is the test response curve of the implanted bioelectrode prepared in this example for measuring glucose solutions under a concentration gradient. Figure 9 It is the linear relationship between the tested glucose concentration and the current, with a linear range of 2mM to 32mM, covering the blood glucose range of normal people and diabetic patients.

[0122] in, Figure 8 The specific testing method is as follows:

[0123] The testing instrument was a Chenhua CHI660 series electrochemical workstation, and the testing method was the potentiostatic method (it curve). The working electrode contact, reference electrode contact, and counter electrode contact of the SEBS flexible electrode were connected to the working electrode clamp, reference electrode clamp, and counter electrode clamp of the workstation, respectively. The probe portion of the electrode was immersed in the test solution, which was a glucose solution prepared with 1*PBS at concentration gradients of 2mM, 4mM, 8mM, 16mM, and 32mM. The potentiostatic setting was 0.6V, the time window was 30s, and the sampling interval was 0.1s.

[0124] Figure 9 for Figure 8 The relationship between current and glucose concentration at 30 seconds during the test was obtained by fitting the curve using Origin software.

[0125] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. An implantable bioelectrode based on SEBS substrate, comprising a sensing probe (7) and a connection structure (16), characterized in that, The implantable bioelectrode comprises: a substrate with a thickness of 10-200 µm, which is composed of a first SEBS electrode carrier (13) and a second SEBS electrode carrier (2); the substrate comprises a sensing probe part and a connecting part; a first conductive layer (8) disposed on the surface of the first SEBS electrode carrier (13) and a working electrode contact (5) connected to the first conductive layer; a sensing area (9) is disposed on the surface of the first conductive layer (8) at the sensing probe part and close to the implantation end; a second conductive layer (10) disposed on the surface of the second SEBS electrode carrier (2) and a reference electrode contact (4) connected to the second conductive layer (10); a reference material layer (11) is disposed on the surface of the second conductive layer (10) at the sensing probe part and close to the implantation end; a first insulating layer (14) disposed on the surface of the second conductive layer (10); a third conductive layer (12) disposed on the surface of the first insulating layer (14) and a counter electrode contact (3) connected to the third conductive layer (12) and disposed on the surface of the second SEBS electrode carrier (2); alternatively, the third conductive layer (12) and the counter electrode contact (3) are disposed on the other surface of the first SEBS electrode carrier (13); a second insulating layer (6) disposed on the surface of the third conductive layer (12).

2. The implantable bioelectrode of claim 1, wherein, The length of the first SEBS electrode carrier (13) is greater than the length of the second SEBS electrode carrier (2); The first conductive layer (8) is disposed at the position of the sensing probe part of the first SEBS electrode carrier (13), and the working electrode contact (5) is disposed at the position of the connecting part of the first SEBS electrode carrier (13); One end of the first SEBS electrode carrier (13) and the second SEBS electrode carrier (2) of the substrate is aligned, and the other end of the first SEBS electrode carrier (13) protrudes from a part of the second SEBS electrode carrier (2), the working electrode contact (5) is disposed on the surface of the part of the first SEBS electrode carrier (13) protruding from the second SEBS electrode carrier (2), and the direction from the one end to the other end is from the connecting part to the sensing probe part.

3. The implantable biopotential electrode of claim 1, wherein: At the implantation end of the sensing probe (7), the first SEBS electrode carrier (13), the first conductive layer (8), the second SEBS electrode carrier (2), the second conductive layer (10), the first insulating layer (14), the third conductive layer (12), and the second insulating layer (6) are sequentially stacked in a stepped structure.

4. The implantable biopotential electrode of claim 1, wherein: A polymer hydrogel layer with a thickness of 10-50 µm is wrapped on the surface of the implantable bioelectrode.

5. The implantable biopotential electrode of claim 1, wherein: An enzyme biochemical sensing layer with a thickness of 10-300 µm is provided on the sensing area (9).

6. The implantable biopotential electrode of claim 1, wherein, The SEBS is a styrene-ethylene-butylene-styrene block copolymer. The conductive material of the first conductive layer (8), the second conductive layer (10) and the third conductive layer (12) is independently gold, silver or carbon, with a thickness of 1 µm~20 µm and a length of 0.05~5 mm; The reference material layer (11) on the second conductive layer (10) is silver and / or silver chloride, with a thickness of 1~20 µm.

7. A method of preparing an implantable bioelectrode as claimed in any one of claims 1 to 6, characterized in that, The method comprises the following steps: A) dispersing SEBS resin particles in a solvent to obtain an SEBS solution; The SEBS solution is coated on a substrate and dried to obtain an SEBS film; B) printing conductive carbon paste on the surfaces of two SEBS films respectively to obtain a first conductive layer and a corresponding working electrode contact, and a second conductive layer and a corresponding working electrode contact; Then print insulating ink on the surface of the second conductive layer to form a first insulating layer; Print conductive carbon paste and insulating ink on the surface of the first insulating layer in sequence to form a third conductive layer and a corresponding working electrode contact, and a second insulating layer on the surface of the first insulating layer; or print conductive carbon paste and insulating ink on the other side surface of the SEBS film with the first conductive layer in sequence to form a third conductive layer and a corresponding working electrode contact, and a second insulating layer on the surface of the SEBS film; C) cut the SEBS films with conductive layers obtained in step B) and bond them into shape; D) composite a layer of catalyst layer on the sensing area of the first conductive layer, and then composite an enzyme biochemical sensing layer; Composite a layer of reference material layer on the corresponding area of the second conductive layer; E) place the electrode obtained in step D) in a polymer hydrogel, dry it, and obtain an implanted bioelectrode.

8. The preparation method according to claim 7, characterized in that, In step A), the mass ratio of the SEBS resin particles to the solvent is 1:2~4; The solvent is selected from toluene or tetrahydrofuran.

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