A textured double-sided flexible sensor and its preparation method and application

Abstract

The present invention provides a textured double-sided flexible sensor and a preparation method and application thereof. The texturing process is achieved by laser etching both sides of a flexible substrate, and the type, depth and spacing of the pattern are optimized to obtain a textured flexible substrate with better performance. The textured flexible substrate can significantly improve the adhesion to the conductive layer / electrocatalytic layer to ensure the overall bending resistance. At the same time, the fixation and adhesion effect of the flexible substrate to the enzyme layer is improved by preparing a double-textured pattern. The sensor is more suitable for preparing a flexible sensor partially implanted in the human body, which is beneficial to improving the life of the sensor and facilitating long-term implantation and use. The processing technology can be effectively simplified, the production cost can be reduced, the detection results are more stable, the batch difference is small, and the sensitivity is high.

Description

Technical Field

[0001] The invention belongs to the field of medical devices and relates to the preparation of an electrochemical biosensor, in particular to a textured double-sided flexible sensor and a preparation method and application thereof. Background Art

[0002] A biosensor is an analytical device used to detect chemical substances, which combines biological components with physical and chemical detectors. A biosensor is an analytical tool or system consisting of immobilized bioactive molecules as recognition elements (including enzymes, antibodies, antigens, microorganisms, cells, tissues, nucleic acids and other bioactive substances), appropriate physical and chemical transducers (such as oxygen electrodes, photosensitive tubes, field effect tubes, piezoelectric crystals, etc.) and signal amplification devices.

[0003] Electrochemical biosensors use solid electrodes as base electrodes to fix bioactive molecules on the electrode surface. Then, through the specific recognition between biomolecules, the bioactive molecules can selectively recognize the target molecules and capture the target molecules on the electrode surface. The base electrode acts as a signal conductor to export the recognition reaction signal occurring on the electrode surface and convert it into a measurable electrical signal, thereby achieving the purpose of quantitative or qualitative analysis of the target object.

[0004] Implantable biosensors have the advantage of continuously measuring certain important physiological or pathological parameters in the body that change over time, such as the concentration of oxygen, glucose, and lactate, thereby obtaining a comprehensive and accurate diagnosis or treatment effect.

[0005] Implantable biosensors based on flexible substrates require the aid of auxiliary devices to complete implantation, but they are comfortable to wear for a long time. Existing flexible implantable sensors usually use flexible polymer films as substrates, on which carbon electrodes are first patterned and printed or gold electrodes are deposited, and an electrochemical detection system is formed by assembling electrodes layer by layer or arranging them in a planar dislocation. During assembly, it may also be necessary to bend the front end to reduce the thickness of the final sensor. Due to the continuous stress at the bend, this can easily cause damage to the sensor. After wearing the sensor, human activities will inevitably cause the sensor to be slightly twisted in the body. Over time, the conductive layer may have small cracks and defects, resulting in inaccurate test results. In addition, the layer-by-layer assembly or planar dislocation arrangement process is complicated and not easy to mass produce, which makes the production cost of such products high and expensive.

[0006] CN105943058A discloses a flexible electrode, which uses chemical plating on both sides of a thin film to prepare a two-electrode system without patterning. However, since it must be operated by chemical plating and needs to be immersed in platinum black, there will be differences in sensitivity between batches during the detection process, resulting in unstable detection results. In addition, long-term use of platinum black will cause "catalyst poisoning", that is, the catalytic effect of platinum black becomes worse than the initial state, thereby affecting the detection results.

[0007] This research team applied for invention patent CN202111135598.1 in 2021, disclosing a new type of double-sided flexible sensor. The flexible sensor is mainly prepared by a multi-layer structure method such as magnetron sputtering coating a conductive layer on a flexible substrate, and an insulating layer is added on both sides of the flexible substrate, thereby enhancing the adhesion and bending resistance of the flexible substrate to the conductive layer / electrocatalytic layer, and improving the accuracy and stability of the detection results; after long-term practice, it is found that although such a preparation method can also achieve certain effects, the preparation process is more complicated. When coating the insulating layer, strict attention must be paid to the coating part. Some parts cannot be glued with the insulating layer. If you are not careful, the front end and the connection position may also be glued and cause insulation, thereby affecting the detection effect of the flexible sensor; and the thickness of the double-sided flexible sensor obtained is increased, and the cost is increased.

[0008] Therefore, it is urgent to find a method that can more simply and efficiently improve the adhesion of the flexible substrate to the conductive layer / bioactive molecule layer and ensure bending resistance, so as to produce a double-sided flexible sensor that is more suitable for biological indicator detection, with more stable and accurate detection results and higher sensitivity. Summary of the invention

[0009] To solve the above problems, the present invention provides a textured double-sided flexible sensor, which realizes texturing by laser etching on both sides of the flexible substrate, and obtains a textured flexible substrate with better performance by optimizing the type, depth and spacing distance of the pattern. The textured flexible substrate can significantly improve the adhesion to the conductive layer / electrocatalytic layer and the overall bending resistance. At the same time, the fixed adhesion effect of the flexible substrate to the enzyme layer is improved by preparing a double textured pattern. It is more suitable for preparing flexible sensors partially implanted in the human body, and the detection results are more stable, the batch differences are small, and the sensitivity is high.

[0010] In one aspect, the present invention provides a flexible sensor, comprising a flexible substrate and a conductive layer, wherein the conductive layer is adhered to a surface of the flexible substrate; and the surface of the flexible substrate has a textured pattern.

[0011] The double-sided flexible sensor provided by the present invention uses a flexible substrate as a substrate and is divided into a front end and a rear end. The front end is used to be implanted in the human body, and the rear end remains outside the body and is connected to other sensor kits. The flexible substrates at the front end and the rear end are both rectangular flat structures (close to a long strip), including a first surface and a second surface. The first surface is based on the flexible substrate, and from the inside to the outside, it is a conductive layer and an electrocatalytic layer. The front end also has a biologically active molecule layer, a multifunctional polymer outer membrane, etc.; the second surface is based on the flexible substrate, and from the inside to the outside, it is a conductive layer and a silver-silver chloride layer. The front end also has a multifunctional polymer outer membrane, etc.

[0012] The adhesion and bending resistance of the flexible substrate and other outer layers such as the conductive layer are the key to ensure that the double-sided flexible sensor can work normally and stably for a long time. If the adhesion between the flexible substrate and the conductive layer is not strong, the sensor will wrinkle and crack during long-term use, and the error of the detection result will increase; if the bending resistance is weak, the sensor will be damaged and the detection result will be inaccurate.

[0013] The present invention has been proved through research that texturing the surface of a flexible substrate can improve the surface energy of the flexible substrate and the bonding force between the flexible substrate and the material thereon (including the conductive layer, etc.), especially when a three-dimensional structure is formed on the surface of the flexible substrate, which is conducive to the upper material entering the interior of the flexible substrate and making the two more closely bonded.

[0014] Therefore, by texturing the surface of the flexible substrate, the adhesion effect that was originally achieved by adding an insulating layer on each side of the flexible substrate (CN202111135598.1) can be achieved. The flexible substrate no longer needs to add an insulating layer, and the conductive layer can be directly prepared, which can ensure the firm adhesion of the flexible substrate and the conductive layer, while also ensuring flexibility and bending resistance. After long-term wearing, the accuracy and stability of the test results can still be guaranteed, and the sensitivity is high.

[0015] Furthermore, the texturing treatment refers to treatment by any one or more methods of laser etching, plasma etching or wet etching.

[0016] Conventional texturing treatments include sandblasting, wet etching, and dry etching (including laser etching and plasma etching). Sandblasting is rarely used now because of its high pollution and difficulty in controlling the texture. Wet etching mainly uses chemical reagents to react with the etched material for etching. The advantages of this etching method are strong adaptability, good uniformity, and suitability for most materials; the disadvantages are poor fidelity of graphic etching, uneven etching line width that is difficult to control, and the etching line width cannot be precise. Laser etching uses a high-energy laser beam to irradiate the surface of the etched workpiece to melt and vaporize it, forming a groove of a certain depth to achieve the purpose of etching the material. The characteristics of laser etching are high etching accuracy, high yield rate, and good reproducibility. It can achieve one-time molding technology for different graphics and angles, no consumables, no pollution, and relatively low cost. Plasma etching refers to the use of high-frequency glow discharge reaction to activate the reaction gas into active particles, such as radicals or free radicals. These active particles diffuse to the etched part, react with the etched material, form volatile products and are removed to achieve the purpose of etching. The disadvantage is that the etching accuracy is not enough and the equipment is expensive. Therefore, the present invention preferably uses laser etching, plasma etching or wet etching, and laser etching is most preferred.

[0017] Furthermore, the texturing treatment is laser etching; the textured pattern is any one of vertical lines, horizontal lines, oblique lines, grid lines, dot-dashed lines, dot matrix, dashed lines, and wavy lines, the vertical lines are lines parallel to the length direction of the flexible substrate, the horizontal lines are lines perpendicular to the length direction of the flexible substrate, the dot-dashed lines, dot matrix, dashed lines, and wavy lines are all lines parallel to or perpendicular to the length direction of the flexible substrate, the grid lines are composed of lines parallel to the length direction of the flexible substrate and lines perpendicular to the length direction of the flexible substrate, and the oblique lines are lines that are neither parallel to nor perpendicular to the length direction of the flexible substrate.

[0018] Furthermore, the textured pattern is vertical lines, and the depth of the texture is 1-10 μm.

[0019] The double-sided flexible sensor provided by the present invention is very soft. After being implanted in the human body with the aid of a needle aid, it is easy to bend in the direction perpendicular to the length of the flexible substrate. At this time, if the textured pattern is a horizontal line, since the horizontal line is consistent with the direction in which the bending is easy to occur, it is easy to crack after long-term use, affecting the bonding force between the flexible substrate and the conductive layer. Therefore, the textured pattern should be parallel to the length direction of the flexible substrate as much as possible, so that it will not be affected even if it is bent horizontally.

[0020] Furthermore, the line width of the vertical lines is 20-25 μm, and the interval between two vertical lines is 30-50 μm.

[0021] Research has shown that the width and spacing of the vertical line pattern will directly affect the bonding strength between the flexible substrate and the conductive layer, the bending resistance of the flexible sensor, and the accuracy and stability of the detection results. Therefore, it is necessary to select an appropriate vertical line width and the spacing between the two vertical lines.

[0022] In some embodiments, the laser etching used in the present invention has specific operating conditions: using an ultraviolet picosecond laser, with a power of 10 W, a cutting speed of 600 mm / s, and a number of cutting times of 3 times.

[0023] Furthermore, the flexible substrate is a flat structure having two surfaces, namely a first surface and a second surface, and conductive layers are adhered to the first surface and the second surface respectively; the surfaces of the first surface and the second surface need to be textured.

[0024] The flexible substrate is a planar structure, divided into a front end and a rear end. The front end is used to be implanted in the human body, and the rear end remains outside the body and is connected to other sensor kits.

[0025] In some embodiments, the flexible substrate is a flat structure with a thickness of 50 to 200 μm, including two upper and lower surfaces. The flexible substrate is prepared with a conductive layer by overall sputtering. Therefore, the first surface, the second surface, and both the front end and the rear end of the flexible substrate need to be textured to improve the adhesion between the flexible substrate and the conductive layer.

[0026] In some embodiments, the first surface, based on the flexible substrate, further comprises a conductive layer, or a conductive layer and an electrocatalytic layer; the second surface, based on the flexible substrate, comprises a conductive layer and a silver-silver chloride layer from inside to outside.

[0027] The conductive layer is one or more of carbon, gold, platinum, titanium, and chromium, with a thickness of 1-10 μm; the electrocatalytic layer is one or more of carbon nanotubes, graphene, platinum, iridium, rhodium, titanium, and osmium, with a thickness of 1-1000 nm; the thickness of the silver-silver chloride layer is 10-30 μm.

[0028] In some embodiments, the first side, based on the flexible substrate, the conductive layer, or the flexible substrate, the conductive layer, and the electrocatalytic layer, further comprises a bioactive molecule layer and a multifunctional polymer outer membrane at the front end; the second side, based on the flexible substrate, the conductive layer, and the silver-silver chloride layer, further comprises a multifunctional polymer outer membrane at the front end;

[0029] The bioactive molecular layer is one or more of enzymes, proteins, microorganisms and DNA; the multifunctional polymer outer membrane is one or more of polyurethane, polyvinyl chloride, Nafion, chitosan and zwitterionic polymers.

[0030] The flexible substrate prepared by the present invention is a double-sided flexible substrate, that is, a single-piece double-sided flexible electrode, which does not require technologies such as photolithography or screen printing, does not require layer-by-layer assembly and insulation treatment, and does not require multiple pieces to be spliced. In addition, the effective working area is larger than that of a single-piece single-sided multi-electrode, which is beneficial to improving the life of the sensor and facilitating long-term implantation and use. It can effectively simplify the processing technology and reduce production costs. At the same time, the single-piece electrode structure can also effectively reduce implantation trauma.

[0031] In a single-piece double-sided flexible electrode, the electrodes are located on both sides of the flexible substrate and are not conductive to each other, but each electrode is conductive to the corresponding connection position.

[0032] In some embodiments, the first surface of the flexible substrate includes a first electrode and a first connection site, and the second surface includes a second electrode and a second connection site; the detection sites of the first electrode and the second electrode (implanted into the human body) are both located at the front end; the first connection site and the second connection site are both located at the rear end. The first electrode and the first connection site are conductive, and the second electrode and the second connection site are conductive.

[0033] Since the flexible sensor provided by the present invention has very good bending resistance, even if it needs to be folded during use, it will not have any adverse effect on its performance.

[0034] Furthermore, the first surface also includes a bioactive molecule layer, and the bioactive molecule layer is located outside the conductive layer; the textured pattern of the first surface is a double textured pattern, and a circular ring pattern is provided on the basis of a vertical line pattern.

[0035] The double textured pattern described in the present invention refers to etching a circular ring pattern directly on the basis of the vertical line pattern after the etching of the vertical line pattern is completed. In this way, it looks like pits are formed on the surface covered with vertical lines, and each circular ring pattern forms a pit.

[0036] Research has shown that the circular pattern added on the basis of the vertical line pattern can improve the adhesion to the active molecules (such as enzymes) in the biologically active molecule layer. This is because the circular pattern forms a pit on the basis of the vertical line pattern, so that the biologically active molecules (such as enzymes) are fixed in the circular pit, making the binding stronger.

[0037] The bioactive molecule layer is only located at the front end of the first surface of the flexible sensor and on the outside of the conductive layer, but each circular pattern will form a pit, and the conductive layer will also have texture after covering it, which will have a limiting effect on the bioactive molecule layer (such as the enzyme layer).

[0038] Furthermore, each circular ring pattern is composed of a group of concentric rings, the diameters of the concentric rings gradually increase from the inside to the outside, the distance between two adjacent concentric rings is 30-50 μm, and the depth of the concentric rings is 1-10 μm.

[0039] In some embodiments, the smallest circle of the circular pattern has a diameter of 30 um, the next smallest circle has a diameter of 90 um (ie, the distance between the circles is 30 um), and the largest circle is less than 30 um from the edge of the electrode.

[0040] In some embodiments, the maximum annular outer diameter does not exceed 330 um.

[0041] Furthermore, the material of the flexible substrate is any one of polyethylene terephthalate, polyethylene naphthalate, polycarbonate or polyimide.

[0042] In some embodiments, the flexible substrate is made of polyimide.

[0043] In another aspect, the present invention provides the use of a textured pattern for preparing a flexible substrate having high adhesion to a conductive layer.

[0044] In another aspect, the present invention provides a method for preparing a textured flexible sensor, which mainly comprises the following steps:

[0045] (1) Texturing is performed on both sides of the substrate;

[0046] (2) preparing a conductive layer, or a conductive layer and an electrocatalytic layer, on a first surface of the flexible substrate;

[0047] (3) preparing a conductive layer and a silver layer on the second surface of the flexible substrate, and chlorinating the silver layer;

[0048] (4) introducing a bioactive molecule at the front end of the first surface;

[0049] (5) after protecting the connection site, spin coating the first surface and the second surface with a multifunctional polymer outer film;

[0050] (6) Double-sided flexible sensors with specific shapes are obtained by laser cutting.

[0051] Furthermore, the coating in step (1) is any one of magnetron sputtering, spraying, dipping or chemical deposition.

[0052] Furthermore, it is preferred to use a magnetron sputtering method for coating.

[0053] The present invention has the following beneficial effects:

[0054] 1. Through texturing treatment, the adhesion of the flexible substrate to the conductive layer / electrocatalytic layer is significantly improved;

[0055] 2. The textured flexible sensor has excellent bending resistance as a whole;

[0056] 3. Through double texturing treatment, the fixation and attachment effect of the flexible substrate on the biological macromolecule layer (such as enzyme layer) is improved;

[0057] 4. The detection results of the prepared textured flexible sensor are more stable, with small batch differences and high sensitivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 A schematic diagram of the structure of a non-folding double-sided flexible sensor provided in Example 1;

[0059] Figure 2 A schematic diagram of the structure of a foldable double-sided flexible sensor provided in Example 1;

[0060] Figure 3 A schematic diagram of the internal multi-layer structure of the double-sided flexible sensor provided in Example 1;

[0061] Figure 4Schematic diagrams of textured patterns of the flexible substrate provided in Example 1, wherein (1) is a schematic diagram of a vertical line textured pattern, and (2) is a schematic diagram of a double textured pattern;

[0062] Figure 5 It curve diagram of the textured double-sided flexible glucose sensor provided in Example 2;

[0063] Figure 6 Examples of different texturing patterns provided for Example 5;

[0064] Figure 7 Examples of different dual texturing patterns provided for Example 8;

[0065] Figure 8 Current response curves of glucose in vivo for 7 consecutive days after the flexible sensors with single vertical line texture and double vertical line texture provided in Example 8 were implanted in the human body. DETAILED DESCRIPTION

[0066] The preferred embodiments of the present invention are further described in detail below in conjunction with the accompanying drawings. It should be pointed out that the following embodiments are intended to facilitate the understanding of the present invention and do not have any limiting effect on it. All features disclosed in the embodiments of the present invention, or all steps in the methods or processes disclosed, except for mutually exclusive features and / or steps, can be combined in any way.

[0067] Embodiment 1 Double-sided flexible sensor provided by the present invention

[0068] The structure of the double-sided flexible sensor provided in this embodiment is as follows Figures 1 to 3 As shown, Figure 1 It is a non-folding double-sided flexible sensor. Figure 2 It is a foldable double-sided flexible sensor. Figure 3 The internal multi-layer structure of the double-sided flexible sensor.

[0069] like Figure 1 As shown, the non-folding double-sided flexible sensor itself is a fold line type, and can be combined with other components without bending or folding during the final assembly. The non-folding double-sided flexible sensor includes a flexible substrate 1, which is divided into a front end 2 (the part implanted in the human body) and a rear end 3. The flexible substrate 1 is a planar structure, including a first surface 4 and a second surface 5. The first surface 4 of the flexible substrate 1 includes a first electrode 6 and a first connection position 7, and the second surface 5 includes a second electrode 8 and a second connection position 9; the detection parts of the first electrode 6 and the second electrode 8 are both located at the front end 2; the first connection position 7 and the second connection position 9 are both located at the rear end 3.

[0070] like Figure 2As shown, the foldable double-sided flexible sensor is a planar structure as a whole, and also includes a front end 12 and a rear end 13. Whether the sensor needs to be bent during the final assembly (mainly refers to the rear end 13 being folded relative to the front end 12) so as to be combined with other components. The foldable double-sided flexible sensor includes a flexible substrate 11, which is divided into a front end 12 (the part implanted in the human body) and a rear end 13. The flexible substrate 11 is a planar structure, including a first surface 14 and a second surface 15. The first surface 14 of the flexible substrate 11 includes a first electrode 16 and a first connection position 17, and the second surface 15 includes a second electrode 18 and a second connection position 19; the detection parts of the first electrode 16 and the second electrode 18 are both located at the front end 12; the first connection position 17 and the second connection position 19 are both located at the rear end 13.

[0071] like Figure 3 As shown, the internal structure of the double-sided flexible sensor (including the non-folding double-sided flexible sensor and the folding double-sided flexible sensor) is a multi-layer structure, and the most basic structure in the middle is the flexible substrate 1. On the first side of the flexible substrate 1, a conductive layer 21 and an electrocatalytic layer 22 are also prepared; on the second side, a conductive layer 21 and a silver-silver chloride layer 23 are also prepared. At the front end of the double-sided flexible sensor, the first side further includes a bioactive molecule layer 24 (only at the front end) on the basis of the flexible substrate 1, the conductive layer 21, and the electrocatalytic layer 22, and the first side also includes a multifunctional polymer outer membrane 25 (both at the front end and the back end); the second side further includes a multifunctional polymer outer membrane 25 (both at the front end and the back end) on the basis of the flexible substrate 1, the conductive layer 21, and the silver-silver chloride layer 23.

[0072] The flexible substrate 1 can be made of polyethylene terephthalate, polyethylene naphthalate, polycarbonate or polyimide, with a thickness of 50-200 μm. In this embodiment, the flexible substrate 1 is preferably made of polyimide with a thickness of 150 μm.

[0073] The conductive layer 21 can be carbon, gold, platinum, titanium or chromium, with a thickness of 1-10μm. In this embodiment, gold is used to prepare the conductive layer 21, with a thickness of 1μm; the electrocatalytic layer 22 is carbon nanotubes, graphene, platinum, iridium, rhodium, titanium or osmium, with a thickness of 1-1000nm, and in this embodiment, a platinum layer is preferably used, with a thickness of 50nm; the thickness of the silver-silver chloride layer 23 is 10-30μm, and in this embodiment, it is preferably 20μm; the bioactive molecule layer 24 is an enzyme, protein, microorganism or DNA, with a thickness of 5μm, and in this embodiment, an enzyme layer such as glucose oxidase is preferably used, with a thickness of 5μm; the multifunctional polymer outer membrane 25 is polyurethane, polyvinyl chloride, Nafion, chitosan or zwitterionic polymer, with a thickness of 10μm, and in this embodiment, it is preferably a polyurethane outer membrane with a thickness of 10μm.

[0074] The flexible sensor provided in this embodiment is subjected to texturing treatment on the surface of the flexible substrate 1, including the first surface, the second surface, and both the front end and the rear end of the flexible substrate 1, so as to improve the adhesion between the flexible substrate 1 and the conductive layer 21.

[0075] The thickness of the flexible substrate 1 is 50-200 μm, and the depth of the texture on both sides is 1-10 μm. In this embodiment, the thickness of the flexible substrate 1 is preferably 150 μm, and the depth of the texture on both sides is 5 μm. The texture is obtained by laser etching. The specific operating conditions are: using an ultraviolet picosecond laser, the power is 10W, the cutting speed is 600 mm / s, and the number of cuttings is 3 times. The texture pattern is vertical lines (such as Figure 4 ), the line width of the vertical line is 20-25 μm, and the interval between two vertical lines is 30-50 μm. In this embodiment, the line width of the vertical line is 20 μm, and the interval between two vertical lines is 30 μm.

[0076] The textured pattern on the first surface of the flexible substrate 1 is a double textured pattern, which includes a vertical line pattern and a circular ring pattern (such as Figure 5 ), which has a limiting effect on the enzyme layer, thereby making the combination more secure. Each circular ring pattern is composed of a group of concentric rings, the diameter of the concentric rings gradually increases from the inside to the outside, the distance between two adjacent concentric rings is 30 to 50 μm, and the depth of the concentric rings is 1-10 μm. In this embodiment, the minimum ring diameter of each circular ring pattern is 30um (radius 15um), and the diameter of the second small ring is 90um (radius 45um), that is, the distance between two adjacent rings is 30um, and the distance is extrapolated in sequence. In this embodiment, the maximum ring diameter is 270um, and the width of the first surface of the flexible substrate 1 is 350um and the length is 8000um.

[0077] The method for preparing the textured flexible sensor provided in this embodiment comprises the following steps:

[0078] (1) performing texturing treatment on both sides of the flexible substrate 1 by laser etching to obtain a textured flexible substrate 1;

[0079] (2) preparing a conductive layer 21 and an electrocatalytic layer 22 on the first surface 4 of the flexible substrate 1 by a magnetron sputtering method;

[0080] (3) preparing a conductive layer 21 and a silver layer on the second surface 5 of the flexible substrate by a magnetron sputtering method, and preparing a silver-silver chloride layer 23 by chlorination;

[0081] (4) introducing the bioactive molecule layer 24 at the front end 5 of the first surface 4 through the enzyme spot device;

[0082] (5) After protecting the connection sites 7 and 9, the first surface 4 and the second surface 5 are spin-coated with a multifunctional polymer outer film 25;

[0083] (6) Laser cutting obtains Figure 1 or Figure 2 A double-sided flexible sensor of a specific shape is shown.

[0084] Example 2 Preparation of double-sided flexible glucose sensor

[0085] This embodiment provides a double-sided flexible glucose sensor, and the preparation method thereof is as follows:

[0086] (1) A polyimide substrate (thickness 150 μm) with a size of 15*15 cm was textured on both sides by laser etching (the textured pattern was a vertical line pattern as described in Example 1, and a double textured pattern of superimposed concentric ring patterns was performed on the front end of the first surface), and the texture depth was 5 μm;

[0087] (2) cleaning the flexible substrate with anhydrous ethanol and deionized water;

[0088] (3) preparing a conductive gold layer and an electrocatalytic platinum layer on the first surface by magnetron sputtering, with thicknesses of 1 μm and 50 nm respectively;

[0089] (4) preparing a conductive gold layer and a silver layer on the second surface, with thicknesses of 1 μm and 20 μm respectively, to protect the rear connection position;

[0090] (5) immersing the silver layer on the second side in a 0.30 mol / L potassium chloride solution and applying a constant current of 5 μA for 60 min to complete chlorination;

[0091] (6) According to the laser cutting pattern, glucose oxidase is introduced into the first front end through the enzyme spot device, and the cross-linking agent glutaraldehyde is added to the enzyme solution. Glutaraldehyde vapor cross-linking can also be used. The glucose oxidase introduced at each position is about 20 μg;

[0092] (7) After protecting the rear connection position, spin-coat the first and second surfaces with a polyurethane outer film, using a 5% polyurethane solution (400 rpm, 30 s);

[0093] (8) Double-sided flexible electrodes can be obtained by laser cutting;

[0094] (9) Connect the first connection point and the second connection point of the sensor to the detection circuit board through the conductive component, and then cooperate with the corresponding detection equipment. The working electrode of CHI 660e is connected to the working electrode of the double-sided flexible sensor, and the reference electrode and the auxiliary electrode are short-circuited and then connected to the reference electrode of the double-sided flexible sensor. Set the constant potential to 0.5V, and the obtained it results are as follows Figure 5 As shown in Figure 2, within the glucose concentration range of 0-30 mol / L, the linear correlation coefficient can reach 0.999.

[0095] Example 3 Effect of Texturing on Flexible Substrates

[0096] In this embodiment, a double-sided flexible glucose sensor is prepared according to the method of Example 2, wherein the flexible substrate is divided into four cases, the first case: only polyimide is used as the flexible substrate, and no vertical line texturing is performed; the second case: polyimide is used as the flexible substrate, and only the vertical line texturing is performed on the first side; the third case: polyimide is used as the flexible substrate, and only the vertical line texturing is performed on the second side; the fourth case: polyimide is used as the flexible substrate, and both the first side and the second side are texturing vertical lines; the fifth case: according to the double-sided flexible sensor provided by CN202111135598.1, an insulating layer of Parylene C is added on both sides of the flexible substrate, the thickness of the flexible substrate is consistent with the others, and the thickness of the insulating layer Parylene C is 20μm. The line width of the vertical line is 20μm, the interval between the two vertical lines is 30μm, and the depth is 5μm. The four flexible substrates prepared were tested for flexibility / bending resistance and adhesion to the conductive layer. The testing method for flexibility / bending resistance referred to the bending method in the test method for metal plating bonding force in SJ1282-1977. The specific testing method was to bend the sensor until the two surfaces formed a 90° angle, and bend it repeatedly until it broke. The coating was observed with the naked eye or a 4-5 times magnifying glass to see whether it was peeling or falling off, and then evaluated by scoring. A score of 95 or more represented very good flexibility and no breakage during the bending process. A score of 90 or more represented good flexibility and 1 to 5 breakages occurred during 50 bendings. A score of 80 or more represented average flexibility and 5 to 10 breakages occurred during 50 bendings. A score of 70 or more represented average flexibility and 10 to 20 breakages occurred during 50 bendings. A score of less than 60 represented poor flexibility and more than 20 breakages occurred during 50 bendings.The detection method for the adhesion of the conductive layer refers to the scratch method in SJ 1282-1977. The specific detection method is to use a steel knife tip to scratch several scratches deep into the substrate on the surface of the part. These scratches are parallel and staggered (the distance between two lines is not more than 2 mm). Use the naked eye or a 4-5 times magnifying glass to observe whether the coating is peeling or falling off, and then evaluate it by scoring. 95 points or more represent very good adhesion, without peeling or falling off. 90 points or more represent good adhesion. Peeling or falling off occurs 1 to 5 times out of 50 times during the scratching process. The adhesion is good, and peeling and falling phenomena occur 5 to 10 times out of 50 times during the scratching process. The adhesion is good, and peeling and falling phenomena occur 10 to 20 times out of 50 times during the scratching process. The adhesion is poor, and peeling and falling phenomena occur more than 20 times out of 50 times during the scratching process. The four prepared double-sided flexible glucose sensors are connected to the detection circuit board through the conductive component to connect the first connection position and the second connection position, and then cooperate with the corresponding detection equipment. The working electrode of CHI 660e is connected to the working electrode of the double-sided flexible sensor, and the reference electrode is short-circuited with the auxiliary electrode and connected to the reference electrode of the double-sided flexible sensor. The constant potential is set to 0.5V, and the glucose concentration of a known concentration of 20mol / L is repeatedly detected in batches. The detection results are shown in Table 1.

[0097] Table 1. Detection results of double-sided flexible glucose sensors prepared using four flexible substrates

[0098]

[0099] As can be seen from Table 1, the textured double-sided flexible glucose sensor prepared by the fourth flexible substrate has better performance and detection ability. Compared with the first type without texturing treatment and the second and third types with texturing treatment on one side of the base layer polyimide, the performance and detection ability of the flexible substrate are significantly better. Therefore, it is most preferred that both sides of the fourth type are textured, that is, both sides of the base layer polyimide are textured at the same time, which can significantly improve the flexibility and bending resistance of the flexible substrate, and at the same time can also improve the adhesion to the conductive layer / electrocatalytic layer. When conducting multiple batches of glucose concentration detection, the stability of batch-to-batch detection is greatly improved, and the detection results are more accurate.

[0100] In addition, by comparing the first, fourth and fifth types, it can be seen that the texturing treatment on both sides provided by the present invention (the fourth type) can perfectly replace the previous method of preparing double-sided flexible sensors (the fifth type), and the flexible substrate surface does not need to be pasted with an insulating layer to achieve very good conductive layer / electrocatalytic layer adhesion, making the prepared double-sided flexible sensor thinner, better in performance, lower in cost, and more stable and accurate in detection results.

[0101] Example 4 Selection of substrate

[0102] In this embodiment, a double-sided flexible glucose sensor is prepared according to the method of Example 2, wherein the substrates are polyethylene terephthalate, polyethylene naphthalate, polycarbonate, polyimide, polyparaxylene, poly(dimethylaminoethyl methacrylate), and polyvinyl alcohol with a thickness of 150 μm respectively, and both sides are subjected to vertical line texturing with a depth of 5 μm, wherein the line width of the vertical line is 20 μm, and the interval between two vertical lines is 30 μm. The flexibility / bending resistance and adhesion to the conductive layer of the flexible substrates made of different substrates were investigated. The detection method for flexibility / bending resistance was referred to the bending method in the test method for metal plating binding force in SJ 1282-1977, and the detection method for adhesion to the conductive layer was referred to the scratch method in the test method for metal plating binding force in SJ 1282-1977; the double-sided flexible glucose sensor made of different substrates was connected to the detection circuit board through the conductive component, and then matched with the corresponding detection equipment, the working electrode of CHI 660e was connected to the working electrode of the double-sided flexible sensor, and the reference electrode and the auxiliary electrode were short-circuited and connected to the reference electrodes of the double-sided flexible sensor. The constant potential was set to 0.5V, and the glucose concentration of a known concentration of 20mol / L was repeatedly detected in batches. The detection results are shown in Table 2.

[0103] Table 2. Detection results of double-sided flexible glucose sensors prepared with different substrates

[0104]

[0105] As can be seen from Table 2, when the substrate is made of polyethylene terephthalate, polyethylene naphthalate, polycarbonate, or polyimide, its flexibility and bending resistance are better, its adhesion to the conductive layer is smaller, its CV% is smaller, and the test results are more stable and more accurate. Among them, polyimide is the most preferred, which can greatly improve the stability of batch-to-batch testing and make the test results more accurate.

[0106] Example 5 Selection of substrate texture pattern

[0107] In this embodiment, a double-sided flexible glucose sensor was prepared according to the method of Example 2, wherein the substrate was made of polyimide, and both sides were textured, with a depth of 5 μm, a line width of 20 μm, and a spacing of 30 μm between two lines. The substrate was textured with different patterns (such as Figure 6 ), the horizontal line refers to the length direction of the textured line perpendicular to the front end of the electrode, and the vertical line ( Figure 6 (d) refers to the length direction of the textured lines parallel to the front end of the electrode, dot-dash lines, dot matrix ( Figure 6 (i))、dashed line( Figure 6 (j)) are all lines parallel to the length direction of the flexible substrate. The grid lines are composed of lines parallel to the length direction of the flexible substrate and lines perpendicular to the length direction of the flexible substrate. The oblique lines ( Figure 6 (e)) is a line with an angle of 45 degrees to the length direction of the flexible substrate. The distance between the two lines is 30 μm. The flexibility / bending resistance and adhesion to the conductive layer of the flexible substrates made with different textured patterns were investigated. The detection method for detecting flexibility / bending resistance refers to the bending method in the test method for the binding force of metal plating in SJ 1282-1977, and the detection method for detecting the adhesion to the conductive layer refers to the scratch method in the test method for the binding force of metal plating in SJ 1282-1977; the double-sided flexible glucose sensor thus prepared connects the first connection position and the second connection position to the detection circuit board through the conductive component, and then cooperates with the corresponding detection equipment, the working electrode of CHI 660e is connected to the working electrode of the double-sided flexible sensor, and the reference electrode is short-circuited with the auxiliary electrode and then connected to the reference electrode of the double-sided flexible sensor. The constant potential was set to 0.5V, and the glucose concentration of a known concentration of 20 mol / L was repeatedly detected in batches. The test results are shown in Table 3.

[0108] Table 3. Detection results of double-sided flexible glucose sensors with different texture patterns

[0109]

[0110] It can be seen from Table 3 that the selection of different textured patterns has a certain influence on the performance of the prepared flexible substrate and the stability of the batch detection when the prepared flexible sensor is tested. When the texture pattern is a diagonal line, a grid line, and a horizontal line, the flexibility of the flexible substrate deteriorates, the bending resistance decreases, and the accuracy and stability of the detection may be affected; when the pattern is a dot matrix, a dotted line, and a dotted line, the bending resistance is improved, but still not as good as the vertical line; only when the pattern is a vertical line, it has better bending resistance, good flexibility, and the detection result is more stable and accurate. Therefore, the substrate texture pattern is preferably a vertical line.

[0111] Example 6 Selection of substrate thickness and texturing depth

[0112] In this embodiment, a double-sided flexible glucose sensor is prepared according to the method of Example 2, wherein the substrate is polyimide, and the vertical lines are textured on both sides. The substrate has different thicknesses and the texturing has different depths. The width of the vertical lines is 20 μm, and the interval between the two vertical lines is 30 μm. The flexibility / bending resistance and the adhesion to the conductive layer of the flexible substrates prepared with different substrate thicknesses and different texturing depths are investigated. The detection method for detecting flexibility / bending resistance refers to the bending method in the test method for metal plating binding force in SJ1282-1977, and the detection method for detecting adhesion to the conductive layer refers to the scratch method in the test method for metal plating binding force in SJ 1282-1977; the double-sided flexible glucose sensor thus prepared connects the first connection position and the second connection position with the detection circuit board through the conductive component, and then cooperates with the corresponding detection equipment, the working electrode of CHI 660e is connected to the working electrode of the double-sided flexible sensor, and the reference electrode is short-circuited with the auxiliary electrode and then connected to the reference electrode of the double-sided flexible sensor. The constant potential was set at 0.5 V, and the glucose concentration with a known concentration of 20 mol / L was repeatedly tested in batches. The test results are shown in Table 4.

[0113] Table 4. Detection results of double-sided flexible glucose sensors prepared with different substrate thicknesses and texturing depths

[0114]

[0115] As can be seen from Table 4, the selection of different substrate thicknesses and different texturing depths has a very important influence on the performance of the prepared flexible substrate and the stability of the batch detection of the prepared flexible sensor. When the substrate thickness increases and the texturing depth decreases, the flexibility of the flexible substrate deteriorates and may affect the accuracy and stability of the detection; when the overall thickness is thin, especially when the texturing depth is small, the bending resistance decreases, thereby affecting the stability of the detection; only when the substrate thickness increases and the texturing depth is appropriate, it is more solid, has better bending resistance, and has good flexibility, and the detection results are more stable and accurate. Therefore, the thickness of the substrate is preferably 50-200μm, the texturing depth of both sides is preferably 1-10μm, and the most preferred thickness of the substrate is 150μm and the texturing depth of both sides is 5μm.

[0116] Example 7 Selection of substrate texturing interval

[0117] In this embodiment, a double-sided flexible glucose sensor is prepared according to the method of embodiment 2, wherein the substrate is polyimide, and vertical lines are textured on both sides. The substrate adopts different texture intervals, that is, the spacing between adjacent lines is different. An ultraviolet picosecond laser is used, and its fixed line width is basically 20μm, so the flexibility / bending resistance and adhesion to the conductive layer of the flexible substrate prepared with different texture intervals of 25-200μm are examined. The detection method for detecting flexibility / bending resistance refers to the bending method in the test method for metal plating binding force in SJ 1282-1977, and the detection method for detecting adhesion to the conductive layer refers to the scratch method in the test method for metal plating binding force in SJ 1282-1977; the double-sided flexible glucose sensor thus prepared connects the first connection position and the second connection position with the detection circuit board through the conductive component, and then cooperates with the corresponding detection equipment, the working electrode of CHI 660e is connected to the working electrode of the double-sided flexible sensor, and the reference electrode is short-circuited with the auxiliary electrode and then connected to the reference electrode of the double-sided flexible sensor. The constant potential was set at 0.5 V, and the glucose concentration with a known concentration of 20 mol / L was repeatedly tested in batches. The test results are shown in Table 5.

[0118] Table 5. Detection results of double-sided flexible glucose sensors prepared with substrates and insulating reinforcement layers of different thicknesses

[0119]

[0120] It can be seen from Table 5 that different texturing intervals have a very important influence on the performance of the prepared flexible substrate and the stability of the batch detection of the prepared flexible sensor. When the texturing interval is 20μm, it is equivalent to the flexible substrate being completely peeled off by one layer, and the flexibility and adhesion of the prepared electrode are not the best effect; when the texturing interval gradually increases, the bending resistance and the adhesion of the conductive layer decrease, thereby affecting the stability of the detection; only when the texturing interval is appropriate, it is more solid, has better bending resistance, and has good flexibility, and the detection results are more stable and accurate. Therefore, the most preferred texturing interval on both sides of the substrate is 30μm.

[0121] Example 8 Double texturing of the front end of the electrode

[0122] In this embodiment, a double-sided flexible glucose sensor was prepared according to the method of Example 2, wherein the substrate was made of polyimide, the thickness of the substrate was 150 μm, the texture depth of both sides was 5 μm, the pattern was vertical lines, and the texture interval was 30 μm, as a control example. On this basis, some substrates were further added with multiple circular textures (such as Figure 7(d)) with a texture depth of 5 μm, a vertical line pattern, and a texture interval of 30 μm as an experimental example. The long-term stability of the control example and the experimental example was investigated. The double-sided flexible glucose sensor thus prepared was implanted in the human body. The current response curve of glucose in the body for 7 consecutive days is shown in the figure. Figure 8 shown.

[0123] Depend on Figure 8 It can be seen that the gray curve is a control example. As time goes by, the baseline drifts and there are more impurities. The black curve is an experimental example. During the entire test, the baseline is stable, there are few impurities, and the stability is good. This shows that adding multiple circular textures at the place where the bioactive molecules are introduced can effectively improve the long-term stability of the bioactive molecules.

[0124] The application of the present invention is not limited thereto. For example, the scope of application of the present invention can be expanded according to the environmental protection aspect. Any person skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the scope defined by the claims.

Claims

1. A use of a flexible substrate for preparing a double-sided flexible glucose sensor for improving the accuracy of glucose concentration detection, characterized in that: The surface of the flexible substrate has a textured pattern; the textured pattern is a vertical line, and the vertical line is a line parallel to the length direction of the flexible substrate; the material of the flexible substrate is polyimide; the flexible substrate is a flat structure, having two upper and lower surfaces, namely a first surface and a second surface, and both the first surface and the second surface are subjected to vertical line treatment; the double-sided flexible glucose sensor comprises a flexible substrate and a conductive layer, and the conductive layer is adhered to the surface of the flexible substrate; the texture treatment refers to treatment by any one or more methods of laser etching, plasma etching or wet etching; the thickness of the flexible substrate is 150 μm; Conductive layers are adhered to the first surface and the second surface respectively; the texturing depth is 5μm; the line width of the vertical line is 20μm, and the interval between two vertical lines is 30μm; the first surface also includes a bioactive molecule layer, and the bioactive molecule layer is located on the outside of the conductive layer; the textured pattern of the first surface is a double textured pattern, and a circular ring pattern is provided on the basis of the vertical line pattern; each circular ring pattern is composed of a group of concentric rings, and the diameter of the concentric rings gradually increases from the inside to the outside, the distance between two adjacent concentric rings is 30 to 50μm, and the depth of the concentric rings is 1-10μm.

2. A double-sided flexible sensor, characterized in that: The invention comprises a flexible substrate and a conductive layer, wherein the conductive layer is adhered to the surface of the flexible substrate; the surface of the flexible substrate has a textured pattern; the textured pattern is a vertical line, and the vertical line is a line parallel to the length direction of the flexible substrate; the material of the flexible substrate is polyimide; the flexible substrate is a flat structure, and has two upper and lower surfaces, which are respectively a first surface and a second surface, and the first surface and the second surface are both processed with vertical lines; the material of the flexible substrate is polyimide; the flexible substrate is a flat structure, and has two upper and lower surfaces, which are respectively a first surface and a second surface, and the first surface and the second surface are both processed with vertical lines; the thickness of the flexible substrate is 150 μm; Conductive layers are adhered to the first surface and the second surface respectively; the texturing depth is 5μm; the line width of the vertical line is 20μm, and the interval between two vertical lines is 30μm; the texturing treatment refers to treatment by any one or more methods of laser etching, plasma etching or wet etching; the first surface also includes a bioactive molecule layer, and the bioactive molecule layer is located on the outside of the conductive layer; the textured pattern of the first surface is a double textured pattern, and a circular ring pattern is also provided on the basis of the vertical line pattern.

3. The flexible sensor according to claim 2, characterized in that: Each circular ring pattern is composed of a group of concentric rings, the diameters of the concentric rings gradually increase from the inside to the outside, the distance between two adjacent concentric rings is 30-50 μm, and the depth of the concentric rings is 1-10 μm.

4. The use of the textured pattern of vertical lines for preparing a double-sided flexible glucose sensor for improving the accuracy of glucose concentration detection, characterized in that: The double-sided flexible glucose sensor comprises a flexible substrate and a conductive layer, wherein the conductive layer is adhered to the surface of the flexible substrate; the surface of the flexible substrate has a textured pattern; the textured pattern is a vertical line, and the vertical line is a line parallel to the length direction of the flexible substrate; the material of the flexible substrate is polyimide; the flexible substrate is a flat structure, having an upper and lower surface, which are respectively a first surface and a second surface, and the first surface and the second surface are both processed with vertical lines; the material of the flexible substrate is polyimide; the flexible substrate is a flat structure, having an upper and lower surface, which are respectively a first surface and a second surface, and the first surface and the second surface are both processed with vertical lines; the thickness of the flexible substrate is 150 μm; Conductive layers are adhered to the first surface and the second surface respectively; the texturing depth is 5μm; the line width of the vertical line is 20μm, and the interval between two vertical lines is 30μm; the texturing treatment refers to treatment by any one or more methods of laser etching, plasma etching or wet etching; the first surface also includes a bioactive molecule layer, and the bioactive molecule layer is located on the outside of the conductive layer; the textured pattern of the first surface is a double textured pattern, and a circular ring pattern is also provided on the basis of the vertical line pattern.

Images