Biocompatible selective outer membrane of implantable biosensor and preparation method of biocompatible selective outer membrane

Abstract

The invention provides a biocompatible selective outer membrane of an implantable biosensor and a preparation method of the biocompatible selective outer membrane, and the preparation method comprises the following steps: preparing an outer membrane diluent, and respectively dissolving a PS-P4VP copolymer, NH2-PEG-NH2 and PEGDGE in the outer membrane diluent to obtain a mixed solution; the ratio of PS to P4VP of the PS-P4VP copolymer is (0.5: 9.5)-(3: 7); coating the surface of an enzyme layer of the in-vivo implanted sensor with the mixed solution, and curing for 48-56 hours at normal temperature, so that an amino group of NH2-PEG-NH2 and a pyridine group of P4VP form a dynamic covalent bond to obtain an inner layer; the inner layer is immersed in deionized water for 1.5 h or above, the uncrosslinked PEG derivative is eluted, and a porous inner layer is obtained; and coating the surface of the porous inner layer with a polysulfobetaine solution to obtain the hydrophobic antifouling coating. By adopting the technical scheme, the mechanical strength and the long-term stability are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of biomaterials, and in particular to a biocompatible selective outer membrane of an implantable biosensor and a preparation method thereof. Background Art

[0002] Traditional in vivo analyte sensors (such as continuous glucose monitoring systems, CGMS) are mainly based on enzyme electrode structures, with glucose sensors being a typical example. Their core consists of: (1) an enzyme layer (such as glucose oxidase, GOx): catalyzing the oxidation of glucose to produce electroactive products (such as H2O2). (2) a mediator layer (such as osmium-based polymers): transferring electrons to the electrode to enhance signal stability. (3) a selective outer membrane: controlling the diffusion rate of the analyte (glucose), reducing the effects of interfering substances (such as uric acid and ascorbic acid), and preventing bioadhesion, such as the adhesion of proteins in the body, which blocks the sensor's material transfer channel.

[0003] However, existing sensors suffer from membrane performance deficiencies, primarily due to rapid drying and poor hydrophilic-hydrophobic balance. The traditional polystyrene-poly(4-vinylpyridine) (PS-P4VP) membrane is prone to rapid solvent evaporation during film formation, resulting in uneven membrane structure and affecting analyte permeability selectivity. Excessive hydrophobicity (e.g., a high proportion of PS) can hinder the diffusion of small molecules (e.g., glucose), while excessive hydrophilicity (e.g., a high proportion of P4VP) can accelerate bioadhesion.

[0004] Chinese patent CN117582218A discloses the use of a multi-enzyme layer stacking design (such as GOx + lactate oxidase LOx), combined with different selective outer membranes, to achieve simultaneous monitoring of glucose and lactate. The response signals of different analytes are distinguished by potential or current signal separation technology (such as different oxidation potential mediators). The outer membrane material uses PS-P4VP copolymer as the outer membrane matrix, and balances the hydrophilicity and hydrophobicity by adjusting the ratio of styrene (PS) and 4-vinylpyridine (P4VP). A porogen (such as PEG) is added to form a microporous structure, but the patented technology does not solve the problem of membrane performance attenuation caused by PEG residue or incomplete elution. Although other existing technologies have attempted multi-analyte integration and membrane material improvement, they are still limited by outer membrane process defects and porogen residue problems, and mechanical strength and long-term stability need to be improved. Summary of the Invention

[0005] In response to the above technical problems, the present invention discloses a biocompatible selective outer membrane of an implantable biosensor and a preparation method thereof, which improves the mechanical strength and long-term stability of the outer membrane by improving the outer membrane material.

[0006] To this end, the technical solution adopted in the present invention is:

[0007] A method for preparing a biocompatible selective outer membrane of an implantable biosensor comprises the following steps:

[0008] Step S1, preparing an outer membrane diluent, dissolving a PS-P4VP copolymer, NH2-PEG-NH2, and PEGDGE in the outer membrane diluent to obtain a mixed solution; the ratio of the PS-P4VP copolymer is PS:P4VP=0.5:9.5 to 3:7; the molecular weight of the NH2-PEG-NH2 is not greater than 20,000;

[0009] Step S2, applying the mixed solution to the surface of the enzyme layer of the sensor implanted in vivo, curing at room temperature for 48 to 56 hours to form a dynamic covalent bond between the amino group of NH2-PEG-NH2 and the pyridine group of P4VP to obtain an inner layer; immersing the inner layer in deionized water for more than 1.5 hours to elute the uncross-linked PEG to obtain a porous inner layer;

[0010] Step S3, coating the surface of the porous inner layer with a polysulfobetaine solution, and drying the solution to obtain a hydrophobic antifouling coating.

[0011] The present invention utilizes a PS-P4VP copolymer with a PS:P4VP ratio of 0.5:9.5 to 3:7 to balance hydrophilicity and hydrophobicity, slowing solvent evaporation. Low-molecular-weight NH2-PEG-NH2 is introduced as a crosslinker and porogen, whose terminal amino groups react with the crosslinker to form irreversible bonds. This dynamic crosslinking network modulates membrane curing kinetics, resulting in a stable, interconnected porous structure. This prevents residual PEG from interfering with permeation selectivity, resulting in a uniform, defect-free outer membrane structure and enhanced mechanical strength and long-term stability. This, combined with an elution process, allows for efficient elution of the porogen, resulting in a uniform, defect-free outer membrane structure. A hydrophilic inner layer and a hydrophobic outer layer create a hydrophilic-hydrophobic gradient design for the outer membrane. The hydrophobic outer layer prevents fouling, while the hydrophilic inner layer facilitates diffusion, enabling the permeation rate of analytes such as glucose and lactate to be individually controlled. This selective outer membrane, coated on the surface of the enzyme layer and spatially isolated from the enzyme layer, reduces H2O2 diffusion crosstalk, enabling highly specific and simultaneous detection of multiple analytes such as glucose, lactate, and ketone bodies. Introducing zwitterionic polymers (such as polysulfobetaine) into the outer membrane can reduce nonspecific protein adsorption, extend the in vivo service life of the sensor, and reduce signal drift.

[0012] As a further improvement of the present invention, the ratio of PS to P4VP in the PS-P4VP copolymer is 1:9, and the molecular weight is 200,000 Daltons.

[0013] As a further improvement of the present invention, the molecular weight of the NH2-PEG-NH2 is 10,000 Daltons. Furthermore, the molecular weight of the PEGDGE is 500 Daltons.

[0014] As a further improvement of the present invention, in step S1, the outer membrane dilution solution is a 10 mM HEPES buffer solution containing ethanol.

[0015] As a further improvement of the present invention, in the mixed solution of step S1, the molar ratio of the active functional groups pyridine, amino, and epoxy of the PS-P4VP copolymer, NH2-PEG-NH2, and PEGDGE is 5000-7000:1:500-1000. Furthermore, in the mixed solution of step S1, the molar ratio of the active functional groups pyridine, amino, and epoxy of the PS-P4VP copolymer, NH2-PEG-NH2, and PEGDGE is 5000-7000:1:800-1000.

[0016] As a further improvement of the present invention, in step S1, the volume ratio of ethanol to HEPES buffer solution is 4:1.

[0017] As a further improvement of the present invention, in step S2, the water washing step involves immersing the inner membrane in deionized water for at least 2 hours at a temperature of 25-40°C. This technical solution can completely remove residual PEG small molecules, retaining intact pores (pore diameter 50-200 nm), and avoiding membrane collapse caused by traditional high-temperature treatment.

[0018] As a further improvement of the present invention, the concentration of the polysulfobetaine solution is 1-5 wt %, and the coating thickness is 10-500 nm.

[0019] As a further improvement of the present invention, the thickness of the inner hydrophilic region is 8-12 μm.

[0020] The invention discloses a method for preparing a biocompatible selective outer membrane of an implantable biosensor. The method for preparing the biocompatible selective outer membrane of an implantable biosensor is used to prepare the membrane.

[0021] As a further improvement of the present invention, the thickness of the inner hydrophilic region is 8-12 μm, and the thickness of the outer hydrophobic antifouling region is 10-500 nm.

[0022] The invention discloses an implantable biosensor, which comprises an electrode layer, an enzyme layer, a selective outer membrane layer and an antifouling layer in sequence. The selective outer membrane layer adopts the biocompatible selective outer membrane of the implantable biosensor as described above.

[0023] Furthermore, the electrode layer consists of a working electrode (WE), a counter electrode (CE), and a reference electrode (RE). The working electrode can be a carbon-printed electrode. The enzyme layer uses glucose oxidase (GOx) cross-linked and solidified on the surface of the carbon-printed electrode to catalyze glucose to produce H2O2. The electron transfer agent in the enzyme transfers electrons from the enzyme surface to the electrode surface, generating a current signal.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] First, the present invention's technical solution utilizes a PS-P4VP copolymer (polystyrene-poly-4-vinylpyridine) in a 1:9 ratio, significantly improving cracking during the outer membrane drying process compared to the traditional 7:3 ratio. It also forms a uniform, defect-free outer membrane structure, enhancing mechanical strength and long-term stability. The PEG derivative NH2-PEG-NH2 (polyethylene glycol diamine) is introduced as a bifunctional reagent, acting both as a crosslinker to form dynamic covalent bonds with the pyridine groups of PS-P4VP and as a porogen. Through a deionized water elution process (2 hours of efficient elution), pores of 50-200 nm are constructed, reducing the PEG residue to below 0.5% compared to physical mixing methods, while retaining 98% pore integrity.

[0026] Second, the gradient structure and function are coordinated. A layered coating process forms a gradient structure of "hydrophilic inner layer - hydrophobic outer layer": the inner hydrophilic area is composed of cross-linked PS-P4VP and NH2-PEG-NH2, and the pore size changes in a gradient from the inside to the outside, which preferentially promotes the rapid penetration of small molecules such as glucose and lactic acid, while blocking the diffusion of large molecular enzymes (such as GOx, LOx) through the pore size screening effect, thus achieving spatial isolation of the reaction area; the outer hydrophobic antifouling area is sprayed with polysulfobetaine (PSB) zwitterionic polymer, which uses its positive and negative charge balance characteristics to reduce protein adsorption, and reduces the attachment of biological pollutants through hydrophobic interactions, and the antifouling performance is improved by 3 times compared with traditional outer membranes.

[0027] Third, the gradient pore size design of the outer membrane in the technical solution of the present invention can accurately separate the reaction areas of glucose oxidase (GOx) and lactate oxidase (LOx): when the sensor is implanted in the body, glucose and lactic acid quickly penetrate into the enzyme layer through the large pores of the inner layer, while the H202 (diameter of about 0.3nm) generated by the reaction can reversely penetrate the small pore structure of the outer layer, avoiding cross-interference between the two enzyme reaction areas (the H202 crosstalk rate is reduced to less than 3%), significantly improving the detection accuracy of the sensor. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The present invention is a flowchart of a biocompatible selective outer membrane of an implantable biosensor and a preparation method thereof.

[0029] Figure 2FIG. 4 is a schematic structural diagram of a continuous blood glucose sensor according to an embodiment of the present invention.

[0030] Figure 3 This is a comparison diagram of the electrodes coated with outer membranes of Example 2 of the present invention and Comparative Example 2 after the electrodes were pierced through the artificial skin three times via a puncture needle.

[0031] Figure 4 This is a signal intensity test diagram of Example 2 of the present invention when the selective outer membrane is coated on the outside of the enzyme electrode at different glucose concentrations.

[0032] Figure 5 This is a diagram showing the effect of different NH2-PEG-NH2 ratios in the selective outer membrane on the sensor signal in Example 10 of the present invention. DETAILED DESCRIPTION

[0033] The preferred embodiments of the present invention are described in further detail below.

[0034] A biocompatible, selective outer membrane for an implantable biosensor comprises an inner hydrophilic layer and an outer hydrophobic, antifouling layer. The outer layer, comprising PS-P4VP (polystyrene-poly-4-vinylpyridine), NH2-PEG-NH2 (polyethylene glycol diamine), and PEGDGE, is cross-linked and can promote the diffusion of small molecules (glucose, lactic acid). The outer layer incorporates polysulfobetaine (PSB, a zwitterionic polymer) to reduce protein adsorption.

[0035] like Figure 1 As shown, the method for preparing the selective outer membrane comprises the following steps:

[0036] (1) Solution preparation: First, prepare the outer membrane diluent, i.e., 10 mM pH 8.0 HEPES buffer solution containing ethanol, wherein the volume ratio of ethanol to HEPES buffer solution is 4:1. Then, dissolve PS-P4VP (1:9 ratio, molecular weight 20w), NH2-PEG-NH2 (molecular weight 10000), and polyethylene glycol diglycidyl ether PEGDGE (molecular weight 500) in the outer membrane diluent to prepare solutions of 100 mg / mL, 3 mg / mL, and 100 mg / mL, respectively. Then, mix the PS-P4VP solution, NH2-PEG-NH2 solution, and PEGDGE solution in a volume ratio of 24:5:4 to obtain the outer membrane stock solution, and finally dilute the outer membrane stock solution to a certain concentration with the outer membrane diluent.

[0037] (2) Coating film formation: The mixed solution was coated on the surface of the enzyme layer by dip coating (thickness ~10 μm).

[0038] (3) Cross-linking and curing: Curing was performed at room temperature for 48 hours to form dynamic covalent bonds between the amino groups of NH2-PEG-NH2 and the pyridine groups of P4VP.

[0039] (4) PEG elution: The membrane was immersed in deionized water for 2 h, and the uncross-linked PEG was completely eluted to form a porous structure.

[0040] (5) Antifouling layer modification: Polysulfobetaine (PSB) solution is sprayed on the outer layer to form a hydrophobic antifouling coating.

[0041] The selective external mold film of this embodiment has no cracks, and the NH2-PEG-NH2 elution rate is greater than 99%.

[0042] The selective outer film is used in continuous blood glucose sensors with carbon electrodes, such as Figure 2 As shown, the continuous blood glucose sensor includes an electrode layer, an enzyme layer, a selective outer membrane layer and an anti-fouling layer.

[0043] Electrode layer: consists of a working electrode (WE), a counter electrode (CE) and a reference electrode (RE). The working electrode can be a carbon printed electrode.

[0044] Enzyme layer: Glucose oxidase (GOx) is cross-linked and solidified on the surface of the carbon printed electrode to catalyze glucose to produce H2O2. The electron transfer agent is used to transfer electrons from the enzyme surface to the electrode surface to form a current signal.

[0045] After testing, the continuous blood glucose sensor has a glucose response time of less than 5 seconds and a lactate response time of less than 10 seconds.

[0046] Comparative Example 1

[0047] Based on Example 1, the difference of this comparative example is that the outer membrane is obtained by physically mixing PS-P4VP (1:9) and PEG in a solvent, and then coating the outer membrane on the enzyme layer.

[0048] After testing, it was found that the outer membrane of Comparative Example 1 was easily damaged during the membrane formation process, the PEG residual rate was ˜20%, and the membrane stability was poor.

[0049] The electrodes of the continuous blood glucose sensors of Example 1 and Comparative Example 1 were compared after the puncture needle passed through the artificial skin three times. Figure 3 The outer membrane surface of Example 1 is smooth and has no damage.

[0050] Example 2

[0051] Based on Example 1, the difference of this example is that the formula of the selective outer membrane in step (1) is different. The formula components and their mass percentages of this example 2 are detailed in Table 1.

[0052] Comparative Example 2

[0053] The selective outer membrane was prepared using the technical solution adopted in the prior art. The formula components and mass percentages of the outer membrane are shown in Table 1.

[0054] Table 1

[0055]

[0056] The selective outer membrane obtained in Example 2 was coated on the outside of the enzyme electrode. The enzyme electrode coated with the outer membrane was tested for signal strength at different glucose concentrations. The test was carried out in solutions with different glucose concentrations (0, 5, 10, 15, 20, 25 mM). The results are shown in FIG. Figure 4 As shown in the data graph, the CV of the slope K value of about 30 electrodes is about 5%, which shows that the consistency of the selective outer membrane obtained in this embodiment is good.

[0057] Example 3

[0058] The biocompatibility of the selective outer membrane materials of Example 2 and Comparative Example 2 was evaluated by performing cytotoxicity tests (e.g., CCK-8 assay) and animal implantation tests to verify the biosafety of the present invention. In vitro cytotoxicity testing was performed in accordance with the ISO 10993 standard (CCK-8 assay using L929 fibroblasts for sensory cytotoxicity) and in accordance with GB / T 16886.12 (ISO 10993-12:2012), Part 5, In Vitro Cytotoxicity Tests, Biological Evaluation of Medical Devices.

[0059] Experimental group 1: electrode substrate - medical PET (polyethylene terephthalate);

[0060] Experimental group 2: the outer film material of comparative example-comparative example 2 is coated on the electrode substrate;

[0061] Experimental group 3: the outer film material of comparative example - Example 2 of the present invention is coated on the electrode substrate;

[0062] The results obtained are shown in Table 2, which shows that the selective outer membrane of the present invention has better biosafety.

[0063] Table 2

[0064] substrate Substrate + outer film of comparative example 2 Substrate + outer film of Example 2 100% extract 95％ 91％ 99％ 50% extract 97％ 97％ 99％

[0065] Example 4 to Example 7

[0066] Based on Example 1, the difference of this example is that the ratio of PS:P4VP is 3:7, 5:5, 7:3, and 9:1, respectively. The comparison table of the relationship between the outer membrane properties of the obtained PS-P4VP copolymer and the ratio is shown in Table 3.

[0067] The selective outer membrane of Example 1 has a superhydrophobic surface that can inhibit protein / cell adsorption; has dense but controllable small molecule channels (pore size <5nm); can strictly block proteins (>99% BSA retention); ultra-low swelling rate (<5%) ensures the stability of the electrode-membrane interface, and is resistant to body fluid pH fluctuations (pH 5-8) and biological enzyme erosion; high modulus (0.2-0.4GPa) resists tissue extrusion; passes the cytotoxicity test (ISO 10993-5), and PS bioinertness reduces foreign body reactions.

[0068] It can be seen that the selection of PS:P4VP=1:9 as the outer membrane material of the continuous glucose monitoring (CGM) sensor is based on its comprehensive advantages in biocompatibility, anti-fouling, dimensional stability, selective permeability and long-term stability.

[0069] Table 3

[0070]

[0071] The performance of the blood glucose sensor using the selective outer membrane of Example 1, i.e., the outer membrane with PS:P4VP=1:9, was tested and the results were as follows: glucose response time (t 90 ) < 2 minutes, clinical error (MARD) 7.9% (in line with ISO 15197 standard); service life 14 days (in vivo); drift rate (daily) < 0.5%.

[0072] Example 8

[0073] Based on Example 1, the difference of this example is that the PS:P4VP ratio is 0.5:9.5. Example 1, Example 4, Example 5, and Example 8 were subjected to signal attenuation test, and pure PS was used as a control example. The results are shown in Tables 4 and 5. It can be seen that the signal attenuation of Example 1 with a ratio of 1:9 is the smallest, the biological contamination is small, and the physical stability is good. The signal attenuation and other indicators of Example 4 and Example 8 are smaller than those of the control example, but the signal attenuation of Example 5 with a ratio of 5:5 is larger. The 14-day MARD of the ratio of 3:7 to 0.5:9.5 is ≤9.1%, which meets the ISO 15197:2013 standard (<15%); while the 1:9 ratio achieves clinical-grade accuracy (<6%), which is close to zero attenuation.

[0074] Table 4

[0075]

[0076] Table 5

[0077] PS: P4VP Day 1 MARD Day 7 MARD Day 14 MARD Attenuation slope 3：7 6.8％ 7.2％ 7.9％ +0.08% / day 1：9 5.1％ 5.3％ 5.5％ +0.03% / day 0.5：9.5 8.5％ 8.7％ 9.1％ +0.04% / day 5：5 7.2％ 12.5％ 18.3％ +0.79% / day

[0078] Example 9

[0079] Based on Example 1, experiments were conducted with different curing times for step (3) crosslinking and curing. The degree of crosslinking was measured, and the results of the change in crosslinking degree with curing time / depth are shown in Table 6. It can be seen that the outer layer reaches a high degree of crosslinking (70%) after 0.5 h, while the inner layer crosslinking lags significantly (only 12%). A gradient crosslinking is formed between the inner and outer layers. The main reason for this is that the low temperature causes the viscosity of the system to rise rapidly, causing the outer layer to reach the glass transition temperature first and freeze, while the inner layer continues to crosslink due to residual solvent, maintaining fluidity. The natural concentration gradient generated by solvent evaporation during spin coating is utilized, and this difference is amplified in combination with low-temperature curing to achieve gradient crosslinking.

[0080] Table 6

[0081] Curing time External surface crosslinking degree Intermediate layer crosslinking degree Inner layer crosslinking degree 0.5h 72.3±3.1％ 38.5±2.8％ 12.1±1.5％ 1h 85.6±2.5％ 63.2±3.0％ 41.7±2.2％ 2h 92.8±1.8％ 81.4±2.1％ 75.3±1.9％

[0082] Example 10

[0083] Based on Example 1, this example adjusted the formula and analyzed the effect of different NH2-PEG-NH2 ratios of the selective outer membrane on the sensor signal. The results are as follows: Figure 5 As shown in Figure 2, it can be seen that with the increase of NH2-PEG-NH2 content, the current signal becomes more sensitive.

[0084] The above is a further detailed description of the present invention in conjunction with specific preferred embodiments, and the specific implementation of the present invention should not be considered to be limited to these descriptions. For those skilled in the art of the present invention, without departing from the concept of the present invention, several simple deductions or substitutions can be made, which should be considered to fall within the scope of protection of the present invention.

Claims

1. A method for preparing a biocompatible selective outer membrane of an implantable biosensor, characterized in that: The steps include: Step S1, preparing an outer membrane diluent, dissolving a PS-P4VP copolymer, NH2-PEG-NH2, and PEGDGE in the outer membrane diluent to obtain a mixed solution; the ratio of the PS-P4VP copolymer is PS:P4VP=0.5:9.5 to 3:7; the molecular weight of the NH2-PEG-NH2 is not greater than 20,000; Step S2, applying the mixed solution to the surface of the enzyme layer of the sensor implanted in vivo, curing at room temperature for 48 to 56 hours to form a dynamic covalent bond between the amino group of NH2-PEG-NH2 and the pyridine group of P4VP to obtain an inner layer; immersing the inner layer in deionized water for more than 1.5 hours, eluting the uncross-linked PEG derivative, and obtaining a porous inner layer; Step S3, coating the surface of the porous inner layer with a polysulfobetaine solution, and drying the solution to obtain a hydrophobic antifouling coating.

2. The method for preparing the biocompatible selective outer membrane of the implantable biosensor according to claim 1, characterized in that: The ratio of the PS-P4VP copolymer is PS:P4VP=1:9, and the molecular weight of the NH2-PEG-NH2 is 1000-20000.

3. The method for preparing the biocompatible selective outer membrane of the implantable biosensor according to claim 2, characterized in that: The molecular weight of the NH2-PEG-NH2 is 10,000; the molecular weight of the PEGDGE is 500.

4. The method for preparing the biocompatible selective outer membrane of an implantable biosensor according to claim 1, wherein: In step S1, the outer membrane dilution solution is a 10 mM HEPES buffer solution containing ethanol; In the mixed solution of step S1, the molar ratio of the active functional groups pyridine, amino and epoxy of the PS-P4VP copolymer, NH2-PEG-NH2 and PEGDGE is 5000-7000:1:500-1000.

5. The method for preparing the biocompatible selective outer membrane of the implantable biosensor according to claim 4, characterized in that: In the mixed solution of step S1, the molar ratio of the active functional groups pyridine, amino and epoxy of the PS-P4VP copolymer, NH2-PEG-NH2 and PEGDGE is 5000-7000:1:800-1000.

6. The method for preparing the biocompatible selective outer membrane of an implantable biosensor according to claim 1, wherein: In step S1, the volume ratio of ethanol to HEPES buffer solution is 4:1; in step S2, the water washing is to immerse the inner membrane in deionized water for at least 2 hours, and the water washing temperature is 25-40°C.

7. The method for preparing the biocompatible selective outer membrane of an implantable biosensor according to claim 1, wherein: The concentration of the polysulfobetaine solution is 1-5 wt %, the coating thickness is 10-500 nm, and the thickness of the inner hydrophilic region is 8-12 μm.

8. A biocompatible selective outer membrane for an implantable biosensor, characterized in that: The biocompatible selective outer membrane of the implantable biosensor is prepared by the method for preparing the biocompatible selective outer membrane of the implantable biosensor according to any one of claims 1 to 7.

9. The biocompatible selective outer membrane of the implantable biosensor according to claim 8, characterized in that: The thickness of the inner hydrophilic region is 8-12 μm, and the thickness of the outer hydrophobic antifouling region is 10-500 nm.

10. An implantable biosensor, characterized in that: It comprises an electrode layer, an enzyme layer, a selective outer membrane layer and an antifouling layer in sequence, wherein the selective outer membrane layer adopts the biocompatible selective outer membrane of the implantable biosensor according to claim 8 or 9.

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