An electrically conductive polymer having immunocompatibility, monomer, dispersion, and preparation method and application thereof

Abstract

The application relates to the technical field of biomaterials, and discloses a conductive polymer with immunocompatibility, a monomer, a dispersion liquid, and a preparation method and application thereof. The conductive polymer has a structure as shown in formula A or formula B. Raw materials including a conductive polymer monomer, polystyrene sulfonic acid, an inorganic alkali, sodium persulfate and iron sulfate are dispersed in water, and then subjected to oxidation chemical polymerization at 0-50 DEG C for 12-36 h; after ion exchange resin is added for post-treatment, the conductive polymer dispersion liquid is obtained through suction filtration; and polystyrene sulfonic acid and water are removed through drying to obtain the conductive polymer. The material has excellent conductive performance, and after being prepared into a dispersion liquid and coated on the surface of a biological substrate, the material has a low inflammation and foreign body reaction level after being implanted in vivo, has long-term stability, and can be applied to coating materials of implantable bioelectronic devices.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological materials, in particular to a conductive polymer with immunocompatibility, a monomer, a dispersion liquid and a preparation method and application thereof. BACKGROUND

[0002] Advanced implantable bioelectronics has revolutionary potential to provide long-term effective functions at biological interfaces, providing diagnostic and therapeutic capabilities for a wide range of diseases and disorders. Although there has been progress in the field of bioelectronics in recent years, the inherent mismatch between traditional metal electrodes (such as silicon and tungsten, whose modulus exceeds 100 GPa) and soft biological tissues (whose modulus is below 1-100 kPa) makes it difficult to achieve long-term stability and biocompatibility of implants. Therefore, long-term use of metal bioelectrodes often triggers inflammatory reactions, such as the accumulation of metabolically active inflammatory cells or glial cells around the implant, and leads to the implant being wrapped in avascular collagen tissue, thereby severely affecting the efficiency of electrical / optical / thermal / chemical exchange at the interface. This limitation constitutes an important obstacle to the rapid innovation and long-term reliability of implantable bioelectronics.

[0003] Conductive polymers (CPs) are considered as important building blocks in the next generation of bioelectronics due to their good biocompatibility, flexible preparation and relatively low cost. However, conductive polymers such as polyacetylene (PA), polyaniline (PANi), polypyrrole (PPy), polythiophene (PTh) and poly(3,4-ethylenedioxythiophene) (PEDOT) are not designed for complex biological applications. When these synthetic polymers are used in biological systems, one of the main challenges is that the body's immune system will recognize them as foreign bodies and trigger corresponding immune responses.

[0004] Foreign body reactions are a universal phenomenon of immune-mediated inflammation and subsequent fibrotic production of dense fibrous tissue. These fibrous tissues isolate the implant from the surrounding tissue, hindering the exchange of materials between the two, leading to a gradual decrease in the conductivity, stability and functionality of the implanted material, and even eventually leading to the failure of medical electronic devices. The device failure caused by foreign body reactions and the risk of secondary surgery faced by patients are one of the key problems currently limiting the development of implantable bioelectronic devices. Therefore, there is an urgent need for conductive biological materials with the ability to suppress foreign body reactions to achieve long-term in vivo stability of implantable bioelectronic devices.

[0005] Related studies have shown that the use of anti-fouling zwitterionic modified conductive polymer PEDOT can significantly reduce the non-specific protein adsorption on the surface of the material. For example, US20182082472A1 discloses a sulfobetaine (SB) modified PEDOT material PSBEDOT. Since the sulfobetaine has adjacent positive and negative charges in structure, the material has good hydration capacity and can effectively inhibit the non-specific adsorption of proteins. At the same time, PSBEDOT has excellent conductivity, which meets the application requirements of bioelectronic devices. In addition, the phosphocholine (PC) zwitterionic modified PEDOT material PEDOT-PC also has good in vitro anti-protein non-specific adsorption capacity. It is reported that the PEDOT-PC modified electrode can significantly improve the in vivo dopamine detection effect after being implanted in the brain for two hours (Liu, X. et al., Angew. Chem., 2017, 129: 11964-11968).

[0006] However, most of the reported modifications of PEDOT for biomedical applications are based on zwitterionic modification. Although these modifications can significantly reduce the non-specific adsorption of proteins in vitro, so far there has been no report that they can maintain good anti-foreign body reaction ability after long-term implantation in vivo and realize long-term stable function of bioelectronic devices. Therefore, there is an urgent need for a conductive polymer material that can reduce long-term foreign body reaction in vivo. SUMMARY

[0007] The present application aims to solve the problem in the prior art that molecular materials are difficult to achieve both conductivity and immunocompatibility. A conductive polymer monomer with immunocompatibility is provided, which has excellent conductivity and low inflammation and foreign body reaction level after in vivo implantation, and has long-term stability, and can be applied to coating materials for implantable bioelectronic devices.

[0008] To achieve the above object, the technical scheme adopted by the present application is:

[0009] A conductive polymer with immunocompatibility, the conductive polymer has a structure as shown in formula A or formula B:

[0010]

[0011] wherein R is selected from hydrogen or methyl; L1 is -(CH2) n , wherein n is an integer from 0 to 22; x represents the number of repeating units of subunit A, which is an integer from 10 to 1000; y represents the number of repeating units of subunit B, which is an integer from 10 to 1000.

[0012] This invention also provides an immunocompatibility conductive polymer dispersion, comprising the aforementioned conductive polymer, polystyrene sulfonic acid, and deionized water. The polystyrene sulfonic acid is used as a solubilizer to aid dissolution. The mass ratio of polystyrene sulfonic acid to the monomers of the conductive polymer is 1:1 to 6:1, and the amount of deionized water used is sufficient to dissolve the polymer.

[0013] The conductive polymer can be obtained by drying the conductive polymer dispersion to remove polystyrene sulfonic acid and water.

[0014] The preparation of the conductive polymer dispersion includes the following steps: dispersing raw materials containing conductive polymer monomers, polystyrene sulfonic acid, inorganic alkali, sodium persulfate, and ferric sulfate in water; oxidative chemical polymerization at 0-50°C for 12-36 hours; post-treatment with ion exchange resin; and filtration to obtain the conductive polymer dispersion. Polystyrene sulfonic acid acts as a solubilizer to assist in dissolving the water-insoluble conductive polymer monomers; the inorganic alkali provides an alkaline environment; sodium persulfate acts as an initiator; and ferric sulfate acts as an oxidant. The dispersion obtained by oxidative polymerization of conductive polymer monomers facilitates the preparation of coatings for practical applications.

[0015] The mass ratio of polystyrene sulfonic acid to conductive polymer monomer is 1:1-6:1; the molar ratio of sodium persulfate to conductive polymer monomer is 1:1-5:1; and the molar ratio of ferric sulfate to conductive polymer monomer is 1:1000-1:20.

[0016] This invention uses oxidative chemical polymerization to prepare conductive polymer dispersions, a method that is relatively simple and requires no equipment.

[0017] The conductive polymer monomer has a structure as shown in formula C or formula D:

[0018]

[0019] Where R is selected from hydrogen or methyl; L1 is -(CH2). n - where n is an integer from 0 to 22.

[0020] The method for preparing the conductive polymer monomer includes the following steps: Step 1, reacting hydroxymethyl EDOT with N,N-carbonyl diimidazole in a solvent, and obtaining the product EDOT-CI after washing with water and drying;

[0021] Step 2-1: React EDOT-CI with the compound shown in Formula I in a solvent, and purify the product to obtain the conductive polymer monomer shown in Formula A.

[0022] Or step 2-1 is replaced by step 2-2, EDOT-Cl and the compound shown in formula II are reacted in a solvent under the action of an acid binding agent, and the product is purified to obtain the conductive polymer monomer shown in formula B;

[0023]

[0024] Wherein, R, L1 are defined as above.

[0025] The solvent in step 1 includes one or more of acetonitrile, dichloromethane, DMF, tetrahydrofuran; the reaction temperature is 0-50℃, the reaction time is 0.5-24h; the molar ratio of hydroxymethyl EDOT to N,N-carbonyldiimidazole is 1:1-1:3;

[0026] The solvent in step 2-1 includes one or more of dichloromethane, tetrahydrofuran, acetonitrile, DMF, the reaction temperature is 0-80℃, the reaction time is 1-36h; the molar ratio of the compound shown in formula I to EDOT-CDI is 1:1-1:3;

[0027] The solvent in step 2-2 includes one or more of dichloromethane, tetrahydrofuran, acetonitrile, DMF; the reaction temperature is 0-80℃, the reaction time is 1-36h; the molar ratio of the compound shown in formula II to EDOT-Cl is 1:1.1-1:1.5;

[0028] The acid binding agent includes any one or more of potassium carbonate, triethylamine, N-ethyldiisopropylamine, and the molar ratio of the acid binding agent to the compound shown in formula II is 1:1-2:1.

[0029] The application also provides a coating with immunocompatibility, the anti-foreign body reaction coating comprising the conductive polymer polymer or the conductive polymer dispersion liquid with immunocompatibility.

[0030] The application also provides a preparation method of the anti-foreign body reaction coating, comprising the steps of:

[0031] Step S1, after the biological substrate is plasma treated and dried, a polyvinyl alcohol adhesion layer is coated on the surface of the substrate, and then annealing is performed to obtain a PVA coated biological substrate;

[0032] Step S2, the conductive polymer dispersion liquid is dissolved in a solvent, coated on the surface of the PVA coated biological substrate, dried, and then annealed on the surface of the biological substrate to obtain the anti-foreign body reaction coating.

[0033] The PVA functions as an adhesion layer to establish a close adhesion between the conductive polymer layer and the substrate, thereby constructing a stable conductive polymer coating. The annealing treatment is to reduce the pores and uneven areas in the coating, so that the coating is more uniform.

[0034] Preferably, the annealing in step S1 is at 60-100℃ for 0.5-4h;

[0035] Preferably, the drying in step S2 is at 5-40℃ for 5-24h, and the annealing is at 100-140℃ for 15-60min;

[0036] The biological substrate includes any one of a prosthesis, an indwelling needle, an implantable catheter, an implantable electrode, an implantable sensor, a cochlear implant, a pacemaker, an implantable defibrillator, an orthopedic product, a valve, a stent, an implantable drug controlled release device, an implantable cell loading instrument, an implantable blood glucose monitor, an insulin pump, a brain-computer interface, an artificial lens, an artificial organ, and other implantable instruments.

[0037] The application also provides an electrically conductive polymer monomer with immunocompatibility, having a structure as shown in formula C or formula D:

[0038]

[0039] wherein R is selected from hydrogen or methyl; L1 is -(CH2) n wherein n is an integer from 0 to 22.

[0040] The electrically conductive polymer monomer with immunoregulatory function in the application has excellent electrical conductivity and low levels of inflammation and foreign body reaction, and can provide a signal with high signal-to-noise ratio and fidelity as a coating of a bioelectronic implant for a long time.

[0041] Preferably, L1 is -(CH2)2-, and R is methyl.

[0042] The application also provides a preparation method of the electrically conductive polymer monomer with immunoregulatory function, characterized by comprising the following steps:

[0043] Step 1: reacting hydroxymethyl EDOT ((3,4)-1,4-dioxyethylene thiophene 2'-methanol 146796-02-3) with N,N-carbonyldiimidazole in a solvent, and obtaining a product EDOT-CI after water washing and drying;

[0044] Step 2-1: reacting EDOT-CI with a compound as shown in formula I in a solvent, and obtaining an electrically conductive polymer monomer as shown in formula A after purification of the product;

[0045] or step 2-1 is replaced by step 2-2: reacting EDOT-CI and a compound as shown in formula II in a solvent under the action of an acid binding agent, and obtaining an electrically conductive polymer monomer as shown in formula B after purification of the product;

[0046]

[0047] wherein R and L1 are defined as above.

[0048] The conductive polymer monomer of the two structures in the application has simple preparation process, mild reaction condition and can realize large-scale industrial production.

[0049] Preferably, the solvent in step 1 comprises one or more of acetonitrile, dichloromethane, DMF, tetrahydrofuran; the reaction temperature is 0-50℃, the reaction time is 0.5-24h; the molar ratio of hydroxymethyl EDOT to N,N-carbonyldiimidazole is 1:1-1:3;

[0050] The solvent in step 2-1 comprises one or more of dichloromethane, tetrahydrofuran, acetonitrile, DMF, the reaction temperature is 0-80℃, the reaction time is 1-36h; the molar ratio of the compound shown in formula I to EDOT-CDI is 1:1-1:3;

[0051] The solvent in step 2-2 comprises one or more of dichloromethane, tetrahydrofuran, acetonitrile, DMF; the reaction temperature is 0-80℃, the reaction time is 1-36h; the molar ratio of the compound shown in formula II to EDOT-Cl is 1:1.1-1:1.5;

[0052] The acid-binding agent comprises any one or more of potassium carbonate, triethylamine, N-ethyldiisopropylamine, and the molar ratio of the acid-binding agent to the compound shown in formula II is 1:1-2:1.

[0053] Compared with the prior art, the application has the following beneficial effects:

[0054] (1) The conductive polymer monomer in the application contains a thiomorpholine 1,1-dioxide structure, can have good conductivity and anti-foreign body reaction, has good immunocompatibility, and can be used in the body as a long-term stable coating of an implant.

[0055] (2) The conductive polymer monomer in the application has simple preparation process, mild reaction condition and is easy to popularize in industry.

[0056] (3) The conductive polymer dispersion liquid in the application can be closely attached to various biological substrates and is suitable for various implantable devices. BRIEF DESCRIPTION OF DRAWINGS

[0057] Figure 1 The H NMR spectrum of EDOT-Cl prepared for Example 1. 1

[0058] Figure 2 The H NMR spectrum of the chemically modified conductive polymer monomer EDOT-TMO prepared for Example 1. 1

[0059] Figure 3 ​​The Raman spectrum of the chemically modified conductive polymer dispersion PEDOT-TMO / PSS prepared in Example 2.

[0060] Figure 4 The cyclic voltammetry curves of PEDOT-TMO / PSS and PEDOT / PSS obtained by cyclic voltammetry in Application Example 1 are shown.

[0061] Figure 5 The electrochemical impedance spectra of PEDOT-TMO / PSS and PEDOT / PSS obtained by electrochemical impedance spectroscopy in Application Example 1 are shown.

[0062] Figure 6 Immunohistochemical images of tissue surrounding PEDOT / PSS-TMO coated silicone sheets, PEDOT / PSS coated silicone sheets, and untreated silicone sheets implanted subcutaneously in the backs of mice two weeks after application example 2.

[0063] Figure 7 This is a statistical graph showing the release levels of inflammatory factors in the surrounding tissues two weeks after subcutaneous implantation of PEDOT / PSS-TMO coated silicone sheets, PEDOT / PSS coated silicone sheets, and untreated silicone sheets in the back of mice, as described in Application Example 2.

[0064] Figure 8 Masson immunohistochemical sections of the surrounding tissue one month after subcutaneous implantation of PEDOT / PSS-TMO coated silicone sheets, PEDOT / PSS coated silicone sheets, and untreated silicone sheets in Example 3.

[0065] Figure 9 The graph shows the fibrosis density of the surrounding tissue at different distances from the plant one month after subcutaneous implantation of PEDOT / PSS-TMO coated silicone sheets, PEDOT / PSS coated silicone sheets, and untreated silicone sheets in Example 3. Detailed Implementation

[0066] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Modifications or equivalent substitutions made by those skilled in the art based on their understanding of the technical solutions of this invention, without departing from the spirit and scope of the invention, should be covered within the protection scope of this invention.

[0067] All raw materials used in the following specific embodiments were purchased commercially. EDOT-TMO was used as a representative immunomodulatory conductive polymer monomer for synthesis, and application tests were conducted, but this does not limit the scope of the present invention.

[0068] Example 1

[0069] Preparation of EDOT-TMO

[0070] First step:

[0071] EDOT-OH (208 mg, 1.21 mmol) was dissolved in 2 mL of dichloromethane. Then CDI (392 mg, 2.42 mmol) was added to the flask. The reaction mixture was stirred at room temperature for 2 h, the product was washed with water in a separatory funnel, leaving the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the product EDOT-Cl as a white solid (59% yield). The reaction scheme is as follows:

[0072]

[0073] The product EDOT-Cl NMR spectrum is shown in Figure 1 , 1 H NMR (400 MHz, CDC13) δ 8.14 (s, 1H), 7.42 (t, J = 1.5 Hz, 1H), 7.09 (dd, J = 1.7, 0.8 Hz, 1H), 6.50 - 6.24 (m, 2H), 4.65 (dd, J = 5.1, 1.3 Hz, 2H), 4.59 - 4.47 (m, 1H), 4.30 (dd, J = 11.8, 2.4 Hz, 1H), 4.14 (dd, J = 11.8, 6.3 Hz, 1H), indicating the product of the structure was successfully prepared.

[0074] Second step:

[0075] EDOT-Cl (190 mg, 0.71 mmol) was dissolved in 2 mL of acetonitrile. Then 4-(2- aminoethyl)thiomorpholine-1,1 -dioxide (127 mg, 0.71 mmol) and diisopropylethylamine (92 mg, 0.71 mmol) were added to the flask. The reaction mixture was stirred at 70 °C for 24 h, the reaction mixture was filtered and concentrated under reduced pressure to give the crude product as a solid. Purification by liquid chromatography (petroleum ether: ethyl acetate mixture, ethyl acetate volume fraction from 0% to 100%) gave the product EDOT-TMO as a white solid (72.0% yield). The reaction scheme is as follows:

[0076]

[0077] The product EDOT-TMO NMR spectrum is shown in Figure 2 , 1H NMR (400 MHz, CDC13) δ 6.36 (q, J = 3.7 Hz, 2H), 5.14 (s, 1H), 4.34 (qq, J = 11.8, 5.4 Hz, 4H), 4.04 (dd, J = 11.7, 7.2 Hz, 1H), 3.33 (d, J = 6.6 Hz, 2H), 3.07 (s, 8H), 2.67 (s, 2H), indicating that the product of the structure was successfully prepared.

[0078] Example 2

[0079] Preparation of conductive polymer dispersion with immunocompatibility, The main step involves a one-step oxidative polymerization reaction.

[0080] A 2 mL aqueous solution of polystyrene sulfonic acid (18 wt%, M w = 75000) was dispersed in 23 mL ultrapure water, stirred for 20 min, then 0.265 g of EDOT-TMO was dissolved in the above solution and bubbled with argon for 20 min. 0.5 g of sodium persulfate and 3.74 mg of ferric sulfate were weighed into 1 mL of ultrapure water, respectively, and injected into the above system, and reacted in an ice water bath at 5°C for 24 h. Then 5.0 g of Amberlyst A-26 and 5.0 g of Amberlyst 15 ion exchange resin were added, and after stirring for 2 h, the insoluble material was filtered off to obtain a chemically modified conductive polymer PEDOT-TMO / PSS dispersion. The Raman spectrum of the product is shown in Figure 3 , indicating that the product of the structure was successfully prepared.

[0081] Application Example 1

[0082] Preparation of conductive polymer coating with surface chemical modification of silica gel substrate

[0083] The preparation of the PEDOT-TMO / PSS coating on the surface of the silica gel substrate involves three steps of surface modification.

[0084] First step:

[0085] The PDMS sheet was ultrasonically cleaned in ethanol for 20 min, dried under a nitrogen stream, then plasma treated for 180 s, then immersed in 50 mL of a silane solution (10 μL of acetic acid, 1% (w / v) 3-aminopropyltrimethoxysilane, 100 mL of ultrapure water) at room temperature for 1 h, then the substrate was thoroughly washed with ultrapure water and dried under a nitrogen stream.

[0086] Second step:

[0087] A 1 wt% PVA (M w= 124000) was dissolved in deionized water at 90 °C, then the PVA solution was dropped on the treated PDMS substrate and spin-coated at 2000 rpm for 30 s to prepare the PVA adhesion layer. After spin-coating, the PVA-coated PDMS was annealed at 80 °C for 1 h.

[0088] Third step:

[0089] Fifteen percent (v / v) of dimethyl sulfoxide was added to the above-prepared aqueous PEDOT-TMO / PSS dispersion, and the mixture was stirred vigorously at room temperature for 6 h. The mixed PEDOT-TMO / PSS dispersion was filtered with a polytetrafluoroethylene filter (pore size of 5 pm), then 100 pL of the PEDOT-TMO / PSS dispersion was dropped on the PVA-coated PDMS substrate, dried at room temperature for 12 h, and annealed at 120 °C for 30 min, finally obtaining a PEDOT / PSS-TMO-coated silica gel sheet with a surface chemically modified conductive polymer PEDOT / PSS-TMO coating. A PEDOT / PSS-coated silica gel sheet was prepared by using the same method as described above with a commercially purchased PEDOT / PSS (Clevious PH1000, Heraeus Electric Materials).

[0090] Application example performance test

[0091] Conductive ability of representative chemically modified conductive polymer

[0092] 1. Cyclic voltammetry test

[0093] Cyclic voltammetry was performed using an electrochemical workstation (CHI660E, Shanghai Chenhua Instrument Co., Ltd.) with a potential scan rate of 150 mV / s, and a PEDOT / PSS-TMO-coated silica gel sheet, a PEDOT / PSS-coated silica gel sheet, an untreated silica gel sheet, or an ITO glass was clamped in an electrochemical cell as a working electrode using a platinum sheet electrode, a Pt mesh as a counter electrode, an Ag / AgCl electrode as a reference electrode, and PBS as an electrolyte. The test results are shown in FIG. 3. The charge-discharge capacity of PEDOT-TMO / PSS was slightly lower than that of the commercially purchased PEDOT / PSS, but did not affect the conductivity of the electrode. Figure 4

[0094] 2. Electrochemical impedance test

[0095] ​Electrochemical impedance measurements were performed using an electrochemical workstation (CHI660E, Shanghai Chenhua Instrument Co., Ltd.) with a platinum sheet electrode clamping the PEDOT / PSS-TMO-coated PDMS sheet, PEDOT / PSS-coated PDMS sheet, untreated PDMS sheet, or ITO glass as the working electrode, a Pt mesh as the counter electrode, an Ag / AgCl electrode as the reference electrode, and PBS as the electrolyte, scanning a frequency range between 0.1 and 100 kHz with a bias potential of open circuit voltage. The results are shown in FIG. 8, where the electrochemical impedance of the PEDOT / PSS-TMO-coated PDMS sheet, PEDOT / PSS-coated PDMS sheet, untreated PDMS sheet, and ITO glass are similar in the high frequency region, while the electrochemical impedance of the PEDOT-TMO / PSS is greater than the commercially purchased PEDOT / PSS and less than the ITO glass in the low frequency region. Figure 5

[0096] Related immune response of representative chemically modified conductive polymer in vivo

[0097] I. Animal surgery procedure

[0098] In this application example, the inflammatory and fibrotic responses of the conductive polymer PEDOT-TMO / PSS in a mouse subcutaneous implantation model are described. Two PEDOT / PSS-TMO-coated PDMS sheets and a PEDOT / PSS-coated PDMS sheet prepared as described in Example 3 (an untreated PDMS substrate as a control) were cut into discs using a biophysical punch (4 mm in diameter), sterilized with ultraviolet irradiation, washed with physiological saline, and implanted subcutaneously into C57BL / 6 female mice.

[0099] Specifically, the PEDOT / PSS-TMO-coated PDMS sheet and the PEDOT / PSS-coated PDMS sheet, as well as the untreated PDMS sheet, were implanted in different areas of the back of the mice, respectively. The implantation procedure was as follows: the mice were anesthetized by intraperitoneal injection of 0.3% pentobarbital, shaved, and the skin was disinfected with iodine. A longitudinal incision of about 8 mm was made on the dorsal surface using surgical scissors to provide access to the subcutaneous space. Then a blunt forceps was used to form a subcutaneous pocket about 0.5 cm away from the incision for implanting the hydrogel sheet. After implantation, the incision was closed using 5-0 tapered tip PGA absorbable suture. The mice were monitored until the anesthesia recovered and were raised for 2 weeks. The mice grew normally after implantation without any signs of discomfort, and no weight loss was observed before the implant was removed.

[0100] II. Inflammation response of representative albumin coating material in vivo

[0101] Immunohistochemical section of inflammatory factors

[0102] The inflammatory response of the albumin-coated material in a mouse subcutaneous implantation model was described in this experimental process.​

[0103] The samples of the elastomer and the nearby tissues implanted in mice for two weeks were removed, fixed in 10% formaldehyde solution for 24 hours, and embedded with paraffin. Each sample was sliced with a thickness of 3-5 pm and mounted on a glass slide for histological staining. Rabbit anti-mouse CCR7 monoclonal antibody was from Abeam (dilution 1:500; catalog number ab253187), goat anti-mouse TNF-a polyclonal antibody was from R&D system (15 pg / mL; catalog number AF-410), goat anti-mouse IL-6 polyclonal antibody was from R&D system (15 pg / mL; catalog number AF-406), and rat anti-mouse IL-17 polyclonal antibody was from R&D system (15 pg / mL; catalog number MAB721). Before immunization, antigen retrieval, endogenous peroxidase elimination, and bovine serum albumin blocking were performed in sequence. The sample slices two weeks after implantation were incubated with primary antibodies at 4°C overnight. The slices were washed with PBS three times and incubated with HRP-labeled goat anti-rabbit antibody (1:300; catalog number SE134 from Solarbio), HRP-labeled goat anti-rat antibody (1:300; catalog number HAF005 from R&D system), or HRP-labeled rabbit anti-goat antibody (1:200; catalog number GB23204 from Servicebio) at room temperature for 50 minutes in the dark. The slices were washed three times, slightly dried, and then incubated with freshly prepared diamine.

[0104] From Figure 6 and Figure 7 It can be observed from the PDMS elastomer implanted for two weeks that a large number of inflammatory factors such as IL-6, TNF-a, IL-17, and chemokine receptor CCR-7 are expressed nearby, which is much higher than the expression level under normal physiological level (Mock). In contrast, the PEDOT / PSS coating sample to some extent reduces the inflammatory response caused by the substrate, and the PEDOT-TMO / PSS coating sample greatly reduces the inflammatory response caused by the substrate.

[0105] III. Fibrosis response of representative albumin coating material in vivo

[0106] H&E and Masson trichrome staining immunohistochemical section

[0107] The experiment process describes the fibrosis reaction of the albumin coating material in the mouse subcutaneous implantation model.

[0108] Elastomers implanted in mice for two and four weeks and the surrounding tissue samples were removed, fixed in 10% formaldehyde solution for 24 hours, and embedded with paraffin. Each sample was sectioned at a thickness of 3-5 μm and mounted on a glass slide for histological staining. Inflammation was examined by staining the tissue sections with hematoxylin and eosin (H&E), which stains the cell nucleus blue and the cytoplasm pink. The formation of collagen and tissue was stained with Masson's trichrome staining, which stains collagen blue, cytoplasm red, and cell nucleus black.

[0109] All images were scanned in a brightfield microscope (Nikon intensilight CHGFI) equipped with NIS Elements AR software. Collagen density was obtained by measuring the intensity of blue pixels of the dense collagen capsules stained blue in the Masson images (step size of 10 μm) of the elastomer-tissue interface.

[0110] From Figure 8 and Figure 9 It can be observed that after one month of implantation, the PDMS was encapsulated by dense collagen tissue, the PEDOT / PSS coated samples reduced the fibrotic response induced by the substrate to some extent, and the PEDOT-TMO / PSS coated samples had the best ability to resist the formation of fibrous capsules.

Claims

1. An electrically conductive polymer having immunocompatibility, characterized by, The conductive polymer has a structure as shown in Formula A or Formula B. wherein R is selected from hydrogen or methyl; L1is -(CH2) n - wherein n is an integer from 0 to 22; x represents the number of repeating units of subunit A, which is an integer from 10 to 1000; y represents the number of repeating units of subunit B, which is an integer from 10 to 1000.

2. An electrically conductive polymer dispersion liquid having immunocompatibility, characterized by, The conductive polymer dispersion liquid comprises the conductive polymer of claim 1, polystyrene sulfonic acid and deionized water.

3. The method for preparing the immunocompatible conductive polymer according to claim 1, characterized in that, The conductive polymer dispersion liquid of claim 2 is dried to remove polystyrene sulfonic acid and water to obtain the conductive polymer.

4. The method for producing an electroconductive polymer dispersion liquid having immunocompatibility according to claim 2, characterized by, The method comprises the steps of: dispersing raw materials comprising a conductive polymer monomer, polystyrene sulfonic acid, an inorganic base, sodium persulfate and ferric sulfate in water, oxidizing chemical polymerization at 0-50℃ for 12-36h, adding ion exchange resin for post-treatment, and then obtaining the conductive polymer dispersion liquid after suction filtration.

5. The method for producing an electroconductive polymer dispersion liquid having immunocompatibility according to claim 4, characterized by, The mass ratio of the polystyrene sulfonic acid to the conductive polymer monomer is 1:1-6:1; the molar ratio of the sodium persulfate to the conductive polymer is 1:1-5:1; and the molar ratio of the ferric sulfate to the conductive polymer is 1:1000-1:

20.

6. The method for producing an electrically conductive polymer dispersion liquid having immunocompatibility according to claim 5, characterized by, The conductive polymer monomer has a structure as shown in Formula C or Formula D. wherein R is selected from hydrogen or methyl; L1is -(CH2) n - wherein n is an integer from 0 to 22.

7. The method for producing an electroconductive polymer dispersion liquid having immunocompatibility according to claim 6, characterized by, The method for preparing the conductive polymer monomer comprises the steps of: step 1, reacting hydroxymethyl EDOT and N,N-carbonyldiimidazole in a solvent, and then obtaining a product EDOT-Cl after water washing and drying; Step 2-1, reacting EDOT-Cl and a compound shown in Formula I in a solvent, and then obtaining a conductive polymer monomer shown in Formula A after purification of the product; Or step 2-1 is replaced by step 2-2, reacting EDOT-Cl and a compound shown in Formula II in a solvent under the action of an acid binding agent, and then obtaining a conductive polymer monomer shown in Formula B after purification of the product. Wherein, R and L1 are defined in claim 6.

8. The method for producing an electrically conductive polymer dispersion liquid having immunocompatibility according to claim 7, characterized by, In step 1, the solvent comprises one or more of acetonitrile, dichloromethane, DMF and tetrahydrofuran; the reaction temperature is 0-50℃, and the reaction time is 0.5-24h; the molar ratio of hydroxymethyl EDOT to N,N-carbonyldiimidazole is 1:1-1:3; In step 2-1, the solvent comprises one or more of dichloromethane, tetrahydrofuran, acetonitrile and DMF; the reaction temperature is 0-80℃, and the reaction time is 1-36h; the input molar ratio of the compound shown in Formula I to EDOT-CDI is 1:1-1:3; In step 2-2, the solvent comprises one or more of dichloromethane, tetrahydrofuran, acetonitrile and DMF; the reaction temperature is 0-80℃, and the reaction time is 1-36h; the input molar ratio of the compound shown in Formula II to EDOT-Cl is 1:1.1-1:1.5; The acid binding agent comprises any one or more of potassium carbonate, triethylamine and N-ethyldiisopropylamine, and the molar ratio of the acid binding agent to the compound shown in Formula II is 1:1-2:

1.

9. A coating having immunocompatibility, characterized in that, The coating with immunocompatibility comprises the conductive polymer with immunocompatibility of claim 1 or comprises the conductive polymer dispersion liquid with immunocompatibility of claim 2.

10. The method of claim 9, wherein the coating is prepared by a process comprising: The method comprises the steps of: Step S1, drying after plasma treatment of a biological substrate, coating a polyvinyl alcohol adhesion layer on the surface of the substrate, and then annealing to obtain a PVA-coated biological substrate; Step S2, dissolving the conductive polymer dispersion liquid of claim 2 in a solvent, coating on the surface of the PVA-coated biological substrate, drying, and then annealing on the surface of the biological substrate to obtain the coating with immunocompatibility.

11. The method of claim 10, wherein the coating having immunocompatibility is prepared by, The annealing in step S1 is at 60-100℃ for 0.5-4h; the drying in step S2 refers to drying at 5-40℃ for 5-24h, and the annealing is at 100-140℃ for 15-60min.

12. The method of claim 10, wherein the coating is prepared by a method comprising: The biological substrate includes any one of a prosthesis, an indwelling needle, an implantable catheter, an implantable electrode, an implantable sensor, a cochlear implant, a pacemaker, an implantable defibrillator, an orthopedic product, a valve, a stent, an implantable drug controlled release device, an implantable cell loading instrument, an implantable blood glucose monitor, an insulin pump, a brain-computer interface, an artificial lens, and an artificial organ.

13. An electrically conductive polymer monomer having immunocompatibility, characterized in that, has a structure as formula C or formula D: wherein R is selected from hydrogen or methyl; L1is -(CH2) n - wherein n is an integer from 0 to 22.

14. The electrically conductive polymer monomer having immunocompatibility according to claim 13, wherein, L1 is -(CH2)2-, and R is methyl.

15. The method of claim 13 or 14, wherein the preparation of the conductive polymer monomer having immunocompatibility is characterized by, The method comprises the following steps: step 1, reacting hydroxymethyl EDOT with N,N-carbonyldiimidazole in a solvent, and obtaining a product EDOT-Cl after water washing and drying; Step 2-1, reacting EDOT-Cl with a compound shown in formula I in a solvent, and obtaining a conductive polymer monomer shown in formula A after purification of the product; Or step 2-1 is replaced by step 2-2, reacting EDOT-Cl and a compound shown in formula II in a solvent under the action of an acid binding agent, and obtaining a conductive polymer monomer shown in formula B after purification of the product; Wherein, R, L1 are defined as in claim 1.

16. The method for preparing an immunocompatible conductive polymer monomer according to claim 15, characterized in that, The solvent in step 1 includes one or more of acetonitrile, dichloromethane, DMF, and tetrahydrofuran; the reaction temperature is 0-50℃, and the reaction time is 0.5-24h; the molar ratio of hydroxymethyl EDOT to N,N-carbonyldiimidazole is 1:1-1:3; The solvent in step 2-1 includes one or more of dichloromethane, tetrahydrofuran, acetonitrile, and DMF; the reaction temperature is 0-80℃, and the reaction time is 1-36h; the molar ratio of the compound shown in formula I to EDOT-CDI is 1:1-1:3; The solvent in step 2-2 includes one or more of dichloromethane, tetrahydrofuran, acetonitrile, and DMF; The reaction temperature is 0-80℃, and the reaction time is 1-36h; the molar ratio of the compound shown in formula II to EDOT-Cl is 1:1.1-1:1.5; The acid binding agent includes any one or more of potassium carbonate, triethylamine, and N-ethyldiisopropylamine; and the molar ratio of the acid binding agent to the compound shown in formula II is 1:1-2:1.

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