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CN115417963B - Biocompatible polycarbonate polyurethane, preparation method and application thereof - Google Patents

Biocompatible polycarbonate polyurethane, preparation method and application thereof Download PDF

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Publication number
CN115417963B
CN115417963B CN202211134824.9A CN202211134824A CN115417963B CN 115417963 B CN115417963 B CN 115417963B CN 202211134824 A CN202211134824 A CN 202211134824A CN 115417963 B CN115417963 B CN 115417963B
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polyurethane
isocyanate
polycarbonate polyurethane
polycarbonate
optionally
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CN115417963A (en
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程荣恩
钱成
刘佳梅
周静
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Diascience Medical Co Ltd
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Diascience Medical Co Ltd
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Priority to PCT/CN2023/113659 priority patent/WO2024060897A1/en
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C08G18/12—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step using two or more compounds having active hydrogen in the first polymerisation step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/44—Polycarbonates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/61—Polysiloxanes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
    • C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
    • C08G18/6633—Compounds of group C08G18/42
    • C08G18/6637—Compounds of group C08G18/42 with compounds of group C08G18/32 or polyamines of C08G18/38
    • C08G18/6648—Compounds of group C08G18/42 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3225 or C08G18/3271 and/or polyamines of C08G18/38
    • C08G18/6651—Compounds of group C08G18/42 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3225 or C08G18/3271 and/or polyamines of C08G18/38 with compounds of group C08G18/3225 or polyamines of C08G18/38
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/76—Polyisocyanates or polyisothiocyanates cyclic aromatic
    • C08G18/7657—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings
    • C08G18/7664—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings containing alkylene polyphenyl groups
    • C08G18/7671—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings containing alkylene polyphenyl groups containing only one alkylene bisphenyl group
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/83—Chemically modified polymers
    • C08G18/836—Chemically modified polymers by phosphorus containing compounds

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Polyurethanes Or Polyureas (AREA)

Abstract

The application relates to the field of medical polymer materials, and provides biocompatible polycarbonate polyurethane, a preparation method and application thereof. Wherein the biocompatible polycarbonate polyurethane comprises the reaction product of directional polymerization of the following raw material components: (a) an isocyanate composition, (b) an isocyanate-reactive group-containing component, optionally (c) a hydroxyl or amino terminated compound, (d) a chain extender, (e) a modifying component and optionally (f) a crosslinker, the polyurethane segments resulting from the reaction of components (a), (b) and (d) containing active sites. The biocompatible polycarbonate polyurethane has better biocompatibility, and the sensor prepared by taking the biocompatible polycarbonate polyurethane as an outer film has excellent in-vitro test performance.

Description

Biocompatible polycarbonate polyurethane, preparation method and application thereof
Technical Field
The application belongs to the field of medical polymer materials, and particularly relates to biocompatible polycarbonate polyurethane, a preparation method and application thereof.
Background
Polyurethane (PU) is mainly obtained by an addition reaction of a diisocyanate composition with a polyether or polyester polyol as a basic raw material, and is produced in 1937 by otto bayer and the like.
Polyurethane materials have been widely used in artificial organs, interventional guides, tube wound dressings, medical adhesives, and the like, with their excellent mechanical properties, fatigue resistance, biocompatibility and workability. The polyurethane material has the advantages of simple synthesis, designability of molecular structure, good stability and the like, is widely applied to the field of biomedical materials, and the polycarbonate polyurethane material has better stability and biocompatibility than other types of polyurethane materials. Among polyester and polyether polyols, polycarbonate diol (PCDL) has been the most excellent in combination properties, and studies on degradability and blood compatibility of polycarbonate polyurethane materials prepared therefrom have been attracting attention.
Polyurethane materials are also used in the field of implantable medical devices for determining the presence and concentration of biological analytes, in which polyurethane is mainly present in the form of a film, the main function being to protect it by its excellent biocompatibility, by modifying and/or physically doping the polyurethane, to allow the film of polyurethane to be simultaneously partially permeable to biological analytes such as: diffusion control of glucose, lactic acid, uric acid, beta-hydroxybutyric acid and the like is performed, so that electrochemical detection is further completed. The conventional polyurethane is linear polyurethane, and the polyurethane film obtained by modification and/or physical doping has poor stability and poor reproducibility, and can be stored for a long time along with certain molecular migration, so that the property of the polyurethane film is changed, and the test result is deviated.
This background is not intended to limit the scope of the claimed subject matter nor is it intended to limit the claimed subject matter to implementations that solve any or all of the disadvantages or problems described above.
It should be noted that the above background section merely represents an understanding of the related art by the applicant and does not constitute prior art.
Disclosure of Invention
In view of one of the problems of the above-mentioned technology, it is an object of the present application to provide a biocompatible polycarbonate polyurethane having good biocompatibility and performance stability.
To this end, as one aspect of the present application, there is provided a biocompatible polycarbonate polyurethane comprising the reaction product of the directional polymerization of the following raw material components:
(a) An isocyanate composition, an isocyanate having at least two isocyanate groups,
(B) An isocyanate-reactive group containing component selected from the group consisting of polycarbonate polyols,
Optionally (c), hydroxy or amino end-capping compounds,
(D) A chain extender selected from trifunctional or higher-functional polyamines, trifunctional or higher-functional polyols, or mixtures thereof,
(E) A modifying component selected from the group consisting of a biocompatible compound, an amino-terminated hydrophilic compound, or a mixture thereof, and
Optionally (f) a crosslinking agent, and (f) is different from (d).
Wherein the polyurethane chain segment obtained after the reaction of (a), (b) and (d) contains an active site, and as a more preferable scheme, the active site is positioned on a branched chain in the polyurethane chain segment.
Wherein the active site is a reactive functional group located on a branch in the polyurethane segment, such as an amino group and/or a hydroxyl group.
The biocompatible polycarbonate polyurethane provided by the application is preferably one or more of diisocyanate and/or polyisocyanate, specifically toluene diisocyanate, diphenylmethane diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate, dicyclohexylmethane diisocyanate, naphthalene diisocyanate, p-phenylene diisocyanate, lysine diisocyanate, 1, 4-cyclohexane diisocyanate, methylcyclohexyl diisocyanate, norbornane diisocyanate, tetramethyl m-phenylene diisocyanate, cyclohexane dimethylene diisocyanate, trimethyl-1, 6-hexamethylene diisocyanate and xylylene diisocyanate.
Similarly, as a preferred embodiment, the isocyanate composition in component (a) may also be selected from the derivatives of the above-mentioned isocyanates, in particular 4,4' -methylenebis (phenyl isocyanate), dicyclohexylmethane 4,4' -diisocyanate, 4' -diphenylmethane diisocyanate and the like.
The biocompatible polycarbonate polyurethane provided according to the present application preferably comprises a polycarbonate diol, in particular a poly (1, 6-hexanediol carbonate) diol, a poly (hexamethylene carbonate) diol, a poly (butylene carbonate) diol, a poly (cyclohexanedimethanol-1, 6-hexanediol carbonate) diol, a poly (1, 5-pentanediol-1, 6-hexanediol carbonate) diol, a poly (ethylene carbonate) diol, a poly (propylene carbonate) diol, a poly (1, 4-butanediol-1, 6-hexanediol carbonate) diol, or a mixture of at least two thereof.
The biocompatible polycarbonate polyurethane provided by the application preferably comprises optional (c) in raw material components, wherein the optional (c) is specifically dihydroxy end-capped polysiloxane, diamino end-capped polysiloxane or a mixture thereof, and the molecular weight is preferably 1000-6000Da, and more preferably 1500-3000Da.
The biocompatible polycarbonate polyurethane provided according to the present application preferably component (d) is in particular tris (2-aminoethyl) amine, triethanolamine, 4' -triaminetrityl methane, or a mixture of at least two thereof.
The biocompatible polycarbonate polyurethane provided according to the present application preferably component (e) is a biocompatible compound, in particular 2-methacryloyloxyethyl phosphorylcholine, or a quaternary ammonium salt.
The biocompatible polycarbonate polyurethane provided by the application is characterized in that preferably, the component (e) is an amino-terminated hydrophilic compound, in particular amino-terminated polyethylene glycol; more preferably, the amino-terminated hydrophilic compound is a double-ended amino-terminated polyethylene glycol, and further, the prepared polycarbonate polyurethane has a network structure.
According to the biocompatible polycarbonate polyurethane provided by the application, the raw material component preferably comprises optional (f), and the optional (f) is specifically any one of glutaraldehyde, glutaric acid and carbodiimide.
As a second aspect of the present application, there is provided a method for preparing the above biocompatible polycarbonate polyurethane, comprising the steps of:
(1) By reacting (a), (b) and optionally (c) in an organic solvent to form an isocyanate-terminated polyurethane prepolymer A,
(2) Chain-extending the polyurethane prepolymer A by (d) to obtain a polyurethane prepolymer B,
(3) Modifying the polyurethane prepolymer B with (e) and optionally (f), and
Optionally, a separation and purification step.
According to the preparation method of the biocompatible polycarbonate polyurethane provided by the application, preferably, the molar quantity of isocyanate groups in the (a) is X, the molar total quantity of hydroxyl groups and/or amino groups in the (b) is Y, and the ratio of X to Y is 1<X/Y is less than or equal to 1.5.
According to the preparation method of the biocompatible polycarbonate polyurethane, the organic solvent is preferably an organic solvent which does not contain active hydrogen groups in the molecule, and specifically is an organic solvent which is inactive to isocyanate groups or has lower activity than the active hydrogen groups of components (a), (b), (c), (d), (e) and (f) and the like.
For example, ketone solvents (acetone, methyl isobutyl ketone, etc.), aromatic hydrocarbon solvents (toluene, o-xylene, m-xylene, etc.), aliphatic hydrocarbon solvents (pentane, cyclopentane, methylcyclohexane, t-hexylcyclohexane, etc.), alcohol solvents (ethanol, t-butanol, etc.), ether solvents (diethyl ether, t-butylmethyl ether, tetrahydrofuran THF, 2-methyltetrahydrofuran, etc.), ester solvents (ethyl acetate, butyl acetate, isobutyl acetate, etc.), glycol ether ester solvents (ethylene glycol ethyl ether acetate, propylene glycol methyl ether acetate), amide solvents (dimethylformamide, N-dimethylformamide DMF, dimethylacetamide, N-methyl-2-pyrrolidone, etc.).
According to the preparation method of the biocompatible polycarbonate polyurethane provided by the application, preferably, the mass ratio of the using amount of the organic solvent to the raw material components is 100 (5-20).
According to the method for preparing the biocompatible polycarbonate polyurethane provided by the application, preferably, the polyurethane prepolymer B contains active amino groups and/or hydroxyl groups.
According to the method for producing a biocompatible polycarbonate polyurethane provided by the present application, preferably, the content of (c) is 0 to 30% by weight based on 100% by weight of the polyurethane prepolymer a.
According to the preparation method of the biocompatible polycarbonate polyurethane provided by the application, preferably, the ratio of the molar total amount of amino groups and/or hydroxyl groups in the (d) to the molar amount of isocyanate groups in the polyurethane prepolymer A is 0.8-1.2.
According to the method for preparing the biocompatible polycarbonate polyurethane provided by the application, preferably, the content of (e) is 10-20 wt% based on 100 wt% of the weight of the polyurethane prepolymer B.
According to the method for producing a biocompatible polycarbonate polyurethane provided by the present application, it is preferable that the content of (f) is 0 to 10% by weight based on 100% by weight of (e).
As a third aspect of the present application there is provided the use of the biocompatible polycarbonate polyurethane described above. For example, after the separated and purified biocompatible polycarbonate polyurethane is dissolved in an organic solvent, a layer of film is formed on the surface of a medical device, particularly an implantable medical device, through coating modes such as knife coating, point coating, dipping and the like, so that the compatibility of the medical device and organisms is improved.
According to the application of the biocompatible polycarbonate polyurethane provided by the application, preferably, the components of the biocompatible polycarbonate polyurethane comprise the components (a), (b), (c), (d), (e) and (f), and the prepared film has selective permeability, for example, can permeate glucose, lactic acid, uric acid, beta-hydroxybutyric acid and other biological metabolites, or has oxygen permeability, and can be used for an outer film of an implantable electrochemical sensor.
Compared with the prior art, the technical scheme of the application has the beneficial effects that:
(1) The biocompatible polycarbonate polyurethane disclosed by the application realizes directional polymerization by adjusting the types of raw material components, and a sensor prepared by taking the biocompatible polycarbonate polyurethane as an outer film has excellent in-vitro test performance;
(2) The addition of active sites, such as active amino groups and/or hydroxyl groups, to the segments of the polycarbonate polyurethane chain-extended by introducing polyamines and/or polyhydroxy compounds and the like as chain extenders facilitates further modification thereof, such as increasing the biocompatibility thereof;
(3) Unlike straight-chain polyurethane with isocyanate as the rigid segment and polyether/polyester diol as the flexible segment in the prior art, the biocompatible polycarbonate polyurethane disclosed by the application increases the active sites of branched chain reaction.
Drawings
FIG. 1 is a platelet adsorption micrograph of a polyurethane film prepared using the procedure of example 1 disclosed herein.
FIG. 2 is a platelet adsorption micrograph of a polyurethane film prepared using the procedure of comparative example 1 disclosed herein.
FIG. 3 is a response current curve of a glucose sensor prepared using the polyurethane disclosed in example 2 and comparative example 1 of the present disclosure.
FIG. 4 is a graph showing the response of sensor current to oxygen content in a low oxygen environment when the biocompatible polycarbonate polyurethane prepared in example 3 of the present application is applied to an electrochemical sensor in the form of a film.
Detailed Description
So that the technical features and content of the present application can be understood in detail, preferred embodiments of the present application will be described in more detail below. While the preferred embodiments of the present application have been described in the examples, it should be understood that the present application may be embodied in various forms and should not be limited to the embodiments set forth herein. The experimental methods of the present application, in which the specific conditions are not specified in the following examples, are generally carried out under conventional conditions, or according to the preparation
Conditions recommended by manufacturers. The various chemicals commonly used in the examples are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.
The term "isocyanate-reactive group" according to the present application refers to a Zerevitinov-active hydrogen containing group, typically Zerevitinov-active hydrogen containing groups are understood in the art to refer to hydroxyl (OH), carboxyl (COOH), amino (NHx).
The term "optional" in the present disclosure means that in some embodiments, the starting components or steps may be selected; in other embodiments, the feed components or steps may not be selected.
The term "and/or" in the present application refers to an association relationship describing an association object, and indicates that three relationships may exist, for example, a and/or B may indicate: a exists alone, A and B exist together, and B exists alone. The character "/" generally indicates that the context-dependent object is an "or" relationship.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
The room temperature or room temperature referred to in the examples below means the room temperature at about 25℃and the glucose solutions used were glucose buffers (G-PBS) of different concentrations.
The present application will be described in detail with reference to specific examples.
Example 1
The method comprises the following specific steps:
(1) At normal temperature, 4g of dehydrated and deoxidized poly (1, 6-hexanediol) diol is taken and dissolved in 50ml of N, N-dimethylformamide; heating to 40-60deg.C for use;
(2) Dissolving 0.6g of 4,4' -diphenylmethane diisocyanate in 50ml of N, N-dimethylformamide at normal temperature; slowly adding the mixture into the poly (1, 6-hexanediol carbonate) glycol solution in the step (1) to continuously react to obtain a prepolymer A;
(3) Adding 0.105ml of tris (2-aminoethyl) amine ((NH 2CH2CH 2) 3N) into the prepolymer A, heating to 70-90 ℃, and continuously reacting to obtain a prepolymer B;
(4) 0.071g of 2-Methacryloyloxyethyl Phosphorylcholine (MPC) was added to prepolymer B, and the temperature was lowered to 40-50℃until the reaction was completed.
Comparative example 1
The method comprises the following specific steps:
(1) At normal temperature, 4g of dehydrated and deoxidized poly (1, 6-hexanediol) diol is taken and dissolved in 50ml of N, N-dimethylformamide; heating to 40-60deg.C for use;
(2) Dissolving 0.6g of 4,4' -diphenylmethane diisocyanate in 50ml of N, N-dimethylformamide at normal temperature; slowly adding the mixture into the poly (1, 6-hexanediol carbonate) glycol solution in the step (1) to continuously react to obtain a prepolymer A;
(3) 0.071g of 2-Methacryloyloxyethyl Phosphorylcholine (MPC) was added to prepolymer A, and the temperature was lowered to 40-50℃until the reaction was completed.
The polyurethane film formed by the method of the steps after separation and purification is shown in fig. 1 and 2, which show the platelet adsorption micrographs of the polyurethane film in the example 1 and the comparative example 1 respectively, and it is clear from the photographs that the further graft modification of the polycarbonate polyurethane by adding 2-Methacryloyloxyethyl Phosphorylcholine (MPC) on the basis that the tris (2-aminoethyl) amine increases the active site of the polycarbonate polyurethane can effectively reduce the adsorption of the polycarbonate polyurethane to the platelets, and can improve the effective service life of the film applied in vivo.
The polyurethane film formed by knife coating after separating and purifying the polyurethane prepared according to the above procedure is shown in fig. 1 and 2, which show the platelet adsorption micrographs of the polyurethane film of example 1 and comparative example 1, respectively, and it is clear from the photographs that the polyurethane film containing the modified component MPC can effectively reduce the platelet adsorption and can improve the effective service life of the film layer applied in vivo.
The platelet adsorption experiment steps and parameters are as follows: healthy human blood was taken, sodium citrate at a concentration of 3.8% was added as an anticoagulant, centrifuged at 1000r/min for 10min, the upper Platelet Rich Plasma (PRP) was collected, diluted with physiological saline (platelet rich plasma/physiological saline=1/4.5), and then a membrane sample (1 cm ×1 cm) was placed in the above diluted solution, and the temperature was kept at 37 ℃ for 0.5h. After sample removal, the samples were rinsed 3 times with phosphate buffered saline (PBS, ph=7.4) and fixed with a 2% glutaraldehyde solution at 4 ℃. After 24h removal, the platelets were dried at room temperature, observed under a DMBA 400-type optical microscope (Motic) for adsorption, and the attached platelets were counted using a microphotography technique.
Example 2
The method comprises the following specific steps:
(1) At normal temperature, 4g of dehydrated and deoxidized poly (1, 6-hexanediol) diol is taken and dissolved in 50ml of N, N-dimethylformamide; heating to 40-60deg.C for use;
(2) Dissolving 0.6g of 4,4' -diphenylmethane diisocyanate in 50ml of N, N-dimethylformamide at normal temperature; slowly adding the mixture into the poly (1, 6-hexanediol carbonate) glycol solution in the step (1) to continuously react to obtain a prepolymer A;
(3) Adding 0.176ml of tri (2-amino ethyl) amine into the prepolymer A, heating to 70-90 ℃, and continuously reacting to obtain a prepolymer B;
(4) Adding 0.071g of 2-methacryloyloxyethyl phosphorylcholine into the prepolymer B, and cooling to 40-50 ℃ to obtain a prepolymer C.
(5) To the prepolymer C was added 0.36g of diamino capped polyethylene glycol to 40-50℃and the reaction was completed.
After the polycarbonate polyurethane prepared in the above example 2 and comparative example 1 was separated and purified, a thin film (outer film) was formed on the outer surface of the electrochemical biosensor by dip coating, and response current curves were measured in glucose solutions of different concentrations.
Wherein the electrochemical biosensor is a double-electrode electrochemical sensor disclosed in the prior art (CN 114767105A), the working electrode is platinum iridium alloy, and the reference electrode is silver/silver chloride electrode.
Fig. 3 shows response current curves of glucose sensors prepared by using different outer membranes (example 2 and comparative example 1), and it can be seen that the addition of the polyurethane membrane modified by the diamino terminated polyethylene glycol in example 2 has a good diffusion limiting effect on glucose which is a small molecular substance to be detected, and the prepared sensor has excellent in-vitro linearity performance. Whereas the sensor prepared without any optimized polyurethane film in comparative example 1 had no channel for glucose diffusion, and could not be used for glucose detection.
In other embodiments, the glucose diffusion barrier formed by modifying the polyurethane film with a diamino terminated polyethylene glycol or an amino terminated polyethylene glycol is also suitable for small molecules such as lactic acid, uric acid, ascorbic acid, and the like. In other embodiments, the flux of small molecule diffusion may be varied by varying the amount of cross-linking agent and the amount of polyethylene glycol.
Example 3
The method comprises the following specific steps:
(1) At normal temperature, taking 2g of dehydrated and deoxidized poly (1, 6-hexanediol) glycol carbonate to be dissolved in 20ml of N, N-dimethylformamide; heating to 40-60deg.C for use;
(2) At normal temperature, 5g of bis (3-aminopropyl) terminated poly (dimethylsiloxane) is taken and dissolved in 30ml of N, N-dimethylformamide and added to the poly (1, 6-hexanediol carbonate) glycol solution of step (1);
(3) Dissolving 0.75g of 4,4' -diphenylmethane diisocyanate in 50ml of N, N-dimethylformamide at normal temperature; slowly adding the mixture into the solution in the step (2), and continuously reacting to obtain a prepolymer A;
(4) Adding 0.131ml of tri (2-amino ethyl) amine into the prepolymer A, heating to 70-90 ℃, and continuously reacting to obtain a prepolymer B;
(5) 0.088g of 2-methacryloyloxyethyl phosphorylcholine is added into the prepolymer B, and the temperature is reduced to 40-50 ℃ to obtain a prepolymer C.
(6) Adding 0.45g of diamino end-capped polyethylene glycol into the prepolymer C to 40-50 ℃ and reacting until the reaction is finished;
After the polycarbonate polyurethane prepared in the above example 3 was separated and purified, a thin film was formed on the surface of the electrochemical biosensor by dip-coating, and the test was performed in a glucose solution of 20 mmol/L.
Wherein the electrochemical biosensor is a double-electrode electrochemical sensor disclosed in the prior art (CN 114767105A), the working electrode is platinum iridium alloy, and the reference electrode is silver/silver chloride electrode.
The test method is as follows: inert gases such as nitrogen or argon are continuously introduced into the glucose solution (20 mmol/L) in a test environment so as to drive off oxygen in the glucose solution, and the oxygen is monitored in real time by an oxygen analyzer, and the specific test result is shown in FIG. 4.
Referring to fig. 4, the oxygen content has little influence on the performance of the sensor, and it can be seen that the introduction of silane into the biocompatible polycarbonate polyurethane disclosed by the application can also improve the oxygen permeability of the polyurethane film, so that the electrochemical sensor requiring oxygen to participate in reaction can be effectively detected in a human body hypoxia environment (0.6-0.9 mg/L).
In other embodiments, a crosslinking agent such as glutaraldehyde, glutaric acid, EDC, etc. may be added to promote the crosslinking reaction between the components based on example 3.
While certain embodiments have been described, these embodiments are presented by way of example only and are not intended to limit the scope of protection. Indeed, the various features and attributes disclosed in the present application may be combined in different ways to form additional embodiments, all of which fall within the scope of the present application.
While the application provides certain preferred embodiments and applications, other embodiments, including embodiments that do not provide all of the features and advantages described herein, which will be apparent to one of ordinary skill in the art are also within the scope of the application.

Claims (11)

1. A biocompatible polycarbonate polyurethane comprising the reaction product of the directional polymerization of the following raw material components:
(a) An isocyanate composition which is an isocyanate having at least two isocyanate groups,
(B) An isocyanate-reactive group containing component selected from a polycarbonate polyol, a polycarbonate polyamine, or a mixture thereof,
Optionally (c), hydroxy or amino end-capping compounds,
(D) A chain extender, wherein the chain extender is tri (2-amino ethyl) amine,
(E) A modifying component comprising 2-methacryloyloxyethyl phosphorylcholine and a diamino-terminated polyethylene glycol, and
Optionally (f) a cross-linking agent, said (f) being different from said (d);
the polyurethane chain segment obtained after the reaction of the (a), (b) and (d) contains active sites.
2. The polycarbonate polyurethane of claim 1, wherein: the raw material component comprises the (c), wherein the (c) is selected from dihydroxy end-capped polysiloxane, diamino end-capped polysiloxane or a mixture thereof.
3. The polycarbonate polyurethane of claim 1, wherein: the raw material component comprises (f) which is any one selected from glutaraldehyde, glutaric acid and EDC.
4. A process for the preparation of a polycarbonate polyurethane as defined in any one of claims 1 to 3, comprising the steps of:
(1) Forming an isocyanate-terminated polyurethane prepolymer A by reacting said (a), said (b) and optionally said (c) in an organic solvent,
(2) Chain-extending the polyurethane prepolymer A with the (d) to obtain a polyurethane prepolymer B,
(3) Modifying said polyurethane prepolymer B with said (e) and optionally said (f), and
Optionally, a separation and purification step.
5. The method of manufacturing according to claim 4, wherein: the molar quantity of isocyanate groups in the (a) is X, the molar total quantity of hydroxyl groups and/or amino groups in the (b) is Y, and the ratio of X to Y is 1<X/Y less than or equal to 1.5.
6. The method of manufacturing according to claim 4, wherein: the polyurethane prepolymer B contains active amino and/or hydroxyl groups.
7. The method of manufacturing according to claim 4, wherein: the content of (c) is 0 to 30% by weight relative to 100% by weight of the polyurethane prepolymer A.
8. The method of manufacturing according to claim 4, wherein: the molar ratio of the total amount of amino groups and/or hydroxyl groups in (d) to the molar amount of isocyanate groups in the polyurethane prepolymer A is 0.8-1.2.
9. The method of manufacturing according to claim 4, wherein: the content of (e) is 10 to 20% by weight based on 100% by weight of the polyurethane prepolymer B.
10. The method of manufacturing according to claim 4, wherein: the content of (f) is 0 to 10% by weight relative to 100% by weight of (e).
11. Use of a polycarbonate polyurethane according to any of claims 1 to 3, wherein: the polycarbonate polyurethane is applied to implantable medical devices in a film form.
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