CN112079961B - Crosslinked polymer, preparation method thereof, drug loading body and biomedical implant material - Google Patents
Crosslinked polymer, preparation method thereof, drug loading body and biomedical implant material Download PDFInfo
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- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
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- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/10—Materials for lubricating medical devices
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses
Abstract
Disclosed is a crosslinked polymer comprising a first repeating unit represented by the following general formula (1), a second repeating unit represented by the general formula (2), and a third repeating unit represented by the general formula (3). The invention also discloses a preparation method of the crosslinked polymer. The invention also discloses a preparation method of the cross-linked polymer. The invention also discloses a drug loading body. The invention also discloses a biomedical implant material.
Description
Technical Field
The invention relates to the technical field of functional materials, in particular to a cross-linked polymer and a preparation method thereof, a drug loading body and a biomedical implant material.
Background
With the rapid development of biomedicine, biomaterials and tissue engineering in recent years, titanium-based biomedical implants have been widely used in clinical treatment of dentistry and orthopedic plastic due to their excellent biocompatibility, osteoconductivity and mechanical properties. However, titanium-based biomedical implants are very susceptible to viral infection due to their lack of antimicrobial activity. Furthermore, implants with poor lubrication properties can cause damage to the soft tissues of the body, leading to a series of consecutive complications.
However, few previous studies have been able to combine the antibacterial and lubricating properties of biomedical implants well. For example, the surface of biomedical implants has been modified with various hydrophilic coatings to improve their lubricious properties, but hydrophilic coatings tend to have poor bacterial resistance.
Disclosure of Invention
Accordingly, it is necessary to provide a crosslinked polymer, a method for preparing the same, a drug-loaded body, and a biomedical implant material, which are directed to the problems of bacterial resistance and poor lubrication effect of biomedical implants.
A crosslinked polymer comprising a first repeating unit represented by the following general formula (1), a second repeating unit represented by the following general formula (2), and a third repeating unit represented by the following general formula (3):
wherein, in the general formula, R1 is a direct bond, alkylene, substituted alkylene, alkoxy or substituted alkoxy, R2 is a direct bond, alkylene, substituted alkylene, alkoxy or substituted alkoxy,
in one embodiment, the substituent in the substituted alkylene is any one or more of hydroxyl, acyl, carboxyl, sulfydryl and amino, and the substituent in the substituted alkoxy is any one or more of hydroxyl, acyl, carboxyl, sulfydryl and amino.
In one embodiment, the substituted alkoxy group is a structure represented by general formula (4):
in one embodiment, the crosslinked polymer is a repeating structure represented by general formula (8):
wherein r represents the random arrangement of the repeating units.
In one embodiment, the molar ratio of each repeating unit in the crosslinked polymer is (1-2): (6.5-7.5): (90-95).
In one embodiment, the relative molecular mass of the crosslinked polymer is from 104.7kDa to 418.4 kDa.
A method for producing the crosslinked polymer, comprising the step of polymerizing a first monomer represented by the general formula (5), a second monomer represented by the general formula (6), and a third monomer represented by the general formula (7),
in one embodiment, the first monomer is prepared by the steps of: reacting dopamine hydrochloride with a double bond-containing compound under alkaline conditions, wherein the double bond-containing compound is selected from any one or two of methacrylic anhydride and glycerol methacrylate.
In one embodiment, the second monomer is prepared by the following steps: and (2) reacting the 6-amino-beta-cyclodextrin with a double bond-containing compound, wherein the double bond-containing compound is any one or two of methacrylic anhydride and glycerol methacrylate.
In one embodiment, the molar ratio of the first monomer to the second monomer to the third monomer is (4.5-5.5) to (2.5-3.5) to (4.5-5.5).
A drug carrier obtained by loading a drug with the crosslinked polymer.
A biomedical implant material comprises a base material and the cross-linked polymer or the drug loading body loaded on the base material, wherein the base material is selected from a pure titanium or titanium alloy base material.
The crosslinked polymers of the invention include random copolymers of modified dopamine, modified cyclodextrin and 2-Methacryloyloxyethyl Phosphorylcholine (MPC). The phosphorylcholine group in the 2-methacryloyloxyethyl phosphorylcholine is a hydrophilic end group of a basic unit (such as lecithin and the like) forming a cell membrane, and is an outermost group in an outer cell membrane, so that the MPC polymer has very good cell compatibility. On the other hand, on the surface of the material modified by the MPC polymer, the phosphorylcholine groups can be combined with water molecules to form a hydrated layer, and the material has the effects of lubrication, protein adsorption resistance and the like. Dopamine, as a molecular structural mimetic of adhesion proteins, can form strong covalent and non-covalent interactions with almost all types of inorganic and organic substances by self-polymerization. The cavity structure of the cyclodextrin molecule can include drug molecules (such as antibacterial or lubricating drugs) so as to improve the stability of the drug molecules and realize the slow release of the drugs. The invention carries out polymerization after modifying the three substances to obtain the cross-linked polymer which can form a coating on the surface of the titanium-based biomedical implant, and the cross-linked polymer coating simultaneously has the hydration lubrication characteristic of MPC, the adhesion of dopamine and the drug-carrying release performance of cyclodextrin, thereby providing a favorable foundation for the adaptability of the biomedical implant in vivo.
Drawings
FIG. 1 shows a DMA of an embodiment of the present invention 1 H NMR spectrum;
FIG. 2 shows an embodiment of the invention of MA-beta-CD 1 H NMR spectrum;
FIG. 3 is a cross-linked terpolymer of one embodiment of the present invention 1 H NMR spectrum;
FIG. 4 is an XPS spectrum of a ternary cross-linked polymer modified titanium alloy biomedical implant material and an unmodified titanium alloy in accordance with one embodiment of the present invention;
FIG. 5 is a result chart of the bacteriostasis experiment of the titanium alloy biomedical implant material after drug loading according to one embodiment of the present invention;
fig. 6 is a bacteriostatic test result diagram of an unmodified titanium alloy sheet.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
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 invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
An embodiment of the present invention provides a crosslinked polymer including a first repeating unit represented by the following general formula (1), a second repeating unit represented by the general formula (2), and a third repeating unit represented by the general formula (3):
the crosslinked polymers of the invention include random copolymers of modified dopamine, modified cyclodextrin and 2-Methacryloyloxyethyl Phosphorylcholine (MPC). The phosphorylcholine group in the 2-methacryloyloxyethyl phosphorylcholine is a hydrophilic end group of a basic unit (such as lecithin and the like) forming a cell membrane, and is an outermost group in an outer cell membrane, so that the MPC polymer has very good cell compatibility. On the other hand, on the surface of the material modified by the MPC polymer, the phosphorylcholine groups can be combined with water molecules to form a hydrated layer, and the material has the effects of lubrication, protein adsorption resistance and the like. Dopamine, as a molecular structure mimetic of adhesion proteins, can form strong covalent and noncovalent interactions with almost all types of inorganic and organic substances by self-polymerization. The cavity structure of the cyclodextrin molecule can include drug molecules (such as antibacterial or lubricating drugs) so as to improve the stability of the drug molecules and realize the slow release of the drugs. The invention carries out polymerization after modifying the three substances to obtain the cross-linked polymer which can form a coating on the surface of the titanium-based biomedical implant, and the cross-linked polymer coating simultaneously has the hydration lubrication characteristic of MPC, the adhesion of dopamine and the drug-carrying release performance of cyclodextrin, thereby providing a favorable foundation for the adaptability of the biomedical implant in vivo.
Wherein, in the general formula, R1 is a direct bond, alkylene, substituted alkylene, alkoxy or substituted alkoxy, and R2 is a direct bond, alkylene, substituted alkylene, alkoxy or substituted alkoxy.
"alkylene" refers to a hydrocarbon group derived from an alkyl group by removal of one hydrogen atom to form a center with two monovalent radicals, which may be a saturated branched alkyl or a saturated straight chain alkyl. For example, "C 1 ～C 9 By "alkylene" is meant an alkyl moiety containing from 1 to 9 carbon atoms and, at each occurrence, being independently C 1 Alkylene radical, C 4 Alkylene radical, C 5 Alkylene radical, C 6 Alkylene radical, C 7 Alkylene radical, C 8 Alkylene or C 9 An alkylene group. Suitable examples include, but are not limited to: methylene (-CH) 2 -), 1-ethyl (-CH (CH) 3 ) -), 1, 2-Ethyl (-CH) 2 CH 2 -), 1-propyl (-CH (CH) 2 CH 3 ) -), 1, 2-propyl (-CH) 2 CH(CH 3 ) -), 1, 3-propyl (-CH) 2 CH 2 CH 2 -) and 1, 4-butyl (-CH) 2 CH 2 CH 2 CH 2 -). The "alkylene group" herein includes straight-chain hydrocarbons or hydrocarbons having a branched chain.
"alkoxy" refers to a group having an-O-alkylene group, i.e., an alkylene group as defined above, attached to the parent core structure via an oxygen atom. Phrases containing the term, e.g., "C 1 ～C 9 Alkoxy "means an alkylene moiety containing from 1 to 9 carbon atoms and, at each occurrence, may be independently C 1 Alkoxy radical, C 4 Alkoxy radical, C 5 Alkoxy radical, C 6 Alkoxy radical, C 7 Alkoxy radical, C 8 Alkoxy or C 9 An alkoxy group. Suitable examples include, but are not limited to: methyleneoxy (-O-CH) 2 -), 1, 2-ethoxy (-CH) 2 CH 2 -O-) and 1, 4-butoxy (-CH) 2 CH 2 CH 2 CH 2 -O-)。
"substituted alkylene" means that on the basis of alkylene at least one carbon atom has a hydrogen replaced by a substituent other than hydrogen and alkyl, such as hydroxy, acyl, carboxy, hydroxy, alkoxy, or the like,And (3) any one or more of sulfydryl and amino. For example, if a hydrogen on a carbon atom of an alkylene group is replaced with a non-alkyl group, the resulting substituted alkylene groups are each hydroxy alkylene groups (e.g., -CH) 2 CHOH-), aminoalkyl (e.g., -CHNH-) 2 -) or an alkylenemercapto group (e.g., -CH 2 CHSH-). Phrases containing the term, e.g., "C 1 ～C 9 Substituted alkylene "refers to substituted alkylene containing 1 to 9 carbon atoms, and at each occurrence, may be independently C 2 Substituted alkylene, C 3 Substituted alkylene, C 4 Substituted alkylene, C 5 Substituted alkylene, C 7 Substituted alkylene, C 8 Substituted alkylene or C 9 A substituted alkylene group.
Similarly, a "substituted alkoxy" is an alkoxy as defined above wherein the hydrogen on at least one carbon atom is replaced by a non-hydrogen and a non-alkyl group, such as any one or more of hydroxy, acyl, carboxy, mercapto, amino.
In some embodiments, the substituent is a hydroxyl group and the substituted alkoxy group is a structure represented by general formula (4):
the substituted alkoxy group may be suitable for use in the first repeat unit or the second repeat unit.
In some embodiments, the crosslinked polymer is a repeating structure represented by general formula (8):
wherein r represents a random arrangement of the respective repeating units. That is, the crosslinked polymer is a random copolymer of the first repeating unit, the second repeating unit, or the third repeating unit. After polymerization, each repeat unit may be directly linked to the same repeat unit itself or may be linked to two more repeat units. Directly linked to the first repeat unit may be the first repeat unit, the second repeat unit, or the third repeat unit; directly linked to the second repeat unit may be the first repeat unit, the second repeat unit, or the third repeat unit; directly linked to the third repeat unit may be the first repeat unit, the second repeat unit or the third repeat unit. Preferably, the number of consecutive linkages of the same repeating unit in the crosslinked polymer is less than 5.
In some embodiments, the molar ratio of each repeating unit in the crosslinked polymer is (1-2): (6.5-7.5): (90-95): the first repeating unit: the second repeating unit: the third repeating unit.
In some embodiments, the relative molecular mass of the crosslinked polymer is from 104.7KDa to 418.4 KDa.
An embodiment of the present invention further provides a method for producing a crosslinked polymer according to any one of the above embodiments, including a step of polymerizing a first monomer represented by general formula (5), a second monomer represented by general formula (6), and a third monomer represented by general formula (7).
In some embodiments, the step of preparing the first monomer is: reacting dopamine hydrochloride with a compound containing double bonds under alkaline conditions. The double bond-containing compound may be selected from either or both of methacrylic anhydride and glycerol methacrylate.
In some embodiments, the step of preparing the second monomer is: 6-amino-beta-cyclodextrin is reacted with a compound containing a double bond. The double bond-containing compound may be selected from either or both of methacrylic anhydride and glycerol methacrylate.
In some embodiments, the molar ratio of the first monomer to the second monomer to the third monomer is (4.5-5.5) to (2.5-3.5) to (4.5-5.5).
The embodiment of the invention also provides a drug loading body, which is obtained by loading a drug on the cross-linked polymer of any embodiment. The medicament is selected from antibacterial, analgesic, lubricant, bone repairing medicine, etc.
The embodiment of the invention also provides a biomedical implant material, which comprises a base material and the cross-linked polymer or the drug loading body of any embodiment loaded on the base material. The base material is selected from pure titanium or titanium alloy base materials.
Compared with the traditional biomedical implant material, the invention has at least the following outstanding advantages:
firstly, the ternary cross-linked polymer synthesized by the invention simultaneously has the hydration lubrication characteristic of MPC, the adhesion of dopamine and the drug-carrying and releasing performance of cyclodextrin.
Secondly, the invention combines the lubricating function and the medicine carrying function, and improves the surface lubricating effect of the titanium-based biomedical implant material from two aspects of lubrication and medicine release. The medicine carrying function of the cyclodextrin can also be loaded with a lubricant, so that the surface lubrication effect of the titanium-based biomedical implant material is improved.
Thirdly, the invention provides a new idea for modifying double bonds by cyclodextrin or dopamine by utilizing the ring-opening reaction of the epoxy functional group and the amino functional group in the aqueous solution.
The following are specific examples.
Example 1
Synthesis of Dopamine Methacrylamide (DMA):
(1) weighing 10g of dopamine hydrochloride into a 500mL flask, adding 20mL of ultrapure water to dissolve the solid, plugging the bottle mouth with a rubber plug in time, adding 20g of sodium borate and 8g of sodium bicarbonate as catalysts during the weighing and dissolving process, and magnetically stirring the solid to dissolve;
(2) weighing 9.4mL of methacrylic anhydride, adding 50mL of Tetrahydrofuran (THF) and uniformly stirring;
(3) adding the THF solution into dopamine hydrochloride phase dropwise through a constant pressure dropping funnel under the condition of stirring, then adjusting the pH of the solution to 8.5 by using 0.2mol/L NaOH solution, and reacting in N 2 Continuously stirring for 12h under the atmosphere;
(4) adjusting the pH of the reacted solution to be below 2 by using 0.2mol/L dilute hydrochloric acid solution to obtain slurry liquid, extracting twice by using 100mL ethyl acetate, collecting an organic phase, drying the organic phase by using excessive anhydrous magnesium sulfate, and performing suction filtration to keep the organic phase;
(5) slowly adding petroleum ether (more than 500mL) into the organic phase under the condition of stirring by a glass rod for recrystallization until no solid is generated any more, carrying out suction filtration under reduced pressure to obtain white to light pink powdery solid, and drying in vacuum for later use, wherein the yield is about 70%. Of DMA 1 The H NMR spectrum is shown in FIG. 1.
Synthesis of double bond-containing beta-cyclodextrin (MA-beta-CD):
(1) weighing 113mg of 6-amino-beta-cyclodextrin and 28.4mg of Glycerol Methacrylate (GMA) in a 50mL flask, adding 10mL of ultrapure water to dissolve the solid, plugging the flask opening with a rubber plug in time, and magnetically stirring for 5 hours;
(2) after the reaction, the solution was dialyzed against water and lyophilized, and the yield was 90%. Of MA-beta-CD 1 The H NMR spectrum is shown in FIG. 2.
Synthesis of ternary crosslinked Polymer (MPC-DMA-CD):
(1) weighing 15mg MPC, 10mg DMA and 40mg MA-beta-CD in a 50mL flask, adding 3mL DMF to dissolve solid, plugging a bottle mouth with a rubber plug in time, introducing nitrogen for 30min to remove oxygen;
(2)1mL THF solution is dissolved with 0.5mg Azobisisobutyronitrile (AIBN), and the solution is added under the protection of nitrogen;
(3) the reaction temperature is 65 ℃, the stirring is carried out for 12h, and after the reaction is finished, the ternary cross-linked polymer product MPC-DMA-CD is obtained by dialysis and freeze-drying in aqueous solution. Of ternary crosslinked polymeric products 1 The H NMR spectrum is shown in FIG. 3.
The chemical reaction equation for the preparation of crosslinked polymers is shown below:
preparing a titanium alloy biomedical implant material:
titanium alloy sheet (Ti) having one polished surface 6 Al 4 V) immersion ternaryThe concentration of the polymer in the aqueous solution was 2 Mg/mL. Taking out the titanium alloy sheet after 24 hours, and vacuum drying the titanium alloy biomedical implant material (Ti) modified by the ternary cross-linked polymer 6 Al 4 V @ DMA-MPC-CD). XPS spectra of the titanium alloy biomedical implant material modified by the ternary cross-linked polymer and the unmodified titanium alloy are shown in FIG. 4.
Example 2
Synthesis of dopamine containing double bonds:
(1) weighing 10g of dopamine hydrochloride into a 500mL flask, adding 20mL of ultrapure water to dissolve the solid, plugging a bottle opening with a rubber plug in time, adding 20g of sodium borate and 8g of sodium bicarbonate as catalysts during weighing and dissolving processes, and magnetically stirring the solid to dissolve;
(2) weighing 7.5g of glycerol methacrylate, adding 50mL of Tetrahydrofuran (THF) and uniformly stirring;
(3) adding the THF solution into dopamine hydrochloride phase dropwise through a constant pressure dropping funnel under the condition of stirring, then adjusting the pH of the solution to 8.5 by using 0.2mol/L NaOH solution, and reacting in N 2 Continuously stirring for 12h under the atmosphere;
(4) adjusting the pH of the reacted solution to be below 2 by using 0.2mol/L dilute hydrochloric acid solution to obtain slurry liquid, extracting twice by using 100mL ethyl acetate, collecting an organic phase, drying the organic phase by using excessive anhydrous magnesium sulfate, and performing suction filtration to keep the organic phase;
(5) slowly adding petroleum ether (more than 500mL) into the organic phase under the condition of stirring by a glass rod for recrystallization until no solid is generated, performing suction filtration under reduced pressure to obtain white to light pink powdery solid, and performing vacuum drying for later use, wherein the yield is about 70%.
Synthesis of beta-cyclodextrin methacrylamide:
0.9g of 6-amino-. beta. -cyclodextrin was weighed out and dissolved in 50mL of NaHCO 3 (0.52g) in the aqueous solution, the pH of the solution was adjusted to about 10 with NaOH as a solid. 150. mu.L of methacrylic anhydride was added dropwise thereto, and the mixture was stirred in an ice bath, and after 6 hours of the reaction, the stirring was stopped. The reacted solution was partially distilled off under reduced pressure to leave about 15mL of the solution, and then added dropwise to 250mL of glacial acetoneThe suspension was filtered to give a white solid as crude product. After placing in a 40 ℃ vacuum oven overnight, the reaction mixture was dried with methanol: water 3: 1, then dropping the solid into 250mL of glacial acetone, filtering and drying to obtain the pure product of beta-cyclodextrin methacrylamide.
The chemical reaction equation for the compound synthesis is as follows:
synthesis of ternary crosslinked Polymer (MPC-DMA-CD):
(1) weighing 15mg MPC, 10mg dopamine containing double bonds and 40mg beta-cyclodextrin methacrylamide in a 50mL flask, adding 3mL DMF to dissolve solids, plugging a bottle opening with a rubber plug in time, and introducing nitrogen for 30min to remove oxygen;
(2)1mL of THF solution is dissolved with 0.5mg of Azobisisobutyronitrile (AIBN), and the solution is added under the condition of nitrogen protection;
(3) the reaction temperature is 65 ℃, the stirring is carried out for 12 hours, and after the reaction is finished, the ternary crosslinking polymer product is obtained by dialysis and freeze-drying in aqueous solution.
The titanium alloy biomedical implant material prepared in example 1 was subjected to the following experiment:
1. lubricating property test experiment:
(1) and (3) adhering the aminated polystyrene microsphere (PS, the diameter is approximately equal to 5 mu m) to the tip of the AFM cantilever without the tip by using ultraviolet curing glue, curing the aminated polystyrene microsphere under the ultraviolet to prepare the AFM friction probe, and irradiating the AFM friction probe for 40 minutes by using ultraviolet.
(2) The friction force between the titanium alloy biomedical implant material and the PS microspheres was tested using atomic force microscopy (transverse force mode). The pressure between the PS microspheres (upper sample) adhered on the AFM probe and the titanium alloy biomedical implant material surface coating (lower sample) is controlled to be between 100nN and 500nN, the reciprocating frequency is controlled to be between 1.0Hz and 3.0Hz, and the friction test is carried out in a water environment. The average value of the friction coefficient was 0.056.
The titanium alloy sheet of unmodified terpolymer exhibited a coefficient of friction of about 0.131.
2. Carrying out medicine loading:
adding the titanium alloy biomedical implant material into ciprofloxacin hydrochloride antibacterial drug solution with the concentration of 2mg/mL, and carrying out 150r min in a shaking table at room temperature -1 Oscillate for 4 h. And after being cleaned by deionized water, the titanium alloy surface coating is dried in vacuum, so that the titanium alloy surface coating has a sterilization function.
3. Bacteriostatic experiments:
gram-positive bacteria staphylococcus aureus (s. aureus) and gram-negative bacteria escherichia coli (e. coli) are selected as strains.
(1) Carrying the drug on the titanium alloy biomedical implant material (Ti) 6 Al 4 V @ DMA-MPC-CD) and unmodified titanium alloy sheet (Ti) 6 Al 4 V) sterilizing and disinfecting for 30min under an ultraviolet lamp, and sterilizing the pipette tip, the liquid and the solid culture medium for 2h by high-temperature steam.
(2) Respectively taking 20 mu L of the thawed staphylococcus aureus and escherichia coli strains to be cultured in 25mL of liquid culture medium by a shaking table for 12h (the rotating speed is 200r min) -1 ) By dilution to a concentration of 1X 10 7 CFU mL -1 The bacterial suspension of (1).
(3)Ti 6 Al 4 Samples V (bare or copolymer coated, four samples in total in parallel) were placed in petri dishes containing 4mL of LB medium and 40. mu.L of the above-described Staphylococcus aureus or Escherichia coli suspension, respectively. Then adding Ti 6 Al 4 V samples were cultured in an aerobic incubator at 37 ℃ for 24 h.
(4) After 24h, the Ti was rinsed with Phosphate Buffered Saline (PBS) respectively 6 Al 4 V samples, then fixed with 2.5% glutaraldehyde at 4 ℃ for 30 minutes, followed by dehydration of the ethanol solution. Finally, coating on Ti by a coating system 6 Al 4 V substrates were sputtered with a thin layer of platinum and examined using SEM.
As shown in FIGS. 5 and 6, the number of colonies on the surface of the titanium alloy biomedical implant material after 1 day of culture was about 5.4X 10 5 CFU mL -1 . The colony number of the surface of the unmodified ternary cross-linked polymer and the titanium alloy sheet without carrying the medicine is about 6.0 multiplied by 10 6 CFU mL -1 。
All possible combinations of the technical features of the above embodiments may not be described for the sake of brevity, but should be considered as within the scope of the present disclosure as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (4)
1. A process for producing a crosslinked polymer, which comprises the step of polymerizing a first monomer represented by the general formula (5), a second monomer represented by the general formula (6) and a third monomer represented by the general formula (7) at a molar ratio of (4.5 to 5.5) to (2.5 to 3.5) to (4.5 to 5.5) to each other,
wherein R1 is a direct bond, alkylene, substituted alkylene, alkoxy or substituted alkoxy, R2 is a direct bond or a linking group of the structure represented by the general formula (4):
the second monomer is prepared by a process comprising the steps of: reacting 6-amino-beta-cyclodextrin with a compound containing double bonds to obtain the second monomer; wherein, the double bond-containing compound is selected from any one or two of methacrylic anhydride and glycerol methacrylate.
2. The method for preparing a crosslinked polymer according to claim 1, wherein the substituent of the substituted alkylene group is any one or more of a hydroxyl group, an acyl group, a carboxyl group, a mercapto group, and an amino group, and the substituent of the substituted alkoxy group is any one or more of a hydroxyl group, an acyl group, a carboxyl group, a mercapto group, and an amino group.
3. The method for producing a crosslinked polymer according to claim 1, wherein the substituted alkoxy group has a structure represented by general formula (4):
4. the method for producing a crosslinked polymer according to any one of claims 1 to 3, wherein the first monomer is produced by: reacting dopamine hydrochloride with a double bond-containing compound under alkaline conditions, wherein the double bond-containing compound is selected from any one or two of methacrylic anhydride and glycerol methacrylate.
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