CN110724245A - Injectable polyurethane and process for its preparation - Google Patents
Injectable polyurethane and process for its preparation Download PDFInfo
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- 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
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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Abstract
The invention relates to injectable polyurethane and a preparation method thereof, belonging to the field of medical biomaterials. The invention aims to solve the problems of high curing expansion rate, environment friendliness and the like of the existing medical polyurethane material, and the technical scheme is to provide C2～6Polyols and C8～18Use of an ester of a fatty acid as a soft segment for the preparation of an injectable polyurethane, wherein said ester contains more than two hydroxyl groups. The injectable polyurethane material prepared by the invention has the advantages of low curing expansion rate, environmental friendliness, high biological safety and wide application prospect.
Description
Technical Field
The invention relates to injectable polyurethane and a preparation method thereof, belonging to the field of medical biomaterials.
Background
Urethane copolymers, namely Polyurethanes (PU), are a generic name for polymers having a repeating urethane bond (-NH-COO-) in the main chain. Because of its excellent physicochemical properties, flexible regulation and control properties and good biocompatibility, it is widely used in the fields of many medical instruments and artificial organ devices, such as artificial blood vessels, artificial hearts, artificial skins, artificial catheters, artificial cartilages, nerve catheters, etc. However, the existing polyurethane-based biomaterial mainly uses the polyurethane material with excellent mechanical properties and good stability after being cured, and the injectable properties of polyurethane have not been studied deeply.
For example, Du Jing et al reported that a castor oil-based polyurethane/nano-Hydroxyapatite (HA) composite bone repair scaffold material (Du J.J., ZuoY, Zuo Q., Sun B., Zhou M.B., Li L.M., ManY, Li Y.B.preparation and in vitro evaluation of polyurethane composite scaffold based on a glycidyl-esterified catalyst and a hydroxy phosphate [ J ] material research Innovations,2014,18(3):160-168.), and the results showed that the three-dimensional scaffold HAs good mechanical properties and biocompatibility. However, the scaffold material prepared by the synthesis technology is highly cross-linked and has no injectability.
The applicant's earlier patent application No. 201210554248.3 entitled injectable fast curing medical Polyurethane composition and preparation method, and LiK, Zuo Y, Zou Q, et al Synthesis and Characterization of injectable Nano-Hydroxyapatite Composite (injectable Nano-Hydroxyapatite/Polyurethane Composite instant Formulations for management of Osteoporosis [ J ]. Journal of Nanocosis and Nanocontrology, 2016,16(12): 12407-12417) reported by LiK, Zuo Y, Zou Q, et al, although the art relates to bone cement materials having injectable properties, the above materials have a high expansion rate of setting (up to 1.5%), may cause a large stress stimulation to the filled site after curing, therefore, the requirement of the injectable material on the oral root canal application standard (YY 0717 dental root canal sealing material) is difficult to meet (the standard requires that the expansion rate is less than or equal to 0.1 percent). Moreover, as the macromolecule polyol polymers used in the soft polyurethane segment, such as polyethylene glycol, polytetrahydrofuran ether glycol, polypropylene glycol, polyether triol, and the like, belong to downstream products in the petroleum industry, with the gradual depletion of petroleum resources and the increasing demand for environmental protection, the development of novel and environmentally-friendly materials is particularly important.
Therefore, the material formula and the process need to be further optimized, and more injectable materials with advantageous characteristics are provided for clinical application.
Disclosure of Invention
The invention aims to provide injectable polyurethane and a preparation method thereof, and solves the problems of high curing expansion rate, environmental friendliness and the like of the existing medical polyurethane material.
The invention provides C2～6Polyols and C8～18Use of an ester of a fatty acid as a soft segment for the preparation of an injectable polyurethane, wherein said ester contains more than two hydroxyl groups.
Further, the curing expansion rate of the injectable polyurethane is less than or equal to 0.5 percent.
Preferably, the injectable polyurethane has a cure swell ratio of 0.1% or less.
Further preferably, the injectable polyurethane has a cure expansion ratio of 0.03% or less.
Further, the hydroxyl value of the ester is 10-500 mg KOH/g.
Preferably, the hydroxyl value of the ester is 50-300 mg KOH/g.
Further preferably, the hydroxyl value of the ester is 100-250 mg KOH/g.
Further, said C2-6The polyol is glycerol.
Further, the ester is derived from a vegetable oil.
Preferably, the vegetable oil is selected from one or more of tung oil, linseed oil, soybean oil, cottonseed oil, castor oil, dehydrated castor oil and coconut oil.
Further preferably, the vegetable oil is castor oil.
Further, when the number of hydroxyl groups contained in the vegetable oil is less than 2, the modification is carried out by adopting the following method:
mixing vegetable oil with C2-6And carrying out alcoholysis reaction on the polyhydric alcohol to obtain the ester containing more than two hydroxyl groups.
Further, said C2-6The polyalcohol is trimethylolpropane or glycerol.
Preferably, said C2-6The polyol is glycerol.
Further, said C2-6The mass ratio of the polyhydric alcohol to the vegetable oil is 1 (0.2-0.8).
Preferably, said C2-6The mass ratio of the polyhydric alcohol to the vegetable oil is 1 (0.3-0.5).
Further, carrying out alcoholysis reaction at 180-250 ℃.
Further, the alcoholysis reaction time is 1-8 h.
Further, the alcoholysis reaction is carried out under a protective atmosphere.
Further, the catalyst is one or more than two of calcium oxide, lead oxide and calcium naphthenate.
Preferably, the catalyst is calcium oxide or calcium naphthenate.
Further, the dosage of the catalyst is vegetable oil and C2-60.01-10% of the total mass of the polyhydric alcohol.
Preferably, the amount of the catalyst is vegetable oil and C2-60.01 to 5% by mass of the total polyol.
The invention provides injectable polyurethane which is prepared from the following raw materials:
prepolymer: soft segment, aliphatic diisocyanate, catalyst and chain extender, wherein,
the soft segment is C2～6Polyols and C8～18Esters of fatty acids, said esters containing more than two hydroxyl groups; and the combination of (a) and (b),
curing agent: the main component is a catalyst;
wherein the isocyanate group in the aliphatic diisocyanate: the molar ratio of hydroxyl groups in the soft segment is (1.0-5.0): 1;
the mass of the catalyst is 0.01-0.5% of the total mass of the soft segment and the aliphatic diisocyanate;
the mass of the chain extender is 1-12% of that of the soft segment;
the mass of the curing agent is 0.1-3% of that of the prepolymer.
Furthermore, the hydroxyl value of the soft segment is 10-500 mg KOH/g.
Preferably, the hydroxyl value of the soft segment is 50-300 mg KOH/g.
Further preferably, the hydroxyl value of the soft segment is 100-250 mg KOH/g.
Further, said C2-6The polyol is glycerol.
Further, the soft segment is derived from vegetable oil.
Preferably, the vegetable oil is selected from one or more of tung oil, linseed oil, soybean oil, cottonseed oil, castor oil, dehydrated castor oil and coconut oil.
Further preferably, the vegetable oil is castor oil.
Further, the aliphatic diisocyanate is one or more selected from isophorone diisocyanate, lysine diisocyanate, 4' -dicyclohexylmethane diisocyanate and hexamethylene diisocyanate.
Preferably, the aliphatic diisocyanate is isophorone diisocyanate.
Further, the isocyanate group in the aliphatic diisocyanate: the molar ratio of hydroxyl groups in the soft segment is (1.2-3.0): 1.
Preferably, the isocyanate groups in the aliphatic diisocyanate: the molar ratio of hydroxyl groups in the soft segment is (1.5-2.0): 1.
Further, the catalyst is a tin-containing catalyst.
Preferably, the catalyst is one or more selected from dibutyltin dilaurate, stannous octoate and stannous chloride.
Further preferably, the catalyst is dibutyltin dilaurate or stannous octoate.
Further, the mass of the catalyst is 0.02-0.05% of the total mass of the soft segment and the aliphatic diisocyanate.
Further, the chain extender is selected from a polyol, a diamine, or a mixture thereof.
Preferably, the chain extender is one or more than two selected from 1, 4-butanediol, 1, 6-hexanediol, glycerol, ethylenediamine, 2-dimethylolpropionic acid and polyethylene glycol.
More preferably, the chain extender is one or more selected from 2, 2-dimethylolpropionic acid, 1, 4-butanediol, ethylenediamine and polyethylene glycol.
Preferably, the molecular weight of the polyethylene glycol is 200-2000.
Further preferably, the molecular weight of the polyethylene glycol is 400-1000.
Further, the mass of the chain extender is 2-6% of that of the soft segment.
Further, the viscosity of the prepolymer is 1000-20000 mPas.
Preferably, the viscosity of the prepolymer is 2000-15000 mPas.
Further preferably, the viscosity of the prepolymer is 2000 to 10000 mPas.
More preferably, the viscosity of the prepolymer is 8400mPa · s.
Further, the prepolymer is prepared by the following method: and under the protective atmosphere, taking the soft segment to perform blending reaction with aliphatic diisocyanate, adding a catalyst to continue the reaction, and adding a chain extender to perform the reaction, thereby obtaining the prepolymer.
Further, the temperature is kept between 40 ℃ and 90 ℃ for reaction.
Preferably, the temperature is kept between 50 and 80 ℃ for reaction.
Further, the blending reaction time is 1-12 h.
Preferably, the blending reaction time is 4-6 h.
And further, adding a catalyst and reacting for 0.5-4 h.
And further, adding a chain extender and reacting for 0.5-10 h.
Preferably, the reaction is carried out for 20min to 5h after the chain extender is added.
Further, the mass of the curing agent is 0.1-1% of that of the prepolymer.
Further, the catalyst is a tin-containing catalyst.
Preferably, the catalyst is one or more selected from dibutyltin dilaurate, stannous octoate and stannous chloride.
Further preferably, the catalyst is dibutyltin dilaurate or stannous octoate.
Further, the curing agent also contains a tertiary amine.
The tertiary amine is added into the curing agent, so that the curing efficiency of the material can be improved, the curing time is shortened, and the crosslinking efficiency is improved.
Further, the tertiary amine is one or more selected from N, N-dimethylcyclohexylamine, bis (2-dimethylaminoethyl) ether, N, N, N ', N' -tetramethylalkylenediamine, triethanolamine and dimethylethanolamine.
Further preferably, the tertiary amine is triethanolamine.
Further, tertiary amine: the mass ratio of the catalyst is (0.5:1) - (4: 1).
Preferably, the tertiary amine: the mass ratio of the catalyst is (0.8:1) - (3: 1).
Further, the injectable polyurethane also contains functional components.
Preferably, the functional ingredient is selected from one or more of apatite, bioglass, antibacterial agent, and X-ray blocking agent.
Preferably, the polyurethane contains 5-40% apatite and/or bioglass by mass of the total mass of the polyurethane.
Further preferably, the polyurethane contains 5 to 30% by mass of apatite and/or bioglass based on the total mass of the polyurethane.
Preferably, the polyurethane contains 1-10% of antibacterial agent based on the total mass of the polyurethane.
More preferably, the polyurethane contains an antibacterial agent accounting for 3-8% of the total mass of the polyurethane.
Preferably, the polyurethane contains 3-20% of X-ray radiation-resistant agent in the total mass of the polyurethane.
More preferably, the polyurethane contains 5-15% of zirconium oxide or bismuth oxide based on the total mass of the polyurethane.
Most preferably, the polyurethane contains 5-15% of bismuth oxide based on the total mass of the polyurethane.
The invention provides a preparation method of the injectable polyurethane, which comprises the following steps: mixing the prepolymer with or without functional components and curing agent to obtain the injectable polyurethane capable of being cured at room temperature.
The polyhydric alcohol of the present invention is an alcohol having two or more hydroxyl groups in the molecule.
Said C of the invention2～6Polyols and C8～18The ester formed by the fatty acid can form more than or equal to 1 ester bond in the molecule, and can be polymerized with the aliphatic diisocyanate as long as the number of hydroxyl groups in the molecule is more than or equal to 2. With C3Polyol glycerol, for example, with C8～18The esters of fatty acids may be mono-, di-or triglycerides.
The apatite can be nano apatite, micro apatite, apatite doped with other ions or groups, such as fluorapatite, carbonate apatite, magnesium doped apatite, zinc doped apatite, etc. Preferably nano-hydroxyapatite or micro-hydroxyapatite particles. More preferably nano-hydroxyapatite spherical particles. The size of the active functional component can be 10-1,000 nm. Preferably 10 to 100 nm. The active functional component can be spherical or rod-shaped crystals, and is preferably spherical crystals. Wherein The preparation method of The nano hydroxyapatite can refer to The release properties of silver from Ag-nHA/TiO2Known methods reported in the literature, including PA66antimicrobial composite catalysts, Xia Wu, Jidong Li, LiWang, Di Huang, Yi Zuo and Yuba Li, BIOMEDICAL MATERIALS,5(2010)044105(7pp) ", etc.
The antimicrobial agent of the present invention may be an inorganic and/or organic antimicrobial agent. The inorganic antibacterial agent contains at least one of nano silver, silver salt, zinc oxide, zinc salt or copper salt. Zinc oxide and zinc salt components are preferred. More preferably nano zinc oxide. The size is 30-50 nm. The organic antibacterial agent contains at least one of imidazole, thiazole, isothiazolone derivatives, quaternary ammonium salt or phenolic preparations. The inorganic antibacterial component and the organic antibacterial component can also be matched according to the application in proportion.
The X-ray radiation-resistant agent consists of medical heavy metal salt and/or oxide of the medical heavy metal salt, and can be at least one of oxide of metal barium, zirconium and bismuth or corresponding metal salt.
In the preferred embodiment of the invention, after the prepolymer is cooled to room temperature, 20-40% of nano-hydroxyapatite and (or) 5% of nano-zinc oxide and (or) 10% of bismuth oxide by mass are added into the target prepolymer, the mixture is continuously stirred for 0.5-3 h at normal temperature, and then the curing agent is added. Preferably stirring for 1-2 h at normal temperature, and then adding the curing agent.
In the above preparation method, different curing modes can be adopted according to different purposes: 1) for medical polyurethane, reactants used in the preparation process can be dried, and a medical polymer material with a low pore structure can be formed after solidification; 2) for the material with higher strength characteristic after the material needs to be solidified, bioactive inorganic components accounting for 5-40% of the mass of the prepolymer can be added; 3) for polyurethane medical materials which need to realize excellent antibacterial performance, the antibacterial agent component can be compounded in the prepolymer; 4) for medical polyurethane materials with X-ray radiation resistance, the X-ray radiation resistance component can be compounded in the prepolymer; 5) for the characteristic that the prepolymer needs to be cured more quickly, the compound content of the curing agent can be properly improved, and is preferably 2-3%; 6) for medical polyurethane materials which need to realize other characteristics, other active ingredients can be added; 8) the different curing methods described above can be used singly or in combination.
The invention provides C2～6Polyols and C8～18The use of the ester formed by the fatty acid as a soft segment for preparing the injectable polyurethane can reduce the curing expansion rate of the prepared polyurethane material to be less than 0.03 percent, so that the polyurethane material is more suitable for root canalFilling and other narrow spaces, and the vegetable oil can be directly used as a raw material, so that the method has the advantage of environmental friendliness compared with a method for preparing polyurethane by using downstream products in the petroleum industry as the raw material.
In addition, the invention also provides injectable polyurethane which has good biocompatibility, hard/soft tissue bonding performance, antibacterial performance, X-ray radiation resistance, physical and chemical properties and the function of meeting various clinical use requirements, can meet the requirements of different medical fields by adjusting the curing rate, and has wide application prospect.
Drawings
FIG. 1 is a graph showing the conversion of reactants within 48 hours of curing of the medical polyurethane material of example 1;
FIG. 2 is a fluorescence staining pattern of the cured medical polyurethane material of example 1, which was co-cultured with mouse fibroblasts for 1,4, and 7 days, and the cells proliferated on the surface of the material;
FIG. 3 is a scanning electron microscope image of the adhesion of bacteria on the surface of the material after the medical polyurethane material of example 2 is solidified and co-cultured with enterococcus faecalis 24.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
The invention provides C2～6Polyols and C8～18Use of an ester of a fatty acid as a soft segment for the preparation of an injectable polyurethane, wherein said ester contains more than two hydroxyl groups.
Compared with the existing injectable polyurethane which takes macromolecular polyol polymers (such as polyethylene glycol, polytetrahydrofuran ether glycol, polypropylene glycol, polyether triol and the like) as soft segment main bodies, the soft segment used by the invention is micromolecular polyol, and the curing expansion rate of the polyurethane material can be obviously reduced, so that the polyurethane material is more suitable for filling narrow spaces.
In addition, the invention can directly adopt vegetable oil as a raw material, has wide source, low cost and environmental protection, and the prepared polyurethane material has higher biosafety and is suitable for biomedical application.
Wherein, if fatty acid with less than 8 carbon atoms and C are used2～6The esters formed from polyols act as soft blocks and it is difficult to ensure that a sufficient degree of crosslinking of the polyurethane is formed, which can adversely affect the curing properties and other physical properties of the material. If the number of carbon atoms is used>18 fatty acid with C2～6The ester formed by the polyhydric alcohol has a low hydroxyl value and weak reaction activity, so that the full polymerization of the material cannot be ensured, and the physical properties of the material are difficult to ensure.
Further, the invention provides injectable polyurethane which is prepared from the following raw materials:
prepolymer: soft segment, aliphatic diisocyanate, catalyst and chain extender, wherein the soft segment is C2～6Polyols and C8～18Esters of fatty acids, said esters containing more than two hydroxyl groups; and the combination of (a) and (b),
curing agent: the main component is a catalyst;
wherein the isocyanate group in the aliphatic diisocyanate: the molar ratio of hydroxyl groups in the soft segment is (1.0-5.0): 1;
the mass of the catalyst is 0.01-0.5% of the total mass of the soft segment and the aliphatic diisocyanate;
the mass of the chain extender is 1-12% of that of the soft segment;
the mass of the curing agent is 0.1-3% of that of the prepolymer.
The polyurethane material provided by the invention has good physical and chemical properties and biocompatibility, and has the advantage of controllable curing rate, for example, the curing time range of tens of minutes to 48 hours can be realized by adjusting the addition amount of the curing agent to 0.1-3%. In a preferred embodiment of the present invention, the curing time can be controlled to about 11 hours by adjusting the addition amount of the curing agent to 0.1 to 1%. Under the condition that faster curing is required, the composite content of the curing agent can be properly increased, and is preferably 2-3%.
On the basis, the polyurethane can also be compounded with various active ingredients, X-ray radiation-resistant ingredients and/or antibacterial ingredients to form a multifunctional biological material so as to meet different clinical tissue filling in various biomedical fields, can be suitable for but not limited to clinical application in the aspects of bone defect repair, root canal filling, dental adhesives, bone adhesives and soft tissue adhesives, and has a good application prospect in the biomedical field.
Example 1 preparation of injectable medical biomaterials of the invention
Preparation of modified castor oil: putting glycerol and castor oil into a three-neck flask according to the molar ratio of hydroxyl groups of 1:0.4 under the protective atmosphere, adding 0.02 wt% of calcium oxide as a catalyst, fully stirring at 200 ℃ for reaction for 1h, and then dropwise adding a proper amount of phosphoric acid to terminate the reaction.
Adding 15g of isophorone diisocyanate and 15g of modified castor oil into a three-neck flask filled with nitrogen, reacting for 4 hours at 60-80 ℃, adding stannous octoate accounting for 0.03% of the total mass of soft segments, continuing to react for 0.5 hour, adding 2, 2-dimethylolpropionic acid accounting for 2% of the mass of the soft segments, keeping the reaction for 1 hour, and cooling to room temperature to obtain a block carbamate prepolymer with the viscosity value of about 8400mPa & s. Nano hydroxyapatite accounting for 20 percent of the total mass is compounded in the urethane prepolymer and stirred for 1.5 hours, then 0.1g of dibutyltin dilaurate and 0.1g of triethanolamine are added into the functional urethane prepolymer as catalysts and mixed to obtain the target injectable medical biomaterial, and the material is cured after about 10-12 hours.
FIG. 1 shows the IR spectrum of the material as a function of time during the curing of the above material (FIG. 1A), and the conversion of isophorone diisocyanate (FIG. 1B). As can be seen from FIG. 1A, the characteristic peak of isocyanate group corresponding to isophorone diisocyanate (2270 cm) is observed as the curing time of the material is prolonged-1) Gradually decaying. The time change trend corresponding to the spectral peak area is calculated by taking the half peak width of the characteristic peak of the NCO as a reference to serve as the reaction conversion rate, and the conversion rate of reactants exceeds 90 percent after the reactants are solidified for 11 hours by analysis, which shows that the material can realize higher monomer conversion rate at normal temperature.
FIG. 2 shows the growth of mouse fibroblast cells L929 on the surface of the material, which is detected by Live/Dead fluorescent staining method, green cells represent Live cells, and red cells represent Dead cells. FIGS. 2A, 2B, 2C represent growth for 1,4, 7 days, respectively. As can be seen from the figure, most cells showed strong cell viability (stained green) after 4 days of culture, and the typical spindle-shaped cells were visible on the surface of the material; after 7 days of culture, living cells are proliferated in a large quantity, and the cells grow in an overlapping way to form thick multilayer cells, which shows that the material has good cell compatibility and can not cause obvious cytotoxicity.
The injectability and curing parameters of the medical urethane polymer material prepared in example 1 were tested with reference to ISO 6876-2001:
(1) curing time test
The mold was placed on a glass plate and filled horizontally with the mixed polyurethane material. After counting 120 + -10 s from the end of the mixing, the device was placed in an incubator at 37 ℃. Carefully press the gilmor needle probe vertically against the cured sealant for 5 seconds. The cure time was measured by the re-compression test after 30 seconds until the tip was unable to make an impression. This step is repeated a number of times after cleaning the probe. After the initial determination of the curing time, 10s intervals were used until there were no impressions on the sealant. The curing time should be timed as the stir time until no indentations can be made, at which time the time from stir to cure is recorded.
(2) Fluidity test
Taking two glass plates, wherein the area of the two glass plates is not less than 40mm multiplied by 40mm, the thickness of the two glass plates is about 5mm, the mass of one glass plate is about 20g, and timing is started when stirring. 0.05. + -. 0.005ml or 0.5ml of the polyurethane material was dropped into the center of the glass plate using a syringe. Pressing another glass plate 180 + -5 s after the start of mixing, adding weight, and applying weight of about 120 g. And after stirring for 10min, removing the heavy object, measuring the maximum and minimum diameters of the distribution of the sealant to be measured, and recording mean value data if the difference between the maximum and minimum diameters is less than 1 mm. If the difference exceeds 1mm, the experiment is repeated. The fluidity should be not less than 17 mm.
(3) Film thickness test
The two glass plates were superimposed with the marked arrow and the thickness of the superimposed two glass plates was measured as A to the accuracy of 1 μm. 0.1ml of polyurethane material is placed in the center of one glass plate, and then the other glass plate is pressed in the same direction according to the marked arrow and placed into an incubator. After 180 + -10 s, a 150N weight was carefully loaded on the glass plates to ensure that the sealant completely filled between the two glass plates. After applying force for 10min, the thickness B of the two glass plates and the sealant was measured using a micrometer. The film thickness was calculated by comparing the difference in thickness between the glass plates when the polyurethane material was present. The film thickness should be no greater than 50 mm.
(4) Volumetric expansion Rate test (i.e., Cure expansion Rate)
A mold (6 mm ID, 12mm tall teflon mold) was placed on top of the polyethylene film, a glass plate was placed on the bottom, and excess sealant was filled. The other glass plate was pressed against the sealant with a polyethylene film interposed therebetween. The mold and the glass plate were then fixed using a C-clamp. After 5min, the device is placed in an incubator with 37 +/-1 ℃ and 95-100% of humidity. For materials with curing times longer than 2 hours, 3 times the curing time is required. After the sample was prepared, both ends of the sample were polished flat using 600 mesh sandpaper. After the sample was removed from the mold, the distance between the two ends was measured to the nearest 10 μm. The measurement was again made after 30 days of distilled water at 37. + -. 1 ℃ to an accuracy of 10 μm. The percentage of length change was calculated. The result should be less than 0.1%.
The test results are given in the following table:
TABLE 1 injectability and curing parameter test results
| Curing time (min) | Fluidity (mm) | Film thickness (μm) | Volume expansion ratio (%) |
| 712±17 | 38.21±1.96 | 37.71±2.54 | 0.030±0.008 |
The test results show that the polyurethane material has excellent physical properties, is favorable for the injection characteristic of the material, particularly has slight expansibility, and is favorable for the sealing performance of the material on tissue filling.
Example 2 preparation of injectable medical biomaterials of the invention
Adding 15g of isophorone diisocyanate and 15g of modified castor oil into a three-neck flask filled with nitrogen, reacting for 4 hours at 60-80 ℃, adding stannous octoate accounting for 0.03 percent of the total mass of a soft segment and a soft segment, continuing to react for 0.5 hour, adding 2, 2-dimethylolpropionic acid accounting for 2 percent of the mass of the soft segment, keeping the reaction for 1 hour, and cooling to room temperature to obtain the block carbamate prepolymer. Nano hydroxyapatite accounting for 20 percent of the total mass and nano zinc oxide powder (4 experimental groups are set, nano zinc oxide accounting for 1 percent of the total mass, nano zinc oxide accounting for 3 percent of the total mass and nano zinc oxide accounting for 5 percent of the total mass are not added respectively) are compounded in the carbamate prepolymer, the mixture is stirred for 1.5 hours, then catalysts of 0.1g of dibutyltin dilaurate and 0.1g of triethanolamine are added into the functional carbamate prepolymer, the mixture is mixed to obtain the target injectable medical biomaterial, and the material is solidified after about 10 to 12 hours.
FIG. 3 shows the adhesion of bacteria to the surface of the material after 24h of co-culturing enterococcus faecalis (Enterococcus faecalis) with the material. Fig. 3A, 3B, 3C, and 3D respectively show the adhesion of bacteria on the surface of functional urethane polymer material without adding nano zinc oxide, with adding nano zinc oxide of 1% of the total mass, with adding nano zinc oxide of 3% of the total mass, and with adding nano zinc oxide of 5% of the total mass, it can be seen that a large amount of bacteria are adhered on the surface of the material without the nano zinc oxide of the antibacterial agent, and the bacteria content on the surface of the material is gradually reduced with the increase of the nano zinc oxide content, which indicates that the material with the antibacterial agent added has good antibacterial ability and antibacterial adhesion ability, and is beneficial to reducing infection or inflammatory reaction which may be caused in the filling and repairing process.
Example 3 preparation of injectable medical biomaterials of the invention
Adding 15g of isophorone diisocyanate and 15g of modified castor oil into a three-neck flask filled with nitrogen, reacting for 4 hours at 60-80 ℃, adding stannous octoate accounting for 0.03 percent of the total mass of a soft segment and a soft segment, continuing to react for 0.5 hour, adding 2, 2-dimethylolpropionic acid accounting for 2 percent of the mass of the soft segment, keeping the reaction for 1 hour, and cooling to room temperature to obtain the block carbamate prepolymer. And (2) compounding 20% of nano-magnesium apatite, 5% of nano-zinc oxide powder and 10% of bismuth oxide powder in the total mass of the carbamate prepolymer, stirring for 1.5h, adding 0.1g of dibutyltin dilaurate and 0.1g of triethanolamine as catalysts into the functional carbamate prepolymer, mixing to obtain the target injectable medical biomaterial with bioactivity, antibacterial activity and X-ray resistance, and curing the material after about 10-12 hours.
Example 4 preparation of injectable medical biomaterials of the invention
In a three-necked flask filled with nitrogen, 15.0g of castor oil and 20.0g of lysine diisocyanate were charged. After reacting for 6 hours at 80 ℃, adding stannous octoate with the total mass of a soft segment and a soft segment being 0.03%, continuing to react for 0.5 hour, then adding 1, 4-butanediol with the mass of the soft segment being 3%, reacting for 2 hours, cooling to room temperature to obtain a block carbamate prepolymer, compounding nano hydroxyapatite with the total mass being 10% and nano zirconia powder with the total mass being 5% in the carbamate prepolymer, stirring for 1.5 hours, and then adding a catalyst of 0.3g of dibutyltin dilaurate and 0.2g N, N-dimethylcyclohexylamine in the functional carbamate prepolymer to obtain the target injectable medical biomaterial with bioactivity and antibacterial activity.
Example 5 preparation of injectable medical biomaterials of the invention
In a three-necked flask filled with nitrogen gas, 25.0g of castor oil and 15.0g of isophorone diisocyanate were charged. After reacting for 4 hours at 60 ℃, adding stannous octoate with the total mass of a soft segment and a soft segment being 0.03%, continuing to react for 0.5 hour, adding 2, 2-dimethylolpropionic acid with the total mass of the soft segment, reacting for 1 hour, cooling to room temperature to obtain a block urethane prepolymer, compounding nano fluorapatite with the total mass being 40% in the urethane prepolymer, stirring for 1.5 hours, and then adding 0.05g of dibutyltin dilaurate and 0.05g of triethanolamine in the functional polyurethane prepolymer to obtain the target injectable medical biomaterial with bioactivity.
Example 6 preparation of injectable medical biomaterials of the invention
Preparing modified linseed oil: putting glycerol and linseed oil into a three-neck flask according to the molar ratio of hydroxyl groups of 1:0.3 under a protective atmosphere, adding 1.2 wt% of calcium naphthenate as a catalyst, fully stirring and reacting for 1-8 hours at 200 ℃ until reactants can be completely dissolved in methanol, and then dropwise adding a proper amount of phosphoric acid to terminate the reaction.
In a three-necked flask filled with nitrogen gas, 15.0g of modified linseed oil and 15.0g of isophorone diisocyanate were charged. After reacting for 5 hours at 80 ℃, adding dibutyltin dilaurate with 0.03 percent of the total mass of soft and hard segments, continuing to react for 0.5 hour, adding ethylenediamine with 3 percent of the mass of the soft segments, reacting for 2 hours, cooling to room temperature to obtain a segmented carbamate prepolymer, compounding 20 percent of micron hydroxyapatite with the total mass and 8 percent of zirconium oxide powder in the carbamate prepolymer, stirring for 1.5 hours, and then adding 0.2g of stannous octoate and 0.1g of triethanolamine into the functional carbamate prepolymer to obtain the target injectable medical biomaterial with bioactivity and X-ray resistance.
Example 7 preparation of injectable medical biomaterials of the invention
Preparing modified soybean oil: putting glycerol and soybean oil into a three-neck flask according to the molar ratio of hydroxyl groups of 1:0.5 under a protective atmosphere, adding 0.5 wt% of calcium oxide serving as a catalyst, fully stirring at 200 ℃ for reacting for 1-8 hours until reactants can be completely dissolved in methanol, and then dropwise adding a proper amount of phosphoric acid to terminate the reaction.
In a three-necked flask filled with nitrogen gas, 30g of modified soybean oil and 20.0g of hexamethylene diisocyanate were charged. After reacting for 6 hours at 60 ℃, adding dibutyltin dilaurate with the total mass of a soft segment and a soft segment being 0.03%, continuing to react for 0.5 hour, adding 2, 2-dimethylolpropionic acid with the mass of the soft segment being 3%, reacting for 1 hour, cooling to room temperature to obtain a block carbamate prepolymer, compounding micron hydroxyapatite spherical particles with the total mass being 20%, nano zinc oxide powder with the total mass being 5% and bismuth oxide powder with the total mass being 10% in the carbamate prepolymer, stirring for 1.5 hours, and then adding 0.2g of stannous octoate, so that the target injectable medical biomaterial with biological activity, antibacterial activity and X-ray resistance can be obtained.
EXAMPLE 8 preparation of injectable medical biomaterials of the present invention
In a three-necked flask filled with nitrogen gas, 20g of modified castor oil and 20.0g of 4,4' -dicyclohexylmethane diisocyanate were charged. After reacting for 6 hours at 70 ℃, adding dibutyltin dilaurate with the total mass of a soft segment and a soft segment being 0.03%, continuing to react for 0.5 hour, adding glycerol with the mass of the soft segment being 2%, reacting for 0.5 hour, then cooling to room temperature to obtain a segmented carbamate prepolymer, compounding nano hydroxyapatite rod-shaped particles with the total mass of 10% and nano zinc oxide powder with the total mass of 5% in the carbamate prepolymer, stirring for 1.5 hours, and then adding 0.1g of stannous octoate and 0.1g of triethanolamine to obtain the target injectable medical biomaterial with bioactivity and antibacterial activity.
Example 9 preparation of injectable medical biomaterials of the invention
Preparation of modified coconut oil: putting glycerol and coconut oil into a three-neck flask according to the molar ratio of hydroxyl groups of 1:0.5 under a protective atmosphere, adding 3 wt% of calcium naphthenate serving as a catalyst, fully stirring and reacting for 1-8 hours at 200 ℃ until reactants can be completely dissolved in methanol, and then dropwise adding a proper amount of phosphoric acid to terminate the reaction.
In a three-necked flask filled with nitrogen, 20.0g of modified coconut oil and 15.0g of lysine diisocyanate were added. Reacting for 4 hours at 90 ℃, adding dibutyltin dilaurate with the total mass of a soft segment being 0.03%, continuing to react for 0.5 hour, adding polyethylene glycol 600 with the mass of the soft segment being 2%, reacting for 0.5 hour, then cooling to room temperature to obtain a segmented carbamate prepolymer, compounding nano hydroxyapatite spherical particles with the total mass being 30% and bismuth oxide powder being 10% in the carbamate prepolymer, stirring for 1.5 hours, and then adding 0.1g of stannous octoate and 0.05g of triethanolamine to obtain the target injectable medical biomaterial with bioactivity and X-ray resistance.
EXAMPLE 10 preparation of injectable medical biomaterials of the present invention
In a three-necked flask filled with nitrogen, 20.0g of modified soybean oil and 25.0g of lysine diisocyanate were charged. After reacting for 8 hours at 60 ℃, adding stannous octoate accounting for 0.03 percent of the total mass of soft and hard segments, continuing to react for 0.5 hour, adding ethylenediamine accounting for 2 percent of the mass of the soft segments, reacting for 0.5 hour, then cooling to room temperature to obtain a block carbamate prepolymer, compounding nano hydroxyapatite rod-shaped particles accounting for 20 percent of the total mass and zinc oxide powder accounting for 5 percent of the total mass in the carbamate prepolymer, stirring for 1.5 hours, and then adding 0.15g of stannous octoate and 0.15g of triethanolamine to obtain the target injectable medical biomaterial with bioactivity and antibacterial activity.
Claims (13)
1.C2～6Polyols and C8～18Use of an ester of a fatty acid as a soft segment for the preparation of an injectable polyurethane, wherein said ester contains more than two hydroxyl groups.
2. Use according to claim 1, characterized in that: at least one of the following is satisfied:
the curing expansion rate of the injectable polyurethane is less than or equal to 0.5 percent;
preferably, the injectable polyurethane has a cure swell ratio of 0.1% or less;
further preferably, the injectable polyurethane has a cure swell ratio of 0.03% or less;
the hydroxyl value of the ester is 10-500 mg KOH/g;
preferably, the hydroxyl value of the ester is 50-300 mg KOH/g;
further preferably, the hydroxyl value of the ester is 100-250 mg KOH/g;
said C is2-6The polyhydric alcohol is glycerol;
the ester is derived from vegetable oil;
preferably, the vegetable oil is selected from one or more of tung oil, linseed oil, soybean oil, cottonseed oil, castor oil, dehydrated castor oil and coconut oil;
further preferably, the vegetable oil is castor oil.
3. Use according to claim 2, characterized in that: when the number of hydroxyl groups contained in the vegetable oil is less than 2, the modification is carried out by adopting the following method: mixing vegetable oil with C2-6And carrying out alcoholysis reaction on the polyhydric alcohol to obtain the ester containing more than two hydroxyl groups.
4. Use according to claim 3, characterized in that: the modification satisfies at least one of the following:
said C is2-6The polyalcohol is trimethylolpropane or glycerol;
preferably, said C2-6The polyhydric alcohol is glycerol;
said C is2-6The mass ratio of the polyhydric alcohol to the vegetable oil is 1 (0.2-0.8);
preferably, said C2-6The mass ratio of the polyhydric alcohol to the vegetable oil is 1 (0.3-0.5);
carrying out alcoholysis reaction at 180-250 ℃;
the alcoholysis reaction time is 1-8 h;
carrying out alcoholysis reaction under a protective atmosphere;
the catalyst is one or more than two of calcium oxide, lead oxide and calcium naphthenate;
preferably, the catalyst is calcium oxide or calcium naphthenate;
the dosage of the catalyst is vegetable oil and C2-60.01-10% of the total mass of the polyhydric alcohol;
preferably, the amount of the catalyst is vegetable oil and C2-60.01 to 5% by mass of the total polyol.
5. An injectable polyurethane characterized by: the material is prepared from the following components:
prepolymer: soft segment, aliphatic diisocyanate, catalyst and chain extender, wherein the soft segment is C2～6Polyols and C8～18Esters of fatty acids, said esters containing more than two hydroxyl groups; and the combination of (a) and (b),
curing agent: the main component is a catalyst;
wherein the isocyanate group in the aliphatic diisocyanate: the molar ratio of hydroxyl groups in the soft segment is (1.0-5.0): 1;
the mass of the catalyst is 0.01-0.5% of the total mass of the soft segment and the aliphatic diisocyanate;
the mass of the chain extender is 1-12% of that of the soft segment;
the mass of the curing agent is 0.1-3% of that of the prepolymer.
6. The injectable polyurethane of claim 5, wherein: the soft segment satisfies at least one of:
the hydroxyl value of the soft segment is 10-500 mg KOH/g;
preferably, the hydroxyl value of the soft segment is 50-300 mg KOH/g;
further preferably, the hydroxyl value of the soft segment is 100-250 mg KOH/g;
said C is2-6The polyhydric alcohol is glycerol;
the soft segment is derived from vegetable oil;
preferably, the vegetable oil is selected from one or more of tung oil, linseed oil, soybean oil, cottonseed oil, castor oil, dehydrated castor oil and coconut oil;
further preferably, the vegetable oil is castor oil.
7. The injectable polyurethane of claim 5, wherein: the aliphatic diisocyanate is selected from one or more of isophorone diisocyanate, lysine diisocyanate, 4' -dicyclohexylmethane diisocyanate and hexamethylene diisocyanate; preferably, the aliphatic diisocyanate is isophorone diisocyanate.
8. The injectable polyurethane of claim 5, wherein: the prepolymer satisfies at least one of the following conditions:
isocyanate group in aliphatic diisocyanate: the molar ratio of hydroxyl groups in the soft segment is (1.2-3.0): 1;
preferably, the isocyanate groups in the aliphatic diisocyanate: the molar ratio of hydroxyl groups in the soft segment is (1.5-2.0): 1;
the catalyst is a tin-containing catalyst;
preferably, the catalyst is selected from one or more of dibutyl tin dilaurate, stannous octoate and stannous chloride;
further preferably, the catalyst is dibutyltin dilaurate or stannous octoate;
the mass of the catalyst is 0.02-0.05% of the total mass of the soft segment and the aliphatic diisocyanate;
the chain extender is selected from a polyol, a diamine or a mixture thereof;
preferably, the chain extender is selected from one or more than two of 1, 4-butanediol, 1, 6-hexanediol, glycerol, ethylenediamine, 2-dimethylolpropionic acid and polyethylene glycol;
further, the chain extender is selected from one or more than two of 2, 2-dimethylolpropionic acid, 1, 4-butanediol, ethylenediamine and polyethylene glycol;
preferably, the molecular weight of the polyethylene glycol is 200-2000;
further preferably, the molecular weight of the polyethylene glycol is 400-1000; the mass of the chain extender is 2-6% of that of the soft segment;
the viscosity of the prepolymer is 1000-20000 mPa s;
preferably, the viscosity of the prepolymer is 2000-15000 mPa & s;
further preferably, the viscosity of the prepolymer is 2000-10000 mPa & s;
more preferably, the viscosity of the prepolymer is 8400mPa · s.
9. The injectable polyurethane of claim 5, wherein: the prepolymer is prepared by the following method: and under the protective atmosphere, taking the soft segment to perform blending reaction with aliphatic diisocyanate, adding a catalyst to continue the reaction, and adding a chain extender to perform the reaction, thereby obtaining the prepolymer.
10. The injectable polyurethane of claim 9, wherein: at least one of the following is satisfied:
keeping the temperature at 40-90 ℃ for reaction;
preferably, the temperature is kept between 50 and 80 ℃ for reaction;
the blending reaction time is 1-12 h;
preferably, the blending reaction time is 4-6 h;
adding a catalyst and reacting for 0.5-4 h;
adding a chain extender and reacting for 0.5-10 h;
preferably, the reaction is carried out for 20min to 5h after the chain extender is added.
11. The injectable polyurethane of claim 5, wherein: the curing agent satisfies at least one of the following:
the mass of the curing agent is 0.1-1% of that of the prepolymer;
the catalyst is a tin-containing catalyst;
preferably, the catalyst is selected from one or more of dibutyl tin dilaurate, stannous octoate and stannous chloride;
further preferably, the catalyst is dibutyltin dilaurate or stannous octoate;
also contains tertiary amine;
the tertiary amine is selected from one or more than two of N, N-dimethylcyclohexylamine, bis (2-dimethylaminoethyl) ether, N, N, N ', N' -tetramethylalkylenediamine, triethanolamine and dimethylethanolamine;
further preferably, the tertiary amine is triethanolamine;
tertiary amine: the mass ratio of the catalyst is (0.5:1) - (4: 1);
preferably, the tertiary amine: the mass ratio of the catalyst is (0.8:1) - (3: 1).
12. The injectable polyurethane according to any one of claims 5 to 11, wherein: also contains functional components; preferably, the functional ingredient is selected from one or more of apatite, bioglass, antibacterial agent, and X-ray blocking agent; preferably, the polyurethane contains 5-40% of apatite and/or bioglass by mass of the total mass of the polyurethane; further preferably, the polyurethane contains 5-30% by mass of apatite and/or bioglass based on the total mass of the polyurethane; preferably, the polyurethane contains an antibacterial agent accounting for 1-10% of the total mass of the polyurethane; further preferably, the polyurethane contains an antibacterial agent accounting for 3-8% of the total mass of the polyurethane; preferably, the polyurethane contains an X-ray radiation-resistant agent accounting for 3-20% of the total mass of the polyurethane; further preferably, the polyurethane comprises 5-15% of zirconium oxide or bismuth oxide by mass of the total polyurethane; most preferably, the polyurethane contains 5-15% of bismuth oxide based on the total mass of the polyurethane.
13. The method for preparing the injectable polyurethane of any one of claims 5 to 12, wherein: mixing the prepolymer with or without functional components and curing agent to obtain the injectable polyurethane capable of being cured at room temperature.
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| PCT/CN2018/118990 WO2020015276A1 (en) | 2018-07-17 | 2018-12-03 | Injectable polyurethane and manufacturing method therefor |
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