CN110078880B - Isocyanate cross-linked polyethylene glycol-polysebacic acid glyceride biological elastomer and preparation method and application thereof - Google Patents
Isocyanate cross-linked polyethylene glycol-polysebacic acid glyceride biological elastomer and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an isocyanate cross-linked polyethylene glycol-polysebacic acid glyceride biological elastomer and a preparation method and application thereof. The structure of the biological elastomer is shown as a formula I, wherein n is an integer of 10-80; m is an integer of 2 to 14. The mechanical strength, hydrophilicity and hydrophobicity, degradation behavior, cell behavior and biocompatibility of the biological elastomer can be regulated and optimized through the content of isocyanate and polyethylene glycol, and the biological elastomer is a soft tissue repair material with a good clinical application prospect.
Description
Technical Field
The invention relates to an isocyanate cross-linked polyethylene glycol-polysebacic acid glyceride biological elastomer and a preparation method and application thereof.
Background
With the progress of tissue engineering technology, the demand of people for repair materials is higher and higher. The biological elastomer material has attracted great attention in biomedicine because of its excellent flexibility, viscoelasticity, mechanical property and other characteristics similar to those of surrounding tissues. Since the 50 s in the 20 th century, polyurethane type bio-elastomers have begun to be applied in the medical and health fields, such as medical catheters, film products and the like, and are the most widely used and researched bio-elastomer materials except for silicone elastomers at present. But during long-term use some problems are exposed, the most important of which is poor biocompatibility.
Polysebacylic acid glyceride (PGS) is a high polymer with good mechanical strength, biocompatibility and biodegradability, and has the function of promoting vascularization, so that the PGS is widely applied to soft tissue engineering in recent years. However, because the polysebacic acid glyceride cross-linking condition is complex, the hydrophilicity is poor after forming, the using performance of the polysebacic acid glyceride cross-linking condition in soft tissues is limited, and the polysebacic acid glyceride cross-linking condition can not be used for loading factors with biological activity such as proteins, medicines and the like.
Therefore, there is an urgent need in the art to develop a bio-elastomer material that can be cured at a low temperature, has simple molding conditions, has excellent biocompatibility, and can be used for loading active factors.
Disclosure of Invention
The invention aims to provide a biological elastomer material which can be cured at low temperature, has simple molding conditions and excellent biocompatibility and can be used for loading active factors.
In a first aspect of the present invention, there is provided a bioelastomer comprising the following structural units:
n is an integer of 10 to 80;
m is an integer of 2 to 14.
In another preferred example, the molar ratio of the sebacic acid to the glycerol and the polyethylene glycol in the biological elastomer is 0.65-2.8.
In another preferred embodiment, the molar ratio of sebacic acid to glycerol and polyethylene glycol in the bioelastomer is 1-1.8, preferably 1.3 or 1.4.
In another preferred embodiment, the molar ratio of the polyethylene glycol to the glycerol in the biological elastomer is less than or equal to 4; the molar ratio of hexamethylene diisocyanate to glycerol is 0.2-1.5.
In another preferred embodiment, the molar ratio of polyethylene glycol to glycerol is 0.1 to 4.
In another preferred embodiment, the molar ratio of polyethylene glycol to glycerol is 0.2 to 4, preferably 0.25, 0.67, 1.5 or 4.
In another preferred embodiment, n is an integer of 15 to 70, 20 to 60 or 30 to 50.
In another preferred embodiment, m is an integer of 3 to 12, 4 to 10, 5 to 8.
In another preferred embodiment, the bioelastomer has one or more of the following characteristics:
(1) the hydrophilic angle can be 20-89 degrees;
(2) young modulus is 0.5-18.0 MPa;
(3) the tensile strength is 0.1-12.0 MPa;
(4) the elongation at break is 23.0-400.0%;
(5) the in vitro degradation is 10-99% in 30 days.
The bioelastomers of the present invention are biodegradable crosslinked polymers.
The biological elastomer can be used for preparing three-dimensional structure elastomers in any shapes by different methods, and the shape of the biological elastomer can be maintained by good enough mechanical properties.
In a second aspect of the present invention, there is provided a method for preparing the bioelastomer of the first aspect, comprising the steps of:
Reacting the polyethylene glycol-polysebacic acid glyceride prepolymer with hexamethylene diisocyanate in a solvent to obtain the biological elastomer,
the solvent is benzene, toluene, xylene, pentane, hexane, octane, cyclohexane, cyclohexanone, toluene cyclohexanone, chlorobenzene, dichlorobenzene, dichloromethane, methanol, ethanol, isopropanol, diethyl ether, epoxypropane, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine, phenol, N-dimethyl amide, tetrahydrofuran or a mixed solvent of more than two of the above.
Preferably, the number average molecular weight of the prepolymer is 4000-9000 and the dispersion coefficient is 1.2-3.0.
In another preferred embodiment, the preparation method further comprises the step of adding a catalyst to the solvent, wherein the catalyst is selected from the group consisting of: stannous octoate, dibutyltin dilaurate, dibutyltin didodecyl sulfide, dibutyltin diacetate, bismuth neodecanoate, zinc isooctanoate, and the like.
In another preferred embodiment, the addition amount of the solvent is 0-100 times of the mass of the polyethylene glycol-polysebacic acid glyceride prepolymer.
In another preferred embodiment, when the amount of the solvent added is not 0 times, the preparation of the bio-elastomer comprises the following steps:
(a) under the atmosphere of argon, dissolving the dried polyethylene glycol-polysebacic acid glyceride prepolymer into anhydrous N, N-dimethyl amide, wherein the concentration of the solution is 0.01 to infinity g/ml;
(b) under the atmosphere of argon, dissolving stannous octoate with the mass volume ratio of less than 0.01 percent in the solution in the step a);
(c) transferring the solution obtained in the step b) into a reaction device under the atmosphere of argon, connecting with a Chilean operating system, and heating at 20-65 ℃ for 10-20 min;
(d) under the argon atmosphere, adding hexamethylene diisocyanate with the corresponding molar weight into the device in the step 3), and slowly dripping the hexamethylene diisocyanate into the solution;
(e) and d) under the argon atmosphere, continuously reacting the solution obtained in the step d) at 20-65 ℃ for 5-12 hours, taking out and transferring the solution to a tetrafluoro mold, standing for 2 days at room temperature, and vacuum-drying for 48 hours at room temperature to obtain the biological elastomer.
Preferably, the number average molecular weight of the prepolymer is 4000-9000 and the dispersion coefficient is 1.2-3.0.
In another preferred embodiment, in step a), the concentration of the solution is 0.05-5g/ml, 0.1-3g/ml, or 0.15-1g/ml, or 0.2-0.5 g/ml.
In another preferred embodiment, in the step a), stannous octoate with the mass volume ratio of 0.0001% to 0.01%, or 0.001% to 0.01%, or 0.005% to 0.01% is dissolved in the solution in the step a).
The biological elastomer can regulate and control various performances by regulating and controlling the contents of polyethylene glycol and hexamethylene diisocyanate, and can be prepared under mild conditions.
In a third aspect of the present invention, there is provided the method for producing a bioelastomer according to the first aspect, wherein the solvent is added in an amount of 0 times, comprising the steps of:
(a) uniformly mixing the dried polyethylene glycol-polysebacic acid glyceride prepolymer with a catalyst with the mass volume ratio of less than 0.05 percent of that of the polyethylene glycol-polysebacic acid glyceride prepolymer;
(b) adding hexamethylene diisocyanate with the molar ratio of 0.2-1.5 to glycerol into the mixture obtained in the step a), and quickly stirring and uniformly mixing;
(c) putting the mixture obtained in the step b) in a dry environment, and continuously reacting for 8-24 hours (preferably 12-14 hours) to obtain the macromolecular elastomer.
In another preferred embodiment, the catalyst in step b) is selected from: stannous octoate, dibutyltin dilaurate, dibutyltin didodecyl sulfide, dibutyltin diacetate, bismuth neodecanoate, zinc isooctanoate, and the like.
In another preferred embodiment, in the step a), the dried polyethylene glycol-polysebacic acid glyceride prepolymer is uniformly mixed with the catalyst with the mass volume ratio of 0.0001-0.05%, 0.001-0.05% or 0.005-0.05% lower than that of the polyethylene glycol-polysebacic acid glyceride prepolymer.
In a fourth aspect of the present invention, there is provided a modified material comprising a base material, and a bioelastomer supported on the base material.
The invention coats the bio-elastomer solution with different concentrations on the surface of the object to be modified in a dripping way, and then obtains the modified material after the steps of solvent volatilization and solvent removal.
Preferably, the concentration of the bio-elastomer solution is between 0.01 and infinity g/ml.
More preferably, the concentration of the bioelastomer solution is 0.1g/ml, 0.2g/ml, 0.3g/ml or ∞ (0 ml of solvent).
Preferably, the substrate material is selected from brittle scaffolds such as calcium phosphate salt scaffold, MBG scaffold and the like, or hydrophobic materials such as PEEK, PMMA and the like.
The biological elastomer can be used for compounding or modifying inorganic or high molecular materials. The mechanical properties of the base material are enhanced by loading the biological elastomer.
In a fifth aspect of the present invention, there is provided a drug releasing material comprising a bioelastomer, and an active factor loaded on the bioelastomer.
The biological elastomer can be used for preparing carriers for cell culture or preparing biological elastomer materials with different morphologies, and can be used for loading and controlling release of protein or drugs.
The bio-elastomer prepared by the 0% solvent route is not demoulded and the surface is coated with the solution of the active factor with proper concentration. After freeze drying, coating another layer of the biological elastomer on the surface of the prepared factor-carrying biological elastomer, and reacting for 12 hours to obtain the biological elastomer film carrying the active factors.
Preferably, the active factor is selected from a biologically active factor such as a protein or a drug.
Preferably, the bioelastomer is in the form of a film, preferably a multilayer can be prepared. More optionally, the bio-elastomer film may be prepared in 2 to 4 layers.
Preferably, the bioelastomeric membrane may be selected from a combination of different prepolymers.
The biological elastomer material has highly customized functions, and when the biological elastomer material is applied to tissue repair of different parts, physicochemical properties similar to those of the applied tissue parts can be realized by regulating and controlling the content of components in the material in the synthesis process of the elastomer.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. For reasons of space, they will not be described in detail.
Drawings
FIG. 1 shows the synthetic route of the bioelastomers of the invention, (A) the preparation of PGS-U and (B) the preparation of PEGS-U.
FIG. 2 shows a tensile test chart (A) and a cyclic tensile test chart (B) of the bio-elastomer of the present invention.
Fig. 3 shows the contact angle (a) and 30 days in vitro degradation (B) of the bioelastomers of the invention.
FIG. 4 shows the results of co-culturing the bioelastomers of the invention with BMSCs stem cells.
FIG. 5 is a photograph of H & E stained sections of the bioelastomers of the present invention implanted subcutaneously for 7 days and 30 days.
FIG. 6 shows the materials of various shapes prepared by the biological elastomer of the invention, wherein (A) is a membrane material, (B) is a porous scaffold, and (C) is a tube material.
FIG. 7 shows the morphology of the bio-elastomer reinforced inorganic material of the present invention, (A) before and after compression at 6% coating content, and (B) the stress-strain curve of the composite stent.
FIG. 8 shows the use of the bioelastomers of the invention for drug release, (A) 24h activity, and (B) release profile of protein over 3 days.
Detailed Description
The inventor of the present application has extensively and deeply studied that polyethylene glycol and hexamethylene diisocyanate are simultaneously introduced into a polyester polymer prepolymer to obtain a low temperature cured biological elastomer material with excellent biocompatibility, the introduction of polyethylene glycol endows polysebacate with excellent hydrophilicity, viscoelasticity and biocompatibility, and the addition of hexamethylene diisocyanate endows the polymer with molding under relatively mild conditions, simplifies molding conditions and endows the material with stronger mechanical properties, and can be used for loading active factors. On the basis of this, the present invention has been completed.
Description of the terms
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.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
As used herein, the terms "CPC", "calcium phosphate cement" are used interchangeably.
As used herein, the terms "PEGS", "polyethylene glycol-polysebacate" are used interchangeably.
As used herein, the terms "PEG", "polyethylene glycol" are used interchangeably.
As used herein, the terms "PEGS 20" and "PEGS 40" refer to polyethylene glycol-polysebacic acid glycerides of different polyethylene glycol contents, wherein the mole fractions of polyethylene glycol relative to glycerol are 20% and 40%, respectively, used interchangeably.
As used herein, the terms "PGS-U" and "PEGS-U" refer to hexamethylene diisocyanate cross-linked polysebacic acid glycerol ester or polyethylene glycol-polysebacic acid glycerol ester.
As used herein, the terms "X-P-mU", "X-P-mU-F", X refers to an abbreviation for prepolymer used in the synthesis of the bioelastomer, wherein 20 denotes PEGS20, 40 denotes PEGS 40; m is the molar ratio of the hexamethylene diisocyanate to glycerol; f means that no solvent is added during the preparation of the bio-elastomer.
Preparation method
As shown in FIG. 1, in a preferred embodiment, 2g of a PEGS series prepolymer or a PGS prepolymer is dissolved in 10ml of anhydrous DMF solvent under an argon atmosphere. Subsequently, 0.01% stannous octoate relative to the total solvent volume was dissolved in 5ml DMF, and after stirring well, transferred into a reaction bulb together with the polymer solution. Under argon atmosphere, the corresponding amount of hexamethylene diisocyanate was dissolved in 5ml of DMF and transferred to a liquid charger after mixing. The device is transferred into a heater, the temperature is raised to 55 ℃, after 10 minutes, the solution of hexamethylene diisocyanate is dripped into the polymer solution at the speed of 10 drops per minute, and the reaction is continued for 5 hours. Removing the solvent to obtain the biological elastomer material PEGS-U or PGS-U.
In the invention, the biological elastomer can be prepared under the condition of adding a solvent, namely the polyethylene glycol-polysebacic acid glyceride prepolymer reacts with hexamethylene diisocyanate in the solvent to obtain the biological elastomer,
the solvent is benzene, toluene, xylene, pentane, hexane, octane, cyclohexane, cyclohexanone, toluene cyclohexanone, chlorobenzene, dichlorobenzene, dichloromethane, methanol, ethanol, isopropanol, diethyl ether, epoxypropane, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine, phenol, N-dimethyl amide, tetrahydrofuran or a mixed solvent of more than two of the above.
In another preferred embodiment, the preparation method further comprises the step of adding a catalyst to the solvent, wherein the catalyst is selected from the group consisting of: stannous octoate, dibutyltin dilaurate, dibutyltin didodecyl sulfide, dibutyltin diacetate, bismuth neodecanoate, zinc isooctanoate, and the like.
In another preferred embodiment, the addition amount of the solvent is 0-100 times of the mass of the polyethylene glycol-polysebacic acid glyceride prepolymer.
In another preferred embodiment, when the solvent is added in an amount of not 0 times, the preparation of the bio-elastomer comprises the following steps:
(a) dissolving the dried polyethylene glycol-polysebacic acid glyceride prepolymer in anhydrous N, N-dimethyl amide under the atmosphere of argon, wherein the concentration of the solution is 0.01 to infinity g/ml;
(b) under the atmosphere of argon, dissolving stannous octoate with the mass volume ratio of less than 0.01 percent in the solution in the step a);
(c) transferring the solution obtained in the step b) into a reaction device under the atmosphere of argon, connecting with a Chilean operating system, and heating at 20-65 ℃ for 10-20 min;
(d) under the argon atmosphere, adding hexamethylene diisocyanate with the corresponding molar weight into the device in the step 3), and slowly dripping into the solution;
(e) and d) under the argon atmosphere, continuously reacting the solution obtained in the step d) at 20-65 ℃ for 5-12 hours, taking out and transferring the solution to a tetrafluoro mold, standing for 2 days at room temperature, and vacuum-drying for 48 hours at room temperature to obtain the biological elastomer.
Preferably, the number average molecular weight of the prepolymer is 4000-9000 and the dispersion coefficient is 1.2-3.0.
The biological elastomer can regulate and control various performances by regulating and controlling the contents of polyethylene glycol and hexamethylene diisocyanate, and can be prepared under mild conditions.
Furthermore, it is also possible to prepare the bioelastomers without using a solvent, i.e. with a solvent addition of 0 times, comprising the following steps:
(a) uniformly mixing the dried polyethylene glycol-polysebacic acid glyceride prepolymer with a catalyst with the mass volume ratio of less than 0.05 percent of that of the polyethylene glycol-polysebacic acid glyceride prepolymer;
(b) adding hexamethylene diisocyanate with the molar ratio of 0.2-1.5 to glycerol into the mixture obtained in the step a), and quickly stirring and uniformly mixing;
(c) putting the mixture obtained in the step b) in a dry environment, and continuously reacting for 8-24 hours (preferably 12-14 hours) to obtain the macromolecular elastomer.
In another preferred embodiment, the catalyst in step b) is selected from: stannous octoate, dibutyltin dilaurate, dibutyltin didodecyl sulfide, dibutyltin diacetate, bismuth neodecanoate, zinc isooctanoate, and the like.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures for which specific conditions are not indicated in the following examples are generally carried out according to conventional conditions (e.g.as described in Sambrook et al, molecular cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or according to the conditions as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
This example relates to the synthesis and purification of PEGS0
The PEGS0 prepolymer is synthesized by a two-step method:
(a) under the argon atmosphere, sebacic acid and glycerol with the molar ratio of 1:1 react for 24 hours at 130 ℃;
(b) and (b) continuously reacting the product obtained in the step a) for 6 hours at the temperature of 150 ℃ under the vacuum condition to obtain a PEGS0 prepolymer.
And (3) purifying the prepolymer by repeated ethanol dissolution-water precipitation operation to remove unreacted monomers and small molecules to obtain the purified PEGS0 prepolymer (polysebacic acid glyceride). The number average molecular weight was 6023Da and the dispersibility index was 3.21.
Example 2
This example relates to the synthesis and purification of PEGS20 (20% polyethylene glycol-polysebacic acid glyceride)
(i) 14.14g of sebacic acid and 20.00g of PEG (number average molecular weight 1000g/mol) are reacted at 130 ℃ for 2 hours under an argon atmosphere;
(ii) continuously reacting the product obtained in the step (a) for 24 hours at the temperature of 130 ℃ under the vacuum condition to obtain a linear prepolymer of sebacic acid and PEG;
(iii) 7.36g of glycerol and 14.14g of sebacic acid are added to the product of step (b) and the reaction is continued at 130 ℃ under vacuum for 48 hours. The molar content of PEG relative to glycerol in this reaction was 20% and the molar ratio of hydroxyl to carboxyl groups of the total reaction was 1.
And (3) purifying the prepolymer by repeated ethanol dissolution-water precipitation operation to remove unreacted monomers and small molecules to obtain the purified PEGS20 prepolymer. The actual PEG content was 19%, the number average molecular weight was 7085Da, and the dispersity coefficient was 1.95.
Example 3
This example relates to the synthesis and purification of PEGS80 (80% polyethylene glycol-polysebacic acid glyceride)
(a) 16.18g of sebacic acid and 80.00g of PEG (number average molecular weight 1000g/mol) are reacted at 130 ℃ for 2 hours under an argon atmosphere;
(b) continuously reacting the product obtained in the step (a) for 24 hours at the temperature of 130 ℃ under the vacuum condition to obtain a linear prepolymer of sebacic acid and PEG;
(c) 1.8414g of glycerol and 6.0675g of sebacic acid are added to the product of step (b) and the reaction is continued at 130 ℃ under vacuum for 48 hours. The molar content of PEG relative to glycerol in this reaction was 80% and the molar ratio of hydroxyl to carboxyl groups of the total reaction was 1: 1.
And (3) purifying the prepolymer by repeated ethanol dissolution-water precipitation operation to remove unreacted monomers and small molecules to obtain the purified PEGS80 prepolymer. The actual PEG content was 76%, the number average molecular weight was 6308Da, and the dispersity coefficient was 2.42.
Example 4
This example relates to a solvent route to 0-P-1.0U bioelastomers
(a) Dissolving 4g of dried PEGS0 prepolymer in 20ml of anhydrous N, N-dimethyl amide under the atmosphere of argon to obtain a high molecular solution;
(b) dissolving 0.002g of stannous octoate in the solution obtained in the step a) under the atmosphere of argon;
(c) transferring the solution obtained in the step b) into a reaction device under the atmosphere of argon, connecting with a Chilean operating system, and heating at 55 ℃ for 10-20 min;
(d) adding 1.969g of hexamethylene diisocyanate into the device in the step c) under an argon atmosphere, and slowly dripping into the solution;
(e) reacting the solution obtained in step d) at 55 ℃ for 5 hours under an argon atmosphere.
And transferring the solution obtained by the reaction into a 10cm disc-shaped polytetrafluoroethylene mold, standing at room temperature for 48 hours, transferring to a vacuum condition, and drying at room temperature for 72 hours to obtain the membrane-shaped biological elastomer material 0-P-1.0U.
Example 5
This example relates to a solvent route to 20-P-1.0U bioelastomers
(a) Dissolving 4g of dried PEGS20 prepolymer in 20ml of anhydrous N, N-dimethyl amide under the atmosphere of argon to obtain a high molecular solution;
(b) dissolving 0.002g of stannous octoate in the solution obtained in the step a) under the atmosphere of argon;
(c) Transferring the solution obtained in the step b) into a reaction device under the atmosphere of argon, connecting with a Chilean operating system, and heating at 55 ℃ for 10-20 min;
(d) adding 1.06g of hexamethylene diisocyanate into the device in the step c) under the argon atmosphere, and slowly dripping into the solution;
(e) reacting the solution obtained in step d) at 55 ℃ for 5 hours under an argon atmosphere.
And transferring the solution obtained by the reaction into a 10cm disc-shaped polytetrafluoroethylene mold, standing at room temperature for 48 hours, transferring to a vacuum condition, and drying at room temperature for 72 hours to obtain the membrane-shaped biological elastomer material 20-P-1.0U.
Example 6
This example relates to a solvent route to 80-P-1.0U bioelastomers
(a) Dissolving 4g of dried PEGS80 prepolymer in 20ml of anhydrous N, N-dimethyl amide under the atmosphere of argon to obtain a high molecular solution;
(b) dissolving 0.002g of stannous octoate in the solution obtained in the step a) under the atmosphere of argon;
(c) transferring the solution obtained in the step b) into a reaction device under the atmosphere of argon, connecting with a Chilean operating system, and heating at 55 ℃ for 10-20 min;
(d) adding 0.134g of hexamethylene diisocyanate into the device in the step c) under the argon atmosphere, and slowly dripping into the solution;
(e) Reacting the solution in the step d) at 55 ℃ for 5 hours under an argon atmosphere.
And transferring the solution obtained by the reaction into a disc-shaped 10cm polytetrafluoroethylene die, standing at room temperature for 48 hours, transferring to a vacuum condition, and drying at room temperature for 72 hours to obtain the membrane-shaped biological elastomer material 80-P-1.0U.
Example 7
This example relates to the solvent method of making a 40-P-1.0U bioelastomer.
This example is essentially the same as example 5 except that the polymer is PEGS40 after dissolving in solvent, 0.601g of hexamethylene diisocyanate was added. After the reaction is finished, transferring and removing the solvent to obtain the 40-P-1.0U biological elastomer.
Example 8
This example relates to the solvent method for preparing 60-P-1.0U bioelastomers
This example is essentially the same as example 5 except that the polymer is PEGS60 after dissolving in solvent, 0.321g of hexamethylene diisocyanate was added. After the reaction is finished, transferring and removing the solvent to obtain the 60-P-1.0U biological elastomer.
Example 9
This example relates to a solvent route to 0-P-0.5U bioelastomers
This example is essentially the same as example 4, except that 0.984g of hexamethylene diisocyanate was added. After the reaction is finished, transferring and removing the solvent to obtain the 0-P-0.5U biological elastomer.
Example 10
This example relates to a solvent route to 20-P-0.5U bioelastomers
This example is essentially the same as example 5, except that the amount of hexamethylene diisocyanate added is 0.531 g. After the reaction is finished, transferring and removing the solvent to obtain the 20-P-0.5U biological elastomer.
Example 11
This example relates to the solvent method for preparing 40-P-0.5U of a bioelastomer.
This example is substantially the same as example 7 except that hexamethylene diisocyanate was added in an amount of 0.300 g. After the reaction is finished, transferring and removing the solvent to obtain the 40-P-0.5U biological elastomer.
Example 12
This example relates to the solvent process for the preparation of 60-P-0.5U of a bioelastomer.
This example is substantially the same as example 8 except that hexamethylene diisocyanate was added in an amount of 0.161 g. After the reaction is finished, transferring and removing the solvent to obtain the 60-P-0.5U biological elastomer.
Example 13
This example relates to the solvent method for preparing 80-P-0.5U of a bioelastomer.
This example is essentially the same as example 6, except that 0.067g of hexamethylene diisocyanate was added. After the reaction is finished, transferring and removing the solvent to obtain the 80-P-0.5U biological elastomer.
Example 14
This example relates to a 20-P-1.0U-F elastomer with a solvent of 0.
(a) Uniformly mixing 4g of the dried PEGS20 prepolymer with stannous octoate with the mass volume ratio of less than 0.05 percent of that of the polyethylene glycol-polysebacic acid glyceride prepolymer;
(b) adding hexamethylene diisocyanate with the molar ratio of 1 to glycerol into the mixture obtained in the step a), and quickly stirring and uniformly mixing;
(c) placing the mixture obtained in the step b) in a dry environment, and continuously reacting for 12 hours to obtain the macromolecular elastomer 20-P-1.0U-F.
Example 15
The present example relates to characterization of a bioelastomeric material
The PEGS-U is prepared by reacting hydroxyl on a high-molecular prepolymer with an isocyanate group on hexamethylene diisocyanate. The content of polyethylene glycol (relative to the amount of the substance containing hydroxyl group) in the prepolymer is controlled to be 0%, 20%, 40%, 60% and 80%, and hexamethylene diisocyanate which is 50-100% relative to glycerol is added to obtain a series of materials which are marked as 0-P-0.5U, 0-P-1.0U, 20-P-0.5U, 20-P-1.0U, 40-P-0.5U, 40-P-1.0U, 60-P-0.5U, 60-P-1.0U, 80-P-0.5U and 80-P-1.0U. The structure, thermal property and various properties such as in vivo and in vitro compatibility of the materials are respectively characterized.
Data results: the structure was confirmed by nuclear magnetic spectroscopy. DSC experiments show that the glass transition temperature of the X-P-mU series of the biological elastomer materials is lower than room temperature, and the biological elastomer materials are elastic around the temperature of a human body (Table 1). The stretching (A in figure 2) and cycle stretching (B in figure 2) experiments prove that the X-P-mU series biological elastomer has good mechanical property and creep resistance. Contact angle (A in FIG. 3) and 30-day in vitro degradation (B in FIG. 3) experiments showed that the hydrophilicity and degradability of the X-P-mU bio-elastomer were controllable, and the results of these experiments showed that the properties of the bio-elastomer were controlled by the content of polyethylene glycol and hexamethylene diisocyanate.
The elastic bodies of 60-P-0.5U, 60-P-1.0U, 80-P-0.5U and 80-P-1.0U have the mechanical strength of less than 0.3MPa and the breaking elongation of less than 40 percent. The prepolymer with PEG content of 20 and 40 has mechanical strength up to 4.27MPa and tensile breaking rate of 272%.
TABLE 1 mechanical Properties and glass transition temperatures of the bioelastomers at Room temperature
Example 16:
this example relates to BMSC Co-culture
1. Rat bone marrow mesenchymal stem cells (rBMSCs) (1, about 80-100g of rat, decapitated and killed, 10min with 75% alcohol.
2. The femur and tibia are stripped aseptically, and the muscles on the bones are stripped off with gauze.
3. The metaphysis was cut off, the marrow cavity was flushed with L-DMEM medium containing 10% fetal bovine serum (not inactivated) using a 5ml syringe, and the prepared single cell suspension was blown up.
4. Centrifuging for 1000r/min and 5 min.
5. Abandoning the supernatant, suspending the cells by a culture medium, blowing the cells into a cell suspension, inoculating the cell suspension into a culture flask, and culturing the cell suspension) as a model, and observing the state of the cells on the surface of the material by using a laser confocal microscope.
As shown in fig. 4: will be 1 × 105After 24h, the cells in each hole are cultured on the material and washed three times by PBS, fixed by 2.5 percent glutaraldehyde for 15min, stained by fluorescein isothiocyanate-labeled Phalloidin (FITC-Phalloidin) for 40 min, washed 5 times by PBS for 5min each time, and observed under laser confocal after sealing by sealing liquid. The phenomenon shows that the cell adhesion quantity and the spreading state on the materials of examples 4, 5 and 7 are increased along with the increase of the PEG content, and the spreading area of the adhered cells on the stent is also increased along with the increase of the PEG content and the coating quantity.
Example 17:
this example relates to animal experiments and evaluation of in vivo biosafety
1) The bioelastic materials of examples 4 and 5 were implanted subcutaneously into the dorsal sites of 8-week-old male C57 mice, respectively, using C57 mice subcutaneously implanted as a model. Mice in each group of examples were sacrificed 1 week and 4 weeks after implantation, and the material was removed along with surrounding tissues for sectioning and staining.
2) After the taken out material and surrounding tissues are made into slices, paraffin in the slices is removed by xylene, and the slices are soaked in ethanol solution with sequentially reduced concentration and finally washed by distilled water.
3) Soaking the slices washed by the distilled water in the step 2) in a hematoxylin solution for a plurality of minutes, soaking the slices in acid water and ammonia water for a plurality of seconds, and then washing the slices by running water and distilled water for 1 hour respectively.
4) Dehydrating the slices in the step 3) by using an ethanol solution, dyeing the slices for 3 minutes by using eosin, treating the slices by using ethanol and xylene, and dripping gum to seal the slices to obtain H & E dyed slices.
As can be seen from fig. 5, all of the bio-elastomers prepared in examples 4, 5, and 7 showed good biocompatibility.
Example 18:
this example relates to the preparation of 20-P-1.0U-F membranes, porous scaffolds and tubular materials
The membranous bioelastomeric material may be prepared by the procedure described in example 7, in accordance with example 7.
Pouring the mixture of step b) of example 7 into a PTFE mold having a diameter of 0.5 to 3cm in the form of holes or circular recesses, placing the mold carrying the mixture in a moist atmosphere, and releasing CO by reaction of the isocyanate with water vapor2Gas, to obtain a 20-P-1.0U-F porous column scaffold material, as shown in FIG. 6B.
The mixture of step b) of example 7 was transferred to a custom built mold consisting of two parts. The combined mold is placed in a dry environment and allowed to continue to react for 12 hours, and the tubular bio-elastomer material is obtained after demolding and taking out, as shown in fig. 6C.
Example 19
This example relates to the preparation of a porous calcium phosphate scaffold
Mixing the calcium phosphate cement powder with sieved pore-making salt (300-500 microns), adding saturated salt water (solid-to-liquid ratio: 1g/0.3mL) as a curing liquid into the powder, quickly preparing into uniform slurry, placing the uniform slurry into a stainless steel die, and performing pressure maintaining for 1 minute at 2MPa by using a tablet machine for compression molding. And (3) placing the columnar sample after compression molding for 72 hours at 37 ℃ and 100% humidity for curing reaction, then soaking the cured material in ultrapure water for 3 days, continuously stirring, changing a batch of new ultrapure water every 12 hours, and preparing the porous CPC support after NaCl particles are completely dissolved out.
Example 20
This example relates to the preparation of a Bioelastomer/CPC composite scaffold at various coating levels and characterization of its properties
The solution described in step e) of example 5, which was still a fluid liquid after 5h of reaction, was uniformly coated and infiltrated with a tip into the porous scaffold prepared in example 19 in a total of 80ul coating amounts of 20. mu.l/time, for a total of 4 times, and left to stand until it completely infiltrated into the scaffold and was uniformly dispersed, and then the coated scaffold was placed in a fume hood for 48 hours, and the solvent was mostly evaporated. Then the scaffold is placed in a vacuum drying oven, and the biological elastomer composite porous CPC scaffold is obtained under the conditions of vacuum at 37 ℃ and 72 hours.
According to the embodiment 5, the concentration of the solution prepared in the step e) is 0.1-0.3 g/ml by regulating and controlling the feeding of the polymer, and according to the coated content, the polymer content (polymer mass/CPC stent mass) of the finally prepared composite stent is 6%.
As shown in FIG. 7, the graph (A) shows the morphology of the composite stent after compression testing at the coating content of 6%, and the graph (B) shows the compression deformation of the material at the coating content.
The compression test shows that the composite scaffold coated with the biological elastomer has a certain degree of enhanced mechanical strength relative to the unmodified CPC porous scaffold.
Example 21
This example relates to the use of bioelastomers for controlled release of active factors
After 12 hours of reaction in a desiccator, a film-like bio-elastomer attached to the glass sheet was obtained without demolding as described in step d) of example 14. The solution of horseradish catalase dissolved at 10mg/ul was slowly dripped on the surface of the material in a dripping manner. After the freeze-drying treatment, the step a) d) in example 14 is repeated on the biological elastomer membrane material loaded with the bioactive factors to obtain the membrane loaded with horseradish catalase and having a layer-by-layer structure.
The enzyme-loaded membrane was soaked in a PBS solution, and then placed in a 37 ℃ incubator, and the released PBS solution was collected at a predetermined time (1, 2, 4, 8, 12, 24, 36, 48, 72) and replaced with new PBS. Here, the enzyme was measured for its content using the absorbance value specific to the enzyme at 405nm, and then the concentration of the enzyme solution was diluted to 0.1ug/ml, and a color developing solution (TMB one-component color developing solution) was added to measure its absorbance coefficient after catalyzing for 10 minutes to characterize the activity of the enzyme.
The 24 hour enzyme activity results in A of FIG. 8 show that the catalase loaded in this protocol still has higher activity, and when the PEG content is increased, the released enzyme activity is relatively higher.
As can be seen from B in FIG. 8, the novel bio-elastomer material has a slow release function, and as the content of PEG increases, the release rate of the enzyme also increases.
The amount of dripping is controlled to be 126ul/cm according to the area of the film material2Meanwhile, the concentration of the solution dissolved with the bioactive factor can be properly adjusted according to the application part.
The film material composition can be selected from hexamethylene diisocyanate cross-linked polysebacic acid glyceride, hexamethylene diisocyanate cross-linked polyethylene glycol-polysebacic acid glyceride, etc. according to the application position.
Depending on the application site, the composition of the film is not limited to 2 layers, and can be adjusted appropriately within this range.
Example 22
This example relates to the use of a bioelastomer for controlled release of a drug
After 12 hours of reaction in a desiccator, a film-like bio-elastomer attached to the glass sheet was obtained without demolding as described in step d) of example 14. The dexamethasone solution dissolved with 10mg/ul is slowly dripped on the surface of the material in a dripping mode. After the freeze-drying treatment, the step a) d in example 14 is repeated on the drug-loaded bio-elastomer membrane material to obtain a drug-loaded thin film with a layer-by-layer structure.
The drug-loaded film was soaked in PBS solution, then placed in a 37 ℃ constant temperature shaking box, and the released PBS solution was collected at a predetermined time (1, 2, 4, 8, 12, 24, 36, 48, 72) and replaced with new PBS. And measuring the absorbance value of the micromolecular drug at the wavelength of 240nm to measure the drug released by the drug-loaded film.
The amount of dripping is controlled to 126ul/cm according to the area of the film material2Meanwhile, the concentration of the solution dissolved with the bioactive factor can be properly adjusted according to the application part.
The film material composition can be selected from hexamethylene diisocyanate cross-linked polysebacic acid glyceride, hexamethylene diisocyanate cross-linked polyethylene glycol-polysebacic acid glyceride, etc. according to the application position.
The composition of the film is not limited to 2 layers depending on the application site, and can be adjusted appropriately within this range.
Comparative example 1
The specific embodiment of this comparative example is the same as that of the prior patent application CN201510107574.3 and the literature (Ma Y, Zhang W, Wang Z, Wang Z, Xie Q, Niu H, et al. acta Biomate 2016; 44: 110-24.).
After the prepolymers in the embodiments 1, 2 and 3 are subjected to high-temperature vacuum crosslinking, the tensile strength is between 100kPa and 1MPa, and the elongation at break is between 20 and 80 percent.
The hexamethylene diisocyanate obtained by the scheme is crosslinked in a mode, the mechanical property of the hexamethylene diisocyanate is greatly improved, the adjustable range is large, and the Young modulus, the tensile strength and the elongation at break of the hexamethylene diisocyanate are respectively 1.01-14.23 MPa, 0.32-7.63 MPa and 53.63-272.84%.
Comparative example 2
The hexamethylene diisocyanate described in the scheme is reacted with prepolymer with smaller molecules (the data molecular weight is lower than 4000), and the product is obtained after the solvent is removed. The product can still be dissolved in DMF for more than 70%, and the mechanical tensile strength and the mechanical strength are respectively lower than 10% and 0.3 MPa.
In the scheme, the prepolymer in the molecular weight range (the number average molecular weight is 4000-9000) can effectively establish a cross-linked network after being cross-linked by hexamethylene diisocyanate, and the tensile strength and the mechanical strength of the prepolymer are relatively excellent.
Comparative example 3
The prepolymer with too high a molecular weight (data molecular weight higher than 9000) according to the present scheme is reacted with hexamethylene diisocyanate, which reacts to form a gel in a time well below that specified, while part of the isocyanate groups are still present in the reaction.
After the prepolymer in the interval (with the number average molecular weight of 4000-9000) is mixed with hexamethylene diisocyanate, a cross-linked network can be slowly and effectively formed under mild reaction conditions, and a period of time for operation and processing is provided after the solvent is discarded.
Comparative example 4
The active factor is immobilized by adopting a thermal crosslinking method
The protein or drug molecules were mixed directly in a suitable manner (solution or solid) with the prepolymers described in examples 1, 2 and 3. After vacuum crosslinking at 130-150 ℃ in a tetrafluoro mold, buffer solutions such as PBS and the like are used as solvents for releasing the loaded active factors in a thermal crosslinking mode. In contrast to the low temperature loading of active factors described in example 9, the factors loaded by thermal crosslinking have lost their activity.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (20)
1. A bioelastomer comprising the following structural units:
n is an integer of 10 to 80;
m is an integer of 2 to 14,
wherein, in the biological elastomer, the molar ratio of the polyethylene glycol to the glycerol is 0.2-0.67;
the molar ratio of hexamethylene diisocyanate to glycerin is 0.2-1.5,
wherein the biological elastomer is obtained by reacting a polyethylene glycol-polysebacic acid glyceride prepolymer with hexamethylene diisocyanate in a solvent,
Wherein the solvent is benzene, toluene, xylene, pentane, hexane, octane, cyclohexane, cyclohexanone, toluene cyclohexanone, chlorobenzene, dichlorobenzene, dichloromethane, methanol, ethanol, isopropanol, diethyl ether, epoxypropane, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine, phenol, N-dimethylformamide, tetrahydrofuran or a mixed solvent of more than two of the above;
the number average molecular weight of the prepolymer is 4000-9000, and the dispersion coefficient is 1.2-3.0.
2. The bioelastomer of claim 1, wherein the bioelastomer has a molar ratio of sebacic acid to glycerol and polyethylene glycol of 0.65-2.8.
3. The bioelastomer of claim 1, wherein the bioelastomer has a molar ratio of sebacic acid to glycerol and polyethylene glycol of 1 to 1.8.
4. The bioelastomer of claim 1, wherein the bioelastomer has a molar ratio of polyethylene glycol to glycerol of from 0.2 to 0.25.
5. The bioelastomer of claim 1 wherein the molar ratio of polyethylene glycol to glycerol in said bioelastomer is 0.25.
6. The bioelastomer of claim 1, wherein n is an integer from 15 to 70.
7. The bioelastomer of claim 1, wherein n is an integer from 20 to 60.
8. The bioelastomer of claim 1, wherein m is an integer from 3 to 12.
9. The bioelastomer of claim 1, wherein m is an integer from 4 to 10.
10. The bioelastomer of claim 1, wherein the bioelastomer has one or more of the following characteristics:
(1) the hydrophilic angle can be 20-89 degrees;
(2) young modulus is 0.5-18.0 MPa;
(3) the tensile strength is 0.1-12.0 MPa;
(4) the elongation at break is 23.0-400.0%;
(5) the in vitro degradation is 10-99% in 30 days.
11. A process for the preparation of a bioelastomer according to claim 1, characterized in that it comprises the following steps:
reacting the polyethylene glycol-polysebacic acid glyceride prepolymer with hexamethylene diisocyanate in a solvent to obtain the biological elastomer,
wherein the solvent is benzene, toluene, xylene, pentane, hexane, octane, cyclohexane, cyclohexanone, toluene cyclohexanone, chlorobenzene, dichlorobenzene, dichloromethane, methanol, ethanol, isopropanol, diethyl ether, epoxypropane, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine, phenol, N-dimethyl amide, tetrahydrofuran or a mixed solvent of more than two of the above,
The number average molecular weight of the prepolymer is 4000-9000, and the dispersion coefficient is 1.2-3.0.
12. The method of claim 11, further comprising the step of adding a catalyst to the solvent, the catalyst selected from the group consisting of: stannous octoate, dibutyltin dilaurate, dibutyltin didodecyl sulfide, dibutyltin diacetate, bismuth neodecanoate, zinc isooctanoate or a mixed catalyst of more than two.
13. The method of claim 11, wherein the preparation of the bioelastomer comprises the steps of:
(a) dissolving the dried polyethylene glycol-polysebacic acid glyceride prepolymer in anhydrous N, N-dimethyl amide under the atmosphere of argon, wherein the concentration of the solution is 0.01 to infinity g/ml;
(b) under the atmosphere of argon, dissolving stannous octoate with the mass volume ratio of 0.0001-0.01% in the solution in the step a);
(c) transferring the solution obtained in the step b) into a reaction device under the atmosphere of argon, connecting with a Chilean operating system, and heating at 20-65 ℃ for 10-20 min;
(d) under the argon atmosphere, adding hexamethylene diisocyanate with the corresponding molar weight into the device in the step 3), and slowly dripping into the solution;
(e) And d) under the argon atmosphere, continuously reacting the solution obtained in the step d) at 20-65 ℃ for 5-12 hours, taking out and transferring the solution to a tetrafluoro mold, standing for 2 days at room temperature, and vacuum-drying for 48 hours at room temperature to obtain the biological elastomer.
14. The method of claim 13, wherein in step b), from 0.001% to 0.01% by weight of stannous octoate is dissolved in the solution of step a).
15. The method of claim 13, wherein in step a), the solution has a concentration of 0.05 to 5 g/ml.
16. The method of claim 13, wherein in step a), the solution has a concentration of 0.1 to 3 g/ml.
17. The method of claim 13, wherein in step b), 0.01% by mass/volume stannous octoate is dissolved in the solution of step a).
18. A modified material comprising a base material, and the bioelastomer of claim 1 supported on the base material.
19. The modified material of claim 18, wherein the substrate material is selected from the group consisting of calcium phosphate scaffolds, MBG scaffolds, PEEK, PMMA.
20. A drug release material comprising the bioelastomer of claim 1, and an active factor supported on the bioelastomer.
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