CN109970956B - Degradable polyester composite material prepared based on carboxylic acid related to Krebs cycle and preparation method and application thereof - Google Patents
Degradable polyester composite material prepared based on carboxylic acid related to Krebs cycle and preparation method and application thereof Download PDFInfo
- Publication number
- CN109970956B CN109970956B CN201910268530.7A CN201910268530A CN109970956B CN 109970956 B CN109970956 B CN 109970956B CN 201910268530 A CN201910268530 A CN 201910268530A CN 109970956 B CN109970956 B CN 109970956B
- Authority
- CN
- China
- Prior art keywords
- prepolymer
- acid
- hours
- calcium
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/60—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from the reaction of a mixture of hydroxy carboxylic acids, polycarboxylic acids and polyhydroxy compounds
Abstract
The invention provides a biodegradable polyester material prepolymer, which is polyester obtained by melt polycondensation of carboxylic acid A and polyalcohol B; wherein the carboxylic acid A is a complex carboxylic acid selected from a mixture of at least two of carboxylic acids and homopolymers thereof involved in the Krebs cycle. The invention also provides a biodegradable composite material suitable for bone repair, which is prepared from 10-99% of the prepolymer and 1-90% of a metal ion-containing compound in percentage by weight. The composite material provided by the invention not only has good biological safety and suitable mechanical properties, but also has a remarkable promoting effect on the regeneration of bone tissues. The invention also provides a method for preparing the composite material.
Description
Technical Field
The invention relates to the field of biomedical materials, in particular to degradable polyester, a preparation method and potential application thereof.
Background
Degradable biological materials such as polylactic acid (PLA), polylactide glycolide (PLGA), Polycaprolactone (PCL) and other linear macromolecules have good biocompatibility and are widely researched and applied in the field of biomedicine. At present, products such as anti-adhesion membranes, bone nails, drug release carriers and the like are put into the market.
However, as an in vivo implant material, the existing degradable biological material still has a plurality of defects such as local inflammatory reaction, mismatching of degradation speed and mechanical property and the like. Meanwhile, the preparation process of the material is complicated, the manufacturing cost is high, and the industrial production and application are not facilitated. Therefore, the search for new biodegradable materials and new preparation methods is the direction of people's constant search. By utilizing the melt polycondensation between carboxylic acid and alcohol, bulk phase crosslinked polyester material can be obtained without adding any catalyst. The method greatly simplifies the preparation, and the performance of the obtained polyester material can meet the application requirement of in vivo implantation.
In the prior art, patent US8911720 discloses the use of citric acid and a diol to prepare thermoplastic elastomers useful as biological scaffolds for implantation in vivo. Furthermore, patent US8568765 describes that a melt polycondensation-derived poly (citric acid glycol ester) (POC) and Hydroxyapatite (HA) composite material formed by POC can be used for tissue engineering and bone fixation devices and bone defect repair materials. Patent US9750845 discloses that the addition of nanofibrous PLLA to poly citric acid diol improves tensile strength, young's modulus and elongation at break with less permanent set; the mechanical property of the product can be adjusted by changing the concentration of the nano-phase PLLA, selecting a diol monomer or adjusting the polymerization conditions, so that the obtained composite elastomer is suitable for cartilage, ligaments and blood vessels. Patent CN107583106A discloses modification of poly citrate obtained by melt polycondensation, so that the poly citrate is suitable for rapid molding of biological scaffolds such as 3D printing. The above researches in the prior art have focused on the poly-citric acid ester, and the reason is that the poly-citric acid ester has ideal biodegradability, and the polymerized monomer citric acid itself has a unique molecular chain structure, and can easily form a three-dimensional network-like chemical structure with mutually cross-linked and mutually interpenetrated molecular chains after undergoing a polycondensation reaction with different alcohols, so that the polyester product has better controllability in terms of mechanical properties, and the poly-citric acid ester is very beneficial to improving the application range and application value of the polyester product.
Soft body materials which can quickly fill up abnormal defects and have excellent bone regeneration performance are needed in clinical repair treatment such as tooth defect repair, repair after bone tumor resection, reconstruction after femoral head necrosis and the like. Therefore, for the bone repair field, the implantable repair material not only needs ideal biodegradability and mechanical properties, but also needs to provide powerful promotion for the bone tissue regeneration process. Therefore, it is necessary to develop a new implantable tissue engineering material aiming at the application requirements in the bone repair field, so as to realize the wide application of the tissue engineering material in the bone repair field.
Disclosure of Invention
In view of the above technical background, the most important objects of the present invention are: the biodegradable polyester material is suitable for bone repair, has good biological safety and suitable mechanical property, and has a remarkable promoting effect on the regeneration of bone tissues.
Another object of the invention is: the method for preparing the polyester material is provided, the preparation process is simplified, the product performance is improved, and the obtained polyester material has practical application value in the field of bone repair.
Yet another object of the present invention is: provides the application of the polyester material as a tissue engineering material.
In order to achieve the purpose, the invention provides the following technical scheme:
firstly, providing a biodegradable polyester material prepolymer, which is polyester obtained by melt polycondensation of carboxylic acid A and polyalcohol B; wherein, the carboxylic acid A is a complex carboxylic acid, is a mixture of at least two selected from carboxylic acids involved in the Krebs cycle process or homopolymers thereof, and is preferably a mixture of any two or more selected from malic acid, citric acid, fumaric acid, succinic acid, polymalic acid and polymalic acid.
In the preferable polyester material prepolymer of the invention, the polyol B comprises but is not limited to any one or a combination of more than two of ethylene glycol, 1, 4-butanediol, 1, 8-octanediol, glycerol, trimethylolpropane, hexanetriol, erythritol, pentaerythritol, dipentaerythritol, xylitol, sorbitol, mannitol or branched polyethylene glycol; more preferably 1, 4-butanediol, glycerol, or branched polyethylene glycol, or a combination of any one or more thereof.
In a preferred embodiment of the present invention, the complex carboxylic acid comprises a carboxylic acid having a structure containing at least two carboxyl groups and one hydroxyl group; more preferably, the carboxylic acid having at least two carboxyl groups and one hydroxyl group in the structure is L-malic acid or citric acid.
In another preferred embodiment of the present invention, the complex carboxylic acid is a mixture of L-malic acid, citric acid and succinic acid.
The invention also provides a biodegradable medical polyester material, which is polyester obtained by the bulk phase crosslinking reaction of the prepolymer in static equipment.
The invention also provides a scaffold for tissue repair, which is prepared by adding a pore-forming agent or a pore-forming structure into the prepolymer. The pore-forming agent comprises but is not limited to sodium chloride particles, glucose microspheres, 3D printing high polymer material scaffolds and polylactic acid microspheres.
The biodegradable polyester material prepolymer contains carboxylic acid related in Krebs cycle process, and the carboxylic acid is used as an intermediate of tricarboxylic acid metabolism of human bodies, has good promotion effect on tissue regeneration, and can be used as an active ingredient in an implant material to play a role.
Based on the biodegradable polyester material prepolymer, the invention further provides a biodegradable composite material suitable for bone repair, which is a composite material prepared from 10-99% of the biodegradable polyester material prepolymer and 1-90% of a metal ion-containing compound in percentage by weight.
In a preferred embodiment of the present invention, the metal ion-containing compound includes calcium, magnesium, and iron compounds, and particularly includes one or a combination of two or more of calcium hydroxide, calcium oxide, ferrous hydroxide, ferric oxide, magnesium hydroxide, magnesium oxide, hydroxyapatite, calcium hydrogen phosphate, calcium dihydrogen phosphate, tetracalcium phosphate, octacalcium phosphate, calcium sulfate, calcium carbonate, calcium citrate, calcium malate, calcium polymalic acid, magnesium polymalic acid, iron polymalic acid, calcium succinate, tricalcium phosphate, ferrous fumarate, ferrous succinate, magnesium malate, and magnesium citrate.
In a preferred scheme of the invention, the biodegradable composite material suitable for bone repair is prepared from 62.5-91 wt% of the polyester material prepolymer and 9-37.5 wt% of a metal ion-containing compound.
The invention also provides a method for preparing the biodegradable composite material suitable for bone repair, which comprises the following steps: firstly, preparing a prepolymer by taking at least two carboxylic acids or homopolymers thereof and polyhydric alcohols involved in the Krebs circulation process as raw materials in a melt polycondensation mode, then adding metal elements and/or inorganic salts into the prepolymer, and continuing a bulk phase crosslinking reaction in static equipment to obtain the composite material.
In the preparation method, the carboxylic acid related in the Krebs circulation process comprises malic acid, citric acid, fumaric acid or succinic acid; the polyhydric alcohol includes but is not limited to any one or a combination of more than two of ethylene glycol, 1, 4-butanediol, 1, 8-octanediol, glycerol, trimethylolpropane, hexanetriol, erythritol, pentaerythritol, dipentaerythritol, xylitol, sorbitol, mannitol or branched polyethylene glycol; preferably 1, 4-butanediol, glycerol, or branched polyethylene glycol, or a combination of any one or more of them.
In a specific embodiment of the preparation method of the present invention, the carboxylic acid involved in the Krebs cycle at least comprises any one of malic acid or citric acid; the preparation method comprises the following steps of taking at least two carboxylic acids and polyhydric alcohols related to Krebs circulation as raw materials to prepare a prepolymer in a melt polycondensation mode, specifically, firstly carrying out homopolymerization on any one of malic acid or citric acid, then adding other carboxylic acids and polyhydric alcohols related to Krebs circulation in the Krebs circulation process, and continuing to carry out melt polycondensation to obtain the prepolymer.
In another specific embodiment of the preparation method of the present invention, the prepolymer is prepared by using at least two carboxylic acids and polyols related to Krebs cycle as raw materials and performing melt polycondensation, specifically, ester exchange reaction is performed between esters of carboxylic acids related to Krebs cycle and the polyols, then carboxylic acids related to other Krebs cycle and the polyols are added, and melt polycondensation is continued to obtain the prepolymer; the ester of a carboxylic acid involved in the Krebs cycle is preferably a fumarate, more preferably methyl or diethyl fumarate.
In the preparation method, the melt polycondensation temperature is preferably 120-180 ℃.
In the preparation method of the present invention, the melt polycondensation time is preferably 1 to 2 hours.
In the preparation method, the temperature for continuous bulk phase crosslinking reaction in static equipment is preferably 130-135 ℃.
In the preparation method, the time for continuing the bulk phase crosslinking reaction in the static equipment is preferably 3-250 hours.
In the preparation method, the static equipment is preferably an electric heating oven or a microwave reactor.
The invention also provides application of the prepolymer or the composite material as a tissue engineering material in repairing blood vessels, cartilages, skins, intervertebral discs or bone tissues and the like.
Compared with the prior art, the prepolymer, the composite material and the preparation method thereof have the following beneficial effects:
1. the polymerization method does not introduce any catalyst, and improves the biological safety.
2. The prepolymer and the composite material have excellent tissue regeneration activity as tissue engineering materials.
The activity is caused by that the polyester is prepared by taking more than two carboxylic acids (marked as 'Krebs carboxylic acid', including malic acid, citric acid, succinic acid or fumaric acid, and the like) involved in the Krebs cycle process as raw materials. Experiments show that the Krebs carboxylic acid has obvious acceleration effect on the regeneration of bone tissues after being prepared into polyester compared with other carboxylic acids; moreover, compared with a single Krebs carboxylic acid polyester, the polyester prepared by more than two Krebs carboxylic acids can obtain an abnormally significant effect on the aspect of promoting the regeneration of bone tissues. The reason for this should be related to the effect of Krebs carboxylic acid on the metabolism of the regeneration process. The tricarboxylic acid cycle is a ubiquitous metabolic pathway in aerobic organisms, is a final metabolic pathway of saccharides, lipids and amino acids, wherein malic acid, citric acid, fumaric acid and succinic acid are intermediate metabolites, and polyesters prepared by Krebs carboxylic acid can accelerate bone regeneration and are realized by regulating the metabolic pathway.
The invention utilizes the regulation characteristic of Krebs carboxylic acid on metabolism, and the prepolymer and the composite material thereof prepared by at least two Krebs carboxylic acids and polyhydric alcohol have good biocompatibility and tissue regeneration activity.
3. The biodegradable composite material of the invention has components and mechanical strength suitable for bone repair.
Compounds containing metal ions are of great importance for the bone repair process. Calcium is necessary for bone tissue, and Hydroxyapatite (HA), beta-tricalcium phosphate (TCP), calcium hydrogen phosphate, dicalcium phosphate and the like are commonly used active materials; magnesium is also an essential element of human body, almost participates in all metabolic processes of human body, and has osteogenic and angiogenetic activities; vascular ingrowth contributes to bone tissue development, while iron also contributes to angiogenic activity. Therefore, the necessary metal elements are introduced or loaded into the medical polyester material, so that the medical polyester material has a remarkable promotion effect on bone tissue regeneration. In addition, the inventor researches and discovers that the composite material of the invention is introduced with the organic or inorganic compound containing metal ions, although the composite material is simply blended, the strength of the material is obviously enhanced. In the prior art, it has long been considered that bulk cross-linked medical polyester materials can only be used as flexible materials for soft tissue repair and regeneration, but cannot be used in the repair field requiring certain mechanical strength, such as bone repair. The inventor finds that the strength of the polyester material can be improved by introducing other chemical structure carboxylic acid such as L-malic acid, and further introduces metal ions into the medical polyester material on the basis, so that the activity of promoting bone tissue regeneration is brought to the polyester material, the medical polyester material also has ideal mechanical strength for bone repair, and conditions are created for the application of the medical polyester material in the field of bone repair.
4. In the preparation method, materials with different properties can be obtained by adjusting the reaction conditions, and the preparation method has wider application range, and is used for medical catheters, anti-adhesion film materials and the like. In the preparation method, the composite materials with different mechanical properties, such as paste, soft elastomers, hard materials and the like, can be obtained by adjusting the composition type, the feeding ratio and/or the bulk phase crosslinking reaction time of the prepolymer raw materials. The obtained moldable material and the soft elastomer material can be used for repairing defected non-bearing bones; the obtained hard elastomer or hard material can be used for bone repair with mechanical supporting effect. Therefore, the method can prepare medical polyester materials with different purposes, and the medical polyester materials not only can be used for repairing soft tissues such as blood vessels, cartilages, skins and intervertebral discs, but also are suitable for repairing hard materials such as bones, teeth and the like.
Drawings
FIGS. 1 to 6 are photographs showing the appearance of the polyester materials prepared in examples 3, 4, 5, 6, 9 and 10 of the present invention, respectively.
Detailed Description
The present invention will be further described with reference to specific examples, but it should not be construed that the scope of the present invention is limited to the examples.
All compounds and reagents used in the following examples are either available products or products that can be prepared by existing methods.
Example 1: polyester material prepared by condensation polymerization of L-malic acid/citric acid/succinic acid/glycerol
Adding 0.1mol of citric acid, 0.1mol of L-malic acid and 0.17mol of glycerol into a double-neck flask, reacting for 1 hour at the temperature of 140-150 ℃ under the protection of nitrogen to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene surface vessel, putting the prepolymer into a 135 ℃ oven for continuous reaction for 3 days, and cooling to obtain a hard material.
Example 2: polyester material prepared by condensation polymerization of L-malic acid/citric acid/succinic acid/1, 4-butanediol
Adding 0.1mol of citric acid, 0.25mol of L-malic acid and 0.1mol of 1, 4-butanediol into a double-neck flask, reacting for 1 hour at the temperature of 150 plus materials and 160 ℃ under the protection of nitrogen to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene surface dish, putting the prepolymer into a 135 ℃ oven for continuous reaction, and measuring the mechanical strength, the tensile strength and the elongation at break of the prepolymer after 1 day of reaction, wherein the tensile strength is 0.73Mpa and the elongation at break is 252.7%.
Example 3: polyester material prepared by L-malic acid/citric acid (self polymerization)/succinic acid/glycerol polycondensation
Adding 0.1mol of citric acid into a double-mouth flask, performing self-polymerization for about 4 hours at 145 ℃, then adding 0.1mol of L-malic acid and 0.25mol of succinic acid respectively, reacting for 1.5 hours at 165-170 ℃ under the protection of nitrogen to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene watch glass, placing the prepolymer into a 135 ℃ oven for continuous reaction, measuring the mechanical strength after 5 days of reaction, wherein the tensile strength is 1.27Mpa, and the elongation at break is 174.6%
Example 4: polyester material prepared by L-malic acid/fumaric acid/1, 4-butanediol polycondensation
Adding 0.05mol of dimethyl fumarate and 0.1mol of 1, 4-butanediol into a double-neck flask, reacting at 145 ℃ for about 2 hours, adding 0.1mol of L-malic acid, continuously reacting for 2 hours to obtain a prepolymer, transferring the prepolymer into a polytetrafluoroethylene surface dish, putting the prepolymer into a 135 ℃ oven, and continuously reacting for 5 days, and measuring the mechanical strength, the tensile strength is 1.93Mpa, and the elongation at break is 122.8%.
Example 5: polyester material prepared by L-malic acid/succinic acid/1, 4-butanediol polycondensation
Adding 0.1mol of L-malic acid, 0.1mol of succinic acid and 0.15mol of 1, 4-butanediol into a double-neck flask, reacting at 120 ℃ for 2 hours to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene watch glass, putting the polytetrafluoroethylene watch glass into a 130 ℃ oven for continuous reaction, and measuring the mechanical strength, the tensile strength and the elongation at break of the mechanical strength after 4 days of reaction, wherein the tensile strength is 8.8Mpa and the elongation at break is 14.1%.
Example 6: polyester material prepared by condensation polymerization of L-malic acid/succinic acid/glycerol
Adding 0.1mol of L-malic acid, 0.1mol of succinic acid and 0.1mol of glycerol into a double-neck flask, reacting for 2 hours at 120 ℃ to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene watch glass, putting the polytetrafluoroethylene watch glass into a 135 ℃ oven for continuous reaction, and measuring the mechanical strength, the tensile strength is 18.3Mpa and the elongation at break is 53.6% after reacting for 7 days.
Example 7: polyester composite material prepared by blending L-malic acid/citric acid/succinic acid/1, 4-butanediol polyester material and Hydroxyapatite (HA)
Adding 0.1mol of citric acid, 0.25mol of L-malic acid and 0.1mol of 1, 4-butanediol into a double-neck flask, reacting for 2 hours at the temperature of 155 ℃ under the protection of nitrogen to obtain a prepolymer, transferring the prepolymer into a polytetrafluoroethylene surface dish, adding Hydroxyapatite (HA) accounting for 10 percent of the total weight of the prepolymer, and blending to obtain the inorganic substance-containing pudding-shaped material.
Example 8: polyester composite material prepared by condensation polymerization of L-malic acid/succinic acid/1, 4-butanediol/HA
Adding 0.1mol of L-malic acid, 0.1mol of succinic acid and 0.15mol of 1, 4-butanediol into a double-neck flask, reacting at 130-140 ℃ for 3 hours to obtain a prepolymer, transferring the prepolymer into a polytetrafluoroethylene surface dish, adding hydroxyapatite accounting for 10 percent of the total weight of the prepolymer, putting the prepolymer into a 135 ℃ oven for continuous reaction, and reacting for 4 days to obtain the pudding-shaped high-viscosity plastic material at normal temperature.
Example 9: polyester composite material prepared by condensation polymerization of L-malic acid/citric acid (self polymerization)/succinic acid/glycerol/HA
Adding 0.15mol of citric acid into a double-neck flask, performing self polymerization for 3 hours at 140 ℃, then adding 0.15mol of L-malic acid and 0.375mol of succinic acid respectively, performing reaction for 1 hour at 150 ℃ under the protection of nitrogen to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene surface dish, adding 30 percent of hydroxyapatite of the total weight, putting the mixture into a 135 ℃ oven, and continuously reacting for 8 hours to obtain a pudding-shaped high-viscosity plastic material at normal temperature, which is suitable for repairing abnormal bone defects.
Example 10: polyester composite material prepared by condensation polymerization of L-malic acid/citric acid (self polymerization)/succinic acid/glycerol/HA
Adding 0.15mol of citric acid into a double-mouth flask, performing self polymerization for 3 hours at 140 ℃, then adding 0.15mol of L-malic acid and 0.375mol of succinic acid respectively, reacting for 1 hour at 150 ℃ under the protection of nitrogen to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene watch glass, adding 30 percent of hydroxyapatite of the total weight of the prepolymer, putting the prepolymer into an oven at 135 ℃ for continuous reaction for 12 hours, curing the material, measuring the mechanical strength, the tensile strength is 2.4Mpa, and the elongation at break is 146.0 percent.
Example 11: polyester composite material prepared by condensation polymerization of L-malic acid/citric acid (self polymerization)/succinic acid/glycerol/HA
Adding 0.15mol of citric acid into a double-mouth flask, performing self polymerization for 3 hours at 140 ℃, then adding 0.15mol of L-malic acid and 0.375mol of succinic acid respectively, reacting for 1 hour at 150 ℃ under the protection of nitrogen to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene surface dish, adding 60 percent of hydroxyapatite of the total weight of the prepolymer, putting the prepolymer into an oven at 135 ℃ for continuous reaction for 12 hours, and curing the material.
Example 12: polyester composite material prepared by condensation polymerization of L-malic acid/citric acid (self polymerization)/succinic acid/glycerin/calcium hydrogen phosphate
Adding 0.15mol of citric acid into a double-mouth flask, performing self polymerization for 3 hours at 140 ℃, then adding 0.15mol of L-malic acid and 0.375mol of succinic acid respectively, reacting for 2 hours at 150 ℃ under the protection of nitrogen to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene surface dish, adding 60 percent of hydroxyapatite of the total weight of the prepolymer, and putting the prepolymer into an oven at 135 ℃ for continuous reaction for 3 hours to obtain the pasty plastic material.
Example 13: polyester composite material prepared by condensation polymerization of L-malic acid/citric acid (self polymerization)/succinic acid/glycerin/calcium hydrogen phosphate
Adding 0.15mol of citric acid into a double-mouth flask, performing self polymerization for 3 hours at 140 ℃, then adding 0.15mol of L-malic acid and 0.375mol of succinic acid respectively, reacting for 2 hours at 140 ℃ under the protection of nitrogen to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene surface dish, adding hydroxyapatite accounting for 60 percent of the total weight of the prepolymer, putting the prepolymer into an oven at 135 ℃ for continuous reaction for 248 hours, and curing the material to obtain the elastomer material.
Example 14: polyester composite material prepared by L-malic acid/succinic acid/four-arm PEG polycondensation
Adding 0.02mol of L-malic acid, 0.01mol of succinic acid and 0.01mol of four-arm PEG (molecular weight 900) into a double-neck flask, reacting at 150 ℃ for 1 hour under the protection of nitrogen to obtain a prepolymer, transferring the prepolymer into a polytetrafluoroethylene surface dish, putting the polytetrafluoroethylene surface dish into an oven at 135 ℃ for continuing to react for 24 hours, and curing the material.
Example 15: l-malic acid/citric acid (self-polymerization)/succinic acid/glycerol/Ca2+/Mg2+Polyester materials prepared by polycondensation
Adding 0.1mol of citric acid into a double-neck flask, performing self polymerization for 4 hours at 145 ℃, then adding 0.1mol of L-malic acid and 0.25mol of succinic acid respectively, reacting for 2 hours to obtain a prepolymer, adding calcium hydroxide and magnesium oxide which respectively account for 5 percent of the total weight of the prepolymer, then transferring the prepolymer into a polytetrafluoroethylene watch glass, and putting the polytetrafluoroethylene watch glass into a 135 ℃ oven for continuous reaction for 3 hours to obtain the orange pasty plastic material.
Example 16: l-malic acid/citric acid (self-polymerization)/succinic acid/glycerol/Ca2+/Mg2+/Fe3+Polyester materials prepared by polycondensation
Adding 0.1mol of citric acid into a double-neck flask, performing self polymerization for 4 hours at 145 ℃, then adding 0.1mol of L-malic acid and 0.25mol of succinic acid respectively, reacting for 2 hours to obtain a prepolymer, adding 3.33 percent of calcium hydroxide, magnesium oxide and ferric oxide respectively based on the total weight of the prepolymer, then transferring the prepolymer into a polytetrafluoroethylene surface dish, and putting the polytetrafluoroethylene surface dish into an oven at 135 ℃ for continuous reaction for 5 hours to obtain a brown pasty plastic material.
Comparative example 1: polyester composite material prepared by L-malic acid/glycerol/HA polycondensation
Adding 0.1mol of L-malic acid and 0.033mol of glycerol into a 100ml double-neck flask, reacting at 120 ℃ for 1 hour to obtain a prepolymer, adding hydroxyapatite accounting for 30 percent of the total weight of the prepolymer, transferring the prepolymer into a polytetrafluoroethylene surface dish, and putting the polytetrafluoroethylene surface dish into an oven at 130 ℃ for continuing to react for 13 hours to obtain the pasty plastic material.
Comparative example 2: polyester composite material prepared by citric acid/glycerin/HA polycondensation
Adding 0.1mol of citric acid and 0.067mol of glycerol into a 100ml double-neck flask, reacting for 2 hours at 140 ℃ to obtain a prepolymer, adding hydroxyapatite accounting for 30 percent of the total weight of the polymer, transferring the prepolymer into a polytetrafluoroethylene surface dish, and putting the polytetrafluoroethylene surface dish into an oven at 130 ℃ to continue reacting for 15 hours to obtain a hard and brittle material.
Comparative example 3: polyester composite material prepared by condensation polymerization of succinic acid/glycerin/HA
Adding 0.1mol of succinic acid and 0.067mol of glycerol into a 100ml double-neck flask, reacting for 2 hours at 130 ℃ to obtain a prepolymer, adding hydroxyapatite accounting for 30 percent of the total weight of the prepolymer, transferring the prepolymer into a polytetrafluoroethylene surface dish, and putting the prepolymer into a 130 ℃ oven to continue reacting for 24 hours to obtain the pasty shapeable material.
Comparative example 4: polyester composite material prepared by fumaric acid/glycerin/HA polycondensation
Adding 0.1mol of dimethyl fumarate and 0.06mol of glycerol into a 100ml double-neck flask, reacting for 2 hours at 120 ℃ to obtain a prepolymer, adding hydroxyapatite accounting for 30 percent of the total weight of the prepolymer, transferring the prepolymer into a polytetrafluoroethylene surface dish, and putting the prepolymer into an oven at 130 ℃ to continue reacting for 24 hours to obtain the pasty shapeable material.
Experimental example 1:
left and right circular 6 mm-diameter craniums were removed from the craniums of SD rats randomly divided into 5 groups, and the sterilized "pudding" materials prepared in examples 8 to 9 and comparative examples 1 to 3 were implanted into the cranial defects of the rats of the corresponding groups, respectively. After 12 weeks, the rat cranium using the materials of examples 8 and 9 and comparative example, both the left and right circular defects of the cranium, were found to have significant new bone formation and to substantially fill the defect space, as determined by X-ray detection and Micro CT analysis; however, the new bone density was found to be at least 27% higher in the groups of examples 8 and 9 than in the groups of comparative examples. The material which is prepared by two or more than two carboxylic acids participating in polycondensation and loading inorganic salt has good bone repair capability, and has obvious improvement on bone repair effect compared with the polyester material which is prepared by one corresponding carboxylic acid and loaded with inorganic salt.
Experimental example 2:
left and right circular 6 mm diameter cranium pieces were removed from the cranium of SD rats randomly divided into 2 groups, and the sterile "pudding" materials prepared in example 3 and example 16 were implanted into the cranial defects of the corresponding groups of rats, respectively. After 12 weeks, X-ray detection and Micro CT analysis show that obvious new bones are formed at the left and right circular defects of the skull of the rat implanted with the material of the embodiment 16 and fill the defect space; although new bone formation also occurred in the skull defect of the rat into which the material of example 3 was implanted, the defect space was not filled. The coverage area and bone density of new bone at the bone defect of each group were measured, and it was found that the coverage area of the group of example 16 was 38% larger than that of the group of example 3; the new bone density of the example 16 group was 49% higher than that of the example 3 group. The paste material which is prepared by two or more than two carboxylic acids participating in polycondensation and loading inorganic salt has better bone repair capability, and has obvious improvement on bone repair effect compared with the polyester material without inorganic salt.
Claims (9)
1. A biodegradable composite material suitable for bone repair is a composite material prepared from 62.5-91% of biodegradable polyester material prepolymer and 9-37.5% of metal ion-containing compound in percentage by weight; the biodegradable polyester material prepolymer is polyester obtained by melt polycondensation of carboxylic acid A and polyalcohol B at 120-180 ℃ for 1-2 hours, wherein the carboxylic acid A is composite carboxylic acid and is a mixture consisting of L-malic acid, citric acid and succinic acid; the polyalcohol B is one or a composition of more than two of ethylene glycol, 1, 4-butanediol, 1, 8-octanediol, glycerol, trimethylolpropane, hexanetriol, erythritol, pentaerythritol, dipentaerythritol, xylitol, sorbitol, mannitol or branched polyethylene glycol; the metal ion-containing compound comprises calcium, magnesium and iron compounds.
2. The composite material of claim 1, wherein: the polyol B is selected from 1, 4-butanediol, glycerol or branched polyethylene glycol or a composition of any one or more than two of the polyols.
3. The composite material of claim 1, wherein: the compound containing metal ions is selected from one or a combination of more than two of calcium hydroxide, calcium oxide, ferrous hydroxide, ferric oxide, magnesium hydroxide, magnesium oxide, hydroxyapatite, calcium hydrogen phosphate, calcium dihydrogen phosphate, tetracalcium phosphate, octacalcium phosphate, calcium sulfate, calcium carbonate, calcium citrate, calcium malate, calcium polymalate, magnesium polymalate, ferric polymalate, calcium succinate, tricalcium phosphate, ferrous fumarate, ferrous succinate, magnesium malate or magnesium citrate.
4. A method of making the biodegradable composite suitable for bone repair of claim 1, comprising: firstly, carrying out melt polycondensation on a composite carboxylic acid consisting of L-malic acid, citric acid and succinic acid and polyhydric alcohol serving as raw materials at 120-180 ℃ for 1-2 hours to prepare a prepolymer, then adding a metal element and/or an inorganic salt into the prepolymer to enable the prepolymer to account for 62.5-91% of the total mass, and continuing to carry out bulk phase crosslinking reaction at 130-135 ℃ for 3-250 hours in static equipment to obtain the composite material; the polyalcohol is one or more of ethylene glycol, 1, 4-butanediol, 1, 8-octanediol, glycerol, trimethylolpropane, hexanetriol, erythritol, pentaerythritol, dipentaerythritol, xylitol, sorbitol, mannitol or branched polyethylene glycol.
5. The method of claim 4, wherein: the polyalcohol is selected from 1, 4-butanediol, glycerol or branched polyethylene glycol or any one or more than two of the compositions.
6. The method of claim 4, wherein: the preparation of the prepolymer in a melt polycondensation mode is specifically that any one of malic acid or citric acid is firstly homopolymerized, then other carboxylic acid in the composite carboxylic acid and the polyalcohol are added into the homopolymerized malic acid or citric acid, and the melt polycondensation is continued to obtain the prepolymer.
7. A method of making the biodegradable composite suitable for bone repair of claim 1, comprising: adding 0.1mol of citric acid, 0.25mol of L-malic acid and 0.1mol of 1, 4-butanediol into a double-neck flask, reacting for 2 hours at the temperature of 155 ℃ under the protection of nitrogen to obtain a prepolymer, transferring the prepolymer into a polytetrafluoroethylene surface dish, adding hydroxyapatite accounting for 10 percent of the total weight of the prepolymer, and blending to obtain the inorganic substance-containing pudding-shaped material.
8. A method of making the biodegradable composite suitable for bone repair of claim 1, comprising: adding 0.15mol of citric acid into a double-neck flask, performing self polymerization for 3 hours at 140 ℃, then adding 0.15mol of L-malic acid and 0.375mol of succinic acid respectively, performing reaction for 1 hour at 150 ℃ under the protection of nitrogen to obtain a prepolymer, then transferring the prepolymer into a polytetrafluoroethylene surface dish, adding 30 percent of hydroxyapatite of the total weight, putting the mixture into a 135 ℃ oven, and continuously reacting for 8 hours to obtain a pudding-shaped high-viscosity plastic material at normal temperature, which is suitable for repairing abnormal bone defects.
9. A method of making the biodegradable composite suitable for bone repair of claim 1, comprising: adding 0.1mol of citric acid into a double-neck flask, performing self polymerization for 4 hours at 145 ℃, then adding 0.1mol of L-malic acid and 0.25mol of succinic acid respectively, reacting for 2 hours to obtain a prepolymer, adding 3.33 percent of calcium hydroxide, magnesium oxide and ferric oxide respectively based on the total weight of the prepolymer, then transferring the prepolymer into a polytetrafluoroethylene surface dish, and putting the polytetrafluoroethylene surface dish into an oven at 135 ℃ for continuous reaction for 5 hours to obtain a brown pasty plastic material.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910268530.7A CN109970956B (en) | 2019-04-04 | 2019-04-04 | Degradable polyester composite material prepared based on carboxylic acid related to Krebs cycle and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910268530.7A CN109970956B (en) | 2019-04-04 | 2019-04-04 | Degradable polyester composite material prepared based on carboxylic acid related to Krebs cycle and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109970956A CN109970956A (en) | 2019-07-05 |
| CN109970956B true CN109970956B (en) | 2021-05-14 |
Family
ID=67082810
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910268530.7A Active CN109970956B (en) | 2019-04-04 | 2019-04-04 | Degradable polyester composite material prepared based on carboxylic acid related to Krebs cycle and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109970956B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111647146B (en) * | 2020-05-12 | 2021-09-21 | 江南大学 | Low-temperature 3D printing biodegradable material, preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005247966A (en) * | 2004-03-03 | 2005-09-15 | Mitsubishi Chemicals Corp | Aliphatic polyester and manufacturing method therefor |
| WO2010025725A1 (en) * | 2008-09-05 | 2010-03-11 | Gumlink A/S | Use of a polyester as an elastomer component for gum bases |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5187150A (en) * | 1987-10-14 | 1993-02-16 | Debiopharm S.A. | Polyester-based composition for the controlled release of polypeptide medicinal substances |
| US7005136B2 (en) * | 2002-03-29 | 2006-02-28 | Ethicon, Inc. | Bone replacement materials utilizing bioabsorbable liquid polymers |
| US20070224245A1 (en) * | 2006-02-08 | 2007-09-27 | Northwestern University | Poly (diol co-citrate) hydroxyapatite composite for tissue engineering and orthopaedic fixation devices |
| CN102127211B (en) * | 2009-03-05 | 2013-05-29 | 绍兴文理学院 | Biomass polyester |
| CN103122056B (en) * | 2013-01-21 | 2016-03-23 | 安徽雪郎生物科技股份有限公司 | A kind of biodegradable poly-succinic fumaric acid butanediol ester and preparation method thereof |
| US20170080125A1 (en) * | 2014-03-17 | 2017-03-23 | The Penn State Research Foundation | Methods of Promoting Bone Growth and Healing |
| FR3025798B1 (en) * | 2014-09-12 | 2016-09-16 | Arkema France | SPECIFIC PROCESS FOR PREPARING BIOSOURCES POLYESTERS. |
| CN104693430B (en) * | 2015-03-03 | 2016-07-06 | 清华大学 | A kind of poly-(succinic acid-butanediol ester-co-malic acid butanediol ester) and preparation method thereof |
| CN108530851B (en) * | 2017-03-02 | 2020-03-17 | 中国科学院化学研究所 | Bioactive composite material and preparation method and application thereof |
| CN109364304B (en) * | 2018-10-16 | 2021-05-14 | 南京邦鼎生物科技有限公司 | Method for preparing degradable uniform multifunctional biological bionic scaffold through 3D printing |
-
2019
- 2019-04-04 CN CN201910268530.7A patent/CN109970956B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005247966A (en) * | 2004-03-03 | 2005-09-15 | Mitsubishi Chemicals Corp | Aliphatic polyester and manufacturing method therefor |
| WO2010025725A1 (en) * | 2008-09-05 | 2010-03-11 | Gumlink A/S | Use of a polyester as an elastomer component for gum bases |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109970956A (en) | 2019-07-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0747072B1 (en) | Biodegradable moldable surgical material | |
| EP1121943B1 (en) | Biological materials | |
| Davachi et al. | Polylactic acid in medicine | |
| Vert et al. | More about the degradation of LA/GA-derived matrices in aqueous media | |
| RU2435797C2 (en) | Resorbable block copolymers of polyethers and polyesters and use thereof in producing medical implants | |
| Gunatillake et al. | Recent developments in biodegradable synthetic polymers | |
| JP5600062B2 (en) | High modulus polyurethane and polyurethane / urea compositions | |
| EP0967933B1 (en) | Polyesteramide, its preparation and surgical devices fabricated therefrom | |
| JP5496457B2 (en) | Biodegradable polyurethane and polyurethaneurea | |
| AU2002310552B2 (en) | Biodegradable polymer systems | |
| Cameron et al. | Synthetic bioresorbable polymers | |
| US8575301B2 (en) | Absorbable polymer formulations | |
| CN109970956B (en) | Degradable polyester composite material prepared based on carboxylic acid related to Krebs cycle and preparation method and application thereof | |
| JP4378442B2 (en) | Anti-adhesion material | |
| KR102249223B1 (en) | Polyglycolic acid based block copolymer with high stiffness and bioresorbability and method of producing thereof | |
| ES2329329B1 (en) | THERMOPLASTIC PASTE FOR REPAIR LIVING FABRICS. | |
| López et al. | Synthesis and characterization of injectable composites of poly [D, L‐lactide‐co‐(ε‐caprolactone)] reinforced with β‐TCP and CaCO3 for intervertebral disk augmentation | |
| KR20200008225A (en) | Biomedical implants comprising surface-modified basic ceramic particles and biodegradable polymers, and preparation method thereof | |
| JP4529005B2 (en) | Biomaterial | |
| JP4374410B2 (en) | Bone regeneration induction material | |
| Schroeter et al. | Biodegradable materials | |
| Dobrzynski et al. | Synthetic biodegradable medical polyesters: Poly (trimethylene carbonate) | |
| Rizzarelli et al. | Analytical methods in resorbable polymer development and degradation tracking | |
| JP2827055B2 (en) | Polymer | |
| Schroeter et al. | Biodegradable polymeric materials |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |