CN114773562B - Biological functional single-component medical adhesive and preparation method and application thereof - Google Patents
Biological functional single-component medical adhesive and preparation method and application thereof Download PDFInfo
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- CN114773562B CN114773562B CN202210450771.5A CN202210450771A CN114773562B CN 114773562 B CN114773562 B CN 114773562B CN 202210450771 A CN202210450771 A CN 202210450771A CN 114773562 B CN114773562 B CN 114773562B
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/4009—Two or more macromolecular compounds not provided for in one single group of groups C08G18/42 - C08G18/64
- C08G18/4018—Mixtures of compounds of group C08G18/42 with compounds of group C08G18/48
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/48—Polyethers
- C08G18/4833—Polyethers containing oxyethylene units
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/21—Acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
Abstract
The invention relates to a preparation method of a biological functional single-component medical adhesive, which comprises the following steps: weighing TCA cycle metabolic organic acid, polyhydroxy tertiary amine, polyalcohol, catalyst and polyisocyanate; mixing the TCA cycle metabolizing organic acid with the polyol to produce an alkaline polyester polyol containing TCA cycle metabolizing organic acid active groups; dehydrating the alkaline polyester polyol containing TCA cycle metabolizing organic acid active groups; mixing the dehydrated alkaline polyester polyol containing TCA (ternary ammonium chloride) circulation metabolic organic acid active groups with the polyisocyanate, and then adding the catalyst to generate the biofunctional single-component medical adhesive with terminal-NCO groups. When the biological functional single-component medical adhesive provided by the method is used, the adhesive has strong adhesiveness to the surface of biological tissues, is degradable, and can promote the healing of tissues such as bones and skin by the TCA circulatory metabolism organic acid released after degradation, has good biocompatibility, and is suitable for being used as an in-vivo implantation material.
Description
Technical Field
The invention relates to the technical field of medical materials, in particular to a biological functional single-component medical adhesive, a preparation method and application thereof.
Background
The medical adhesive for tissue adhesion is widely applied to regeneration and repair of soft/hard tissue injuries of skin, subcutaneous tissue, internal organs, bones, teeth and the like. However, the conventional medical adhesive has a certain limitation in performance and is only suitable for the specific field. For example, the non-degradable alpha-cyanoacrylate adhesive developed from industrial adhesives (502 adhesives and all-purpose adhesives) can be crosslinked under the promotion of water molecules on the surface of biological tissues, and has strong adhesiveness to the biological tissues, but the alpha-cyanoacrylate adhesive cannot be degraded, and formaldehyde generated after decomposition has high toxicity, so that the alpha-cyanoacrylate adhesive can only be applied to the adhesion of epidermis wounds and cannot be used as an in-vivo implantation material.
U.S. Medical lnc developed a polyurethane Medical adhesive TissuGlue, which was approved by the U.S. Food and Drug Administration (FDA) in 2015 and was applicable to in vivo implantation, patent No. US7264823B2, but the adhesive only had a cohesive effect, and degradation products could not exert a beneficial effect on the human body, and it was difficult to promote tissue healing.
Disclosure of Invention
Based on the above, it is necessary to provide a bio-functional single-component medical adhesive which can improve the bonding strength, can be degraded and the degradation product can promote tissue healing, and is suitable for in vivo implantation, and a preparation method and application thereof.
The invention provides a preparation method of a biological functional single-component medical adhesive, which comprises the following steps:
weighing 0.1 to 10 parts of TCA cycle metabolism organic acid, 0.05 to 8 parts of tertiary amine containing polyhydroxy, 2 to 140 parts of polyol, 0 to 0.5 part of catalyst and excessive polyisocyanate according to parts by mass; the polyalcohol comprises 0 to 60 parts of micromolecular polyalcohol and 2 to 80 parts of polymer polyalcohol;
mixing the TCA cycle metabolic organic acid with part or all of the polyhydroxyl tertiary amine-containing and part or all of the polyalcohol, and reacting under heating to generate alkaline polyester polyol containing TCA cycle metabolic organic acid active groups;
dehydrating the alkaline polyester polyol containing the TCA cycle metabolic organic acid active group under heating and negative pressure;
mixing the dehydrated alkaline polyester polyol containing TCA (ternary ammonium chloride) circulation metabolism organic acid active groups with the polyisocyanate, reacting under the conditions of protective gas atmosphere and heating to generate polyurethane prepolymer, removing free polyisocyanate, and adding the catalyst to prepare the biofunctional type single-component medical adhesive with terminal-NCO groups.
In one embodiment, the method comprises the following steps:
1 to 5 parts of TCA cycle metabolism organic acid, 0.1 to 4 parts of tertiary amine containing polyhydroxy, 1 to 15 parts of micromolecular polyol, 10 to 65 parts of polymer polyol, 20 to 160 parts of polyisocyanate and 0.01 to 0.1 part of catalyst are weighed according to mass parts.
In one embodiment, in the step of forming the alkaline polyester polyol containing TCA cycle metabolizing organic acid active groups, the heating is at a temperature of from 100℃to 280 ℃; and/or
In the step of dehydrating the polyester polyol containing TCA cycle metabolic organic acid active groups, the heating temperature is 80-150 ℃; and/or
In the step of forming the polyurethane prepolymer, the heating temperature is 40-90 ℃.
In one embodiment, the small molecule polyol has a molecular weight of 60Da to 300Da; and/or
The molecular weight of the polymer polyol is 100 Da-10000 Da.
In one embodiment, the TCA cycle metabolizing organic acid is a mixture of one or more of citric acid, malic acid, succinic acid, alpha-ketoglutaric acid, fumaric acid, and oxaloacetic acid; and/or
The polyhydroxyl tertiary amine is one or more of triethanolamine, triisopropanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N-N-propyldiethanolamine, tert-butyldiethanolamine, N-ethyldiethanolamine, 3-dimethylamino-1-propanol, N-dimethylisopropanolamine and 4-hydroxy-1-methylhexahydroazepine; and/or
The small molecular polyalcohol is one or more of glycerol, ethylene glycol, 1, 4-butanediol, 1, 6-hexanediol and 1, 8-octanediol; and/or
The polymer polyol is a mixture of one or more of polyether polyol, polyester polyol and polyglycerol; and/or
The polyisocyanate is one or more of hexamethylene diisocyanate, 4-bis (isocyanate cyclohexyl) methane, toluene cyclohexylene diisocyanate, 2, 4-trimethylhexamethylene diisocyanate, 2, 6-diisocyanate methyl caproate and isophorone diisocyanate.
In one embodiment, the polyether polyol is a blend of one or more of polytetrahydrofuran polyol, polypropylene glycol polyol, polyethylene glycol polyol, polypropylene glycol-ethylene glycol polyol, and polytetrahydrofuran-butylene glycol polyol.
In one embodiment, the polyester polyol is a blend of one or more of a poly (epsilon-caprolactone) polyol, a polycarbonate polyol, a polyglycolic acid, a polylactic acid, and a polyglycolide polyol.
In one embodiment, the catalyst is a mixture of one or more of an organotin-based catalyst, an organobismuth-based catalyst, and an amine-based catalyst.
In one embodiment, in the step of forming a polyester polyol containing TCA cycle metabolizing organic acid active groups, the polyol that is mixed comprises the polymer polyol, the polymer polyol having a molecular weight of 100Da or less than 2000Da.
The invention provides a biological functional single-component medical adhesive which comprises TCA (ternary ammonium chloride) circulation metabolism organic acid active groups and terminal-NCO groups, wherein the mass fraction of the TCA circulation metabolism organic acid active groups is 0.1% -30%.
In one embodiment, the mass fraction of the TCA cycle metabolizing organic acid active group is 1% -20%.
In one embodiment, the preparation method of the biological functional single-component medical adhesive is as described in any embodiment.
The invention also provides a biological functional medical adhesive film which is characterized by being obtained by curing the biological functional single-component medical adhesive in any embodiment.
According to the preparation method of the biological functional type single-component medical adhesive, TCA (ternary ammonium chloride) circulating metabolism organic acid active groups are introduced, the biological functional type single-component medical adhesive is provided with terminal-NCO groups and a large number of active groups capable of performing cross-linking reaction, when the biological functional type single-component medical adhesive is used, the biological functional type single-component medical adhesive can be solidified into the surface of biological tissues through the cross-linking reaction with water and/or amine on the surface of the biological tissues to provide strong adhesion, the biological functional type single-component medical adhesive is strong in adhesion to the surface of the biological tissues, is nontoxic and degradable, and the TCA circulating metabolism organic acid released after degradation can promote the healing of tissues such as bones, skin, tendons and the like, so that the biological functional type single-component medical adhesive is good in biocompatibility and suitable for being used as an in-vivo implantation material. Furthermore, the method introduces the polyhydroxy tertiary amine to be beneficial to accelerating the curing rate of the medical adhesive and shortening the curing time when preparing the alkaline polyester polyol containing the TCA (ternary ammonium chloride) circulatory metabolism organic acid active group, and simultaneously, the polyhydroxy tertiary amine can improve the degradation rate of the medical adhesive in the degradation process of the medical adhesive, prevent the medical adhesive from influencing the health of a human body due to overlong degradation time in vivo, and the polyhydroxy tertiary amine can play a certain role in neutralizing the TCA circulatory metabolism organic acid released in the degradation process, prevent obvious inflammatory reaction caused by the degradation and release of the TCA circulatory metabolism organic acid, and weaken the uncomfortable feeling of the medical adhesive to the human body in the use process.
Detailed Description
In order to facilitate understanding of the present invention, the biofunctional one-component medical adhesive of the present invention, and the preparation method and application thereof, are more fully described below with reference to examples. This invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
In the description of the present invention, "plural" means at least two-membered, such as two-membered, three-membered, etc., and "plural" means at least two, such as two, three, etc., unless specifically defined otherwise.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
In the invention, the technical characteristics described in an open mode comprise a closed technical scheme composed of the listed characteristics and also comprise an open technical scheme comprising the listed characteristics.
The invention provides a preparation method of a biological functional type single-component medical adhesive, which comprises the following steps of S110 to S140.
Step S110: according to the mass parts, 0.1 to 10 parts of TCA cycle metabolism organic acid, 0.05 to 8 parts of tertiary amine containing polyhydroxy, 2 to 140 parts of polyol, 0 to 0.5 part of catalyst and excessive polyisocyanate are weighed.
The tricarboxylic acid cycle (tricarboxylic acid cycle, TCA cycle) is a metabolic pathway in organisms, and TCA cycle metabolizes organic acids as the main intermediate metabolites in the tricarboxylic acid cycle.
In a specific example, the TCA cycle metabolizing organic acid may be, but is not limited to, a mixture of one or more of citric acid, malic acid, succinic acid, alpha-ketoglutaric acid, fumaric acid, and oxaloacetic acid.
In a specific example, the polyhydroxyl-containing tertiary amine has at least one hydroxyl group, preferably 2 to 3 hydroxyl groups, in the molecule. The polyhydroxyl tertiary amine has at least one tertiary amine group, preferably 1 to 2 tertiary amine groups in the molecule. Specifically, the polyhydroxy-containing tertiary amine may be, but is not limited to, one or more of triethanolamine, triisopropanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N-N-propyldiethanolamine, t-butyldiethanolamine, N-ethyldiethanolamine, 3-dimethylamino-1-propanol, N-dimethylisopropanolamine, and 4-hydroxy-1-methylhexahydroazepine.
The polyol comprises 0 to 60 parts by mass of small-molecule polyol and 2 to 80 parts by mass of polymer polyol.
It will be appreciated that in this embodiment, the polyol must include a polymer polyol, but may not include a small molecule polyol.
A small molecule polyol refers to a lower molecular weight polyol having multiple hydroxyl groups that does not have repeating units. Specifically, the molecular weight of the small molecule polyol is 60Da to 300Da. More specifically, the molecular weight of the small molecule polyol is 60Da to 150Da.
In a specific example, the small molecule polyol may be, but is not limited to, a mixture of one or more of glycerol, ethylene glycol, 1, 4-butanediol, 1, 6-hexanediol, and 1, 8-octanediol.
Polymer polyols refer to polyols having repeating units with a plurality of hydroxyl groups, and are typically prepared by polymerization. Specifically, the molecular weight of the polymer polyol is 100Da to 10000Da. More specifically, the molecular weight of the polymer polyol is 100Da to 2000Da.
In a specific example, the polymer polyol may be, but is not limited to, a blend of one or more of polyether polyols, polyester polyols, and polyglycerols.
Further, the polyether polyol may be, but is not limited to, a blend of one or more of polytetrahydrofuran polyol, polypropylene glycol polyol, polyethylene glycol polyol, polypropylene glycol-ethylene glycol polyol, and polytetrahydrofuran-butylene glycol polyol.
Further, the polyester polyol may be, but is not limited to, a blend of one or more of poly (epsilon-caprolactone) polyol, polycarbonate polyol, polyglycolic acid, polylactic acid, and polyglycolide-lactide polyol.
In this embodiment, the polyisocyanate is benzene ring-free isocyanate, so that the harm to human body, such as cancer, caused by the residue of benzene ring isocyanate in vivo is avoided. In a specific example, the polyisocyanate may be, but is not limited to, a mixture of one or more of hexamethylene diisocyanate, 4-bis (isocyanate cyclohexyl) methane, toluene cyclohexylene diisocyanate, 2, 4-trimethylhexamethylene diisocyanate, 2, 6-diisocyanate methylhexanoate, and isophorone diisocyanate.
In a specific example, the method comprises the following steps:
1 to 5 parts of TCA cycle metabolism organic acid, 0.1 to 4 parts of tertiary amine containing polyhydroxy, 1 to 15 parts of micromolecular polyol, 10 to 65 parts of polymer polyol, 20 to 160 parts of polyisocyanate and 0.01 to 0.1 part of catalyst are weighed according to the mass parts.
Step S120: mixing TCA circulation metabolism organic acid with part or all of tertiary amine containing polyhydroxy and part or all of polyalcohol, and reacting under heating condition to obtain alkaline polyester polyalcohol containing TCA circulation metabolism organic acid active group.
The alkaline polyester polyol generated by the reaction of TCA circulation metabolism organic acid, polyhydroxy tertiary amine and polyol has multi-functionality, can improve the crosslinking density of the biological functional type single-component medical adhesive which is coated on the surface of biological tissues and then is crosslinked with water and/or amine, and can improve the viscosity and the adhesive strength of the biological functional type single-component medical adhesive.
The tertiary amine containing polyhydroxy is alkaline, has catalytic activity, can accelerate the curing rate of medical adhesive and shortens the curing time. Further, the medical adhesive can be accelerated to degrade by the tertiary amine containing the polyhydroxy, and the release of the active groups of the organic acid of TCA circulation metabolism is accelerated, so that the tissue regeneration is accelerated, the recovery time is shortened, and the medical adhesive is prevented from influencing the human health due to overlong degradation time in vivo. Meanwhile, the degradation speed of the polymer in the later period can be faster, and the complete degradation time is greatly shortened. The tertiary amine containing polyhydroxy can play a certain role in neutralizing TCA (ternary ammonium chloride) circulatory metabolism organic acid released in the degradation process, prevent obvious inflammatory reaction caused by degradation and release of the TCA circulatory metabolism organic acid, and weaken uncomfortable feeling of the medical adhesive to a human body in the use process.
It will be appreciated that some or all of the polyols may include only small molecule polyols, only polymer polyols, and both small molecule and polymer polyols.
The TCA cycle metabolizing organic acid active group is understood to mean the TCA cycle metabolizing organic acid residue which is attached to the molecular chain of the basic polyester polyol after the reaction of the TCA cycle metabolizing organic acid with the polyol.
In a specific example, the polyol mixed in step S120 includes a polymer polyol having a molecular weight of 100Da or less and 2000Da or less. Further, the polyol to be mixed in step S120 includes a polymer polyol having a molecular weight of 100Da or less and 1000Da or less. It is understood that the polyol mixed in step S120 includes a polymer polyol, that is, the polyol mixed in step S120 is a polymer polyol, or the polyol mixed in step S120 is a mixture of a small molecule polyol and a polymer polyol.
In a specific example, the temperature of the heating in step S120 is 100 ℃ to 280 ℃. Further, the heating temperature is 100-230 ℃. Further, the heating temperature is 120-170 ℃. It is understood that the heating temperature may be 120 ℃, 130 ℃, 140 ℃, 150 ℃, 160 ℃, 170 ℃ or the like, for example.
In a specific example, the reaction time of step S120 is 1h to 72h. Further, the reaction time is 1 to 24 hours. It is understood that the reaction time may be, for example, 1h, 5h, 10h, 15h, 20h, 24h, etc.
Step S130: and dehydrating the alkaline polyester polyol containing the TCA cycle metabolic organic acid active group under heating and negative pressure.
In a specific example, in the step of dehydrating the polyester polyol containing TCA cycle metabolizing organic acid active groups, the heating temperature is 80℃to 150 ℃. Further, the heating temperature during dehydration is 90-120 ℃. It is understood that the temperature to be heated at the time of dehydration may be, for example, 90 ℃, 100 ℃, 110 ℃, 120 ℃ or the like.
In a specific example, in the step of dehydrating the basic polyester polyol containing the TCA cycle metabolizing organic acid active group, the dehydration time is 1 to 6 hours. Further, the dehydration time is 2 to 4 hours.
It is understood that the polyhydric hydroxyl-containing tertiary amine mixed in step S120 is a part or all of the polyhydric hydroxyl-containing tertiary amine. That is, the mass part of the polyvalent hydroxyl group-containing tertiary amine to be mixed in step S120 may be equal to the mass part of the polyvalent hydroxyl group-containing tertiary amine weighed in step S110, and at this time, the polyvalent hydroxyl group-containing tertiary amine weighed in step S110 is entirely charged into the reaction system of step S120; the mass parts of the polyvalent hydroxyl group-containing tertiary amine to be mixed in step S120 may be smaller than the mass parts of the polyvalent hydroxyl group-containing tertiary amine weighed in step S110, and only a part of the polyvalent hydroxyl group-containing tertiary amine weighed in step S110 is fed into the reaction system of step S120, and the polyvalent hydroxyl group-containing tertiary amine remains after step S120.
It is understood that the polyol to be mixed in step S120 is a part or all of the polyol. That is, the mass part of the polyol mixed in step S120 may be equal to the mass part of the polyol weighed in step S110, and at this time, the polyol weighed in step S110 is entirely charged into the reaction system of step S120; the mass parts of the polyol to be mixed in step S120 may be smaller than the mass parts of the polyol weighed in step S110, and only a part of the polyol weighed in step S110 is fed into the reaction system of step S120, and the remaining polyol remains after step S120.
It will be understood that when only a portion of the tertiary amine and/or polyol containing a polyhydric alcohol weighed in step S110 is fed into the reaction system of step S120, and the tertiary amine and/or remaining polyol containing a polyhydric alcohol remain after step S120, the tertiary amine and/or remaining polyol containing a polyhydric alcohol also need to be dehydrated before being fed into the subsequent reaction system. It will be appreciated that when step S120 is followed by the remaining polyhydroxyl-containing tertiary amine and/or the remaining polyol, step S130 is correspondingly adapted to step S130'.
Step S130': and dehydrating the alkaline polyester polyol containing TCA (ternary ammonium chloride) circulation metabolic organic acid active groups and the rest of the tertiary amine containing polyhydroxy and/or the rest of the polyol under heating and negative pressure.
It will be appreciated that in the step of dehydrating the remaining tertiary amine containing polyhydric hydroxyl groups and/or the remaining polyol, the heating temperature is from 80℃to 150 ℃. Further, the heating temperature during dehydration is 90-120 ℃. It is understood that the temperature to be heated at the time of dehydration may be, for example, 90 ℃, 100 ℃, 110 ℃, 120 ℃ or the like.
Further, in the step of dehydrating the remaining polyhydroxyl-containing tertiary amine and/or the remaining polyol, the dehydration time is 1 to 6 hours. Further, the dehydration time is 2 to 4 hours.
It is understood that in the present embodiment, the negative pressure condition means that the reaction system is evacuated to a vacuum degree of less than-0.09 MPa.
Step S140: mixing the dehydrated alkaline polyester polyol containing TCA circulation metabolism organic acid active groups with polyisocyanate, reacting under the conditions of protective gas atmosphere and heating to generate polyurethane prepolymer, removing free isocyanate, and then adding a catalyst to prepare the biological functional single-component medical adhesive with terminal-NCO groups.
The dehydrated polyester polyol containing TCA circulation metabolism organic acid active group is a hydroxyl-containing compound with multiple functionalities, the hydroxyl-containing compound with multiple functionalities reacts with isocyanate groups in excessive polyisocyanate to generate the biological functional single-component medical adhesive with terminal-NCO groups, and the biological functional single-component medical adhesive has a plurality of active groups which can be used for further crosslinking, and can form the adhesive suitable for bonding different materials after further crosslinking. Further, after the biological functional type single-component medical adhesive in the embodiment is coated on the surface of biological tissues, the adhesive can react and crosslink with water and/or amine on the surface of the biological tissues, the cured adhesive has high crosslinking degree and good bonding performance, is nontoxic and degradable, is suitable for in vivo implantation, and the TCA (ternary polymerization) circulatory metabolic organic acid released after degradation can promote tissue healing.
In a specific example, the heating temperature of step S140 is 40 ℃ to 90 ℃. Further, the heating temperature is 50-80 ℃. It is understood that the temperature of heating may be, for example, 50 ℃, 55 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃ and the like.
In a specific example, the reaction time of step S140 is 1h to 72h. Further, the reaction time is 2-48 h. It is understood that the reaction time may be, for example, 2h, 6h, 8h, 12h, 20h, 24h, 28h, 30h, 40h, 48h, etc.
In one specific example, a thin film evaporator is used to remove the free polyisocyanate.
The catalyst can catalyze the crosslinking reaction rate of the biological functional single-component medical adhesive on the surface of biological tissues and water and/or amine, and the curing rate of the adhesive on the surface of the biological tissues is improved. Further, the catalyst may be, but is not limited to, a mixture of one or more of an organotin-based catalyst, an organobismuth-based catalyst, and an amine-based catalyst. Further, the organotin-based catalyst may be, for example, but not limited to, stannous octoate, stannous chloride, etc., the organobismuth-based catalyst may be, for example, but not limited to, bismuth isooctanoate, bismuth laurate, bismuth neodecanoate, bismuth naphthenate, bismuth oxide, bismuth nitrate, etc., and the amine-based catalyst may be, for example, but not limited to, triethanolamine, etc.
In the embodiment, the catalyst is added after the polyurethane prepolymer is generated, so that the prepared biological functional type single-component medical adhesive has proper viscosity and bonding strength.
In the embodiment, after the step S120 is performed to mix and react the TCA cycle metabolism organic acid with part or all of the polyhydric tertiary amine and part or all of the polyhydric alcohol to generate the alkaline polyester polyol containing the TCA cycle metabolism organic acid active group, the subsequent reaction step S130 and the step S140 are performed to prepare the biological functional single-component medical adhesive, so that the degradation rate of the TCA cycle metabolism organic acid active group in the biological functional single-component medical adhesive can be improved, and the degradation release of the TCA cycle metabolism organic acid through degradation is facilitated, thereby promoting tissue repair. Meanwhile, the TCA cycle metabolism organic acid has multiple functionalities, carboxyl in the TCA cycle metabolism organic acid reacts with alcohol hydroxyl to generate polyester polyol with a certain crosslinking degree, so that the crosslinking degree of the biological functional single-component medical adhesive in the subsequent crosslinking reaction with water and/or amine on the surface of biological tissues can be improved, and the adhesive strength of the biological functional single-component medical adhesive is improved.
It will be appreciated that when there is still remaining polyhydroxyl-containing tertiary amine and/or remaining polyol after step S120, the remaining polyhydroxyl-containing tertiary amine and/or remaining polyol is dehydrated through step S130 'and then put into the subsequent reaction system, and accordingly, step S140 is adjusted to step S140'.
Step S140': mixing the dehydrated alkaline polyester polyol containing TCA (ternary ammonium chloride) circulation metabolism organic acid active groups, the dehydrated residual polyol containing polyhydroxy tertiary amine and/or the dehydrated residual polyol with polyisocyanate, reacting under the conditions of protective gas atmosphere and heating to generate polyurethane prepolymer, removing free isocyanate, and then adding a catalyst to generate the biological functional single-component medical adhesive with terminal-NCO groups.
It will be appreciated that step S140' simultaneously comprises the dehydrated alkaline polyester polyol containing TCA cycle metabolizing organic acid active groups, and the dehydrated residual polyhydroxyl tertiary amine and/or dehydrated residual polyol to form a hydroxyl-containing mixture, further increasing the polyfunctional degree in the reaction system.
The embodiment of the invention also provides a biological functional single-component medical adhesive which comprises TCA (ternary ammonium chloride) circulatory metabolism organic acid active groups and terminal-NCO groups, wherein the mass fraction of the TCA circulatory metabolism organic acid active groups is 0.1-30%. The content of the TCA circulation metabolism organic acid active group can ensure that the medical adhesive has good tissue regeneration promoting effect in the range, if the content is too low, the effect cannot be achieved, and if the content is too high, the performance of the medical adhesive can be adversely affected. Further, the mass fraction of the TCA cycle metabolism organic acid active group is 1% -20%. Further, the mass fraction of the TCA cycle metabolizing organic acid active group is 2% -12%.
In a specific example, the biofunctional single-component medical adhesive may be prepared by the preparation method of the biofunctional single-component medical adhesive in any of the above examples.
After the biological functional type single-component medical adhesive is coated on the surface of biological tissues, active groups in the biological functional type single-component medical adhesive can be subjected to crosslinking reaction with water and/or amine on the surface of the biological tissues and solidified to bond the surface of the biological tissues, the solidified biological functional type single-component medical adhesive has high crosslinking degree and good cohesiveness, and the solidifying speed of the adhesive is moderate, so that the adhesive can be suitable for various different medical scenes. The biological functional single-component medical adhesive has biodegradability, and can release TCA (ternary content addressable memory) circulatory metabolism organic acid after degradation, so that the TCA circulatory metabolism organic acid is beneficial to promoting healing of tissues such as bones and skin, and recovery time is shortened. Furthermore, the raw materials of the biological functional single-component medical adhesive have good biocompatibility, do not contain organic solvents, are nontoxic and harmless in the using process, can effectively reduce inflammatory reaction, and are suitable for being used as in-vivo implantation materials. Furthermore, the medical adhesive is a single-component adhesive, and when in use, the medical adhesive is directly coated on the surface of biological tissues, so that the operation is simple and the use is convenient.
The embodiment of the invention also provides a biological functional medical adhesive film which is obtained by curing the biological functional single-component medical adhesive in any one example.
The following are specific examples. In the following examples, all materials are commercially available unless otherwise specified.
Example 1:
step 1: preparing materials:
according to the mass parts, 5 parts of citric acid, 2 parts of N-methyldiethanolamine, 8.9 parts of 1, 8-octanediol, 50 parts of polyethylene glycol (PEG, 400 Da), 100 parts of Hexamethylene Diisocyanate (HDI) and 0.05 part of stannous octoate are respectively weighed.
Step 2: preparing a biological functional single-component medical adhesive:
5 parts of citric acid and 2 parts of N-methyldiethanolamine, and 8.9 parts of 1, 8-octanediol are added into a first reactor, and after stirring and reacting for 10 hours at 140 ℃, alkaline polyester polyol containing TCA cycle metabolizing organic acid active groups is generated.
And (3) reducing the temperature of a reaction system of the alkaline polyester polyol containing the TCA circulation metabolism organic acid active group to 100 ℃, vacuumizing to a vacuum degree of less than-0.09 MPa, and dehydrating for 3 hours to obtain the dehydrated alkaline polyester polyol containing the TCA circulation metabolism organic acid active group.
50 parts of PEG (400 Da) is added into a second reactor, the temperature is kept at 100 ℃, and the vacuum is pumped until the vacuum degree is less than-0.09 MPa for dehydration for 3 hours, so as to obtain dehydrated PEG (400 Da).
Adding 100 parts of HDI into a third reactor, heating to 50 ℃, introducing nitrogen for protection, adding dehydrated alkaline polyester polyol containing TCA (ternary ammonium carbonate) circulation metabolic organic acid active groups and dehydrated PEG (400 Da) under stirring, keeping the temperature at 50 ℃, stirring for 24 hours, removing free HDI by using a thin film evaporator, adding 0.05 part of stannous octoate, and stirring uniformly to obtain the biological functional single-component medical adhesive with terminal-NCO groups.
Example 2:
step 1: preparing materials:
1 part of citric acid, 0.5 part of N-methyldiethanolamine, 1 part of 1, 8-octanediol, 13 parts of polyethylene glycol (PEG, 400 Da), 20 parts of Hexamethylene Diisocyanate (HDI) and 0.05 part of stannous octoate are respectively weighed according to parts by mass.
Step 2: preparing a biological functional single-component medical adhesive:
1 part of citric acid and 0.5 part of N-methyldiethanolamine and 1 part of 1, 8-octanediol are added into a first reactor, and after stirring and reacting for 1 hour at 130 ℃, alkaline polyester polyol containing TCA (ternary ammonium chloride) circulation metabolic organic acid active groups is generated.
And (3) reducing the temperature of a reaction system of the alkaline polyester polyol containing the TCA circulation metabolism organic acid active group to 90 ℃, vacuumizing to a vacuum degree of less than-0.09 MPa, and dehydrating for 3 hours to obtain the dehydrated alkaline polyester polyol containing the TCA circulation metabolism organic acid active group.
13 parts of PEG (400 Da) are added into a second reactor, the temperature is kept at 100 ℃, and the vacuum is pumped until the vacuum degree is less than-0.09 MPa for dehydration for 3 hours, so as to obtain dehydrated PEG (400 Da).
Adding 20 parts of HDI into a third reactor, heating to 50 ℃, introducing nitrogen for protection, adding dehydrated alkaline polyester polyol containing TCA (ternary ammonium carbonate) circulation metabolic organic acid active groups and dehydrated PEG (400 Da) under stirring, keeping the temperature at 60 ℃, stirring and reacting for 12 hours, removing free HDI by using a thin film evaporator, adding 0.05 part of stannous octoate, and uniformly stirring to obtain the biological functional single-component medical adhesive with terminal-NCO groups.
Example 3:
step 1: preparing materials:
2.5 parts of citric acid, 0.5 part of triethanolamine, 3.8 parts of 1, 8-octanediol, 30 parts of polyethylene glycol (PEG, 400 Da), 80 parts of Hexamethylene Diisocyanate (HDI) and 0.05 part of stannous octoate are respectively weighed according to parts by mass.
Step 2: preparing a biological functional single-component medical adhesive:
2.5 parts of citric acid and 0.5 part of triethanolamine and 3.8 parts of 1, 8-octanediol are added into a first reactor, and after stirring and reacting for 5 hours at 130 ℃, alkaline polyester polyol containing TCA (ternary ammonium chloride) circulation metabolic organic acid active groups is generated.
And (3) reducing the temperature of a reaction system of the alkaline polyester polyol containing the TCA circulation metabolism organic acid active group to 90 ℃, vacuumizing to a vacuum degree of less than-0.09 MPa, and dehydrating for 3 hours to obtain the dehydrated alkaline polyester polyol containing the TCA circulation metabolism organic acid active group.
30 parts of PEG (400 Da) is added into a second reactor, the temperature is kept at 100 ℃, and the vacuum is pumped until the vacuum degree is less than-0.09 MPa for dehydration for 3 hours, so as to obtain dehydrated PEG (400 Da).
Adding 80 parts of HDI into a third reactor, heating to 50 ℃, introducing nitrogen for protection, adding dehydrated alkaline polyester polyol containing TCA (ternary ammonium carbonate) circulation metabolic organic acid active groups and dehydrated PEG (400 Da) under stirring, keeping the temperature at 70 ℃, stirring for reaction for 6 hours, removing free HDI by using a thin film evaporator, adding 0.05 part of stannous octoate, and uniformly stirring to obtain the biological functional single-component medical adhesive with terminal-NCO groups.
Example 4:
step 1: preparing materials:
according to the mass parts, 5 parts of citric acid, 1 part of N-methyldiethanolamine, 11 parts of polyethylene glycol (PEG, 200 Da), 50 parts of polyethylene glycol (PEG, 400 Da), 100 parts of Hexamethylene Diisocyanate (HDI) and 0.05 part of stannous octoate are respectively weighed.
Step 2: preparing a biological functional single-component medical adhesive:
5 parts of citric acid, 1 part of N-methyldiethanolamine and 11 parts of polyethylene glycol (PEG, 400 Da) are added into a first reactor, and after stirring and reacting for 24 hours at 130 ℃, alkaline polyester polyol containing TCA (ternary ammonium chloride) circulation metabolic organic acid active groups is generated.
And (3) reducing the temperature of a reaction system of the alkaline polyester polyol containing the TCA circulation metabolism organic acid active group to 100 ℃, vacuumizing to a vacuum degree of less than-0.09 MPa, and dehydrating for 3 hours to obtain the dehydrated alkaline polyester polyol containing the TCA circulation metabolism organic acid active group.
50 parts of PEG (400 Da) is added into a second reactor, the temperature is kept at 100 ℃, and the vacuum is pumped until the vacuum degree is less than-0.09 MPa for dehydration for 3 hours, so as to obtain dehydrated PEG (400 Da).
Adding 100 parts of HDI into a third reactor, heating to 50 ℃, introducing nitrogen for protection, adding dehydrated alkaline polyester polyol containing TCA (ternary ammonium carbonate) circulation metabolic organic acid active groups and dehydrated PEG (400 Da) under stirring, keeping the temperature at 70 ℃, stirring for reaction for 6 hours, removing free HDI by using a thin film evaporator, adding 0.05 part of stannous octoate, and stirring uniformly to obtain the biological functional single-component medical adhesive with terminal-NCO groups.
Example 5:
step 1: preparing materials:
according to the mass parts, 5 parts of citric acid, 1 part of N-methyldiethanolamine, 30 parts of polyethylene glycol (PEG, 400 Da), 160 parts of Hexamethylene Diisocyanate (HDI) and 0.01 part of stannous octoate are respectively weighed.
Step 2: preparing a biological functional single-component medical adhesive:
5 parts of citric acid and 1 part of N-methyldiethanolamine, and 30 parts of polyethylene glycol (PEG, 400 Da) are added into a first reactor, and after stirring and reacting for 12 hours at 140 ℃, alkaline polyester polyol containing TCA cycle metabolizing organic acid active groups is generated.
And (3) reducing the temperature of a reaction system of the alkaline polyester polyol containing the TCA circulation metabolism organic acid active group to 110 ℃, vacuumizing to a vacuum degree of less than-0.09 MPa, and dehydrating for 2 hours to obtain the dehydrated alkaline polyester polyol containing the TCA circulation metabolism organic acid active group.
160 parts of HDI is added into a second reactor, heated to 60 ℃, nitrogen is introduced for protection, dehydrated alkaline polyester polyol containing TCA circulation metabolism organic acid active groups is added under stirring, the temperature is kept at 60 ℃ for stirring reaction for 12 hours, free HDI is removed by using a thin film evaporator, 0.01 part of stannous octoate is added, and the mixture is stirred uniformly to obtain the biological functional single-component medical adhesive with terminal-NCO groups.
Comparative example 1:
step 1: preparing materials:
according to the mass parts, 5 parts of adipic acid, 2 parts of N-methyldiethanolamine, 8.9 parts of 1, 8-octanediol, 50 parts of polyethylene glycol (PEG, 400 Da), 100 parts of Hexamethylene Diisocyanate (HDI) and 0.05 part of stannous octoate are respectively weighed.
Step 2: preparing a biological functional single-component medical adhesive:
5 parts of adipic acid and 2 parts of N-methyldiethanolamine, 8.9 parts of 1, 8-octanediol were added to the first reactor and reacted with stirring at 140℃for 10 hours to give an alkaline polyester polyol.
And (3) reducing the temperature of a reaction system of the alkaline polyester polyol to 100 ℃, vacuumizing to a vacuum degree of less than-0.09 MPa, and dehydrating for 3 hours to obtain the dehydrated alkaline polyester polyol.
50 parts of PEG (400 Da) is added into a second reactor, the temperature is kept at 100 ℃, and the vacuum is pumped until the vacuum degree is less than-0.09 MPa for dehydration for 3 hours, so as to obtain dehydrated PEG (400 Da).
Adding 100 parts of HDI into a third reactor, heating to 50 ℃, introducing nitrogen for protection, adding dehydrated alkaline polyester polyol and dehydrated PEG (500 Da) under stirring, keeping the temperature at 50 ℃, stirring for reaction for 24 hours, removing free HDI by using a thin film evaporator, adding 0.05 part of stannous octoate, and uniformly stirring to obtain the biological functional type single-component medical adhesive with terminal-NCO groups.
Comparative example 2:
step 1: preparing materials:
2 parts of N-methyldiethanolamine, 8.9 parts of 1, 8-octanediol, 50 parts of polyethylene glycol (PEG, 400 Da), 100 parts of Hexamethylene Diisocyanate (HDI) and 0.05 part of stannous octoate are respectively weighed according to the parts by mass.
Step 2: preparing a single-component medical adhesive:
2 parts of N-methyldiethanolamine, 11 parts of 1, 8-octanediol and 50 parts of PEG (400 Da) are added into a first reactor, the temperature is kept at 100 ℃, and the mixture is vacuumized until the vacuum degree is less than-0.09 MPa and dehydrated for 3 hours, so that dehydrated mixture of the N-methyldiethanolamine, the 1, 8-octanediol and the PEG (400 Da) is obtained.
100 parts of HDI is added into a second reactor, heated to 50 ℃, nitrogen is introduced for protection, a dehydrated mixture of 1, 8-octanediol and PEG (400 Da) is added under stirring, the temperature is kept at 50 ℃ for stirring reaction for 24 hours, a thin film evaporator is used for removing free HDI, 0.05 part of stannous octoate is added, and the single-component medical adhesive with terminal-NCO groups is obtained after stirring uniformly.
Comparative example 3:
step 1: preparing materials:
according to the mass parts, 5 parts of citric acid, 2 parts of N-methyldiethanolamine, 11 parts of 1, 8-octanediol, 50 parts of polyethylene glycol (PEG, 400 Da), 100 parts of Hexamethylene Diisocyanate (HDI) and 0.05 part of stannous octoate are respectively weighed.
Step 2: preparing a biological functional single-component medical adhesive:
5 parts of citric acid, 2 parts of N-methyldiethanolamine, 11 parts of 1, 8-octanediol and 50 parts of polyethylene glycol (PEG, 400 Da) are added into a first reactor, the temperature is kept at 90 ℃, and vacuum pumping is carried out until the vacuum degree is less than-0.09 MPa for dehydration for 3 hours, so that a dehydrated mixture of the N-methyldiethanolamine, the citric acid, the 1, 8-octanediol and the PEG (400 Da) is obtained.
Adding 100 parts of HDI into a second reactor, heating to 50 ℃, introducing nitrogen for protection, adding a dehydrated mixture of N-methyldiethanolamine, citric acid, 1, 8-octanediol and PEG (400 Da) under stirring, keeping the temperature at 50 ℃, stirring for 24 hours, removing free HDI by using a thin film evaporator, adding 0.05 part of stannous octoate, and stirring uniformly to obtain the biofunctional type single-component medical adhesive with terminal-NCO groups.
Comparative example 4:
step 1: preparing materials:
according to the mass parts, 5 parts of citric acid, 2 parts of N-methyldiethanolamine, 29.3 parts of 1, 8-octanediol, 100 parts of Hexamethylene Diisocyanate (HDI) and 0.05 part of stannous octoate are respectively weighed.
Step 2: preparing a biological functional single-component medical adhesive:
5 parts of citric acid and 2 parts of N-methyldiethanolamine, 29.3 parts of 1, 8-octanediol are added into a first reactor, and after stirring and reacting for 10 hours at 140 ℃, alkaline polyester polyol containing TCA cycle metabolizing organic acid active groups is generated.
And (3) reducing the temperature of a reaction system of the alkaline polyester polyol containing the TCA circulation metabolism organic acid active group to 100 ℃, vacuumizing to a vacuum degree of less than-0.09 MPa, and dehydrating for 3 hours to obtain the dehydrated alkaline polyester polyol containing the TCA circulation metabolism organic acid active group.
Adding 100 parts of HDI into a second reactor, heating to 50 ℃, introducing nitrogen for protection, adding dehydrated alkaline polyester polyol containing TCA (ternary ammonium carbonate) circulation metabolic organic acid active groups under stirring, keeping the temperature at 50 ℃, stirring for reaction for 24 hours, removing free HDI by using a thin film evaporator, adding 0.05 part of stannous octoate, and uniformly stirring to obtain the biological functional single-component medical adhesive with terminal-NCO groups.
Comparative example 5:
according to the mass parts, 5 parts of citric acid, 2 parts of N-methyldiethanolamine, 11 parts of 1, 8-octanediol, 50 parts of polyethylene glycol (PEG, 400 Da), 100 parts of Hexamethylene Diisocyanate (HDI) and 0.05 part of stannous octoate are respectively weighed.
Step 2: preparing a biological functional single-component medical adhesive:
5 parts of citric acid and 2 parts of N-methyldiethanolamine, and 11 parts of 1, 8-octanediol are added into a first reactor, and after stirring and reacting for 10 hours at 300 ℃, alkaline polyester polyol containing TCA cycle metabolizing organic acid active groups is generated.
And (3) reducing the temperature of a reaction system of the polyester polyol containing the TCA circulation metabolic organic acid active groups to 100 ℃, vacuumizing to a vacuum degree of less than-0.09 MPa, and dehydrating for 3 hours to obtain the dehydrated polyester polyol containing the TCA circulation metabolic organic acid active groups.
50 parts of PEG (400 Da) is added into a second reactor, the temperature is kept at 100 ℃, and the vacuum is pumped until the vacuum degree is less than-0.09 MPa for dehydration for 3 hours, so as to obtain dehydrated PEG (400 Da).
Adding 100 parts of HDI into a third reactor, heating to 50 ℃, introducing nitrogen for protection, adding dehydrated alkaline polyester polyol containing TCA (ternary ammonium carbonate) circulation metabolic organic acid active groups and dehydrated PEG (400 Da) under stirring, keeping the temperature at 50 ℃, stirring for 24 hours, removing free HDI by using a thin film evaporator, adding 0.05 part of stannous octoate, and stirring uniformly to obtain the biological functional single-component medical adhesive with terminal-NCO groups.
Comparative example 6:
step 1: preparing materials:
according to the mass parts, 5 parts of citric acid, 11 parts of 1, 8-octanediol, 50 parts of polyethylene glycol (PEG, 400 Da), 100 parts of Hexamethylene Diisocyanate (HDI) and 0.05 part of stannous octoate are respectively weighed.
Step 2: preparing a biological functional single-component medical adhesive:
5 parts of citric acid and 11 parts of 1, 8-octanediol are added into a first reactor, and after stirring and reacting for 10 hours at 140 ℃, polyester polyol containing active groups of TCA cycle metabolic organic acids is produced.
And (3) reducing the temperature of a reaction system of the polyester polyol containing the TCA circulation metabolic organic acid active groups to 100 ℃, vacuumizing to a vacuum degree of less than-0.09 MPa, and dehydrating for 3 hours to obtain the dehydrated polyester polyol containing the TCA circulation metabolic organic acid active groups.
50 parts of PEG (400 Da) is added into a second reactor, the temperature is kept at 100 ℃, and the vacuum is pumped until the vacuum degree is less than-0.09 MPa for dehydration for 3 hours, so as to obtain dehydrated PEG (400 Da).
Adding 100 parts of HDI into a third reactor, heating to 50 ℃, introducing nitrogen for protection, adding dehydrated polyester polyol containing TCA circulation metabolic organic acid active groups and dehydrated PEG (400 Da) under stirring, keeping the temperature at 50 ℃, stirring for 24 hours, removing free HDI by using a thin film evaporator, adding 0.05 part of stannous octoate, and stirring uniformly to obtain the biological functional single-component medical adhesive with terminal-NCO groups.
The biofunctional single-component medical adhesives prepared in examples 1 to 5 and comparative examples 1 to 6 were subjected to various performance tests including adhesive viscosity, preliminary curing time test, adhesive strength test, skin irritation index (PII) test, skin sensitization test, biodegradation test, biotoxicity test, and accelerated combination regeneration test. The specific test method is as follows:
viscosity test: the adhesive was tested for viscosity at 37℃using an NDJ-79 digital display rotational viscometer.
Preliminary cure time test (tack free time): the biological functional type single-component medical adhesive is smeared on the surface of wet pigskin, and when the surface of the biological functional type single-component medical adhesive is touched, the phenomenon of sticking hands does not exist, namely the primary curing time of the biological functional type single-component medical adhesive.
Adhesive strength test: two pigskin pieces with the size of 60 x 20 x 2mm are taken, the surfaces of the pigskin pieces are kept moist, a 25 x 10mm area is marked on each of the surface of the two pigskin pieces, the biological functional single-component medical adhesive is uniformly smeared on the marking positions of the two pigskin pieces, then the two pigskin pieces are adhered together, and the pigskin pieces are cured for 60 minutes in a room temperature moist state, so that a tensile testing machine can be used for testing.
Skin irritation index (PII) test: the method is carried out according to the method specified in GB/T16886.10-2000, the acute contact is required for 24 hours, and the index is not more than 0.5.
Skin sensitization test: the method is carried out according to the closed sensitization test method specified in GB/T16886.10-2000.
Biodegradation test: weighing a proper amount of biological functional single-component medical adhesive sample in a round flat-bottomed polytetrafluoroethylene disc, uniformly leveling the sample by utilizing the fluidity of the colloid, curing the sample in a room-temperature wet environment to form an adhesive film, molding the adhesive film, and drying the adhesive film in a vacuum drying oven at 60 ℃. The dried film was weighed (cut into 2cmx2 cm) and then placed in 1.5mg/mL PBS buffer solution, the test environment was maintained at 37℃for 7 weeks, the film was removed, washed with distilled water and dried in a vacuum oven for 48 hours, and the weight change was calculated. The in vitro biodegradation rate was calculated using the following formula:
degradation rate (%) = (W) o One W d )/W o ×100％
Wherein W is o And W is d Dry weight of the samples before and after degradation are shown, respectively.
Biotoxicity test: taking 0.2g of the cured adhesive, implanting into a rat subcutaneously for 4 weeks, observing the apparent change (color, temperature and exudation) of the skin of the material, and adopting eosin-Hematoxylin (HE) staining of animal material paraffin sections to evaluate subcutaneous tissue structure and inflammatory cell quantity after 4 weeks, and quantitatively analyzing the biocompatibility and cytotoxicity of the material. Biotoxicity test comparative commercially available alpha-cyanoacrylate adhesives. Inflammatory cell fractionation criteria are shown in table 1 below.
TABLE 1 inflammatory cell fractionation criteria
Tissue regeneration promotion test: the measurement was performed by the MTT method. MTT is commercially available as thiazole blue, the yellow substance can be reduced into purple formazan crystal by living cells, and the reduction amount of the yellow substance is measured at 570nm wavelength by an enzyme-linked immunosorbent assay (enzyme-labeled instrument for short) to quantitatively judge the proliferation condition of the cells.
(1) Preparation of a film sample: the adhesive film was prepared by the same method as the adhesive film preparation method in the biodegradation test, and 1g of the adhesive film was placed in a sterile sample tube. Then, 1mL of absolute ethanol was added to each tube, and the tubes were placed under ultraviolet light for sterilization for 1 hour. After the excess alcohol in the sample has evaporated, the sample is washed several times with sterile PBS buffer solution (ph=7.4).
(2) Cell culture and proliferation assay: cell culture medium (MEM medium containing 10% Fetal Bovine Serum (FBS) and 1% streptomycin by volume) was added to the sample tube and the film samples were incubated with the medium at 37 ℃ for 72h. During this period, the osteoblast precursor cells MC3T3 were grown at 5X 10 3 Cell/well density was seeded into 96-well plates each containing 100 μl of cell culture medium and allowed to incubate at 37deg.C with 5% CO 2 And (5) culturing in an adherence manner for 24 hours in the environment. After the end of the incubation, 10 μl of sample medium was added to each well, with sterile PBS buffer (ph=7.4) as control, and incubated at 37 ℃ for 24h. 100. Mu.L of fresh medium containing 1% MTT (5 mg/mL MTT in PBS buffer) was pipetted into the wells. After 4h, the medium was aspirated and removed 100 μl DMSO to dissolve the ozane crystals. Finally, the light absorbance values were read on a microplate reader based on linear absorbance for the number of living cells in the culture.
The method for testing the content of the active groups of the organic acid in the TCA cycle metabolism comprises the following steps: and after the medical adhesive is prepared, the mass of the product is weighed, and the mass of the organic acid active group metabolized by the TCA cycle is divided by the mass of the product and multiplied by 100 percent, so that the content of the organic acid active group metabolized by the TCA cycle in the biological functional single-component adhesive is obtained.
The viscosity, the primary curing time and the adhesion strength of the biofunctional type single-component medical adhesives prepared in examples 1 to 5 and comparative examples 1 to 6 are shown in table 2 below.
TABLE 2 viscosity, primary cure time, adhesive Strength of medical Adhesives
Skin irritation index (PII) test results: the biofunctional single-component medical adhesive prepared in examples 1 to 5 and comparative examples 1 to 6 all had skin irritation index of 0.
Skin sensitization test results: the biofunctional single-component medical adhesives prepared in examples 1 to 5 and comparative examples 1 to 6 all have no skin sensitization reaction.
The results of the biodegradation test, the biotoxicity test, and the tissue regeneration promotion test of the biofunctional single-component medical adhesives prepared in examples 1 to 5 and comparative examples 1 to 6 are shown in table 3 below.
TABLE 3 biodegradation, biotoxicity and tissue regeneration promoting Properties of medical Adhesives
The results of the TCA cycle organic acid active group content test of the biofunctional type single-component medical adhesives prepared in examples 1 to 5 and comparative examples 1 to 6 are shown in Table 4 below.
TABLE 4 content of TCA organic acid active groups of medical adhesives
From the test results, the biological functional single-component medical adhesive with proper viscosity, moderate curing speed, high adhesive strength, high degradation speed, low toxicity and high tissue regeneration promoting capability can be prepared in all the examples 1 to 5.
Compared with the commercially available alpha-cyanoacrylate adhesive, the biological functional single-component medical adhesive prepared in the examples 1-5 only forms a slight inflammatory reaction to organisms, and has better biocompatibility and low biotoxicity.
Compared with comparative examples 1 and 2, the viscosity of the single-component medical adhesive glue of example 1 is relatively higher, but the use of the adhesive is not affected, and the prepared biological functional single-component medical adhesive has stronger adhesive strength, and the prepared biological functional single-component medical adhesive has the advantages that the TCA (ternary aliphatic carboxylic acid) is firstly reacted with a certain mass portion of polyalcohol to generate the multifunctional alkaline polyester polyol containing TCA (ternary aliphatic carboxylic acid) metabolic organic acid active groups, so that the crosslinking density of the biological functional single-component medical adhesive can be improved, and the adhesive strength of the biological functional single-component medical adhesive is enhanced. And example 1 has a remarkable effect of promoting bone cell proliferation compared with the blank sample for promoting tissue regeneration, while comparative example 1 and comparative example 2 have no effect of promoting bone cell proliferation compared with the blank sample for promoting tissue regeneration, and the inflammatory reaction and biotoxicity of comparative example 1 are larger.
Compared with comparative example 3, the formula of example 1 is the same, the degradation speed of example 1 is faster, and the tissue regeneration promoting effect is more remarkable, and it can be seen that the preparation method of preparing the bio-functional single-component medical adhesive by firstly preparing the alkaline polyester polyol containing the TCA cycle metabolism organic acid active group and then reacting with the polyisocyanate in example 1 is beneficial to preparing the bio-functional single-component medical adhesive with faster degradation speed and more beneficial to promoting tissue regeneration. In contrast, in comparative example 3, instead of preparing the alkaline polyester polyol containing the TCA (ternary ammonium salt) circulation metabolic organic acid active group, the biofunctional single-component medical adhesive is prepared by directly mixing and reacting the TCA circulation metabolic organic acid, the polyol and the polyisocyanate, the obtained biofunctional single-component medical adhesive is difficult to degrade, the TCA circulation metabolic organic acid structure is damaged, and the tissue regeneration is difficult to promote.
Compared with comparative example 4, the biofunctional single-component medical adhesive prepared in comparative example 4 has higher viscosity, which is unfavorable for the use of the adhesive, whereas the viscosity of example 1 is relatively low, the adhesive strength is higher, and the tissue regeneration promoting capability is stronger. It can be seen that the preparation method of example 1 contains polymer polyol, and the preparation of the bio-functional single-component medical adhesive by using the polymer polyol can reduce the viscosity of the adhesive, improve the adhesion strength of the bio-functional single-component medical adhesive, and is beneficial to promoting cell proliferation.
In example 1, the viscosity of the biofunctional type single-component medical adhesive prepared in comparative example 5 was higher than that of comparative example 5, which was disadvantageous for the use of the adhesive, whereas example 1 was not only low in viscosity but also higher in adhesive strength, and the tissue regeneration promoting ability of example 1 was stronger. It can be seen that in example 1, in the step of generating the alkaline polyester polyol containing the TCA cycle metabolic organic acid active group, the reaction temperature is 140 ℃, and the prepared bio-functional single-component medical adhesive can have stronger adhesive strength and capability of promoting cell proliferation. In the step of generating the polyester polyol containing the TCA cycle metabolism organic acid active group, the reaction temperature adopted is 300 ℃, the reaction temperature is too high, the structure of part of TCA cycle metabolism organic acid is destroyed, the crosslinking degree of the polyester polyol is too high, certain byproducts are generated, the viscosity of the bio-functional single-component medical adhesive is too high, the adhesion strength is reduced, the cell proliferation effect is weakened, the tissue regeneration is not facilitated, the inflammatory reaction of the comparative example 5 is increased, and the biotoxicity is high.
Compared with comparative example 6, in the stage of synthesizing the basic polyester polyol containing TCA cycle metabolic organic acid active groups of the biological functional single-component medical adhesive prepared in example 6, the polyhydroxy tertiary amine is not added, so that the degradation rate of the adhesive is slower, the tissue regeneration promoting effect is reduced, the complete degradation time of the adhesive is obviously prolonged, healing is not facilitated, and the medical adhesive prepared in example 6 finally without the polyhydroxy tertiary amine is slow in curing rate, difficult to completely cure and weak in bonding strength.
The technical features of the above embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The foregoing examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (8)
1. The preparation method of the biological functional single-component medical adhesive is characterized by comprising the following steps:
weighing 1-5 parts of citric acid, 0.1-4 parts of tertiary amine containing polyhydroxy, 1-15 parts of 1,8 octanediol, 10-65 parts of polyethylene glycol, 0.01-0.1 part of catalyst and 20-160 parts of hexamethylene diisocyanate according to parts by mass;
mixing the citric acid with the polyhydroxyl tertiary amine and the 1, 8-octanediol, and reacting under the heating condition of 120-170 ℃ to generate alkaline polyester polyol containing citric acid active groups;
Respectively dehydrating the alkaline polyester polyol containing the citric acid active groups and the polyethylene glycol under heating and negative pressure;
mixing the dehydrated alkaline polyester polyol containing citric acid active groups, the polyethylene glycol and the hexamethylene diisocyanate, reacting under the protection gas atmosphere and heating conditions to generate polyurethane prepolymer, removing the free hexamethylene diisocyanate, and then adding the catalyst to prepare the biofunctional monocomponent medical adhesive with terminal-NCO groups;
the polyhydroxyl tertiary amine is one or a mixture of more of triethanolamine, triisopropanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N-N-propyldiethanolamine and tert-butyldiethanolamine.
2. The method for preparing a biofunctional single-component medical adhesive according to claim 1, wherein in the step of dehydrating the polyester polyol containing the citric acid active group, the heating temperature is 80 ℃ to 150 ℃.
3. The method for preparing a biofunctional single-component medical adhesive according to claim 1, wherein in the step of producing the polyurethane prepolymer, the heating temperature is 40 ℃ to 90 ℃.
4. The method for preparing a biofunctional single-component medical adhesive according to any one of claims 1 to 3, wherein the molecular weight of the polyethylene glycol is 100Da or less and 2000Da or less.
5. The method for preparing a biofunctional single-component medical adhesive according to any one of claims 1 to 3, wherein the catalyst is a mixture of one or more of an organotin-based catalyst, an organobismuth-based catalyst and an amine-based catalyst.
6. The biological functional single-component medical adhesive is characterized by comprising a citric acid active group and a terminal-NCO group, wherein the mass fraction of the citric acid active group is 0.1% -30%;
the biological functional type single-component medical adhesive is prepared by the preparation method of the biological functional type single-component medical adhesive in any one of claims 1-5.
7. The biofunctional single-component medical adhesive according to claim 6, wherein the mass fraction of the citric acid active groups is 1% -20%.
8. A biofunctional medical adhesive film, characterized in that it is obtained by curing the biofunctional single-component medical adhesive according to any one of claims 6-7.
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