CN113769152B - Composite adhesive and preparation method and application thereof - Google Patents

Composite adhesive and preparation method and application thereof Download PDF

Info

Publication number
CN113769152B
CN113769152B CN202110744192.7A CN202110744192A CN113769152B CN 113769152 B CN113769152 B CN 113769152B CN 202110744192 A CN202110744192 A CN 202110744192A CN 113769152 B CN113769152 B CN 113769152B
Authority
CN
China
Prior art keywords
adhesive
water
alcohol
prepolymer
bone
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
Application number
CN202110744192.7A
Other languages
Chinese (zh)
Other versions
CN113769152A (en
Inventor
郭金山
赵益涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Southern Medical University
Original Assignee
Southern Medical University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Southern Medical University filed Critical Southern Medical University
Priority to CN202110744192.7A priority Critical patent/CN113769152B/en
Publication of CN113769152A publication Critical patent/CN113769152A/en
Application granted granted Critical
Publication of CN113769152B publication Critical patent/CN113769152B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic 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
    • 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
    • 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
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • 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
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
    • 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
    • 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
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Surgery (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Materials Engineering (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Materials For Medical Uses (AREA)
  • Dental Preparations (AREA)

Abstract

The invention discloses a composite adhesive and a preparation method and application thereof, wherein the composite adhesive comprises a component A and a component B; the component A comprises water, alcohol or a water/alcohol mixed solution of an adhesive prepolymer and an inorganic metal ion source dispersed in the water, alcohol or water/alcohol mixed solution of the adhesive prepolymer; the component B comprises water, alcohol or water/alcohol mixed solution of a crosslinking initiator. According to the invention, the crosslinking initiator is added into the compound of the water/alcohol-soluble adhesive prepolymer and the inorganic metal ion source, so that the composite adhesive for tendon-bone healing is successfully prepared, the bonding force between an implanted tendon and a bone tunnel can be improved by providing the adhesion force to an organic/inorganic interface, and the osteogenesis and maturation of the tendon-bone interface and the bone tunnel are promoted by the biological effects of hemostasis, osteogenesis promotion and the like provided by metal ions and natural organic acid.

Description

Composite adhesive and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medical materials, and particularly relates to a composite adhesive and a preparation method and application thereof.
Background
Anterior Cruciate Ligament (ACL) injury is one of the most common sports injuries that result in decreased Anterior stability and dysfunction of the knee, such as untimely treatment that can lead to cartilage, meniscus injury and osteoarthritis, eventually necessitating knee replacement (Paterno MV, et. al. am. j. sports med.2014,42, 1567-. ACL reconstruction patients exceed 20 million each year in the united states with direct costs of up to 30 million dollars (ateskk, et. al.j. bone Joint surg. am.2014,96, 513-. China is a large population base with a greater number of patients requiring ACL reconstruction each year. Although conventional ACL reconstruction can restore partial knee joint function, the healing process often produces "bungee effect" and "wiper effect" due to ligament relaxation, and 30% of young patients can also have recurrent ACL injuries after exercise recovery. Natural ACL osseointegration sites four-layered tissue structures have evolved to transition from bone, mineralized fibrocartilage, unmineralized fibrocartilage to ligaments in order to accommodate stress transmission from hard to soft tissue (Tang Y, et al biomaterials 2020,242,119837). Traditional ACL reconstruction does not achieve effective healing of the transplanted tendon and bone marrow tract (tendon-bone). Poor tendon-bone healing (especially in the early stages of ACL reconstruction) and massive infiltration of fibroblasts into the tendon-bone interface leading to scar healing are the main causes of the clinical non-ideal effect of ACL reconstruction (mengstab PY, et. al. proc. natl. acad. sci. u.s.a.2020,117, 28655-28666.). Strengthening the osseointegration of transplanted tendon, promoting the bone ingrowth of bone marrow tract (shrinking tendon-bone cavity) and the maturation of tendon-bone interface tissue, and inhibiting fibroblast infiltration are common means for promoting tendon-bone healing.
Tendon-bone healing is slower (months) and less complete than bone-bone healing (around 6 weeks). To promote tendon-bone healing, some researchers have wrapped periosteum around transplanted tendons to promote chondrogenesis
It is of great scientific interest to develop a tendon-bone healing promoting method that is highly efficient and universally applicable to improve the initial physical integration of transplanted tendons with bone tunnels and promote subsequent bone ingrowth into the bone marrow tract.
Disclosure of Invention
The first technical problem to be solved by the invention is as follows:
a composite adhesive is provided.
The second technical problem to be solved by the invention is:
provides a preparation method of the composite adhesive.
The third technical problem to be solved by the invention is:
the application of the composite adhesive is provided.
In order to solve the first technical problem, the invention adopts the technical scheme that:
a composite adhesive comprises a component A and a component B;
the component A comprises water, alcohol or a water/alcohol mixed solution of an adhesive prepolymer and an inorganic metal ion source dispersed in the water, alcohol or water/alcohol mixed solution of the adhesive prepolymer;
the component B comprises water, alcohol or water/alcohol mixed solution of a crosslinking initiator;
the inorganic metal ion source includes at least one of hydroxyapatite, calcium carbonate, whitlockite, magnesium-doped hydroxyapatite, zinc-doped hydroxyapatite, and zinc oxide.
According to an embodiment of the invention, when the composite adhesive is coated on the autologous tendon, the component a is coated first, and then the component B is coated, so that the condition that the crosslinking reaction is finished soon after the component a and the component B are mixed, and the use effect is affected is avoided.
According to one embodiment of the invention, the adhesive prepolymer is prepared from the following raw materials in parts by mass:
5-45 parts of natural polybasic acid and/or polybasic acid salt;
10-55 parts of water/alcohol-soluble polymer polyol;
0-20 parts of a diol monomer containing side chain carboxyl or carboxylate;
1-20 parts of a compound containing catechol groups or gallic acid groups;
0-30 parts of at least one of metal carbonate, metal bicarbonate and tertiary amine.
According to an embodiment of the invention, the adhesive prepolymer further comprises 0-1 part of a catalyst.
According to an embodiment of the present invention, the crosslinking initiator includes at least one of sodium periodate, tetrabutylammonium periodate, silver nitrate, and ferric chloride.
According to one embodiment of the present invention, the crosslinking initiator is dissolved in water, alcohol or a water/alcohol mixed solvent, and preferably tetrabutylammonium periodate.
According to an embodiment of the present invention, the mass concentration of the crosslinking initiator in the water, the alcohol or the water/alcohol mixed solvent is 0.1 to 20 wt%.
According to an embodiment of the present invention, the alcohol solvent in the alcohol or water/alcohol solvent is at least one of ethanol, isopropanol and butanol.
According to an embodiment of the present invention, the volume ratio of water to alcohol in the water/alcohol mixed solvent is 10: 0.01-0.01: 10.
according to an embodiment of the present invention, the natural polybasic acid includes at least one of malic acid, citric acid and succinic acid.
The natural polybasic acid has good biocompatibility, so that the composite adhesive has better biocompatibility, and if the natural polybasic acid is replaced by polybasic acid containing benzene rings, the biocompatibility of the adhesive is adversely affected.
According to an embodiment of the present invention, the polybasic acid salt is at least one of a carboxyl group-ionized malate salt and a carboxyl group-ionized citrate salt.
According to one embodiment of the present invention, the water/alcohol-soluble polymer polyol comprises poly (ethylene glycol), poly (propylene glycol), poly (ethylene glycol) -poly (propylene glycol) -poly (ethylene glycol) triblock copolymer, poly (epsilon-caprolactone), and the molecular weight of the polymer is 100-20000 Da;
the diol monomer containing a side chain carboxyl group or a carboxylate is at least one selected from 2, 2-bis (hydroxymethyl) propionic acid (DMAP) and dihydroxyethylglycine (bicine);
the above compound containing catechol (cathhol) group or gallic acid (gallol) group is at least one selected from dopa, dopamine, 3, 4-dihydroxybenzoic acid, gallic acid, caffeic acid, and dihydrocaffeic acid.
According to an embodiment of the present invention, the metal carbonate is at least one selected from sodium carbonate, calcium carbonate, magnesium carbonate, basic magnesium carbonate, zinc carbonate, and the like.
According to an embodiment of the present invention, the catechol group-or gallic acid group-containing compound may be an alcohol compound, an amine compound, or an acid compound.
According to an embodiment of the present invention, the metal bicarbonate is selected from sodium bicarbonate.
According to an embodiment of the present invention, the tertiary amine is at least one selected from triethylamine and N, N-dimethylethanolamine.
According to an embodiment of the present invention, the catalyst is at least one selected from sulfuric acid, stannous isooctanoate, tetrabutyl titanate and the like.
In order to solve the second technical problem, the invention adopts the technical scheme that:
a method for preparing the composite adhesive comprises the following steps:
and mixing the adhesive prepolymer with the inorganic metal ion source, and adding a crosslinking initiator to perform crosslinking reaction.
According to an embodiment of the present invention, the adhesive prepolymer includes an alcohol-soluble adhesive prepolymer or a water-soluble adhesive prepolymer.
According to an embodiment of the present invention, the preparation method of the water-soluble adhesive prepolymer/alcohol-soluble adhesive prepolymer comprises:
(1) mixing natural polybasic acid and/or polybasic acid salt, water/alcohol-soluble polymer polyol, diol monomer containing side chain carboxyl or carboxylate and compound containing catechol group or gallic acid group to obtain water/alcohol-soluble adhesive prepolymer;
(2) dissolving the water/alcohol-soluble adhesive prepolymer in a solvent, and mixing the water/alcohol-soluble adhesive prepolymer solution with an inorganic metal ion source to obtain a composite water/alcohol-soluble adhesive prepolymer solution; preferably, in order to increase the water solubility of the water-soluble adhesive prepolymer solution or convert the alcohol-soluble prepolymer solution into a water-soluble prepolymer solution, at least one of metal carbonate, metal bicarbonate and tertiary amine is added into the water/alcohol-soluble adhesive prepolymer solution to react to generate a water-soluble adhesive prepolymer;
(3) and mixing the composite water/alcohol-soluble adhesive prepolymer solution with a crosslinking initiator to obtain the composite adhesive.
According to an embodiment of the present invention, the solvent in the step (2) is water, alcohol or a water/alcohol mixed solution.
According to an embodiment of the present invention, in the step (2), the inorganic metal ion source accounts for 0 to 70% by mass of the water/alcohol-soluble adhesive prepolymer solution.
According to an embodiment of the present invention, in the step (3), the crosslinking initiator is dissolved in water, alcohol or a hydroalcoholic solution to obtain a crosslinking initiator solution; mixing the composite water/alcohol-soluble adhesive prepolymer solution and the crosslinking initiator solution in a volume ratio of 1: 1-10: 1 and mixing.
According to one embodiment of the present invention, the product obtained in the step (1) is further subjected to separation, purification and drying.
According to an embodiment of the present invention, the reaction process is further performed after the mixing in the step (1), the reaction includes a heating process, and the temperature for heating the reaction is 110 to 150 ℃.
According to an embodiment of the present invention, the reaction time in the step (1) is 24 to 240 hours.
In another aspect, the invention also relates to the application of the composite adhesive in preparing materials for treating anterior cruciate ligament injury and rotator cuff injury.
In another aspect of the invention, the medical material comprises the composite adhesive.
The invention has the beneficial effects that:
(1) the adhesive disclosed by the invention can form covalent bond adhesion with the surface of soft tissue, and can strongly adhere to the surface of an inorganic object by forming hydrogen bond, surface bonding or polyphenol-metal coordination, so that the adhesive can be well used for improving the bonding between an implanted tendon and a bone tunnel, avoiding the early tendon loosening and providing a good physical and mechanical environment for promoting tendon-bone healing.
(2) The adhesive disclosed by the invention is beneficial to metal ions such as calcium and the like introduced into a polymer side chain and an inorganic metal ion source, and due to the corresponding functions of the metal ions, such as the calcium ions can promote hemostasis, the adhesive disclosed by the invention has a good in-situ blood coagulation function, and partially has a tendon-bone healing promoting function similar to platelet-rich plasma.
(3) The adhesive disclosed by the invention can release natural (hydroxyl) polybasic acid during degradation due to the polymer (such as citric acid or malic acid and the like), so that the adhesive has good cartilage and bone promoting properties; it is also beneficial that the inorganic metal ion source can release metal ions (such as magnesium ion-releasing whitlockite, zinc ion-releasing zinc oxide, calcium ion-releasing calcium carbonate, etc.), and the released metal ions can promote the increase of bone quality or osteogenesis speed, so that the adhesive can promote the bone ingrowth of bone tunnels and the formation of a bone-mineralized cartilage-tendon biomimetic tendon-bone transitional structure at tendon-bone interfaces, promote the bone tunnel shrinkage and tendon-bone interface maturation.
(4) The inorganic metal ion sources can be selected or combined according to requirements to reflect healing effects of different aponeuroses, for example, the white apatite selectively releasing magnesium ions has stronger capability of promoting periosteum osteogenesis, for example, the zinc oxide selectively releasing zinc ions has stronger capability of promoting bone quality improvement and osteogenesis speed, for example, the calcium carbonate selectively releasing calcium ions is biased to mature bone matrix, and in addition, different inorganic metal ion sources have different influences on the strength and viscosity of the adhesive.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a schematic diagram of the synthesis of a water/alcohol soluble adhesive prepolymer;
FIG. 2 shows iCMBA-PCL and iCMBA-PCL-Ca in example 1 2+ A synthetic scheme of (a);
FIG. 3 is a schematic view of the composite adhesive of example 1 used for tendon-bone healing;
FIG. 4 is coagulation performance data for the prepolymer in example 3;
FIG. 5 is a staining image of a tissue section of the adhesive-treated tendon-bone interface of example 3;
FIG. 6 shows iMBA-PCL-Ca in example 6 2+ Schematic synthesis of (a).
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to the same or similar elements or elements having the same or similar function throughout.
The embodiments described below with reference to the accompanying drawings are illustrative only for the purpose of explaining the present invention, and are not to be construed as limiting the present invention.
In the description of the present invention, if there are first, second, third, etc. described only for the purpose of distinguishing technical features, it is not to be understood that relative importance is indicated or implied or that the number of indicated technical features is implicitly indicated or that the precedence of the indicated technical features is implicitly indicated.
In the description of the present invention, it should be understood that the orientation or positional relationship referred to in the description of the orientation, such as the upper, lower, left, right, etc., is based on the orientation or positional relationship shown in the drawings, and is only for convenience of description and simplification of description, and does not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and thus, should not be construed as limiting the present invention.
In the description of the present invention, it should be noted that unless otherwise explicitly defined, terms such as setup, installation, connection, etc. should be understood broadly, and those skilled in the art can reasonably determine the specific meaning of the terms in the present invention in combination with the specific contents of the technical solutions.
In order to explain the technical content, the objects and the effects of the present invention in detail, the following description will be given with reference to the embodiments.
Example 1
The embodiment provides a composite adhesive, and a preparation method thereof includes the following steps:
(1) 11.528g of citric acid, 50g of poly (epsilon-caprolactone) (PCL with the molecular weight of 1000Da) and 2.844g of dopamine hydrochloride are placed in a single-neck round-bottom glass flask provided with a magnetic stirrer, the citric acid and the dopamine hydrochloride are dissolved in the PCL under 160 ℃ oil bath to obtain a uniform reaction mixture, 5mL of deionized water is added to assist dissolution, and 0.5g of tetrabutyl titanate is added as a catalyst; then, the temperature of the oil bath is reduced to 140 ℃, so that the reaction mixture is continuously stirred under the vacuum condition (the rotating speed is 600rpm) for reaction, and the rotating speed is gradually reduced according to the viscosity of the polymer in the polymerization process until the viscosity of a reaction system is increased to the extent that a stirrer is difficult to rotate at 60 rpm; heating was stopped to give an alcohol-soluble prepolymer (designated iCMBA-PCL).
(2) To the alcohol-soluble prepolymer was added 150mL of absolute ethanol to dissolve the prepolymer. Then 20g of calcium carbonate powder (excess) was added at room temperature and reacted overnight with high stirring (1200 rpm) (alcohol-soluble prepolymer can also be used as such).
(3) The mixture was then dialyzed against deionized water (molecular weight cut-off of the dialysis bag in this example was 1000Da, which was adjusted depending on the molecular weight of PCL in the reactant), and the deionized water was replaced every 24h for 3 days until no more tan polymer was present in the dialysate. Filtering to remove excess calcium carbonate, and freeze-vacuum drying the aqueous polymer solution for about one week to obtain a purified water-soluble prepolymer (labeled iCMBA-PCL-Ca) 2+ ). The polymer synthesis process is shown in figure 2.
(4) And (3) synthesis of iCMBA-PCL: 3.33g of the above iCMBA-PCL-Ca was taken 2+ Adding 6.67g of deionized water, shaking for 1h to dissolve to obtain 33 wt% of iCMBA-PCL-Ca 2+ And compounded with 1.43g of hydroxyapatite as component a; 8 wt% NaIO is prepared 4 The solution is used as component B; mixing the component A and the component B according to a volume ratio of 2: 1 to obtain the adhesive (marked as WA-HA-1).
(5)iCMBA-PCL-Ca 2+ The synthesis of (2): 3.33g of the above iCMBA-PCL was dissolved with shaking for 1h in 6.67g of ethanol/water mixed solvent (v/v. 80/20) to give a 33 wt% ethanol/water solution of the iCMBA-PCL, which was combined with 1.43g of hydroxyapatite as component a; preparing 8 wt% tetrabutyl ammonium periodate solution as a component B; mixing the component A and the component B according to a volume ratio of 2: 1 to obtain the adhesive (marked as EA-HA-1).
This example prepares water/alcohol soluble adhesive prepolymers iCMBA-PCL and iCMBA-PCL-Ca 2+ The synthetic scheme of (A) is shown in FIG. 2.
Constructing a rat Anterior Cruciate Ligament (ACL) injury model, taking an autologous tendon, respectively coating the component A and the component B of the composite adhesive of the embodiment on the collected autologous tendon, penetrating the collected autologous tendon into a manufactured bone tunnel, crosslinking to obtain the composite adhesive, adhering and implanting the tendon and the bone tunnel (as shown in figure 3), and noting that the component A and the component B cannot be mixed and then coated on the collected autologous tendon, otherwise, the crosslinking reaction can be quickly finished after the component A and the component B are mixed, and the application effect of the composite adhesive has great difference. Calcium ions in the adhesive can help blood coagulation and partially play a role of platelet-rich plasma, citric acid and hydroxyapatite can promote bone, promote bone ingrowth in bone tunnels and ossification of tendon-bone interfaces, and promote bone healing.
Example 2
This example provides a composite adhesive, which is prepared by the method and materials similar to those of example 1, except that 50g of PCL (molecular weight 1000Da) in example 1 is replaced by 55g of poly (ethylene glycol) -block-poly (propylene glycol) -block-poly (ethylene glycol) (PEG-PPG-PEG, EPE, 1100Da), and the obtained water-soluble prepolymer is iCMBA-EPE-Ca 2+ 。
The adhesive obtained in this example WAs labeled WA-HA-2.
Constructing a rat Anterior Cruciate Ligament (ACL) injury model, taking autologous tendons, smearing the composite adhesive on the collected autologous tendons, penetrating the collected autologous tendons into a manufactured bone tunnel, crosslinking to obtain the composite adhesive, and adhering and implanting the prepared autologous tendons and the bone tunnel. The presence of calcium ions in the adhesive aids clotting and in part functions as platelet rich plasma (the clotting effect of the prepolymer is shown in figure 4). The magnesium ions, citric acid and hydroxyapatite released by the adhesive can promote bone growth, promote bone ingrowth of bone tunnels and ossification of tendon-bone interfaces, and promote bone-strengthening healing. Histological sections of tendon-bone combinations after 4, 8 and 12 weeks of treatment with the complex adhesive were stained as shown in fig. 5.
Example 3
This example provides a composite adhesive, which is prepared by a method and using raw materials similar to those of example 1, except that HA is replaced by natural mineral Whitlockite (WH) which can release magnesium ions.
The adhesive obtained in this example WAs designated WA-WH-1.
Constructing a rat Anterior Cruciate Ligament (ACL) injury model, taking autologous tendons, smearing the composite adhesive on the collected autologous tendons, penetrating the collected autologous tendons into a manufactured bone tunnel, crosslinking to obtain the composite adhesive, and adhering and implanting the prepared autologous tendons and the bone tunnel. The presence of calcium ions in the adhesive aids clotting and in part functions as platelet rich plasma (the clotting effect of the prepolymer is shown in figure 4). Magnesium ions released by the whitlockite and citric acid released by the degradation of the adhesive can promote bones, promote the bone tunnel to grow inwards and the tendon-bone interface to ossify, and promote the bone healing.
Example 4
The embodiment provides a composite temperature-sensitive composite adhesive, the preparation method and raw materials of which are similar to those of embodiment 3, and the only difference is that the sodium periodate solution in embodiment 3 is replaced by FeCl 3 Solutions of + 。
The adhesive obtained in this example WAs designated as T-WA-WH-1. The composite adhesive is liquid at room temperature, and the body temperature is changed into solid.
Constructing a rat Anterior Cruciate Ligament (ACL) injury model, taking autologous tendons, smearing the composite adhesive on the collected autologous tendons, penetrating the collected autologous tendons into a manufactured bone tunnel, crosslinking to obtain the composite adhesive, and adhering and implanting the prepared autologous tendons and the bone tunnel. Magnesium ions, citric acid and hydroxyapatite which are degraded and released by the adhesive can promote bones, promote the bone ingrowth of bone tunnels and ossification of tendon-bone interfaces, and promote the healing of bones.
Example 5
The embodiment provides a malic acid based composite adhesive, and a preparation method of the malic acid based composite adhesive comprises the following steps:
(1) 8.045g malic acid, 35g PCL (molecular weight 1000Da), 2.012g 2, 2-bis (hydroxymethyl) propionic acid (DMAP) and 2.552g gallic acid are put into a single-mouth round bottom glass flask with a magnetic stirrer with a proper size, the malic acid, the 2, 2-bis (hydroxymethyl) propionic acid and the gallic acid are dissolved in EPE under 160 ℃ oil bath to obtain a uniform reaction mixture, a small amount of deionized water is added to assist the dissolution, and 0.5g stannous isooctanoate is added as a catalyst; then reducing the temperature of the oil bath to 140 ℃, enabling the reaction mixture to be continuously stirred under the vacuum condition (the rotating speed is 600rpm) for reaction, and gradually reducing the rotating speed according to the viscosity of the polymer in the polymerization process until the viscosity of the reaction system is increased to the extent that a stirrer is difficult to rotate at 60 rpm; stopping heating to obtain a reaction product: an alcohol soluble prepolymer.
(2) To the reaction product was added 150mL of anhydrous ethanol to dissolve the polymer. 20g of sodium bicarbonate powder (excess) was added at room temperature and reacted overnight with high speed stirring.
(3) The mixture was then dialyzed against deionized water (cut-off of the dialysis bag in this example was 1000Da) and the deionized water was replaced every 24h and dialyzed for 3 days until no more tan polymer was present in the dialysate. The excess calcium carbonate was removed by filtration and the aqueous polymer solution was freeze-dried in vacuo for about one week to give a purified water-soluble prepolymer (designated iMBA-PCL-Na) + ，iMBA-PCL-Na + A schematic of the synthesis of (a) is shown in fig. 6).
(4) Taking 3.33gimBA-PCL-Na + Adding 6.67g of deionized water, shaking for 1.5h to dissolve to obtain 33 wt% of iMBA-PCL-Na + And complexed with 1.43gHA as component A; 8 wt% NaIO is prepared 4 The solution is used as component B; mixing the component A and the component B according to a volume ratio of 2: 1, mixing to obtain the adhesive (marked as WA-HA-5).
Constructing a rat Anterior Cruciate Ligament (ACL) injury model, taking autologous tendons, smearing the composite adhesive on the collected autologous tendons, penetrating the collected autologous tendons into a manufactured bone tunnel, crosslinking to obtain the composite adhesive, and adhering and implanting the prepared autologous tendons and the bone tunnel. Magnesium ions, citric acid and hydroxyapatite which are degraded and released by the adhesive can promote bones, promote the bone ingrowth of bone tunnels and ossification of tendon-bone interfaces, and promote the healing of bones.
In FIG. 1, the polymer synthesis adopts a heating polycondensation reaction, and the polybasic acid or the polybasic acid salt reacts with water-soluble polyalcohol such as polyethylene glycol (PEG) to obtain water-soluble prepolymer; reacting with an alcohol-soluble polyol such as poly (epsilon-caprolactone) to obtain an alcohol-soluble prepolymer. In order to transform the alcohol-soluble prepolymer into a water-soluble prepolymer, the prepolymer and metal carbonate/bicarbonate or tertiary amine can be subjected to acid-base synthesis to form a salt, so that the water solubility or water dispersibility of the prepolymer is improved.
As shown in the schematic diagram of fig. 3, the adhesive is only applied to the surface of the autologous tendon, and fills the space between the autologous tendon and the bone tunnel when the autologous tendon passes through the bone tunnel, and plays a certain role in adhesion.
FIG. 4 shows a calcium salt free citric acid based adhesive prepolymer (iC-EPE) and a calcium containing citric acid based adhesive prepolymer (iC-EPE-Ca) 2+ ) The results of the blood coagulation test of (1). Sodium citrate is a commonly used anticoagulant in the clinic, so that calcium salt-free prepolymers can have longer clotting times than blank samples, while calcium salt-containing prepolymers have significantly reduced clotting times than blank samples.
Fig. 5 is the results of Masson trichrome staining with H & E stain after 4, 8 and 12 weeks after ACL reconstruction of autologous tendons treated with adhesive.
Fig. 6 shows the synthesis of a calcium salt-containing malic acid based adhesive prepolymer.
The above description is only an example of the present invention and is not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention in the specification or the related technical fields, which are directly or indirectly applied, are included in the scope of the present invention.

Claims (3)

1. A composite adhesive is characterized in that:
comprises a component A and a component B;
the component A comprises an aqueous solution of an adhesive prepolymer and an inorganic metal ion source dispersed in the aqueous solution of the adhesive prepolymer;
the component B comprises an aqueous solution of a crosslinking initiator;
the inorganic metal ion source is whitlockite;
the method for preparing the composite adhesive comprises the following steps:
s1, mixing citric acid, poly epsilon-caprolactone and dopamine hydrochloride to obtain an alcohol-soluble adhesive prepolymer;
s2, dissolving the alcohol-soluble adhesive prepolymer in an alcohol solvent to obtain an alcohol-soluble adhesive prepolymer solution;
in order to convert the alcohol-soluble adhesive prepolymer solution into a water-soluble adhesive prepolymer solution, adding calcium carbonate into the alcohol-soluble adhesive prepolymer solution, and reacting to generate a water-soluble adhesive prepolymer;
mixing the water-soluble adhesive prepolymer and the whitlockite in an aqueous solution to obtain a water-soluble adhesive prepolymer solution;
s3, mixing the water-soluble adhesive prepolymer solution with a crosslinking initiator to obtain the composite adhesive.
2. Use of the composite adhesive of claim 1 for preparing a material for treating anterior cruciate ligament injury and rotator cuff injury.
3. A medical material characterized by: comprising the composite adhesive of claim 1.
CN202110744192.7A 2021-06-30 2021-06-30 Composite adhesive and preparation method and application thereof Active CN113769152B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110744192.7A CN113769152B (en) 2021-06-30 2021-06-30 Composite adhesive and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110744192.7A CN113769152B (en) 2021-06-30 2021-06-30 Composite adhesive and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN113769152A CN113769152A (en) 2021-12-10
CN113769152B true CN113769152B (en) 2022-08-16

Family

ID=78836055

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110744192.7A Active CN113769152B (en) 2021-06-30 2021-06-30 Composite adhesive and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN113769152B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114369441A (en) * 2021-12-27 2022-04-19 哈尔滨工程大学 Polyphenol-based medical tissue adhesive, and preparation method and application thereof
CN114681657B (en) * 2022-04-19 2023-02-17 南方医科大学 Degradable antioxidant adhesive with scar growth prevention function and preparation method and application thereof
CN115192765A (en) * 2022-06-30 2022-10-18 南方医科大学 Adhesive and preparation method and application thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2539568C (en) * 2003-09-23 2013-09-10 Orthotherapeutics, Llc Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects
US20110208305A1 (en) * 2008-08-05 2011-08-25 University Of Miami Composite bone grafts, particulate bone-calcium sulfate constructs, and methods of treating joint injuries
CN105770979A (en) * 2016-02-29 2016-07-20 广西大学 Preparation method of tissue adhesive
CN109355057B (en) * 2018-11-07 2021-03-30 哈尔滨工程大学 Polyamino acid-based mussel bionic tissue adhesive and preparation method thereof
CN111635728B (en) * 2020-05-22 2021-05-07 浙江亚撒生物科技有限公司 Degradable temperature-sensitive adhesive and preparation method and application thereof

Also Published As

Publication number Publication date
CN113769152A (en) 2021-12-10

Similar Documents

Publication Publication Date Title
CN113769152B (en) Composite adhesive and preparation method and application thereof
EP1984032B1 (en) Novel adhesives for medical applications
EP1799277B1 (en) Porous biomaterial-filler composite and a method for making the same
CA1092026A (en) Synthetic membrane for wound-dressings
AU667906B2 (en) Biomaterials for bone replacements
US20010037014A1 (en) Thin mineralized collagen membrane and method of making same
JPH08215299A (en) Hard tissue bone cement and substitution
CN108744055B (en) Silk fibroin bone cement biological adhesive and preparation method thereof
JP2014205059A (en) Delayed self-gelling alginate system and use thereof
JP2000000295A (en) Tricalcium phosphate-containing biocement paste containing coagulation accelerator
JPS63145327A (en) Re-absorbable homopolymer and copolymer containing no catalyst
US8741982B2 (en) Bioactive bone cement and method for the production thereof
EP0389629B1 (en) Medical and dental curable material
CN109912791B (en) Carboxylated PEG derivative, hydrogel based on PEG derivative, and preparation method and application of carboxylated PEG derivative and hydrogel
JPH04506971A (en) artificial biofilm
CN114470320A (en) Bone adhesive, preparation method and application thereof
CN111635728B (en) Degradable temperature-sensitive adhesive and preparation method and application thereof
DE2620890B2 (en)
Kang et al. Polydopamine coating-mediated immobilization of BMP-2 on polyethylene terephthalate-based artificial ligaments for enhanced bioactivity
Yuan et al. Citrate-based mussel-inspired magnesium whitlockite composite adhesives augmented bone-to-tendon healing
JP2001505809A (en) Improved hydrogel for tissue processing
CN113384746B (en) Bone cement composite material and preparation method thereof
Gomez d'Ayala et al. Development of a new calcium sulphate‐based composite using alginate and chemically modified chitosan for bone regeneration
CN110665056B (en) Injectable bone cement with tissue self-bonding performance and preparation method and application thereof
WO2004105825A1 (en) Biomaterial for osteogenesis, injection preparation containing the material, kit for preparing the material and osteogenesis method using the same

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