CN111875822A - Bi-component cross-linked composite material applied to plastic surgery and preparation method thereof - Google Patents
Bi-component cross-linked composite material applied to plastic surgery and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/246—Intercrosslinking of at least two polymers
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- 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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
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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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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- C08J2487/00—Characterised by the use of unspecified macromolecular compounds, obtained otherwise than by polymerisation reactions only involving unsaturated carbon-to-carbon bonds
Abstract
The invention provides a bi-component cross-linked composite material applied to plastic surgery and a preparation method thereof. The double-component cross-linked composite material applied to the plastic surgery has good adaptability, can tightly seal the wound surface formed after the plastic surgery without gaps, plays a role of physical barrier, provides a wet healing environment, has the characteristics of good elasticity, stretchability, cohesiveness and the like, can prevent the wound surface from being connected, and promotes the healing effect after the plastic surgery.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a bi-component cross-linked composite material applied to plastic surgery and a preparation method thereof.
Background
Plastic surgery is primarily concerned with the repair or reconstruction of wounds, diseases, congenital or acquired tissue or organ defects and abnormalities of the skin, muscle and bone. The orthopedic surgery methods are mainly classified into minimally invasive and open methods, wherein minimally invasive methods are simple to care for a wound surface due to the small wound surface, and even care is not needed, and only simple disinfection is needed, such as dermal tissue or muscle tissue filling. However, for open plastic surgery, due to the formation of relatively large wounds, these large wounds are usually from the incised skin and muscle tissue by surgical instruments, or from the excision of native tissue by surgical instruments, or from the impact, friction, etc. of human tissue with hard foreign bodies. These wounds often have the characteristics of large area, deep wounds, irregular wounds including deep, shallow, long and wide wounds, exposure to external irritant environment, susceptibility to virus and bacterial infection and the like, and the wounds must be effectively nursed after operation, otherwise various postoperative complications are easily caused, such as strong pain, long healing period, weak reparative healing, inflammation, red swelling, suppuration and other problems, which may cause failure of the overall operation and bring great harm to patients.
Hyaluronic acid, a high molecular viscous polysaccharide composed of disaccharide units D-glucuronic acid and N-acetylglucosamine as basic structures, has very excellent water retention and moisture retention properties, and the aqueous solution thereof has good rheological property, good biocompatibility and safety, is rich in human eye spheroids, joint lubricating fluid and human intercellular substance, plays an irreplaceable and important human body function, and therefore has higher clinical application value, and is widely applied to various ophthalmic surgeries, such as crystal implantation, corneal transplantation, anti-glaucoma surgeries and the like, and also widely applied to the treatment of arthritis at present. However, its application in accelerating wound healing, especially in accelerating wound healing after open plastic surgery, is slow and has achieved low clinical value, mainly due to: (1) although the hyaluronic acid solution has good water retention and moisture retention properties and can provide a benign wet healing environment for the wound surface, the hyaluronic acid solution is applied to the wound surface after the open plastic surgery, and the solution can not adhere to the wound surface due to strong rheological property, so that the hyaluronic acid solution can not exert the capability of promoting the wound surface healing; (2) the hyaluronic acid solution has no mechanical strength, cannot provide a physical barrier for the wound surface, and further cannot protect the wound surface from external stimulation; (3) the hyaluronic acid solution has no three-dimensional rigid stereo structure and has no functions of suction, seepage and drainage; (4) hyaluronic acid can transform itself into a cross-linked hyaluronic acid gel with three-dimensional network stereo structure and mechanical strength by means of chemical cross-linking, and rheological property is reduced or eliminated. The application of the wound protecting agent for wound protection is researched at present, but the wide application and acceptance in clinic are not found, which is due to the following reasons: the cross-linked hyaluronic acid gel is fixed in shape before use, has no rheological property, is low in adhesive force and easy to shift, is separated from a wound surface on the wound surface, cannot effectively protect the wound surface, and cannot play the roles of water absorption, water retention and wound healing promotion of hyaluronic acid. Meanwhile, due to the lack of adhesion force, secondary dressing such as medical adhesive tape, medical gauze and band-aid is inevitably needed, which brings inconvenience.
Therefore, the advanced research on the improved hyaluronic acid molecules and the integration of new technology can improve the original performance characteristics of the hyaluronic acid molecules, further improve the high value of the clinical application of the hyaluronic acid, such as the improvement of the application of the hyaluronic acid in the wound surface of the plastic surgery, and greatly improve the healing and repair of the wound surface after the plastic surgery.
Disclosure of Invention
The invention provides a bi-component cross-linked composite material applied to plastic surgery and a preparation method thereof, on the premise of not damaging the original functional characteristics of hyaluronic acid such as water absorption, moisture retention, wound healing promotion and the like, modifying the molecular structure of hyaluronic acid, and fusing the modified hyaluronic acid with in-situ rapid instant (less than 1s) gelling technology to form a double-component cross-linked composite material taking hyaluronic acid as a matrix, so that the hyaluronic acid solution can be quickly and instantly phase-transformed in situ on the wound surface after plastic surgery, and transformed from a mobile phase to a stationary phase, the hyaluronic acid-based bi-component cross-linked composite material of the stationary phase can be tightly attached to the wound surface without gaps, and has good adaptability, can completely seal each part of the wound surface, protect the wound surface from external stimulation, prevent bacterial infection and accelerate wound surface healing.
In a first aspect, embodiments of the present application provide a two-component crosslinked composite material for use in orthopedic surgery comprising a first component comprising a thiol-terminated polyamidoamine-bonded hyaluronic acid and a thiol-terminated polyamidoamine-bonded oligoglutamic acid, the first component having branches each having a thiol group at the end thereof, and a second component comprising a modified oligoglutamic acid multi-site crosslinker and a modified low molecular weight hyaluronic acid polysaccharide crosslinker.
Preferably, the thiol-terminated polyamidoamine-bonded hyaluronic acid is formed by chemically bonding thiol-terminated polyamidoamine having 8 or 16 branches each having a thiol group at the end thereof to hyaluronic acid, wherein the polyamidoamine is bonded to hyaluronic acid in a number of at least 20.
Preferably, the thiol-terminated polyamidoamine-linked oligoglutamic acid is formed by bonding the thiol-terminated polyamidoamine to the oligoglutamic acid via an amide linkage (-CO-NH-).
Preferably, the molecular weight of the oligoglutamic acid is 4000-40000 daltons.
Preferably, the molecular weight of the hyaluronic acid is 150000-500000 daltons.
Preferably, the second component modified oligoglutamic acid multi-site cross-linking agent is vinylsulfonyl modified oligoglutamic acid or maleimide modified oligoglutamic acid, and the second component modified low molecular weight hyaluronic acid polysaccharide cross-linking agent is maleimide modified low molecular weight hyaluronic acid.
Preferably, the molecular weight of the low molecular weight hyaluronic acid in the second component is 6000-50000 dalton.
In a second aspect, embodiments of the present application provide a method for preparing a two-component cross-linked composite material for use in orthopedic surgery, comprising the steps of:
s1: dissolving the first component in a first component buffer solution to obtain a first component solution;
s2: dissolving the second component in a second component buffer solution to obtain a second component solution;
s3: and uniformly mixing the first component solution and the second component solution to form the double-component cross-linked medical composite material.
Spraying or coating a layer of first component solution on the wound surface after the plastic surgery, then spraying or coating a layer of second component solution, and instantly forming the hyaluronic acid-based bi-component cross-linked composite material on the wound surface in situ after the first component solution and the second component solution are mixed and contacted. The hyaluronic acid-based bi-component cross-linked composite material is formed by cross-linking two components, the two components are liquid with strong fluidity before use, and can quickly and instantly form a fixed phase hyaluronic acid-based bi-component cross-linked composite material adaptive to the shape and the appearance of a wound surface (less than 1s) in situ according to the shape and the appearance of the wound surface when in use.
Preferably, the pH range of the buffer solution of the first component is 7.5-9.0, and the pH range of the buffer solution of the second component is 7.5-9.0.
Preferably, the mass concentration of the first component in the first component solution is 1.0-2.5%, and the mass concentration of the second component in the second component solution is 0.8-3.0%.
The invention relates to a bi-component cross-linked composite material applied to plastic surgery and a preparation method thereof, which modify the molecular structure of hyaluronic acid, and the hyaluronic acid has good water absorption and retention capacity, the solution has certain cohesive force but no stretchability, and the solution is fused with the in-situ rapid instant (less than 1s) gelling technology to form the hyaluronic acid-based bi-component cross-linked composite material, so that the hyaluronic acid-based bi-component cross-linked composite material has good tensile property and cohesive property, if the tensile property is low, the bi-component cross-linked composite material brings tight feeling to the wound surface, the bi-component cross-linked composite material is easy to break, the cohesive force is too strong, the bi-component cross-linked composite material is easy to cause poor deformability, the foreign body feeling of the wound surface is strong, and the wound surface is uncomfortable. The first component of the hyaluronic acid based bi-component cross-linked composite material is characterized by having a large number of branched chains as shown in a chemical structural formula, wherein the tail end of each branched chain is provided with a large number of thiol groups which have chemical reaction activity and can rapidly perform click chemical reaction with a second component having vinylsulfonyl and maleimide, and the first component and the second component rapidly perform cross-linking reaction to realize phase transformation and form a solid-phase hyaluronic acid based bi-component cross-linked composite material. The liquid with strong fluidity is used before the phase transformation, the stationary phase without fluidity is used after the phase transformation, and the phase transformation is not a gradual process but a rapid and instant process, so that the bi-component cross-linked composite material has good adaptability on wound surfaces. The hyaluronic acid-based bi-component cross-linked composite material of the stationary phase is a three-dimensional reticular space rigid structure, has the capability of absorbing, permeating and draining, is favorable for eliminating swelling and pain, has good mechanical strength, plays a role of physical barrier, exerts a protection effect on a wound surface, can resist or buffer the stimulation and damage of an external environment to the wound surface, and provides a wet healing environment which is favorable for the healing of the wound surface.
Drawings
The accompanying drawings are included to provide a further understanding of the embodiments and are incorporated in and constitute a part of this specification. The drawings illustrate embodiments and together with the description serve to explain the principles of the invention. Other embodiments and many of the intended advantages of embodiments will be readily appreciated as they become better understood by reference to the following detailed description. The elements of the drawings are not necessarily to scale relative to each other. Like reference numerals designate corresponding similar parts.
FIG. 1 is a G2-8NH according to one embodiment of the invention2A schematic of the molecular structure of the polyamide-amine;
FIG. 2 is a block diagram of G3-16NH according to one embodiment of the present invention2Molecules of polyamidoaminesA schematic structural diagram;
FIG. 3 is a schematic representation of the molecular structure of hyaluronic acid according to one embodiment of the invention;
FIG. 4 is a schematic molecular structure diagram of an oligoglutamic acid according to an embodiment of the present invention;
FIG. 5 is a schematic representation of the molecular structure of G2-8SH polyamidoamine according to one embodiment of the invention;
FIG. 6 is a schematic representation of the molecular structure of G3-16SH polyamidoamine according to one embodiment of the present invention;
FIG. 7 is a schematic molecular structure diagram of G2-8 SH-bonded oligoglutamic acid according to one embodiment of the present invention;
FIG. 8 is a schematic representation of the molecular structure of G2-8SH polyamide-amine bonded hyaluronic acid according to one embodiment of the invention;
FIG. 9 is a schematic molecular structure diagram of a maleimide-modified oligoglutamic acid according to an embodiment of the present invention;
FIG. 10 is a schematic molecular structure diagram of a vinylsulfonyl-modified oligoglutamic acid according to an embodiment of the present invention;
FIG. 11 is a schematic representation of the molecular structure of a maleimide-modified low molecular weight hyaluronic acid according to one embodiment of the present invention;
fig. 12(1) is a schematic illustration of the use of the two-component cross-linked composite of the present invention to promote wound repair healing after medical plastic surgery, according to one embodiment of the present invention;
fig. 12(2) is a schematic illustration of wound repair healing after medical plastic surgery without the use of the two-component cross-linked composite material of the present invention, according to one embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention clearer, the present invention will be described in further detail with reference to the accompanying drawings, and it is apparent that the described embodiments are only a part of the embodiments of the present invention, not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
G2-8NH2Obtainment of polyamidoamine (starting material of first component):
G2-8NH2the polyamidoamine has 8 branched chains, each branched chain end contains an amino group, the molecular structure is shown in figure 1, the generation number: g2 (second generation) available from wechen molecular new materials limited.
Example 2
G3-16NH2Obtaining of Polyamide-amine (starting Material of first component)
G3-16NH2The polyamide-amine has 16 branches, each branch end contains an amino active group, the molecular structure is shown in figure 2, the generation number is as follows: g3 (third generation) available from wechen molecular new materials limited.
Example 3-1
Obtaining hyaluronic acid (first component raw material)
Hyaluronic acid, average molecular weight 200000-400000 daltons, purchased from Huaxi biotechnology limited.
Examples 3 to 2
Obtaining of Low molecular weight sodium hyaluronate (second component raw material)
(1) Dissolving 20-50 parts by mass of sodium hyaluronate (with a molecular weight of 200000-400000 daltons and purchased from Huaxi Biotechnology Limited) in 1000 parts by mass of purified water;
(2) carrying out high-temperature high-pressure reaction on the solution at the temperature of 121 ℃ for 30-180 min;
(3) cooling the solution after the high-temperature and high-pressure reaction, and dialyzing by using a dialysis bag with the molecular weight cut-off of about 6000 to remove hyaluronic acid with the molecular weight less than 6000;
(4) finally, the hyaluronic acid was freeze-dried by a vacuum freezer to obtain a white porous fluffy hyaluronic acid with a low molecular weight, and the molecular structure is shown in FIG. 3.
Example 4
Obtaining of low molecular weight polyglutamic acid (first, second component raw material)
(1) Dissolving 20-50 parts by mass of polyglutamic acid (purchased from Huaxi Biotechnology Co., Ltd.) in 1000 parts by mass of purified water, and dissolving at 45-60 ℃ to form a solution;
(2) carrying out high-temperature high-pressure reaction on the solution at the temperature of 121 ℃ for 30-180 min;
(3) cooling the solution after the high-temperature and high-pressure reaction, and then dialyzing and purifying by using a dialysis bag with the molecular weight cutoff of about 4000 to remove polyglutamic acid with the molecular weight of less than 4000;
(4) finally, freeze-drying by a vacuum freezer to obtain the low molecular weight polyglutamic acid with white porous fluffy appearance, wherein the molecular structure is shown in figure 4.
Example 5
Preparation of G2-8SH polyamidoamine:
preparing main raw materials: g2-8NH from example 12Polyamidoamine, thiopropanoic acid (CAS number: 107-96-0), N' -Dicyclohexylcarbodiimide (DCC) (CAS number: 538-75-0), 1-Hydroxybenzotriazole (HOBT) (CAS number: 2592-95-2).
The preparation principle is as follows: the thiopropanoic acid has carboxyl in its molecular structure, and the carboxyl can react with G2-8NH under the catalytic action of DCC and HOBT catalysts2The amido on the polyamide-amine is chemically reacted to generate amido bond (-CO-NH-), and G2-8SH polyamide-amine with each branch end containing a thiol active group is generated.
The preparation process comprises the following steps:
(1) dissolving 135 parts by mass of thiopropanoic acid in 2000 parts by mass of solvent N, N-Dimethylformamide (DMF);
(2) continuously adding 60-90 parts by mass of G2-8NH2Polyamide-amine, stirring and dissolving;
(3) respectively adding 10-25 parts by mass of DCC and 10-25 parts by mass of HOBT, and stirring for dissolving to form a mixed solution;
(4) continuously reacting the mixed solution at the temperature of 0-20 ℃ for 12-72 h to generate G2-8SH polyamide-amine;
(5) purifying G2-8SH polyamide-amine by adopting a separation-redissolution-separation mode repeatedly, wherein a separation solvent is ethanol or isopropanol, and a redissolution solvent is purified water;
(6) and (3) redissolving the purified G2-8SH polyamide-amine, and removing residual water and residual alcohol by using a vacuum freeze dryer to obtain the G2-8SH polyamide-amine high molecular compound.
The G2-8SH polyamide-amine has 8 branched chains, each branched chain end contains a thiol group active group, the appearance of the polyamide-amine is white, porous and fluffy, the polyamide-amine is easy to dissolve in water, and the molecular structure is shown in figure 5.
Example 6
Preparation of G3-16SH polyamidoamine:
preparing main raw materials: g3-16NH from example 12Polyamidoamine, thiopropanoic acid (CAS number: 107-96-0), N' -Dicyclohexylcarbodiimide (DCC) (CAS number: 538-75-0), 1-Hydroxybenzotriazole (HOBT) (CAS number: 2592-95-2).
The preparation principle is as follows: the thiopropanoic acid has carboxyl in its molecular structure, and the carboxyl can react with G3-16NH under the catalytic action of DCC and HOBT catalysts2The amido on the polyamide-amine is chemically reacted to generate amido bond (-CO-NH-), and G3-16SH polyamide-amine with each branch end containing a thiol active group is generated.
The preparation process comprises the following steps:
(1) mixing 135 parts by mass of thiopropanoic acid, 20 parts by mass of 2-amino-3-mercaptopropionic acid and 2000 parts by mass of solvent N, N-Dimethylformamide (DMF), stirring and dissolving;
(2) continuously adding 50-75 parts by mass of G3-16NH2Polyamide-amine, stirring and dissolving;
(3) respectively adding 20-40 parts by mass of DCC and 15-30 parts by mass of HOBT, and stirring for dissolving to form a mixed solution;
(4) continuously reacting the mixed solution at the temperature of 0-20 ℃ for 18-72 h to generate G3-16SH polyamide-amine;
(5) purifying G3-16SH polyamide-amine by dialysis, wherein the cut-off molecular weight of a dialysis bag is 2000 daltons;
(6) vacuum freeze-drying to obtain G3-16SH polyamide-amine compound.
G3-16SH polyamidoamine has 16 branches, each branch end contains a thiol group active group, the appearance of the polyamidoamine is porous and fluffy, and the molecular structure is shown in figure 6.
Example 7
Preparation of G2-8SH polyamidoamine-bonded hyaluronic acid
1. First, a trace amount of maleimide-modified hyaluronic acid was prepared:
preparing main raw materials: hyaluronic acid, 1, 6-hexanediamine (CAS number: 124-09-4), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl), maleimidocaproic acid succinimidyl ester (CAS number: 55750-63-5) of example 3.
The preparation principle is as follows: firstly, under the action of a catalyst, an amino group on the 1, 6-hexamethylene diamine and a carboxyl group on the hyaluronic acid are subjected to chemical reaction, and a trace amount of amino groups are further input. Secondly, the amino group on the modified hyaluronic acid and maleimide caproic acid succinimide ester generate nucleophilic substitution reaction in an organic solvent, and maleimide group is modified on the hyaluronic acid to form the maleimide group modified hyaluronic acid.
The preparation process comprises the following steps:
(1) dissolving 30 parts by mass of hyaluronic acid in 1000 parts by mass of purified water, and stirring for dissolving;
(2) continuously adding 4 parts by mass of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), and activating for 15 min;
(3) adding 4 parts by mass of 1, 6-hexanediamine, stirring, dissolving and reacting for 1-3 h;
(4) dialyzing and purifying the reacted solution by a dialysis bag with molecular weight cutoff of about 8000 daltons;
(5) freeze-drying with a vacuum freezer to obtain amino-modified hyaluronic acid with fluffy appearance;
(6) dissolving 30 parts by mass of hyaluronic acid in the step (5) and 3 parts by mass of triethylamine in 1000 parts by mass of a mixed solvent of dimethyl sulfoxide and dichloromethane, adding 4 parts by mass of maleimide caproic acid succinimide ester, and reacting at room temperature for 24 hours;
(7) dialyzing and purifying by using a dialysis bag with the molecular weight cutoff of about 8000 Dalton, and freeze-drying by using a vacuum freezer to generate trace maleimide modified hyaluronic acid.
2. Next, G2-8SH polyamide-amine bound hyaluronic acid was prepared:
preparing main raw materials: g2-8SH polyamidoamine of example 5, and a trace amount of maleimide-modified hyaluronic acid of this example.
The preparation principle is as follows: one thiol group (-SH) on the G2-8SH polyamide-amine reacts with a small amount of maleimide groups on the maleimide group modified hyaluronic acid to bond the G2-8SH polyamide-amine on the hyaluronic acid, so that the G2-8SH polyamide-amine bonded hyaluronic acid is generated.
The preparation process comprises the following steps:
(1) dissolving 40 parts by mass of G2-8SH polyamide-amine in 1000 parts by mass of purified water, stirring and dissolving to form a solution, adjusting the pH value to 8.5, and maintaining the temperature of the solution at 8-16 ℃;
(2) dissolving 50 parts by mass of trace maleimide-modified hyaluronic acid in 1000 parts by mass of purified water to form a solution, adjusting the pH value of the solution to 9.0, and maintaining the temperature of the solution at 8-16 ℃;
(3) dropwise adding the solution obtained in the step (2) into the solution obtained in the step (1) while stirring, and reacting for 2.0 h;
(4) after the reaction is finished, dialyzing and purifying by adopting a dialysis bag with molecular weight cutoff of about 8000 Dalton;
(5) lactose and mannitol were added after purification, and then freeze-dried with a vacuum freezer to obtain G2-8SH polyamidoamine-bonded hyaluronic acid with porous fluffy appearance, which is easily soluble in water and has a molecular structure as shown in fig. 7.
Example 8
Preparation of G2-8SH polyamidoamine-bonded oligoglutamic acid
1. First, a trace amount of maleimide-modified oligoglutamic acid was prepared:
preparing main raw materials: oligomeric glutamic acid (average molecular weight about 7500), 1, 6-hexanediamine (CAS number: 124-09-4), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl), maleimidocaproic acid succinimidyl ester (CAS number: 55750-63-5) of example 3.
The preparation principle is as follows: firstly, under the action of a catalyst, monoamino on 1, 6-hexamethylene diamine and carboxyl on oligoglutamic acid are subjected to chemical reaction, and then a trace amount of amino is bonded on the oligoglutamic acid. Secondly, the amino group on the modified oligoglutamic acid and maleimide caproic acid succinimidyl ester generate nucleophilic substitution reaction in an organic solvent, and maleimide group is modified on the oligoglutamic acid to form the maleimide group modified oligoglutamic acid.
The preparation process comprises the following steps:
(1) dissolving 50 parts by mass of oligoglutamic acid (average molecular weight of about 7500) in 1000 parts by mass of purified water, and stirring to dissolve;
(2) continuously adding 4 parts by mass of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), and activating for 15 min;
(3) adding 4 parts by mass of 1, 6-hexanediamine, stirring, dissolving and reacting for 1-3 h;
(4) dialyzing and purifying the solution after reaction by using a dialysis bag with molecular weight cutoff of about 3500 daltons;
(5) after purification, freeze-drying by using a vacuum freezer to obtain amino-modified oligoglutamic acid with fluffy appearance;
(6) dissolving 50 parts by mass of the oligoglutamic acid obtained in the step (5) in 1000 parts of a dimethyl sulfoxide/dichloromethane mixed solvent, adding 4.5 parts by mass of maleimide caproic acid succinimide ester, and reacting at room temperature for 24 hours;
(7) after the reaction is finished, dialysis purification is carried out by adopting a dialysis bag with the molecular weight cutoff of about 3500 Dalton, and freeze drying is carried out by using a vacuum freezer, so that trace maleimide modified oligoglutamic acid is generated.
2. Next, G2-8SH polyamide-amine bonded oligoglutamic acid was prepared:
preparing main raw materials: g2-8SH polyamidoamine of example 5, a trace amount of maleimide-modified oligoglutamic acid of this example.
The preparation principle is as follows: one thiol group (-SH) on the G2-8SH polyamide-amine reacts with a maleimide group on a trace amount of maleimide group modified oligoglutamic acid to bond the G2-8SH polyamide-amine on the oligoglutamic acid, so that the G2-8SH polyamide-amine bonded oligoglutamic acid is generated.
The preparation process comprises the following steps:
(1) dissolving 40 parts by mass of G2-8SH polyamide-amine in 1000 parts by mass of purified water, stirring and dissolving to form a solution, adjusting the pH value to 8.5, and maintaining the temperature of the solution at 8-16 ℃;
(2) dissolving 60 parts by mass of trace maleimide-modified oligoglutamic acid in 1000 parts by mass of water to form a solution, adjusting the pH value of the solution to 9.0, and maintaining the temperature of the solution at 8-16 ℃;
(3) dropwise adding the solution obtained in the step (2) into the solution obtained in the step (1) while stirring, and reacting at room temperature for 2.0 h;
(5) after the reaction is finished, dialyzing and purifying by using a dialysis bag with molecular weight cutoff of about 3500 daltons;
(6) lactose and mannitol were added after purification, and then freeze-dried with a vacuum freezer to obtain G2-8SH polyamidoamine-bonded hyaluronic acid with porous fluffy appearance, which is easily soluble in water and has a molecular structure as shown in fig. 8.
Example 9
Vinylsulfonyl modified oligoglutamic acid (second component)
Preparing main raw materials: divinyl sulfone (DVS, CAS number: 77-77-0), 3-thiol-1-propanol (CAS number: 19721-22-3), dicyclohexylcarbodiimide (DCC, CAS number: 538-75-0).
The preparation principle is as follows: first, vinylsulfonyl-modified propanol is formed by reacting vinylsulfone with 3-thiol-1-propanol. Secondly, the hydroxyl on the vinyl sulfonyl modified propanol and the carboxyl on the oligomeric glutamic acid are subjected to esterification reaction under the action of a catalyst Dicyclohexylcarbodiimide (DCC) and a dehydrating agent and a catalyst 4-dimethylaminopyridine p-methylbenzenesulfonic acid (DPTS), so that the vinyl sulfonyl is modified on the oligomeric glutamic acid.
The preparation process comprises the following steps:
(1) dissolving 50 parts by mass of vinyl sulfone (DVS) in 200 parts by mass of DMSO under the protection of nitrogen;
(2) adding 15-25 parts by mass of 3-thiol-1-propanol, stirring and dissolving, and reacting for 5-10 hours in a dark place;
(3) dissolving 30 parts by mass of oligoglutamic acid (average molecular weight of about 7500) in 1000 parts by mass of anhydrous DMSO, adding 15-30 parts by mass of Dicyclohexylcarbodiimide (DCC) and 5 parts by mass of 4-dimethylaminopyridine p-methylbenzenesulfonic acid (DPTS) catalyst, and stirring and dissolving to form a mixed solution;
(4) adding the mixed solution obtained in the step (3) into the mixed solution obtained in the step (2), and reacting for 16-48 h in a dark place in a nitrogen atmosphere;
(5) after the reaction is finished, filtering to remove a byproduct Dicyclohexylurea (DCU), and dialyzing and purifying by adopting a dialysis bag with the molecular weight cutoff of about 2000 daltons;
(6) and adding lactose and mannitol after purification, and then carrying out freeze drying by using a vacuum freezer to obtain the vinylsulfonyl modified oligomeric polyglutamic acid multi-site cross-linking agent which is porous and fluffy in appearance and is easy to dissolve in water.
Wherein, the preparation method of the 4-dimethylaminopyridine p-methylbenzene sulfonic acid (DPTS) catalyst comprises the following steps: boiling and distilling 10 parts by mass of p-toluenesulfonic acid (PTSA) and 250 parts by mass of toluene to remove moisture; 6.5 parts by mass of 4-Dimethylaminopyridine (DMAP) are dissolved in 70 parts by mass of hot toluene (60-80 ℃); adding the hot 4-dimethylaminopyridine solution into a p-toluenesulfonic acid solution, stirring and reacting for 4-8 hours at the temperature of 65 ℃, then cooling and filtering; then recrystallizing with dichloroethane solvent to obtain the 4-dimethylamino pyridine p-methyl benzene sulfonic acid (DPTS) with white needle-shaped appearance.
Example 10
Maleimido-modified oligoglutamic acid
Preparing main raw materials: 1, 6-hexanediamine (CAS number: 124-09-4), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl), maleimidocaproic acid succinimidyl ester (CAS number: 55750-63-5).
The preparation principle is as follows: firstly, under the action of a catalyst, an amino group on 1, 6-hexamethylene diamine chemically reacts with a carboxyl group on the oligoglutamic acid, and then a certain amount of amino group is bonded on the oligoglutamic acid. Secondly, the amino group on the modified oligoglutamic acid and maleimide caproic acid succinimidyl ester generate nucleophilic substitution reaction in an organic solvent, and maleimide group is modified on the oligoglutamic acid to form the maleimide group modified oligoglutamic acid.
The preparation process comprises the following steps:
(1) dissolving 50 parts by mass of oligoglutamic acid (average molecular weight of about 7500) in 1000 parts by mass of purified water, and stirring to dissolve;
(2) continuously adding 10 parts by mass of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), and activating for 20 min;
(3) adding 12 parts by mass of 1, 6-hexanediamine, stirring, dissolving and reacting for 1-3 h;
(4) dialyzing and purifying the solution after reaction by using a dialysis bag with molecular weight cutoff of about 3500 daltons;
(5) and (3) carrying out freeze drying by using a vacuum freezer to obtain fluffy amino-modified oligoglutamic acid.
(6) Dissolving 40 parts by mass of the oligoglutamic acid obtained in the step (5) in 500 parts by mass of a dimethyl sulfoxide/dichloromethane mixed solvent, adding 12 parts by mass of maleimide caproic acid succinimide ester, and reacting at room temperature for 24-48 h;
(7) dialyzing and purifying by using a dialysis bag with molecular weight cutoff of about 3500 Dalton, and freeze-drying by using a vacuum freezer to obtain the maleimide-modified oligoglutamic acid.
Example 11
Preparation of maleimide modified low molecular weight hyaluronic acid
Preparing main raw materials: low molecular weight hyaluronic acid of example 3 (average molecular weight about 8000), 1, 6-hexanediamine (CAS No. 124-09-4), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (edc. hcl), maleimidocaproic acid succinimidyl ester (CAS No. 55750-63-5).
The preparation principle is as follows: firstly, under the action of a catalyst, an amino group on 1, 6-hexamethylene diamine and a carboxyl group on low molecular weight hyaluronic acid are subjected to chemical reaction, and then a certain amount of amino groups are bonded on the low molecular weight hyaluronic acid. Secondly, the amino group on the modified low molecular weight hyaluronic acid and maleimide caproic acid succinimide ester generate nucleophilic substitution reaction in an organic solvent, and maleimide group is modified on the low molecular weight hyaluronic acid to form the maleimide group modified low molecular weight hyaluronic acid.
The preparation process comprises the following steps:
(1) dissolving 50 parts by mass of low molecular weight hyaluronic acid (average molecular weight about 8000) in 1000 parts by mass of purified water, and stirring for dissolution;
(2) continuously adding 12 parts by mass of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), and activating for 20 min;
(3) adding 12 parts by mass of 1, 6-hexanediamine, stirring, dissolving and reacting for 1-3 h;
(4) dialyzing and purifying the solution after reaction by using a dialysis bag with molecular weight cutoff of about 3500 daltons;
(5) and (3) carrying out freeze drying by using a vacuum freezer to obtain fluffy amino modified low-molecular-weight hyaluronic acid.
(6) And (3) dissolving 50 parts by mass of the low molecular weight hyaluronic acid obtained in the step (5) in 1000 parts of a dimethyl sulfoxide/dichloromethane mixed solvent, adding 15 parts by mass of maleimide caproic acid succinimide ester, and reacting at room temperature for 24-48 h.
(7) Dialyzing and purifying by using a dialysis bag with molecular weight cut-off of about 3500 Dalton, and freeze-drying by using a vacuum freezer to obtain the maleimide modified low-molecular-weight hyaluronic acid.
Example 12
Preparation of bi-component cross-linked composite material applied to plastic surgery, application of bi-component cross-linked composite material to fresh pig muscle tissue and performance detection of bi-component cross-linked composite material
1. The preparation of the two-component cross-linked composite material for plastic surgery and the application thereof on fresh pig muscle tissue comprise the following steps:
s1: dissolving the first component in a first buffer solution to obtain a first component solution;
s2: dissolving the second component in a second buffer solution to obtain a second component solution;
s3: the first component solution is uniformly coated or sprayed with a thin layer on the muscle tissue of a fresh pig, then the second component solution is uniformly covered on the muscle tissue of the fresh pig, and the first component and the second component are rapidly crosslinked in situ on the muscle tissue of the fresh pig to form the double-component crosslinked composite material.
2. A performance test of a two-component cross-linked composite material prepared for plastic surgery on fresh pig muscle tissue comprises the following steps:
in-situ gelling time, the test method comprises the following steps:
the method comprises the following steps:
s1: weighing 100g of the first component solution by using a 200mL beaker, and rapidly stirring the first component solution by using a magnetic stirrer (the rotating speed is 200-400 rpm) to form an obvious vortex;
s2: weighing 25g of the second component solution by using a 100mL beaker, quickly pouring the second component solution into the first component solution at one time, and immediately timing by using a stopwatch;
s3: when the fixed two-component cross-linked composite was formed in the beaker, the gel formation time was timed and recorded, and the criteria for forming the fixed two-component cross-linked composite were: the vortex of the solution in the beaker disappears, the mixed solution does not rotate along with the stirring, or the magnetic stirrer is obviously prevented from rotating or loses the stirring and mixing effect on the mixed system, namely the timing end point.
Remarking: since the two-component crosslinked composite is formed in a short time, the second component solution should be added to the first component solution at the same time as the first component solution is accurately timed.
The method 2 comprises the following steps:
s1: shearing fresh pig muscle tissue with the area of about 4cm x 4cm, and smearing or spraying a thin layer of first component solution on the fresh pig muscle tissue;
s2: coating or spraying a thin layer of the second component solution on the fresh pig muscle tissue, and using a stopwatch to time;
s3: and (3) suspending and turning the fresh pig muscle tissue for 180 ℃ while spraying the second component, and observing whether an obvious double-component cross-linked composite material layer is formed on the fresh pig muscle tissue, wherein the double-component cross-linked composite material does not flow, is fixed in shape and seals the fresh pig muscle tissue. And (4) judging the standard: the double-component cross-linked composite material layer does not flow, the shape is fixed, the fresh pig muscle tissue is sealed, and the gelling time of the first component solution and the second component solution is less than or equal to 1 s.
(2) A test method for adhesion testing of two-component cross-linked composites for use in orthopedic surgery:
s1: shearing fresh pig muscle tissue with the area of about 4cm x 4cm, and smearing or spraying a thin layer of the first component solution on the fresh pig muscle tissue;
s2: coating or spraying a layer of second component solution on the fresh pig muscle tissue to form a bi-component cross-linked composite material in situ;
s3: horizontally placing a weight of 100-250 g on the fresh pig muscle tissue, horizontally pulling the weight by using a spring tension meter, enabling the tension meter to generate and display a tensile force which is more than or equal to 240N, and observing whether the double-component cross-linked composite material layer on the fresh pig muscle tissue shifts or translocates.
(3) A test method for the sealing performance of a two-component cross-linked composite material layer applied to plastic surgery on fresh pig muscle tissues comprises the following steps:
s1: shearing fresh pig muscle tissue with the area of about 4cm x 4cm and the thickness of about 0.5cm, and pricking 8-16 needle holes on the fresh pig muscle tissue by using an injection needle so that water can freely pass through the needle holes;
s2: coating or spraying a first component solution thin layer on fresh pig muscle tissue, and coating or spraying a second component solution on the fresh pig muscle tissue to form a double-component cross-linked composite material layer;
s3: forming water pressure of 500 mm-600 mm on fresh pig muscle tissue;
s4: after 300s, it was observed whether there was significant water track penetrating the pig muscle tissue and dripping.
(4) Method for testing the displacement and wrinkle resistance of a two-component cross-linked composite on fresh porcine muscle tissue:
s1: cutting fresh pig muscle tissue with area of about 6cm x 4cm, and smearing or spraying a thin layer of first component solution on the fresh pig muscle tissue;
s2: coating or spraying a layer of second component solution on the fresh pig muscle tissue to form a bi-component cross-linked composite material in situ;
s3: the method comprises the following steps of flatly placing fresh pig muscle tissues, simultaneously applying appropriate force to the edges of the two ends in the length direction respectively to enable the fresh pig muscle tissues to form wrinkles, and removing the force after about 10 seconds to restore the fresh pig muscle tissues to a stretched state. After repeating the folding-unfolding process 10 times, observing the state of the bi-component cross-linked composite material on the fresh pig muscle tissue, comprising: whether the displacement occurs or not, whether the bi-component cross-linked composite material falls off or not and whether the falling proportion exists or not.
Example 12-1
S1: preparing a first component solution: g2-8SH polyamidoamine-bonded oligoglutamic acid of example 7, G2-8SH polyamidoamine-bonded hyaluronic acid of example 8 were dissolved in a phosphate buffer (pH of phosphate buffer is 7.9) to form first component solutions with mass contents of 0.8% and 1.2%, respectively;
s2: preparing a second component solution: dissolving the maleimide-modified oligoglutamic acid of example 9 and the maleimide-modified low-molecular-weight hyaluronic acid of example 11 in a phosphate buffer (pH of the phosphate buffer is 7.9) to form second component solutions having mass contents of 0.8% and 0.8%, respectively;
s3: the first component solution is uniformly coated or sprayed with a thin layer on the muscle tissue of a fresh pig, and then the second component solution is uniformly coated or sprayed on the muscle tissue of the fresh pig, so that the first component and the second component quickly form the double-component cross-linked composite material on the muscle tissue of the fresh pig in situ.
The bicomponent crosslinked composite was tested for in situ gel time, adhesion, blocking, and displacement and wrinkle resistance according to the test methods described.
Remarking: the concentrations of the first component solution and the second component solution of S1 and S2 marked by contents do not include lactose and mannitol which are auxiliary materials for freeze-drying.
Example 12-2
S1: preparing a first component solution: g2-8SH polyamidoamine-bonded oligoglutamic acid of example 7, G2-8SH polyamidoamine-bonded hyaluronic acid of example 8 were dissolved in a phosphate buffer (pH of the phosphate buffer was 8.3) to form first component solutions having mass contents of 1.2% and 1.2%, respectively;
s2: preparing a second component solution: dissolving the maleimide-modified oligoglutamic acid of example 9 and the maleimide-modified low-molecular-weight hyaluronic acid of example 11 in a phosphate buffer (pH of the phosphate buffer is 8.3) to form second component solutions having mass contents of 0.6% and 1.0%, respectively;
s3: the first component solution is uniformly coated or sprayed with a thin layer on the muscle tissue of a fresh pig, and then the second component solution is uniformly coated or sprayed on the muscle tissue of the fresh pig, so that the first component and the second component quickly form the double-component cross-linked composite material on the muscle tissue of the fresh pig in situ.
The bicomponent crosslinked composite was tested for in situ gel time, adhesion, blocking, and displacement and wrinkle resistance according to the test methods described.
Remarking: the concentrations of the first component solution and the second component solution of S1 and S2 marked by contents do not include lactose and mannitol which are auxiliary materials for freeze-drying.
Examples 12 to 3
S1: preparing a first component solution: g2-8SH polyamidoamine-bonded oligoglutamic acid of example 7, G2-8SH polyamidoamine-bonded hyaluronic acid of example 8 were dissolved in a phosphate buffer (pH of phosphate buffer is 7.9) to form first component solutions with mass contents of 0.8% and 1.2%, respectively;
s2: preparing a second component solution: dissolving the vinylsulfonyl-modified oligoglutamic acid of example 10 and the maleimide-modified low-molecular-weight hyaluronic acid of example 11 in a phosphate buffer (pH of the phosphate buffer is 7.9) to form second component solutions having mass contents of 0.8% and 0.8%, respectively;
s3: uniformly coating or spraying a thin layer of the first component solution of S1 on the muscle tissue of a fresh pig, and uniformly coating or spraying the second component solution of S2 on the muscle tissue of the fresh pig, wherein the first component and the second component quickly form a two-component cross-linked composite material on the in-situ fresh muscle tissue of the pig.
The bicomponent crosslinked composite was tested for in situ gel time, adhesion, blocking, and displacement and wrinkle resistance according to the test methods described.
Remarking: the concentrations of the first component solution and the second component solution of S1 and S2 marked by contents do not include lactose and mannitol which are auxiliary materials for freeze-drying.
Examples 12 to 4
S1: preparing a first component solution: g2-8SH polyamidoamine-bonded oligoglutamic acid of example 7, G2-8SH polyamidoamine-bonded hyaluronic acid of example 8 were dissolved in a phosphate buffer (pH of the phosphate buffer was 8.3) to form first component solutions having mass contents of 1.2% and 1.2%, respectively;
s2: preparing a second component solution: dissolving the vinylsulfonyl-modified oligoglutamic acid of example 10 and the maleimide-modified low-molecular-weight hyaluronic acid of example 11 in a phosphate buffer (pH of the phosphate buffer is 8.3) to form second component solutions having mass contents of 0.6% and 1.0%, respectively;
s3: uniformly coating or spraying a thin layer of the first component solution of S1 on the muscle tissue of a fresh pig, and uniformly coating or spraying the second component solution of S2 on the muscle tissue of the fresh pig, wherein the first component and the second component quickly form a two-component cross-linked composite material on the in-situ fresh muscle tissue of the pig.
The bicomponent crosslinked composite was tested for in situ gel time, adhesion, blocking, and displacement and wrinkle resistance according to the test methods described.
Remarking: the concentrations of the first component solution and the second component solution of S1 and S2 marked by contents do not include lactose and mannitol which are auxiliary materials for freeze-drying.
The results of the in situ gel formation time, adhesion, blocking, displacement resistance and wrinkle resistance tests for 4 different orthopaedic two-component crosslinked composites are given in tables 1, 2, 3 and 4 below.
TABLE 1 Bi-component crosslinked composites in situ formation time data sheet
As shown in the table 1 of the data table of the in-situ formation time of the two-component crosslinked composite material, the formation time of the 4 different two-component crosslinked composite materials on the muscle tissue of the fresh pig is less than or equal to 1s when the 4 different two-component crosslinked composite materials in the examples 12-1 to 12-4 are coated or sprayed on the muscle tissue of the fresh pig, which indicates that the two-component crosslinked composite material of the present invention can be rapidly formed on the wound in situ.
TABLE 2 adhesion test results for two-component crosslinked composites
| Examples | tension/N | Displacement and translocation No |
| 12-1 | 280 | Whether or not |
| 12-2 | 275 | Whether or not |
| 12-3 | 278 | Whether or not |
| 12-4 | 282 | Whether or not |
As shown in the adhesion test results of the two-component crosslinked composite material in Table 2, the adhesion test results of the two-component crosslinked composite materials of examples 10-1 to 10-4 showed that the 4 different two-component crosslinked composite materials of examples 10-1 to 10-4 did not shift or translocate on the muscle tissue of fresh pigs under the tensile force of 240N or more, indicating that the two-component crosslinked composite material layer of the present invention has good adhesion.
TABLE 3 blocking test results for two-component crosslinked composites
| Examples | Hydrostatic pressure | Time of day | Sealing property |
| 12-1 | 500mm | 300s | Without leakage |
| 12-2 | 510mm | 300s | Without leakage |
| 12-3 | 515mm | 300s | Without leakage |
| 12-4 | 520mm | 300s | Without leakage |
As shown in the results of the two-component cross-linked composite sealing test in Table 3, it can be seen that the water pressure of about 500mm is formed on the fresh pig muscle tissue when the 4 different two-component cross-linked composites in examples 12-1 to 12-4 are coated or sprayed on the fresh pig muscle tissue, and no water leakage is found, indicating that the two-component cross-linked composite of the present invention has good sealing performance.
TABLE 4 displacement and wrinkle resistance test results for two-component crosslinked composites
As shown in the test results of the displacement resistance and the wrinkle resistance of the two-component cross-linked composite material in Table 3, the results of the wrinkle resistance test of the two-component cross-linked composite material of the invention, which are applied or sprayed on the muscle tissue of fresh pigs, of 4 different two-component cross-linked composite materials in examples 12-1 to 12-4, show that the two-component cross-linked composite material of the invention has good displacement resistance and wrinkle resistance on the muscle tissue of fresh pigs.
Example 13
Application of bi-component cross-linked composite material in protecting wound surface and promoting wound surface healing after plastic surgery
Test groups:
s1: preparing a first component solution: the irradiation sterilized G2-8SH polyamidoamine-bonded oligoglutamic acid of example 7 and G2-8SH polyamidoamine-bonded hyaluronic acid of example 8 were dissolved in a phosphate buffer (pH of the phosphate buffer was 8.3) to form first component solutions with mass contents of 1.6% and 1.2%, respectively, for use;
s2: preparing a second component solution: the vinyl sulfonyl group-modified oligoglutamic acid of example 10 and the maleimide group-modified low molecular weight hyaluronic acid of example 11, which were subjected to radiation sterilization, were dissolved in a phosphate buffer (pH of the phosphate buffer was 8.3) to form second component solutions having mass contents of 0.6% and 1.2%, respectively, for use;
s3: in medical double-fold eyelid operation (an orthopedic surgery), before the wound surface is sutured, a thin layer of the first component solution of S1 is uniformly coated or sprayed on the debrided postoperative wound surface, and then the second component solution of S2 is uniformly covered on the wound surface to quickly form a two-component cross-linked composite material on the wound surface in situ, so that the wound surface is sealed, isolated and protected. After the wound surface is sutured, the first component solution of S1 is uniformly coated or sprayed with a thin layer on the postoperative sutured wound surface, and then the second component solution of S2 is uniformly covered on the postoperative sutured wound surface to quickly form a bi-component cross-linked composite material in situ, so that the sutured wound surface is sealed, isolated and protected.
S4: after 7 days of the operation, the wound healing after the operation was observed, and the results are shown in fig. 12 (1).
Control group:
the wound surface is not treated with the double-component cross-linked medical composite material of the invention, but is treated according to the traditional post-operation treatment method.
Fig. 12(1) is a schematic diagram of promoting wound healing after a medical plastic operation by using the two-component cross-linked composite material of the present invention, as shown in fig. 12(1), the use of the two-component cross-linked composite material of the present invention shows an obvious effect of promoting wound healing, and the wound surface benefits from the physical sealing and protecting effect of the two-component cross-linked composite material, and the hyaluronic acid of the two-component cross-linked composite material forms a promoting and repairing effect, an anti-adhesion effect, and the like on the wound surface, so that the wound surface after the operation is well healed, and is beautiful, and postoperative complications such as redness, swelling, inflammation, and the like do not occur. Fig. 12(2) is a schematic diagram of wound repair and healing after medical plastic surgery without using the two-component cross-linked composite material of the present invention, as shown in fig. 12(2), the wound repair and healing are slow due to the fact that the wound is not timely and properly sealed and protected by adopting a traditional post-operative treatment method, and severe red swelling, inflammation, pain and other phenomena occur.
While the principles of the invention have been described in detail in connection with the preferred embodiments thereof, it will be understood by those skilled in the art that the foregoing embodiments are merely illustrative of exemplary implementations of the invention and are not limiting of the scope of the invention. The details of the embodiments are not to be interpreted as limiting the scope of the invention, and any obvious changes, such as equivalent alterations, simple substitutions and the like, based on the technical solution of the invention, can be interpreted without departing from the spirit and scope of the invention.
Claims (10)
1. A two-component cross-linked composite material for use in orthopedic surgery comprising a first component comprising a thiol-terminated polyamidoamine-bonded hyaluronic acid and a thiol-terminated polyamidoamine-bonded oligoglutamic acid, said first component having branches each containing a thiol group, and a second component comprising a modified oligoglutamic acid multi-site cross-linking agent and a modified low molecular weight hyaluronic acid polysaccharide cross-linking agent.
2. The two-component cross-linked composite material for orthopedic applications according to claim 1, wherein said thiol-terminated polyamidoamine-bonded hyaluronic acid is formed by chemically bonding thiol-terminated polyamidoamine with hyaluronic acid, wherein the number of the polyamidoamine molecules bonded to each hyaluronic acid is at least 20, said thiol-terminated polyamidoamine has 8 or 16 branches, and each branch end contains a thiol group.
3. The two-component crosslinked composite material for orthopedic applications according to claim 1, characterized in that the thiol-terminated polyamidoamine-linked oligoglutamic acid is formed by bonding thiol-terminated polyamidoamine to oligoglutamic acid via an amide bond (-CH-NH-).
4. The two-component crosslinked composite material for orthopedic applications according to claim 3, wherein the molecular weight of the oligoglutamic acid is 4000 to 40000 daltons.
5. The two-component crosslinked composite material for orthopedic applications according to claim 2, wherein the molecular weight of the hyaluronic acid is 150000 to 50000 daltons.
6. The two-component crosslinked composite material for orthopedic applications according to claim 1, wherein the second-component modified oligoglutamic acid multi-site crosslinking agent is a vinylsulfonyl-modified oligoglutamic acid or a maleimide-modified oligoglutamic acid, and the second-component modified low-molecular-weight hyaluronic acid polysaccharide crosslinking agent is a maleimide-modified low-molecular-weight hyaluronic acid.
7. The two-component cross-linked composite material for orthopedic applications according to claim 6, wherein the low molecular weight hyaluronic acid has a molecular weight of 6000 to 50000 daltons.
8. A method for preparing a two-component cross-linked composite material for use in orthopaedic applications according to any of claims 1 to 7, comprising the steps of:
s1: dissolving the first component in a first component buffer solution to obtain a first component solution;
s2: dissolving the second component in a second component buffer solution to obtain a second component solution;
s3: and uniformly mixing the first component solution and the second component solution to form the double-component cross-linked medical composite material.
9. The method of claim 8, wherein the pH of the first component buffer is 7.5 to 9.0, and the pH of the second component buffer is 7.5 to 9.0.
10. The method of claim 8, wherein the first component solution has a first component concentration of 1.0-2.5% by mass, and the second component solution has a second component concentration of 0.8-3.0% by mass.
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| CN113999630B (en) * | 2021-09-24 | 2023-11-28 | 广东省科学院健康医学研究所 | Adhesive, and preparation method and application thereof |
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