CN114712550B - Hydrogel adhesive capable of being injected for rapid hemostasis and preparation method and application thereof - Google Patents

Hydrogel adhesive capable of being injected for rapid hemostasis and preparation method and application thereof Download PDF

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CN114712550B
CN114712550B CN202210416401.XA CN202210416401A CN114712550B CN 114712550 B CN114712550 B CN 114712550B CN 202210416401 A CN202210416401 A CN 202210416401A CN 114712550 B CN114712550 B CN 114712550B
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chitosan
hydrogel
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polysaccharide
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CN114712550A (en
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臧剑锋
杨月莹
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Huazhong University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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    • A61L24/001—Use of materials characterised by their function or physical properties
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
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    • 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
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/104—Gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
    • C08H1/00—Macromolecular products derived from proteins
    • 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
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
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    • 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
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
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    • 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
    • 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
    • A61L2400/06—Flowable or injectable implant compositions

Abstract

The invention belongs to the technical field of medical high polymer materials, and discloses an injectable rapid hemostasis hydrogel adhesive, a preparation method and application thereof, wherein a precursor of the injectable rapid hemostasis hydrogel adhesive comprises a first component and a second component, and the first component simultaneously comprises a chitosan component and a polyacrylic acid hydrogel component; the second component simultaneously comprises non-aldehydized polysaccharide, dialdehyde polysaccharide and cationic salt solution; the first component and the second component can be crosslinked in situ by Schiff base reaction after being mixed to form hydrogel, and can be used as hydrogel adhesive for rapid hemostasis. The hydrogel adhesive based on two components is obtained by improving the components of the hydrogel adhesive and the precursor thereof, has the characteristics of injectability and quick gelling, has no requirements on the position and the shape of a wound surface in the using process, and can effectively overcome the difficulty of the existing hemostatic material in hemostasis of wounds with irregular shapes and irrepressibility.

Description

Hydrogel adhesive capable of being injected for rapid hemostasis and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medical high polymer materials, and particularly relates to an injectable rapid hemostasis hydrogel adhesive, and a preparation method and application thereof.
Background
Controlling wound bleeding is a very important issue, with over 30% of all traumatic deaths worldwide being caused by uncontrolled blood loss, with over half of the deaths occurring before first aid arrives. Rapid and effective hemostasis of irregularly shaped, incompressible wounds is also a great challenge in surgery. Excessive blood loss can lead to hypotension, impaired organ function and even death.
The existing hemostatic materials comprise gauze, medical sponge, hemostatic gel and hemostatic powder. Gauze and medical sponge promote the coagulation of the body itself by absorbing a large amount of liquid components in blood, thereby increasing the concentration of coagulation factors at the wound. The existing gauze and medical sponge are also based on polysaccharide, and the chitosan or cellulose can promote the aggregation of red blood cells and blood platelets to accelerate the hemostasis speed. However, gauze and medical sponge cannot adhere to biological tissues, so that compression-assisted hemostasis is required, which is not suitable for hemostasis of many irregular shapes in vivo and wounds which cannot be compressed, and wounds which have continuous bleeding subsequently. The hemostatic gel is mainly medical hydrogel adhesive, achieves the aim of hemostasis by adhering to tissues to form a physical shielding layer, but a great amount of blood of a bleeding wound can weaken the adhesion of the hydrogel and the tissues, so that a good hemostatic effect cannot be achieved. The existing hemostatic powder mainly achieves the purpose of rapid hemostasis by absorbing liquid components in blood, improving the concentration of blood coagulation factors at wounds and gathering red blood cells and blood platelets, can be used for hemostasis of wounds which are irregular in shape and not pressed, but has poor adhesion with tissues, is easy to wash away, and is easy to remain in vivo to cause inflammatory reaction, thereby influencing wound healing.
Chinese patent literature discloses an injectable tissue adhesive hemostasis modified chitosan material, hydrogel thereof and a preparation method thereof, and the application publication number is CN201911171070.2. The invention relates to an injectable tissue adhesive hemostasis modified chitosan material, which is prepared by taking chitosan as a base material, alkaline activating hydroxymethyl on the chitosan to graft 1, 2-butylene oxide to obtain temperature-sensitive injectable hydroxybutyl chitosan, and activating amino on the hydroxybutyl chitosan by using an EDC/NHS composite activator to react with carboxyl on 3, 4-dihydroxyphenylacetic acid to obtain a catechol-hydroxybutyl modified chitosan material.
Chinese patent CN 11040404083A discloses an injectable hydrogel material and a preparation method and application thereof, and although the injectable hydrogel material is also disclosed to react with an auxiliary cross-linking agent and an aldehydized contrast agent based on carboxymethyl chitosan, dialdehyde polysaccharide and an auxiliary cross-linking agent, the injectable hydrogel only depends on the reaction of the carboxymethyl chitosan and a dynamic Schiff base of the dialdehyde polysaccharide to form gel, and the problem of low strength still exists, and the carboxymethyl chitosan has the problem of rapid disintegration after being completely swelled in vivo due to good water solubility.
Disclosure of Invention
In view of the above drawbacks or needs for improvement in the prior art, the present invention provides an injectable hydrogel adhesive capable of rapidly stopping bleeding, and a preparation method and an application thereof, wherein the hydrogel adhesive and a precursor thereof are improved in composition, and a two-component hydrogel adhesive is obtained by using a hemostatic powder (first component) and a hemostatic adhesive (second component) with specific components, and has the characteristics of injectability and rapid gel formation; moreover, the hydrogel adhesive is based on hemostatic powder (a first component) and hemostatic glue (a second component), is a hemostatic material compounded by hemostatic powder and hemostatic gel, has no requirements on wound position and shape in the using process, and can effectively overcome the difficulty of the existing hemostatic material in hemostasis of wounds with irregular shapes and irrepressibility. In addition, the hydrogel adhesive can also be used as a drug carrier to play a role of slowly releasing drugs.
To achieve the above objects, according to one aspect of the present invention, there is provided an injectable rapid hemostatic hydrogel adhesive precursor, characterized by comprising a first component and a second component, wherein,
the first component simultaneously comprises a chitosan component and a polyacrylic acid hydrogel component, wherein the chitosan component is selected from chitosan, chitosan derivatives, cellulose and chitin; the main body of the polyacrylic acid hydrogel component is polyacrylic acid hydrogel, polyacrylamide hydrogel or poly N-isopropyl acrylamide hydrogel, and the polyacrylic acid hydrogel component is grafted with N-hydroxysuccinimide ester;
the second component simultaneously comprises non-aldehydized polysaccharide, dialdehyde polysaccharide and cationic salt solution; the cation is selected from calcium ion and ferrous ion;
the first component and the second component can be subjected to in-situ crosslinking by virtue of Schiff base reaction after being mixed to form hydrogel, and the hydrogel has hemostasis and bonding effects and can be used as a hydrogel adhesive for rapid hemostasis.
As a further preferred aspect of the present invention, in the first component, the chitosan-based component is preferably selected from chitosan and chitosan derivatives; more preferably, the chitosan component is one or a mixture of chitosan, carboxymethyl chitosan and carboxyethyl chitosan;
for the second component, the non-aldehydized polysaccharide is at least one of sodium alginate, gelatin, hyaluronic acid, genipin and guar gum;
the dialdehyde polysaccharide is at least one of aldehyde-terminated sodium alginate, aldehyde-terminated gelatin, aldehyde-terminated hyaluronic acid, aldehyde-terminated genipin and aldehyde-terminated guar gum.
As a further preferred of the present invention, the chitosan derivative is carboxyethyl chitosan;
the first component comprises the following components in percentage by mass (2-6): (10-40): (0.1-1): (0.5-1) carboxyethyl chitosan, polyacrylic acid grafted with N-hydroxysuccinimide ester, a crosslinking agent and a photoinitiator;
or comprises the following components in percentage by mass (2-6): (10-40): (0.1-1): (0.5-1) carboxyethyl chitosan, polyacrylamide grafted with N-hydroxysuccinimide ester, a cross-linking agent and a photoinitiator;
or comprises the following components in percentage by mass (2-6): (10-40): (0.1-1): (0.5-1) carboxyethyl chitosan, poly (N-isopropylacrylamide) grafted with N-hydroxysuccinimide ester, a crosslinking agent and a photoinitiator;
preferably, the cross-linking agent is methacrylic acid anhydrified gelatin, and the photoinitiator is alpha-ketoglutaric acid;
the mass ratio of non-aldehydized polysaccharide to dialdehyde polysaccharide to cationic salt in the second component is (0.300-1.900): (0.950-13.000): (0.003-4.700).
As a further preferred aspect of the present invention, the chitosan derivative is carboxyethyl chitosan, which is synthesized by the following method:
under the condition of 20-50 ℃, dissolving 1-10wt% of chitosan powder in acrylic acid aqueous solution to obtain mixed solution, wherein the mass percentage concentration of chitosan in the mixed solution is 1-10 wt%; then reacting the mixed solution at 50 ℃ for 1-3 days, then adjusting the pH value to 10-12, and dialyzing in deionized water to obtain a carboxyethyl chitosan solution; and then drying the carboxyethyl chitosan solution, and grinding to obtain the carboxyethyl chitosan powder.
As a further preferred aspect of the present invention, the aldehyde-terminated sodium alginate is synthesized by the following method: adding sodium periodate into 1-4wt% sodium alginate solution at 10-25 deg.C, and reacting for 12-24h in dark place; adding polyethylene glycol to react for 0.5-2h, dialyzing in deionized water, drying, and grinding to obtain aldehyde-terminated sodium alginate powder;
the aldehyde-terminated gelatin is synthesized by the following method: adding sodium periodate into 1-4wt% gelatin solution at 10-25 deg.c, and light shielding reaction for 12-24 hr; adding polyethylene glycol to react for 0.5-2h, dialyzing in deionized water, drying, and grinding to obtain aldehyde group-terminated gelatin powder;
the aldehyde-terminated hyaluronic acid is synthesized by the following method: adding sodium periodate into 1-4wt% hyaluronic acid solution at 10-25 deg.C, and reacting for 12-24h in dark; adding polyethylene glycol to react for 0.5-2h, dialyzing in deionized water, drying, and grinding to obtain aldehyde-terminated hyaluronic acid powder;
the aldehyde-terminated genipin is synthesized by the following method: adding sodium periodate into 1-4wt% genipin solution at 10-25 deg.C, and reacting for 12-24h in dark; adding polyethylene glycol to react for 0.5-2h, dialyzing in deionized water, drying, and grinding to obtain aldehyde-terminated genipin powder;
the aldehyde-terminated guar gum is synthesized by the following method: adding sodium periodate into 1-4wt% guar gum solution at 10-25 deg.C, and reacting for 12-24h in dark; and then adding polyethylene glycol to react for 0.5-2h, dialyzing in deionized water, drying, and grinding to obtain the aldehyde-terminated guar gum powder.
According to another aspect of the present invention, there is provided an injectable rapid hemostatic hydrogel adhesive, wherein the hydrogel adhesive is obtained by rapidly injecting a first component and a second component of a precursor of the injectable rapid hemostatic hydrogel adhesive into a mold or a target region to be repaired, and performing in-situ curing and molding.
As a further preference of the present invention, the first component and the second component of the injectable rapid hemostatic hydrogel adhesive precursor are specifically injected based on a two-shot injection process or injected in multiple shots.
According to another aspect of the present invention, there is provided a method for preparing a precursor of the injectable rapid hemostatic hydrogel adhesive, which comprises preparing a first component and preparing a second component, wherein:
the first component is prepared by dissolving chitosan components in deionized water at 20-50 ℃, adding a monomer, a cross-linking agent, N-acryloyloxy succinimide and a photoinitiator, carrying out polymerization reaction under the condition of ultraviolet light, drying, and grinding to obtain hydrogel powder for rapid hemostasis; wherein the monomer is an acrylic acid monomer, an acrylamide monomer or an N-isopropyl acrylamide monomer;
the second component is prepared by mixing non-aldehydized polysaccharide and dialdehyde polysaccharide in metal cation salt solution at 10-25 ℃; wherein the synthesis process of the dialdehyde polysaccharide comprises the following steps: dissolving non-aldehydized polysaccharide in deionized water at 10-25 deg.c to obtain 1-4wt% non-aldehydized polysaccharide solution, adding sodium periodate into the non-aldehydized polysaccharide solution for light-shielding reaction for 12-24 hr, and adding polyglycol for reaction for 0.5-2 hr; then, dialyzing the reaction system in deionized water, drying, and grinding to obtain the dialdehyde polysaccharide.
As a further preferable aspect of the present invention, for the preparation of the first component, the mass ratio of the chitosan-based component, the monomer, the crosslinking agent, the N-acryloyloxy succinimide, and the photoinitiator is (2-6): (10-40): (0.1-1): (0.5-2): (0.5-1);
for the preparation of the second component, non-aldehydic polysaccharide is dissolved in deionized water to obtain a non-aldehydic polysaccharide solution with the concentration of 1-4wt%, dialdehyde polysaccharide is dissolved in deionized water to obtain a dialdehyde polysaccharide solution with the concentration of 2-20wt%, and cationic salt is dissolved in deionized water to obtain a cationic salt solution with the solute concentration of 1-10 wt%; then, mixing the non-aldehydized polysaccharide solution, the dialdehyde polysaccharide solution and the cationic salt solution according to the mass ratio of the non-aldehydized polysaccharide solution to the dialdehyde polysaccharide solution of 0.5-10 and the mass ratio of the non-aldehydized polysaccharide solution to the cationic salt solution of 1-100, so as to obtain the hydrogel which is the anti-blocking hydrogel adhesive;
preferably, the cationic salt is calcium chloride, calcium sulfate, ferrous chloride or ferrous sulfate.
According to another aspect of the present invention, the present invention provides a precursor of the above injectable rapid hemostatic hydrogel adhesive or the use of the above injectable rapid hemostatic hydrogel adhesive in the preparation of a medical hemostatic material or a slow release drug carrier.
Compared with the prior art, the hydrogel adhesive prepared from the first component and the second component with specific compositions has the characteristics of injectability, quick gelling, no requirement on wound position and shape, quick hemostasis and the like. The two components are AB two components, wherein in the precursor, the component A (namely, the first component) is hemostatic powder consisting of chitosan derivatives and polyacrylic acid hydrogel with high viscosity, and the component B (namely, the second component) is hemostatic glue consisting of polysaccharide, dialdehyde polysaccharide and cationic salt solution. The component A and the component B can be mutually subjected to in-situ crosslinking by virtue of Schiff base reaction to form hydrogel (for example, the component A and the component B can be subjected to a duplex injection process or a split injection process to generate a hydrogel adhesive in situ), on one hand, the component A can be used for constructing hydrogel powder for rapid hemostasis by taking chitosan components (such as biopolymers of chitosan, chitosan derivatives, cellulose and chitin) and polyacrylic hydrogel grafted with N-hydroxysuccinimide ester as main components, and the polyacrylic hydrogel molecular chain is provided with the N-hydroxysuccinimide ester, so that the component A can be subjected to ester exchange reaction with biological tissues to form strong adhesion to seal wound parts, and thus, the situation that the wound parts are not required to be sealed by the adhesion of biological tissues is avoidedPressing to stop bleeding quickly; the hydrogel powder for rapidly stopping bleeding can absorb liquid components in blood, increase blood coagulation factor concentration, cause erythrocyte aggregation, and improve platelet activity, thereby rapidly stopping bleeding. And, on the other hand, rapid ionic crosslinking (Ca) can be formed by the cations in the B component 2+ Ions, fe 2+ Ions of the metal ions are connected with polysaccharide by coordinate bonds to generate stable chelate, and then Schiff base can be formed by the chitosan derivative in the component A and the dialdehyde polysaccharide in the component B, so the hydrogel adhesive has the advantage of quick gelling.
And the component A is a hemostatic powder consisting of a chitosan derivative and polyacrylic acid hydrogel with high viscosity, can absorb liquid components in blood, improve the concentration of blood coagulation factors, cause erythrocyte aggregation, improve platelet activity and further realize rapid hemostasis, and hydroxyl succinimide ester is preferably arranged on a molecular chain of the polyacrylic acid hydrogel and can perform ester exchange reaction with biological tissues to form a tough adhesive closed wound part. In addition, the component A is in a powder state, so the medicine can be mixed with the medicine according to any proportion and then applied to the wound to achieve the effect of slow release of the medicine.
Specifically, the present invention can achieve the following advantageous effects:
(1) The hydrogel adhesive capable of being injected and rapidly stopping bleeding provided by the invention maintains biocompatibility and good bioactivity by modifying the existing natural biological macromolecules, improves the mechanical property of the hydrogel adhesive, can help wounds to rapidly stop bleeding, and can form tough adhesion with tissues.
(2) The hydrogel adhesive capable of being injected with rapid hemostasis consists of hemostatic powder and hemostatic gel, so that the hydrogel adhesive has no special requirements on the position and the shape of a wound surface, and is compatible with minimally invasive surgery besides being used in an open surgery. And the operation is simple, not only can be used for hemostasis in clinical operation, but also can be used for emergency treatment.
(3) The hydrogel adhesive capable of being injected and rapidly stopping bleeding can be mixed with clinical medical reagents such as powdery or liquid medicines, growth factors and the like based on the forms of hemostatic powder and hemostatic gel, and provides a new mode for medicine slow release, wound treatment and the like.
(4) The hydrogel adhesive capable of being injected and rapidly stopping bleeding has the advantages that the surface layer is the hemostatic gel which can resist adhesion, so that the hydrogel adhesive can be used for wound closure and can prevent postoperative tissues from being adhered.
Drawings
Figure 1 is a functional schematic of an injectable rapid hemostatic hydrogel adhesive of the present invention.
Fig. 2 is a gelling mechanism for injectable rapid hemostatic hydrogel adhesives of the invention.
Fig. 3 shows FTIR results of three components of the injectable rapid hemostatic hydrogel adhesive of the present invention, the first component alone and the second component alone.
FIG. 4 is an in vitro clotting effect of an injectable rapid hemostatic hydrogel adhesive of the present invention; the right sample is added into anticoagulated pig blood correspondingly, the left sample is control anticoagulated pig blood, the two samples are overturned to the centrifuge tube, the left pig blood is not coagulated, the anticoagulated pig blood added with the hydrogel adhesive on the right side is coagulated, and the blood does not flow down.
Fig. 5 shows the in vitro adhesion effect of the injectable rapid hemostatic hydrogel adhesive of the present invention to pigskin (skin), pig liver (liver), pig kidney (kidney), and pig heart (heart) (in the figure, the arrows are placed in PBS buffer solution for 24 hours before and after the immersion).
Fig. 6 is a graph showing the hemostatic effect of the injectable rapid hemostatic hydrogel adhesive of the present invention on various parts (i.e., liver, kidney, auricular vein) of normal rats and coagulation-impaired rats. Wherein, a in fig. 6 corresponds to the liver, and corresponds to the bleeding position schematic, the hemostatic effect of the rat with normal blood coagulation and the hemostatic effect of the rat with blood coagulation disorder in turn from left to right; in fig. 6, b corresponds to kidney, and corresponds to bleeding position indication, hemostasis effect of rat with normal blood coagulation and hemostasis effect of rat with blood coagulation disorder in sequence from left to right; in fig. 6, c corresponds to the auricular venous bleeding, and corresponds to the bleeding position, the hemostatic effect of the rats with normal blood coagulation and the hemostatic effect of the rats with blood coagulation disorder in sequence from left to right. The hemostatic effect of both the normoagulant and dysoagulant rats was 2 minutes after treatment with the injectable rapid hemostatic hydrogel adhesive of the present invention.
FIG. 7 shows the hemostatic effect of the injectable rapid hemostatic hydrogel adhesive of the present invention on the heart of normal rats (the front and back arrows in the figure correspond to the time before hemostasis and the time after 2 minutes of treatment with the injectable rapid hemostatic hydrogel adhesive of the present invention).
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
In general, the injectable rapid hemostatic hydrogel adhesive of the present invention comprises a first component (i.e., a component a) and a second component (i.e., a component B); the component A simultaneously comprises a chitosan component and a polyacrylic acid hydrogel component, wherein the chitosan component is selected from chitosan, chitosan derivatives, cellulose and chitin; the main body of the polyacrylic acid hydrogel component is polyacrylic acid hydrogel, polyacrylamide hydrogel or poly N-isopropyl acrylamide hydrogel, and the polyacrylic acid hydrogel component is grafted with N-hydroxysuccinimide ester; the component B is non-aldehydized polysaccharide, dialdehyde polysaccharide and cationic salt solution.
The injectable hydrogel adhesive may be formed in situ from component A and component B using a split injection process (e.g., injecting component A first, then component B). In practical application, the ratio of the component A to the component B is not particularly required, and the amount of the component A and the amount of the component B can be flexibly controlled according to the application of the wound, for example, the component A serving as the hemostatic powder only needs to be capable of covering the wound, and the component B serving as the hemostatic glue only needs to be capable of wrapping the component A.
The following are specific examples:
example 1
(1) 2g of chitosan was dissolved in 90ml of water at room temperature, and 10g of acrylic acid was added thereto overnight.
(2) To 20g of the above solution were added 0.2g of methacrylic anhydrified gelatin, 0.2g of α -ketoglutaric acid and 0.2g of N-acryloyloxy succinimide, and the mixture was stirred until it became transparent.
(3) And pouring the mixture into a mold of an acrylic plate to be crosslinked in an ultraviolet crosslinking box for 30min.
(4) The samples were removed and lyophilized using a vacuum lyophilizer.
(5) The lyophilized sample was put into a milling jar and milled at 50Hz for 1min to obtain the first component.
(6) Adding sodium periodate into 4wt% sodium alginate solution at normal temperature (certainly, other temperature condition of 10-25 deg.C), and reacting for 12h in dark place; and then adding polyethylene glycol to react for 2 hours, dialyzing in deionized water, drying, and grinding to obtain aldehyde-group-blocked sodium alginate powder, namely oxidized sodium alginate.
(7) 20g of oxidized sodium alginate was dissolved in 80g of water to obtain an oxidized sodium alginate solution.
(8) 4g of sodium alginate was dissolved in 96g of water to obtain a sodium alginate solution.
(9) Calcium chloride was dissolved in deionized water to obtain a cationic salt solution having a calcium chloride concentration of 10 wt%. And then mixing the sodium alginate solution, the oxidized sodium alginate solution and the cationic salt solution according to the weight ratio of the sodium alginate solution: the mass ratio of the oxidized sodium alginate solution is 10: and mixing the cationic salt solution in a mass ratio of 1. At this time, the mass ratio of sodium alginate, oxidized sodium alginate and cationic salt in the second component is 1.9.
(10) An injectable hydrogel adhesive was obtained by in situ split injection of 0.2g of the first component with 1.2ml of the second component.
Example 2
(1) At room temperature, 2g of carboxyethyl chitosan was dissolved in 90ml of water, and 10g of acrylic acid was added thereto overnight.
(2) To 20g of the above solution were added 0.2g of methacrylic anhydrified gelatin, 0.2g of α -ketoglutaric acid and 0.2g of N-acryloyloxy succinimide, and the mixture was stirred until it became transparent.
(3) Pouring into a mold of an acrylic plate, and crosslinking in an ultraviolet crosslinking box for 30min.
(4) The samples were removed and lyophilized using a vacuum lyophilizer.
(5) The lyophilized sample was put into a milling jar and milled at 50Hz for 1min to obtain the first component.
(6) Adding sodium periodate into a 4wt% sodium alginate solution at normal temperature, and reacting for 12 hours in a dark place; and adding polyethylene glycol for reaction for 2 hours, dialyzing in deionized water, drying, and grinding to obtain the aldehyde-group-blocked sodium alginate powder.
(7) 20g of oxidized sodium alginate was dissolved in 80g of water to obtain an oxidized sodium alginate solution.
(8) 4g of sodium alginate was dissolved in 96g of water to obtain a sodium alginate solution.
(9) Calcium chloride was dissolved in deionized water to obtain a cationic salt solution having a calcium chloride concentration of 10 wt%. And then mixing the sodium alginate solution, the oxidized sodium alginate solution and the cationic salt solution according to the ratio of the sodium alginate solution: the mass ratio of the oxidized sodium alginate solution is 10: and mixing the cationic salt solution in a mass ratio of 1. At this time, the mass ratio of sodium alginate, oxidized sodium alginate and cationic salt in the second component is 1.9.
(10) Injectable hydrogel adhesives were obtained by in situ fractional injection of 0.2g of the first component with 1.2ml of the second component.
Example 3
(1) At room temperature, 6g of chitosan was dissolved in 60ml of water, and 40g of acrylic acid was added overnight.
(2) To 20g of the above solution were added 0.02g of methacrylic anhydrified gelatin, 0.1g of α -ketoglutaric acid and 0.2g of N-acryloyloxy succinimide, and the mixture was stirred until it became transparent.
(3) Pouring into a mold of an acrylic plate, and crosslinking in an ultraviolet crosslinking box for 30min.
(4) The samples were removed and lyophilized using a vacuum lyophilizer.
(5) The lyophilized sample was put into a milling jar and milled at 50Hz for 1min to obtain the first component.
(6) Adding sodium periodate into a 4wt% sodium alginate solution at normal temperature, and reacting for 12 hours in a dark place; and adding polyethylene glycol for reaction for 2 hours, dialyzing in deionized water, drying, and grinding to obtain the aldehyde-group-blocked sodium alginate powder.
(7) 20g of oxidized sodium alginate was dissolved in 80gl water to obtain oxidized sodium alginate solution.
(8) 1g of sodium alginate was dissolved in 99g of water to obtain a sodium alginate solution.
(9) Calcium chloride was dissolved in deionized water to obtain a cationic salt solution having a calcium chloride concentration of 1 wt%. And then mixing the sodium alginate solution, the oxidized sodium alginate solution and the cationic salt solution according to the weight ratio of the sodium alginate solution: the mass ratio of the oxidized sodium alginate solution is 1: and mixing the cationic salt solution in a mass ratio of 100. In this case, the mass ratio of sodium alginate to oxidized sodium alginate to cationic salt in the second component is 0.33.
(10) An injectable hydrogel adhesive was obtained by in situ split injection of 0.2g of the first component with 1.2ml of the second component.
Example 4
(1) At room temperature, 6g of carboxyethyl chitosan was dissolved in 60ml of water, and 40g of acrylic acid was added overnight.
(2) To 20g of the above solution were added 0.02g of methacrylic anhydrified gelatin, 0.1g of α -ketoglutaric acid and 0.2g of N-acryloyloxy succinimide, and the mixture was stirred until it became transparent.
(3) Pouring into a mold of an acrylic plate, and crosslinking in an ultraviolet crosslinking box for 30min.
(4) The samples were removed and lyophilized using a vacuum lyophilizer.
(5) The lyophilized sample was put into a milling jar and milled at 50Hz for 1min to obtain the first component.
(6) At normal temperature, adding sodium periodate into a 4wt% sodium alginate solution, and reacting for 12 hours in a dark place; and adding polyethylene glycol for reaction for 2 hours, dialyzing in deionized water, drying, and grinding to obtain the aldehyde-group-blocked sodium alginate powder.
(7) 20g of oxidized sodium alginate was dissolved in 80g of water to obtain an oxidized sodium alginate solution.
(8) 1g of sodium alginate was dissolved in 99gl water to obtain a sodium alginate solution.
(9) Calcium chloride was dissolved in deionized water to obtain a cationic salt solution having a calcium chloride concentration of 1 wt%. And then mixing the sodium alginate solution, the oxidized sodium alginate solution and the cationic salt solution according to the weight ratio of the sodium alginate solution: the mass ratio of the oxidized sodium alginate solution is 1: and mixing the cation salt solution in a mass ratio of 100. At this time, the mass ratio of sodium alginate, oxidized sodium alginate and cationic salt in the second component is 0.33.
(10) An injectable hydrogel adhesive was obtained by in situ split injection of 0.2g of the first component with 1.2ml of the second component.
Example 5
(1) At room temperature, 2g of chitosan, 2g of carboxyethyl chitosan were dissolved in 70ml of water, and 30g of acrylic acid was added overnight.
(2) The solution 20g, add 0.05g methacrylic acid anhydridized gelatin, 0.1g alpha ketoglutaric acid, 0.2g N-acryloxysuccinimide, stir until transparent.
(3) Pouring into a mold of an acrylic plate, and crosslinking in an ultraviolet crosslinking box for 30min.
(4) The samples were removed and lyophilized using a vacuum lyophilizer.
(5) The lyophilized sample was put into a milling jar and milled at 50Hz for 1min to obtain the first component.
(6) Adding sodium periodate into a 4wt% sodium alginate solution at normal temperature, and reacting for 12 hours in a dark place; and then polyethylene glycol is added for reaction for 2 hours, and then dialysis is carried out in deionized water, and then drying and grinding are carried out to obtain the aldehyde-group-terminated sodium alginate powder.
(7) 20g of oxidized sodium alginate was dissolved in 80g of water to obtain an oxidized sodium alginate solution.
(8) 1g of sodium alginate was dissolved in 99g of water to obtain a sodium alginate solution.
(9) Calcium chloride was dissolved in deionized water to obtain a cationic salt solution having a calcium chloride concentration of 1 wt%. And then mixing the sodium alginate solution, the oxidized sodium alginate solution and the cationic salt solution according to the weight ratio of the sodium alginate solution: the mass ratio of the oxidized sodium alginate solution is 1: and mixing the cation salt solution in a mass ratio of 100. In the second component, the mass ratio of sodium alginate to oxidized sodium alginate to cationic salt is 0.49.
(10) The injectable hydrogel adhesive of this example was obtained by mixing 0.1g of the first component with 0.6ml of the second component homogeneously for subsequent testing.
Example 6
(1) The first component powders obtained in example 1 and example 2 were mixed in the following ratio of 5:1,4:1,3:1,2:1,1:1,1:2,1:3,1:4,1:5 may also be mixed to obtain the first component.
(2) At normal temperature, dissolving 10g of oxidized sodium alginate in 88g of water, adding 2g of sodium alginate, and mixing with a calcium chloride solution with the calcium chloride concentration of 1wt% at a ratio of 20.
(3) An injectable hydrogel adhesive was obtained by in situ split injection of 0.2g of the first component with 1.2ml of the second component.
Example 7
(1) At room temperature, 2g of chitosan was dissolved in 90ml of water, and 10g of acrylic acid was added thereto overnight.
(2) Taking 20g of the above solution, adding 0.2g of methacrylic anhydride gelatin, 0.2g of alpha-ketoglutaric acid and 0.2g of N-acryloyloxy succinimide, and stirring until the solution is transparent.
(3) Pouring into a mold of an acrylic plate, and crosslinking in an ultraviolet crosslinking box for 30min.
(4) The samples were removed and lyophilized using a vacuum lyophilizer.
(5) The lyophilized sample was put into a milling jar and milled at 50Hz for 1min to obtain the first fraction.
(6) At normal temperature, adding sodium periodate into a 4wt% sodium alginate solution, and reacting for 12 hours in a dark place; and then adding polyethylene glycol to react for 2 hours, dialyzing in deionized water, drying, and grinding to obtain aldehyde-group-blocked sodium alginate powder, namely oxidized sodium alginate.
(7) 20g of oxidized sodium alginate was dissolved in 80g of water to obtain an oxidized sodium alginate solution.
(8) 4g of sodium alginate was dissolved in 96g of water to obtain a sodium alginate solution.
(9) Dissolving ferrous chloride in deionized water to obtain a cationic salt solution with the ferrous chloride concentration of 10 wt%. And then mixing the sodium alginate solution, the oxidized sodium alginate solution and the cationic salt solution according to the ratio of the sodium alginate solution: the mass ratio of the oxidized sodium alginate solution is 10: and mixing the cationic salt solution in a mass ratio of 1. In the second component, the mass ratio of the sodium alginate to the oxidized sodium alginate to the cationic salt is 1.9.
(10) An injectable hydrogel adhesive was obtained by in situ split injection of 0.2g of the first component with 1.2ml of the second component.
Example 8
(1) At room temperature, 2g of carboxyethyl chitosan was dissolved in 90ml of water, and 10g of acrylic acid was added thereto overnight.
(2) To 20g of the above solution were added 0.2g of methacrylic anhydrified gelatin, 0.2g of α -ketoglutaric acid and 0.2g of N-acryloyloxy succinimide, and the mixture was stirred until it became transparent.
(3) And pouring the mixture into a mold of an acrylic plate to be crosslinked in an ultraviolet crosslinking box for 30min.
(4) The samples were removed and lyophilized using a vacuum lyophilizer.
(5) The lyophilized sample was put into a milling jar and milled at 50Hz for 1min to obtain the first component.
(6) Adding sodium periodate into a 4wt% sodium alginate solution at normal temperature, and reacting for 12 hours in a dark place; and adding polyethylene glycol for reaction for 2 hours, dialyzing in deionized water, drying, and grinding to obtain the aldehyde-group-blocked sodium alginate powder.
(7) 20g of oxidized sodium alginate was dissolved in 80g of water to obtain an oxidized sodium alginate solution.
(8) 4g of sodium alginate was dissolved in 96g of water to obtain a sodium alginate solution.
(9) Dissolving ferrous chloride in deionized water to obtain a cationic salt solution with the ferrous chloride concentration of 10 wt%. And then mixing the sodium alginate solution, the oxidized sodium alginate solution and the cationic salt solution according to the ratio of the sodium alginate solution: the mass ratio of the oxidized sodium alginate solution is 10: and (3) mixing the cation salt solution in a mass ratio of 1. At this time, the mass ratio of sodium alginate, oxidized sodium alginate and cationic salt in the second component is 1.9.
(10) Injectable hydrogel adhesives were obtained by in situ fractional injection of 0.2g of the first component with 1.2ml of the second component.
Example 9
(1) At room temperature, 6g of chitosan was dissolved in 60ml of water, and 40g of acrylic acid was added overnight.
(2) To 20g of the above solution were added 0.02g of methacrylic anhydrified gelatin, 0.1g of α -ketoglutaric acid and 0.2g of N-acryloyloxy succinimide, and the mixture was stirred until it became transparent.
(3) And pouring the mixture into a mold of an acrylic plate to be crosslinked in an ultraviolet crosslinking box for 30min.
(4) The samples were removed and lyophilized using a vacuum lyophilizer.
(5) The lyophilized sample was put into a milling jar and milled at 50Hz for 1min to obtain the first component.
(6) Adding sodium periodate into a 4wt% sodium alginate solution at normal temperature, and reacting for 12 hours in a dark place; and adding polyethylene glycol for reaction for 2 hours, dialyzing in deionized water, drying, and grinding to obtain the aldehyde-group-blocked sodium alginate powder.
(7) 20g of oxidized sodium alginate was dissolved in 80gl water to obtain oxidized sodium alginate solution.
(8) 1g of sodium alginate was dissolved in 99g of water to obtain a sodium alginate solution.
(9) Dissolving ferrous chloride in deionized water to obtain a cationic salt solution with the ferrous chloride concentration of 1 wt%. And then mixing the sodium alginate solution, the oxidized sodium alginate solution and the cationic salt solution according to the ratio of the sodium alginate solution: the mass ratio of the oxidized sodium alginate solution is 1: and mixing the cationic salt solution in a mass ratio of 100. At this time, the mass ratio of sodium alginate, oxidized sodium alginate and cationic salt in the second component is 0.33.
(10) An injectable hydrogel adhesive was obtained by in situ split injection of 0.2g of the first component with 1.2ml of the second component.
Example 10
(1) At room temperature, 6g of carboxyethyl chitosan was dissolved in 60ml of water, and 40g of acrylic acid was added overnight.
(2) Taking 20g of the above solution, adding 0.02g of methacrylic anhydride gelatin, 0.1g of alpha-ketoglutaric acid and 0.2g of N-acryloyloxy succinimide, and stirring until the solution is transparent.
(3) And pouring the mixture into a mold of an acrylic plate to be crosslinked in an ultraviolet crosslinking box for 30min.
(4) The samples were removed and lyophilized using a vacuum lyophilizer.
(5) The lyophilized sample was put into a milling jar and milled at 50Hz for 1min to obtain the first component.
(6) Adding sodium periodate into a 4wt% sodium alginate solution at normal temperature, and reacting for 12 hours in a dark place; and adding polyethylene glycol for reaction for 2 hours, dialyzing in deionized water, drying, and grinding to obtain the aldehyde-group-blocked sodium alginate powder.
(7) 20g of oxidized sodium alginate was dissolved in 80g of water to obtain an oxidized sodium alginate solution.
(8) 1g of sodium alginate was dissolved in 99gl water to obtain a sodium alginate solution.
(9) Dissolving ferrous chloride in deionized water to obtain a cationic salt solution with the ferrous chloride concentration of 1 wt%. And then mixing the sodium alginate solution, the oxidized sodium alginate solution and the cationic salt solution according to the weight ratio of the sodium alginate solution: the mass ratio of the oxidized sodium alginate solution is 1: and mixing the cationic salt solution in a mass ratio of 100. At this time, the mass ratio of sodium alginate, oxidized sodium alginate and cationic salt in the second component is 0.33.
(10) An injectable hydrogel adhesive was obtained by in situ split injection of 0.2g of the first component with 1.2ml of the second component.
Example 11
(1) At room temperature, 2g of chitosan, 2g of carboxyethyl chitosan were dissolved in 70ml of water, and 30g of acrylic acid was added overnight.
(2) To 20g of the above solution were added 0.05g of methacrylic anhydrified gelatin, 0.1g of α -ketoglutaric acid and 0.2g of N-acryloyloxy succinimide, and the mixture was stirred until it became transparent.
(3) Pouring into a mold of an acrylic plate, and crosslinking in an ultraviolet crosslinking box for 30min.
(4) The samples were removed and lyophilized using a vacuum lyophilizer.
(5) The lyophilized sample was put into a milling jar and milled at 50Hz for 1min to obtain the first component.
(6) Adding sodium periodate into a 4wt% sodium alginate solution at normal temperature, and reacting for 12 hours in a dark place; and then polyethylene glycol is added for reaction for 2 hours, and then dialysis is carried out in deionized water, and then drying and grinding are carried out to obtain the aldehyde-group-terminated sodium alginate powder.
(7) 20g of oxidized sodium alginate was dissolved in 80g of water to obtain an oxidized sodium alginate solution.
(8) 1g of sodium alginate was dissolved in 99g of water to obtain a sodium alginate solution.
(9) Dissolving ferrous chloride in deionized water to obtain a cationic salt solution with the ferrous chloride concentration of 1 wt%. And then mixing the sodium alginate solution, the oxidized sodium alginate solution and the cationic salt solution according to the weight ratio of the sodium alginate solution: the mass ratio of the oxidized sodium alginate solution is 1: and mixing the cation salt solution in a mass ratio of 100. In the second component, the mass ratio of sodium alginate to oxidized sodium alginate to cationic salt is 0.49.
(10) An injectable hydrogel adhesive was obtained by in situ split injection of 0.2g of the first component with 1.2ml of the second component.
And (3) performance testing:
the injectable hydrogel adhesive for rapid hemostasis obtained in example 5 above was first taken at room temperature for FTIR test, the FTIR test result of the first component is the middle curve of FIG. 3, and 1160cm can be seen -1 And 1232cm -1 Is characterized by a characteristic peak of N-hydroxysuccinimide ester at 2000-3500cm -1 The large number of amino groups shows that the first component has amino groups which can react with aldehyde groups to form Schiff bases and N-hydroxysuccinimide ester groups which can react with amino groups on biological tissues to form strong chemical bonds and further achieve strong adhesion, and the FTIR test result of the second component is the upper curve of FIG. 3, and 1700cm can be seen -1 The peak is the characteristic peak of aldehyde group, which indicates that the second component has aldehyde group which can form Schiff base with the first component. In addition, an in vitro hemostatic effect test is performed on the hydrogel adhesive capable of injecting rapid hemostasis in example 2, as shown in fig. 4, the hydrogel adhesive is added into a centrifugal tube containing anticoagulated pig blood on the right side, the anticoagulated pig blood itself is on the left side, the pig blood on the left side flows down after the centrifugal tube is overturned, it is proved that the anticoagulated pig blood cannot coagulate, but the pig blood added with the hydrogel adhesive on the right side does not flow down, and it is proved that the hydrogel adhesive can effectively coagulate blood.
The injectable rapid hemostatic hydrogel adhesives obtained in the above examples were subjected to in vitro porcine tissue adhesion tests, respectively, and the results are shown in fig. 5. As shown in FIG. 5, the hydrogel adhesive of example 1 can adhere to pigskin, and is not detached after being soaked in PBS for 24 hours and washed by high-pressure water, so that the long-term strong adhesion effect of the hydrogel adhesive of example 1 and the in-vitro pigskin can be fully illustrated.
As shown in figure 5, the example 2 can be adhered to the pork liver, and the pork liver is not detached after being soaked in PBS for 24 hours and washed by high-pressure water, so that the long-term strong adhesion effect of the example 2 and the isolated pork liver can be fully illustrated.
As shown in figure 5, the hemostatic powder of example 4 can adhere to pig kidney, and is not detached after being soaked in PBS for 24 hours and washed by high-pressure water, so that the long-term strong adhesion effect of the hemostatic powder of example 4 and the isolated pig kidney can be fully illustrated.
As shown in figure 5, the hemostatic powder of example 3 can be adhered to the pig heart, and is not detached after being soaked in PBS for 24 hours and washed by high-pressure water, so that the long-term strong adhesion effect of the hemostatic powder of example 3 and the in-vitro pig heart can be fully illustrated.
As shown in FIG. 6, examples 3,4 and 5 were added to the bleeding sites of the liver, kidney and auricle veins of normal rats (i.e., thrombophilia) and thrombophilia rats, respectively, to achieve effective hemostasis within 2min, and the dotted circles represent the hemostasis sites of the hydrogel adhesive.
As shown in figure 7, the hydrogel adhesive composed of the first components with the mass ratio of 1 is selected in example 6, and is coated on the wound of a rat with a 2mm diameter defect of the heart, and the bleeding can be effectively stopped within 2 min. The above rats were in good condition 14 days after the operation, and the wounds were recovered to normal.
Examples 7-11 have similar adhesion effects to the examples shown in fig. 5 and 6 when they are applied to biological tissues, except that the cationic component of the second component is different.
Taking the hydrogel adhesive obtained in example 1 as an example, the results of comparing the material obtained in the present invention with other commercially available hemostatic materials, performing hemostasis by applying each material to a rat model of partial nephrectomy bleeding, and comparing the hemostatic time are shown in table 1.
TABLE 1 comparison of the Performance of the invention and a portion of the hemostatic materials
Figure BDA0003604899920000191
As can be seen from the table 1, compared with other hemostatic materials, the hemostatic material of the invention has the advantages of short hemostatic time, better performance, applicability to both dry and wet environments, simple use method and direct application to wounds.
Also taking the hydrogel adhesive obtained in example 1 as an example, the results of comparing the blood loss of the present invention with the blood loss of a part of the clinical hemostatic means or hemostatic material in liver injury and auricular venous bleeding of rats are shown in table 2.
TABLE 2 amount of blood lost in rat liver injury and auricular venous hemorrhage by the present invention and other hemostatic means or materials
Figure BDA0003604899920000192
Figure BDA0003604899920000201
As can be seen from table 2, compared to other hemostatic methods or hemostatic materials, the present invention has less blood loss in the liver injury model, and has very little blood loss similar to the ali scan hemostatic powder in the scenario where the auricle venous hemorrhage is less. Therefore, the invention is particularly suitable for application scenes of massive bleeding, and the hemostatic effect is more prominent; for the application scene of a small amount of bleeding, the hemostatic effect is equal to or better than that of the commercial hemostatic material.
In addition, the above examples are only illustrative, and for example, calcium salts other than calcium chloride, such as sulfate, etc., may be used; the ferrous ion salt works in the same way. The first component can adopt other cationic high molecular polymers with amino groups, such as chitosan derivatives, cellulose and chitin, besides chitosan and carboxyethyl chitosan, and the second component can adopt other polysaccharide which can be dialdehyde, such as gelatin, hyaluronic acid, genipin, guar gum and the like, besides oxidized sodium alginate.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (11)

1. A precursor of an injectable rapid hemostatic hydrogel adhesive, comprising a first component and a second component, wherein,
the first component simultaneously comprises a chitosan component and a polyacrylic acid hydrogel component, wherein the chitosan component is selected from chitosan, chitosan derivatives and chitin; the main body of the polyacrylic acid hydrogel component is polyacrylic acid hydrogel, polyacrylamide hydrogel or poly N-isopropyl acrylamide hydrogel, and the polyacrylic acid hydrogel component is grafted with N-hydroxysuccinimide ester; the first component is prepared by the following steps: dissolving chitosan components in deionized water at the temperature of 20-50 ℃, adding a monomer, a cross-linking agent, N-acryloyloxy succinimide and a photoinitiator, carrying out polymerization reaction under the condition of ultraviolet light, drying, and grinding; wherein the monomer is an acrylic acid monomer, an acrylamide monomer or an N-isopropyl acrylamide monomer;
the second component simultaneously comprises non-aldehydized polysaccharide, dialdehyde polysaccharide and cationic salt solution; the cation is selected from calcium ion and ferrous ion;
the first component and the second component can be subjected to in-situ crosslinking by virtue of Schiff base reaction after being mixed to form hydrogel, and the hydrogel has hemostasis and bonding effects and can be used as a hydrogel adhesive for rapid hemostasis.
2. A precursor of an injectable rapid hemostatic hydrogel adhesive according to claim 1, wherein for the first component, the chitosan-based component is selected from the group consisting of chitosan and chitosan derivatives;
for the second component, the non-aldehydized polysaccharide is at least one of sodium alginate, hyaluronic acid and guar gum;
the dialdehyde polysaccharide is at least one of aldehyde-terminated sodium alginate, aldehyde-terminated hyaluronic acid and aldehyde-terminated guar gum.
3. The injectable rapid hemostatic hydrogel adhesive precursor of claim 2 wherein the chitosan-based component is a mixture of one or more of chitosan, carboxymethyl chitosan, carboxyethyl chitosan.
4. A precursor of injectable rapid hemostatic hydrogel adhesive according to claim 1 wherein the chitosan derivative is carboxyethyl chitosan;
the first component comprises the following components in percentage by mass (2-6): (10-40): (0.1-1): (0.5-1) carboxyethyl chitosan, polyacrylic acid grafted with N-hydroxysuccinimide ester, a crosslinking agent and a photoinitiator;
or comprises the following components in percentage by mass (2-6): (10-40): (0.1-1): (0.5-1) carboxyethyl chitosan, polyacrylamide grafted with N-hydroxysuccinimide ester, a crosslinking agent and a photoinitiator;
or comprises the following components in percentage by mass (2-6): (10-40): (0.1-1): (0.5-1) carboxyethyl chitosan, poly (N-isopropylacrylamide) grafted with N-hydroxysuccinimide ester, a crosslinking agent and a photoinitiator;
the cross-linking agent is methacrylic acid anhydrified gelatin, and the photoinitiator is alpha-ketoglutaric acid;
the mass ratio of non-aldehydized polysaccharide, di-aldehydized polysaccharide and cationic salt in the second component is (0.300-1.900): (0.950-13.000): (0.003-4.700).
5. An injectable rapid hemostatic hydrogel adhesive precursor according to claim 1 wherein the chitosan derivative is carboxyethyl chitosan synthesized by the following method:
dissolving 1-10wt% of chitosan powder in an acrylic acid aqueous solution at the temperature of 20-50 ℃ to obtain a mixed solution, wherein the mass percentage concentration of chitosan in the mixed solution is 1-10wt%; then reacting the mixed solution at 50 ℃ for 1 to 3 days, adjusting the pH value to 10 to 12, and dialyzing in deionized water to obtain a carboxyethyl chitosan solution; and then drying the carboxyethyl chitosan solution, and grinding to obtain the carboxyethyl chitosan powder.
6. The injectable rapid hemostatic hydrogel adhesive precursor according to claim 2, wherein the aldehyde-terminated sodium alginate is synthesized by the following method: adding sodium periodate into 1-4wt% sodium alginate solution at 10-25 deg.C, and reacting for 12-24h in dark place; adding polyethylene glycol to react for 0.5-2h, dialyzing in deionized water, drying, and grinding to obtain aldehyde-terminated sodium alginate powder;
the aldehyde-terminated hyaluronic acid is synthesized by the following method: adding sodium periodate into 1-4wt% hyaluronic acid solution at 10-25 deg.C, and reacting for 12-24h in dark; adding polyethylene glycol for reaction for 0.5-2h, dialyzing in deionized water, drying, and grinding to obtain aldehyde-terminated hyaluronic acid powder;
the aldehyde-terminated guar gum is synthesized by the following method: adding sodium periodate into 1-4wt% guar gum solution at 10-25 deg.C, and reacting for 12-24h in dark; and then adding polyethylene glycol to react for 0.5-2h, dialyzing in deionized water, drying, and grinding to obtain the aldehyde-terminated guar gum powder.
7. An injectable rapid hemostatic hydrogel adhesive, wherein the hydrogel adhesive is obtained by rapidly injecting the first component and the second component of the injectable rapid hemostatic hydrogel adhesive precursor according to any one of claims 1-6 into a mold or a target area to be repaired, and performing in-situ curing and molding.
8. The hydrogel adhesive of claim 7, wherein the first component and the second component of the injectable rapid hemostasis hydrogel adhesive precursor are injected in a two-shot injection process or in multiple shots.
9. A method of preparing a precursor of an injectable rapid hemostatic hydrogel adhesive according to any one of claims 1 to 6 comprising the preparation of a first component and the preparation of a second component, wherein:
the first component is prepared by dissolving chitosan components in deionized water at the temperature of 20-50 ℃, adding a monomer, a cross-linking agent, N-acryloyloxy succinimide and a photoinitiator, carrying out polymerization reaction under the condition of ultraviolet light, then drying, and grinding to obtain hydrogel powder for rapid hemostasis; wherein the monomer is an acrylic acid monomer, an acrylamide monomer or an N-isopropyl acrylamide monomer;
the second component is prepared by mixing non-aldehydized polysaccharide and dialdehyde polysaccharide in metal cation salt solution at 10-25 ℃; wherein the synthesis process of the dialdehyde polysaccharide comprises the following steps: dissolving non-aldehydized polysaccharide in deionized water at 10-25 deg.c to obtain 1-4wt% non-aldehydized polysaccharide solution, adding sodium periodate into the non-aldehydized polysaccharide solution for light-shielding reaction for 12-24 hr, and adding polyglycol for reaction for 0.5-2 hr; then, dialyzing the reaction system in deionized water, drying, and grinding to obtain the dialdehyde polysaccharide.
10. The method according to claim 9, wherein the reaction mixture,
for the preparation of the first component, the mass ratio of the chitosan-based component, the monomer, the cross-linking agent, the N-acryloyloxy succinimide and the photoinitiator is (2-6): (10-40): (0.1-1): (0.5-2): (0.5-1);
for the preparation of the second component, non-aldehydized polysaccharide is dissolved in deionized water to obtain a non-aldehydized polysaccharide solution with the concentration of 1-4wt%, dialdehyde polysaccharide is dissolved in deionized water to obtain a dialdehyde polysaccharide solution with the concentration of 2-20wt%, and cationic salt is dissolved in deionized water to obtain a cationic salt solution with the solute concentration of 1-10 wt%; then, mixing the non-aldehydized polysaccharide solution, the dialdehyde polysaccharide solution and the cationic salt solution according to the mass ratio of the non-aldehydized polysaccharide solution to the dialdehyde polysaccharide solution of 0.5-10 and the mass ratio of the non-aldehydized polysaccharide solution to the cationic salt solution of 1-100, so as to obtain the hydrogel which is the anti-blocking hydrogel adhesive;
the cationic salt is calcium chloride, calcium sulfate, ferrous chloride or ferrous sulfate.
11. Use of a precursor of an injectable rapid hemostatic hydrogel binder according to any one of claims 1 to 6 or an injectable rapid hemostatic hydrogel binder according to any one of claims 7 to 8 for the preparation of a medical hemostatic material or a slow release drug carrier.
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