CN115068666B - Anti-adhesion hemostatic hydrogel and preparation method and application thereof - Google Patents

Anti-adhesion hemostatic hydrogel and preparation method and application thereof Download PDF

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CN115068666B
CN115068666B CN202110262418.XA CN202110262418A CN115068666B CN 115068666 B CN115068666 B CN 115068666B CN 202110262418 A CN202110262418 A CN 202110262418A CN 115068666 B CN115068666 B CN 115068666B
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hemostatic
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hemostatic hydrogel
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CN115068666A (en
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刘颖
孙迪
陈春英
赵宇亮
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GBA National Institute for Nanotechnology Innovation
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
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    • A61LMETHODS 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
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    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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Abstract

The invention discloses an anti-adhesion hemostatic hydrogel and a preparation method and application thereof. The anti-adhesion hemostatic hydrogel comprises the following components in percentage by weight: 5-15% of the A component, 15-25% of the B component, 0.1-5% of the enzyme cross-linking agent and the balance of water, wherein the carbonyl of the A component and the amino of the B component are subjected to Schiff base reaction cross-linking to obtain the enzyme cross-linked hemostatic hydrogel. The anti-adhesion hemostatic hydrogel provided by the invention has viscoelasticity and fluidity, can be injected into tissues at a bleeding part in vitro, forms solid gel under the action of an enzyme crosslinking agent when reaching a specific temperature and tissues, can quickly stop blood and has firm tissue adhesion, the wound can quickly stop blood and heal after operation, has no adhesion phenomenon and no inflammatory reaction, can bear blood pressure from blood vessels in the wound and pressure for external auxiliary hemostasis of the wound, and can be widely applied to preparation of quick hemostasis and anti-adhesion products.

Description

Anti-adhesion hemostatic hydrogel and preparation method and application thereof
Technical Field
The invention relates to the technical field of hemostatic materials, in particular to an anti-adhesion hemostatic hydrogel and a preparation method and application thereof.
Background
Adhesion occurs after 95% of invasive surgery, such as abdominal surgery, and many patients experience post-operative complications associated with adhesion, such as severe pain and/or organ dysfunction, with 15-30% of patients requiring a second surgery to release the adhesion, and post-operative adhesion prevention is therefore critical.
The hydrogel is a novel bioactive functional polymer material with better performance than the traditional hemostatic dressing, and can be used for postoperative wound of a patient due to the characteristics of softness, high tissue water content and good tissue compatibility, and is used for hemostasis and postoperative anti-adhesion. However, conventional in situ hydrogels have poor tissue adhesion, do not adhere to wet tissue, and do not simultaneously prevent post-operative tissue adhesion, thereby severely limiting their use in repairing internal tissues. In addition, the traditional in-situ hydrogel product at present also has some defects in terms of structure and performance, and the most critical is that the mechanical property is lower. Compression hemostasis by external force is required in the face of massive hemorrhage or massive vascular hemorrhage in war wound or surgery, and the hemostatic material used in the method must be capable of bearing the blood pressure from the blood vessel in the wound and the pressurizing force for auxiliary hemostasis outside the wound, but the mechanical strength of most in-situ hydrogels cannot meet the above conditions.
CN107261198A discloses a preparation method of an anti-seepage anti-adhesion porous hemostatic gel dressing, which comprises the following steps: adding a composite cross-linking agent beta-diimine zinc complex, an aqueous solution of 1,2,7, 8-diepoxy octane and an inorganic salt aqueous solution in a mass ratio of 1:3-3:1 into a mixed solution of water-soluble human-like collagen and chitosan, uniformly mixing, adjusting the pH value of the solution to 2-5.5, and placing the solution in a water bath environment for cross-linking reaction to obtain saline-containing hydrogel; and (3) performing high-pressure steam treatment and distilled water soaking washing on the crosslinked saline-containing gel twice, removing inorganic salt and residual monomer crosslinking agent, and performing drying and Co-60 sterilization treatment to obtain the impermeable anti-adhesion porous medical hemostatic gel dressing. The hydrogel dressing prepared by the technology has a super-porous structure, has high porosity, good penetrability and reasonable pore size, can quickly absorb water in blood to promote hemagglutination to realize quick hemostasis, and has smaller roughness and difficult adhesion compared with the traditional gauze or hemostatic sponge on the surface of the hydrogel material; the good penetrability of the pore canal makes the drug administration very convenient; while the smaller pore size of the material also prevents wound infection. The hemostatic gel dressing mainly aims at improving hemostatic performance only, is not improved through optimization of hemostatic gel material components and a gelling process, but is improved through structural adjustment, and has a hemostatic performance through a porous structure, and the hemostatic gel dressing has no specific confirmation of corresponding anti-adhesion effect.
Disclosure of Invention
The invention aims to solve the technical problems that the in-situ hydrogel tissue of the existing in-situ hydrogel has weak adhesion, can not adhere to wet tissues and can not simultaneously prevent postoperative tissue adhesion, and provides an anti-adhesion hemostatic hydrogel which is obtained by adopting a multi-response multi-component system enzyme response catalytic crosslinking, has viscoelasticity and fluidity, can form solid gel when reaching specific temperature and tissues, and has excellent hemostatic effect and firm tissue adhesion.
Another object of the present invention is to provide a method for preparing an anti-adhesion hemostatic hydrogel.
It is a further object of the present invention to provide an anti-adhesion hemostatic hydrogel for use in the preparation of a rapid hemostatic and anti-adhesion article.
It is a further object of the present invention to provide a rapid hemostatic and anti-adhesion article.
It is a further object of the present invention to provide a system for preparing a rapid hemostatic and anti-adhesion article.
The above object of the present invention is achieved by the following technical scheme:
an anti-adhesion hemostatic hydrogel comprises the following components in percentage by weight: 1 to 20 percent of component A, 10 to 30 percent of component B, 0.1 to 5 percent of enzyme cross-linking agent and the balance of water,
wherein the component A is one or more of alanylglutamine, D-glutamine, DL-glutamine, BOC-L-glutamine, N-CBZ-L-glutamine, anisaldehyde, CHO-PEG-CHO, cinnamaldehyde, vanillin, cyclodextrin aldehyde or Plutonic block copolymer;
the component B is one or more of aminated graphene, aminated gelatin, aminated polysaccharide or aminated chitin.
Under the catalysis and crosslinking action of an enzyme crosslinking agent, the hemostatic hydrogel is crosslinked through Schiff base reaction of carbonyl of the component A and amino of the component B to obtain the enzyme-state crosslinked hemostatic hydrogel.
The water of the present invention may be non-deionized water.
The enzyme cross-linking agent not only has the function of a catalyst, but also has the effect of a cross-linking agent, and can promote the catalytic cross-linking of the A component and the B component corresponding to the enzyme to prepare the hemostatic hydrogel.
The hemostatic hydrogel disclosed by the invention is an enzymatically crosslinked hemostatic hydrogel, can be prevented from adhesion, has viscoelasticity and fluidity by adopting a two-component system with enzyme response, can be injected into tissues at a bleeding part in vitro, forms solid gel when reaching a specific temperature and tissues, has a hemostatic effect, has firm tissue adhesion, can be locally reserved in a body for one month, can be well healed at the bleeding part after operation, has no adhesion phenomenon and no inflammatory reaction, and overcomes the product defects of adhesion phenomenon existing in the conventional common hydrogel products.
In order to further optimize the hemostatic properties and anti-adhesion effect of the hemostatic hydrogel, it is preferable to include the following components in weight percent: 5-15% of component A, 15-25% of component B, 0.5-3% of cross-linking agent and the balance of water.
Preferably, the enzyme cross-linking agent is transglutaminase. The transglutaminase is selected as an enzyme cross-linking agent, so that the A component and the B component can be better matched for catalytic cross-linking to prepare the hemostatic hydrogel product.
Further, in order to inhibit the growth and reproduction of microorganisms and bacteria and promote the healing of wounds, the hemostatic hydrogel preferably further comprises a preservative and a bacteriostatic agent.
Wherein the bacteriostatic agent can be tea polyphenol bacteriostatic agent, and the preservative can be commercial preservative.
The invention also provides a preparation method of the anti-adhesion hemostatic hydrogel, which comprises the following steps: dissolving the component A in water to obtain a solution S1; dissolving the component B and the cross-linking agent in water to obtain a solution S2; the solution S1 and the solution S2 are mixed and crosslinked to form the anti-adhesion hemostatic hydrogel.
In the preparation method of the hemostatic hydrogel, the solution S1 containing the component A and the solution S2 containing the component B and the crosslinking agent are mixed and crosslinked at normal temperature, and the preparation method is convenient and quick.
In practical applications, the application of the anti-adhesion hemostatic hydrogel in preparing rapid hemostatic and anti-adhesion products is also within the protection scope of the invention.
The hemostatic hydrogel material has excellent hemostatic performance and firm tissue adhesion, can bear blood pressure from blood vessels in a wound and pressurizing force for auxiliary hemostasis outside the wound, can quickly stop and heal the wound after operation, has no adhesion phenomenon and no inflammatory reaction, and can be widely applied to preparation of quick hemostasis and anti-adhesion products.
The invention also specifically protects a rapid hemostatic and anti-adhesion product which is prepared from the raw materials comprising the anti-adhesion hemostatic hydrogel.
For better application to hemostasis and anti-adhesion of invasive surgery, the invention also protects a system for preparing the rapid hemostasis and anti-adhesion product, which comprises a syringe A and a syringe B, wherein the syringe A comprises a mixed solution of a component A and a cross-linking agent in a component A solution syringe B.
When the rapid hemostatic and anti-adhesion product is specifically used, the syringe A containing the S1 solution containing the A component and the syringe B containing the S2 solution containing the B component and the cross-linking agent can be injected simultaneously, the two components can reach hemostatic positions simultaneously, and solid gel can be formed at normal body temperature (usually in the range of 10-40 ℃) of a human body or an animal, so that the hemostatic and adhesion effects can be achieved through adhesion with tissues.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention provides an anti-adhesion hemostatic hydrogel, which comprises a carbonyl component A and an amino group-containing component B, has a multi-response component system, has viscoelasticity and fluidity, can be injected into tissues of a bleeding part in vitro, forms solid gel under the action of a cross-linking agent when reaching a specific temperature and the tissues, and has firm tissue adhesion.
2. The anti-adhesion hemostatic hydrogel can be quickly gelled when reaching the temperature of an action part and tissues, the gelling time is 10-120 s, and the hemostatic performance is excellent.
3. The anti-adhesion hemostatic hydrogel provided by the invention has the advantages that after the anti-adhesion hemostatic hydrogel acts on a specific operation site, the postoperative wound is quickly healed, the adhesion phenomenon is avoided, and the inflammatory reaction is avoided.
4. The anti-adhesion hemostatic hydrogel can bear blood pressure from blood vessels in a wound and pressurizing force for auxiliary hemostasis outside the wound, and has a tensile strength of 70-100 KPa.
5. The preparation method of the anti-adhesion hemostatic hydrogel is simple, convenient and quick.
Drawings
FIG. 1 shows the practical use of the hemostatic hydrogel of the present invention.
FIG. 2 is a graph of HE staining of the hemostatic hydrogel of the invention after two weeks of use.
FIG. 3 is a scanning electron microscope image of a hemostatic hydrogel of the present invention after two weeks of use.
Fig. 4 is a photograph of a hemostatic site after two weeks of use of the hemostatic hydrogel of the invention.
Fig. 5 is a photograph showing the hemostatic hydrogel of example 1 of the present invention after one month of use.
Fig. 6-9 are pictures of hemostatic sites after two weeks of use of the hemostatic hydrogels of examples 2-5 of the present invention.
Fig. 10 is a photograph of a hemostatic hydrogel of a comparative example of the present invention after two weeks of use.
Detailed Description
The invention will be further described with reference to the following specific embodiments, but the examples are not intended to limit the invention in any way. Raw materials reagents used in the examples of the present invention are conventionally purchased raw materials reagents unless otherwise specified.
Example 1
An anti-adhesion hemostatic hydrogel comprises the following components in percentage by weight: 10% of a component A, 20% of a component B, 1% of an enzyme cross-linking agent and the balance of water.
Wherein, the A component is D-glutamine;
the component B is aminated chitin;
wherein the enzyme cross-linking agent is transglutaminase.
The preparation method of the anti-adhesion hemostatic hydrogel comprises the following steps:
dissolving the component A in water to obtain a solution S1; dissolving the component B and the cross-linking agent in water to obtain a solution S2; the solution S1 and the solution S2 are mixed and crosslinked to form the anti-adhesion hemostatic hydrogel.
Example 2
An anti-adhesion hemostatic hydrogel comprises the following components in percentage by weight: 5% of a component A, 25% of a component B, 3% of an enzyme cross-linking agent and the balance of water.
Wherein, the A component is alanyl glutamine;
the component B is aminated chitin;
wherein the enzyme cross-linking agent is transglutaminase.
The preparation method of the anti-adhesion hemostatic hydrogel comprises the following steps:
dissolving the component A in water to obtain a solution S1; dissolving the component B and the cross-linking agent in water to obtain a solution S2; the solution S1 and the solution S2 are mixed and crosslinked to form the anti-adhesion hemostatic hydrogel.
Example 3
An anti-adhesion hemostatic hydrogel comprises the following components in percentage by weight: 15% of a component A, 15% of a component B, 0.5% of an enzyme cross-linking agent and the balance of water.
Wherein, the A component is BOC-L-glutamine;
the component B is aminated chitin;
wherein the enzyme cross-linking agent is transglutaminase.
The preparation method of the anti-adhesion hemostatic hydrogel comprises the following steps:
dissolving the component A in water to obtain a solution S1; dissolving the component B and the cross-linking agent in water to obtain a solution S2; the solution S1 and the solution S2 are mixed and crosslinked to form the anti-adhesion hemostatic hydrogel.
Example 4
An anti-adhesion hemostatic hydrogel comprises the following components in percentage by weight: 1% of a component A, 10% of a component B, 0.1% of an enzyme cross-linking agent and the balance of water.
Wherein, the A component is N-CBZ-glutamine;
the component B is aminated chitin;
wherein the enzyme cross-linking agent is transglutaminase.
The preparation method of the anti-adhesion hemostatic hydrogel comprises the following steps:
dissolving the component A in water to obtain a solution S1; dissolving the component B and the cross-linking agent in water to obtain a solution S2; the solution S1 and the solution S2 are mixed and crosslinked to form the anti-adhesion hemostatic hydrogel.
Example 5
An anti-adhesion hemostatic hydrogel comprises the following components in percentage by weight: 20% of a component A, 30% of a component B, 5% of an enzyme cross-linking agent and the balance of water.
Wherein, the component A is cyclodextrin aldehyde;
the component B is aminated graphene;
wherein the enzyme cross-linking agent is transglutaminase.
The preparation method of the anti-adhesion hemostatic hydrogel comprises the following steps:
dissolving the component A in water to obtain a solution S1; dissolving the component B and the cross-linking agent in water to obtain a solution S2; the solution S1 and the solution S2 are mixed and crosslinked to form the anti-adhesion hemostatic hydrogel.
Example 6
An anti-adhesion hemostatic hydrogel comprises the following components in percentage by weight: 10% of a component A, 20% of a component B, 1% of an enzyme cross-linking agent and the balance of water.
Wherein, the A component is vanillin;
the component B is amino gelatin;
wherein the enzyme cross-linking agent is transglutaminase.
The preparation method of the anti-adhesion hemostatic hydrogel comprises the following steps:
dissolving the component A in water to obtain a solution S1; dissolving the component B and the cross-linking agent in water to obtain a solution S2; the solution S1 and the solution S2 are mixed and crosslinked to form the anti-adhesion hemostatic hydrogel.
Example 7
An anti-adhesion hemostatic hydrogel comprises the following components in percentage by weight: 10% of a component A, 20% of a component B, 1% of an enzyme cross-linking agent and the balance of water.
Wherein, the component A is Plutonic block copolymer;
the component B is aminated polysaccharide;
wherein the enzyme cross-linking agent is transglutaminase.
The preparation method of the anti-adhesion hemostatic hydrogel comprises the following steps:
dissolving the component A in water to obtain a solution S1; dissolving the component B and the cross-linking agent in water to obtain a solution S2; the solution S1 and the solution S2 are mixed and crosslinked to form the anti-adhesion hemostatic hydrogel.
Example 8
An anti-adhesion hemostatic hydrogel comprises the following components in percentage by weight: 10% of a component A, 20% of a component B, 1% of an enzyme cross-linking agent and the balance of water.
Wherein, the A component is CHO-PEG-CHO;
the component B is aminated graphene;
wherein the enzyme cross-linking agent is transglutaminase.
The preparation method of the anti-adhesion hemostatic hydrogel comprises the following steps:
dissolving the component A in water to obtain a solution S1; dissolving the component B and the cross-linking agent in water to obtain a solution S2; the solution S1 and the solution S2 are mixed and crosslinked to form the anti-adhesion hemostatic hydrogel.
Example 9
A rapid hemostatic and anti-adhesion article prepared from the anti-adhesion hemostatic hydrogels of examples 1-4, the article comprising a syringe a and a syringe B, the syringe a comprising a mixed solution of a component a and a cross-linking agent in a component a solution syringe B.
The hemostatic product is applied to various hemostatic positions for postoperative hemostatic healing.
Comparative example 1
Commercial domestic medical hydrogel.
Result detection
(1) Hemostatic Properties
As shown in figure 1, the practical application of the rapid hemostatic and anti-adhesion product is that the liver position of the abdomen of a rabbit is selected as an experimental part, the skin is transversely scratched by a blade, a syringe A filled with an S1 solution containing an A component and a syringe B filled with an S2 solution containing a B component and a crosslinking agent are rapidly injected into a wound at the same time, and the two components reach the hemostatic part at the same time to form solid gel, so that the hemostatic and adhesion effects with tissues are achieved.
The hemostatic hydrogel of the embodiment 1 is applied to the abdominal wound of the rabbit, and can be seen to reach the wound to form solid gel, so that the hemostatic hydrogel can effectively stop bleeding.
The gel time of the hemostatic water gel of the invention is measured, and as shown in table 1, the hemostatic hydrogel of the invention has a fast gel forming time, and can achieve the effect of fast hemostasis.
TABLE 1 gel time test results
From the data in table 1, it can be seen that the hemostatic water of the present invention has a shorter gelling time, within 120s, and has significantly improved and excellent hemostatic performance compared with the conventional 180s gelling time.
(2) Tissue adhesion and post-operative adhesion prevention
Fig. 2 is a graph showing HE staining of example 1 of the present invention after two weeks of use, and it can be seen from fig. 2 that the hemostatic hydrogel of the present invention is effective in hemostasis and adhesion of wounds.
FIG. 3 is a scanning electron microscope image of example 1 of the present invention after two weeks of use, and it can be seen from FIG. 3 that the two-component hydrogel has no inflammatory reaction with liver tissue after two weeks.
Fig. 4 is a photograph of a hemostatic site after two weeks of use in example 1 of the present invention, and it can be seen that the post-operative hemostatic site does not undergo an adhesion reaction after two weeks.
Fig. 5 is a photograph of a hemostatic site of example 1 of the present invention after one month, and it can be seen that the hydrogel remained locally in the body after one month, and did not fall off, indicating that the hemostatic hydrogel of the present invention has good adhesion.
Fig. 6 to 9 are pictures of hemostatic parts after two weeks of use in examples 2 to 5 of the present invention, and it can be seen that the hemostatic parts after two weeks of operation do not have adhesion reaction, and have good anti-adhesion effect.
Fig. 10 is a picture of the hemostatic sites after application of the commercial hemostatic hydrogel of comparative example 1, from which it can be seen that significant adhesion occurred.
Gel strength measurements were performed on the hemostatic hydrogels of the examples of the present invention, and the test results are shown in table 2.
TABLE 2 gel strength test results
As can be seen from the data in Table 2, the hemostatic water of the present invention has a good gel strength, a certain adhesive strength above 100KPa, and can withstand the blood pressure from the blood vessel inside the wound and the pressure of the auxiliary hemostasis outside the wound, and has a firm tissue adhesion.
It is to be understood that the above examples of the present invention are provided by way of illustration only and not by way of limitation of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.

Claims (7)

1. An anti-adhesion hemostatic hydrogel is characterized by comprising the following components in percentage by weight: 5-15% of component A, 15-25% of component B, 0.5-3% of enzyme cross-linking agent and the balance of water,
wherein the component A is one or more of alanylglutamine, D-glutamine, DL-glutamine, BOC-L-glutamine or N-CBZ-L-glutamine;
the component B is aminated chitin; the enzyme cross-linking agent is transglutaminase.
2. The anti-adhesion hemostatic hydrogel of claim 1, wherein the a component is D-glutamine and the B component is an aminated chitin.
3. The anti-adhesion hemostatic hydrogel according to claim 1 or 2, further comprising a preservative and a bacteriostatic agent.
4. An anti-adhesion hemostatic hydrogel according to claim 3, wherein said bacteriostatic agent is a tea polyphenol bacteriostatic agent.
5. A method for preparing the anti-adhesion hemostatic hydrogel according to any one of claims 1 to 4, comprising the following steps: dissolving the component A in water to obtain a solution S1; dissolving the component B and an enzyme cross-linking agent in water to obtain a solution S2; the solution S1 and the solution S2 are mixed and crosslinked to form the anti-adhesion hemostatic hydrogel.
6. Use of the anti-adhesion hemostatic hydrogel according to any one of claims 1-4 for preparing a rapid hemostatic and anti-adhesion article.
7. A rapid hemostatic and anti-adhesion article prepared from a raw material comprising the anti-adhesion hemostatic hydrogel of any one of claims 1-4.
CN202110262418.XA 2021-03-10 2021-03-10 Anti-adhesion hemostatic hydrogel and preparation method and application thereof Active CN115068666B (en)

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EP0686401A2 (en) * 1994-06-10 1995-12-13 Ajinomoto Co., Inc. Living-tissue adhesive and blood coagulant
CN104208742A (en) * 2013-05-31 2014-12-17 北京纳通科技集团有限公司 Hemostatic crosslinked composition, its preparation method and use, and hemostatic antistick material prepared from hemostatic crosslinked composition

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GB2362100B (en) * 2000-05-08 2002-05-08 Maelor Pharmaceuticals Ltd Wound gels
DE60323943D1 (en) * 2002-02-21 2008-11-20 Encelle Inc IMMOBILIZED BIOACTIVE HYDROGEL MATRICES FOR SURFACE COATINGS
DE102006033167A1 (en) * 2006-07-10 2008-01-24 Gelita Ag Use of gelatin and a crosslinking agent for the preparation of a crosslinking medical adhesive

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0686401A2 (en) * 1994-06-10 1995-12-13 Ajinomoto Co., Inc. Living-tissue adhesive and blood coagulant
CN104208742A (en) * 2013-05-31 2014-12-17 北京纳通科技集团有限公司 Hemostatic crosslinked composition, its preparation method and use, and hemostatic antistick material prepared from hemostatic crosslinked composition

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