CN115252880A - Biological glue based on phase separation and preparation method and application thereof - Google Patents
Biological glue based on phase separation and preparation method and application thereof Download PDFInfo
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- CN115252880A CN115252880A CN202211036763.2A CN202211036763A CN115252880A CN 115252880 A CN115252880 A CN 115252880A CN 202211036763 A CN202211036763 A CN 202211036763A CN 115252880 A CN115252880 A CN 115252880A
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- phase separation
- dopa
- biological glue
- pectin
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- 238000002360 preparation method Methods 0.000 title description 8
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- 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
- C08B37/0045—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Galacturonans, e.g. methyl ester of (alpha-1,4)-linked D-galacturonic acid units, i.e. pectin, or hydrolysis product of methyl ester of alpha-1,4-linked D-galacturonic acid units, i.e. pectinic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/08—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Surgery (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Materials For Medical Uses (AREA)
Abstract
The biological glue with biocompatibility based on the separation of dopa modified polysaccharide and protein can be applied to organic tissue adhesion in gas phase and liquid phase environments or the adhesion of an organic tissue and an inorganic substrate, so that the adhesion of the organic tissue in different environments is realized, and the fixation of the inorganic substrate and the organic tissue is realized. The biological glue based on phase separation has excellent biocompatibility and can still be normally used in underwater environment.
Description
Technical Field
The invention relates to the field of new materials, in particular to biological glue based on phase separation and a preparation method and application thereof.
Background
The biological adhesive has important significance for fixing surgical suture and in-vivo health monitoring devices, and compared with the traditional suture, the biological adhesive has the advantages of simplicity in use, time-saving operation, capability of preventing related complications and the like. Ideal bioadhesives need to achieve fast and stable adhesion to a variety of moist organic tissues or inorganic devices, which requires strong and fast interfacial adhesion of the adhesive. In addition, the inherent strength of the bioadhesive itself needs to be sufficient to resist the stresses caused by pulling by the adherent, which requires a strong cohesion. In general, bioadhesives can be divided into glue forms and patch forms. Compared with patch type biological adhesives, the glue type adhesives are particularly suitable for in-situ adhesion due to the injectability and in-situ adhesion curing characteristics. However, glue-type adhesives often fail to achieve transient tissue adhesion because of the slow cure required for adhesion. And most of the current glue-type organic tissue adhesives are basically based on molecular polymerization of cyanoacrylate, have high cytotoxicity and cannot be degraded. Another mainstream biological glue is a fibrin glue adhesive, but the adhesive strength of the glue is low, the speed is slow, and the glue can quickly diffuse in an aqueous environment and cannot be directly used in an underwater environment. Therefore, it remains challenging to construct a glue-type bioadhesive suitable for the adhesion of moist organic tissue.
In recent years, phase separation has been reported to play an important role in natural bioadhesive systems. For example, mussel foot protein 5 (Pvfp-5) forms a liquid-liquid phase separation during underwater attachment. In the biological adhesive, the phase separation of the protein can obviously improve the bonding strength and accelerate the internal curing process. Meanwhile, a post-translational amino acid l-3, 4-dihydroxyphenylalanine (Dopa) containing dihydroxyphenylalanine is widely reported, which contributes to the enhancement of the water-resistant adhesion ability of mussels. Dopa can form dynamic interactions (charge-charge interactions, cation-pi interactions, coordination, hydrogen bonding, and hydrophobic effects) and covalent bonding (covalent bonds between oxidized Dopa and amino/thiols) with various substrates.
Therefore, the applicant hopes to design a glue type biological adhesive with fast adhesive property, strong adhesive property and high biocompatibility, namely biological glue, by utilizing the cohesive property of protein-polysaccharide phase separation and the adhesive property of dopa, wherein the glue type biological adhesive can be used for fast, efficient and super-strong adhesion between organic tissues or between the organic tissues and an inorganic substrate, and can still be normally adhered underwater.
Disclosure of Invention
The invention aims to solve the problem that an innovative scheme is provided aiming at the defects in the prior art, and the glue type biological adhesive with quick adhesive property, strong adhesive property and high biocompatibility is designed by utilizing the cohesion of protein-polysaccharide phase separation and the adhesion advantage of dopa.
In order to solve the problems, the invention adopts the following scheme: the biological glue based on phase separation is characterized in that the biological glue is a phase separation structure formed by dopa-modified polysaccharide and protein; dopa-modified polysaccharides form cohesive forces with proteins through charge interactions and cation-pi interactions, forming phase separation.
Further, the biological glue based on phase separation is characterized in that the dopa-modified polysaccharide is dopa-pectin (pectin-dopa), and is obtained by condensation reaction of carboxyl groups of pectin side chains and amino groups of dopa under catalysis of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) by dopamine and pectin.
Further, the phase separation based biological glue is characterized in that the protein is beta-lactoglobulin.
A preparation method of biological glue based on phase separation is characterized in that dopa-modified polysaccharide and beta-lactoglobulin are dissolved in phosphate buffer solution and are subjected to ultrasonic oscillation mixing treatment to obtain the biological glue with a phase separation structure.
Further, the preparation method of the biological glue based on the phase separation is characterized in that the dopa-modified polysaccharide and the beta-lactoglobulin are dissolved in a phosphate buffer solution according to a mass ratio of 1.
Further, the biological glue based on phase separation is characterized in that the preparation method of the dopa modified polysaccharide comprises the following steps: dissolving pectin and dopamine in deionized water, adding sodium ascorbate, then respectively adding EDC and NHS into the mixture, removing dissolved oxygen with nitrogen, stirring at moderate temperature in ice bath, continuously reacting, dialyzing the resultant with a dialysis bag with a cut-off molecular weight of 3.5kDa, dialyzing in deionized water, removing unreacted reactants, lyophilizing the dialyzed liquid to obtain dopa-pectin powder, and storing at 4 ℃.
Further, the biological glue based on phase separation is characterized in that pectin, dopamine, sodium ascorbate, EDC and NHS are added in the following weight parts of 10:2:10, configuring.
Further, the biological glue based on phase separation is characterized in that the biological glue based on phase separation is applied to various medical instruments and medicines.
The biological glue based on phase separation can be used for the adhesion of various in-vivo and/or in-vitro organic tissues and the adhesion of various in-vivo and in-vitro organic tissues, so that the sealing and tissue adhesion of in-vivo and in-vitro wounds are realized, the bleeding is quickly stopped, and the wound healing is promoted. The separated biological glue can be applied to the preparation of external wound spraying dressing and adhesive bandage, and the adhesion and fixation of in vivo and in vitro sensing monitoring devices.
The invention has the following technical effects: 1. compared with the traditional adhesive, the biological adhesive can provide quick and effective wet adhesion strength and has excellent biocompatibility and degradation characteristics.
2. Compared with the traditional adhesive, the biological glue has the adhesion characteristic in a liquid phase environment, wherein the dopa-modified polysaccharide and the protein interact with cations-pi through charge interaction to form an enhanced phase separation structure, and still exhibit a condensed form in the liquid phase environment, so that the normal adhesion characteristic in an underwater environment is ensured.
3. Compared with the traditional adhesive interface connection and solidification mechanism, the method mainly depends on pectin-dopa to realize the connection of the biological glue and the surface of the organic tissue, and the dopa forms covalent connection with sulfydryl or amino on the surface of the organic tissue after oxidation to finally realize long-term stable adhesion.
4. Compared with the traditional biological adhesive, the biological adhesive provided by the invention mainly depends on hydrogen bonds formed by dopa and a hydrophilic surface, the carboxyl of the polysaccharide side chain has negative charges, an electrical interaction can be formed between the polysaccharide side chain and an organic tissue interface, and the hydrogen bonds are combined with the electrical interaction, so that short-term rapid adhesion in a wet environment is ensured.
5. Compared with the traditional biological adhesive, the biological adhesive disclosed by the invention is composed of dopa-modified polysaccharide and protein, and has excellent biological safety and degradation characteristics due to biocompatibility of dopa, polysaccharide and protein and the degradability of biological macromolecules.
6. The adhesive strength of the biological glue can be regulated and controlled by adjusting the proportion of dopa in pectin-dopa in the glue and the proportion of pectin-dopa and beta-lactoglobulin in the glue.
Drawings
FIG. 1 is a schematic diagram of a biological glue based on phase separation.
FIG. 2A synthesis route of dopa-modified pectin polysaccharides.
FIG. 3 is a phase separation structure characterization based on phase separation of biogum.
Fig. 4 is based on the surface adhesion strength of the organic and inorganic materials of the bio-glue in phase separation.
Fig. 5 is based on phase separation of biological glue underwater environmental organic tissue adhesion.
FIG. 6 is based on the rapid adhesion of phase separated biogenic glue to different organic tissues in vitro.
FIG. 7 biogum adhesion strength control and cytotoxicity characterization based on phase separation.
Figure 8 characterization of the in vivo inflammatory response and degradation characteristics of the biogenic glue based on phase separation.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings.
A biological glue based on phase separation, as shown in fig. 1, the phase separation glue can still realize stable adhesion to organic tissues in the presence of water and maintain a high-strength adhesion effect for a long time; the biological glue is composed of a dopa modified polysaccharide polymer and a protein; the dopa-modified polysaccharide macromolecules and proteins form a phase separation structure through charge interaction and cation-pi interaction, and a coacervation state in an aqueous phase environment is maintained.
Dissolving the dopa-modified polysaccharide and the beta-lactoglobulin in a phosphate buffer (10 mM concentration, pH 7.4) according to a mass ratio of 1.
Further, the synthesis and preparation steps of the dopa-modified polysaccharide polymer are as follows.
The polysaccharide is dopa-pectin (pectin-dopa), and is obtained by condensation reaction of carboxyl of pectin side chain and amino of dopa catalyzed by 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (FIG. 2). Pectin and dopamine were dissolved in deionized water at a concentration of 50mg/mL each. EDC and NHS were then added to the mixture at concentrations of 50 and 25mg/mL, respectively, and sodium ascorbate was added at a concentration of 10mg/mL. After removing dissolved oxygen with nitrogen, the reaction was carried out for 12 hours while stirring in an ice bath. The resultant was dialyzed with a dialysis bag having a cut-off molecular weight of 3.5kDa in deionized water to remove unreacted reactants. Lyophilizing the dialyzed liquid to obtain pectin-dopa powder, and storing at 4 deg.C.
The following examples are conducted to test the properties of the present invention.
Example 1 phase separation-based characterization of the phase separation structure in biogenic glue according to the present invention.
In the invention, the phase separation structure of the phase-separated biological glue is characterized by optical microscope observation. As shown in fig. 3A-B, there was no significant phase separation in the pectin-dopa (PD) solution alone, indicating that pectin-dopa alone did not coagulate. Significant phase separation occurred in the mixture of pectin and beta-lactoglobulin (P-L), and the mixture of pectin-dopa and beta-lactoglobulin (PD-L), indicating that the introduction of dopa in pectin did not affect the phase separation of pectin-dopa and beta-lactoglobulin. And the area of the coagulants in the PD-L biological gel is larger than that of the P-L, and the distance between adjacent coagulants is smaller, which shows that the modification of the pectin by the dopa can further improve the phase separation of the pectin-dopa and the beta-lactoglobulin. Applicants have conducted a quantitative evaluation of the coacervate diameter of biological glue phase separation using Dynamic Light Scattering (DLS). As can be seen from FIGS. 3C to D, the phase-separated aggregates of PD-L had diameters in the range of 1.2 to 5.5 μm, and were concentrated at 4.6. Mu.m. The P-L had a coacervate diameter in the range of 2.2 to 9.6. Mu.m, centered at 3.9. Mu.m, in agreement with the results for the optical images. This example demonstrates that the introduction of dopa groups into pectin in the present invention does not affect the phase separation structure of pectin from beta-lactoglobulin, but rather, the introduction of dopa groups enhances the phase separation structure.
Example 2 surface adhesion strength of phase separation-based biogum bonding organic and inorganic materials in accordance with the invention
To test the adhesion strength of the phase separation based biogenic glue of the present invention to organic and inorganic materials. Moist pigskin was chosen as the model tissue because its mechanical and biological properties are similar to those of human skin. Two types of mechanical tests (shear strength test and tensile strength test of the adhesive) were used to evaluate the adhesion properties of the biological glues. Pectin-dopa (PD), a mixture of pectin and beta-lactoglobulin (P-L) was set as a control group. As can be seen from FIGS. 4A-C, the biological glue of the present invention has a long-term adhesion strength higher than 0.5MPa for the adhesion between organic tissues (skin-skin), the adhesion between organic tissues and glass (skin-glass), and even higher than 1.48MPa for the adhesion between organic tissues. In addition, the short-term adhesion (adhesion time less than 1 minute) shear strength of the biological glue of the invention to organic tissues and inorganic substrates reaches 0.27MPa, which is more than that of most commercial biological glues. The adhesion strength (PD-L) of the biological glue is much higher than that of the control group (P-L and PD). Likewise, a similar trend was exhibited in the tensile strength test of adhesion. The short-term bonding tensile strength (figure 4D-F) of the biogum reaches 0.22MPa, the long-term bonding tensile strength is more than 0.4MPa, and the bonding strength to pigskin is more than 0.72MPa. As can be seen from FIGS. 4G and H, the bonding to the biological glue is performedThe interface toughness of the pigskin is tested for long-term adhesion, and the interface toughness is found to be 880J m -2 The biological glue of the invention is one of the biological glues with the highest adhesive interface toughness at present. The experimental test results in this section show that the biological glue of the present invention has fast and stable adhesion to both organic tissues and non-substrate materials.
Example 3 biological glue based phase separation in accordance with the invention underwater environmental organic tissue adhesion.
In the aspect of adhesion tests with different organic tissues and inorganic material surfaces, the PD-L biogel based on pectin-dopa and beta-lactoglobulin has the advantage that it can even remain in an aggregated state in solution, which indicates that the biogel in the present invention can work directly in an aqueous environment. As shown in figure 5A, the biological glue of the present invention is applied underwater to the surface of the pigskin, the glue still remains in an aggregate state, and another pigskin is covered on the surface to clamp the glue. After 12 hours of curing, the bond strength was measured in deionized water using a standard shear test. The long-term bonding shear strength measured reaches 0.78MPa (figure 5B), which shows that the biological glue has good underwater bonding performance. In the bonding operation and the curing process, the phase separation behavior prevents the glue from diffusing to the water environment, so that the adhesive has strong bonding capability in the water environment.
Example 4 the phase separation based bio-glue of the present invention rapidly adheres to different organic tissues in vitro.
The biological glue based on phase separation has super-strong rapid adhesion capability to various organic tissues. In this example, different in vitro organic tissue adhesion tests were performed using the bio-glue of the present invention. The short-term and long-term adhesion strength of tissues such as pig liver, heart, kidney, stomach, lung, etc. was tested using biological glue. As shown in FIGS. 6A-C, the shear strength of the short-term adhesion exceeded 20kPa for all organic tissues (liver 22.1kPa, heart 25.5kPa, kidney 31.2kPa, stomach 19.4kPa, lung 21.8 kPa). The shear strength of the long-term adhesion exceeded 270kPa (liver 349kPa, heart 398kPa, kidney 381kPa, stomach 274kPa, lung 368 kPa). The long-term adhesion strength of the biological glue in the invention to different tissues is obviously higher than that of fibrinogen biological glue (the shear strength of fibrinogen glue is usually less than 30 kPa). Likewise, applicants have also tested the tensile adhesion strength of all tissues. The short-term adhesion tensile strength was higher than 10kPa (liver 16.1kPa, heart 15.5kPa, kidney 12.2kPa, stomach 20.4kPa, lung 17.8 kPa) and the long-term adhesion tensile strength was higher than 270kPa (liver 319kPa, heart 308kPa, kidney 291kPa, stomach 274kPa, lung 248 kPa) for each type of organic tissue (FIGS. 6D-F). These results indicate that the bioplasticizes of the present invention have excellent instantaneous and long-term adhesion to various organic tissues.
Example 5 phase separation based cytolytic toxicity characterization of biogum in accordance with the present invention.
In order to demonstrate the biological safety of the phase separation based bio-glue of the present invention, it was subjected to cytotoxicity test. As shown in FIGS. 7A to C, the applicant evaluated the cytotoxicity of the biogenic glue using L929 and HeLa cells as model cells. The biological glue of the invention is added into a cell culture medium with the concentration of 50mg/mL for cell culture. After 24 hours incubation in a carbon dioxide incubator, the cells were tested for viability using fluorescent staining of live and dead cells. The live and dead cell staining photographs showed (fig. 7A) that the presence of dead cells was barely observed in both the presence and absence of biological glue. Further, counting and statistics of live and dead cells were performed, which showed that the survival rate of both L929 and hMSC cells was higher than 80% in the presence of the bio-glue (fig. 7B), indicating that the bio-glue has good biocompatibility and no significant cytotoxicity.
Example 6 biocompatibility and degradability tests of the invention.
In order to demonstrate the biocompatibility of the bio-glue of the present invention, the applicant conducted in vivo implantation experiments of animal models in this example. As shown in fig. 8, the inflammatory response test of the back subcutaneous biofouling implantation was performed using a mouse as an experimental subject, and 2 days after the implantation, the implantation site was sampled and sectioned and subjected to hematoxylin-eosin (HE) staining. From the slicing results, it can be found that the control group (sham operation group) and the experimental group implanted with the biological glue have no obvious inflammatory cell infiltration, and the edge of the implanted cavity is clear, and no obvious cell necrosis exists. This example demonstrates that the biological glue of the present invention has excellent biocompatibility without causing a drastic inflammatory reaction of living tissues.
Claims (8)
1. The biological glue based on phase separation is characterized in that the biological glue is a phase separation structure formed by dopa modified polysaccharide and protein.
2. The phase separation based biogum according to claim 1, wherein the dopa-modified polysaccharide forms phase separation by forming cohesive force with protein through charge interaction and cation-pi (cation-pi) interaction.
3. The biological glue based on phase separation as claimed in claim 1, wherein the dopa-modified polysaccharide is dopa-pectin (pectin-dopa), obtained by condensation reaction of carboxyl groups of pectin side chains and amino groups of dopa catalyzed by 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS); the protein is beta-lactoglobulin.
4. The method for preparing biological glue based on phase separation according to claim 1, wherein dopa-modified polysaccharide and beta-lactoglobulin are dissolved in phosphate buffer and mixed by ultrasonic oscillation to obtain the biological glue with a phase separation structure.
5. The method for preparing biological glue based on phase separation according to claim 4, wherein dopa-modified polysaccharide and β -lactoglobulin are dissolved in phosphate buffer at a mass ratio of 1.
6. The phase separation based biological glue of claim 1, wherein the dopa-modified polysaccharide is prepared by a method comprising: dissolving pectin and dopamine in deionized water, adding sodium ascorbate, then respectively adding EDC and NHS into the mixture, removing dissolved oxygen with nitrogen, then carrying out moderate temperature and stirring in an ice bath, continuously reacting, finally dialyzing the synthetic product with a dialysis bag with the cut-off molecular weight of 3.5kDa, carrying out dialysis in deionized water, removing unreacted reactants, and freeze-drying the liquid obtained by dialysis to obtain dopa-pectin powder.
7. The phase separation based biogum according to claim 6, wherein pectin, dopamine, sodium ascorbate, EDC and NHS are formulated in a mass ratio of 10.
8. The phase separation based biological glue of claim 1, wherein the phase separation based biological glue is applied to various medical devices and medicines.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180311403A1 (en) * | 2017-05-01 | 2018-11-01 | The Brigham And Women's Hospital, Inc. | Pectin-Carboxymethylcellulose Mesothelial Sealants and Protectants |
| CN110192643A (en) * | 2019-04-18 | 2019-09-03 | 中国农业科学院农产品加工研究所 | Potato pectin-albumen composite emulsifying liquid and the preparation method and application thereof |
| WO2021006426A1 (en) * | 2019-07-09 | 2021-01-14 | 연세대학교 산학협력단 | Biomimetic tissue-adhesive hydrogel patch and use thereof |
| CN113563681A (en) * | 2021-07-16 | 2021-10-29 | 南京大学 | Degradable wet-state adhesive hydrogel material and preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180311403A1 (en) * | 2017-05-01 | 2018-11-01 | The Brigham And Women's Hospital, Inc. | Pectin-Carboxymethylcellulose Mesothelial Sealants and Protectants |
| CN110192643A (en) * | 2019-04-18 | 2019-09-03 | 中国农业科学院农产品加工研究所 | Potato pectin-albumen composite emulsifying liquid and the preparation method and application thereof |
| WO2021006426A1 (en) * | 2019-07-09 | 2021-01-14 | 연세대학교 산학협력단 | Biomimetic tissue-adhesive hydrogel patch and use thereof |
| CN113563681A (en) * | 2021-07-16 | 2021-10-29 | 南京大学 | Degradable wet-state adhesive hydrogel material and preparation method and application thereof |
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