CN117844065A - Low-swelling-degree double-network medical hydrogel and preparation method and application thereof - Google Patents
Low-swelling-degree double-network medical hydrogel and preparation method and application thereof Download PDFInfo
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title abstract description 16
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000000661 sodium alginate Substances 0.000 claims abstract description 42
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 42
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 42
- -1 succinimidyl Chemical group 0.000 claims abstract description 41
- 125000004185 ester group Chemical group 0.000 claims abstract description 39
- 229920001661 Chitosan Polymers 0.000 claims abstract description 32
- 230000008961 swelling Effects 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000011065 in-situ storage Methods 0.000 claims abstract description 11
- 238000007789 sealing Methods 0.000 claims abstract description 10
- 230000008439 repair process Effects 0.000 claims abstract description 9
- 208000031737 Tissue Adhesions Diseases 0.000 claims abstract description 8
- 238000011049 filling Methods 0.000 claims abstract description 8
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims abstract description 7
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 7
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 5
- 230000023597 hemostasis Effects 0.000 claims abstract description 4
- 239000000872 buffer Substances 0.000 claims description 31
- 239000007853 buffer solution Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 10
- 159000000007 calcium salts Chemical class 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 8
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 6
- 239000005714 Chitosan hydrochloride Substances 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 6
- 229910021641 deionized water Inorganic materials 0.000 claims description 6
- HDFXRQJQZBPDLF-UHFFFAOYSA-L disodium hydrogen carbonate Chemical compound [Na+].[Na+].OC([O-])=O.OC([O-])=O HDFXRQJQZBPDLF-UHFFFAOYSA-L 0.000 claims description 6
- 239000001488 sodium phosphate Substances 0.000 claims description 6
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 6
- 235000011152 sodium sulphate Nutrition 0.000 claims description 6
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 5
- 239000001110 calcium chloride Substances 0.000 claims description 5
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 5
- 229960002713 calcium chloride Drugs 0.000 claims description 5
- 235000011148 calcium chloride Nutrition 0.000 claims description 5
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 claims description 5
- 239000001527 calcium lactate Substances 0.000 claims description 5
- 235000011086 calcium lactate Nutrition 0.000 claims description 5
- 229960002401 calcium lactate Drugs 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims description 4
- 239000008363 phosphate buffer Substances 0.000 claims description 4
- 159000000001 potassium salts Chemical class 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229910021538 borax Inorganic materials 0.000 claims description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 2
- 239000001639 calcium acetate Substances 0.000 claims description 2
- 229960005147 calcium acetate Drugs 0.000 claims description 2
- 235000011092 calcium acetate Nutrition 0.000 claims description 2
- 239000004227 calcium gluconate Substances 0.000 claims description 2
- 229960004494 calcium gluconate Drugs 0.000 claims description 2
- 235000013927 calcium gluconate Nutrition 0.000 claims description 2
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 claims description 2
- UQGFMSUEHSUPRD-UHFFFAOYSA-N disodium;3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane Chemical compound [Na+].[Na+].O1B([O-])OB2OB([O-])OB1O2 UQGFMSUEHSUPRD-UHFFFAOYSA-N 0.000 claims description 2
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229940054190 hydroxypropyl chitosan Drugs 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 239000001508 potassium citrate Substances 0.000 claims description 2
- 229960002635 potassium citrate Drugs 0.000 claims description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 2
- 235000011082 potassium citrates Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 235000011151 potassium sulphates Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 239000004328 sodium tetraborate Substances 0.000 claims description 2
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 2
- HXMWJLVXIHYART-UHFFFAOYSA-M sodium;2-hydroxypropane-1,2,3-tricarboxylic acid;hydroxide;hydrochloride Chemical compound [OH-].[Na+].Cl.OC(=O)CC(O)(C(O)=O)CC(O)=O HXMWJLVXIHYART-UHFFFAOYSA-M 0.000 claims description 2
- 230000009977 dual effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
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- 125000003277 amino group Chemical group 0.000 abstract description 3
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 2
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- 208000014674 injury Diseases 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 5
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
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Landscapes
- Materials For Medical Uses (AREA)
Abstract
The invention provides a double-network medical hydrogel with low swelling degree, a preparation method and application thereof, wherein in the hydrogel, a hydrogel network with high adhesion and low swelling property is constructed by in-situ polymerization by utilizing the simultaneous action of ionic bonds and covalent bonds, and the hydrogel has great application prospect in the fields of tissue adhesion, sealing, filling, sealing, hemostasis and bone repair. In the gelling process, the succinimidyl ester group on the sodium alginate can react with the amino group on the chitosan to generate a covalent bond, and the carboxyl group on the sodium alginate reacts with Ca 2+ The ionic bonding effect can occur between the hydrogel and the hydrogel, the coordination effect can occur between the chitosan and anions in sodium salt and/or potassium salt, and the triple effects can occur simultaneously, so that the hydrogel generated in situ has better mechanical property, stronger tissue adhesion and swelling degree as low as about 50 percent, and compared with the swelling of the existing in situ polymerized gel which is multiplied by a constant even tens of times.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and in particular relates to a covalent-ion dual-network medical hydrogel which has the advantages of low swelling degree, strong adhesiveness, good biocompatibility, in vivo degradation and absorption, tissue adhesion, filling, sealing and repairing, and a preparation method and application thereof.
Background
With the annual improvement of the domestic industrialization level, accidental injuries and accidents are also increasing. In addition to war and natural disasters, a large number of wounded persons are caused, and in daily work, wounds caused by various factors such as traffic accident injury, falling injury, mechanical injury, sharp tool injury, falling injury, sprain and the like are very common. All wounds (including body surfaces, internal wounds) require immediate closure and repair to prevent infection and promote healing.
Suturing is the most common technique for achieving wound closure and repair, but common problems with suturing are unavoidable penetration of surrounding tissue, nerve damage and possible post-operative adhesions, and ischemia and necrosis of the tissue caused by capillary damage. For the urgent clinical need, medical hydrogel adhesives have emerged to replace traditional suturing techniques or as a complementary means of suturing.
The wound management areas include hemostatic, occlusive, and repair areas, and a number of functional materials have been developed. However, with preformed dressings, irregular wounds cannot be fitted, and the ability to absorb water is weak, only for small areas of bleeding. Cyanoacrylate with in-situ polymerization characteristics is low in price and strong in adhesiveness, but has poor degradation performance, and the formed polymer film is hard in texture, and is easy to scratch surrounding soft tissues during in-vivo application, so that new wounds are caused. The hydrogel formed in situ is represented by fibrin glue, and has high price, low mechanical strength and harsh storage condition. Another common polyethylene glycol-based gel (e.g., duraSeal TM 、As high as SprayGel) and has high swelling capacity, and can press surrounding tissues during use, thereby causing secondary injury. In the face of complex practical application, the existing hydrogel still has a plurality of challenges, and the development of the hydrogel with low swelling, high adhesion, convenient use and optimized performance has important clinical value.
Alginate and chitosan are two types of ionic polymers that are widely used in the biomedical field. Carboxylate anions on alginate molecular chains and amine cations on chitosan molecular chains form macromolecular complexes in aqueous solution due to electrostatic attraction, and are a common pair of hydrogel materials. In the aspect of in-situ polymerized hydrogel for tissue filling and sealing, aldehyde groups (-CHO), polyphenol groups represented by dopamine or succinimidyl ester groups (-NHS) are formed by chemically modifying alginate, and the hydrogel with high adhesion performance can be formed by utilizing the reaction of the groups with chitosan and amino groups on tissue surface proteins. However, such materials tend to have excellent water absorption and retention properties, and expand several times or even tens times after absorbing a large amount of water in the body, squeezing wounds, compressing tissues and nerves. Too high a degree of swelling is one of the key issues limiting the application of such polysaccharide hydrogels in the field of tissue sealing and filling.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide the covalent-ion double-network medical hydrogel which has low swelling degree, strong adhesiveness, good biocompatibility, and can be degraded and absorbed in vivo, and has the functions of tissue adhesion, filling, sealing and repairing, and the preparation method and the application thereof.
The invention aims at realizing the following technical scheme:
a medical hydrogel comprising a first component and a second component: the first component comprises chitosan and calcium salt; the second component comprises sodium alginate containing succinimidyl ester groups and sodium and/or potassium salts.
According to an embodiment of the invention, the first component consists of chitosan and a calcium salt; the second component consists of sodium alginate containing succinimidyl ester groups and sodium salt and/or potassium salt.
According to an embodiment of the invention, the mass ratio of the first component to the second component is 1:5 to 5:1, such as 3:1, 2:1, 1:1, 1:2 or 1:3.
According to an embodiment of the present invention, the chitosan is selected from one or more of chitosan hydrochloride, hydroxypropyl chitosan, methyl chitosan, ethyl chitosan, carboxymethyl chitosan, chitosan phosphate, chitosan perchlorate.
According to an embodiment of the present invention, the calcium salt is selected from one or more of calcium chloride, calcium acetate, calcium lactate, calcium gluconate, calcium nitrate.
According to an embodiment of the invention, the mass ratio of the calcium salt to chitosan is 1:50-5:1, such as 1:50, 1:40, 1:30, 1:20, 1:10, 1:2, 1:1, 3:2, 2:1, 5:4, 5:2, 3:1, 7:2 or 4:1.
According to an embodiment of the present invention, the sodium salt is selected from one or more of sodium chloride, sodium sulfate, sodium phosphate, sodium citrate; the potassium salt is selected from one or more of potassium chloride, potassium sulfate, potassium phosphate and potassium citrate.
According to an embodiment of the invention, the mass ratio of the sodium salt and/or potassium salt to the sodium alginate containing succinimidyl ester groups is 1:50 to 5:1, such as 1:50, 1:40, 1:30, 1:20, 1:10, 1:3, 1:1, 3:2, 2:1, 5:2, 3:1, 7:2 or 4:1.
According to an embodiment of the present invention, the viscosity (1% aqueous solution) of the sodium alginate containing a succinimidyl ester group is 20 to 200mpa·s, for example, 20 to 50mpa·s,50 to 100mpa·s,100 to 200mpa·s.
According to an embodiment of the present invention, in the sodium alginate containing a succinimidyl ester group, the substitution degree of the succinimidyl ester group is 10 to 35%.
According to an embodiment of the invention, the sodium alginate containing succinimidyl ester groups is prepared by the following method:
(a) Dissolving sodium alginate in a buffer solution, and adding N-hydroxysuccinimide and a dehydrating agent to perform esterification reaction to obtain sodium alginate containing succinimidyl ester groups.
According to an embodiment of the invention, the method further comprises the steps of:
(b) After the esterification reaction, adding a precipitant into the solution, and separating out white solid, thus obtaining sodium alginate containing succinimidyl ester groups.
According to an embodiment of the invention, the method further comprises the steps of:
(c) Dissolving the white solid in water, adding a precipitator, and centrifuging or filtering to separate the white solid;
(d) Repeating the step (c) for 3-4 times, and vacuum drying the white solid separated in the last time to obtain the sodium alginate containing succinimidyl ester groups.
According to an embodiment of the invention, in step (a), the buffer is a buffer solution known in the art, such as a Mes buffer, the pH of which is 4 to 7, preferably the pH of which is 4 to 5.5.
According to an embodiment of the present invention, in the step (a), the adding amount of the sodium alginate is 0.5% -10% of the total mass of the mixed system (sodium alginate and buffer solution).
According to an embodiment of the invention, in step (a), the dehydrating agent is selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
According to an embodiment of the invention, in step (a), the molar ratio of the N-hydroxysuccinimide to the carboxylic groups in the sodium alginate is from 1:10 to 3:1, for example 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1 or 3:1; the molar ratio of the dehydrating agent to the N-hydroxysuccinimide is 1:1 to 5:1, for example 1:1, 2:1, 3:1, 4:1 or 5:1.
According to an embodiment of the present invention, in the step (a), the temperature of the esterification reaction is room temperature, and the time of the esterification reaction is 2 to 24 hours.
According to an embodiment of the invention, in step (b) and step (c), the volume ratio of the precipitant to the polysaccharide solution containing succinimidyl ester groups is from 1:1 to 5:1, for example 1:1, 2:1, 3:1, 4:1 or 5:1.
According to an embodiment of the present invention, in step (b) and step (c), the precipitating agent is selected from at least one of methanol, ethanol, isopropanol, acetone and tetrahydrofuran.
According to an embodiment of the present invention, in the step (d), the vacuum drying temperature is 30 to 70 ℃ for 4 to 24 hours.
The invention provides a medical hydrogel, which is formed by reacting a first component and a second component, wherein the first component comprises chitosan and calcium salt; the second component comprises sodium alginate containing succinimidyl ester groups and sodium and/or potassium salts.
According to an embodiment of the invention, the medical hydrogel is a covalent-ionic double network in situ polymerized hydrogel.
According to an embodiment of the present invention, the swelling degree of the medical hydrogel is 50% or less (swelling degree in phosphate buffer solution of pH 7.4 at 37 ℃).
The invention also provides a preparation method of the medical hydrogel, which comprises the following steps:
and dissolving the first component in a first buffer solution, dissolving the second component in deionized water or a second buffer solution, and then mixing and standing to form the medical hydrogel.
According to an embodiment of the invention, the pH of the first buffer is 7.5-12.0, such as 7.6-11.0.
According to an embodiment of the invention, the first buffer comprises, but is not limited to, phosphate buffer, sodium carbonate-sodium bicarbonate buffer, sodium tetraborate buffer, tris-HCl buffer.
According to an embodiment of the invention, the mass ratio of the first buffer solution to the first component is 5:1 to 200:1, such as 12:1 to 100:1.
According to an embodiment of the invention, the pH of the second buffer solution is 3.0-7.0, such as 3.5-6.0.
According to an embodiment of the invention, the second buffer comprises, but is not limited to, mes buffer, phosphate buffer, disodium hydrogen phosphate-citrate buffer, citrate-sodium hydroxide-hydrochloride buffer.
According to an embodiment of the invention, the mass ratio of the water or the second buffer and the second component is 5:1 to 200:1, such as 12:1 to 100:1.
The invention also provides application of the medical hydrogel in aspects of tissue adhesion, filling, sealing, hemostasis and bone repair.
The beneficial effects are that:
in the chitosan hydrogel system, the ionic bond and the covalent bond are used for simultaneously acting, the hydrogel network with high adhesion and low swelling property is constructed by in-situ polymerization, and the method has great application prospect in the fields of tissue adhesion, sealing, filling, sealing, hemostasis and bone repair. In the gelling process, the succinimidyl ester group on the sodium alginate can react with the amino group on the chitosan to generate a covalent bond, and the carboxyl group on the sodium alginate reacts with Ca 2+ The ionic bonding effect can be generated between the hydrogel and the hydrogel, the coordination effect can be generated between the chitosan and anions in sodium salt and/or potassium salt, and the triple effects can be generated simultaneously, so that the hydrogel generated in situ has better mechanical property, stronger tissue adhesion and swelling degree as low as about 50 percent, and compared with the swelling of the existing in situ polymerized gel with the constant times or tens times, the medical use with low swelling degreeThe hydrogel can effectively reduce the compression and injury to surrounding tissues and nerves in clinical application. In addition, the invention adopts a post-treatment mode of precipitant-separation-vacuum drying to replace the common aqueous solution dialysis-freeze drying method, thus the operation can save the reaction time and the cost and is beneficial to mass production. More importantly, the post-treatment method can greatly reduce the time of exposing the sodium alginate containing the succinimidyl ester group to the aqueous solution, effectively reduce the reverse hydrolysis reaction of the succinimidyl ester group, thereby obtaining a product with high substitution degree, increasing covalent crosslinking sites in the gelling process, and being beneficial to inhibiting the swelling level of the hydrogel.
Detailed Description
The present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; the reagents, materials, etc. used in the examples described below are commercially available unless otherwise specified.
Example 1
Preparation of sodium alginate containing succinimidyl ester groups:
(1) 2.0g of sodium alginate was dissolved in 80mL of Mes buffer pH 5.5, followed by addition of 1.2. 1.2g N-hydroxysuccinimide and 2.3g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the reaction was stopped after stirring at room temperature for 12 hours.
(2) 120mL of absolute ethanol was added to the reaction mixture, and the mixture was suction-filtered to obtain a white solid.
(3) The white solid was dissolved in 80mL of water, and then 120mL of absolute ethanol was added thereto, followed by suction filtration to obtain a white solid.
(4) Repeating the step (3) for 3 times, and vacuum drying the white solid separated from the last time at 60 ℃ for 10 hours to obtain the sodium alginate containing succinimidyl ester groups. The degree of substitution of the succinimidyl ester group was determined to be 34%.
Preparation of double-network hydrogel:
(1) 0.04g of chitosan hydrochloride and 0.02g of calcium chloride are weighed and dissolved in 1mL of Tris-HCl buffer with pH of 8.5;
(2) Weighing 0.06g of sodium alginate containing succinimidyl ester groups and 0.02g of sodium phosphate, and dissolving the sodium alginate and the sodium phosphate in 1mL of Mes buffer solution;
(3) And (3) uniformly mixing the solutions in the step (1) and the step (2) through an extrusion device, applying the mixture to a required position, and standing the mixture to obtain the double-network hydrogel.
Example 2
Preparation of double-network hydrogel:
(1) 0.04g of chitosan hydrochloride and 0.05g of calcium chloride are weighed and dissolved in 1mL of Tris-HCl buffer with pH of 8.5;
(2) Sodium alginate containing succinimidyl ester group prepared in example 1, 0.06g, sodium phosphate 0.05g were weighed and dissolved in 1mL of Mes buffer;
(3) And (3) uniformly mixing the solutions in the step (1) and the step (2) through an extrusion device, applying the mixture to a required position, and standing the mixture to obtain the double-network hydrogel.
Example 3
Preparation of double-network hydrogel:
(1) 0.04g of chitosan hydrochloride and 0.08g of calcium chloride are weighed and dissolved in 1mL of Tris-HCl buffer with pH of 8.5;
(2) Sodium alginate containing succinimidyl ester group prepared in example 1, 0.06g, sodium phosphate 0.08g were weighed and dissolved in 1mL of Mes buffer;
(3) And (3) uniformly mixing the solutions in the step (1) and the step (2) through an extrusion device, applying the mixture to a required position, and standing the mixture to obtain the double-network hydrogel.
Example 4
Preparation of sodium alginate containing succinimidyl ester groups:
(1) 2.0g of sodium alginate was dissolved in 80mL of Mes buffer pH 5.5, and 0.7. 0.7g N-hydroxysuccinimide and 1.2g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added thereto, followed by stirring at room temperature for 12 hours, and the reaction was stopped.
(2) 120mL of absolute ethanol was added to the reaction mixture, and the mixture was suction-filtered to obtain a white solid.
(3) The white solid was dissolved in 80mL of water, and then 120mL of absolute ethanol was added thereto, followed by suction filtration to obtain a white solid.
(4) Repeating the step (3) for 3 times, and vacuum drying the white solid separated from the last time at 60 ℃ for 10 hours to obtain the sodium alginate containing succinimidyl ester groups. The degree of substitution of the succinimidyl ester group was determined to be 12%.
Preparation of double-network hydrogel:
(1) 0.05g of carboxymethyl chitosan and 0.02g of calcium lactate are weighed and dissolved in 1mL of sodium carbonate-sodium bicarbonate buffer solution with pH 9;
(2) Weighing 0.05g of sodium alginate containing succinimidyl ester groups and 0.02g of sodium sulfate, and dissolving the sodium alginate and the sodium sulfate in 1mL of deionized water;
(3) And (3) uniformly mixing the solutions in the step (1) and the step (2) through an extrusion device, applying the mixture to a required position, and standing the mixture to obtain the double-network hydrogel.
Example 5
Preparation of double-network hydrogel:
(1) 0.05g of carboxymethyl chitosan and 0.05g of calcium lactate are weighed and dissolved in 1mL of sodium carbonate-sodium bicarbonate buffer solution with pH 9;
(2) Weighing 0.05g of sodium alginate containing succinimidyl ester groups prepared in example 4 and 0.05g of sodium sulfate, and dissolving in 1mL of deionized water;
(3) And (3) uniformly mixing the solutions in the step (1) and the step (2) through an extrusion device, applying the mixture to a required position, and standing the mixture to obtain the double-network hydrogel.
Example 6
Preparation of double-network hydrogel:
(1) 0.05g of carboxymethyl chitosan and 0.08g of calcium lactate are weighed and dissolved in 1mL of sodium carbonate-sodium bicarbonate buffer solution with pH 9;
(2) 0.05g of sodium alginate containing succinimidyl ester group prepared in example 4 and 0.08g of sodium sulfate were weighed and dissolved in 1mL of deionized water;
(3) And (3) uniformly mixing the solutions in the step (1) and the step (2) through an extrusion device, applying the mixture to a required position, and standing the mixture to obtain the double-network hydrogel.
Comparative example 1
Preparation of single network hydrogels:
(1) 0.04g of chitosan hydrochloride was weighed and dissolved in 1mL of Tris-HCl buffer pH 8.5;
(2) 0.06g of sodium alginate containing succinimidyl ester group prepared in example 1 was weighed and dissolved in 1mL of Mes buffer;
(3) And (3) uniformly mixing the solutions in the step (1) and the step (2) through an extrusion device, applying the mixture to a required position, and standing the mixture to obtain the single-network hydrogel.
Comparative example 2
Preparation of single network hydrogels:
(1) Carboxymethyl chitosan 0.05g was weighed and dissolved in 1mL sodium carbonate-sodium bicarbonate buffer pH 9;
(2) Weighing 0.05g of sodium alginate containing succinimidyl ester group prepared in example 4 and dissolving in 1mL of deionized water;
(3) And (3) uniformly mixing the solutions in the step (1) and the step (2) through an extrusion device, applying the mixture to a required position, and standing the mixture to obtain the single-network hydrogel.
Test example 1
Measurement of the swelling degree of hydrogels.
The hydrogel was prepared into a disk shape having a diameter of 10mm and a height of 5mm, and the resultant was weighed (W 0 ). Placing into 50mL of phosphate buffer solution with pH of 7.4 at 37deg.C until weight is no longer increased, and the maximum value of weight is denoted as W t . The swelling degree of the hydrogel was calculated as:
swelling degree (%) = (W) t -W 0 )/W 0 ×100％
The test results are shown in the following table.
Test example 2
The adhesion capacity was tested using pigskin.
The pigskin was cut into 2 strips of length by width 30mm by 10 mm. The solutions of step (1) and step (2) obtained in the above examples and comparative examples were uniformly mixed by an extrusion device and then extruded onto an area of about 10mm×10mm at one end of the pigskin, respectively. Finally, the coated areas of the 2 pigskin strips were butted together and placed in a moist environment under 20N pressure for 2 hours. The bonding strength of the medical adhesive to pigskin was tested by using a universal tensile machine, and the test results are shown in the following table.
Test example 3
And testing the mechanical properties of the gel by adopting a universal tensile machine.
Cylindrical hydrogels with a diameter of 10mm and a height of 5mm were prepared in a cylindrical mold, the size of each sample was precisely measured, and the compressive strength was tested using a universal tensile machine. The speed of the compression test was 1mm/min, and it was pressed straight until the sample broke. The test results are shown in the following table.
The hydrogels of comparative examples 1 and 2 were not additionally added with salt, except that the single-network hydrogels formed by covalent bonding of chitosan and sodium alginate containing succinimidyl ester groups, and the swelling degree, adhesiveness and mechanical properties of the hydrogels were mainly affected by the substitution degree of succinimidyl ester groups on sodium alginate. The substitution degree is regulated by the feeding amount of the N-hydroxysuccinimide in the reaction process. The more the feeding amount is, the higher the substitution degree is, the higher the crosslinking density of the gel is, the corresponding swelling degree is lower, and the adhesion performance and mechanical property are stronger. Single network hydrogels already have lower swelling and comparable adhesive properties, compressive strength than commercial gels.
By comparing comparative example 1 with examples 1 to 3, comparative example 2 with examples 4 to 6, the degree of swelling decreases and the adhesive strength and compressive strength increase with the addition amount of the salt in the first component and the second component under the other conditions unchanged. The swelling degree can be reduced to less than half of the initial value, and the minimum can be 44%. The higher adhesiveness and the limited swelling degree have great advantages for the application of the hydrogel in nerve repair, tissue closure, bone repair and the like.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A medical hydrogel, wherein the medical hydrogel comprises a first component and a second component: the first component comprises chitosan and calcium salt; the second component comprises sodium alginate containing succinimidyl ester groups and sodium and/or potassium salts.
2. The medical hydrogel of claim 1, wherein the mass ratio of the first component to the second component is 1:5-5:1.
3. The medical hydrogel of claim 1, wherein the chitosan is selected from one or more of chitosan hydrochloride, hydroxypropyl chitosan, methyl chitosan, ethyl chitosan, carboxymethyl chitosan, chitosan phosphate, chitosan perchlorate;
and/or the calcium salt is selected from one or more of calcium chloride, calcium acetate, calcium lactate, calcium gluconate and calcium nitrate;
and/or the mass ratio of the calcium salt to the chitosan is 1:50-5:1.
4. The medical hydrogel of claim 1, wherein the sodium salt is selected from one or more of sodium chloride, sodium sulfate, sodium phosphate, sodium citrate; the potassium salt is selected from one or a combination of more of potassium chloride, potassium sulfate, potassium phosphate and potassium citrate;
and/or the mass ratio of the sodium salt and/or the potassium salt to the sodium alginate containing succinimidyl ester groups is 1:50-5:1.
5. The medical hydrogel of claim 1, wherein the sodium alginate containing succinimidyl ester groups has a viscosity of 20-200 mPa-s;
and/or, in the sodium alginate containing the succinimidyl ester group, the substitution degree of the succinimidyl ester group is 10-35%.
6. A medical hydrogel formed by reacting a first component and a second component, the first component comprising chitosan and a calcium salt; the second component comprises sodium alginate containing succinimidyl ester groups and sodium and/or potassium salts.
7. The medical hydrogel of any one of claims 1-6, wherein the medical hydrogel is a covalent-ionic dual network in situ polymerized hydrogel;
and/or, the swelling degree of the medical hydrogel is less than or equal to 50%.
8. A method of preparing the medical hydrogel of any one of claims 1-7, the method comprising:
and dissolving the first component in a first buffer solution, dissolving the second component in deionized water or a second buffer solution, and then mixing and standing to form the medical hydrogel.
9. The method according to claim 8, wherein the pH of the first buffer is 7.5 to 12.0;
and/or, the first buffer comprises phosphate buffer, sodium carbonate-sodium bicarbonate buffer, sodium tetraborate buffer, tris-HCl buffer;
and/or the mass ratio of the first buffer solution to the first component is 5:1-200:1;
and/or the pH value of the second buffer solution is 3.0-7.0;
and/or, the second buffer comprises Mes buffer, phosphate buffer, disodium hydrogen phosphate-citric acid buffer, citric acid-sodium hydroxide-hydrochloric acid buffer;
and/or the mass ratio of the water or the second buffer to the second component is 5:1-200:1.
10. Use of the medical hydrogel according to any one of claims 1-7 for tissue adhesion, filling, sealing, hemostasis and bone repair.
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