CN116421744A - Absorbable medical hydrogel and preparation method thereof - Google Patents
Absorbable medical hydrogel and preparation method thereof Download PDFInfo
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- CN116421744A CN116421744A CN202310436615.8A CN202310436615A CN116421744A CN 116421744 A CN116421744 A CN 116421744A CN 202310436615 A CN202310436615 A CN 202310436615A CN 116421744 A CN116421744 A CN 116421744A
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 114
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- -1 succinimidyl ester Chemical class 0.000 claims abstract description 42
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 36
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 35
- 239000007924 injection Substances 0.000 claims abstract description 22
- 238000002347 injection Methods 0.000 claims abstract description 22
- 125000000524 functional group Chemical group 0.000 claims abstract description 19
- 239000002872 contrast media Substances 0.000 claims abstract description 17
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 78
- 229960001025 iohexol Drugs 0.000 claims description 12
- 239000008055 phosphate buffer solution Substances 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 6
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 claims description 5
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
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- 125000003277 amino group Chemical group 0.000 claims description 3
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- 229960002611 ioxilan Drugs 0.000 claims description 3
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- FBJVWRITWDYUAC-UHFFFAOYSA-N 5-amino-2,4,6-triiodobenzene-1,3-dicarbonyl chloride Chemical compound NC1=C(I)C(C(Cl)=O)=C(I)C(C(Cl)=O)=C1I FBJVWRITWDYUAC-UHFFFAOYSA-N 0.000 claims description 2
- JEZJSNULLBSYHV-UHFFFAOYSA-N 5-amino-2,4,6-triiodobenzene-1,3-dicarboxylic acid Chemical compound NC1=C(I)C(C(O)=O)=C(I)C(C(O)=O)=C1I JEZJSNULLBSYHV-UHFFFAOYSA-N 0.000 claims description 2
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- 229960002603 iopromide Drugs 0.000 claims description 2
- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 claims description 2
- 229960004537 ioversol Drugs 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 claims description 2
- 150000002513 isocyanates Chemical group 0.000 claims description 2
- 150000002540 isothiocyanates Chemical group 0.000 claims description 2
- 125000003977 lipoyl group Chemical group S1SC(C([H])([H])C(C(C(C(=O)[*])([H])[H])([H])[H])([H])[H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- 125000000864 peroxy group Chemical group O(O*)* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 150000003141 primary amines Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims 1
- 229960004359 iodixanol Drugs 0.000 claims 1
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 claims 1
- 229960000824 iopentol Drugs 0.000 claims 1
- IUNJANQVIJDFTQ-UHFFFAOYSA-N iopentol Chemical compound COCC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I IUNJANQVIJDFTQ-UHFFFAOYSA-N 0.000 claims 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 claims 1
- KRURGYOKPVLRHQ-UHFFFAOYSA-N trithionic acid Chemical compound OS(=O)(=O)SS(O)(=O)=O KRURGYOKPVLRHQ-UHFFFAOYSA-N 0.000 claims 1
- 239000000499 gel Substances 0.000 abstract description 23
- 238000001727 in vivo Methods 0.000 abstract description 6
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- 238000012360 testing method Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 4
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- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0457—Semi-solid forms, ointments, gels, hydrogels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to an absorbable medical hydrogel and a preparation method thereof, wherein the absorbable medical hydrogel comprises a first component serving as a chemically modified contrast agent and a second component serving as a base material, and the first component comprises iodide and functional groups; the second component is succinimidyl ester terminated multi-arm polyethylene glycol; the medical hydrogel is a degradable medical hydrogel formed by in-situ crosslinking after the first component and the second component are physically mixed by bi-component injection; make up for the defects of slow curing time and low gel strength of the temperature-sensitive hydrogel, and can be polymerized without open ultraviolet irradiation, thus being suitable for in vivo injection.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to an absorbable medical hydrogel and a preparation method thereof.
Background
Hydrogels are three-dimensional networks formed from hydrophilic polymer chains that are crosslinked chemically or physically. It can fully absorb water and is insoluble in water, and can be obviously swelled by itself while still maintaining its original three-dimensional structure. The hydrogel contains a large amount of water (up to 90%), is soft in texture, variable in shape, similar to biological tissues in physical property, excellent in biocompatibility, capable of loading different materials, extremely strong in inclusion, adjustable in mechanical property and excellent in biological material. It is widely applicable to many fields of environmental engineering, flexible sensing, electrochemistry and the like, especially biomedical fields including tissue engineering, drug delivery systems, wound dressings, biosensors, contact lenses and the like.
The common hydrogels are temperature-sensitive hydrogels and photosensitive hydrogels, the temperature-sensitive hydrogels need to be injected into the body in a liquid form at low temperature and gradually solidify to form gel at body temperature, but the temperature-sensitive hydrogels have the defects of low curing speed, low gel strength and the like because chemical crosslinking does not occur, and the mechanical properties can not meet the requirements on hydrogel adhesives, sealants, in-situ isolation and the like; however, the photosensitive hydrogel needs to be polymerized under the irradiation of open ultraviolet light, and is not suitable for hydrogel polymerization of closed injection in vivo.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide absorbable medical hydrogel and a preparation method thereof, so as to solve the technical problems in the background art.
In order to solve the problems, the invention adopts the following technical scheme.
An absorbable medical hydrogel comprising a first component that is a chemically modified contrast agent comprising iodide and functional groups, wherein the functional groups may be selected from the group consisting of, but not limited to, isocyanate, isothiocyanate, carboxyl, amino, mercapto, hydroxyl, succinimidyl, maleimido, azido, azo, carbonyl, ether linkage, alkynyl, alkenyl, acrylate, methacrylate, silyl, lipoyl, pyridine, mercaptopyridine, hydrazide, amide, imino, primary amine, secondary amine, tertiary amine, quaternary ammonium salt, imide, cyano, diphenylcyclooctyne, halogen atom, nitro, nitroso, nitrite, phenyl, benzyl, carbonate, ester, peroxy, phosphine, phosphate, phosphite, sulfonic acid, thioether, sulfonyl, sulfinyl, thiocyanate, disulfide bond, and a second component that is a succinimide ester-capped multi-arm polyethylene glycol.
Preferably, the iodide in the first component may be selected from at least one of ioxilan, ioxitol, iopromide, iohexol, iobitol, iopamidol, ioversol, triiodoisophthalic acid (5-amino-2, 4, 6-triiodoisophthalic acid), triiodoisophthaloyl chloride (5-amino-2, 4, 6-triiodoisophthaloyl chloride), iohexol iodide (N, N '-bis (2, 3-dihydroxypropyl) -5-amino-2, 4, 6-triiodoisophthalamide), acetyl iodide (N, N' -bis (2, 3-dihydroxypropyl) -5-acetamido-2, 4, 6-triiodoisophthalamide), chloroacetyl iodide (N, N '-bis (2, 3-dihydroxypropyl) -5-chloroacetamido-2, 4, 6-triiodoisophthalamide), hydroxyacetyl iodide (N, N' -bis (2, 3-dihydroxypropyl) -5-hydroxyacetamido-2, 4, 6-triiodoisophthalamide), preferably from the ioxisol.
Still further, the functional group in the first component is preferably an amino group, and the first component as a chemically modified contrast agent is preferably a triaminoiohexol.
Preferably, the second component is a multi-arm polyethylene glycol with at least 2 polyethylene glycol arms, preferably a four-arm polyethylene glycol capped with succinimidyl ester and an eight-arm polyethylene glycol capped with succinimidyl ester, and the molecular weight is 1000-100000.
Preferably, the molar ratio of active functional groups of the first component to the second component is 1:1.
an absorbable medical hydrogel is prepared through dissolving the first component in physiological saline or phosphate buffer solution to form a first solution, dissolving the second component in physiological saline or phosphate buffer solution to form a second solution, and mixing the first solution with the second solution by dual-component injection system.
Compared with the prior art, the invention has the following outstanding characteristics:
1. the absorbable medical hydrogel provided by the invention has the advantages that the medical hydrogel has multifunctional development, the first component in the hydrogel is a chemically modified contrast agent, the imaging support can be provided for visualization of the hydrogel in vivo, the accurate position is provided for operation, and the operation is facilitated;
2. after the first component and the second component are mixed, the gel time is short, and the gel can be formed in situ within 1-8 seconds after mixing;
3. the absorbable medical hydrogel does not contain aldehyde substances, does not generate toxicity to local biological tissues, and has better biocompatibility;
4. the injectable hydrogel material has good motion tolerance, has the functions of multi-mode development and controllable degradation, and achieves the effect of integrating the functions of protection, customized treatment and the like;
5. the medical hydrogel has good biodegradability in vivo, and the degradation and absorption time in vivo can be adjusted by changing the proportion of components;
6. the hydrogel spacer is implanted in an injection mode, so that pain and cost caused by surgical implantation are avoided, the hydrogel spacer has a relatively quick learning curve, has great significance on clinical transformation, and has wide application prospect in the field of diagnosis and treatment integration.
Drawings
FIG. 1 is a three-dimensional perspective view of a two-component injection system;
FIG. 2 is a molecular structural formula of a tri-amino iohexol;
FIG. 3 is a mass spectrum of a tri-amino iohexol;
FIG. 4 is a molecular structural formula of a succinimidyl ester capped four-ARM polyethylene glycol (4 ARM-SG);
FIG. 5 is a molecular structural formula of a succinimidyl ester capped eight-ARM polyethylene glycol (8 ARM-SG);
FIG. 6 is a molecular structural formula of a succinimidyl ester capped four-ARM polyethylene glycol (4 ARM-SS);
FIG. 7 is a molecular structural formula of a succinimidyl ester capped eight-ARM polyethylene glycol (8 ARM-SS);
FIG. 8 is an external view showing the medical hydrogel prepared in example 1;
FIG. 9 is an external view showing the medical hydrogel prepared in example 2;
FIG. 10 is an external view showing the medical hydrogel prepared in example 3;
FIG. 11 is an external view showing the medical hydrogel prepared in example 4;
FIG. 12 is a photograph of the medical hydrogel prepared in example 1 under extrusion by an electronic universal tester;
FIG. 13 is a section of tissue from a site of subcutaneous implantation of the medical hydrogel of example 3 into a rat at 24 hours of dissection;
FIG. 14 is a view of a tissue section of a site of subcutaneous implantation of the medical hydrogel of example 3 in a rat at 1 week of dissection;
fig. 15 is a section of tissue from a site where the medical hydrogel of example 3 was subcutaneously implanted in rats at 4 weeks of dissection.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention; it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments, and that all other embodiments obtained by persons of ordinary skill in the art without making creative efforts based on the embodiments in the present invention are within the protection scope of the present invention.
An absorbable medical hydrogel and a preparation method thereof are provided, specifically, the first component is dissolved in normal saline or phosphate buffer to form a first solution, the second component is dissolved in normal saline or phosphate buffer to form a second solution, and then the first solution and the second solution are mixed through a two-component injection system to obtain the medical hydrogel; the three-dimensional perspective view of the two-component injection system is shown in fig. 1, more specifically, according to the requirement of the injection site, an injection needle can be connected to a Y-shaped joint site in the two-component injection system, a first component is dissolved in physiological saline or phosphate buffer solution to form a first solution, a second component is dissolved in the physiological saline or phosphate buffer solution to form a second solution, the first component and the second component solution are respectively sucked into two syringes, the two syringes are assembled in the two-component injection system, the first component and the second component solution flow through the Y-shaped joint during the injection process, the mixing is completed in the injection needle connected with the Y-shaped joint, and then the mixture is injected into a living body.
Based on the above scheme, in order to more specifically understand the optimal adding proportion of the tri-amino iohexol contrast agent, the following more specific preparation examples are carried out, wherein the molecular structure diagram of the tri-amino iohexol is shown in fig. 2, and the molecular structure diagram of the tri-amino iohexol contains three amino groups, and the mass spectrum test result is shown in fig. 3, and is consistent with the theoretical molecular weight of the tri-amino iohexol:
example 1
According to the mole ratio of the active functional groups of the first component to the second component of 1:1, 57mg of a triaminoiohexol contrast agent (molecular weight 851 g/mol) was dissolved in 2.5mL of physiological saline having a pH of 7.2 to prepare 22.8mg/mL of a first component solution; 500mg of succinimidyl ester capped four-ARM polyethylene glycol (4 ARM-SG-10K, molecular weight 10000 g/mol) is dissolved in 2.5mL of physiological saline with pH of 7.2 to prepare 200mg/mL of second component solution; extruding the first component solution and the second component solution in equal dosage through a duplex mixer to form the medical hydrogel.
Example 2
According to the mole ratio of the active functional groups of the first component to the second component of 1:1, 28mg of a triaminoiohexol contrast agent (molecular weight 851 g/mol) was dissolved in 2.5mL of physiological saline having a pH of 7.2 to prepare 11.2mg/mL of a first component solution; 500mg of succinimidyl ester capped four-ARM polyethylene glycol (4 ARM-SG-20K, molecular weight 20000 g/mol) is dissolved in 2.5mL of physiological saline with pH of 7.2, and 200mg/mL of second component solution is prepared; extruding the first component solution and the second component solution in equal dosage through a duplex mixer to form the medical hydrogel.
Example 3
According to the mole ratio of the active functional groups of the first component to the second component of 1:1, 113mg of a triaminoiohexol contrast agent (molecular weight 851 g/mol) was dissolved in 2.5mL of physiological saline having a pH of 7.2 to prepare 45.2mg/mL of a first component solution; 500mg of succinimidyl ester capped eighth-ARM polyethylene glycol (8 ARM-SG-10K, molecular weight 10000 g/mol) is dissolved in 2.5mL of physiological saline with pH of 7.2 to prepare 200mg/mL of second component solution; extruding the first component solution and the second component solution in equal dosage through a duplex mixer to form the medical hydrogel.
Example 4
According to the mole ratio of the active functional groups of the first component to the second component of 1:1, 57mg of a triaminoiohexol contrast agent (molecular weight 851 g/mol) was dissolved in 2.5mL of physiological saline having a pH of 7.2 to prepare 22.8mg/mL of a first component solution; 500mg of succinimidyl ester capped eighth-ARM polyethylene glycol (8 ARM-SG-20K, molecular weight 20000 g/mol) is dissolved in 2.5mL of physiological saline with pH of 7.2 to prepare 200mg/mL of second component solution; extruding the first component solution and the second component solution in equal dosage through a duplex mixer to form the medical hydrogel.
Example 5
According to the mole ratio of the active functional groups of the first component to the second component of 1:1, 57mg of a triaminoiohexol contrast agent (molecular weight 851 g/mol) was dissolved in 2.5mL of physiological saline having a pH of 7.2 to prepare 22.8mg/mL of a first component solution; 500mg of succinimidyl ester capped four-ARM polyethylene glycol (4 ARM-SS-10K, molecular weight 10000 g/mol) is dissolved in 2.5mL of physiological saline with pH of 7.2 to prepare 200mg/mL of second component solution; extruding the first component solution and the second component solution in equal dosage through a duplex mixer to form the medical hydrogel.
Example 6
According to the mole ratio of the active functional groups of the first component to the second component of 1:1, 28mg of a triaminoiohexol contrast agent (molecular weight 851 g/mol) was dissolved in 2.5mL of physiological saline having a pH of 7.2 to prepare 11.2mg/mL of a first component solution; 500mg of succinimidyl ester capped four-ARM polyethylene glycol (4 ARM-SS-20K, molecular weight 20000 g/mol) was dissolved in 2.5mL of physiological saline with pH of 7.2 to prepare 200mg/mL of a second component solution; extruding the first component solution and the second component solution in equal dosage through a duplex mixer to form the medical hydrogel.
Example 7
According to the mole ratio of the active functional groups of the first component to the second component of 1:1, 113mg of a triaminoiohexol contrast agent (molecular weight 851 g/mol) was dissolved in 2.5mL of physiological saline having a pH of 7.2 to prepare 45.2mg/mL of a first component solution; 500mg of succinimidyl ester capped eighth-ARM polyethylene glycol (8 ARM-SS-10K, molecular weight 10000 g/mol) is dissolved in 2.5mL of physiological saline with pH of 7.2 to prepare 200mg/mL of second component solution; extruding the first component solution and the second component solution in equal dosage through a duplex mixer to form the medical hydrogel.
Example 8
According to the mole ratio of the active functional groups of the first component to the second component of 1:1, 57mg of a triaminoiohexol contrast agent (molecular weight 851 g/mol) was dissolved in 2.5mL of physiological saline having a pH of 7.2 to prepare 22.8mg/mL of a first component solution; 500mg of succinimidyl ester capped eighth-ARM polyethylene glycol (8 ARM-SS-20K, molecular weight 20000 g/mol) was dissolved in 2.5mL of physiological saline with pH 7.2 to prepare 200mg/mL of a second component solution; extruding the first component solution and the second component solution in equal dosage through a duplex mixer to form the medical hydrogel.
Example 9
According to the mole ratio of the active functional groups of the first component to the second component of 1:1, 57mg of a triaminoiohexol contrast agent (molecular weight 851 g/mol) was dissolved in 2.5mL of physiological saline having a pH of 7.2 to prepare 22.8mg/mL of a first component solution; 250mg of succinimidyl ester capped eighth-ARM polyethylene glycol (8 ARM-SG-10K, molecular weight 10000 g/mol) is dissolved in 2.5mL of physiological saline with pH of 7.2 to prepare 100mg/mL of second component solution; extruding the first component solution and the second component solution in equal dosage through a duplex mixer to form the medical hydrogel.
Example 10
According to the mole ratio of the active functional groups of the first component to the second component of 1:1, 226mg of a triaminoiohexol contrast agent (molecular weight 851 g/mol) is taken and dissolved in 2.5mL of physiological saline with pH of 7.2 to prepare 90.4mg/mL of a first component solution; 1000mg of succinimidyl ester capped eighth-ARM polyethylene glycol (8 ARM-SG-10K, molecular weight 10000 g/mol) is dissolved in 2.5mL of physiological saline with pH of 7.2 to prepare 400mg/mL of second component solution; extruding the first component solution and the second component solution in equal dosage through a duplex mixer to form the medical hydrogel.
The detection method for the medical hydrogel prepared by the method comprises the following steps:
s1, gel curing time measurement: the first component is dissolved in physiological saline or phosphate buffer to form a first solution, the second component is dissolved in physiological saline or phosphate buffer to form a second solution, then the first solution and the second solution are mixed through a two-component injection system, the mixture is injected into a preheated thermostat with the temperature of 37 ℃, the time is counted immediately after gel is injected until hydrogel is formed (gel is picked up by a syringe needle), and the gel time is recorded.
S2, detection of swelling ratio (%): the swelling ratio refers to the mass increase percentage in the swelling process of the hydrogel in the phosphate buffer after the hydrogel is crosslinked and solidified; dissolving a first component in normal saline or phosphate buffer solution to form a first solution, dissolving a second component in normal saline or phosphate buffer solution to form a second solution, mixing the first solution and the second solution through a two-component injection system, injecting into a cylinder cavity mold with the inner diameter of 10mm and the height of 10mm to form a cylinder hydrogel with the diameter of 10mm and the height of 10mm, taking out a hydrogel sample, precisely weighing and transferring the hydrogel sample into a culture dish, immersing the culture dish in preheated neutral phosphate buffer solution with the temperature of 37 ℃, placing the culture dish into a constant temperature box with the temperature of 37 ℃, taking out the hydrogel sample every 5min, sucking surface moisture by filter paper, and weighing the weight of the sample after water absorption until the weight of the hydrogel sample is not increased any more. Gel swell ratio was calculated according to the following formula:
s3: mechanical property test: the first component was dissolved in physiological saline or phosphate buffer to form a first solution, the second component was dissolved in physiological saline or phosphate buffer to form a second solution, and then the first solution and the second solution were mixed by a two-component injection system, injected into a cylindrical cavity mold having an inner diameter of 10mm and a height of 10mm to form a cylindrical hydrogel having a diameter of 10mm and a height of 10mm, and the hydrogel sample was taken out and placed in an electronic universal tester (INSTRON 5982) compression test module to test the force-displacement curve, stress-strain curve, compressive strength and compressive modulus of the hydrogel, as shown in fig. 12.
S4: in vitro degradation test: dissolving a first component in normal saline or phosphate buffer solution to form a first solution, dissolving a second component in normal saline or phosphate buffer solution to form a second solution, mixing the first solution and the second solution through a two-component injection system, injecting into a cylinder cavity mold with the inner diameter of 10mm and the height of 10mm to form a cylinder hydrogel with the diameter of 10mm and the height of 10mm, taking out a hydrogel sample, immersing the hydrogel sample into the neutral phosphate buffer solution with the temperature of 37 ℃, observing the hydrogel every day until the hydrogel cannot be distinguished by naked eyes, and marking as the in-vitro degradation time of the hydrogel.
S5: in vivo toxicity test: adult male SD rats are selected as experimental animals, and subcutaneous implantation is adopted to test the biotoxicity of medical hydrogels. Rats were anesthetized with isoflurane gas and fixed on an operating table in the prone position, shaved on the back and sterilized with iodine and ethanol. The first component is dissolved in normal saline or phosphate buffer to form a first solution, the second component is dissolved in normal saline or phosphate buffer to form a second solution, and then the first solution and the second solution are mixed by a two-component injection system and injected into subcutaneous tissue of the rat through an injection needle. Rats were dissected on days 1, 7 and 30 post-implantation, and hydrogel peripheral tissues were subjected to pathological section and HE staining.
The test data of the medical hydrogels prepared in examples 1 to 8 were compared according to the above test method as follows:
table 1 comparison of the Properties of different second Components for the preparation of medical hydrogels
The specific description is as follows:
1. the second component used in examples 1 and 2 was a succinimidyl ester capped tetra-ARM polyethylene glycol (4 ARM-SG) with a molecular structure shown in FIG. 4;
2. the second component used in examples 3 and 4 was a succinimidyl ester capped eight-ARM polyethylene glycol (8 ARM-SG) with a molecular structure shown in FIG. 5;
3. the second component used in examples 5 and 6 was a succinimidyl ester capped tetra-ARM polyethylene glycol (4 ARM-SS), the molecular structure of which is shown in FIG. 6;
4. the second component used in examples 7 and 8 was succinimidyl ester capped octaarm polyethylene glycol (8 ARM-SS), the molecular structure of which is shown in FIG. 7.
Through experimental comparison:
the medical hydrogel prepared in example 1 has the appearance shown in fig. 8, which is a yellowish transparent hydrogel, but cannot be formed into a viscous gel;
the medical hydrogel prepared in example 2 has the appearance shown in fig. 9, which is a yellowish transparent hydrogel, but cannot be formed into a viscous gel;
the medical hydrogel prepared in example 3 has the appearance shown in fig. 10, is light yellow transparent hydrogel, can be molded, and has good elasticity;
the medical hydrogel prepared in example 4 has the appearance shown in fig. 11, is light yellow transparent hydrogel, can be molded, has good elasticity, but has obviously weaker mechanical strength than that of example 3;
the medical hydrogel prepared in example 5 was a viscous gel in appearance, gel time, swelling ratio and compression modulus similar to those of example 1;
the medical hydrogel prepared in example 6 was a viscous gel in appearance, gel time, swelling ratio and compression modulus similar to those of example 2;
the medical hydrogel prepared in example 7 has similar appearance, gel time, swelling rate and compression modulus to those of example 3, is light yellow transparent hydrogel, can be molded, and has good elasticity;
the medical hydrogel prepared in example 8 has similar appearance, gel time, swelling rate and compression modulus to those of example 4, is light yellow transparent hydrogel, can be molded, and has good elasticity;
from comparison of examples 1 and 5, examples 2 and 6, examples 3 and 7, and examples 4 and 8, it was determined that there was no significant difference in physical properties of the medical hydrogels prepared using the same number of ARMs and molecular weight of PEG as the second component, but that the medical hydrogels prepared using 8ARM-SG-10K in example 3 had slightly better properties than the medical hydrogels prepared using 8ARM-SS-10K in example 7.
According to the comparison of the data of the medical hydrogels of the examples 1 and 3, the examples 2 and 4, the examples 5 and 7 and the examples 6 and 8, it can be judged that the medical hydrogel prepared from the eight-ARM polyethylene glycol has far better performance than the four-ARM polyethylene glycol under the second component with the same molecular weight, and the hydrogel of the example 3 with the second component of 8ARM-SG-10K has short gel time and strong compression modulus; the reason for this analysis is that at the same molecular weight, the higher the concentration of succinimide active groups, the faster the reaction with tri-amino iohexol, the more chemical bonds formed, the shorter the time to form the hydrogel, and the higher the strength.
According to the comparison of the data of the medical hydrogels of example 3 and example 4 and the data of the medical hydrogels of example 7 and example 8, under the condition of the second component of polyethylene glycol with the same ARM number, the medical hydrogel prepared by the polyethylene glycol of the second component with smaller molecular weight has stronger physical properties, the hydrogel of example 3 with the second component of 8ARM-SG-10K has obviously shorter gel time than the hydrogel of example 4 prepared by 8ARM-SG-20K, and the compression modulus is obviously higher than that of example 4. The reason is that the smaller the molecular weight of polyethylene glycol is, the smaller the molecular weight of single arm is in the molecular structure, the stronger the rigidity is, and the higher the mechanical strength is.
Judging according to the in-vitro degradation time, wherein the degradation of the medical hydrogel is related to ester bonds in polyethylene glycol, and the more ester bonds are easily degraded; the hydrogel of example 3 had the most internal ester bonds and the significantly shortest degradation time.
TABLE 2 comparison of Properties of medical hydrogels prepared with first and second Components at different concentrations
Comparative example 9, example 3 and example 10, the gel time of the medical hydrogels was significantly shortened, the swelling rate and compression modulus were significantly increased and the in vitro degradation time was significantly prolonged as the concentrations of the first and second components were increased; however, example 9 had too long a gel time, while example 10 had too short a gel time, which tended to block the needle during injection.
According to the comparison of the physical properties of the examples, the performance of example 3 is obviously superior to that of other examples, and the medical hydrogel prepared in example 3 is injected into subcutaneous tissue of rats to observe the toxicity of the hydrogel to local tissues. As shown in fig. 13, the medical hydrogel of example 3 was injected into subcutaneous tissue for 24 hours without significant inflammatory reaction around the tissue, animal activity and diet were not affected, and as shown in fig. 14 and 15, the hydrogel was injected at the site of implantation for 1 week and 4 weeks without inflammatory reaction. The medical hydrogel disclosed by the invention has no toxic or side effect on the local part of organisms.
The above description is only of the preferred embodiments of the present invention; the scope of the invention is not limited in this respect. Any person skilled in the art, within the technical scope of the present disclosure, may apply to the present invention, and the technical solution and the improvement thereof are all covered by the protection scope of the present invention.
Claims (6)
1. An absorbable medical hydrogel comprising a first component that is a chemically modified contrast agent and a second component that is a binder, characterized in that: the first component includes iodide and functional groups, wherein the functional groups may be selected from the group consisting of, but not limited to, isocyanate, isothiocyanate, carboxyl, amino, mercapto, hydroxyl, succinimidyl, maleimidyl, azido, azo, carbonyl, ether bond, alkynyl, alkenyl, acrylate, methacrylate, silyl, lipoyl, pyridine, mercaptopyridine, hydrazide, amide, imino, primary amine, secondary amine, tertiary amine, quaternary ammonium salt, imide, cyano, diphenylcyclooctyne, halogen atom, nitro, nitroso, nitrite, phenyl, benzyl, carbonate, ester, peroxy, phosphine, phosphate, phosphite, sulfo, thioether, sulfonyl, sulfinyl, thiocyanate, disulfide bond, and the second component is a multi-arm polyethylene glycol capped with succinimidyl ester.
2. The absorbable medical hydrogel of claim 1, wherein: the iodide in the first component may be selected from at least one of ioxilan, iopentol, iodixanol, iopromide, iohexol, iobitol, iopamidol, ioversol, triiodoisophthalic acid (5-amino-2, 4, 6-triiodoisophthalic acid), triiodoisophthaloyl chloride (5-amino-2, 4, 6-triiodoisophthaloyl chloride), iohexol iodide (N, N '-bis (2, 3-dihydroxypropyl) -5-amino-2, 4, 6-triiodoisophthalamide), acetyl iodide (N, N' -bis (2, 3-dihydroxypropyl) -5-acetamido-2, 4, 6-triiodoisophthalamide), chloroacetyl iodide (N, N '-bis (2, 3-dihydroxypropyl) -5-chloroacetamido-2, 4, 6-triiodoisophthalamide), hydroxyacetyl iodide (N, N' -bis (2, 3-dihydroxypropyl) -5-hydroxyacetylamino-2, 4, 6-triiodoisophthalamide), preferably iohexol.
3. An absorbable medical hydrogel as set forth in claim 2 wherein: the functional group in the first component is preferably an amino group, and the first component as a chemically modified contrast agent is preferably a triaminoiohexol.
4. The absorbable medical hydrogel of claim 1, wherein: the second component is multi-arm polyethylene glycol, the number of polyethylene glycol arms is at least 2, and the four-arm polyethylene glycol capped by succinimidyl ester and the eight-arm polyethylene glycol capped by succinimidyl ester are preferable, and the molecular weight is 1000-100000.
5. The method for preparing the absorbable medical hydrogel, which is characterized by comprising the following steps of: the molar ratio of the active functional groups of the first component to the second component is 1:1.
6. an absorbable medical hydrogel and a preparation method thereof are characterized in that: and dissolving the first component in normal saline or phosphate buffer solution to form a first solution, dissolving the second component in normal saline or phosphate buffer solution to form a second solution, and then mixing the first solution and the second solution through a two-component injection system to obtain the medical hydrogel.
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US20090324721A1 (en) * | 1996-09-23 | 2009-12-31 | Jack Kennedy | Hydrogels Suitable For Use In Polyp Removal |
CN105778124A (en) * | 2012-09-28 | 2016-07-20 | 山东赛克赛斯药业科技有限公司 | Biodegradable medicine hydrogel and preparation method and application thereof |
CN110643057A (en) * | 2019-10-23 | 2020-01-03 | 赛克赛斯生物科技股份有限公司 | Application of polyethylene glycol activated ester in preparation of low-swelling hydrogel and low-swelling hydrogel comprising same |
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