CN116603102B - Collagen/hyaluronic acid composite filling solution and preparation method thereof - Google Patents
Collagen/hyaluronic acid composite filling solution and preparation method thereof Download PDFInfo
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- 102000008186 Collagen Human genes 0.000 title claims abstract description 83
- 108010035532 Collagen Proteins 0.000 title claims abstract description 83
- 229920001436 collagen Polymers 0.000 title claims abstract description 83
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 71
- 239000002131 composite material Substances 0.000 title claims abstract description 54
- 238000011049 filling Methods 0.000 title claims abstract description 51
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 50
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000011159 matrix material Substances 0.000 claims abstract description 26
- 239000002245 particle Substances 0.000 claims abstract description 15
- OUPZKGBUJRBPGC-UHFFFAOYSA-N 1,3,5-tris(oxiran-2-ylmethyl)-1,3,5-triazinane-2,4,6-trione Chemical compound O=C1N(CC2OC2)C(=O)N(CC2OC2)C(=O)N1CC1CO1 OUPZKGBUJRBPGC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 10
- 230000002500 effect on skin Effects 0.000 claims abstract description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000008367 deionised water Substances 0.000 claims description 16
- 229910021641 deionized water Inorganic materials 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000005303 weighing Methods 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 10
- 238000004132 cross linking Methods 0.000 claims description 5
- 238000000502 dialysis Methods 0.000 claims description 5
- 230000014759 maintenance of location Effects 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 230000007246 mechanism Effects 0.000 claims description 2
- 230000007547 defect Effects 0.000 abstract description 4
- 230000017423 tissue regeneration Effects 0.000 abstract description 3
- 229940102223 injectable solution Drugs 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 65
- 239000000463 material Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000008614 cellular interaction Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
Classifications
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- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/362—Skin, e.g. dermal papillae
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- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
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Abstract
The invention relates to the technical field of medical science, in particular to a collagen/hyaluronic acid composite filling solution and a preparation method thereof, comprising the following steps: s1, modifying hyaluronic acid by using triglycidyl isocyanurate; s2, mixing the acellular dermal matrix particles with the collagen solution to obtain a collagen matrix composite filling solution; and S3, further modifying the collagen matrix composite filling solution obtained in the step S2 by using the modified hyaluronic acid obtained in the step S1 to obtain a collagen/hyaluronic acid composite filling solution. The collagen/hyaluronic acid composite filling solution can solve the problems of general filling property, relatively insufficient stability and the like of collagen, can improve the performance defect that hyaluronic acid only plays a role of occupying, has excellent biocompatibility, good wettability and stability, can induce tissue regeneration capacity and the like, and can be widely applied to aspects of injectable solution, medical filling solution and the like.
Description
Technical Field
The invention relates to the technical field of medical science, in particular to a collagen/hyaluronic acid composite filling solution and a preparation method thereof.
Background
With the progress and development of the medical field, fillers such as collagen, hyaluronic acid and the like are injected into the parts such as the periocular region, the temple region and the like, so that the problem of depression caused by serious loss of facial collagen is solved, and the method is an important field of attention of researchers and doctors. Four cosmetic shell absorbable materials that have been approved by the FDA (united states food and drug administration) include: collagen, sodium hyaluronate, hydroxyapatite and polylactic acid.
The hyaluronic acid exists at different parts of our body, has the functions of moisturizing and maintaining the form, has strong crosslinking property, high stability and viscosity, is suitable for subcutaneous injection in the medical field to perform defect supplement, contour shaping and other purposes, but only plays a role of occupying space when entering the body, and does not trigger regeneration of autologous tissues. Collagen exists in many forms, and collagen solution is an optimal filling material because of its good biocompatibility, mechanical properties, moisture retention, degradability, low immunogenicity and cell interaction characteristics, but collagen itself is generally not sufficiently filled and relatively stable. The decellularized dermal matrix particles (mADM) are solid collagen substances, can play a role in supporting and inducing tissue remodeling when being used for subcutaneous injection of a human body, and are lack of proper solvent in practical application and need to be used in combination with other materials. The hyaluronic acid and the collagen are compounded to exert the common effects of the hyaluronic acid and the collagen, so that the positive synergistic effect is achieved, but the interaction between the hyaluronic acid and the collagen is weaker, and the stability of the structure and the performance of the composite material is affected.
Disclosure of Invention
The invention aims to provide a collagen/hyaluronic acid composite filling solution and a preparation method thereof, which can solve the problems of general filling property, relatively insufficient stability and the like of collagen, can improve the performance defect that hyaluronic acid only plays a role of occupying, has excellent biocompatibility, good wettability and stability, can induce tissue regeneration capacity and the like, and can be widely applied to aspects of injectable solution, medical filling solution and the like.
In a first aspect of the present invention, there is provided a method for preparing a collagen/hyaluronic acid composite filling solution, comprising the steps of:
s1, modifying hyaluronic acid by using triglycidyl isocyanurate;
s2, mixing the acellular dermal matrix particles with the collagen solution to obtain a collagen matrix composite filling solution;
and S3, further modifying the collagen matrix composite filling solution obtained in the step S2 by using the modified hyaluronic acid obtained in the step S1 to obtain a collagen/hyaluronic acid composite filling solution.
Preferably, step S1 includes:
s11, dissolving hyaluronic acid in deionized water;
s12, dissolving triglycidyl isocyanurate in dimethyl sulfoxide (DMSO);
and S13, mixing the two solutions obtained in the steps S11 and S12, and reacting to obtain the modified hyaluronic acid.
Preferably, step S1 includes:
s11, weighing 1-20 parts by mass of hyaluronic acid, and dissolving in 5-100 parts by mass of deionized water;
s12, weighing 1-20 parts by mass of triglycidyl isocyanurate in 10-200 parts by mass of dimethyl sulfoxide;
s13, mixing the two solutions obtained in the steps S11 and S12 for reaction, adding 1-10 times of deionized water after the reaction is finished, and filling the mixture into a dialysis bag with a retention of 500 daltons, and separating out dimethyl sulfoxide remained in the reaction in a deionized water environment to obtain the modified hyaluronic acid.
Preferably, step S2 includes: weighing 1-10 parts by mass of acellular dermal matrix particles and 3-30 parts by mass of collagen solution, and mixing to obtain the collagen matrix composite filling solution.
Preferably, the decellularized dermal matrix microparticles have a particle size of no greater than 2.0mm; more preferably, the decellularized dermal matrix particles have a particle size of 0.5 to 2.0mm; further, the particle size of the decellularized dermal matrix particles is: 0.5, 1.0, 2.0mm.
Preferably, step S3 includes: and (2) adding the modified hyaluronic acid solution obtained in the step (S1) into the collagen matrix composite solution obtained in the step (S2), and adding a sodium hydroxide solution to react to obtain the collagen/hyaluronic acid composite filling solution.
Preferably, step S3 includes: weighing 4-20 parts by mass of the modified hyaluronic acid solution obtained in the step S1, adding 20-100 parts by mass of the collagen matrix composite solution obtained in the step S2, dropwise adding 1-5 parts by mass of 1.0M sodium hydroxide solution, rapidly stirring at room temperature to adjust the pH of the solution to 5.0-8.5, preferably to 7.5, and reacting to obtain the collagen/hyaluronic acid composite filling solution.
Preferably, the modified hyaluronic acid has the principle general formula:
preferably, the crosslinking mechanism of the modified hyaluronic acid and the collagen is as follows:
in a second aspect of the present invention, there is provided a collagen/hyaluronic acid composite filling solution prepared by the above-described method for preparing a collagen/hyaluronic acid composite filling solution.
The invention has the beneficial effects that:
(1) The triglycidyl isocyanurate is used for modifying the hyaluronic acid, so that the chemical reactivity of the hyaluronic acid is further increased on the premise of ensuring the good biological safety of the hyaluronic acid, the hyaluronic acid can be covalently combined with protein, and the stability of a protein composite system is enhanced.
(2) The mADM/collagen composite material has more advantageous filling properties and biodegradability compared to conventional collagen filling solutions. Meanwhile, mADM introduction further causes fibroblast proliferation and autologous collagen secretion and deposition, and the mADM and the collagen solution together play a synergistic effect.
(3) The modified hyaluronic acid and collagen are compounded, covalent interaction occurs between the modified hyaluronic acid and collagen, and the composite system structure and performance are more stable. The composite of the two can solve the problems of general filling property, relatively insufficient stability and the like of collagen, can also improve the performance defect that the hyaluronic acid only plays a role of occupying, has excellent biocompatibility, good wettability and stability, can induce tissue regeneration capacity and the like.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is an SEM characterization diagram of a composite material lyophilized from a collagen/hyaluronic acid composite filling solution prepared in example 1 of the present invention;
FIG. 2 is a graph showing the comparison of the thermal stability of collagen after treatment with different modified materials according to example 1 of the present invention and comparative example.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular forms also include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The embodiment provides a preparation method of a collagen/hyaluronic acid composite filling solution, which comprises the following steps:
1 part by mass of hyaluronic acid is weighed in 5 parts by mass of deionized water, uniformly stirred, 1 part by mass of triglycidyl isocyanurate is weighed in 10 parts by mass of DMSO solvent, uniformly stirred, the two solutions are mixed at room temperature and stirred for reaction for 10 hours, after the reaction is finished, 5 parts by mass of deionized water is added, the mixture is filled into a dialysis bag with a retention of 500 daltons, and the rest DMSO after the reaction is separated out in a deionized water environment, so that the modified hyaluronic acid is obtained.
1 part by mass of mADM with the particle size of 2.0mm and 3 parts by mass of collagen solution are weighed and uniformly stirred to obtain a collagen matrix composite filling solution.
4 parts by mass of the modified hyaluronic acid solution obtained in the step 1 are weighed, 20 parts by mass of the collagen matrix composite solution obtained in the step 2 are added, 1 part by mass of 1.0M sodium hydroxide solution is added dropwise, the solution is rapidly stirred at room temperature to adjust the pH to 7.5, and then the solution is stirred at room temperature to react for 2 hours, so that the collagen/hyaluronic acid composite filling solution is obtained.
The collagen/hyaluronic acid composite filling solution prepared by the embodiment is freeze-dried, and microscopic morphology of the freeze-dried composite material is observed by adopting SEM, and as can be seen from the figure 1, each component of the freeze-dried composite material is not layered, and the three-dimensional porous network space structure is typical, so that favorable conditions can be provided for proliferation and growth of cells.
Example 2
The embodiment provides a preparation method of a collagen/hyaluronic acid composite filling solution, which comprises the following steps:
and (3) weighing 10 parts by mass of hyaluronic acid in 50 parts by mass of deionized water, uniformly stirring, weighing 10 parts by mass of triglycidyl isocyanurate in 100 parts by mass of DMSO solvent, uniformly stirring, mixing the two solutions, stirring at room temperature for 24 hours, adding 8 times by mass of deionized water after the reaction is finished, filling into a dialysis bag with a cutoff amount of 500 daltons, and precipitating the residual DMSO in the deionized water environment to obtain the modified hyaluronic acid.
Weighing 5 parts by mass of mADM with the particle size of 1.0mm and 9 parts by mass of collagen solution, and uniformly stirring to obtain the collagen matrix composite filling solution.
10 parts by mass of the modified hyaluronic acid solution obtained in the step 1 is weighed, 50 parts by mass of the collagen matrix composite solution obtained in the step 2 is added, 5 parts by mass of 1.0M sodium hydroxide solution is added dropwise, the solution is rapidly stirred at room temperature to adjust the pH to 7.5, and then the solution is stirred at room temperature to react for 6 hours, so that the collagen/hyaluronic acid composite filling solution is obtained.
Example 3
The embodiment provides a preparation method of a collagen/hyaluronic acid composite filling solution, which comprises the following steps:
and (3) weighing 20 parts by mass of hyaluronic acid in 100 parts by mass of deionized water, uniformly stirring, weighing 20 parts by mass of triglycidyl isocyanurate in 200 parts by mass of DMSO solvent, uniformly stirring, mixing the two solutions, stirring at room temperature for 24 hours, adding 10 times by mass of deionized water after the reaction is finished, loading into a dialysis bag with a retention of 500 daltons, and precipitating the residual DMSO in the deionized water environment to obtain the modified hyaluronic acid.
10 parts by mass of mADM with the particle size of 0.5mm and 30 parts by mass of collagen solution are weighed and uniformly stirred, so as to obtain the collagen matrix composite filling solution.
20 parts by mass of the modified hyaluronic acid solution obtained in the step 1 are weighed, 100 parts by mass of the collagen matrix composite solution obtained in the step 2 are added, 5 parts by mass of 1.0M sodium hydroxide solution is added dropwise, the solution is rapidly stirred at room temperature to adjust the pH to 7.5, and then the solution is stirred at room temperature to react for 8 hours, so that the collagen/hyaluronic acid composite filling solution is obtained.
Comparative example
The comparison example is a conventional collagen crosslinking mode, and glutaraldehyde modified collagen is obtained by directly crosslinking and modifying collagen with glutaraldehyde.
The heat stability temperatures of the collagen/hyaluronic acid composite filling solution prepared in example 1, the glutaraldehyde-modified collagen prepared in the control example and the pure collagen are detected through DSC experiments, and the results are shown in fig. 2, wherein the heat stability temperature of the pure collagen is only 49.8 ℃, and the heat stability temperature of the glutaraldehyde-modified collagen is 70.9 ℃, compared with the heat stability temperature of the collagen/hyaluronic acid composite filling solution prepared in the previous two, the heat stability temperature of the collagen/hyaluronic acid composite filling solution prepared in the invention is obviously improved and reaches 77.6 ℃ at most.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (2)
1. The preparation method of the collagen/hyaluronic acid composite filling solution is characterized by comprising the following steps of:
s1, modifying hyaluronic acid by using triglycidyl isocyanurate, wherein the specific operation is as follows:
s11, weighing 1 part by mass of hyaluronic acid, and dissolving in 5 parts by mass of deionized water;
s12, weighing 1 part by mass of triglycidyl isocyanurate to be dissolved in 10 parts by mass of dimethyl sulfoxide;
s13, mixing the two solutions obtained in the steps S11 and S12 for reaction for 10 hours, adding 5 times of deionized water after the reaction is finished, and filling into a dialysis bag with a retention amount of 500 daltons, and separating out dimethyl sulfoxide remained in the reaction in a deionized water environment to obtain modified hyaluronic acid;
s2, mixing the acellular dermal matrix particles with the collagen solution to obtain a collagen matrix composite filling solution, wherein the specific operation is as follows: weighing 1 part by mass of acellular dermal matrix particles with the particle size of 2.0mm and 3 parts by mass of collagen solution, and mixing to obtain a collagen matrix composite filling solution;
s3, further modifying the collagen matrix composite filling solution obtained in the step S2 by using the modified hyaluronic acid obtained in the step S1 to obtain a collagen/hyaluronic acid composite filling solution, wherein the specific operation is as follows: weighing 4 parts by mass of the modified hyaluronic acid solution obtained in the step S1, adding 20 parts by mass of the collagen matrix composite solution obtained in the step S2, dropwise adding 1 part by mass of 1.0M sodium hydroxide solution, rapidly stirring at room temperature to adjust the pH of the solution to 7.5, and then stirring at room temperature to react for 2 hours to obtain a collagen/hyaluronic acid composite filling solution;
the principle general formula of the modified hyaluronic acid is as follows:
the crosslinking mechanism of the modified hyaluronic acid and the collagen is as follows:
2. the collagen/hyaluronic acid composite filling solution prepared by the method of preparing a collagen/hyaluronic acid composite filling solution according to claim 1.
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