CN115770323B - Recombinant collagen gel dressing and preparation method and application thereof - Google Patents
Recombinant collagen gel dressing and preparation method and application thereof Download PDFInfo
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- CN115770323B CN115770323B CN202211656646.6A CN202211656646A CN115770323B CN 115770323 B CN115770323 B CN 115770323B CN 202211656646 A CN202211656646 A CN 202211656646A CN 115770323 B CN115770323 B CN 115770323B
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- recombinant collagen
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- phosphate
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- 239000000512 collagen gel Substances 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 102000008186 Collagen Human genes 0.000 claims abstract description 113
- 108010035532 Collagen Proteins 0.000 claims abstract description 113
- 229920001436 collagen Polymers 0.000 claims abstract description 113
- 208000027418 Wounds and injury Diseases 0.000 claims abstract description 58
- 206010052428 Wound Diseases 0.000 claims abstract description 56
- 239000002245 particle Substances 0.000 claims abstract description 48
- 239000007864 aqueous solution Substances 0.000 claims abstract description 38
- 239000002562 thickening agent Substances 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 238000004132 cross linking Methods 0.000 claims abstract description 23
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 21
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 21
- 239000010452 phosphate Substances 0.000 claims abstract description 21
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 19
- 238000001035 drying Methods 0.000 claims abstract description 15
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- 238000000034 method Methods 0.000 claims description 13
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 9
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- AZKVWQKMDGGDSV-BCMRRPTOSA-N Genipin Chemical compound COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12 AZKVWQKMDGGDSV-BCMRRPTOSA-N 0.000 claims description 6
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
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- 101710137510 Saimiri transformation-associated protein Proteins 0.000 claims description 2
- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 claims description 2
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- 238000000855 fermentation Methods 0.000 claims description 2
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- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 claims description 2
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 235000019691 monocalcium phosphate Nutrition 0.000 claims description 2
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 claims description 2
- 235000019830 sodium polyphosphate Nutrition 0.000 claims description 2
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- 235000019818 tetrasodium diphosphate Nutrition 0.000 claims description 2
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- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims 2
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- 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 2
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Classifications
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a recombinant collagen gel dressing, a preparation method and application thereof, and belongs to the technical field of collagen gel dressing. The invention adopts the recombinant collagen cross-linked particles obtained by cross-linking and crushing of the cross-linking agent as a matrix raw material, is mixed with the aqueous solution of the thickening agent, and is added with phosphate as a stabilizing agent, thus the recombinant collagen gel dressing can be obtained without drying, and the morphology and the performance of the dressing can be adjusted by adjusting the dosage of the recombinant collagen cross-linked particles and the thickening agent. The dressing can be directly coated on the wound surface, is convenient to use and is not limited by the position and the shape of the wound surface; the degradation resistance is good, and the repair requirement of the wound surface which needs to be recovered for a long time can be met; the humidity is moderate, the absorption performance is good, tissue fluid exuded by a wound can be rapidly absorbed, and the wound healing is promoted; no intradermal irritation, no potential cytotoxicity, and no sensitization reaction.
Description
Technical Field
The invention belongs to the technical field of collagen gel dressing, and particularly relates to a recombinant collagen gel dressing, and a preparation method and application thereof.
Background
Skin tissue is often damaged by mechanical, physical, chemical, biological and other factors, and the process by which such damage is repaired by the body is called tissue repair. According to the wound healing period, acute wound and chronic wound can be classified, wherein the acute wound generally refers to abrasion, incised wound, gunshot wound, operation incision, burn, chemical injury and the like, and the chronic wound refers to diabetic foot ulcer, leg ulcer, pressure sore and the like. For common wounds, normal organisms can repair themselves, however, for some wounds with oversized damaged areas or chronic wounds, the self-repair of the organisms cannot heal completely, and medical intervention auxiliary treatment is needed. The tooth extraction wound is a wound left after a tooth extraction operation, once the tooth extraction wound is poorly healed, complications such as postoperative bleeding, pain, swelling, infection and the like can be caused, and the bone tissue healing time is prolonged, so that the chewing function and daily life of a patient are greatly influenced.
Various dressings are commonly used as skin repairing materials in medicine, the traditional dressings are mostly inert dressings in a solid state, and the traditional dressings comprise absorbent cotton, gypsum, gauze and bandages, are used for covering wound surfaces and preventing wound infection, have no promoting effect on wound healing, have only physical protection effect, and have the advantages of low price and simple manufacture; the defect is that the wound adhesion is easy to generate, the secondary wound is caused during dressing change, and the wound healing time is prolonged. With the development of science and technology, the interactive wound repair dressing is brand-new, and the dressing mainly comprises a foam dressing, a hydrogel dressing, a hydrocolloid dressing and an alginate dressing, and although the dressing has the characteristics of ventilation, bacteria isolation, high water content or high absorptivity, the foam dressing and the hydrocolloid dressing need to be changed frequently, and foam scraps are easy to remain in wounds to cause scar increase; the hydrogel dressing is easy to grow bacteria and is not suitable for infection and severe drainage wounds; the alginate dressing can dehydrate and delay healing of wounds, and is not suitable for dry wounds.
Winter in the early 60 th century brings forward a moist wound healing theory, the development and application of skin wound healing materials are revolutionarily changed, and a plurality of novel wound healing materials are developed successively. The bioactive wound dressing is mainly made of natural materials or artificial synthetic materials, has natural bioactive components, can maintain local moist environment of the wound, has the characteristics of good biocompatibility, biodegradability and extracellular matrix macromolecular similarity and low cytotoxicity, and can promote wound healing and reduce scar generation.
Patent (CN 109985271A) discloses a composite collagen dressing for repairing wound difficult to heal, which is prepared by dispersing type I collagen and type III collagen in a solvent according to a proportion, homogenizing, and then compounding and molding.
Patent (CN 113975448A) discloses a preparation method of a collagen composite dressing, which comprises the following steps: dissolving chitosan in a solvent to prepare a chitosan solution; preparing chitosan film from chitosan solution through electrostatic spinning, and removing solvent in the chitosan film after shaping to obtain chitosan matrix material; adding collagen into the Chinese medicine extract, and completely swelling to obtain collagen mixed solution; and covering the surface of the chitosan matrix with the collagen mixed solution, drying, and repeating the operation for 3-10 times to obtain the collagen composite dressing. The composite dressing can effectively solve the problems of poor air permeability, high humidity of a wound part and poor wound healing effect of the existing dressing.
Patent (CN 108273122 a) discloses a recombinant collagen hydrogel wound dressing, which is prepared by compounding recombinant collagen, sodium chloride, a thickener and deionized water and sterilizing, belongs to an external gel dressing, has good moisturizing, hemostatic and adhesive properties, can promote wound healing and protect wound neogenesis tissues, reduces scar formation, is suitable for the treatment of wounds such as ulcers, burns, postoperative wounds and scratches, and is simple to prepare, low in production cost and suitable for mass production.
Patent (CN 114470314 a) discloses a recombinant humanized collagen gel dressing comprising: 0.001% -0.05% of recombinant humanized collagen; fibronectin 0.005% -0.02%; sodium hyaluronate 0.5% -2%; heparan sulfate 0.1% -0.8%; 1% -10% of sugar alcohol compounds; 0.5% -3% of 1, 2-pentanediol; 3% -8% of polydatin; the balance being water. The collagen gel dressing is prepared from fibronectin, sodium hyaluronate, heparan sulfate, sugar alcohol compounds and polydatin which have good biocompatibility with recombinant humanized collagen, and the gel dressing formed by adding 1, 2-pentanediol and water (purified water), has no stimulation and toxicity, can promote the materials such as the recombinant humanized collagen, the fibronectin, the polydatin and the like to be slowly released, promote the cell growth of a wound site, and has a very mild effect on wound repair.
However, the collagen gel dressing disclosed in the prior art also has some problems, such as poor mechanical strength, fragility and inconvenient use; poor degradation resistance, and degradation and corrosion easily occur under the condition of enzyme or aqueous solution, so that the retention time of the material in the body is insufficient to support the recovery of the wound of a patient; poor absorption performance, unfavorable wound recovery, and the like. Therefore, it is necessary to provide a recombinant collagen gel dressing which has good degradability, good absorbability, good biocompatibility and convenient use.
Disclosure of Invention
The invention provides a recombinant collagen gel dressing, a preparation method and application thereof, aiming at the problems existing in the prior art. The dressing can be directly coated on the wound surface, is convenient to use and is not limited by the position and the shape of the wound surface; the degradation resistance is good, and the repair requirement of the wound surface which needs to be recovered for a long time can be met; the humidity is moderate, the absorption performance is good, tissue fluid exuded by a wound can be rapidly absorbed, and the wound healing is promoted; no intradermal irritation, no potential cytotoxicity, and no sensitization reaction.
To achieve the above object, in a first aspect, the present application provides a recombinant collagen gel dressing, comprising the following raw materials: recombinant collagen cross-linked particles, thickener aqueous solution, phosphate;
wherein the recombinant collagen crosslinking particles are obtained by crosslinking and crushing recombinant collagen and a crosslinking agent, and the mass ratio of the recombinant collagen to the crosslinking agent is (4-20): 1, wherein the mass concentration of the thickener aqueous solution is 0.5% -5.0%, and the mass ratio of the recombinant collagen cross-linked particles to the thickener aqueous solution is 1 (2-15). After comminution, the D90 of the recombinant collagen cross-linked particles is preferably 50-800. Mu.m.
The recombinant collagen is crosslinked by the crosslinking agent to form a crosslinked network, so that the recombinant collagen can be endowed with certain mechanical strength and better degradation resistance, but the dosage of the crosslinking agent is moderate. If the amount of the cross-linking agent is too small, the cross-linking effect is limited, and the mechanical strength and the degradation resistance of the dressing can not be improved well. If the amount of the crosslinking agent is large, on one hand, the chemical crosslinking agent has certain irritation and toxicity, and excessive use of the chemical crosslinking agent can cause intradermal irritation, potential cytotoxicity and sensitization reaction, and on the other hand, after the recombinant collagen is excessively crosslinked, the absorption performance is limited, and the recombinant collagen cannot be well redispersed in the thickener aqueous solution, so that the dressing with stable performance and meeting expectations is prepared.
Preferably, the recombinant collagen is collagen produced by fermentation by a genetic engineering method, including recombinant human collagen, recombinant human-like collagen and recombinant collagen-like protein, and more preferably type III humanized recombinant collagen.
Preferably, the crosslinking agent is at least one of carbodiimide, propylene oxide, diphenyl phosphate, hexamethylene diisocyanate, genipin, formaldehyde and glutaraldehyde. Further preferred is at least one of genipin, formaldehyde and glutaraldehyde. Most preferred is glutaraldehyde.
Preferably, the thickener is a cellulosic thickener. Further preferably, the cellulose thickener is at least one of hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose or a soluble salt of the above cellulose. Most preferred is a soluble salt of carboxymethyl cellulose. The addition of the thickener can make the recombinant collagen cross-linked particles swell in the thickener aqueous solution, and the dressing with the required viscosity is prepared and obtained, which is convenient to use.
Preferably, the phosphate is at least one of calcium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium polyphosphate, sodium pyrophosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate, and the dosage of the phosphate is 0.2-1% of the total dosage of the recombinant collagen cross-linked particles, the thickener aqueous solution and the phosphate. The addition of phosphate can improve the stability of the recombinant collagen gel dressing.
Preferably, the water meets pharmaceutical or medicinal standards, such as water for injection.
In a second aspect, the present application provides a method for preparing the recombinant collagen gel dressing, which includes the following steps:
(1) Preparation of recombinant collagen crosslinked particles:
1a, dissolving recombinant collagen in water, stirring and foaming to obtain a collagen solution;
1b, adding a cross-linking agent into the collagen solution obtained in the step 1a to carry out a cross-linking reaction to obtain a reaction solution 1;
1c, drying and crushing the reaction liquid 1 obtained in the step 1b to obtain recombinant collagen cross-linked particles;
(2) Preparation of thickener aqueous solution: dissolving a formula amount of thickener in water to prepare a thickener aqueous solution;
(3) Adding the recombinant collagen cross-linked particles obtained in the step (1) and phosphate into the thickener aqueous solution obtained in the step (2), and uniformly stirring to obtain the recombinant collagen gel dressing.
Preferably, the stirring condition in the step 1a is 500-5000r/min, the stirring speed is too low, the dissolution of the recombinant collagen is slower, and the stirring speed is too high, so that the degradation of the recombinant collagen can be caused.
Preferably, the mass concentration of the collagen solution in the step 1a is 0.1% -5%.
Preferably, step 1d employs heat drying or freeze drying; the heat drying temperature is preferably 50 to 90 ℃.
In a third aspect, the application provides an application of the recombinant collagen gel dressing in wound repair. The recombinant collagen gel dressing has wide applicability, and can meet the use requirements of various wound surfaces, such as tooth extraction wound, dental ulcer, abrasion, cutting wound, scald, burn, electric burn, diabetic foot, venous ulcer and the like.
The invention has the following beneficial effects:
1. the invention adopts the recombinant collagen cross-linked particles obtained by cross-linking and crushing of the cross-linking agent as a matrix raw material, is mixed with the aqueous solution of the thickening agent, and is added with phosphate as a stabilizing agent, thus the recombinant collagen gel dressing can be obtained without drying, and the morphology and the performance of the dressing can be adjusted by adjusting the dosage of the recombinant collagen cross-linked particles and the thickening agent. The dressing can be directly coated on the wound surface, is convenient to use and is not limited by the position and the shape of the wound surface; the degradation resistance is good, and the repair requirement of the wound surface which needs to be recovered for a long time can be met; the humidity is moderate, the absorption performance is good, tissue fluid exuded by a wound can be rapidly absorbed, and the wound healing is promoted; no intradermal irritation, no potential cytotoxicity, and no sensitization reaction.
2. The preparation process of the recombinant collagen gel dressing is simple, and is suitable for mass production.
3. The recombinant collagen gel dressing has wide applicability, and can meet the use requirements of various wound surfaces, such as tooth extraction wound, dental ulcer, abrasion, cutting wound, scald, burn, electric burn, diabetic foot, venous ulcer and the like.
The specific embodiment is as follows:
it is to be noted that the raw materials used in the present invention are all common commercial products, and the sources thereof are not particularly limited. The technical scheme of the invention is described below through specific examples.
The following raw material sources are exemplary illustrations:
recombinant collagen: type III recombinant humanized collagen with weight average molecular weight of 10 Wandall, which is commercially available;
and (3) a thickening agent: sodium carboxymethyl cellulose and sodium hydroxymethyl cellulose, with a weight average molecular weight of 15 kalman, are commercially available;
crosslinking agent: glutaraldehyde, genipin, commercially available;
phosphate: potassium dihydrogen phosphate, disodium hydrogen phosphate, commercially available;
water: water for injection, commercially available.
Example 1
The recombinant collagen gel dressing is prepared from 10g of recombinant collagen cross-linked particles, 100g of sodium carboxymethylcellulose aqueous solution with the mass concentration of 3%, and 0.3g of monopotassium phosphate, and the specific process is as follows:
(1) Preparation of recombinant collagen crosslinked particles:
1a, dissolving 20g of recombinant collagen in 380g of injection water, stirring and foaming to obtain a collagen solution with the mass concentration of 5%;
1b, adding 2g of glutaraldehyde into the collagen solution obtained in the step 1a for crosslinking reaction to obtain a reaction solution 1;
1c, drying and crushing the reaction liquid 1 obtained in the step 1b to obtain recombinant collagen cross-linked particles; wherein the D90 of the recombinant collagen cross-linked particles is 251 μm.
(2) Preparation of sodium carboxymethylcellulose aqueous solution: 3g of sodium carboxymethyl cellulose is dissolved in 97g of water to prepare sodium carboxymethyl cellulose water solution with the mass concentration of 3 percent;
(3) Adding 10g of the recombinant collagen cross-linked particles obtained in the step (1) and 0.3g of phosphate into the sodium carboxymethylcellulose aqueous solution prepared in the step (2), and uniformly stirring to obtain the recombinant collagen gel dressing.
Example 2
The recombinant collagen gel dressing is prepared from 10g of recombinant collagen cross-linked particles, 60g of hydroxymethyl cellulose sodium aqueous solution with mass concentration of 2% and 0.2g of disodium hydrogen phosphate, and comprises the following specific processes:
(1) Preparation of recombinant collagen crosslinked particles:
1a, dissolving 20g of recombinant collagen in 380g of injection water, stirring and foaming to obtain a collagen solution with the mass concentration of 5%;
1b, adding 1g of glutaraldehyde into the collagen solution obtained in the step 1a to carry out a crosslinking reaction to obtain a reaction solution 1;
1c, drying and crushing the reaction liquid 1 obtained in the step 1b to obtain recombinant collagen cross-linked particles; wherein the D90 of the recombinant collagen cross-linked particles is 276 μm.
(2) Preparation of aqueous sodium hydroxymethyl cellulose solution: 1.2g of hydroxymethyl cellulose is dissolved in 58.8g of water to prepare a sodium hydroxymethyl cellulose water solution with the mass concentration of 2%;
(3) Adding 10g of the recombinant collagen cross-linked particles obtained in the step (1) and 0.2g of phosphate into the sodium hydroxymethyl cellulose aqueous solution prepared in the step (2), and uniformly stirring to obtain the recombinant collagen gel dressing.
Example 3
The recombinant collagen gel dressing is prepared from 10g of recombinant collagen cross-linked particles, 120g of sodium carboxymethyl cellulose water solution with the mass concentration of 5% and 0.4g of monopotassium phosphate, and the specific process is as follows:
(1) Preparation of recombinant collagen crosslinked particles:
1a, dissolving 20g of recombinant collagen in 380g of injection water, stirring and foaming to obtain a collagen solution with the mass concentration of 5%;
1b, adding 4g of genipin into the collagen solution obtained in the step 1a to carry out a crosslinking reaction to obtain a reaction solution 1;
1c, drying and crushing the reaction liquid 1 obtained in the step 1b to obtain recombinant collagen cross-linked particles; wherein the D90 of the recombinant collagen cross-linked particles is 298 μm.
(2) Preparation of sodium carboxymethylcellulose aqueous solution: 6g of sodium carboxymethyl cellulose is dissolved in 114g of water to prepare sodium carboxymethyl cellulose water solution with the mass concentration of 5%;
(3) Adding 10g of the recombinant collagen cross-linked particles obtained in the step (1) and 0.4g of phosphate into the sodium carboxymethylcellulose aqueous solution prepared in the step (2), and uniformly stirring to obtain the recombinant collagen gel dressing.
Comparative example 1
The recombinant collagen gel dressing is prepared from 10g of recombinant collagen cross-linked particles, 100g of sodium carboxymethylcellulose aqueous solution with the mass concentration of 3%, and 0.3g of monopotassium phosphate, and the specific process is as follows:
(1) Preparation of recombinant collagen crosslinked particles:
1a, dissolving 20g of recombinant collagen in 380g of injection water, stirring and foaming to obtain a collagen solution with the mass concentration of 5%;
1b, adding 0.4g glutaraldehyde into the collagen solution obtained in the step 1a for crosslinking reaction to obtain a reaction solution 1;
1c, drying and crushing the reaction liquid 1 obtained in the step 1b to obtain recombinant collagen cross-linked particles; wherein the D90 of the recombinant collagen cross-linked particles is 246 μm.
(2) Preparation of sodium carboxymethylcellulose aqueous solution: 3g of sodium carboxymethyl cellulose is dissolved in 97g of water to prepare sodium carboxymethyl cellulose water solution with the mass concentration of 3 percent;
(3) Adding 10g of the recombinant collagen cross-linked particles obtained in the step (1) and 0.3g of phosphate into the sodium carboxymethylcellulose aqueous solution prepared in the step (2), and uniformly stirring to obtain the recombinant collagen gel dressing.
Comparative example 2
The recombinant collagen gel dressing is prepared from 10g of recombinant collagen cross-linked particles, 100g of sodium carboxymethylcellulose aqueous solution with the mass concentration of 3%, and 0.3g of monopotassium phosphate, and the specific process is as follows:
(1) Preparation of recombinant collagen crosslinked particles:
1a, dissolving 20g of recombinant collagen in 380g of injection water, stirring and foaming to obtain a collagen solution with the mass concentration of 5%;
1b, adding 8g of glutaraldehyde into the collagen solution obtained in the step 1a for crosslinking reaction to obtain a reaction solution 1;
1c, drying and crushing the reaction liquid 1 obtained in the step 1b to obtain recombinant collagen cross-linked particles; wherein the D90 of the recombinant collagen cross-linked particles is 247 μm.
(2) Preparation of sodium carboxymethylcellulose aqueous solution: 3g of sodium carboxymethyl cellulose is dissolved in 97g of water to prepare sodium carboxymethyl cellulose water solution with the mass concentration of 3 percent;
(3) Adding 10g of the recombinant collagen cross-linked particles obtained in the step (1) and 0.3g of phosphate into the sodium carboxymethylcellulose aqueous solution prepared in the step (2), and uniformly stirring to obtain the recombinant collagen gel dressing.
Comparative example 3
The recombinant collagen gel dressing is prepared from 9.09g of recombinant collagen, 100g of sodium carboxymethylcellulose aqueous solution with the mass concentration of 3% and 0.3g of monopotassium phosphate. The specific process is as follows:
(1) Preparation of sodium carboxymethylcellulose aqueous solution: 3g of sodium carboxymethyl cellulose is dissolved in 97g of water to prepare sodium carboxymethyl cellulose water solution with the mass concentration of 3 percent;
(2) Adding 9.09g of recombinant collagen and 0.3g of phosphate into the sodium carboxymethyl cellulose aqueous solution prepared in the step (1), and uniformly stirring to obtain the recombinant collagen gel dressing.
Comparative example 4
The recombinant collagen gel dressing is prepared from 9.09g of recombinant collagen, 100g of sodium carboxymethylcellulose aqueous solution with the mass concentration of 3%, 0.3g of monopotassium phosphate and 0.91g of glutaraldehyde. The specific process is as follows:
(1) Preparation of thickener aqueous solution: 3g of sodium carboxymethyl cellulose is dissolved in 97g of water to prepare sodium carboxymethyl cellulose water solution with the mass concentration of 3 percent;
(2) Adding 9.09g of recombinant collagen and 0.91g of glutaraldehyde into the sodium carboxymethylcellulose aqueous solution prepared in the step (1) for crosslinking reaction, adding 0.3g of phosphate after the reaction is finished, and uniformly stirring to obtain the recombinant collagen gel dressing.
Test examples
Performance tests were performed on the dressings of examples 1-3 and comparative examples 1-4, the test performances including: fold absorption, in vitro degradation performance, intradermal stimulation, cytotoxicity, delayed type hypersensitivity reactions, results are shown in Table 1.
1. And (3) water absorption multiple measurement: 10g of dressing (m 0 ) Soaking in 1000mL physiological saline for 24 hr, filtering to remove excessive physiological saline, absorbing excessive water on the surface with filter paper, and weighing (m 1 ). Finally, the water absorption is calculated, each sample is measured for 3 times and then the average value is taken, and the water absorption multiple= (m) 1 -m 0 )/m 0 And (5) 100%, namely the saturated water absorption.
2. In vitro degradation performance: 10g of dressing (mass after freeze-drying: m) was weighed 0 ) Immersed in 100mL of PBS (pH=7.4) with collagenase content of 12.5U/mL and digested in a constant temperature incubator at 37℃for 7 days. Filtering to remove the solution, and removingThe seeds are washed for 3 times, the quality (mt) is called after freeze drying, and the in vitro degradation rate of the dressing is as follows: degradation rate= (m 0 -m t )/m 0 ×100％。
3. Intradermal stimulation, delayed hypersensitivity reaction: reference standard GB/T16886.10-2017 medical device biological evaluation part 10: the irritation and skin sensitization test is carried out, the leaching proportion of the sample is 0.1g/mL, two solvents of 0.9% sodium chloride solution (dosage) and sesame oil (nonpolar) are used, the sample is sterilized for 20min at 121 ℃ in advance, and the sample is leached for 72+/-2 h at 37+/-1 ℃ in an incubator for test.
4. Cytotoxicity: reference standard GB/T16886.5-2017 medical device biological evaluation part 5: in vitro cytotoxicity test section 12, GB/T16886.12-2017 medical device biology evaluation: sample preparation and reference materials, sample extraction ratio of 0.1g/mL, sample sterilization at 121℃for 20min, adding DMEM medium containing 10% fetal bovine serum according to extraction ratio, extracting at 37℃for 24h in an incubator to obtain 100% extract, diluting again to obtain 50% extract, testing cell viability at 100% and 50% extract, cell viability at 100% extract > 70% and cell viability at 50% extract > 100% extract, representing no potential cytotoxicity.
TABLE 1
As can be seen from table 1, the recombinant collagen gel dressing prepared in examples 1 to 3 is an extrusion flowable viscous body, and can be very conveniently applied to a wound surface; has good degradation resistance and good water absorbability, can meet longer service time, and can absorb tissue fluid exuded from the wound surface to promote wound surface recovery; has no intradermal irritation and cytotoxicity, and no sensitization, and can be directly used for wound surface.
As can be seen from comparative example 1 and comparative example 1, when glutaraldehyde is used in an excessively small amount, the crosslinking degree of the recombinant collagen crosslinked particles is limited, and the prepared recombinant collagen gel dressing has a certain viscosity, but is not thick enough, and is easy to overflow and shape when being directly coated on a wound surface, and the water absorption performance and the degradation performance are poor due to the limited crosslinking degree.
As can be seen from comparative examples 1 and 2, when glutaraldehyde is used too much and the recombinant collagen cross-linked particles are excessively cross-linked, on one hand, the prepared recombinant collagen gel dressing has a certain sensitization and improved cytotoxicity, and on the other hand, because the recombinant collagen cross-linked particles are excessively cross-linked, the recombinant collagen gel dressing is difficult to swell in a sodium carboxymethyl cellulose solution, and the prepared recombinant collagen gel dressing is an uneven fluid with visible particles having a certain consistency, has insufficient viscosity, cannot be directly used for wound surfaces, and has a relatively reduced water absorption performance.
As can be seen from comparative examples 1 and 3, when the recombinant collagen is not crosslinked with glutaraldehyde, the prepared product is thin, cannot be directly used for wound surface without drying and dewatering, and has poor water absorption and degradation properties.
As can be seen from comparative examples 1 and 4, when the recombinant collagen was directly dissolved in a sodium carboxymethyl cellulose solution without using glutaraldehyde for crosslinking, and then crosslinked, the prepared dressing was lump-shaped aggregate, had no fluidity, could not be applied to wound surface in the form of extrusion, and had poor water absorption and degradation resistance. On one hand, after the recombinant collagen is directly dissolved in a sodium carboxymethyl cellulose solution, the sodium carboxymethyl cellulose has fewer active groups capable of carrying out crosslinking reaction with glutaraldehyde, and can interfere the crosslinking reaction of the recombinant collagen, so that the overall crosslinking degree of a reaction system is not high; on the other hand, the recombinant collagen is directly dissolved in the sodium carboxymethyl cellulose solution, and the concentration of the recombinant collagen in the prepared dispersion liquid is high, so that the crosslinking reaction is not facilitated, and therefore, the finally obtained recombinant collagen gel dressing has low crosslinking degree and poor water absorption performance and degradation resistance.
The technical scheme of the invention is not limited to the technical means disclosed by the technical means, and also comprises the technical scheme formed by any combination of the technical features. While the foregoing is directed to embodiments of the present invention, it will be appreciated by those skilled in the art that changes and modifications may be made without departing from the principles of the invention, and such changes and modifications are intended to be included within the scope of the invention.
Claims (10)
1. The recombinant collagen gel dressing is characterized by comprising the following raw materials: recombinant collagen cross-linked particles, thickener aqueous solution, phosphate;
wherein the recombinant collagen crosslinking particles are obtained by crosslinking and crushing recombinant collagen and a crosslinking agent, and the mass ratio of the recombinant collagen to the crosslinking agent is (4-20): 1, wherein the mass concentration of the thickener aqueous solution is 0.5% -5.0%, and the mass ratio of the recombinant collagen cross-linked particles to the thickener aqueous solution is 1 (2-15).
2. The recombinant collagen gel dressing according to claim 1, wherein the recombinant collagen is collagen produced by fermentation using a genetic engineering method, and comprises recombinant human collagen, recombinant human-like collagen and recombinant collagen-like protein.
3. The recombinant collagen gel dressing according to claim 1, wherein the cross-linking agent is at least one of carbodiimide, propylene oxide, diphenyl phosphate, hexamethylene diisocyanate, genipin, formaldehyde, and glutaraldehyde; the thickening agent is a cellulose thickening agent; the phosphate is at least one of calcium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium polyphosphate, sodium pyrophosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate, and the dosage of the phosphate is 0.2-1% of the total dosage of the recombinant collagen cross-linked particles, the thickener aqueous solution and the phosphate.
4. The recombinant collagen gel dressing of claim 3, wherein the cross-linking agent is at least one of genipin, formaldehyde, and glutaraldehyde; the cellulose thickener is at least one of hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose or soluble salt of above cellulose.
5. The recombinant collagen gel dressing according to claim 4, wherein the cross-linking agent is glutaraldehyde; the cellulose thickener is carboxymethyl cellulose soluble salt.
6. The method of preparing a recombinant collagen gel dressing according to any one of claims 1 to 5, comprising the steps of:
(1) Preparation of recombinant collagen crosslinked particles:
1a, dissolving recombinant collagen in water, stirring and foaming to obtain a collagen solution;
1b, adding a cross-linking agent into the collagen solution obtained in the step 1a to carry out a cross-linking reaction to obtain a reaction solution 1;
1c, drying and crushing the reaction liquid 1 obtained in the step 1b to obtain recombinant collagen cross-linked particles;
(2) Preparation of thickener aqueous solution: dissolving a formula amount of thickener in water to prepare a thickener aqueous solution;
(3) Adding the recombinant collagen cross-linked particles obtained in the step (1) and phosphate into the thickener aqueous solution obtained in the step (2), and uniformly stirring to obtain the recombinant collagen gel dressing.
7. The method of claim 6, wherein: the mass concentration of the collagen solution in the step 1a is 0.1% -5%, and the stirring condition is 500-5000r/min.
8. The method of claim 6, wherein: the step 1c adopts heating drying or freeze drying; the heating and drying temperature is 50-90 ℃.
9. Use of a recombinant collagen gel dressing according to any one of claims 1 to 5 or prepared by a method according to any one of claims 6 to 8 in the preparation of a product for wound repair.
10. The use according to claim 9, wherein: the wound surface is tooth extraction wound, dental ulcer, abrasion, incised wound, scald, burn, electric burn, diabetic foot, and venous ulcer.
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