CN117563038A - Multifunctional hemostatic repair sponge of composite polypeptide and preparation method thereof - Google Patents
Multifunctional hemostatic repair sponge of composite polypeptide and preparation method thereof Download PDFInfo
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- 230000008439 repair process Effects 0.000 title claims abstract description 30
- 230000002439 hemostatic effect Effects 0.000 title claims abstract description 28
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000002131 composite material Substances 0.000 title abstract description 6
- 229920001184 polypeptide Polymers 0.000 title abstract description 3
- 102000004196 processed proteins & peptides Human genes 0.000 title abstract description 3
- 108010022355 Fibroins Proteins 0.000 claims abstract description 71
- 101100322245 Caenorhabditis elegans des-2 gene Proteins 0.000 claims abstract description 24
- 239000000243 solution Substances 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- 238000007710 freezing Methods 0.000 claims description 50
- 230000008014 freezing Effects 0.000 claims description 50
- 238000000502 dialysis Methods 0.000 claims description 34
- 150000007524 organic acids Chemical class 0.000 claims description 26
- 101000952227 Drosophila melanogaster Sphingolipid delta(4)-desaturase DES1 Proteins 0.000 claims description 25
- 102100037416 Sphingolipid delta(4)-desaturase DES1 Human genes 0.000 claims description 25
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- 239000004475 Arginine Substances 0.000 claims description 16
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 16
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims description 14
- 229960000401 tranexamic acid Drugs 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 238000004108 freeze drying Methods 0.000 claims description 11
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims description 11
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 claims description 10
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 claims description 10
- 239000001685 glycyrrhizic acid Substances 0.000 claims description 10
- 229960004949 glycyrrhizic acid Drugs 0.000 claims description 10
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 claims description 10
- 235000019410 glycyrrhizin Nutrition 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 6
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000001630 malic acid Substances 0.000 claims description 6
- 235000011090 malic acid Nutrition 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 4
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960002510 mandelic acid Drugs 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 238000003958 fumigation Methods 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- -1 but not limited to Chemical class 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 31
- 239000011148 porous material Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 4
- 230000000740 bleeding effect Effects 0.000 abstract description 3
- 230000010261 cell growth Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000001727 in vivo Methods 0.000 abstract description 3
- 239000010410 layer Substances 0.000 description 84
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 28
- 238000009835 boiling Methods 0.000 description 21
- 238000005303 weighing Methods 0.000 description 17
- 238000001035 drying Methods 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 238000000605 extraction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000003513 alkali Substances 0.000 description 10
- 206010052428 Wound Diseases 0.000 description 8
- 208000027418 Wounds and injury Diseases 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 7
- 238000011068 loading method Methods 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 238000007789 sealing Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000015271 coagulation Effects 0.000 description 4
- 238000005345 coagulation Methods 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 230000035602 clotting Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000023597 hemostasis Effects 0.000 description 2
- 239000011229 interlayer Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
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- 239000010839 body fluid Substances 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940074774 glycyrrhizinate Drugs 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0036—Porous materials, e.g. foams or sponges
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
-
- 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
- A61L2400/04—Materials for stopping bleeding
Landscapes
- Health & Medical Sciences (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention discloses a multifunctional hemostatic repair sponge of composite polypeptide and a preparation method thereof, belonging to the field of medical appliances; the middle layer consists of silk fibroin and DES-2, has smaller pore diameter, can stop bleeding and has anti-inflammatory function; the outer layer consists of silk fibroin and short peptide, and has a repairing function. The sponge material prepared by the invention has good biocompatibility and biodegradability, can effectively release drugs in vivo, and promotes cell growth and repair.
Description
Technical Field
The invention relates to the field of medical appliances, in particular to a porous sponge preparation with wound hemostasis, anti-inflammatory and repair functions and a preparation method thereof.
Background
Wound therapy is an important direction in the medical field. Hemostatic repair materials have wide application in wound treatment such as trauma and surgery. Traditional hemostatic materials often have only a single function and cannot meet the multiple needs of different wounds. Therefore, the development of a multifunctional hemostatic repair material has important practical significance.
Currently, some hemostatic repair materials with multiple functions have been developed. For example, some materials containing bioactive substances (e.g., growth factors, antimicrobial agents, etc.) have been used in wound therapy. In addition, some materials containing multiple components are also used in wound therapy. However, these materials still have problems such as poor biocompatibility and stability, uncontrollable composition, and the like. Therefore, there is a need to develop a multifunctional hemostatic repair material with good biocompatibility and stability.
Sponge preparations are a common hemostatic repair material. It has a large number of pore structures and can interact with liquids such as body fluids. Therefore, the sponge preparation has higher tissue compatibility and biological activity and can be used for wound treatment. However, the conventional sponge preparation still has some problems such as unstable pore structure, insufficient utilization of the pore structure, and the like.
Therefore, the development of a porous sponge preparation with good biocompatibility and stability has important practical significance.
Disclosure of Invention
The invention aims to provide a multifunctional hemostatic repair sponge and a preparation method thereof, and the sponge has the functions of rapid hemostasis, anti-inflammatory, repair and the like and can be widely applied to wound treatment.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a multifunctional porous hemostatic repair sponge, the sponge comprising:
an inner layer: is prepared from silk fibroin and DES-1 series; an intermediate layer: consists of silk fibroin and DES-2 series; an outer layer: consists of silk fibroin and short peptide;
wherein, the DES-1 is prepared from tranexamic acid and organic acid; the DES-2 is prepared from arginine and organic acid; the sequence of the short peptide is KIIK (SEQ NO ID: 1), KKIIKK (SEQ NO ID: 2), RRIIRR (SEQ NO ID: 3), KRIIKR (SEQ NO ID: 4), KRIIKR (SEQ NO ID: 5), KKIIKK (SEQ NO ID: 6) or RRIIIIRR (SEQ NO ID: 7).
In one embodiment, the DES-1 comprises 0.1% to 3%, preferably 0.5% to 2.5%, and may be 0.5%, 1%, 2% or 2.5% of the mass of the silk fibroin in the inner layer.
In one embodiment, the intermediate layer comprises DES-2 in an amount of 0.1% to 6%, preferably 1% to 5%, and may be 1%, 2%, 3% or 5% of the mass of the silk fibroin.
In one embodiment, the short peptide comprises 0.1% to 5%, preferably 0.5% to 3%, and may be 0.5%, 2% or 3% of the mass of the silk fibroin in the outer layer.
In one embodiment, the mass ratio of silk fibroin in the inner layer, the middle layer and the outer layer is 1:2-4:2-6
In one embodiment, the DES-1 is prepared according to a molar ratio of 1:1-5:1 of the tranexamic acid to the organic acid, wherein the organic acid comprises any one or more of malic acid, citric acid, tartaric acid and mandelic acid, the organic acid and the tranexamic acid are respectively weighed according to the molar ratio of 1:1-5:1, dissolved in a solvent, placed in an inert atmosphere, stirred and reacted for 6-24 hours at 30-80 ℃, redundant solvent is removed, and dialysis and purification are carried out to obtain the DES-1. Preferably, the solvent is water.
In one embodiment, the DES-2 is prepared according to the molar ratio of arginine to organic acid of 1:1-5:1, the organic acid comprises any one of glycyrrhizic acid, malic acid, citric acid, lactic acid and the like, the organic acid and the arginine are respectively weighed according to the molar ratio of 1:1-2 and dissolved in a solvent, the solvent is placed in an inert atmosphere and stirred for reaction for 6-24 hours at 30-80 ℃, the redundant solvent is removed, and the DES-1 is obtained through dialysis and purification. Preferably, the solvent is water.
In one embodiment, the silk fibroin can be extracted by the following method: 1. degumming: 1) 25.44g of anhydrous Na 2 CO 3 Adding 12L of pure water heated to boiling, and fully dissolving; 2) Weighing 30g of silk, adding water after boiling, and boiling for 30min; 3) Taking out, and repeatedly rubbing with pure water for 3-5 times; 4) Drying overnight in a kitchen. 2. Dissolving: 1) Preparing a 9.3M lithium bromide solution; 2) Weighing 5g of degummed silk, adding 20mL of lithium bromide solution, fully immersing the silk, and sealing with tinfoil paper; 3) After being placed in an oven at 60 ℃ for 4 hours, the mixture is taken out. 3. And (3) dialysis: 1) Loading the dissolved silk fibroin into a dialysis bag; 2) Each dialysis bag was placed in a vat containing at least 4L of purified water for dialysis for 36 hours; 3) Intermittent water exchange is performed at least 5 times or dialysis is performed using running water.
In one embodiment, the multifunctional porous hemostatic repair sponge: the inner layer is prepared from silk fibroin and DES-1, has a larger aperture, and can quickly stop bleeding; the middle layer consists of silk fibroin and DES-2, has smaller pore diameter, can stop bleeding and has anti-inflammatory function; the outer layer consists of silk fibroin and short peptide, and has a repairing function.
The invention also provides a preparation method of the multifunctional porous hemostatic repair sponge, which comprises the following steps:
(1) Preparing DES-1 and DES-2 according to the proportion respectively;
(2) According to different layer requirements, the silk fibroin is respectively mixed with DES-1, DES-2 and short peptide to respectively obtain an inner layer solution, an intermediate layer solution and an outer layer solution, wherein the solvent is water;
(3) Freezing through an inner layer solution; then placing the frozen inner layer structure under the middle layer solution, and freezing again; then placing the frozen structure under the outer layer solution for freezing;
(4) Freeze-drying the frozen porous structure obtained in the step (3);
(5) And (3) performing steam treatment on the freeze-dried sponge.
In one embodiment, in step (3), the freezing is preferably gradient freezing: and (3) carrying out gradient freezing on the mixed solution, wherein the temperature is between 80 ℃ below zero and 0 ℃ below zero, and the treatment time is between 2 and 72 hours.
In one embodiment, the concentration of silk fibroin in the inner layer solution, the middle layer solution and the outer layer solution is 5-20wt%, 5-20wt% and 5-20wt%, respectively.
In one embodiment, in the step (3), the inner layer is frozen at-20 ℃ and-80 ℃ in a gradient way, then the middle layer is poured on the inner layer, the inner layer is frozen at-20 ℃ and-80 ℃ in a gradient way, then the outer layer solution is covered on the upper layer, and the inner layer is frozen at-20 ℃ and-80 ℃.
In one embodiment, in step (4), the time of freeze drying (cold trap-65 ℃) is 48h-96h.
In one embodiment, in step (5), the steam treatment is fumigation with steam at 50-60 ℃ for 12-72 hours.
Finally, the invention also provides a medical device comprising the multifunctional porous hemostatic repair sponge.
Compared with the prior art, the invention has the following advantages:
(1) The method provided by the invention can be used for preparing the sponge material containing DES, and the material is suitable for the fields of medicine slow release, tissue engineering, biomedical application and the like.
(2) The invention adopts unique composition and structure, combines the processes of freeze drying, steam treatment and the like, and forms a porous sponge structure. These processes are capable of maintaining the stability and activity of DES and provide good pore structure and biocompatibility for the sponge material.
(3) The sponge material prepared by the invention has good biocompatibility and biodegradability, can effectively release drugs in vivo, and promotes cell growth and repair.
Drawings
Fig. 1 is a physical diagram of a multifunctional hemostatic repair sponge of a composite short peptide prepared in example 1.
FIG. 2 is a microscopic morphology of a multifunctional hemostatic repair sponge of the composite short peptide prepared in example 1.
FIG. 3 is a graph showing the comparison of the coagulation indexes of the cotton prepared in examples 1 to 2 and comparative examples 1 to 2.
FIG. 4 is a statistical graph of cell proliferation rate of a multifunctional hemostatic repair sponge of a composite short peptide prepared in example 1.
Detailed Description
The present invention is further illustrated by the following specific examples, which are not intended to be limiting and are intended to be illustrative only.
Example 1:
(1) Extraction of silk fibroin: extraction of silk fibroin: 1. degumming: 1) 25.44g of anhydrous Na 2 CO 3 Adding 12L of pure water heated to boiling, and fully dissolving; 2) Weighing 30g of silk, adding water after boiling, and boiling for 30min; 3) Taking out, and repeatedly rubbing with pure water for 3-5 times; 4) Drying overnight in a kitchen. 2. Dissolving: 1) Preparing a 9.3M lithium bromide solution; 2) Weighing 5g of degummed silk, adding 20mL of lithium bromide solution, fully immersing the silk, and sealing with tinfoil paper; 3) After being placed in an oven at 60 ℃ for 4 hours, the mixture is taken out. 3. And (3) dialysis: 1) Loading the dissolved silk fibroin into a dialysis bag; 2) Each dialysis bag was placed in a vat containing at least 4L of purified water for dialysis for 36 hours; 3) Intermittently changing water for at least 5 times or dialyzing with flowing water, and drying to obtain silk fibroin;
the preparation method of DES comprises the following steps: the organic acid and alkali powder are respectively weighed according to the mol ratio of 1:1, dissolved in a sample bottle, placed under the nitrogen atmosphere, heated (40 ℃) and stirred for 6 hours, the excess water is evaporated by a rotary evaporator, and the DES is obtained by dialysis and purification. Wherein, the tranexamic acid malic acid is DES-1, and the arginine glycyrrhizic acid is DES-2.
(2) Inner layer solution: silk fibroin (6%) was mixed well with 0.5% DES-1, interlayer solution: silk fibroin (6%) was mixed well with 2% DES-2, outer layer solution: uniformly mixing silk fibroin (6%) and 0.5% of short peptide (sequence KKIIKK), wherein the mass ratio of silk fibroin in the inner layer, the middle layer and the outer layer is 1:2:2;
(3) Gradient freezing the solution according to the sequence of the inner layer, the middle layer and the outer layer; the parameters of gradient freezing are: refrigerating the inner layer at 4deg.C for 2 hr, freezing at-20deg.C for 5 hr, and freezing at-80deg.C for 10 hr; freezing the middle layer at-20deg.C for 5 hr, freezing at-80deg.C for 10 hr, and freezing the outer layer at-20deg.C for 5 hr, freezing at-80deg.C for 10 hr;
(4) Freeze-drying the frozen porous structure for 72h;
(5) The lyophilized sponge was subjected to steam treatment for 12 hours.
Example 2:
(1) Extraction of silk fibroin: extraction of silk fibroin: 1. degumming: 1) 25.44g of anhydrous Na 2 CO 3 Adding 12L of pure water heated to boiling, and fully dissolving; 2) Weighing 30g of silk, adding water after boiling, and boiling for 30min; 3) Taking out, and repeatedly rubbing with pure water for 3-5 times; 4) Drying overnight in a kitchen. 2. Dissolving: 1) Preparing a 9.3M lithium bromide solution; 2) Weighing 5g of degummed silk, adding 20mL of lithium bromide solution, fully immersing the silk, and sealing with tinfoil paper; 3) After being placed in an oven at 60 ℃ for 4 hours, the mixture is taken out. 3. And (3) dialysis: 1) Loading the dissolved silk fibroin into a dialysis bag; 2) Each dialysis bag was placed in a vat containing at least 4L of purified water for dialysis for 36 hours; 3) Intermittently changing water for at least 5 times or dialyzing with flowing water, and drying to obtain silk fibroin;
the preparation method of DES comprises the following steps: and respectively weighing the organic acid powder and the alkali powder according to the molar ratio of 1:2, dissolving the organic acid powder and the alkali powder in a sample bottle, heating the sample bottle under the nitrogen atmosphere (50 ℃) and stirring the sample bottle for 12 hours, evaporating the excessive water by using a rotary evaporator, and dialyzing and purifying the mixture to obtain the DES. The organic acids include: mandelic acid and glycyrrhizic acid, and the alkali comprises tranexamic acid and arginine. The tranexamic acid mandelic acid is DES-1, and the arginine glycyrrhizic acid is DES-2.
(2) Inner layer solution: silk fibroin (8%) was mixed well with 1% DES-1, middle layer solution: silk fibroin (8%) was mixed uniformly with 3% DES-2, outer layer solution: uniformly mixing silk fibroin (8%) and 1% of short peptide (with a sequence of RRIIIIRR), wherein the mass ratio of silk fibroin in the inner layer, the middle layer and the outer layer is 1:2:4;
(3) Gradient freezing the solution according to the sequence of the inner layer, the middle layer and the outer layer; the parameters of gradient freezing are: refrigerating the inner layer at 4deg.C for 4 hr, freezing at-20deg.C for 7 hr, and freezing at-80deg.C for 15 hr; freezing the middle layer at-20deg.C for 5 hr, freezing at-80deg.C for 10 hr, and freezing the outer layer at-20deg.C for 5 hr, freezing at-80deg.C for 10 hr;
(4) Freeze-drying the frozen porous structure for 96 hours;
(5) The lyophilized sponge was subjected to steam treatment for 24 hours.
Example 3:
(1) Extraction of silk fibroin: extraction of silk fibroin: 1. degumming: 1) 25.44g of anhydrous Na 2 CO 3 Adding 12L of pure water heated to boiling, and fully dissolving; 2) Weighing 30g of silk, adding water after boiling, and boiling for 30min; 3) Taking out, and repeatedly rubbing with pure water for 3-5 times; 4) Drying overnight in a kitchen. 2. Dissolving: 1) Preparing a 9.3M lithium bromide solution; 2) Weighing 5g of degummed silk, adding 20mL of lithium bromide solution, fully immersing the silk, and sealing with tinfoil paper; 3) After being placed in an oven at 60 ℃ for 4 hours, the mixture is taken out. 3. And (3) dialysis: 1) Loading the dissolved silk fibroin into a dialysis bag; 2) Each dialysis bag was placed in a vat containing at least 4L of purified water for dialysis for 36 hours; 3) Intermittently changing water for at least 5 times or dialyzing with flowing water, and drying to obtain silk fibroin;
the preparation method of DES comprises the following steps: and respectively weighing the organic acid powder and the alkali powder according to the molar ratio of 1:2, dissolving the organic acid powder and the alkali powder in a sample bottle, heating the sample bottle under a nitrogen atmosphere (60 ℃) and stirring the sample bottle for 24 hours, evaporating the excessive water by using a rotary evaporator, and dialyzing and purifying the mixture to obtain the DES. The organic acids include: citric acid, glycyrrhizic acid, and alkali including tranexamic acid and arginine. The citric acid of tranexamic acid is DES-1, and the malic acid of arginine is DES-2.
(2) Inner layer solution: silk fibroin (14%) was mixed well with 2% DES-1, interlayer solution: silk fibroin (14%) was mixed uniformly with 4% arginine glycyrrhizinate DES-2, outer layer solution: uniformly mixing silk fibroin (10%) and 1.5% of 8 peptide (sequence KKIIKK), wherein the mass ratio of silk fibroin in the inner layer, the middle layer and the outer layer is 1:3:5;
(3) Gradient freezing the solution according to the sequence of the inner layer, the middle layer and the outer layer; the parameters of gradient freezing are: refrigerating the inner layer at 4deg.C for 6 hr, freezing at-20deg.C for 9 hr, and freezing at-80deg.C for 18 hr; freezing the middle layer at-20deg.C for 5 hr, freezing at-80deg.C for 10 hr, and freezing the outer layer at-20deg.C for 5 hr, freezing at-80deg.C for 10 hr;
(4) Freeze-drying the frozen porous structure for 72h;
(5) The lyophilized sponge was subjected to steam treatment for 48 hours.
Example 4:
(1) Extraction of silk fibroin: extraction of silk fibroin: 1. degumming: 1) 25.44g of anhydrous Na 2 CO 3 Adding 12L of pure water heated to boiling, and fully dissolving; 2) Weighing 30g of silk, adding water after boiling, and boiling for 30min; 3) Taking out, and repeatedly rubbing with pure water for 3-5 times; 4) Drying overnight in a kitchen. 2. Dissolving: 1) Preparing a 9.3M lithium bromide solution; 2) Weighing 5g of degummed silk, adding 20mL of lithium bromide solution, fully immersing the silk, and sealing with tinfoil paper; 3) After being placed in an oven at 60 ℃ for 4 hours, the mixture is taken out. 3. And (3) dialysis: 1) Loading the dissolved silk fibroin into a dialysis bag; 2) Each dialysis bag was placed in a vat containing at least 4L of purified water for dialysis for 36 hours; 3) Intermittently changing water for at least 5 times or dialyzing with flowing water, and drying to obtain silk fibroin;
the preparation method of DES comprises the following steps: and respectively weighing the organic acid powder and the alkali powder according to the molar ratio of 1:2, dissolving the organic acid powder and the alkali powder in a sample bottle, heating the sample bottle under a nitrogen atmosphere (80 ℃) and stirring the sample bottle for 6 hours, evaporating the excessive water by using a rotary evaporator, and dialyzing and purifying the mixture to obtain the DES. The organic acids include: citric acid, glycyrrhizic acid, and alkali including tranexamic acid and arginine. The citric acid of tranexamic acid is DES-1, and the arginine glycyrrhizic acid is DES-2.
(2) Inner layer solution: silk fibroin (12%) was mixed well with 2.5% tranexamic acid, DES-1, middle layer solution: silk fibroin (10%) and 5% arginine glycyrrhizic acid DES-2 were mixed uniformly, outer layer solution: uniformly mixing silk fibroin (17%) and 2% of short peptide (sequence KKIIKK), wherein the mass ratio of silk fibroin in the inner layer, the middle layer and the outer layer is 1:2:4;
(3) Gradient freezing the solution according to the sequence of the inner layer, the middle layer and the outer layer; the parameters of gradient freezing are: refrigerating the inner layer at 4deg.C for 5 hr, freezing at-20deg.C for 8 hr, and freezing at-80deg.C for 16 hr; freezing the middle layer at-20deg.C for 5 hr, freezing at-80deg.C for 16 hr, and freezing the outer layer at-20deg.C for 5 hr, freezing at-80deg.C for 16 hr;
(4) Freeze-drying the frozen porous structure for 72h;
(5) The lyophilized sponge was subjected to steam treatment for 48 hours.
The method provided by the invention can be used for preparing the sponge material containing DES, and the material is suitable for the fields of medicine slow release, tissue engineering, biomedical application and the like.
Comparative example 1
(1) Extraction of silk fibroin: extraction of silk fibroin: 1. degumming: 1) 25.44g of anhydrous Na 2 CO 3 Adding 12L of pure water heated to boiling, and fully dissolving; 2) Weighing 30g of silk, adding water after boiling, and boiling for 30min; 3) Taking out, and repeatedly rubbing with pure water for 3-5 times; 4) Drying overnight in a kitchen. 2. Dissolving: 1) Preparing a 9.3M lithium bromide solution; 2) Weighing 5g of degummed silk, adding 20mL of lithium bromide solution, fully immersing the silk, and sealing with tinfoil paper; 3) After being placed in an oven at 60 ℃ for 4 hours, the mixture is taken out. 3. And (3) dialysis: 1) Loading the dissolved silk fibroin into a dialysis bag; 2) Each dialysis bag was placed in a vat containing at least 4L of purified water for dialysis for 36 hours; 3) Intermittently changing water for at least 5 times or dialyzing with flowing water, and drying to obtain silk fibroin;
(2) The silk fibroin solution (6%) was refrigerated at 4℃for 2 hours, -20℃for 5 hours, -80℃for 10 hours;
(3) Freeze-drying the frozen porous structure for 72h;
(4) The lyophilized sponge was subjected to steam treatment for 48 hours.
Comparative example 2
(1) Extraction of silk fibroin: extraction of silk fibroin: 1. degumming: 1) 25.44g of anhydrous Na 2 CO 3 Adding 12L of pure water heated to boiling, and fully dissolving; 2) Weighing 30g of silk, adding water after boiling, and boiling for 30min; 3) Taking out, and repeatedly rubbing with pure water for 3-5 times; 4) Drying overnight in a kitchen. 2. Dissolving: 1) Preparing a 9.3M lithium bromide solution; 2) Weighing 5g of degummed silk, adding 20mL of lithium bromide solution, fully immersing the silk, and sealing with tinfoil paper; 3) Placing at 60deg.CAfter 4 hours in the oven, the mixture was taken out. 3. And (3) dialysis: 1) Loading the dissolved silk fibroin into a dialysis bag; 2) Each dialysis bag was placed in a vat containing at least 4L of purified water for dialysis for 36 hours; 3) Intermittently changing water for at least 5 times or dialyzing with flowing water, and drying to obtain silk fibroin;
(2) Inner layer solution: silk fibroin (6%) was mixed with 2% arginine glycyrrhizic acid DES-2 (preparation method same as example 1), outer layer solution: uniformly mixing silk fibroin (6%) and 0.5% of short peptide (sequence KKIIKK), wherein the mass ratio of silk fibroin in the inner layer solution to silk fibroin in the outer layer solution is 1:1;
(3) Gradient freezing the solution according to the sequence of the inner layer and the outer layer; the parameters of gradient freezing are: refrigerating the inner layer at 4deg.C for 2 hr, freezing at-20deg.C for 5 hr, and freezing at-80deg.C for 10 hr; freezing the outer layer at-20deg.C for 5 hr, and freezing at-80deg.C for 10 hr;
(4) Freeze-drying the frozen porous structure for 72h;
(5) The lyophilized sponge was subjected to steam treatment for 12 hours.
In the embodiment of the invention, six different types of DES sponge materials are prepared by mixing silk fibroin serving as a template material with DES of different formulas. The physical properties and biological activity of these materials have been tested and evaluated in the laboratory.
The sponge materials obtained in examples 1 to 2 and comparative examples 1 to 2 were tested for coagulation index and water absorption.
The results of the coagulation index test (judging the blood coagulation rate by the absorbance value of the hemoglobin solution) are shown in fig. 3, wherein 3M refers to a tergaderm model hemostatic sponge purchased from 3M company, and the normal group refers to an experimental condition without intervention. It can be seen that the hemostatic effect of example 1 of the present invention is optimal, the coagulation index is 58% at 30s, and the hemostatic speed is faster. The hemostatic sponge of example 2 and commercially available 3M were comparable in level and also were sponge materials with excellent clotting effects, with comparative example 1 having little difference from the normal set and essentially no effective clotting effects, and the addition of DES-2 in comparative example 2 was effective in increasing clotting rate, but still inferior to the sponge materials of examples 1-2 and 3M of the present invention.
FIG. 4 shows the effect of the extract of the repair sponge on L929 cell proliferation by detection using an enzyme-labeled instrument according to the genus Dragon of the Biyundian CCK-8 kit. The results of reference standard G/B16886 show that the repair sponge prepared by us has good biological safety.
The water absorption of the sponge materials obtained in examples 1 to 2 and comparative examples 1 to 2 of the present invention was measured, and the results are shown in Table 1.
TABLE 1 Water absorption of sponge materials obtained in examples 1 to 2 and comparative examples 1 to 2 of the present invention
Therefore, the sponge material has excellent water absorption effect and high water absorption speed. The same sponges prepared in examples 3 to 4 of the present invention were used for the above test, and the same effects as those of example 1 were obtained.
When the short peptide KKIIKK in example 1 was replaced with KIIK, KKIIKK, RRIIRR, KRIIKR, KRIIIIKR or RRIIIIRR, the properties of the prepared sponge material were not quite as different from those of example 1.
In the examples of the present invention, we use freeze drying and steam treatment to form a porous sponge structure. These processes are capable of maintaining the stability and activity of DES and provide good pore structure and biocompatibility for the sponge material.
In experiments, the prepared sponge material has good biocompatibility and biodegradability, can effectively release drugs in vivo, and promotes cell growth and repair. The data show that the prepared DES sponge material has wide application prospect and can be used in the fields of medicine slow release, tissue engineering, biomedical application and the like.
Therefore, the method and the material provided by the invention can meet the demands of people on high-efficiency, stable and biocompatible sponge materials, and have important industrial and medical application values.
While the present invention has been described in detail through the foregoing description of the preferred embodiment, it should be understood that the foregoing description is not to be considered as limiting the invention. Many modifications and substitutions of the present invention will become apparent to those of ordinary skill in the art upon reading the foregoing. Accordingly, the scope of the invention should be limited only by the attached claims.
Claims (10)
1. A multifunctional porous hemostatic repair sponge, the sponge comprising:
an inner layer: is prepared from silk fibroin and DES-1 series; an intermediate layer: consists of silk fibroin and DES-2 series; an outer layer: consists of silk fibroin and short peptide;
wherein, the DES-1 is prepared from tranexamic acid and organic acid; the DES-2 is prepared from arginine and organic acid; the sequence of the short peptide is KIIK, KKIIKK, RRIIRR, KRIIKR, KRIIIIKR, KKIIIIKK or RRIIIIRR.
2. A multifunctional porous hemostatic repair sponge according to claim 1 wherein DES-1 comprises 0.1% to 3% of the mass of silk fibroin in the inner layer; in the intermediate layer, DES-2 accounts for 0.1% -6% of the mass of the silk fibroin; in the outer layer, the short peptide accounts for 0.1% -5% of the mass of the silk fibroin.
3. The multifunctional porous hemostatic repair sponge according to claim 1, wherein the mass ratio of silk fibroin in the inner layer, the middle layer and the outer layer is 1:2-4:2-6.
4. A multifunctional porous hemostatic repair sponge according to any one of claims 1-3, wherein DES-1 is prepared according to a molar ratio of tranexamic acid to organic acid of 1:1-5:1, wherein the organic acid comprises any one or more of malic acid, citric acid, tartaric acid and mandelic acid, the organic acid and tranexamic acid are respectively weighed according to a molar ratio of 1:1-5:1, dissolved in a solvent, stirred and reacted for 6-24 hours at 30-80 ℃ under an inert atmosphere, excess solvent is removed, and DES-1 is obtained by dialysis and purification.
5. The multifunctional porous hemostatic repair sponge according to claim 4, wherein DES-2 is prepared according to a molar ratio of arginine to organic acid of 1:1-5:1, the organic acid including, but not limited to, any one of glycyrrhizic acid, malic acid, citric acid, lactic acid, etc., the organic acid and arginine are respectively weighed according to a molar ratio of 1:1-2, dissolved in a solvent, stirred and reacted at 30-80 ℃ under an inert atmosphere for 6-24 hours, excess solvent is removed, and DES-1 is obtained by dialysis and purification.
6. The method for preparing a multifunctional porous hemostatic repair sponge according to any one of claims 1 to 5, comprising the steps of:
(1) Preparing DES-1 and DES-2 according to the proportion respectively;
(2) According to different layer requirements, the silk fibroin is respectively mixed with DES-1, DES-2 and short peptide to respectively obtain an inner layer solution, an intermediate layer solution and an outer layer solution, wherein the solvent is water;
(3) Freezing through an inner layer solution; then placing the frozen inner layer structure under the middle layer solution, and freezing again; then placing the frozen structure under the outer layer solution for freezing;
(4) Freeze-drying the frozen porous structure obtained in the step (3);
(5) And (3) performing steam treatment on the freeze-dried sponge.
7. The method of claim 6, wherein in step (3), the freezing is gradient freezing: and (3) carrying out gradient freezing on the mixed solution, wherein the temperature is between 80 ℃ below zero and 0 ℃ below zero, and the treatment time is between 2 and 72 hours.
8. The preparation method according to claim 6, wherein the concentration of silk fibroin in the inner layer solution, the middle layer solution and the outer layer solution is 5-20wt%, 5-20wt% and 5-20wt%, respectively.
9. The method according to any one of claims 6 to 8, wherein in the step (5), the steam treatment is fumigation with steam at 50 to 60 ℃ for 12 to 72 hours.
10. A medical device comprising the multifunctional porous hemostatic repair sponge of any one of claims 1-5.
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