CN1234424C - Collagen based composite sponge and production thereof - Google Patents
Collagen based composite sponge and production thereof Download PDFInfo
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- CN1234424C CN1234424C CN 01142070 CN01142070A CN1234424C CN 1234424 C CN1234424 C CN 1234424C CN 01142070 CN01142070 CN 01142070 CN 01142070 A CN01142070 A CN 01142070A CN 1234424 C CN1234424 C CN 1234424C
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Abstract
The present invention provides collagen-based composite sponge and a preparation method thereof, which relates to the field of a medical material and a preparation method thereof. The present invention aims to provide collagen-based composite sponge with the advantages of favorable wound surface hemostasis and repair effect and low price, and a preparation method thereof. The collagen-based composite sponge of the present invention is composed of the following substances by the weight portions: 50 to 90 of collagen, 8 to 48 of chitosan and 0.5 to 5 of glycerol. The preparation method for the collagen-based composite sponge comprises the following processes: 1) dissolving the collagen in 0.01 to 0.1% of acetate solution to be prepared into 1 to 3% of collagen solution; 2) dissolving the chitosan in 0.01 to 0.1% of acetate solution to be prepared into 1 to 3% of chitosan solution; 3) uniformly mixing 50 to 90 of obtained collagen solution, 8 to 48 of obtained chitosan solution and 0.5 to 5 of glycerol according to the weight portion, and freezing the mixture for 1 to 5 days at the temperature of-10 DEG C to 80 DEG C to obtain a spongy material after the processes of freezing and drying; 4) fixing the spongy material in a gas generator by a crosslinking agent of aldehyde substances for 20 to 100 minutes at the temperature of 40 to 50DEGC; 5) cleaning the spongy material by glycerol water solution, and then drying the spongy material in vacuum to obtain the collagen-based composite sponge.
Description
Technical field
The present invention relates to material of a kind of medical grade and preparation method thereof, particularly relate to a kind of collagen base composite sponge and preparation method thereof.
Background technology
Collagen protein is the rich in protein of animal body intensive amount, is the main component of extracellular matrix (Extracellular Matrix).Collagen protein have antigenicity low, big with the cell affinity, produce characteristics such as hemagglutinative function with platelet, thereby be widely used at field of medicaments.Have been found that 20 kinds of collagen protein types that gene are different at present, its maximum feature is the structure of three collagen protein spirals.With the maximum type i collagen albumen of amount is example, and about 95% of collagen molecules is three coiled strand fields, and remaining about 5% is the terminal peptide chain structure field of noncollagen protein.The antigenicity of collagen protein is low, mainly is because three coiled strand fields of collagen protein lack tyrosine residue, the outer main peptide chain from collagen protein N and C terminal of the antigenicity removal of impurity of collagen protein product in the market.
Research and development based on the curable product of collagen protein, having obtained a lot of achievements, mainly is that collagen protein is made different dosage form, as solution, gel, powder, sponge, fiber, thin film etc., or carry out various modifications, make it have different medical or medical functions.But existing collagen protein sponge suppleness is relatively poor on the market, and it is very limited in the application of soft tissue wound surface (reparation is filled in the hemostasis as the department of cerebral surgery wound surface).In addition, price factor also is one of condition of coming into the market of restriction collagen protein series products scale.
Summary of the invention
It is good with repairing effect to the purpose of this invention is to provide a kind of wound surface hemostasis, the collagen base composite sponge that price is lower.
For achieving the above object, the present invention by the following technical solutions.
A kind of collagen base composite sponge, it is made up of the material of following ratio of weight and number:
Collagen protein 50-90
Chitosan 8-48
Glycerol 0.5-5
Described collagen protein can be commercially available collagen protein primary product (mainly being type i collagen albumen), also can be to adopt following method preparation:
1) animal tissue's machinery that will be rich in collagen protein is removed impurity such as epidermal area, muscle and fat, cleans up after the pulverizing;
2) dilute alkaline soln and the defat of alcohols material solution washing of usefulness pH8.5-10.5, the preferred sodium hydroxide of dilute alkaline soln: sodium bicarbonate: water=0.1-1: 5-10: 89-94.9 (ratio of weight and number) wherein, alcohols material aqueous solution preferred alcohol: isopropyl alcohol: water=5-10: 2-5: 85-93 (ratio of weight and number);
3) be dissolved in the dilute acid soln of pH5.5-6.5, wherein preferable formic acid, acetic acid, propanoic acid or hydrochloric acid;
4) add compound protease in above-mentioned solution, the ratio of weight and number of collagen protein and compound protease is 100-1000: 1,30-35 ℃ following stir culture 10-15 hour;
5) add NaCl in the supernatant of centrifugal collection, make concentration reach 2mol/L, 0-10 ℃ was stirred 10-20 hour down, collects the precipitate that obtains;
6) precipitate is dissolved in the 0.1-0.5% acetic acid solution centrifugal collection supernatant;
7) add NaCl in the supernatant again, make concentration reach 1mol/L, stir and obtain precipitate; Repetitive operation 3-4 time obtains the purpose product.
More excellent for the quality that makes collagen base composite sponge, it is 70-90% that described chitosan is selected deacetylation for use, and viscosity-average molecular weight is (1.0-4.0) * 10
5Product.
Second purpose of the present invention provides a kind of preparation method of collagen base composite sponge.
A kind of preparation method of collagen base composite sponge may further comprise the steps:
1) collagen protein is dissolved in the 0.01-0.1% acetic acid solution, makes the 1-3% collagen solution;
2) chitosan is dissolved in the 0.01-0.1% acetic acid solution, makes the 1-3% chitosan solution;
3) mixed of 50-90: 8-48: 0.5-5 is even by ratio of weight and the number of copies with the above-mentioned collagen solution that obtains, chitosan solution and glycerol, at-10 ℃--80 ℃ freezing 1-5 days down, lyophilizing obtains spongy material;
4) above-mentioned spongy material is placed gas generator, use aldehyde material cross-linking agent fixedly 20-100 minute down for 40-50 ℃;
5) with after the glycerine water solution cleaning, vacuum drying obtains collagen base composite sponge.
In order to make the collagen base composite sponge character that obtains more good, used collagen protein can adopt following method to make with extra care:
1) commercially available collagen protein primary product is dissolved in the dilute acid soln of pH5.5-6.5, wherein preferable formic acid, acetic acid, propanoic acid or hydrochloric acid;
2) add compound protease in above-mentioned solution, the ratio of weight and number of collagen protein and compound protease is 100-1000: 1,30-35 ℃ following stir culture 10-15 hour;
3) add NaCl in the supernatant of centrifugal collection, make concentration reach 2mol/L, 0-10 ℃ was stirred 10-20 hour down, collects the precipitate that obtains;
4) precipitate is dissolved in the 0.1-0.5% acetic acid solution centrifugal collection supernatant;
5) add NaCl in the supernatant again, make concentration reach 1mol/L, stir and obtain precipitate; Repetitive operation 3-4 time obtains the purpose product.
Used collagen protein can also adopt following method to obtain in the raw animal tissue:
1) animal tissue's machinery that will be rich in collagen protein is removed impurity such as epidermal area, muscle and fat, cleans up after the pulverizing;
2) dilute alkaline soln and the defat of alcohols material solution washing of usefulness pH8.5-10.5, the preferred sodium hydroxide of dilute alkaline soln: sodium bicarbonate: water=0.1-1: 5-10: 89-94.9 (ratio of weight and number) wherein, alcohols material aqueous solution preferred alcohol: isopropyl alcohol: water=5-10: 2-5: 85-93 (ratio of weight and number);
3) be dissolved in the dilute acid soln of pH5.5-6.5, wherein preferable formic acid, acetic acid, propanoic acid or hydrochloric acid;
4) add compound protease in above-mentioned solution, the weight ratio of collagen protein and compound protease is 100-1000: 1,30-35 ℃ following stir culture 10-15 hour;
5) add NaCl in the supernatant of centrifugal collection, make concentration reach 2mol/L, 0-10 ℃ was stirred 10-20 hour down, collects the precipitate that obtains;
6) precipitate is dissolved in the 0.1-0.5% acetic acid solution centrifugal collection supernatant;
7) add NaCl in the supernatant again, make concentration reach 1mol/L, stir and obtain precipitate; Repetitive operation 3-4 time obtains the purpose product.
In the subtractive process of above-mentioned collagen protein, used compound protease by specific activity is: gastric enzyme: pancreatin: three kinds of protease of carase=1: 1: 0.5 are formed.
In process of production, it is 70-90% that described chitosan is selected deacetylation for use, and viscosity-average molecular weight is (1.0-4.0) * 10
5Product for well; Described aldehyde material cross-linking agent can be formaldehyde, methyl-glyoxal or glutaraldehyde; Described with in the glycerine water solution cleaning step, the prescription of glycerine water solution is glycerol: water=0.1-10: 90-99.9.
The collagen base composite sponge that obtains through the packing,
60It behind the Co radiation sterilization finished product.
The present invention unites utilization with collagen protein, chitosan and glycerol dexterously, and the performance of product is obviously strengthened.Sneaking into of chitosan not only increases the molecular polarity of collagen base composite sponge, and makes hemostasis produce synergism, makes the sponge of the present invention first aid occasion that is applied to stop blooding become possibility.Glutaraldehyde crosslinked makes composite sponge of the present invention have stronger biological and chemical stability.The processing of glycerol improves the suppleness of composite sponge, and hardness stimulates damage and the misery that wound surface and patient are caused when alleviating operation greatly, product go for fully the soft tissue wound surface hemostasis, fill and reparation.The effect that experiment showed, this product obviously is better than normal clinically at present wound surface hemostasis and the repair materials that uses, as gelfoam, and carboxymethyl cellulose etc., and production technology is simple, cheap.
The ungrease treatment of diluted alkaline and alcohols material aqueous solution makes the fat content of final products reduce to minimum.In view of collagen protein product antigenicity mainly from the N and the C terminal peptide chain of collagen protein, the present invention creatively handles collagen protein with compound enzyme, further cuts away the terminal peptide chain, makes the antigenicity of product reduce to minimum.
In gas generator, material is carried out crosslinked fixing, can avoid the impurity (as the cyclic compound in the glutaraldehyde solution) in the cross-linking agent solution to introduce in the material, thereby make biology performance excellence of the present invention.
By the abundant Chemical Modifications of Chitosan of glutaraldehyde and source, not only reduce cost, and optimize its performance, but and the analog cell epimatrix be used for tissue or cell culture.
Collagen base composite sponge bleeding stopping period of the present invention is short, and the ability that adheres to wound tissue is strong, and has the fibroblast of promotion activity, brings out characteristics such as various somatomedin, can be used as hemostasis first aid, wound repair and packing material.
The invention will be further described below in conjunction with specific embodiment.
The specific embodiment
Embodiment 1, produce collagen base composite sponge of the present invention with the original structure of animal, concrete steps are as follows:
1, will be rich in the tissue (Corii Sus domestica, Corii Bovis seu Bubali, heel string etc.) of collagen protein, machinery is removed impurity such as epidermal area, muscle and fat, cleans with tap water and pure water respectively after the pulverizing;
Water=0.5: 7.5: 92) and alcohols material aqueous solution (ratio of weight and number, ethanol: isopropyl alcohol: water=7: 4: 89) 2, the dilute alkaline soln of preparation pH9.5 (ratio of weight and number, sodium hydroxide: sodium bicarbonate:;
3, with the dilute alkaline soln and the resulting animal tissue of the alcohols material solution washing first step of above-mentioned preparation, make its defat;
4, it is dissolved in the dilute formic acid solution of pH6.0;
5, add compound protease in above-mentioned solution, the weight ratio of collagen protein and compound protease is 800: 1, and compound protease by specific activity is: gastric enzyme: pancreatin: three kinds of protease of carase=1: 1: 0.5 are formed, 33 ℃ of following stir culture 13 hours;
6, centrifugal, and collect supernatant, in supernatant, add NaCl, make concentration reach 2mol/L, 5 ℃ were stirred 15 hours down, collect the precipitate that obtains;
7, precipitate is dissolved in 0.3% acetic acid solution centrifugal collection supernatant;
8, add NaCl in the supernatant again, make concentration reach 1mol/L, stir and obtain precipitate; Repetitive operation 3 times, the collecting precipitation thing;
9, precipitate is dissolved in 0.05% acetic acid solution, makes 2% collagen solution;
10, with deacetylation 80%, viscosity-average molecular weight 3.0 * 10
5Chitosan be dissolved in 0.05% acetic acid solution, make 2% chitosan solution;
11, with the above-mentioned collagen solution that obtains, chitosan solution and 70: 28: 2 by ratio of weight and the number of copies mixed of glycerol, to descend freezing 2 days at-70 ℃, lyophilizing obtains spongy material;
12, above-mentioned spongy material is placed gas generator, fix 60 minutes with the formaldehyde crosslinking agent down for 45 ℃;
13, clean with glycerine water solution, the prescription of glycerine water solution is a glycerol: water=1: 99;
14, vacuum drying obtains collagen base composite sponge;
15, collagen base composite sponge through the packing,
60Put in storage behind the Co radiation sterilization.
In the collagen base composite sponge that makes with said method, about 70: 28: 0.8 of the ratio of collagen protein and chitosan, glycerol.
Embodiment 2, produce collagen base composite sponge of the present invention with commercially available collagen protein primary product, concrete steps are as follows:
1, commercially available collagen protein is dissolved in the dilute hydrochloric acid solution of pH5.8;
2, add compound protease in above-mentioned solution, the weight ratio of collagen protein and compound protease is 500: 1, and compound protease by specific activity is: gastric enzyme: pancreatin: three kinds of protease of carase=1: 1: 0.5 are formed, 34 ℃ of following stir culture 11 hours;
3, centrifugal, and collect supernatant, in supernatant, add NaCl, make concentration reach 2mol/L, 8 ℃ were stirred 12 hours down, collect the precipitate that obtains;
4, precipitate is dissolved in 0.2% acetic acid solution centrifugal collection supernatant;
5, add NaCl in the supernatant again, make concentration reach 1mol/L, stir and obtain precipitate; Repetitive operation 4 times, the collecting precipitation thing;
6, precipitate is dissolved in 0.08% acetic acid solution, makes 1.8% collagen solution;
7, with commercially available deacetylation 75%, viscosity-average molecular weight 2.0 * 10
5Chitosan be dissolved in 0.08% acetic acid solution, make 1.8% chitosan solution;
8, the above-mentioned collagen solution that obtains, chitosan solution and 80: 18: 4 by ratio of weight and the number of copies mixed of glycerol is even, to descend freezing 4 days at-30 ℃, lyophilizing obtains spongy material;
9, above-mentioned spongy material is placed gas generator, fix 30 minutes with the glutaraldehyde cross-linking agent down for 48 ℃;
10, clean with glycerine water solution, the prescription of glycerine water solution is a glycerol: water=7: 93;
11, vacuum drying obtains collagen base composite sponge;
12, collagen base composite sponge through the packing,
60Put in storage behind the Co radiation sterilization.
In the collagen base composite sponge that makes with said method, about 80: 18 of the ratio of collagen protein and chitosan.
Claims (14)
1, a kind of collagen base composite sponge, it is made up of the material of following ratio of weight and number:
Collagen protein 50-90
Chitosan 8-48
Glycerol 0.5-5
2, a kind of collagen base composite sponge according to claim 1 is characterized in that: described collagen protein is commercially available collagen protein primary product.
3, a kind of collagen base composite sponge according to claim 1 is characterized in that: described collagen protein is to adopt following method preparation:
1) animal tissue's machinery that will be rich in collagen protein is removed impurity such as epidermal area, muscle and fat, cleans up after the pulverizing;
2) dilute alkaline soln and the defat of alcohols material solution washing of usefulness pH8.5-10.5;
3) be dissolved in the dilute acid soln of pH5.5-6.5;
4) add compound protease in above-mentioned solution, the ratio of weight and number of collagen protein and compound protease is 100-1000: 1,30-35 ℃ following stir culture 10-15 hour;
5) add NaCl in the supernatant of centrifugal collection, make concentration reach 2mol/L, 0-10 ℃ was stirred 10-20 hour down, collects the precipitate that obtains;
6) precipitate is dissolved in the 0.1-0.5% acetic acid solution centrifugal collection supernatant;
7) add NaCl in the supernatant again, make concentration reach 1mol/L, stir and obtain precipitate; Repetitive operation 3-4 time obtains the purpose product.
4, a kind of collagen base composite sponge according to claim 3, it is characterized in that: the dilute alkaline soln described step 2) is made up of sodium hydroxide, sodium bicarbonate and water, their ratio of weight and number is sodium hydroxide: sodium bicarbonate: water=0.1-1: 5-10: 89-94.9; Described alcohols material aqueous solution is made up of ethanol, isopropyl alcohol and water, and their ratio of weight and number is ethanol: isopropyl alcohol: water=5-10: 2-5: 85-93; Dilute acid soln in the described step 3) is formic acid, acetic acid, propanoic acid or hydrochloric acid.
5, according to claim 1 or 2 or 3 or 4 described a kind of collagen base composite sponges, it is characterized in that: the deacetylation of described chitosan is 70-90%, and viscosity-average molecular weight is (1.0-4.0) * 10
5
6, a kind of preparation method of collagen base composite sponge may further comprise the steps:
1) collagen protein is dissolved in the 0.01-0.1% acetic acid solution, makes the 1-3% collagen solution;
2) chitosan is dissolved in the 0.01-0.1% acetic acid solution, makes the 1-3% chitosan solution;
3) mixed of 50-90: 8-48: 0.5-5 is even by ratio of weight and the number of copies with the above-mentioned collagen solution that obtains, chitosan solution and glycerol, at-10 ℃--80 ℃ freezing 1-5 days down, lyophilizing obtains spongy material;
4) above-mentioned spongy material is placed gas generator, use aldehyde material cross-linking agent fixedly 20-100 minute down for 40-50 ℃;
5) with after the glycerine water solution cleaning, vacuum drying obtains collagen base composite sponge.
7, the preparation method of a kind of collagen base composite sponge according to claim 6 is characterized in that: used collagen protein is to adopt following method preparation:
1) commercially available collagen protein primary product is dissolved in the dilute acid soln of pH5.5-6.5;
2) add compound protease in above-mentioned solution, the ratio of weight and number of collagen protein and compound protease is 100-1000: 1,30-35 ℃ following stir culture 10-15 hour;
3) add NaCl in the supernatant of centrifugal collection, make concentration reach 2mol/L, 0-10 ℃ was stirred 10-20 hour down, collects the precipitate that obtains;
4) precipitate is dissolved in the 0.1-0.5% acetic acid solution centrifugal collection supernatant;
5) add NaCl in the supernatant again, make concentration reach 1mol/L, stir and obtain precipitate; Repetitive operation 3-4 time obtains the purpose product.
8, the preparation method of a kind of collagen base composite sponge according to claim 7 is characterized in that: the dilute acid soln in the described step 1) is formic acid, acetic acid, propanoic acid or hydrochloric acid.
9, the preparation method of a kind of collagen base composite sponge according to claim 6 is characterized in that: used collagen protein is to adopt following method preparation:
1) animal tissue's machinery that will be rich in collagen protein is removed impurity such as epidermal area, muscle and fat, cleans up after the pulverizing;
2) dilute alkaline soln and the defat of alcohols material solution washing of usefulness pH8.5-10.5;
3) be dissolved in the dilute acid soln of pH5.5-6.5;
4) add compound protease in above-mentioned solution, the weight ratio of collagen protein and compound protease is 100-1000: 1,30-35 ℃ following stir culture 10-15 hour;
5) add NaCl in the supernatant of centrifugal collection, make concentration reach 2mol/L, 0-10 ℃ was stirred 10-20 hour down, collects the precipitate that obtains;
6) precipitate is dissolved in the 0.1-0.5% acetic acid solution centrifugal collection supernatant;
7) add NaCl in the supernatant again, make concentration reach 1mol/L, stir and obtain precipitate; Repetitive operation 3-4 time obtains the purpose product.
10, the preparation method of a kind of collagen base composite sponge according to claim 9, it is characterized in that: the dilute alkaline soln described step 2) is made up of sodium hydroxide, sodium bicarbonate and water, their ratio of weight and number is sodium hydroxide: sodium bicarbonate: water=0.1-1: 5-10: 89-94.9; Described alcohols material aqueous solution is made up of ethanol, isopropyl alcohol and water, and their ratio of weight and number is ethanol: isopropyl alcohol: water=5-10: 2-5: 85-93; Dilute acid soln in the described step 3) is formic acid, acetic acid, propanoic acid or hydrochloric acid.
11, according to the preparation method of any described a kind of collagen base composite sponge among the claim 6-10, it is characterized in that: described compound protease by specific activity is: gastric enzyme: pancreatin: three kinds of protease of carase=1: 1: 0.5 are formed.
12, according to the preparation method of any described a kind of collagen base composite sponge among the claim 6-10, it is characterized in that: the deacetylation of described chitosan is 70-90%, and viscosity-average molecular weight is (1.0-4.0) * 10
5
13, according to the preparation method of any described a kind of collagen base composite sponge among the claim 6-10, it is characterized in that: described aldehyde material cross-linking agent is formaldehyde, methyl-glyoxal or glutaraldehyde; Described with in the glycerine water solution cleaning step, the prescription of glycerine water solution is glycerol: water=0.1-10: 90-99.9.
14, according to the preparation method of any described a kind of collagen base composite sponge among the claim 6-10, it is characterized in that: the collagen base composite sponge that obtains through the packing,
60It behind the Co radiation sterilization finished product.
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| CN 01142070 CN1234424C (en) | 2001-09-10 | 2001-09-10 | Collagen based composite sponge and production thereof |
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| CN 01142070 CN1234424C (en) | 2001-09-10 | 2001-09-10 | Collagen based composite sponge and production thereof |
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| CN1234424C true CN1234424C (en) | 2006-01-04 |
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| CN100444902C (en) * | 2005-08-15 | 2008-12-24 | 上海其胜生物制剂有限公司 | Technique for preparing sponge produced from collagen |
| CN100415304C (en) * | 2006-03-13 | 2008-09-03 | 西北大学 | Biological degradable hemostatic sponge material and its preparing method |
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| CN101816802B (en) * | 2010-02-05 | 2013-04-17 | 深圳兰度生物材料有限公司 | Chitosan-based medical dressing |
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