CN1310946C - Method for preparing injection collagen, and product and use thereof - Google Patents
Method for preparing injection collagen, and product and use thereof Download PDFInfo
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- CN1310946C CN1310946C CNB021567972A CN02156797A CN1310946C CN 1310946 C CN1310946 C CN 1310946C CN B021567972 A CNB021567972 A CN B021567972A CN 02156797 A CN02156797 A CN 02156797A CN 1310946 C CN1310946 C CN 1310946C
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Abstract
The present invention relates to a method for preparing injection collagen protein, a product thereof and application. Original collagen protein fiber is purified orderly by steps of ferment, acid washing and brine change from animal body tissues, the collagen protein which is in purification step is further prepared into collagen protein suspension liquid by a buffer solution, and then is in steps of homogenizing, crushing, miniaturization, etc. so as to obtain the magnitude of the injection collagen protein fiber suitable for a needle head with a 30 specification or even smaller specification; thus, the fiber is original collagen protein fiber has high purity, high production, low cost, low immunological rejection, and high biologic compatibility. The injection collagen protein prepared by the method of the present invention is very suitable for the filling of human soft tissues, such as skin tissues, bladder tissues, throat tissues, breast tissues, reproductive organs and hard bone tissues.
Description
Technical field
The present invention is the preparation method who is relevant to a kind of collagen protein, particularly about the preparation method of a kind of injectivity collagen protein (injectable collagen), especially about a kind of preparation method who is applied to the injectivity collagen protein that organism is soft, sclerous tissues fills up and products thereof.
Background technology
As everyone knows, collagen protein is the rich in protein of content in the reticular tissue, also is one of composition main in the intercellular substance (extracellular matrix).Because its special triple helix (triple-hellx) structure makes collagen protein that the skeleton of an organizational composition not only is provided, also provide cell a very good growing environment simultaneously.
Collagen protein has more characteristics such as bio-compatibility, biodegradability, nontoxicity and low anaphylaxis, therefore the purposes on life is used is very extensive, spread all over biomedical material, Medicines, makeup, foodstuffs industry and industrial chemicals, product by various form, form, effect and purposes, be the very high series products of economic worth.
Aspect biomedical material, because the immunogen reactivity extremely low (lowimmunogenicity) of collagen protein is used in the repairing and treating of various tissues just widely, comprise heart valve, burn and scald dressing, and the use of subcutaneous implant etc.Especially, collagen protein is applied to biological soft, hard tissue repair and fills up the aspect, at present suitable especially hot topic and the extremely interested problem of everybody.
Tradition is obtained the method for collagen protein, is to utilize acidic protein ferment break-up tissue fiber, and collagen protein is suspended in the solution fully, again from wherein extracting pure collagen protein, and then the pressure control temperature control, make the fibrous tissue that recovers collagen protein.
United States Patent (USP) U.S.P.No.3 for example, 949,073 have narrated with the traditional method preparation, obtain noncrosslinked collagen protein composition (trade name: Zyderm II);
United States Patent (USP) U.S.P.No.4,582,640 narrations prepare crosslinked with collagen protein composition (trade name: Zyplast) with this method.
Since main being fit to animal skins such as ox-hides in the above-mentioned processing procedure as the main acquisition source of collagen protein, and skin makes before purification step owing to comprise lipid layer, hair etc. in addition, must increase steps such as removing hair and processing high-content lipid layer.And, when carrying out step such as degreasing, expansion with various organic solvents such as acetone,, can make again to become an extremely scabrous problem by follow-up organic solvent residual owing to be to adopt chemical mode to handle.Even impurity such as antigenic determining factor is residual, all causes unnecessary immune response.
Because above-mentioned condition, current problem is exactly how when collagen purification albumen, can be main source with the tendon, fast, high-level efficiency and obtain collagen protein in large quantities.And, as much as possible not with traditional chemical purification method, and make collagen protein can keep the triple helix structure always.This for the active collagen that acquisition has the triple helix structure, rather has the significance in its medical treatment at purpose.In addition, how can remove various impurity and all contaminations in the lump expeditiously in processing procedure, also be important striving direction.
In addition, after above-mentioned collagen protein processing procedure,, must make collagen fabric granular more if the injectivity collagen protein will further be obtained the time.Above-mentioned two class collagen compositions (that is, United States Patent (USP) U.S.P.No.3,949,073 and United States Patent (USP) U.S.P.No.4,582, shown in 640) in, can be tough through crosslinked collagen composition than the non-crosslinked person, but take traditional method to obtain owing to be all, that is the collagen protein through recombinating after decomposing, its common issue with is exactly that structure is comparatively loose, easily degraded and can not resist vacillate (resistmi gration), cause the collagen protein of the affected part that is implanted in injection or after the injection colloid synersis (syneresis) phenomenon can take place, and cause the implantation viscosity inhomogeneous, the absorption that easily is decomposed, and (persistence) lastingly.
For improving persistence and reducing colloid synersis phenomenon, one of its method is to increase the concentration that is applied to collagen protein in the composition that biology is soft, sclerous tissues fills up, but it is quite high in the degree of difficulty of affected part to inject high concentration composition, has many people all once to make great efforts in the solution of this problem.
For instance, United States Patent (USP) U.S.P.No.4,803,075 suggestions will be through crosslinked syringeability collagen protein and the lubricant of a liquid state, but obviously also can't effectively solve the problem of colloid synersis phenomenon;
United States Patent (USP) U.S.P.No.4,424,208 narrations, one collagen composition, it comprises the collagen fabric through crosslinked syringeability collagen protein and recovery (Reconstituted), its persistence is enhanced, but the syringeability ability of the injection needle tube of coming in and going out does not solve.
United States Patent (USP) U.S.P.No.5,428,024 teaching reduces the granular size of collagen fabric with homogeneous method (Homogenization), through behind the homogeneous of suitable homogenizer, can reduce at least 25% through crosslinked collagen protein average fiber size with non-, and reduce at least 50% through crosslinked collagen protein average fiber size.
Yet, because its purification step still adopts the chemical process of aforementioned conventional, therefore still have problems such as step is complicated, organic solvent residual, and the collagen fabric particle still can be assembled after for some time once more, form fiber grain not of uniform size, still cause the destruction of injectivity collagen protein homogeneity and stability, an above-mentioned majority patent is head it off all successfully, so the direction that also becomes now to be needed to be resolved hurrily.
Summary of the invention
Main purpose of the present invention provides a kind of preparation method of injectivity collagen protein, is that the step of utilizing Cowhells to wash by ferment/pickling/salt is purified into primary collagen fabric; Preparing collagen protein suspension with buffered soln, this collagen protein suspension is homogenized with clarifixator again, is 150-250 μ m with the collagen fabric size that obtains to preset; The collagen protein suspension of this homogenization treatment, again with crusher with the collagen fabric microminiaturization to 50-100 μ m; Overcome the drawback of prior art, reach the purpose that injectivity collagen protein homogeneity and stability are provided,
Another object of the present invention provides a kind of preparation method of injectivity collagen protein, for preventing that the collagen fabric particle from the consistence that (aggregate) phenomenon changes the collagen fabric size taking place to assemble once more, by further in collagen protein suspension, adding dispersion agent, reach the homogeneity and stable purpose of promoting the injectivity collagen protein.
A further object of the present invention provides a kind of injectivity collagen protein, by the easy and harmless collagen protein purification step and the process that homogenizes, reach provide have high density, the purpose of persistence, syringeability and good conservatory injectivity collagen protein.
The object of the present invention is achieved like this: a kind of preparation method of injectivity collagen protein is characterized in that: it comprises the steps:
(1) animal tissues that will contain collagen protein adds and is suspended in the proteolytic enzyme solution, and this tissue is decomposed;
(2) continue this suspended state, noncollagen protein material contained in animal tissues all is decomposed, and does not destroy the fibrous tissue of collagen protein;
(3) separate remaining ferment and noncollagen protein material, obtain collagen protein;
(4) this collagen protein is suspended in the buffered soln,, makes it become the suspension that does not dissolve primary collagen fabric that contains concentration 20-120mg/ml so that do not destroy the primary structure and the triple helix structure of collagen protein;
(5) utilize a mechanism that this collagen fabric suspension is homogenized,, make collagen fabric can pass through 30 specifications or littler syringe needle to reduce its mean particle size.
This animal tissues comprises Cowhells.This buffered soln comprises alcohols/aqueous glycerin solution.This mechanism comprises clarifixator or high pressure crusher.This clarifixator comprises polytropy (polytron) clarifixator.This high pressure crusher more comprises micrometer adjusting screw (Microfluidizer) or the serial clarifixator of microscopic capacity change detecting circuit (Microfluidics International Corporation).More can use a linking agent or physical crosslinking method behind this homogenization step, be mixed with crosslinked with collagen albumen and the proteic collagen protein suspension of noncrosslinked collagen to form one.This linking agent comprises carbodiimide or glutaraldehyde.More can add one behind this homogenization step and be used to the dispersion agent that prevents that the collagen fabric particle from assembling once more.This dispersion agent comprises gelatin, alginate or pectin.This dispersion agent comprises that also temperature is 0-10 ℃ a gelatin.
The present invention also provides a kind of injectivity collagen protein product, it is characterized in that: it is to be purified into primary collagen fabric from the step that animal body is washed by ferment/pickling/salt successively; Preparing collagen protein suspension with buffered soln, this collagen protein suspension is homogenized with clarifixator again, is 150-250 μ m with the collagen fabric size that obtains to preset; The collagen protein suspension of this homogenization treatment, again with crusher with the collagen fabric microminiaturization to 50-100 μ m, make collagen fabric can pass through 30 specifications or littler syringe needle; It also comprises further adds dispersion agent in collagen protein suspension, with the homogeneity and the stability of promoting the injectivity collagen protein.
The present invention provides a kind of injectivity Application of Collagen again, it is characterized in that: it is applicable to the agent of filling up of making biological soft, sclerous tissues.This biology is soft, sclerous tissues comprises human soft, sclerous tissues.These mankind's soft, sclerous tissues comprises skin histology, bladder body, throat tissue, breast tissue, reproductive organ tissue and os osseum tissue.
Further specify below in conjunction with preferred embodiment.
Embodiment
Embodiment 1
The purifying processing procedure of injectivity collagen protein of the present invention comprises the steps:
Raw material is to obtain from the mammal body, and it comprises skin, tendon, blood vessel, endocranium (duramater), ligament (ligament) and heart valve (heart valve) etc.In the present embodiment, we to adopt Cowhells be the proteic raw material of collagen purification.Before ingressing, must Cowhells raw material excess tissue and fat-removal is clean.Ingress Cowhells after finishing at low temperatures earlier with first buffered soln, and after for example alcohol solution cleaned, again with second buffered soln, for example mixed aqueous solution such as neutral sodium phosphate/sodium-chlor carried out cleaning second time.Cowhells after cleaning then put into refrigerating box carry out-20 ℃ freezing.
Then, freezing Cowhells is carried out slicing treatment, so that obtain the Cowhells section of pre-determined thickness or weight.Present embodiment is an example, and the weight of this Cowhells section is about 1000 grams.
Then, 2 liters are contained the 0.5N acidic solution of 0.5g/L ferment and 1M salt (as sodium-chlor), comprise that addings such as acetic acid, lactic acid are equipped with in the stainless steel vessel of Cowhells section.Wherein, this ferment comprises Pepsin ferment (pepsin) or pawpaw Pepsin (papain), but because the easy deactivation (deactivated) of Pepsin ferment, and from the collagen protein processing procedure, remove easily, so be the best with the Pepsin ferment again in the present embodiment.Through the digestion of suitable mixing and ferment, repeat above-mentioned steps after, solution is stored in the 0-4 ℃ of refrigerator more than 48 hours at least.
After the ferment reaction, collagen solution filters with filter cloth, and in the mode of extruding excessive solution in the filter cake is extruded, and fully collagen protein is pressed dry, and the weight that makes collagen protein is in the scope that is predetermined.
Then, to contain the 0.5N acidic solution of 1M salt (as sodium-chlor), for example thorough mixing such as acetic acid, lactic acid stirs formed dough (dough) shape collagen protein, with unreacted completely the Pepsin ferment wash out.Then, filter with the press filtration method again, and repeat above-mentioned steps most times.
Collagen protein after overpickling is again with the 4M balanced salt solution, and for example mixed aqueous solution such as sodium phosphate/sodium-chlor cleans and filters and press dry.Above-mentioned steps is most times repeatedly.At last, collagen protein is returned back to neutrality (the pH value is about 6.8-7.2), and control weight is in pre-determined range (for example 600-640 gram).
Salt is washed later collagen protein again with 4 liter alcohol solutions, for example isopropanol water solution (Virahol: water=1: 4) clean and filter and press dry.Above-mentioned steps is most times repeatedly, makes the weight (for example about 600-680 restrains) in predefined weight range of collagen protein.At last, this doughy collagen protein is stored in-20 ℃ of refrigerators, for conveniently taking.
In the above-mentioned collagen protein purifying processing procedure of the present invention, collagen protein is organized under the special conditions, decompose the fibrillar collagen albumen substrate via Pepsin, remove the noncollagen protein material, and can obtain high purity, high yield by easy processing procedure, low cost can not produce the immunity system rejection, and primary (native) collagen fabric of tool height bio-compatibility.
Compared to traditional collagen protein purification technique, it is tough that purifying processing procedure of the present invention can obtain structural integrity, low degradation property, and fiber size approximately is 100 times a primary collagen protein of recombined collagen.
Embodiment 2
The processing procedure of preparation injectivity collagen protein of the present invention (1) is as follows:
The fixed weight of the primary collagen protein of above-mentioned preparation is prepared the 2 liter collagen protein suspension that concentration is approximately 5-15mg/ml with the buffered soln (for example 10% (v/v) alcohols/10% (v/v) aqueous glycerin solution) of lower concentration.
Then, again with this collagen protein suspension in about 15 ℃ or be lower than under 15 ℃ the temperature, homogenized most minutes with clarifixator (homogenizer, for example polytron), with the collagen fabric size that obtains to preset, for example be 150-250 μ m.
Then, again with the collagen protein suspension of this muddy (slurry) with high pressure crusher, for example the broken microminiaturization of MicrofluidizerM-110Y (Microfluidics International Corporation) is most minutes, to reach evenly and to be applicable to about 30 specifications (gauge) or even the collagen fabric size of small pinhead more.With the present embodiment is example, and this moment, the collagen fabric size was about 50-100 μ m.
What this should specify be:
1, collagen protein suspension, if handle m without homogenizing to 150-250 μ, directly handle and have the situation of stopping up the crusher tube seat, and can't handle, so suitable homogeneous turns to the necessary pre-treatment step that collagen fabric is continued broken microminiaturization by above-mentioned crusher;
2, because can influencing it, collagen fabric particulate size is applied to the persistence that biology is soft, sclerous tissues fills up, that is, the collagen fabric size is littler, vacillate to other places from the injection position more easily, and can't form agglomerate, and product preservation prolongation in time, and colloid synersis phenomenon appears, therefore homogenize and the step of microminiaturization in, it will be important in the extreme controlling the collagen fabric size really.
Then, this collagen protein suspension is centrifugal with whizzer, or handle with the special filter membrane vacuum filtration of about 5 μ m pore sizes, collect collagen deposition thing or filter cake.The concentration of control collagen protein makes in predefined scope (for example about 40-50mg/ml).
At last, with the buffered soln of lower concentration, for example 10% (v/v) alcohols/10% (v/v) aqueous glycerin solution dilutes the injectivity collagen protein that is prepared into about the about 35mg/ml of concentration with collagen deposition thing or filter cake again.The concentration of this collagen protein can be adjusted by repeating filtration/centrifugal number of times according to required.
At this, what be worth paying special attention to is: the main purpose that adds glycerine is to be used as a dispersion agent, in order to preventing that the collagen fabric particle from take place assembling phenomenon, even form fiber grain not of uniform size, and destroy the homogeneity and stability of injection-type collagen protein.
At last, with the injectivity collagen solution of above-mentioned preparation insert in the fixed injection needle tube, after the dense packing, be sent to sterilization.
Because injectivity collagen protein of the present invention is just to have determined its fixed sturcture before injecting the target tissue, so can see its effect immediately after injection.This point pole is different from other tradition invention to be needed in injecting the human body reorganization again of rising again after for some time, to form required firmer structure.
Injectivity collagen protein of the present invention is to belong to primary collagen protein, the complete densification of the recombined collagen that structure is more traditional, so physical strength is big, and the persistence that is filled in affected part promotes greatly.
In addition,, can cooperate crosslinking technological to handle again, for example use the linking agent of carbodiimide (carbondiimide), to form the more fine and close crosslinked with collagen albumen that reaches more difficult degraded of structure for the compactness of the former thiozell of strong rubber more.
Utilize to mix and crosslinkedly to do mutual matched combined with noncrosslinked collagen albumen and use, more can promote the persistence that it is filled in affected part, and reach that optimal biology is soft, effect is filled up by sclerous tissues.
Embodiment 3
The processing procedure of preparation injectivity collagen protein of the present invention (2) is as follows:
Repeat the step of embodiment 1, to obtain the collagen protein of fixed weight.
This collagen protein is prepared the 2 liter collagen protein suspension that concentration is 5mg/ml with the buffered soln (for example 10% (v/v) alcohols/10% (v/v) aqueous glycerin solution) of lower concentration.
Repeat the step of embodiment 2 again, until with the buffered soln (for example 10% (v/v) alcohols/10% (v/v) aqueous glycerin solution) of lower concentration with the centrifugal suction filtration of collagen protein filter cake, and make the injectivity collagen protein that concentration is about 38-45mg/ml.
Then, in the injectivity collagen protein, add another and have the gelatin substance of dispersion agent effect, as gelatin, alginate, pectin etc.The source of this gelatin for example can be dissolved in the collagen protein of aforementioned doughs shape in the water for injection, and it is about 1% to be modulated into concentration, the unit for uniform suspension of the about 2.5-4 of pH value.Then heat to temperature and be approximately 100-180 ℃, continue to place under the room temperature and cool off after about 45-75 minute.At last, filter, and filtrate is adjusted to the about 6.8-7.2 of pH value, promptly get the required gelatin of this experiment with the filter cloth of special pore size distribution size.
, the concentration of above-mentioned making about 1% gelatin added in the aforementioned injectivity collagen protein that make, adjust this injectivity collagen concentration to being about 35mg/ml thereafter.
At last, the injectivity collagen solution of above-mentioned preparation is inserted be sent to sterilization again in the fixed injection needle tube.Injectivity collagen protein after the sterilization is stored in low temperature, can form jelly state, and this jelly state will make the unlikely gathering of collagen fabric, or causes the condensing phenomenon of product dehydration.That is the characteristic that the homogeneous of fiber is small can be by complete preservation.
Above-mentioned only is preferred embodiment of the present invention, and the present invention is not limited to these embodiment, allly does in disclosed spirit, all should be covered by among the scope of the present invention.All any bio-compatibles and the syringeability that meets infirmary and need are given birth to doctor's material and all can be incorporated the present invention into and be used.
Comparative example
Now according to United States Patent (USP) U.S.P.No.3,949,073, United States Patent (USP) U.S.P.No.4,582,640 and United States Patent (USP) U.S.P.No.5,428,024 described collagen protein purifying processing procedure (conventional art) with the embodiment of the invention 1 described comparing, can be found following difference: consult table 1.
Table 1
| Project | Conventional art | The present invention |
| The purifying mode | Utilize acidic protein ferment break-up tissue fiber, collagen protein is suspended in the solution fully, by repeatedly with salt precipitation, heavy molten, tissue fibers structure again. | Do not destroy the fibrous tissue of collagen protein, directly impurity is removed in washing from Cowhells, to retain collagen protein. |
| The rate of recovery | Production degree step is many, and product recovery rate is low. | The production sequence step is less, the product recovery rate height. |
| Injectivity collagen fabric size | Syringe needle by 20 specifications | By 30 specifications or fine needle head more |
| Injectivity collagen fabric formulation stability | Fiber suspension is in normal saline solution, fiber is easily assembled and then is caused product colloid synersis or condensing, particle uneven distribution, and the difficult problem of injection.Or by the improvement of raising collagen content, but can cause the implant calcification phenomenon at injection position and injection difficulty to increase. | By dispersion agent glycerine and gelatin, interpolations such as alginate, possible condensing phenomenon be can effectively solve, and fiber homogeneous permanence and injection easness improved. |
Claims (12)
1, a kind of preparation method of injectivity collagen protein, it is characterized in that: it comprises the steps:
(1) animal tissues that will contain collagen protein adds and is suspended in the proteolytic enzyme solution, and this tissue is decomposed;
(2) continue this suspended state, noncollagen protein material contained in animal tissues all is decomposed, and does not destroy the fibrous tissue of primary collagen protein;
(3) separate remaining ferment and noncollagen protein material, obtain collagen protein;
(4) this collagen protein is suspended in the buffered soln,, makes it become the suspension that does not dissolve primary collagen fabric that contains concentration 20-120mg/ml so that do not destroy the primary structure and the triple helix structure of collagen protein;
(5) utilize a mechanism that this collagen fabric suspension is homogenized,, make collagen fabric can pass through 30 specifications or littler syringe needle to reduce its mean particle size.
2, the preparation method of injectivity collagen protein according to claim 1 is characterized in that: the animal tissues of this step (1) comprises Cowhells.
3, the preparation method of injectivity collagen protein according to claim 1 is characterized in that: the buffered soln of this step (4) comprises alcohols/aqueous glycerin solution.
4, the preparation method of injectivity collagen protein according to claim 1 is characterized in that: the mechanism of this step (5) comprises clarifixator or high pressure crusher.
5, the preparation method of injectivity collagen protein according to claim 4 is characterized in that: this clarifixator comprises the polytropy clarifixator.
6, the preparation method of injectivity collagen protein according to claim 4 is characterized in that: this high pressure crusher comprises the microjet clarifixator.
7, the preparation method of injectivity collagen protein according to claim 1, it is characterized in that: behind the homogenization step of this step (5), re-use a linking agent or physical crosslinking method, be mixed with crosslinked with collagen albumen and the proteic collagen protein suspension of noncrosslinked collagen to form one.
8, the preparation method of injectivity collagen protein according to claim 7 is characterized in that: the linking agent of this step (5) comprises carbodiimide or glutaraldehyde.
9, the preparation method of injectivity collagen protein according to claim 1 is characterized in that: behind the homogenization step of this step (5), add and be used to the dispersion agent that prevents that the collagen fabric particle from assembling once more.
10, the preparation method of injectivity collagen protein according to claim 9 is characterized in that: this dispersion agent comprises gelatin, alginate or pectin.
11. the preparation method of injectivity collagen protein according to claim 9 is characterized in that: this dispersion agent comprises that also temperature is 0-10 ℃ a gelatin.
12, a kind of injectivity collagen protein is characterized in that: it is the primary collagen fabric that the step of washing by ferment/pickling/salt successively in the driven object tissue is purified into; Preparing collagen protein suspension with buffered soln, this collagen protein suspension is homogenized with clarifixator again, is 150-250 μ m with the collagen fabric size that obtains to preset; The collagen protein suspension of this homogenization treatment, again with crusher with the collagen fabric microminiaturization to 50-100 μ m, make collagen fabric can pass through 30 specifications or littler syringe needle; It also is included in the collagen protein suspension adds dispersion agent, with the homogeneity and the stability of promoting the injectivity collagen protein.
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| CNB021567972A CN1310946C (en) | 2002-12-18 | 2002-12-18 | Method for preparing injection collagen, and product and use thereof |
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| CNB021567972A CN1310946C (en) | 2002-12-18 | 2002-12-18 | Method for preparing injection collagen, and product and use thereof |
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| CN1310946C true CN1310946C (en) | 2007-04-18 |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1294994C (en) * | 2004-07-05 | 2007-01-17 | 暨南大学 | Injectable type collagen-based soft tissue filling material and preparation method thereof |
| EP2540287A1 (en) * | 2011-07-01 | 2013-01-02 | FutureChemistry | Continuous flow production of gelatin nanoparticles |
| CN102350007B (en) * | 2011-10-18 | 2015-03-04 | 崇州市地龙海龙生物制品开发研究所 | Preparation method of human-body-absorbable medical face-lifting product |
| EA201591621A1 (en) * | 2013-03-04 | 2015-12-30 | ДЕРМЕЛЛ, ЭлЭлСи ди/би/эй ИТЕРНОДЖЕН, ЭлЭлСи | SUITABLE FOR INJECTION ABLE FOR POLYMERIZATION IN SITU COLLAGENIC COMPOSITION |
| CN105983094A (en) * | 2015-02-09 | 2016-10-05 | 广州创尔生物技术股份有限公司 | Preparation method of sterile collagen liquid having bio-activity and preparation method of sterile collagen dressing having bio-activity |
| CN107048075B (en) * | 2016-12-21 | 2019-07-23 | 湖州海皇生物科技有限公司 | A kind of Micropterus salmonoides fry mixed feed |
| CN106721659B (en) * | 2016-12-27 | 2019-10-25 | 湖州海皇生物科技有限公司 | A kind of smooth lip fish artifical compound feed |
| CN107308494A (en) * | 2017-07-27 | 2017-11-03 | 北京华信佳音医疗科技发展有限责任公司 | A kind of injection collagen, preparation method and filler |
| WO2023039833A1 (en) * | 2021-09-17 | 2023-03-23 | 谢达仁 | Use of collagen particles to promote hair follicle formation or angiogenesis |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5428024A (en) * | 1992-02-28 | 1995-06-27 | Collagen Corporation | High concentration homogenized collagen compositions |
| CN1210019A (en) * | 1998-09-10 | 1999-03-10 | 战丽芬 | Medical collagen sponge and manufacture thereof |
-
2002
- 2002-12-18 CN CNB021567972A patent/CN1310946C/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5428024A (en) * | 1992-02-28 | 1995-06-27 | Collagen Corporation | High concentration homogenized collagen compositions |
| CN1210019A (en) * | 1998-09-10 | 1999-03-10 | 战丽芬 | Medical collagen sponge and manufacture thereof |
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