CN102492032B - Human-like collagen and injectable human-like collagen soft-tissue filling material - Google Patents
Human-like collagen and injectable human-like collagen soft-tissue filling material Download PDFInfo
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- CN102492032B CN102492032B CN201110363121.9A CN201110363121A CN102492032B CN 102492032 B CN102492032 B CN 102492032B CN 201110363121 A CN201110363121 A CN 201110363121A CN 102492032 B CN102492032 B CN 102492032B
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Abstract
The invention relates to human-like collagen and an injectable human-like collagen soft-tissue filling material. Compared with the same type of the existing soft-tissue filling material widely used in clinic, the injectable human-like collagen soft-tissue filling material is prepared by a simple production technology, has good biocompatibility, thoroughly eliminates unavoidable virus hidden troubles of animal collagen, has high safety, and can realize degradation time control through adjustment of a hydroxyapatite size and a solution proportion in a certain range.
Description
Technical field
The invention belongs to protein engineering, biomedical materials field, be specifically related to Human-like Collagen, injection-type Human-like Collagen soft tissue filling material and preparation method thereof.
Background technology
Shaping and beauty industry is just fast-developing along with improving constantly of people's living standard, enlarges the bosom, augmentation rhinoplasty, smoothing wrinkle, face's shaping etc. pursue by people all.The demand of facial plasty comprises at present: dispel wrinkle, improve face contour, fill and lead up depressed scar or lip, repair injured tissue etc.Therefore, the soft tissue filling material huge market demand.
The nineties in 19th century so far, people have successively studied the materials such as Chinese wax, fat transfer, silicone resin, gel implant for soft tissue shaping, clinical application is found: all exist sclerosis, warty lump, absorb the problems such as too fast, chronic inflammatory diseases.In the last few years, U.S. FDA has been ratified several products of filling for soft tissue in succession, its main component is bovine collagen, hyaluronate sodium, PMMA bead etc., has had good effect, still exists and uses position redness, allergy and degrade the situation such as too fast for part user.
Collagen protein, is called again collagen, is that vertebrates in-vivo content is the abundantest, the one group of scleroprotein the most widely that distributes, and is the important materials of vertebrates body structure, is also the abundantest albumen of content in Mammals.Collagen, by polysaccharide protein molecular composition, is the major protein composition of reticular tissue, accounts for 20～30% of body total protein.In body, only about half of collagen protein is present in skin, and collagen protein accounts for 70% of corium and muscle tendon dry weight, is equivalent to 6% of body weight.Human-like Collagen is that one section of mRNA reverse transcription of human body known array collagen protein is generated after cDNA, repeat and modify through particular sequence, transform in intestinal bacteria, and obtain through high density fermentation, separation and Extraction and purifying, by Xi'an, (Chinese invention patent ZL.01106757.8) invented and produced without competition in giant's biological gene technical concern company limited.It has fundamentally solved animal extracts water-insoluble and the viral hidden danger (mad cow disease, swine fever epidemic disease, bird flu) of collagen protein.
Hyaluronate sodium is the physiologically active substance that is extensively present in animal and human's body, in human skin, synovium of joint liquid, umbilical cord, aqueous humor and vitreum, all has distribution.Its solution has high viscoelasticity and profiling, is the current generally acknowledged fabulous bio-medical material of biocompatibility, is the auxiliary of ophthalmologic operation, and has protection endothelial cell and eye inner tissue, reduces postoperative complication, promotes the effect of wound healing.
Hydroxyapatite, claims again hydroxylapatite, is apatite calcium (Ca
5(PO4)
3(OH) naturally mineralizing).But often write as (Ca
10(PO
4)
6(OH)
2) form be dimeric to give prominence to it: hydroxyl and phosphatic rock.Hydroxyapatite has good physico-chemical property and biological property, makes it be widely used in many fields.Hydroxyapatite is as the use material of the coating of inorganic materials and the inorganic matrix of matrix material, give biological property that material is good and certain mechanics of machinery character and be widely used in biomaterial, being widely used in now the exploitation of the products such as artificial bone.
Summary of the invention
The object of this invention is to provide a kind of injection-type Human-like Collagen soft tissue filling material and preparation method thereof, this material preparation process is simple, prepared Human-like Collagen soft tissue filling material stable newly good, biocompatibility is excellent, virus-free hidden danger, soft tissue filling and repairing effect are good.
The inventor finds through further investigation: Human-like Collagen, hyaluronate sodium and hydroxyapatite all have good biocompatibility, three carries out compound with suitable proportioning, the Human-like Collagen soft tissue filling material preparing has virus-free hidden danger, good biocompatibility, can boosting operation position cell the feature such as appropriate propagation, there is good soft tissue filling effect, thereby completed the present invention.
, the present invention is as follows:
1. a recombined collagen, it is made up of the aminoacid sequence shown in SEQ ID NO:1.
2. the nucleic acid of the recombined collagen described in coding item 1.
3. imported the carrier of the nucleic acid described in 2.
4. the transformant obtaining with the carrier transformed host cell of item 3.
5. a preparation method for injection-type Human-like Collagen soft tissue filling material, is characterized in that comprising the following steps:
1) Human-like Collagen being dissolved into massfraction with water for injection is 1.0%～5.0% solution;
2) sodium hyaluronate being dissolved into massfraction with water for injection is 0.5%～2.0% solution;
1) add a certain amount of medical grade hydroxyapatite after above-mentioned two kinds of solution are mixed by a certain percentage, mix and blend adds appropriate medical grade glycerine in the process stirring, and mixes final vacuum deaeration, obtains finished product again.
6. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 5, is characterized in that: described Human-like Collagen is recombined collagen claimed in claim 1.
7. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 5, is characterized in that: the molecular weight of described sodium hyaluronate is 1,000,000～2,500,000.
8. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 5, is characterized in that: described medical grade hydroxyapatite is spherical, and its diameter is 20～80 μ m.
9. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 5, is characterized in that: the volume ratio of described Human-like Collagen solution and sodium hyaluronate solution is 1: 1～10.
10. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 5, is characterized in that: the quality of described medical hydroxyapatite accounts for 3%～20% of finished product total mass.
The preparation method of 11. injection-type Human-like Collagen soft tissue filling materials according to claim 5, is characterized in that: medical glycerine quality used accounts for 0.5%～2% of finished product total mass.
12. according to the preparation method of a kind of injection-type Human-like Collagen soft tissue filling material described in any one in claim 5～11, and it also comprises the steps:
4) described finished product is filling in disposable glass syringe and complete outer packaging under aseptic condition.
The preparation method of 13. injection-type Human-like Collagen soft tissue filling materials according to claim 12, is characterized in that: step 4) in, syringe used can be made any specification according to clinical demand.
The 14. injection-type Human-like Collagen soft tissue filling materials that obtain by the preparation method of the injection-type Human-like Collagen soft tissue filling material described in any one in claim 5～13.
Soft tissue filling material provided by the invention has suitable viscosity, has good biocompatibility and controlled degradation rate, for various soft tissue defects with agingly have certain repairing effect.Compared with the soft tissue filling material of current wide clinical application, Human-like Collagen soft tissue filling material has significant advantage: its immune rejection is more weak, and thoroughly stop the inevitable viral hidden danger of animal collagen, and can stimulate to a certain extent the appropriate hyperplasia of injection site soft tissue, there is comparatively significant filling and repairing effect.
Accompanying drawing explanation
Photo when subcutaneous 2 weeks of Fig. 1 injection-type Human-like Collagen soft tissue filling material injection mouse.
Photo when subcutaneous 4 weeks of Fig. 2 injection-type Human-like Collagen soft tissue filling material injection mouse.
Photo when subcutaneous 8 weeks of Fig. 3 injection-type Human-like Collagen soft tissue filling material injection mouse.
Photo when subcutaneous 12 weeks of Fig. 4 injection-type Human-like Collagen soft tissue filling material injection mouse.
The embodiment of invention
The scientific and technical terminology of mentioning in this specification sheets has the identical implication of implication of conventionally understanding with those skilled in the art, is as the criterion with the definition in this specification sheets if any conflict.
recombined collagen of the present invention, nucleic acid, carrier and transformant
One aspect of the present invention relates to a kind of recombined collagen (being called for short recombined collagen of the present invention), and it is made up of the aminoacid sequence shown in SEQ ID NO:1.
SEQ ID NO：1：
HDP VVL QRR DWE NPG VTQ LNR HLA HAH PPF ASD
HPM GAP GPA GAP GPP GAP GPA GPP GSA GAP GPP
GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP
GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA
GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA
GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP GAH
GPA GAL GAH GPA GPL GPA GPP GSA GAP GAH GPA
GPL GAH GPA GPL GAH GPA GPL GAH GPA GPL GAP
GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP
GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP
GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA
GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA
GPP GSA GAP GPP GAH GPA GPL GAH GPA
GPL GAH GPA GPL GAH GPA GPL GAP GPA GSA GAP
GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA
GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA
GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP GAP
GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP GPP
GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA GAP
GPP GAH GPA GPL GAH GPA GPL GAH GPA GPL GAH
GPA GPL GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA
GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GSA GAP
GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP GSA
GAP GPP GAP GPA GPP GSA GAP GPP GAP GPA GPP
GSA GAP GPP GAP GPA GPP GSA GAP GPP GAH GPA
GPL GAH GPA GPL GAH GPA GPL GAM GAP GAT GLS
AGA THG LVT CGL
Recombined collagen of the present invention is the Human-like Collagen claimed in claim 1 of the open CN1371919A of Chinese patent application, it has three chains, triple-helix structure, and it can adopt disclosed gene engineering expression method in the open CN1371919A of for example this Chinese patent application to prepare.Recombined collagen of the present invention is by the professor Fan Daidi invention of NW China university, is therefore called again Fan Shi recombined collagen or Fan Human-like Collagen (Fan ' s Human-like Collagen, FHLC).
In addition the invention still further relates to, the nucleic acid of the recombined collagen of coding the invention described above.
In addition, the invention still further relates to the carrier that has imported above-mentioned nucleic acid.
In addition, the invention still further relates to the transformant obtaining with above-mentioned carrier transformed host cell.
Above-mentioned nucleic acid, carrier, transformant can be manufactured by the aminoacid sequence based on recombined collagen of the present invention, its manufacture method is well-known in the art, for example can be referring to: the molecular cloning experiment guide third edition [U.S.] J. Sha nurse Brooker Zhu Huang Pei Tangdengyi Science Press in September, 2002.
Below, by embodiment, the present invention is carried out to more specific description, but the present invention is not subject to the restriction of these embodiment.
the preparation of preparation example 1 recombined collagen
Prepare Human-like Collagen (being formed by the aminoacid sequence shown in SEQ ID NO:1) by method described in the open CN1371919A of Chinese patent application, confirmed that its molecular weight is about 90kD.Here, by this recombined collagen referred to as Human-like Collagen, and for the following examples.
Embodiment 1:
Human-like Collagen is dissolved into 1.0% solution with water for injection, the hyaluronate sodium that is 2,500,000 by molecular weight is dissolved as 1.0% solution with water for injection, be to mix at 1: 1 the two according to volume ratio, then (diameter 40 μ m) are finished product with a small amount of medical glycerine the also vacuum defoamation that stirs to add respectively appropriate medical grade hydroxyapatite, making final medical grade hydroxyapatite shared mass ratio in finished product is 10%, and medical glycerine shared mass ratio in finished product is 0.5%.
Embodiment 2:
Human-like Collagen is dissolved into 2.0% solution with water for injection, the hyaluronate sodium that is 2,000,000 by molecular weight is dissolved as 1.5% solution with water for injection, be to mix at 1: 3 the two according to volume ratio, then (diameter 60 μ m) are finished product with a small amount of medical glycerine the also vacuum defoamation that stirs to add respectively appropriate medical grade hydroxyapatite, making final medical grade hydroxyapatite shared mass ratio in finished product is 12%, and medical glycerine shared mass ratio in finished product is 1.0%.
Embodiment 3:
Human-like Collagen is dissolved into 3.0% solution with water for injection, the hyaluronate sodium that is 1,500,000 by molecular weight is dissolved as 2.0% solution with water for injection, be to mix at 1: 5 the two according to volume ratio, then (diameter 50 μ m) are finished product with a small amount of medical glycerine the also vacuum defoamation that stirs to add respectively appropriate medical grade hydroxyapatite, making final medical grade hydroxyapatite shared mass ratio in finished product is 8%, and medical glycerine shared mass ratio in finished product is 1.5%.
Embodiment 4:
Human-like Collagen is dissolved into 2.5% solution with water for injection, the hyaluronate sodium that is 1,000,000 by molecular weight is dissolved as 2.0% solution with water for injection, be to mix at 1: 8 the two according to volume ratio, then (diameter 20 μ m) are finished product with a small amount of medical glycerine the also vacuum defoamation that stirs to add respectively appropriate medical grade hydroxyapatite, making final medical grade hydroxyapatite shared mass ratio in finished product is 15%, and medical glycerine shared mass ratio in finished product is 0.5%.
Embodiment 5:
Human-like Collagen is dissolved into 4.0% solution with water for injection, the hyaluronate sodium that is 2,500,000 by molecular weight is dissolved as 1.5% solution with water for injection, be to mix at 1: 4 the two according to volume ratio, then (diameter 30 μ m) are finished product with a small amount of medical glycerine the also vacuum defoamation that stirs to add respectively appropriate medical grade hydroxyapatite, making final medical grade hydroxyapatite shared mass ratio in finished product is 10%, and medical glycerine shared mass ratio in finished product is 0.5%.
Embodiment 6:
Human-like Collagen is dissolved into 5.0% solution with water for injection, the hyaluronate sodium that is 1,500,000 by molecular weight is dissolved as 2.0% solution with water for injection, be to mix at 1: 10 the two according to volume ratio, then (diameter 80 μ m) are finished product with a small amount of medical glycerine the also vacuum defoamation that stirs to add respectively appropriate medical grade hydroxyapatite, making final medical grade hydroxyapatite shared mass ratio in finished product is 6%, and medical glycerine shared mass ratio in finished product is 1.0%.
Embodiment 7:
Depilation preserved skins in trichogen backs for 20 healthy adult kunming mices, after second day first water cleaning skin with the tincture of iodine to mouse preserved skin skin degerming, take off iodine with 75% alcohol.Disposable syringe is drawn the injection-type Human-like Collagen soft tissue filling material of preparation in embodiment 1.Subcutaneous every the injection 0.2ml of mouse.
The mouse of injecting is placed under identical environment and is raised, respectively at 2 weeks, 4 weeks, 8 weeks, after 12 weeks, put to death, put to death 5 at every turn.Put to death and adopt disconnected neck method, then get its back injection place epidermis, take pictures, injection position operation on skin cutter is cut to neutral formalin fixing.
Experimental result as shown in Figure 1,2,3, 4, injection-type Human-like Collagen soft tissue filling material injection mouse is after subcutaneous 2 weeks, 4 weeks, 8 weeks, 12 weeks, along with the prolongation of time, material has a slight degraded subcutaneous, without significantly inflammatory reaction, during by 12 weeks, still can fill object in subcutaneous realization, and the appropriate hyperplasia of surrounding tissue, be a kind of new soft tissue packing material with broad prospect of application.Hence one can see that, injection-type Human-like Collagen soft tissue filling material good biocompatibility, and degradation in vivo is comparatively slow, can effectively solve conventional softer tissue filling Biocompatibility poor, the too fast problem of can not degrading or degrade.
Also it should be noted that, can implement and the not obvious prerequisite of running counter to purport of the present invention under, equally also go for other technical scheme as the described arbitrary technical characterictic of component part of a certain technical scheme or the combination of technical characterictic in this manual; And, can implement and the not obvious prerequisite of running counter to purport of the present invention under, between the described technical characterictic of component part as different technologies scheme, also can combine in any way, form other technical scheme.The present invention is also contained in above-mentioned situation by combining the technical scheme obtaining, and these technical schemes are equivalent to record in this manual.
Below describe the present invention through the specific embodiment and the embodiment, but it will be understood by those skilled in the art that these are not intended to scope of the present invention to limit, scope of the present invention should be determined by claims.
Industrial applicibility
The invention provides a kind of injection-type Human-like Collagen soft tissue filling material and preparation method thereof, this material preparation process is simple, prepared Human-like Collagen soft tissue filling material stable newly good, biocompatibility is excellent, virus-free hidden danger, soft tissue fill and repairing effect good.
Claims (9)
1. a preparation method for injection-type Human-like Collagen soft tissue filling material, is characterized in that comprising the following steps:
1) Human-like Collagen being dissolved into massfraction with water for injection is 1.0%～5.0% solution;
2) sodium hyaluronate being dissolved into massfraction with water for injection is 0.5%～2.0% solution;
3) add a certain amount of medical grade hydroxyapatite after above-mentioned two kinds of solution are mixed by a certain percentage, mix and blend adds appropriate medical grade glycerine in the process stirring, and mixes final vacuum deaeration, obtains finished product again;
Wherein, described Human-like Collagen is made up of the aminoacid sequence shown in SEQ ID NO:1.
2. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 1, is characterized in that: the molecular weight of described sodium hyaluronate is 1,000,000～2,500,000.
3. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 1, is characterized in that: described medical grade hydroxyapatite is spherical, and its diameter is 20～80 μ m.
4. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 1, is characterized in that: the volume ratio of described Human-like Collagen solution and sodium hyaluronate solution is 1:1～10.
5. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 1, is characterized in that: the quality of described medical hydroxyapatite accounts for 3%～20% of finished product total mass.
6. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 1, is characterized in that: medical glycerine quality used accounts for 0.5%～2% of finished product total mass.
7. according to the preparation method of a kind of injection-type Human-like Collagen soft tissue filling material described in any one in claim 1～6, it also comprises the steps:
4) described finished product is filling in disposable glass syringe and complete outer packaging under aseptic condition.
8. the preparation method of injection-type Human-like Collagen soft tissue filling material according to claim 7, is characterized in that: in step 4), syringe used can be made any specification according to clinical demand.
9. the injection-type Human-like Collagen soft tissue filling material obtaining by the preparation method of the injection-type Human-like Collagen soft tissue filling material described in any one in claim 1～8.
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| US9370469B2 (en) * | 2014-03-14 | 2016-06-21 | Suneva Medical, Inc | Injectable alloplastic implants and methods of use thereof |
| CN104043150B (en) * | 2014-05-27 | 2016-07-13 | 台北科技大学 | The purposes of glue compositions |
| CN106492276B (en) * | 2016-11-28 | 2019-07-12 | 北京奥精医药科技有限公司 | A kind of injectable beauty and shaping material and preparation method thereof |
| CN109078220A (en) * | 2018-08-27 | 2018-12-25 | 白晋 | A kind of compound formulation comprising autologous collagen albumen and its application |
| CN111375088B (en) * | 2020-04-29 | 2022-06-14 | 陕西巨子生物技术有限公司 | Double-layer osteochondral tissue repair scaffold and preparation method thereof |
| CN112546297A (en) * | 2020-11-02 | 2021-03-26 | 周军臣 | Preparation method of hump nose rib bone slurry |
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| CN1371919A (en) * | 2001-02-21 | 2002-10-02 | 范代娣 | Human like collagen and production method thereof |
| CN101584884A (en) * | 2009-06-22 | 2009-11-25 | 西北大学 | Method for preparing biomimetic artificial bone materials for biodegradable tissue engineering |
| CN101695581A (en) * | 2009-10-26 | 2010-04-21 | 西北大学 | Method for preparing human-like collagen haemostatic sponge in scale |
| CN102229705A (en) * | 2011-06-02 | 2011-11-02 | 陕西巨子生物技术有限公司 | Collagen temperature-sensitive hydrogel and preparation method thereof |
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|---|---|---|---|---|
| CN1371919A (en) * | 2001-02-21 | 2002-10-02 | 范代娣 | Human like collagen and production method thereof |
| CN101584884A (en) * | 2009-06-22 | 2009-11-25 | 西北大学 | Method for preparing biomimetic artificial bone materials for biodegradable tissue engineering |
| CN101695581A (en) * | 2009-10-26 | 2010-04-21 | 西北大学 | Method for preparing human-like collagen haemostatic sponge in scale |
| CN102229705A (en) * | 2011-06-02 | 2011-11-02 | 陕西巨子生物技术有限公司 | Collagen temperature-sensitive hydrogel and preparation method thereof |
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