CN1376514A - Injection-type bone morphogenetic protein using fibrin as carrier - Google Patents
Injection-type bone morphogenetic protein using fibrin as carrier Download PDFInfo
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- CN1376514A CN1376514A CN 02114506 CN02114506A CN1376514A CN 1376514 A CN1376514 A CN 1376514A CN 02114506 CN02114506 CN 02114506 CN 02114506 A CN02114506 A CN 02114506A CN 1376514 A CN1376514 A CN 1376514A
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Abstract
本发明公开了一种以纤维蛋白为载体的注射型骨形态发生蛋白,适用于临床骨折、骨不连、骨缺损的治疗。它是以从患者血液或健康献血员血液中分离出来的纤维蛋白为载体,复合牛骨形态发生蛋白直接经皮注射于损伤局部,发挥载体的缓释作用和骨形态发生蛋白促进新骨生长和骨折愈合、加速创伤修复的作用。本发明不存在免疫原性和排斥反应,植入体内后无不良反应。纤维蛋白使用前为液态,可在体内迅速固化,可以任意塑型。同时,纤维蛋白的止血、粘接作用有利于防治局部血肿的形成,为骨的再生和愈合提供良好的局部环境。本发明经动物实验和临床试验证实治疗效果确切,适用范围广泛,操作简便,安全可靠。The invention discloses an injection-type bone morphogenetic protein with fibrin as a carrier, which is suitable for the treatment of clinical fractures, nonunions and bone defects. It is based on the fibrin isolated from the blood of patients or healthy blood donors as a carrier, and the compound bovine bone morphogenetic protein is directly injected percutaneously into the injured part to exert the sustained release effect of the carrier and the bone morphogenetic protein to promote new bone growth and Fracture healing and accelerated wound repair. The invention has no immunogenicity and rejection reaction, and no adverse reaction after being implanted in the body. Fibrin is in a liquid state before use, and can be rapidly solidified in the body and can be shaped arbitrarily. At the same time, the hemostatic and adhesive effects of fibrin are beneficial to prevent the formation of local hematoma and provide a good local environment for bone regeneration and healing. The present invention has the advantages of definite therapeutic effect, wide application range, simple and convenient operation, safety and reliability as confirmed by animal experiments and clinical tests.
Description
One, affiliated field
The present invention relates to a kind of protein injection agent of medical domain, particularly a kind ofly be used for disease treatments such as clinical fracture, bone does not connect, bone be damaged and can inject the bone morphogenetic protein of use.
Two, background technology
The main effect of bone morphogenetic protein is to promote that undifferentiated mesenchymal cell and bone are raising of cell and to osteoblast differentiation.Because it has bone-inducting active efficiently, therefore promote union of fracture, the treatment bone is damaged and bone does not connect aspect fabulous potential applicability in clinical practice is arranged.The method in clinical use of having now mostly is bone morphogenetic protein is compounded on the solid material, implant wound site, complicated operation, cost height by operation, restricted application does not especially need the case of operative treatment to be difficult to use to the maximum closed fracture of clinical appearance and other.
Three, summary of the invention
The defective or the deficiency that partly exist according to above-mentioned prior art, the objective of the invention is, a kind of damaged patient of bone does not connect, bone who needing not only to can be used for operative treatment is provided, can also uses ordinary syringe percutaneous direct injection, thereby available all patients with bone injury.Having human fiber's albumen that the scope of application is extensive, easy and simple to handle, therapeutic effect is good is the injection-type bone morphogenetic protein of carrier.
To achieve these goals, the technical conceive that the present invention adopts is, use blood samples of patients or blood bank's healthy adult human blood, prepare the carrier of Fibrinogen fast by the low-temperature centrifugation method, be converted into fibrin clot after the effect by thrombin and aprotinin during use makes Fibrinogen/bone morphogenetic protein complex in being expelled to body as bone morphogenetic protein.Utilize fibrin clot bone morphogenetic protein to be slowly released by the characteristic that body slowly absorbs, thereby make bone morphogenetic protein all bring into play its biological action, reach the effect of inducing new bone formation and promoting repair in trauma in the overall process of repair in trauma.
The technical scheme that is adopted is:
With the fibrin is the injection-type bone morphogenetic protein of carrier, according to the following steps preparation:
1) obtains the preceding aseptic patient's of the taking autogenous vein blood of health adult's anticoagulation or treatment from hospital blood bank/blood station;
2) centrifugal 20 minutes separated plasmas of 3000RPM, refrigerated centrifugation extracts Fibrinogen, adds the Bovine Bone Morphoge Protnetin extract, and ratio is (2～5) mg:1mg (Fibrinogen: bone morphogenetic protein); It is standby that floccule is made in said mixture-40 a ℃ lyophilizing;
3) Fibrinogen/bone morphogenetic protein mixture being made into concentration with normal saline is that the suspension of 4mg/ml～8mg/ml is as composition A; With the calcium chloride solution compound concentration is that 250IU/ml～400IU/ml thrombin solution is composition B;
4) adding concentration in composition B is the aprotinin of 0.5mg/ml～50mg/ml.
Another characteristics of the present invention are, described Bovine Bone Morphoge Protnetin extract, it is the artificial according to a conventional method multiple bone morphogenetic protein mixture that extracts from the fresh cortical bone of calf, key step is defat, deproteinization, guanidine hydrochloride, urea extraction, room temperature is dry down, has bone-inducting active through mice flesh bag experiment confirm.
The present invention utilizes fibrinogenic dissolution characteristics to can be made into injection, thereby needing not only to can be used for the damaged patient of bone does not connect, bone of operative treatment, can also use ordinary syringe percutaneous direct injection, thereby can be used for all patients with bone injury.Add respectively in two tubes of dual barrel syringe with isopyknic composition A and composition B during use, mixing gets final product in the process of injection.The present invention has advantages such as the scope of application is extensive, easy and simple to handle, therapeutic effect is definite.From human blood, extract fibrin and be used further to human body, do not have immunogenicity and rejection, have no adverse reaction after implanting.Especially before treatment, extract the propagation that patient's autoblood can also be avoided hematologic disease.Owing to only use the plasma fraction in the blood, other can feed back to the patient after becoming divisional processing, thereby patient's blood system is not had harmful effect.Be liquid before fibrin uses, can solidify rapidly in vivo, arbitrarily plastotype.Simultaneously, fibrinous hemostasis, bonding effect help preventing and treating the formation of local hematoma, for the regeneration and the healing of bone provides good local environment.
Four, the specific embodiment
The present invention is described in further detail below in conjunction with embodiment.
Embodiment 1: by technical scheme of the present invention, is the injection-type bone morphogenetic protein of carrier with the fibrin, and preparation according to the following steps:
1) obtains the preceding aseptic patient's of the taking autogenous vein blood of health adult's anticoagulation or treatment from hospital blood bank/blood station;
2) centrifugal 20 minutes separated plasmas of 3000RPM, refrigerated centrifugation extracts Fibrinogen, adds the Bovine Bone Morphoge Protnetin extract, and ratio is 2mg: a 1mg (Fibrinogen: bone morphogenetic protein); It is standby that floccule is made in said mixture-40 a ℃ lyophilizing;
The Bovine Bone Morphoge Protnetin extract, be the artificial according to a conventional method multiple bone morphogenetic protein mixture that extracts from the fresh cortical bone of calf, key step is defat, deproteinization, guanidine hydrochloride, urea extraction, room temperature is dry down, has bone-inducting active through mice flesh bag experiment confirm;
3) Fibrinogen/bone morphogenetic protein mixture being made into concentration with normal saline is that the suspension of 8mg/ml is as composition A; With the calcium chloride solution compound concentration is that the 250IU/ml thrombin solution is composition B;
4) adding concentration in composition B is the aprotinin of 50mg/ml.
Embodiment 2: they by technical scheme of the present invention, are the injection-type bone morphogenetic protein of carrier with the fibrin, and preparation according to the following steps:
1) obtains the preceding aseptic patient's of the taking autogenous vein blood of health adult's anticoagulation or treatment from hospital blood bank/blood station;
2) centrifugal 20 minutes separated plasmas of 3000RPM, refrigerated centrifugation extracts Fibrinogen, adds the Bovine Bone Morphoge Protnetin extract, and ratio is 4mg: a 1mg (Fibrinogen: bone morphogenetic protein); It is standby that floccule is made in said mixture-40 a ℃ lyophilizing;
The Bovine Bone Morphoge Protnetin extract, be the artificial according to a conventional method multiple bone morphogenetic protein mixture that extracts from the fresh cortical bone of calf, key step is defat, deproteinization, guanidine hydrochloride, urea extraction, room temperature is dry down, has bone-inducting active through mice flesh bag experiment confirm;
3) Fibrinogen/bone morphogenetic protein mixture being made into concentration with normal saline is that the suspension of 4mg/ml is as composition A; With the calcium chloride solution compound concentration is that the 300IU/ml thrombin solution is composition B;
4) adding concentration in composition B is the aprotinin of 30mg/ml.
Embodiment 3: they by technical scheme of the present invention, are the injection-type bone morphogenetic protein of carrier with the fibrin, and preparation according to the following steps:
1) obtains the preceding aseptic patient's of the taking autogenous vein blood of health adult's anticoagulation or treatment from hospital blood bank/blood station;
2) centrifugal 20 minutes separated plasmas of 3000RPM, refrigerated centrifugation extracts Fibrinogen, adds the Bovine Bone Morphoge Protnetin extract, and ratio is 5mg: a 1mg (Fibrinogen: bone morphogenetic protein); It is standby that floccule is made in said mixture-40 a ℃ lyophilizing;
The Bovine Bone Morphoge Protnetin extract, be the artificial according to a conventional method multiple bone morphogenetic protein mixture that extracts from the fresh cortical bone of calf, key step is defat, deproteinization, guanidine hydrochloride, urea extraction, room temperature is dry down, has bone-inducting active through mice flesh bag experiment confirm;
3) Fibrinogen/bone morphogenetic protein mixture being made into concentration with normal saline is that the suspension of 6mg/ml is as composition A; With the calcium chloride solution compound concentration is that the 400IU/ml thrombin solution is composition B;
4) adding concentration in composition B is the aprotinin of 0.5mg/ml.
Embodiment 4: they by technical scheme of the present invention, are the injection-type bone morphogenetic protein of carrier with the fibrin, and preparation according to the following steps:
1) obtains the preceding aseptic patient's of the taking autogenous vein blood of health adult's anticoagulation or treatment from hospital blood bank/blood station;
2) centrifugal 20 minutes separated plasmas of 3000RPM, refrigerated centrifugation extracts Fibrinogen, adds the Bovine Bone Morphoge Protnetin extract, and ratio is 3mg: a 1mg (Fibrinogen: bone morphogenetic protein); It is standby that floccule is made in said mixture-40 a ℃ lyophilizing;
The Bovine Bone Morphoge Protnetin extract, be the artificial according to a conventional method multiple bone morphogenetic protein mixture that extracts from the fresh cortical bone of calf, key step is defat, deproteinization, guanidine hydrochloride, urea extraction, room temperature is dry down, has bone-inducting active through mice flesh bag experiment confirm;
3) Fibrinogen/bone morphogenetic protein mixture being made into concentration with normal saline is that the suspension of 6mg/ml is as composition A; With the calcium chloride solution compound concentration is that the 350IU/ml thrombin solution is composition B;
4) adding concentration in composition B is the aprotinin of 15mg/ml.
Above-mentioned calcium chloride solution compound concentration can be adjusted between 250IU/ml～400IU/ml, and the aprotinin concentration that adds among the B is adjusted between 0.5mg/ml～50mg/ml, can both reach purpose of the present invention.
Instantiation 1: fracture, fracture surgery bone does not connect patient is as follows with this repair materials therapeutic process: manual reduction, observe under the TV X-ray machine perspective fracture end para-position satisfied after, get this material 10ml, percutaneous injection is to fracture site under the perspective.Gypsum Fibrosum or external fixer are fixed, and the 4 visible union of fracture in week back are good.Show this material accelerating bone healing speed effectively, can avoid operation for the second time for the treatment of bone does not connect.
Instantiation 2: the vertebral compression fracture patient is venous blood samples liquid before operation, make fibrin, and compound bone morphogenetic protein is standby.With the reduction of the fracture or strut the vertebral body of compression, use internal fixation by operation, with fibrin/bone morphogenetic protein of preparing before the art be expelled to vertebral body after composition B mixes, conventional method is closed wound.Autohemic cell component can feed back in operation process gives the patient with losing blood in the compensation operation.In this type of trauma care, this material not only can promote union of fracture, can also induce new bone formation in vertebral body inside, recovers original form of vertebral body and mechanical strength.
Syringe is a special designs, disposable use.Feature is: 1. the bitubular is parallel, and volume is 5ml, and two propeller rear ends link to each other, and uses one to advance handle.2. two exit passages are spiral type, converge in end, are convenient to two kinds of composition mix homogeneously.3. 3 at external syringe needle, fine needle head are No. 12 common syringe needles of steel, use for percutaneous injection; Thick needle is special hour hand head, and internal diameter 1.8mm is for using in the operation; Shower nozzle is special, can make atomisation behind the liquid mixing.
Add an amount of aprotinin among the composition B, reach the purpose of slowing down the fibrin infiltration rate.
The scope of application of the present invention has orthopedics, neurosurgery, oral surgery etc.
Before using equal-volume composition A and composition B are added respectively in two tubes of dual barrel syringe, external special-purpose syringe needle, percutaneous is injected directly into the damage part under the guiding of TV X-ray machine.
Advantage of the present invention is: promote union, accelerated bone forms and the knitting definite effect; Use letter Just, indication is extensive; Histocompatbility is good, and is safe and reliable.
Claims (2)
1. one kind is the injection-type bone morphogenetic protein of carrier with the fibrin, it is characterized in that, according to the following steps preparation:
1) obtains the preceding aseptic patient's of the taking autogenous vein blood of health adult's anticoagulation or treatment from hospital blood bank/blood station;
2) extract Fibrinogen after the separated plasma, the Bovine Bone Morphoge Protnetin extract that adds doses is standby;
3) Fibrinogen/bone morphogenetic protein mixture being made into concentration with normal saline is that the suspension of 4mg/ml～8mg/ml is as composition A; With the calcium chloride solution compound concentration is that 250IU/ml～400IU/ml thrombin solution is composition B;
4) adding concentration in composition B is the aprotinin of 0.5mg/ml～50mg/ml.
2. according to claim 1 is the injection-type bone morphogenetic protein of carrier with human fiber's albumen, it is characterized in that: described Bovine Bone Morphoge Protnetin extract, it is the artificial multiple bone morphogenetic protein mixture that extracts from the fresh cortical bone of calf, extracting method is: defat, deproteinization, guanidine hydrochloride, urea extraction have bone-inducting active through mice flesh bag experiment confirm.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 02114506 CN1200728C (en) | 2002-04-09 | 2002-04-09 | Injection-type bone morphogenetic protein using fibrin as carrier |
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| CN 02114506 CN1200728C (en) | 2002-04-09 | 2002-04-09 | Injection-type bone morphogenetic protein using fibrin as carrier |
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| CN1376514A true CN1376514A (en) | 2002-10-30 |
| CN1200728C CN1200728C (en) | 2005-05-11 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106389393A (en) * | 2016-11-23 | 2017-02-15 | 中国人民解放军第三军医大学第附属医院 | Biological protein glue-triamcinolone acetonide slow release agent as well as preparation method and application of slow release agent |
| CN106474550A (en) * | 2016-12-02 | 2017-03-08 | 中国人民解放军第八十八医院 | A kind of construction method of tendon osseous tissue bone sex camplex |
| CN115998848A (en) * | 2023-01-18 | 2023-04-25 | 天津中津生物发展有限公司 | A preparation method of various protein mixtures promoting human bone formation |
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2002
- 2002-04-09 CN CN 02114506 patent/CN1200728C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106389393A (en) * | 2016-11-23 | 2017-02-15 | 中国人民解放军第三军医大学第附属医院 | Biological protein glue-triamcinolone acetonide slow release agent as well as preparation method and application of slow release agent |
| CN106474550A (en) * | 2016-12-02 | 2017-03-08 | 中国人民解放军第八十八医院 | A kind of construction method of tendon osseous tissue bone sex camplex |
| CN115998848A (en) * | 2023-01-18 | 2023-04-25 | 天津中津生物发展有限公司 | A preparation method of various protein mixtures promoting human bone formation |
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| CN1200728C (en) | 2005-05-11 |
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