CN101721743B - Method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint - Google Patents
Method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint Download PDFInfo
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- CN101721743B CN101721743B CN200910312220A CN200910312220A CN101721743B CN 101721743 B CN101721743 B CN 101721743B CN 200910312220 A CN200910312220 A CN 200910312220A CN 200910312220 A CN200910312220 A CN 200910312220A CN 101721743 B CN101721743 B CN 101721743B
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Abstract
The invention discloses a method for strengthening joint stability by using an rhBMP-2 release coating on the surface of an artificial joint, which relates to a method for strengthening the joint stability. The invention solves the problem that a function of inducing the bone formation of BMP-2 is difficult to realize in the whole process of forming a new bone by using a method of combining an HA coating and the BMP-2 on the surface of the traditional artificial joint, and the action time of the release is not controllable by using a method of combining the BMP-2 and polyethylene glycol. The method comprises the following steps of: 1, adding EC and PEG 4000 into chloroform, ultrasonically dissolving the EC and PEG 4000, adding BMP-2 and carrying out ultrasonic dispersion to obtain a BMP-2 mixed liquid; and 2, spraying the BMP-2 mixed liquid on an artificial thighbone steam, placing the artificial thighbone steam in an ultra-clean working table to air, packaging into a seal bag, and sterilizing the seal bag at a low temperature to complete the process. The invention has the advantages of even and tight combination of the rhBMP-2 release coating and the joint surface, smooth coating layer, difficult damage, strengthened stability of the artificial joint and adjustable release performance.
Description
Technical field
The present invention relates to strengthen the method for stability of joint.
Background technology
The prosthetic replacement has become orthopaedics conventional therapy means, but the loosening of prosthese is the primary complication of artificial joint replacement.Stability is the key of decision joint service life and application quality, and for the fixed artificial joint of biomechanics, the synostosis degree at interface is its stable determiner.It is a complicacy of being regulated by multiple factor and orderly process that osseous tissue forms; Bone morphogenetic protein (BMP) is the somatomedin of wherein unique inducing mesenchymal cell separately to the differentiation of osseous tissue direction; It is the regulatory factor of most critical in the osseous tissue forming process; Through the adjusting of pair cell acceptor levels, collaborative with other factor, inducing cell transforms to bone and cartilage direction.
At present, artificial joint adopts HA (hydroxyapatite hydroxyapatite) coating more, and the prosthese of HA coating is in the fastness that combines that promotes between prosthese and the bone, and accelerates prosthese stability aspect very big effect is all arranged; But the HA coating can only play certain bone conduction effect, will progressively degrade in vivo, and bone-inducing factor and osteocyte can not be provided, and finally still can influence prosthesis stability, causes joint mobilization.The example that adopts the HA coating to combine with BMP-2 on the artificial joint surface is also arranged; But direct application of BMP-the 2nd, disposable dispensing; And be applied to the very fast diluted and tissue absorption of intravital BMP-2; BMP-2 half-life while is very short, and (t1/2＜0.1day), do not meet the natural law of BMP-2 induced osteogenesis causes BMP-2 to be difficult to its induced osteogenesis effect of performance in new osteoplastic overall process.Adopt BMP-2 and the research that Polyethylene Glycol (PEG) combines in addition, reached the effect of slow release, but the time of the effect of slow release is uncontrollable.
Summary of the invention
The present invention exists BMP-2 to be difficult in new osteoplastic overall process, bring into play its induced osteogenesis effect for the method that solves existing artificial joint surface and adopt the HA coating to combine with BMP-2; There is uncontrollable problem action time of slow release in the method that adopts BMP-2 to combine with Polyethylene Glycol, and the method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint is provided.
The method of strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint realizes according to the following steps: one, the ethyl cellulose (EC) of 35～60mg and the Polyethylene Glycol (PEG) 4000 of 8～12mg are joined in the chloroform of 1.5～3ml; Then at 25 ℃ of following ultrasonic dissolutions; The BMP-2 that adds 1mg again gets the BMP-2 mixed liquor behind the ultra-sonic dispersion; Two, the BMP-2 mixed liquor is sprayed on the artificial femur handle, places superclean bench to dry then, be packaged in the sealed bag, cold sterilization is promptly accomplished; Wherein BMP-2 mixed liquor coating thickness is 30 ± 10 μ m in the step 2.
Polyethylene Glycol (PEG) chemical constitution that the present invention adopts: HO (CH
2CH
2O)
nH is formed by ethylene oxide polymerization, has the extensive compatibility with all kinds of solvents; Be good solvent and solubilizing agent, stable, not perishable, drug compatibility is good; Promote the release and the absorption of medicine, and make medical surfaces glossy and level and smooth, simultaneously not fragile; Ethyl cellulose (EC) chemical constitution that adopts: [C
6H
7O
2(OC
2H
5)
3]
n, have good physical stability, the performance unique effect at aspects such as medicament slow release releases, the difference of consumption can effectively be regulated release rate of drugs.The present invention is mixed and made into artificial joint handle controlled-release coating with rhBMP-2, EC and PEG; RhBMP-2 is combined with articular surface evenly, and closely, coating is smooth; Loss is little in the art; Not fragile, can reach the good slow release effect through the effect of EC again, artificial joint stability strengthens.Do not use materials such as PLGA among the present invention, need pharmaceutical protein be prepared into microsphere earlier yet.The present invention utilizes that protein self has formed microgranule in the medicament freeze-drying powder; Then this microgranule is dispersed in (protein microbeads remains unchanged in this process) in the chloroformic solution with slow-releasing and controlled-releasing action material through the simple physics operation, volatilizes solvent and form the medicament slow release system.Sustained release performance of the present invention can be adjusted as required voluntarily, delays drug release like needs, and the ratio that increases ethyl cellulose gets final product; Accelerate drug release like needs, then only need to increase the ratio of PEG4000, the slow-release time easy-regulating.
Description of drawings
Fig. 1 is that the X line of implanting HA coating prosthese in the specific embodiment seven is taken the photograph sheet figure; Fig. 2 is that the X line of implanting non-slow release rhBMP-2 coating prosthese in the specific embodiment seven is taken the photograph sheet figure; Fig. 3 is that the X line of implantation slow release rhBMP-2 coating prosthese in the specific embodiment seven is taken the photograph sheet figure; Fig. 4 is the CT figure that implants HA coating prosthese in the specific embodiment seven; Fig. 5 is the CT figure that implants non-slow release rhBMP-2 coating prosthese in the specific embodiment seven; Fig. 6 is the CT figure of implantation slow release rhBMP-2 coating prosthese in the specific embodiment seven.
The specific embodiment
Technical scheme of the present invention is not limited to the following cited specific embodiment, also comprises the combination in any between each specific embodiment.
The specific embodiment one: the method for this embodiment strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint realizes according to the following steps: one, the ethyl cellulose (EC) of 35～60mg and the Polyethylene Glycol (PEG) 4000 of 8～12mg are joined in the chloroform of 1.5～3ml; Then at 25 ℃ of following ultrasonic dissolutions; The BMP-2 that adds 1mg again gets the BMP-2 mixed liquor behind the ultra-sonic dispersion; Two, the BMP-2 mixed liquor is sprayed on the artificial femur handle, places superclean bench to dry then, be packaged in the sealed bag, cold sterilization is promptly accomplished; Wherein BMP-2 mixed liquor coating thickness is 30 ± 10 μ m in the step 2.
Will to use mass concentration be that 70% ethanol is cleaned sterilization to artificial femur handle in this embodiment.
Artificial femur handle is the artificial femur handle of existing various materials in this embodiment, and has the HA coating on the artificial femur handle.
The specific embodiment two: what this embodiment and the specific embodiment one were different is in the step 1 ethyl cellulose (EC) of 35mg and the Polyethylene Glycol (PEG) 4000 of 8mg to be joined in the chloroform of 1.5ml.Other step and parameter are identical with the specific embodiment one.
The specific embodiment three: what this embodiment and the specific embodiment one were different is in the step 1 ethyl cellulose (EC) of 60mg and the Polyethylene Glycol (PEG) 4000 of 12mg to be joined in the chloroform of 3ml.Other step and parameter are identical with the specific embodiment one.
The specific embodiment four: what this embodiment and the specific embodiment one were different is in the step 1 ethyl cellulose (EC) of 40～55mg and the Polyethylene Glycol (PEG) 4000 of 9～11mg to be joined in the chloroform of 2～2.5ml.Other step and parameter are identical with the specific embodiment one.
The specific embodiment five: what this embodiment and the specific embodiment one were different is in the step 1 ethyl cellulose (EC) of 45mg and the Polyethylene Glycol (PEG) 4000 of 10mg to be joined in the chloroform of 2.8ml.Other step and parameter are identical with the specific embodiment one.
The specific embodiment six: what this embodiment and the specific embodiment one were different is in the step 1 ethyl cellulose (EC) of 50mg and the Polyethylene Glycol (PEG) 4000 of 11mg to be joined in the chloroform of 2ml.Other step and parameter are identical with the specific embodiment one.
The specific embodiment seven: the method for this embodiment strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint realizes according to the following steps: one, the ethyl cellulose (EC) of 35～60mg and the Polyethylene Glycol (PEG) 4000 of 8～12mg are joined in the chloroform of 1.5～3ml; Then at 25 ℃ of following ultrasonic dissolutions; The BMP-2 that adds 1mg again gets the BMP-2 mixed liquor behind the ultra-sonic dispersion; Two, the BMP-2 mixed liquor is sprayed on the artificial femur handle, places superclean bench to dry then, be packaged in the sealed bag, cold sterilization is promptly accomplished; Wherein BMP-2 mixed liquor coating thickness is 30 ± 10 μ m in the step 2.
Adopt the method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint in this embodiment; Preparation gained artificial joint; Be used for zoopery: 7 healthy adult dogs, male and female are not limit, the about 12-15kg of body weight; Observe, raise by Clinical Medicine College No.1, Harbin Medical Univ.'s experimental surgery, confirm to experimentize after animal health, the free from infection.Be divided into three groups (A, B, C groups) at random, 2 of A groups are implanted HA coating prosthese, and 2 of B groups are implanted non-slow release rhBMP-2 coating prosthese; 3 of C groups, slow release rhBMP-2 coating prosthese was observed 2 months.Put to death experimental animal in 8 weeks of postoperative, hind leg femur along the complete taking-up of former operative approach left side.
The animal after-operation response: clear-headed in laboratory animal postoperative 1～2h, second day after operation is pulled out drainage tube, and each dog all can normally be taken food, and wound healing is all right, and postoperative was taken out stitches on the 12nd day, did not see obvious inflammatory reaction and disruption of wound; But dog opens four-footed and stands up and walk in the activity of standing of three days tripodias of second day after operation to the about 20 days, gait is recovered normally gradually, and it is movable unusual not have dislocation and art limb; Postoperative does not have digestion, breathes the generation that waits other system's complication.
Observe: put to death experimental animal in 8 weeks of postoperative, hind leg femur along the complete taking-up of former operative approach left side.
Experimental dog is all healthy when drawing materials, and left side hind leg outward appearance is no abnormal, soft tissue NIP reaction performance; After drawing materials, see that all Periprosthetics do not have obvious inflammatory reaction, the good non-corroding performance of artificial thigh bone lustrous surface.
The X line is taken the photograph sheet and CT examination: have or not synostosis scope and the eburnation degree of lucent area, Periprosthetic, Periprosthetic sclerotin to have or not absorption between inspection prosthese and bone bed.
The X line is taken the photograph sheet and CT examination result, like Fig. 1,2,3,4, shown in 5 and 6, around the HA coating group new bone formation shadow is arranged, and peripheral clearance is more obvious, and boundary is clear between cortical bone, near the prosthese side low-density shadow is arranged; Non-slow release rhBMP-2 coating group prosthese shank has freshman bone tissue's shadow, but does not cover prosthese fully as yet, and area of new bone density is lower than the peripheral cortex bone; Do not had obvious boundary around the slow release rhBMP-2 coating group prosthese handle and between the archipallium bone, the gap is not obvious, and area of new bone density and surrounding bone are suitable.
Osseous tissue morphometric and stereologic analysis: the synostosis rate of measuring three groups of prosthese outer boundaries; Calculate the synostosis rate by following formula: synostosis rate (%)=B1/A1 * 100%; Wherein Al is the total length that bone contacts with prosthese, and B1 is that bone and prosthese are synosteotic physical length; As a result, the prosthese outer boundary synostosis rate of HA coating group is X ± S=27.68 ± 5.91, and the prosthese outer boundary synostosis rate of non-slow release group is X ± S=58.22 ± 11.74, and the prosthese outer boundary synostosis rate of slow release group is X ± S=89.44 ± 2.55.
Statistical procedures: use the Spss software kit to carry out statistical analysis, the measurement data data represent that with mean scholar standard deviation two groups of indexs relatively adopt the between group variable analysis.P＜0.05 expression significant difference, P＜0.01 expression difference highly significant.
Result: the synostosis rate of three class boundary faces is carried out variance analysis, F=1.070E3, p＜0.01; Explain between each group to have highly significant difference, compare F=52.481 between slow release rhBMP-2 coating group and non-slow release rhBMP-2 coating group are organized; F=27.400 is compared in p＜0.01 between controlled-release coating group and HA organize; F=11.651 is compared in p＜0.01 between non-controlled-release coating group and HA organize; The difference that all has highly significant between each synostosis rate of organizing is explained in p＜0.01, and the prosthese outer boundary synostosis rate of slow release group is high.
Claims (6)
1. the method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint; The method that it is characterized in that strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint realizes according to the following steps: one, the ethyl cellulose of 35～60mg and the Macrogol 4000 of 8～12mg are joined in the chloroform of 1.5～3ml; Then at 25 ℃ of following ultrasonic dissolutions; The rhBMP-2 that adds 1mg again gets the rhBMP-2 mixed liquor behind the ultra-sonic dispersion; Two, the rhBMP-2 mixed liquor is sprayed on the artificial femur handle, places superclean bench to dry then, be packaged in the sealed bag, cold sterilization is promptly accomplished; Wherein rhBMP-2 mixed liquor coating thickness is (30 ± 10) μ m in the step 2.
2. the method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint according to claim 1 is characterized in that in the step 1 ethyl cellulose of 35mg and the Macrogol 4000 of 8mg being joined in the chloroform of 1.5ml.
3. the method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint according to claim 1 is characterized in that in the step 1 ethyl cellulose of 60mg and the Macrogol 4000 of 12mg being joined in the chloroform of 3ml.
4. the method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint according to claim 1 is characterized in that in the step 1 ethyl cellulose of 40～55mg and the Macrogol 4000 of 9～11mg being joined in the chloroform of 2～2.5ml.
5. the method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint according to claim 1 is characterized in that in the step 1 ethyl cellulose of 45mg and the Macrogol 4000 of 10mg being joined in the chloroform of 2.8ml.
6. the method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint according to claim 1 is characterized in that in the step 1 ethyl cellulose of 50mg and the Macrogol 4000 of 11mg being joined in the chloroform of 2ml.
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| CN200910312220A CN101721743B (en) | 2009-12-24 | 2009-12-24 | Method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint |
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|---|---|---|---|
| CN200910312220A CN101721743B (en) | 2009-12-24 | 2009-12-24 | Method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint |
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| CN101721743B true CN101721743B (en) | 2012-09-05 |
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| CN105420229B (en) * | 2016-01-08 | 2018-07-17 | 中南大学 | A kind of lysate and method of extraction ancient biological bone DNA |
| CN110433342A (en) * | 2019-08-20 | 2019-11-12 | 曲彦隆 | A kind of preparation method of compound VEGF and rhBMP-2 biphase coating articular prosthesis |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1220169A (en) * | 1998-12-21 | 1999-06-23 | 冶金工业部钢铁研究总院 | Artificial joint coated with bone morphogenesis protein and its making method |
| CN1618473A (en) * | 2003-11-21 | 2005-05-25 | 王岩 | Artificial biological prothesis, and its prepn. method |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1220169A (en) * | 1998-12-21 | 1999-06-23 | 冶金工业部钢铁研究总院 | Artificial joint coated with bone morphogenesis protein and its making method |
| CN1618473A (en) * | 2003-11-21 | 2005-05-25 | 王岩 | Artificial biological prothesis, and its prepn. method |
Non-Patent Citations (1)
| Title |
|---|
| 陈嘉利,等.骨形态发生蛋白诱导成骨增加人工关节稳定性的相关研究.<<中国组织工程研究与临床康复>>.2008,第12卷(第26期),5117-5119. * |
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