CN1325124C - Artificial biological prothesis, and its prepn. method - Google Patents
Artificial biological prothesis, and its prepn. method Download PDFInfo
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- CN1325124C CN1325124C CNB2003101153805A CN200310115380A CN1325124C CN 1325124 C CN1325124 C CN 1325124C CN B2003101153805 A CNB2003101153805 A CN B2003101153805A CN 200310115380 A CN200310115380 A CN 200310115380A CN 1325124 C CN1325124 C CN 1325124C
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- Materials For Medical Uses (AREA)
- Prostheses (AREA)
Abstract
The present invention relates to an artificial biological prosthesis containing bone morphogenetic protein (BMP), more specifically an artificial prosthesis with BMP infiltrated into the prosthesis through a coating membrane with a plurality of micropores on the surface of the prosthesis. The present invention also relates to a method for preparing the artificial biological prosthesis. The surface of prosthesis material is covered with a coating membrane with a plurality of micropores, and the surface of the coating membrane with a plurality of micropores is covered with a layer of bone morphogenetic protein (BMP).
Description
Technical field
The present invention relates to a kind of artificial joint bioprosthesis that contains bone form generation albumen (BMP), specifically is the artificial prosthesis that BMP is infiltrated prosthese inside through a plurality of micropore overlay films of prosthetic surface.The invention still further relates to the preparation method of above-mentioned artificial bio-membrane's prosthese.
Background technology
The prosthetic replacement is the ultimate treatment means of treatment osteoarthrosis serious pathological changes, and it is made over can only the dependance on walking stick walking, even patient that can only amputation, can walk as the normal person.But phenomenons such as the artificial prosthesis of prior art exists that the joint is easy to wear, prosthese aseptic loosening and the dissolving of carrying out property bone.
For addressing the above problem, many Human To Human workers have carried out multiple improvement in the joint, realize the fixing of prosthese by setting up between implant and surrounding tissue to cooperatively interact, particularly invented biological fixation type artificial joint, on artificial joint, spray one deck hydroxyapatite as Chinese patent 98125674.0, apply one deck bone morphogenetic protein (BMP) at the hydroxyapatite surface repaste then, to solve the physiology fixation problem.But in the method, BMP is difficult to infiltrate artificial joint prosthesis inside, can not effectively induce osteogenesis.Chinese patent 00107241.2 is provided with the cavity of hollow in prosthese, fill bone morphogenetic protein-carrier complexes in cavity body, and is biological integrated to realize prosthese.But hollow prosthesis will influence the intensity of prosthese.
Summary of the invention
The purpose of this invention is to provide a kind of novel artificial joint prosthesis, make bone morphogenetic protein and false this more effective combination, help induction of bone growth, and do not influence the intensity of prosthese.
The technical problem to be solved in the present invention is that bone morphogenetic protein (BMP) is penetrated into prosthese inside through prosthetic surface, to prepare novel artificial joint bioprosthetic material.
Technical scheme of the present invention is as follows:
Described artificial joint bioprosthesis is: have the overlay film of a plurality of micropores at surface coverage one deck of prosthetic material, at surface coverage one deck bone morphogenetic protein (BMP) of described micropore overlay film.So that BMP more effectively combines with prosthetic material by micropore, promote osseous tissue to grow in the micropore of prosthese, above-mentioned overlay film is a hydroxyapatite, the aperture of described micropore is 240～500 μ m; Thickness is 30-110 μ m, granularity 0.3～0.9mm.
Described prosthetic material is titanium alloy, cobalt-base alloys, PMMA, ultra high molecular polyethylene, porous material, as the Ti-6A1-4V alloy, the Ti-6A1-7Nb alloy, casting Co-Cr-Mo alloy etc. is artificial prosthetic material, and other various prosthetic materials well known to those skilled in the art;
Described micropore overlay film is hydroxyapatite (HA), metal porous coating and composite coating; Wherein metal porous coating comprises bead porous coating, the tinsel texture coating that is obtained by vacuum brazing technique, and the metal dust porous coating that adopts plasma spray coating process to make; Comprise that also Ducheyne equals the technical methods well known in the art such as use active biological ceramic coating on porous surface of proposition in 1980.
Described bone morphogenetic protein (BMP) comprises the BMP that various sources obtain, as the reorganization BMP-2 that obtains by Protocols in Molecular Biology (as transgenic method);
The artificial prosthesis of indication of the present invention comprises various artificial jointes, as: hip joint, knee joint, ankle joint, shoulder joint, elbow joint and carpal joint etc.
The preparation method of artificial joint bioprosthesis of the present invention is: the overlay film that has a plurality of micropores at surface coverage one deck of prosthetic material, surface coverage one deck bone morphogenetic protein (BMP) at described micropore overlay film, above-mentioned overlay film is a hydroxyapatite, and the aperture of described micropore is 240～500 μ m; Thickness is 30-110 μ m, granularity 0.3～0.9mm.
The method of the surface coverage micropore overlay film of described prosthetic material comprises technologies such as plasma spraying, ion beam sputter depositing, electrophoretic deposition, sintering, and other the whole bag of tricks well known to those skilled in the art.
The method of the surface coverage bone morphogenetic protein (BMP) of described micropore overlay film is: BMP is dissolved in the appropriate solvent, then the aforementioned prosthetic material that is coated with a plurality of micropore overlay films is immersed in this solution, making BMP see through a plurality of micropores through deposition is deposited in the prosthetic material, remove molten emerging middle impurity then, sterilization forms, above-mentionedly be deposited as 4 ℃, the 12h deposition.
Above-mentioned appropriate solvent comprises guanidine hydrochloride aqueous solution, CuHCl/CaCl
2Mixed aqueous solution etc.;
The above-mentioned impurity method of removing in the solution is with distill water dialysis, evacuation, lyophilizing under the low temperature then; Above-mentioned sterilization method is directly to sterilize with oxirane, or vacuum-packed back cobalt 60 illumination-based disinfections.
The present invention has carried out following experiment: at porous metals surface implants (PCA) and compound rhBMP
2The PCA implant of (gene recombinaton BMP), HA coating implant and PCA surface spraying HA implant are implanted the dog cortical bone, and integrated use X line is taken the photograph, and methods such as sheet, the photograph of soft X line, undecalcified osseous tissue abrasive disc, fluorescence microscopy, bone histomorphometry's analysis and biological mechanics determining are grown into to the bone at bone-implant interface and the bond strength at interface compares analysis.The result shows: compound rhBMP
2Implant 4 when week the area of new bone formation rate and interface shear strength all obviously be better than other each group, statistical analysis shows compound rhBMP
2There is highly significant difference between group and other each group.Prove technology of the present invention the bone that promotes early stage bone-prosthese interface grow into and bond strength aspect be better than other the whole bag of tricks, help combining and fixing between early stage bone and prosthese.Make prosthese when implant into body and the compatibility of tissue better, promote osseous tissue to grow in the micropore of prosthese, avoid prosthese aseptic loosening and carrying out property bone dissolution phenomena, reduce the wearing and tearing of artificial joint.
The specific embodiment
Embodiment 1Ti-6A1-4V alloy artificial hip joint bioprosthesis
1) be the hydroxyapatite of 0.3～0.5mm in Ti-6Al-4V alloy artificial hip joint surface spraying one deck granularity, hydroxyapatite thickness is that 30 μ m are cellular, and its aperture is 240～350 μ m.
2) 20mg BMP is dissolved in the 4mol/L guanidine hydrochloride solution.
3) in above-mentioned guanidine hydrochloride solution, put into 1) described in the artificial joint of spraying hydroxyapatite, through 4 ℃, 12h deposition, distill water dialysis 48h, evacuation, put behind-30 ℃ of lyophilizing, the oxirane disinfection standby.
The artificial knee joint bioprosthesis of embodiment 2Ti-6Al-7Nb alloy
1) be the hydroxyapatite of 0.4～0.7mm in Ti-6Al-7Nb alloy artificial knee joint surface spraying one deck granularity, hydroxyapatite thickness is that 60 μ m are cellular, and its aperture is 300～400 μ m.
2) 20mg BMP is dissolved in 4mol/LCuHCl/CaCl
2In the mixed aqueous solution.
3) in above-mentioned mixed aqueous solution, put into 1) described in the artificial joint of spraying hydroxyapatite, through 4 ℃, 12h deposition, distill water dialysis 48h, evacuation, put-30 ℃ of lyophilizing, after the vacuum packaging, standby with cobalt 60 illumination-based disinfections.
The artificial ankle bioprosthesis of embodiment 3 casting Co-Cr-Mo alloys
In the artificial ankle joint of casting Co-Cr-Mo alloy surface spraying one deck granularity is the hydroxyapatite of 0.6～0.9mm, and hydroxyapatite thickness is that 110 μ m are cellular, and its aperture is 350～500 μ m.
All the other steps are with step 2 among the embodiment 1), 3).
Embodiment 4 reorganization BMP are applied to artificial joint biological fixation zoopery
One, experiment material and method
(1) experiment material:
1. porous metals surfaces implant (PCA): adopt the cylindrical implant of vitallium, external diameter 5mm, length 12mm.The surface sintering has three layers of vitallium microballon, and the aperture is 220 μ m, and porosity is 30%.
2.rhBMP
2Compound porous metal surface implant (PCA+BMP): with the type i collagen is the compound 500 microgram rhBMP of every PCA implant surfaces of carrier
2
3. spray the PCA implant (PCA+HA) of HA: sintering process prepares the HA coating after the capable surface sand-blasting alligatoring of diameter 4.9mmPCA cobalt surface chrome molybdenum implant, about 30 ± 10 microns of HA coating layer thickness.
4. hydroxyapatite coating layer implant (HA): diameter 4.8mm vitallium cylinder, length 12mm, the alligatoring of row surface sand-blasting, sintering process prepares the HA coating then, about 100 ± 50 microns of coating layer thickness.
Porous metals surface implant and hydroxyapatite are made by capital boat company and are provided.Hydroxyapatite purity 95%, Ca/P is 1.67.RhBMP
2With Beijing lark gram biological product company product, purity 95%.Complex method is with quantitative rhBMP
2Be added to 10%I Collagen Type VI solution and fully stir into uniform suspension, pipettor quantitatively drops to implant surfaces, and evacuation in the vacuum freeze drier, lyophilization and repeatedly for several times are according to rhBMP
2The dosage of concentration, volume calculation surface recombination is until reaching 500 micrograms.
(2) laboratory animal: 16 of adult healthy hybrid dogs, male and female are not limit, 20 ~ 25 kilograms of body weight; Be divided into by the observation cycle and organize 4 of per time groups in 4 weeks, 8 weeks, 12 weeks, a time 24 Thursdays, choosing the bilateral femur is growing area, and every side femur of every dog is implanted 4 pieces of implants, implants each 1 piece of 4 kinds of implant, implantation position random alignment in every side respectively.
(3) operation method: under the aseptic condition, row lateral side of femur straight cut is about 12cm, successively cuts skin and soft tissue, separates through Alm gap passivity, appears femur; Cut and peel off lateral periosteum, bore four holes with the 5.3mm drill bit successively in the femoral shaft outside and penetrate single-side cortex, normal saline washing cooling simultaneously; The about 1.5cm of pitch of holes, the normal saline washing art behind the open country inserts in the hole implant, and tapping puts in place, washes and sews up the incision.
(4) detection method: the capable soft X line of histological observation is taken a picture, undecalcified osseous tissue abrasive disc, fluorescence microscopy and computer image analysis; Biomechanics adopts the push-out method to measure interface shear strength.
Two, experimental result
(1) take the photograph the sheet inspection:
Each time organize various implants with osseous tissue interface and near there is no that bone is damaged, euphotic zone and bone density lower phenomenon.
(2) soft X line is taken a picture:
The compound rhBMP of specimen around the postoperative
2Group sees between bone and implant and contact well not have obvious euphotic zone, and can see a little less than osseous tissue density shadow to the hole internal migration.There is euphotic zone between all visible bone of other three groups of specimen and the implant.Postoperative respectively organize implant 8 whens week soft X line take the photograph that euphotic zone narrows down between all visible bone of sheet-implant interface, the contact area increase and the freshman bone tissue of bone and implant grow in hole.Euphotic zone by freshman bone tissue's filling, be can't see in bone-implant interface in the time of around 12 weeks, 20.
(3) undecalcified osseous tissue abrasive disc:
See compound rhBMP around implanting the back
2Existing more lamellar bone and the small amount of fibers tissue of growing ringwise around implant surfaces of group, area of new bone are grown in the hole, and as seen new vessels and Haversian canal structure; Area of new bone girder along the hole growth has been grown between the 2nd, the 3 layer of microballon, and the subregion is that woven bone, osteoid are mixed in together.Other three groups at the peripheral position of implant and osseous tissue interface as seen to new bone formation is arranged, the visible freshman bone tissue in fraction zone and only in the hole above the 2nd layer of microballon.The visible circumcrescent lamellar bone of HA group in bone-implant interface new life, inwardly have and be the coating that podocytic process shape area of new bone is stretched to implant surfaces, also have the subregion to form osseous tissue and be attached directly to the HA coating surface, other parts still can be seen fibrous tissue between area of new bone and coating.
The all visible interface freshman bone tissue of each group increases around implanting eight weeks of back, 12 weeks and 20, and grow into gradually implant and HA coating porosity.
(4) fluorescence microscopy:
The visible compound rhBMP of the capable fluorescence microscopy of abrasive disc in the time of around the postoperative
2The fluorescence that group becomes band in bone bed surface and implant hole, lamellar distributes, and visible fluorescence divides a word with a hyphen at the end of a line along interpore bead surface, illustrates that the calcification forward position is in intrapore bead surface; PCA organizes the fluorescence that zonal distribution is arranged between rarely seen implant surfaces and part hole, illustrates that the calcification forward position is in the implant surfaces part; The composite coating group sees and mainly concentrates on interface between bone and the implant along the fluorescence of implant surfaces band shape, annular spread that part fluorescence is attached to coating surface; As seen HA group as seen around the fluorescence of implant zonal distribution, and is attached to coating surface and is the lamellar fluorescence of phalangeal process shape under fluorescence microscope; Each group all shows as the fluorescence distribution scope in the time of around eight weeks, 12 weeks and 20 increases, and intrapore fluorescent labeling increases, and the composite coating group increases obviously, illustrates that the area of new bone of intrapore calcification increases in time; HA organizes fluorescently-labeled scope to be increased, the coating of pressing close to implant surfaces more.
(5) bone histomorphometry analyzes:
Because the implant that adopts in the experiment is a porous surface,, therefore adopt the shared ratio of freshman bone tissue to come each group implant is compared in the grow into ability of hole of osseous tissue in the out-of-shape of histology's abrasive disc The midsagittal plane; Get that each 6 of per time of each implant group undecalcified osseous tissue abrasive discs are examined under a microscope, the collection of machine image capturing system comprises implant at interior general image as calculated, and the image after gathering is analyzed by the pathological image analytical system; Judge that freshman bone tissue also calculates its area, with interface between bone and the area of new bone with interior area as the gross area, calculate relative area of new bone formation rate then, and carry out statistical analysis.
Area of new bone formation rate (%)=freshman bone tissue's area/gross area * 100%
Statistical analysis shows: BMP group and highly significant difference is arranged on the area of new bone formation rate between other three groups in the time of after surgery.All there is not significant difference between other each group and between postoperative 8 all 12 all each groups.
(6) biological mechanics determining:
MTS 858 mini Biotex biomechanics test machines, setting continuous operation is displacement 0.5mm/min.The instant loading curve of record pressure, its peak value is the yield stress point; Measure the thickness (h) that cortical bone contacts with implant and the diameter (d) of implant simultaneously.
Calculate the shear strength of releasing experiment with following formula:
Peak shear strength (MPa)=maximum shear stress (N)/bone and implant contact area (mm
2)
The contact area of bone and implant: S=π * d*h
Statistical analysis shows: BMP group and between other three groups highly significant difference is arranged on interface shear strength in the time of after surgery.Reach 8 weeks of postoperative, 12 weeks between other each group, 24 weeks respectively do not have significant difference between the group.
Claims (8)
1, a kind of artificial joint prosthesis, the overlay film that has a plurality of micropores at surface coverage one deck of prosthetic material, surface coverage one deck bone morphogenetic protein at described micropore overlay film, described overlay film is a hydroxyapatite, the aperture that it is characterized in that the micropore of described hydroxyapatite overlay film is 240～500 μ m, thickness is 30～110 μ m, granularity 0.3～0.9mm.
2, the described artificial joint prosthesis of claim 1 is characterized in that described prosthetic material is titanium alloy, cobalt-base alloys, PMMA, ultra high molecular polyethylene or porous material.
3, claim 1 or 2 described artificial joint prosthesis is characterized in that described bone morphogenetic protein comprises by Protocols in Molecular Biology, and described Protocols in Molecular Biology is the reorganization BMP-2 that transgenic method obtains.
4, claim 1 or 2 described artificial joint prosthesis comprise artificial hip joint, knee joint, ankle joint, shoulder joint, elbow joint and carpal joint.
5, the preparation method of the described artificial joint prosthesis of claim 1, the hydroxyapatite overlay film that has a plurality of micropores at surface coverage one deck of prosthetic material, surface coverage one deck bone morphogenic protein BMP-2 at described micropore overlay film, coverage mode is for to be dissolved in BMP in the appropriate solvent, then the aforementioned prosthetic material that is coated with a plurality of micropore overlay films is immersed in this solution, making BMP see through a plurality of micropores through deposition is deposited in the prosthetic material, remove impurity in the solution then, sterilization forms, the aperture that it is characterized in that the micropore of described hydroxyapatite overlay film is 240～500 μ m, thickness is 30～110 μ m, granularity 0.3～0.9mm.
6, the preparation method of the described artificial joint prosthesis of claim 5 is characterized in that the method for the surface coverage micropore overlay film of described prosthetic material comprises plasma spraying, ion beam sputter depositing, electrophoretic deposition or sintering process.
7, the preparation method of claim 5 or 6 described artificial joint prosthesis is characterized in that described appropriate solvent comprises guanidine hydrochloride aqueous solution, CuHCl/CaCl
2Mixed aqueous solution; The described impurity method of removing in the solution is with distill water dialysis, evacuation, lyophilizing under the low temperature then; Described sterilization method is directly to sterilize with oxirane, or vacuum-packed back cobalt 60 illumination-based disinfections.
8,, it is characterized in that described sedimentary condition is that temperature is 4 ℃, 12 hours deposition according to the preparation method of claim 5 or 6 described artificial joint prosthesis.
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| CN1325124C true CN1325124C (en) | 2007-07-11 |
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| CA2752956C (en) | 2009-02-19 | 2017-02-28 | Smith & Nephew Orthopaedics Ag | Medical implant producing wear particles with benign body response |
| CN101708343B (en) * | 2009-11-03 | 2013-03-20 | 厦门大学 | Preparation method of micro-nanometer ordered structure hard tissue biomaterial film |
| CN101721743B (en) * | 2009-12-24 | 2012-09-05 | 曲彦隆 | Method for strengthening joint stability by using rhBMP-2 release coating on surface of artificial joint |
| CN101732762B (en) * | 2010-01-01 | 2013-04-03 | 东南大学 | Bioactive artificial joint capable of slowly releasing trace element selenium |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1266670A (en) * | 2000-04-29 | 2000-09-20 | 蔡谞 | Biologically compounded artificial hollow joint |
| CN1081591C (en) * | 1997-09-04 | 2002-03-27 | 吉第联合股份公司 | Method and unit for feeding blanks to user machine |
| CN1451367A (en) * | 2003-02-28 | 2003-10-29 | 华南理工大学 | Induction ossified bio-active artificial tooth root implant material and preparing method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1081591C (en) * | 1997-09-04 | 2002-03-27 | 吉第联合股份公司 | Method and unit for feeding blanks to user machine |
| CN1266670A (en) * | 2000-04-29 | 2000-09-20 | 蔡谞 | Biologically compounded artificial hollow joint |
| CN1451367A (en) * | 2003-02-28 | 2003-10-29 | 华南理工大学 | Induction ossified bio-active artificial tooth root implant material and preparing method thereof |
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