CN105641753A - RhBMP composited 3D-printed degradable stent enabling vessel transfer - Google Patents
RhBMP composited 3D-printed degradable stent enabling vessel transfer Download PDFInfo
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/043—Proteins; Polypeptides; Degradation products thereof
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/146—Porous materials, e.g. foams or sponges
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B28—WORKING CEMENT, CLAY, OR STONE
- B28B—SHAPING CLAY OR OTHER CERAMIC COMPOSITIONS; SHAPING SLAG; SHAPING MIXTURES CONTAINING CEMENTITIOUS MATERIAL, e.g. PLASTER
- B28B1/00—Producing shaped prefabricated articles from the material
- B28B1/001—Rapid manufacturing of 3D objects by additive depositing, agglomerating or laminating of material
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y10/00—Processes of additive manufacturing
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/242—Applying crosslinking or accelerating agent onto compounding ingredients such as fillers, reinforcements
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Abstract
The invention discloses an rhBMP-2 composited 3D-printed degradable stent enabling vessel transfer through composite rhBMP-2, prepared via the following process: first, preparing a three-dimensional through porous stent; second, injecting a sustained release system loading rhBMP-2 into the above-mentioned porous stent, and cooling and drying to obtain the 3D-printed degradable stent. The composite degradable stent prepared by the invention has bionic feature, good biocompatibility and good degrading performance, can release rhBMP-2 slowly, can also be a vascular stent so that osteogenic capability of the stent is enhanced, good nutrient supply and discharge and metabolic waste can be provided for newborn bone tissues, and the ability of the stent to repair bone injury is improved.
Description
Technical field
The invention belongs to technical field of biomedical materials, the 3D of the realized blood vessel transfer being specifically related to a kind of compound rhBMP-2 prints biodegradable stent.
Background technology
The Cranial defect that the diseases such as fracture, tumor cause generally requires bone collection to carry out repair and reconstruction. Bone collection operation be in clinic except transfuse blood except modal tissue transplantation art, it is estimated that have 500,000 examples in the U.S. every year, have more than 2,000,000 example bone collection in the whole world and be applied to orthopaedics, neurosurgery and Oral and Maxillofacial Surgery. Autologous bone transplanting is owing to having osteoinductive, bone conductibility and not causing the characteristics such as antigen-reactive and be considered the goldstandard for the treatment of Cranial defect, but there is the shortcoming of limited source and take bone place and there is the potential risk of the complication such as hemorrhage, infection, chronic pain. Homogeneous allogenic bone transplantation may cause rejection even to spread disease as conventional alternative.
The research and development of therefore new bone alternate material have broad application prospects. Development recently as biomaterial and tissue engineering, occur in that titanium alloy, calcium phosphate (TCP), hydroxyapatite (HA) and Poly(D,L-lactide-co-glycolide (PLGA) etc. have the organizational project bone alternate material of good biocompatibility.
But the treatment of Cranial defect is still that the great challenges that puzzlement is clinical, especially when the disease such as wound, tumor causes large segmental bone defect, above-mentioned means are difficult to obtain more satisfactory result. Its main cause has following three points: 1, the avascular of bone graft or bone alternate material: in osseous tissue, effective disperse distance only 200 ��m of oxygen and nutrient substance, therefore only has near vessels osseous tissue within the scope of this just can obtain effective oxygen and nutrition supply and be survived. And traditional bone graft and organizational project bone alternate material newly developed are do not carry vascular system mostly. Although after transplanting, spontaneous vascularization process can occur around graft, but the speed that blood vessel grows in graft only has a few tenths of a mm/every day, and the central area of graft cannot obtain required oxygen and nutrient substance, consequently, it is possible to cause Bone graft healing failure.Vascular bundle is implanted into support and can quickly realize the vascularization of support, provide required oxygen and nutrient substance supply for newborn osseous tissue, to promote the reparation of Cranial defect. 2, research it turned out, and aperture is porous support the growing into most beneficial for osteocyte of 200 ��m-600 ��m, and the porous support of traditional handicraft manufacture is difficult to meet pore size and be distributed homogeneous requirement. In addition the support that the also limit conventional art manufacture application in this field that comes in every shape of Cranial defect. And the 3D printing technique of rising in recent years can well meet the support demand to various internal structures and distinctive appearance. 3, although studying more titanium alloy support at present there is good biocompatibility, but owing to it has higher elastic modelling quantity and non-biodegradable, often cause the problem that internal stent stress shielding and bone and mount interface stress are concentrated.
Bone morphogenesis protein-2 (BMP-2) has the very strong ability promoting skeletonization, but the effective acting time played when directly discharging is very short, and a large amount of releases even can cause the untoward reaction of local. Therefore BMP-2 is loaded into slow-released system and realizes the trend that the slow releasing of medicine is clinical practice.
Summary of the invention
The invention provides the 3D of the realized blood vessel of a kind of compound rhBMP-2 transfer and print biodegradable stent, described biodegradable stent includes three-dimensional through porous support, is positioned at the three-dimensional micro rack within the through porous support of described three-dimensional and is positioned at described three-dimensional rhBMP-2 slow-released system composition within micro rack; Described three-dimensional micro rack is in three-dimensional through porous network structure; The middle part of the through porous support of described three-dimensional arranges the central passage of a up/down perforation; / 3rd columns of the through porous support of described three-dimensional detachably and again assemble, it is achieved thereby that the opening or closing of described central passage.
Further, the diameter of the central passage of described up/down perforation is 4-8mm.
Further, the aperture of the through porous support of described three-dimensional is 200-600 ��m; Porosity is 60-80%.
Further, the aperture of described three-dimensional micro rack is 50-100 ��m;
Further, the through porous support of described three-dimensional is prepared from by PLGA and ��-TCP; Further, the through porous support of described three-dimensional is prepared from according to the ratio of 4:1 by PLGA and ��-TCP.
The combination of PLGA and ��-TCP can be substituted by other biological degradable material, include but not limited to, vinegar in aliphatic poly, in cruel between copolymer, the interior cruel copolymer with polyethers, interior cruel same aminoacid, the copolymer of maleic acid, and the same natural polymer of vinegar family macromolecule in poly-, various poly-in cruel between, or the same chitin of vinegar in poly-, blend between alginate, or gather interior vinegar with through base apatite, Corallium Japonicum Kishinouye, the blend of tricalcium phosphate, polylactic acid (PLA), polyglycolic acid (PGA), albumin, collagen protein, poly butyric ester, poly-own propyl ester and hy-droxybutyl, polycaprolactone (PCL), lactic acid-caprol acton copolymer (PLA-CL), one or more in hydroxybutyric acid-hydroxycaproic acid copolymer (PHBHHx).
The combination of PLGA and ��-TCP by degradable alloy replacing, can also include but not limited to, Mg-Sn-Mn system alloy or Mg-Sn-Mn-Zn system alloy.
Further, described three-dimensional micro rack is prepared from by gelatin.
Gelatin can be formed the material substitution of porous network structure by other degradables simultaneously, include but not limited to, natural macromolecular material: one or more in collagen, fibroin albumen, zein, alginate, chitosan, hyaluronate sodium, sodium alginate, dextran sulfate, heparin sodium, chondroitin sulfate or keratan sulfate;Hydroxyapatite powder; Calcium phosphate, tricalcium phosphate, calcium sulfate, polyester (polyesters), polydioxanone (polydioxanone), one or more of poly-fumaric acid two hydroxypropyl acrylate (propylenefumarate, PPF), poe (polyorthoesters), polyanhydride (polyanhydrides) and polyurethane (polyurethanes) etc.
Further, described rhBMP-2 slow-released system is made up of with common slow-released carrier rhBMP-2. Described slow-released carrier includes but not limited to: (1) tradition slow-released carrier: collagen, decalcified bone matrix, Fibrin Glue, bioactivity glass, tricalcium phosphate, biphasic calcium phosphate, calcium sulfate, calcium phosphate, hydroxyapatite, Corallium Japonicum Kishinouye, Gypsum Fibrosum, hyaluronic acid; (2) microsphere sustained-release carrier: polylactic acid (polylacticacid, PLA), polyglycolic acid (polyglycolicacid, PGA), gelatin, polysaccharide-based hydrogel, chitosan, Sargassum salt; (4) nano controlled-release carrier; (5) other: hyaluronic acid, cellulose, chondroitin sulfate, silkworm silk and agarose, polyvinylpyrrolidine (polyvinylpyrrolidone, PVP); (6) composite slow release carrier. In specific embodiments of the present invention, described slow-released carrier is chitosan.
Present invention also offers the 3D of the realized blood vessel of the foregoing compound rhBMP-2 transfer preparation method printing biodegradable stent, concrete operation step is as follows:
(1) conventional tissue engineered porous scaffold preparation technology is utilized to prepare the through porous support of foregoing three-dimensional;
(2) rhBMP-2 slow-released system is prepared;
(3) rhBMP-2 slow-released system prepared by natural macromolecular material and/or bioceramic and step (2) is prepared into mixed liquor;
(4) being filled into by mixed liquor prepared by step (3) in the through porous support of three-dimensional prepared by step (1), the 3D of the realized blood vessel transfer of the compound rhBMP-2 of freeze-dried preparation cost invention prints biodegradable stent.
In specific embodiments of the present invention, the concrete operations of above-mentioned steps (1) are as follows:
A, CT image is imported the three-dimensional imaging software such as Mimics or CAD, obtain the 3-D view of targeted bony tissue, with regular hexahedron or the filling of regular dodecahedron structural units, extend this image, obtain the porous connection three-dimensional digital model of personalization, average Kong Zhuwei 100-1000 ��m (intermediate value 500 ��m), aperture are 200-600 ��m (intermediate value 400 ��m), porosity is 60%-80%, the diameter 4-8mm (determining according to Cranial defect position) of carriage center passage, the column of support 1/3rd detachably and again assembles.
B, employing Bioscaffolder2.1 (GeSiM, Germany) the Low-temperature Deposition Manufacturing system of 3D printer and Tsing-Hua University's research and development, porous, degradable support is printed for raw material with ��-TCP and PLGA, PLGA/ ��-TCP=4:1, according to the printing porous cylindrical support that designs a model, solid support can be formed after-80 DEG C of lyophilizing.
In specific embodiments of the present invention, the concrete operation step of above-mentioned steps (2) is as follows: adopt emulsion-crosslinking method to prepare rhBMP-2/ chitosan microball. First 300mg chitosan is dissolved in 10ml formic acid solution, adds about 2.7mgrhBMP-2, be sufficiently stirred for. Be added dropwise in the liquid paraffin containing surfactant span80 again, 45 DEG C be sufficiently stirred for after add cross-linking agent vanillin, continue stirring 6-7h, precipitate washed, namely obtains rhBMP-2/ chitosan microball after lyophilization.
In specific embodiments of the present invention, the concrete operation step of above-mentioned steps (3) is as follows: joined by gelatin particle in deionized water, and at 37 DEG C, in the magnetic stirring apparatus of 300r/min, 2h is to thoroughly dissolving, the final concentration of 1.5-20% of gelatin; It is subsequently adding rhBMP-2/ chitosan microball Homogeneous phase mixing prepared by step (2).
Preferably, the final concentration of 3-5% of described gelatin; It is furthermore preferred that described gelatin final concentration of 4%.
In specific embodiments of the present invention, the concrete operation step of above-mentioned steps (4) is as follows:
A, mixed liquor step (3) prepared inject in the through porous support of three-dimensional prepared with syringe pressurization, and are immersed in mixed liquor, place 4 DEG C of refrigerator freezings.
B, take out the gel piece after above-mentioned freezing, strike off gel unnecessary in porous scaffold surface and hollow region, add 0.1mol/L glycine solution, soak, same to method, then soak with deionized water, clean.
C, above-mentioned process thing is put into container, add deionized water and do not have the upper surface of porous support, then put into-80 DEG C of refrigerator freezings.
D, taking out frozen thing, put in vacuum freeze drier ,-46 DEG C of refrigerator freezings dry, and the 3D of the realized blood vessel transfer namely obtaining the compound rhBMP-2 of the present invention prints biodegradable stent.
Preferably, in step (a), 4 DEG C of refrigerator freezing times are 12h.
Preferably, in step (b), glycine soaking conditions is: 37 DEG C, soaks 2h in the magnetic stirring apparatus of 300r/min.
Preferably ,-80 DEG C of refrigerator freezing 4h in step (c).
Preferably ,-46 DEG C of refrigerator freezing 48h in step (d).
Advantages of the present invention and beneficial effect:
The 3D of the realized blood vessel transfer of the compound rhBMP-2 of the present invention is printed biodegradable stent and is formed by 3D printing, there is bionical feature, good biocompatibility and degradability, the BMP-2 microsphere of slow release the ability of its skeletonization can be strengthened by compound, by performing the operation the blood vessel (arteriovenous as deep in the stock near femur near Cranial defect, the deep arteriovenous of the upper arm near humerus and vascular bundle etc. between the bone near forearm) the central passage district that is implanted into support can realize the vascularization of support to strengthen its osteogenic ability, and good nutrient substance supply and excretion metabolism refuse are provided for newborn osseous tissue, promote its repair ability to Cranial defect.
Accompanying drawing explanation
Fig. 1 shows that the 3D of the realized blood vessel transfer of compound rhBMP-2 prints the structural representation of biodegradable stent;
Fig. 2 shows that the 3D of the realized blood vessel transfer of compound rhBMP-2 prints the cross section structure schematic diagram of biodegradable stent;
Fig. 3 shows that rhBMP-2/ chitosan sustained-release system is loaded into containing the close-up schematic view in gelatin three-dimensional micro rack;
Fig. 4 shows that the 3D of the realized blood vessel transfer of compound rhBMP-2 prints the application schematic diagram of biodegradable stent.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further, is only used for explaining the present invention, and is not considered as limiting the invention.
The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition or according to manufacturer it is proposed that condition examinations.
The reagent in unreceipted source in the following example, all can obtain from commercial routes.
The 3D of the realized blood vessel transfer of embodiment 1 compound rhBMP-2 prints biodegradable stent
The 3D of the realized blood vessel transfer of a kind of compound rhBMP-2 prints biodegradable stent, this composite degradable support includes three-dimensional through porous support, is positioned at the three-dimensional micro rack within three-dimensional through porous support and is positioned at the three-dimensional composition of rhBMP-2 slow-released system within micro rack;Three-dimensional micro rack is in three-dimensional through porous network structure; Three-dimensional through porous support middle part arranges the central passage of a up/down perforation; / 3rd columns of three-dimensional through porous support detachably and again assemble, it is achieved thereby that the opening or closing of central passage.
The diameter of the central passage of up/down perforation is 4mm.
The aperture of three-dimensional through porous support is 200 ��m; Porosity is 60%.
The aperture of three-dimensional micro rack is 50 ��m;
Three-dimensional through porous support is prepared from according to the ratio of 4:1 by PLGA and ��-TCP.
During use, by performing the operation the blood vessel (arteriovenous as deep in the stock near femur near Cranial defect, the deep arteriovenous of the upper arm near humerus and vascular bundle etc. between the bone near forearm) the central passage district that is implanted into support can realize the vascularization of support to strengthen its osteogenic ability, and good nutrient substance supply and excretion metabolism refuse are provided for newborn osseous tissue, promote its repair ability to Cranial defect.
The 3D of the realized blood vessel transfer of embodiment 2 compound rhBMP-2 prints biodegradable stent
The 3D of the realized blood vessel transfer of a kind of compound rhBMP-2 prints biodegradable stent, this composite degradable support includes three-dimensional through porous support, is positioned at the three-dimensional micro rack within three-dimensional through porous support and is positioned at the three-dimensional composition of rhBMP-2 slow-released system within micro rack; Three-dimensional micro rack is in three-dimensional through porous network structure; Three-dimensional through porous support middle part arranges the central passage of a up/down perforation; / 3rd columns of three-dimensional through porous support detachably and again assemble, it is achieved thereby that the opening or closing of central passage.
The diameter of the central passage of up/down perforation is 8mm.
The aperture of three-dimensional through porous support is 600 ��m; Porosity is 80%.
The aperture of three-dimensional micro rack is 100 ��m;
Three-dimensional through porous support is prepared from according to the ratio of 4:1 by PLGA and ��-TCP.
During use, by performing the operation the blood vessel (arteriovenous as deep in the stock near femur near Cranial defect, the deep arteriovenous of the upper arm near humerus and vascular bundle etc. between the bone near forearm) the central passage district that is implanted into support can realize the vascularization of support to strengthen its osteogenic ability, and good nutrient substance supply and excretion metabolism refuse are provided for newborn osseous tissue, promote its repair ability to Cranial defect.
The 3D of the realized blood vessel transfer of embodiment 3 compound rhBMP-2 prints biodegradable stent
The 3D of the realized blood vessel transfer of a kind of compound rhBMP-2 prints biodegradable stent, this composite degradable support includes three-dimensional through porous support, is positioned at the three-dimensional micro rack within three-dimensional through porous support and is positioned at the three-dimensional composition of rhBMP-2 slow-released system within micro rack; Three-dimensional micro rack is in three-dimensional through porous network structure; Three-dimensional through porous support middle part arranges the central passage of a up/down perforation; / 3rd columns of three-dimensional through porous support detachably and again assemble, it is achieved thereby that the opening or closing of central passage.
The diameter of the central passage of up/down perforation is 5mm.
The aperture of three-dimensional through porous support is 400 ��m; Porosity is 70%.
The aperture of three-dimensional micro rack is 75 ��m;
Three-dimensional through porous support is prepared from according to the ratio of 4:1 by PLGA and ��-TCP.
During use, by performing the operation the blood vessel (arteriovenous as deep in the stock near femur near Cranial defect, the deep arteriovenous of the upper arm near humerus and vascular bundle etc. between the bone near forearm) the central passage district that is implanted into support can realize the vascularization of support to strengthen its osteogenic ability, and good nutrient substance supply and excretion metabolism refuse are provided for newborn osseous tissue, promote its repair ability to Cranial defect.
The 3D of the realized blood vessel transfer of embodiment 4 compound rhBMP-2 prints the preparation of biodegradable stent
Step is as follows:
1, CT image is imported the three-dimensional imaging software such as Mimics or CAD, obtain the 3-D view of targeted bony tissue, with regular hexahedron or the filling of regular dodecahedron structural units, extend this image, obtain the porous connection three-dimensional digital model of personalization, average Kong Zhuwei 100 ��m, aperture are 200 ��m, porosity is 60%, and the diameter 4mm (determining according to Cranial defect position) of carriage center passage, the column of support 1/3rd detachably and again assembles.
2, Bioscaffolder2.1 (GeSiM is adopted, Germany) the Low-temperature Deposition Manufacturing system of 3D printer and Tsing-Hua University's research and development, porous, degradable support is printed for raw material with ��-TCP and PLGA, PLGA/ ��-TCP=4:1, according to the printing porous cylindrical support that designs a model, solid support can be formed after-80 DEG C of lyophilizing.
3, adopt emulsion-crosslinking method to prepare chitosan microball load rhBMP-2, form rhBMP-2/ chitosan microball. First 300mg chitosan is dissolved in 10ml formic acid solution, adds about 2.7mgrhBMP-2, be sufficiently stirred for. Be added dropwise in the liquid paraffin containing surfactant span80 again, 45 DEG C be sufficiently stirred for after add cross-linking agent vanillin, continue stirring 6-7h, precipitate washed, namely obtains rhBMP-2/ chitosan microball after lyophilization.
4, joining in deionized water by gelatin particle, at 37 DEG C, in the magnetic stirring apparatus of 300r/min, 2h is to thoroughly dissolving, gelatin final concentration of 1.5%; It is subsequently adding rhBMP-2/ chitosan microball Homogeneous phase mixing prepared by step (2).
5, mixed liquor step (4) prepared injects in the through porous support of three-dimensional prepared with syringe pressurization, and is immersed in mixed liquor, places 4 DEG C of refrigerator freezing 12h.
6, take out the gel piece after above-mentioned freezing, strike off gel unnecessary in porous scaffold surface and hollow region, add 0.1mol/L glycine solution, 37 DEG C, the magnetic stirring apparatus of 300r/min soaks 2h, same to method, then soaks with deionized water, clean 3 times.
7, above-mentioned process thing is put into container, add deionized water and do not have the upper surface of porous support, then put into-80 DEG C of refrigerator freezing 4h.
8, taking out frozen thing, put in vacuum freeze drier ,-46 DEG C of dry 48h of refrigerator freezing, the 3D of the realized blood vessel transfer namely obtaining the compound rhBMP-2 of the present invention prints biodegradable stent.
The 3D of the realized blood vessel transfer of embodiment 5 compound rhBMP-2 prints the preparation of biodegradable stent
Step is as follows:
1, CT image is imported the three-dimensional imaging software such as Mimics or CAD, obtain the 3-D view of targeted bony tissue, with regular hexahedron or the filling of regular dodecahedron structural units, extend this image, obtain the porous connection three-dimensional digital model of personalization, average Kong Zhuwei 1000 ��m, aperture are 600 ��m, porosity is 80%, and the diameter 8mm (determining according to Cranial defect position) of carriage center passage, the column of support 1/3rd detachably and again assembles.
2, Bioscaffolder2.1 (GeSiM is adopted, Germany) the Low-temperature Deposition Manufacturing system of 3D printer and Tsing-Hua University's research and development, porous, degradable support is printed for raw material with ��-TCP and PLGA, PLGA/ ��-TCP=4:1, according to the printing porous cylindrical support that designs a model, solid support can be formed after-80 DEG C of lyophilizing.
3, adopt emulsion-crosslinking method to prepare chitosan microball load rhBMP-2, form rhBMP-2/ chitosan microball.First 300mg chitosan is dissolved in 10ml formic acid solution, adds about 2.7mgrhBMP-2, be sufficiently stirred for. Be added dropwise in the liquid paraffin containing surfactant span80 again, 45 DEG C be sufficiently stirred for after add cross-linking agent vanillin, continue stirring 6-7h, precipitate washed, namely obtains rhBMP-2/ chitosan microball after lyophilization.
4, joining in deionized water by gelatin particle, at 37 DEG C, in the magnetic stirring apparatus of 300r/min, 2h is to thoroughly dissolving, gelatin final concentration of 20%; It is subsequently adding rhBMP-2/ chitosan microball Homogeneous phase mixing prepared by step (2).
5, mixed liquor step (4) prepared injects in the through porous support of three-dimensional prepared with syringe pressurization, and is immersed in mixed liquor, places 4 DEG C of refrigerator freezing 12h.
6, take out the gel piece after above-mentioned freezing, strike off gel unnecessary in porous scaffold surface and hollow region, add 0.1mol/L glycine solution, 37 DEG C, the magnetic stirring apparatus of 300r/min soaks 2h, same to method, then soaks with deionized water, clean 3 times.
7, above-mentioned process thing is put into container, add deionized water and do not have the upper surface of porous support, then put into-80 DEG C of refrigerator freezing 4h.
8, taking out frozen thing, put in vacuum freeze drier ,-46 DEG C of dry 48h of refrigerator freezing, the 3D of the realized blood vessel transfer namely obtaining the compound rhBMP-2 of the present invention prints biodegradable stent.
The 3D of the realized blood vessel transfer of embodiment 6 compound rhBMP-2 prints the preparation of biodegradable stent
Step is as follows:
1, CT image is imported the three-dimensional imaging software such as Mimics or CAD, obtain the 3-D view of targeted bony tissue, with regular hexahedron or the filling of regular dodecahedron structural units, extend this image, obtain the porous connection three-dimensional digital model of personalization, average Kong Zhuwei 500 ��m, aperture are 400 ��m, porosity is 70%, and the diameter 5mm (determining according to Cranial defect position) of carriage center passage, the column of support 1/3rd detachably and again assembles.
2, Bioscaffolder2.1 (GeSiM is adopted, Germany) the Low-temperature Deposition Manufacturing system of 3D printer and Tsing-Hua University's research and development, porous, degradable support is printed for raw material with ��-TCP and PLGA, PLGA/ ��-TCP=4:1, according to the printing porous cylindrical support that designs a model, solid support can be formed after-80 DEG C of lyophilizing.
3, adopt emulsion-crosslinking method to prepare chitosan microball load rhBMP-2, form rhBMP-2/ chitosan microball. First 300mg chitosan is dissolved in 10ml formic acid solution, adds about 2.7mgrhBMP-2, be sufficiently stirred for. Be added dropwise in the liquid paraffin containing surfactant span80 again, 45 DEG C be sufficiently stirred for after add cross-linking agent vanillin, continue stirring 6-7h, precipitate washed, namely obtains rhBMP-2/ chitosan microball after lyophilization.
4, joining in deionized water by gelatin particle, at 37 DEG C, in the magnetic stirring apparatus of 300r/min, 2h is to thoroughly dissolving, gelatin final concentration of 3%; It is subsequently adding rhBMP-2/ chitosan microball Homogeneous phase mixing prepared by step (2).
5, mixed liquor step (4) prepared injects in the through porous support of three-dimensional prepared with syringe pressurization, and is immersed in mixed liquor, places 4 DEG C of refrigerator freezing 12h.
6, take out the gel piece after above-mentioned freezing, strike off gel unnecessary in porous scaffold surface and hollow region, add 0.1mol/L glycine solution, 37 DEG C, the magnetic stirring apparatus of 300r/min soaks 2h, same to method, then soaks with deionized water, clean 3 times.
7, above-mentioned process thing is put into container, add deionized water and do not have the upper surface of porous support, then put into-80 DEG C of refrigerator freezing 4h.
8, taking out frozen thing, put in vacuum freeze drier ,-46 DEG C of dry 48h of refrigerator freezing, the 3D of the realized blood vessel transfer namely obtaining the compound rhBMP-2 of the present invention prints biodegradable stent.
The 3D of the realized blood vessel transfer of embodiment 7 compound rhBMP-2 prints the preparation of biodegradable stent
Step is as follows:
1, CT image is imported the three-dimensional imaging software such as Mimics or CAD, obtain the 3-D view of targeted bony tissue, with regular hexahedron or the filling of regular dodecahedron structural units, extend this image, obtain the porous connection three-dimensional digital model of personalization, average Kong Zhuwei 500 ��m, aperture are 400 ��m, porosity is 70%, and the diameter 5mm (determining according to Cranial defect position) of carriage center passage, the column of support 1/3rd detachably and again assembles.
2, Bioscaffolder2.1 (GeSiM is adopted, Germany) the Low-temperature Deposition Manufacturing system of 3D printer and Tsing-Hua University's research and development, porous, degradable support is printed for raw material with ��-TCP and PLGA, PLGA/ ��-TCP=4:1, according to the printing porous cylindrical support that designs a model, solid support can be formed after-80 DEG C of lyophilizing.
3, adopt emulsion-crosslinking method to prepare chitosan microball load rhBMP-2, form rhBMP-2/ chitosan microball. First 300mg chitosan is dissolved in 10ml formic acid solution, adds about 2.7mgrhBMP-2, be sufficiently stirred for. Be added dropwise in the liquid paraffin containing surfactant span80 again, 45 DEG C be sufficiently stirred for after add cross-linking agent vanillin, continue stirring 6-7h, precipitate washed, namely obtains rhBMP-2/ chitosan microball after lyophilization.
4, joining in deionized water by gelatin particle, at 37 DEG C, in the magnetic stirring apparatus of 300r/min, 2h is to thoroughly dissolving, gelatin final concentration of 5%; It is subsequently adding rhBMP-2/ chitosan microball Homogeneous phase mixing prepared by step (2).
5, mixed liquor step (4) prepared injects in the through porous support of three-dimensional prepared with syringe pressurization, and is immersed in mixed liquor, places 4 DEG C of refrigerator freezing 12h.
6, take out the gel piece after above-mentioned freezing, strike off gel unnecessary in porous scaffold surface and hollow region, add 0.1mol/L glycine solution, 37 DEG C, the magnetic stirring apparatus of 300r/min soaks 2h, same to method, then soaks with deionized water, clean 3 times.
7, above-mentioned process thing is put into container, add deionized water and do not have the upper surface of porous support, then put into-80 DEG C of refrigerator freezing 4h.
8, taking out frozen thing, put in vacuum freeze drier ,-46 DEG C of dry 48h of refrigerator freezing, the 3D of the realized blood vessel transfer namely obtaining the compound rhBMP-2 of the present invention prints biodegradable stent.
The 3D of the realized blood vessel transfer of embodiment 8 compound rhBMP-2 prints the preparation of biodegradable stent
Step is as follows:
1, CT image is imported the three-dimensional imaging software such as Mimics or CAD, obtain the 3-D view of targeted bony tissue, with regular hexahedron or the filling of regular dodecahedron structural units, extend this image, obtain the porous connection three-dimensional digital model of personalization, average Kong Zhuwei 500 ��m, aperture are 400 ��m, porosity is 70%, and the diameter 5mm (determining according to Cranial defect position) of carriage center passage, the column of support 1/3rd detachably and again assembles.
2, Bioscaffolder2.1 (GeSiM is adopted, Germany) the Low-temperature Deposition Manufacturing system of 3D printer and Tsing-Hua University's research and development, porous, degradable support is printed for raw material with ��-TCP and PLGA, PLGA/ ��-TCP=4:1, according to the printing porous cylindrical support that designs a model, solid support can be formed after-80 DEG C of lyophilizing.
3, adopt emulsion-crosslinking method to prepare chitosan microball load rhBMP-2, form rhBMP-2/ chitosan microball. First 300mg chitosan is dissolved in 10ml formic acid solution, adds about 2.7mgrhBMP-2, be sufficiently stirred for. Be added dropwise in the liquid paraffin containing surfactant span80 again, 45 DEG C be sufficiently stirred for after add cross-linking agent vanillin, continue stirring 6-7h, precipitate washed, namely obtains rhBMP-2/ chitosan microball after lyophilization.
4, joining in deionized water by gelatin particle, at 37 DEG C, in the magnetic stirring apparatus of 300r/min, 2h is to thoroughly dissolving, gelatin final concentration of 4%; It is subsequently adding rhBMP-2/ chitosan microball Homogeneous phase mixing prepared by step (2).
5, mixed liquor step (4) prepared injects in the through porous support of three-dimensional prepared with syringe pressurization, and is immersed in mixed liquor, places 4 DEG C of refrigerator freezing 12h.
6, take out the gel piece after above-mentioned freezing, strike off gel unnecessary in porous scaffold surface and hollow region, add 0.1mol/L glycine solution, 37 DEG C, the magnetic stirring apparatus of 300r/min soaks 2h, same to method, then soaks with deionized water, clean 3 times.
7, above-mentioned process thing is put into container, add deionized water and do not have the upper surface of porous support, then put into-80 DEG C of refrigerator freezing 4h.
8, taking out frozen thing, put in vacuum freeze drier ,-46 DEG C of dry 48h of refrigerator freezing, the 3D of the realized blood vessel transfer namely obtaining the compound rhBMP-2 of the present invention prints biodegradable stent.
Embodiment described above only have expressed the several embodiments of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention. It should be pointed out that, for the person of ordinary skill of the art, without departing from the inventive concept of the premise, it is also possible to making some deformation and improvement, these broadly fall into protection scope of the present invention. Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (9)
1. the 3D of the realized blood vessel transfer of a compound rhBMP-2 prints biodegradable stent, described biodegradable stent includes three-dimensional through porous support, is positioned at the three-dimensional micro rack within the through porous support of described three-dimensional and is positioned at described three-dimensional rhBMP-2 slow-released system composition within micro rack; Described three-dimensional micro rack is in three-dimensional through porous network structure; The middle part of the through porous support of described three-dimensional arranges the central passage of a up/down perforation; / 3rd columns controlling the through porous support of described three-dimensional of described central passage opening and closing are detachably and again to assemble.
2. biodegradable stent according to claim 1, it is characterised in that the diameter of the central passage of described up/down perforation is 4-8mm.
3. biodegradable stent according to claim 1, it is characterised in that the aperture of the through porous support of described three-dimensional is 200-600 ��m; Porosity is 60-80%.
4. biodegradable stent according to claim 1, it is characterised in that the aperture of described three-dimensional micro rack is 50-100 ��m.
5. biodegradable stent according to claim 1, it is characterised in that the through porous support of described three-dimensional is prepared from by PLGA and ��-TCP.
6. biodegradable stent according to claim 1, it is characterized in that, described rhBMP slow-released system is to be prepared from the slow-released carrier selected from following group by rhBMP: (1) tradition slow-released carrier: collagen, decalcified bone matrix, Fibrin Glue, bioactivity glass, tricalcium phosphate, biphasic calcium phosphate, calcium sulfate, calcium phosphate, hydroxyapatite, Corallium Japonicum Kishinouye, Gypsum Fibrosum, hyaluronic acid; (2) microsphere sustained-release carrier: polylactic acid, polyglycolic acid, gelatin, polysaccharide-based hydrogel, chitosan, Sargassum salt; (4) nano controlled-release carrier; (5) other: hyaluronic acid, cellulose, chondroitin sulfate, silkworm silk and agarose, polyvinylpyrrolidine; (6) composite slow release carrier.
7. biodegradable stent according to claim 1, it is characterised in that described slow-released carrier is chitosan.
8. the preparation method of the biodegradable stent according to any one of a claim 1-7, it is characterised in that described preparation method comprises the following steps:
(1) conventional tissue engineered porous scaffold preparation technology is utilized to prepare the through porous support of foregoing three-dimensional;
(2) rhBMP-2 slow-released system is prepared;
(3) rhBMP-2 slow-released system prepared by natural macromolecular material and/or bioceramic and step (2) is prepared into mixed liquor;
(4) being filled into by mixed liquor prepared by step (3) in the through porous support of three-dimensional prepared by step (1), the 3D of the realized blood vessel transfer of the Bone Morphogenetic Protein-2 of freeze-dried preparation cost invention prints biodegradable stent.
9. preparation method according to claim 8, it is characterised in that described preparation method comprises the following steps:
(1) CT image is imported the three-dimensional imaging software such as Mimics or CAD, obtain the 3-D view of targeted bony tissue, with regular hexahedron or the filling of regular dodecahedron structural units, extend this image, obtain the porous connection three-dimensional digital model of personalization, average Kong Zhuwei 100-1000 ��m, aperture are 200-600 ��m, porosity is 60%-80%, the diameter 4-8mm of carriage center passage, and the column of support 1/3rd detachably and again assembles;
(2) Bioscaffolder2.13D printer and the Low-temperature Deposition Manufacturing system of Tsing-Hua University's research and development are adopted, porous, degradable support is printed for raw material with ��-TCP and PLGA, PLGA/ ��-TCP=4:1, according to the printing porous cylindrical support that designs a model, the through porous support of three-dimensional of solid can be formed after-80 DEG C of lyophilizing;
(3) adopt emulsion-crosslinking method to prepare chitosan microball load rhBMP-2, form rhBMP-2/ chitosan microball;
(4) joining in deionized water by gelatin particle, at 37 DEG C, in the magnetic stirring apparatus of 300r/min, 2h is to thoroughly dissolving, the final concentration of 1.5-20% of gelatin; It is subsequently adding rhBMP-2/ chitosan microball Homogeneous phase mixing prepared by step (3);
(5) mixed liquor step (4) prepared injects in the through porous support of three-dimensional prepared with syringe pressurization, and is immersed in mixed liquor, places 4 DEG C of refrigerator freezings;
(6) take out the gel piece after above-mentioned freezing, strike off gel unnecessary in porous scaffold surface and hollow region, add 0.1mol/L glycine solution, soak, same to method, then soak with deionized water, clean;
(7) just above-mentioned process thing puts into container, adds deionized water and did not have the upper surface of porous support, then puts into-80 DEG C of refrigerator freezings;
(8) taking out frozen thing, put in vacuum freeze drier ,-46 DEG C of refrigerator freezings dry, and the 3D of the realized blood vessel transfer namely obtaining the Bone Morphogenetic Protein-2 of the present invention prints biodegradable stent.
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| CN112552035A (en) * | 2020-12-11 | 2021-03-26 | 湖北联结生物材料有限公司 | Inducible bioactive 3D printing ceramic and preparation method thereof |
| CN112704555A (en) * | 2021-01-26 | 2021-04-27 | 山东建筑大学 | Preparation method of degradable porous ulna middle-end fracture connector |
| CN113144285A (en) * | 2021-03-09 | 2021-07-23 | 东华大学 | Three-dimensional printing composite inorganic nanofiber support and preparation and application thereof |
| CN113368304A (en) * | 2021-06-17 | 2021-09-10 | 福建师范大学 | Method for preparing multifunctional sodium alginate scaffold embedded with drug-loaded microspheres by using in-situ emulsification-based 3D printing technology |
| CN113368304B (en) * | 2021-06-17 | 2022-02-15 | 福建师范大学 | Method for preparing multifunctional sodium alginate scaffold embedded with drug-loaded microspheres by using in-situ emulsification-based 3D printing technology |
| CN114259604A (en) * | 2021-12-17 | 2022-04-01 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method of 3D printing ordered vascularization promoting drug-loaded bone repair scaffold, product and application thereof |
| CN114533968A (en) * | 2022-01-12 | 2022-05-27 | 重庆医科大学 | Vascularizable stent and preparation method thereof |
| CN114848900A (en) * | 2022-04-02 | 2022-08-05 | 深圳大学总医院 | Artificial bone material and preparation method thereof |
| CN114870092A (en) * | 2022-05-20 | 2022-08-09 | 广州骊贝生物科技有限公司 | Bone substitute complex and preparation method and application thereof |
| CN114870092B (en) * | 2022-05-20 | 2023-08-22 | 广州骊贝生物科技有限公司 | Bone substitute complex, preparation method and application thereof |
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