CN103143065A - Tissue engineering scaffold with multi-growth-factor sequential release characteristic - Google Patents
Tissue engineering scaffold with multi-growth-factor sequential release characteristic Download PDFInfo
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- CN103143065A CN103143065A CN2013100877485A CN201310087748A CN103143065A CN 103143065 A CN103143065 A CN 103143065A CN 2013100877485 A CN2013100877485 A CN 2013100877485A CN 201310087748 A CN201310087748 A CN 201310087748A CN 103143065 A CN103143065 A CN 103143065A
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Abstract
The invention provides a tissue engineering scaffold with multi-growth-factor sequential release characteristic, and belongs to the technical field of dosage form variation and preparation method. In the tissue engineering scaffold, together with the characteristics of microspheres sustained release system and scaffold, PLLA/PEG (poly-lactic acid/polyethylene glycol) sustained release microspheres of growth factors such as BMP-2 (bone morphogenetic protein), VEGF (vascular endothelial growth factor), bFGF (basic fibroblast growth factor) are prepared respectively by the multiple emulsion method, so as to construct the tissue engineering scaffold with multi-growth-factor sequential release characteristic. The method is high in drug activity maintaining degree, low in organic solvent residue and easy to operate. The prepared microspheres are narrow in particle size distribution and have an excellent sustained release effect. The pore size distribution of the composite scaffold is 150-300mu m, the connectivity is excellent, the porosity is 76.84%, the compressive strength is 5.11MPa, and the accumulative release amount of 21 days is 60.6%. The scaffold prepared according to the invention has an application prospect in tissue engineering restoration.
Description
Technical field
The present invention is a kind of tissue engineering bracket with many somatomedin order release characteristics, belong to pharmaceutical dosage form change and preparation method thereof technical field, particularly utilize the method for supercritical fluid technology to prepare a kind of tissue engineering bracket with multiple somatomedin of order release characteristics, be expected to the Regeneration and Repair for osseous tissue.
Background technology
In the process of the formation of tissue engineered bone, growth and reparation, various somatomedin are most important to the regulation and control of local organization, cell, act on respectively not phase simultaneously, and have mutual coordinative role.The direct use of the soluble cell factor exists the half-life short, needs operation repeatedly to replenish and waits the application obstacle.Therefore, build a kind of controlled release system and be used for controllably carrying multiple somatomedin to bring into play its maximum synergistic function biology lastingly, have significant clinical value.Yet, at present usually take single microsphere or support as slow-released carrier, lacks a kind of multiple somatomedin take physiology reparation situation as pattern release vehicle system one after another.this project is based on different somatomedin coordinated regulation osteanagenesis repair mechanisms, in conjunction with microsphere and support slow-released system characteristics separately, adopt emulsifying-solvent evaporation method with bone morphogenetic protein (BMP-2), vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF) are embedded in biodegradable macromolecular material polylactic acid/Polyethylene Glycol (PLLA/PEG), be prepared into different year growth factor slow-release microspheres, recycling supercritical foaming technology is written into different microspheres in poly lactic-co-glycolic acid/hydroxyapatite (PLGA/HA) porous support, design a kind of growth factor release initial stage take VEGF and bFGF as main, middle and late stage is take BMP-2 as main tissue engineering bracket.We are intended to prepare a kind of multiple somatomedin controlled release system with lasting controlled order release characteristics, are applied to the tissue engineering bracket of bone defect repair.
Emulsifying-solvent evaporation method is a kind of preparation method of the most frequently used polymer microballoon, it be with medicine and polymer be dissolved in together certain can not with the miscible volatility solvent of water in, then by the effect of emulsifying agent, use high speed agitator, emulsify at a high speed device or ultraemulsifier, form emulsion or suspended dispersed liquid, through continuous stirring, filtration, drying, namely get medicine carrying microballoons.The factors such as composition that can be by changing polymer in preparation process, molecular weight are controlled the physicochemical properties of microsphere and the release rule of medicine.
Traditional preparation method of support is a lot, such as solution-cast/particle leaching method, situ aggregation method, foam impregnation method, sol-gel technique, thermic phase detachment technique etc., but there are many problems, as complicated operation, organic solvent residual, preparation process condition harshness is difficult to introduce somatomedin etc.And supercritical carbon dioxide (sc-CO
2) the foaming environmental protection, do not relate to high temperature and organic solvent in process, be conducive to adding of somatomedin, can be used for preparing porous support materials.Sc-CO
2Foaming is that polymers capable of swelling is inserted among specific mould, uses sc-CO
2Soak the polymer certain hour and make its swelling, until the CO in polymer
2Then the state that reaches capacity promptly is down to normal temperature and pressure.Because the thermodynamic phase of gas causes bubble nucleating and growth, form three-dimensional pore space structure.
Purpose of the present invention: provide a kind of emulsifying-solvent evaporation method that utilizes to prepare the growth factor slow-release microsphere take polylactic acid/Polyethylene Glycol (PLLA/PEG) as carrier material, and then utilize the supercritical carbon dioxide foaming technology take the method for poly lactic-co-glycolic acid/hydroxyapatite (PLGA/HA) the controlled order release of multiple somatomedin tissue engineering bracket as carrier material prepares.
Basic conception of the present invention: the growth factor slow-release system can not only limit to and discharges single somatomedin, and under the situation pattern, the ratio with the best discharges multiple somatomedin to the targeted cells that needs and should repair at a kind of similar physiology.Blood vessel class somatomedin and bone induce that the collocation of class somatomedin is compound may have important hope to the osteanagenesis reparation, but at present method commonly used is take the microsphere of various materials or support as slow-released carrier, lacks a kind of time dependence take the somatomedin effect and is basic multiple growth factor carrier system.Therefore, if microsphere and support are carried out compound, BMP-2, VEGF and bFGF are written into respectively microsphere and support, make three kinds of somatomedin reach different release rule, to satisfy time under the osteanagenesis physiological situation and the somatomedin needs on the space.
In order to prepare the degradable stephanoporate support, traditional preparation method complicated operation of support, the preparation process condition is harsh, relates to high temperature, organic solvent residual, is difficult to introduce somatomedin etc.Sc-CO
2The foaming environmental protection, the product organic solvent-free is residual, do not relate to high temperature in process, be conducive to adding of somatomedin, can be used for preparing porous support materials.
The structure of this heterogeneous growth factor slow-release system, repair different phase based on bone and need the different bioactive functions mechanism of multiple somatomedin Coordinated Play, the features of bound drug slow release and timbering material, utilize emulsifying-solvent evaporation method that BMP-2, VEGF and three kinds of key growth factors of bFGF are written into sustained-release micro-spheres separately, then adopt sc-CO
2Foaming technique combines sustained-release micro-spheres and forms heterogeneous carrier controlled release system as bone tissue engineering scaffold with porous material, can repair the initial stage with the master that is released to of VEGF and bFGF at bone, middle and late stage is with the master that is released to of BMP-2, be intended to discharge multiple somatomedin to the targeted cells that needs, the Regeneration and Repair of collaborative realization to osseous tissue in the ratio with the best under a kind of similar physiology reparation situation pattern.
Summary of the invention
The object of the present invention is to provide a kind of method that can discharge one after another multiple growth factor slow-release support in conjunction with the preparation of emulsifying-solvent evaporation method and supercritical fluid technology.
Purpose of the present invention mainly realizes by following technology path: adopt the W/O/W multi-emulsion method, PLLA and PEG are dissolved in organic solvent, pharmaceutical aqueous solution is dispersed in the w/o type emulsion that wherein forms water soluble drug, prepares the aqueous solution that contains stabilizing agent and make outside water.The w/o type emulsion that makes is distributed to outside aqueous phase forms W/O/W type emulsion under the condition that stirs.Obtain medicine carrying PLLA microsphere through evaporation, filtration, drying.Take the PEG of the PLLA of different molecular weight and different additions as carrier, embedding BMP-2, VEGF and bFGF, have the characteristic of different release dynamics to obtaining three kinds of somatomedin respectively.Recycling sc-CO
2The BMP-2-PLLA that the fluid foaming technique will prepare, VEGF-PLLA and bFGF-PLLA carried medicine sustained-release microsphere have the heterogeneous complex carrier system of certain mechanical strength according to the formation of design releasing dosage and PLGA/HA composite particles blend post-foaming.Sc-CO
2It is as follows that foaming technique prepares the compound rest process: the tetrafluoroethene mould is put into autoclave, the carbon dioxide in steel cylinder is cooling after, by high-pressure plunger pump pressurization, by heat exchanger constantly with CO
2Pump in autoclave, after meeting the requirements of pressure, holding temperature and pressure, after insulation reaches the specific time, sc-CO
2Immerse fully in the high polymer base material.Open rapidly valve venting, when temperature and pressure returned back to the normal temperature and pressure state, the opening high pressure still took out sample.
Purposes of the present invention: the present invention discharges the slow release stent of multi-medicament mainly for the preparation of controlled order, keep the medicine biological activity, improves drug bioavailability, reduces toxic and side effects, improves therapeutic effect.
Advantage of the present invention: this method preparation process is gentle, environmental protection, and toxicity is little, and is simple to operate, and prepared growth factor slow-release support possesses good physicochemical property and controlled order release characteristics.
Description of drawings
Fig. 1. BMP-2-PLLA medicine carrying microballoons morphology observation
Fig. 2 .VEGF-PLLA medicine carrying microballoons morphology observation
Fig. 3. bFGF-PLLA medicine carrying microballoons morphology observation
Fig. 4. BMP-2-PLLA, VEGF-PLLA and bFGF-PLLA medicine carrying microballoons release rule
Fig. 5. the form electron microscopic observation of compound rest
Fig. 6. the albumen slow release effect of trypsin-HA/PLGA support (a), trypsin-PLLA microsphere (b), trypsin-PLLA microsphere/HA/PLGA support (c)
The specific embodiment
Instantiation below in conjunction with the inventor provides is described in further detail the medicine order releasing bracket of inventing.But the present invention is not limited in the scope of following embodiment.
Example one preparation BMP-2-PLLA, VEGF-PLLA and bFGF-PLLA medicine carrying microballoons
(1) respectively BMP-2, VEGF and the bFGF of 10 μ g is dissolved in 250 uL PBS as interior water.
(2) the PLLA(molecular weight that takes 250 mg is 1～100,000) and Polyethylene Glycol (PEG, molecular weight is 400～10000), the mass ratio of PLLA and PEG is 1:2～2:1, is dissolved in the 5mL dichloromethane as oil phase (interior water and oil phase volume ratio are 1:20).
(3) interior water is slowly poured in oil phase, high-speed stirred 2 minutes forms colostrum (W/O).
(4) colostrum is slowly splashed into 10 mL, in the PVA of 1 %, high-speed stirred 5 minutes forms emulsion (WO/W).
(5) emulsion is slowly splashed into 250mL, in the PVA of 0.1 %, stirring at room 4 hours, 500 r/min are used for the volatilization organic solvent.
Centrifugal 10 minutes of (6) 4000 r/min collect microsphere, deionized water wash 3 times, and lyophilization is collected.
RhBMP-2-PLLA, VEGF-PLLA and the bFGF-PLLA medicine carrying microballoons of above process preparation are smooth, spherical, mean diameter is respectively 32.2 μ m, 4.8 μ m and 2.2 μ m, the drug loading of microsphere is 0.10%～0.14%, envelop rate is 57.9%～80.1%, the growth factor slow-release microsphere of different condition preparation has different release characteristics, and concrete outcome can be referring to accompanying drawing.
Example 2 preparations contain the HA/PLGA porous support of trypsin sustained-release micro-spheres
(1) with the PLGA(PLA:PLG=50:50 that buys, M
W=100,000Da) to grind with the ratio of 1:4 with the HA powder, milling time is 8 hours, then adds 10% trypsin sustained-release micro-spheres and the abundant mixing of powder.
(2) accurately weighing mixed-powder 0.125g to put into diameter be that the cylindrical die of 5mm is suppressed, pressure is 10MPa, and the press time is 1min, and obtaining diameter is 5mm, height is about the sequin of 3mm, puts into after taking-up among the tetrafluoroethene mould of laboratory customization.
(3) the tetrafluoroethene mould is put into autoclave, open the supercritical foaming device, refrigeration system is started working, and setting reaction temperature is 39 ℃, and pressure is 8Mpa, the opening high pressure plunger displacement pump, and constant water bath box and drum drying baker are to the reactor intensification of boosting.Regulating venting valve and temperature detect switch (TDS) makes the temperature of reactor, constant pressure be setting value.After reaction 8h, supercritical CO
2Be immersed in polymeric matrix fully.Open rapidly valve venting, when temperature and pressure returned back to the normal temperature and pressure state, the opening high pressure still took out sample.
The compound rest pore-size distribution of above process preparation is at 150 ~ 300 μ m, and the connectedness in hole is better, and porosity is 76.84%, and comprcssive strength is 5.11MPa, and the trypsin sustained-release micro-spheres is evenly distributed on support.Trypsin-HA/PLGA support, the cumulative release amount of trypsin 48h reaches more than 85%; Trypsin-PLLA microsphere, trypsin 48h accumulative total release rate is 65.2%; Trypsin-PLLA microsphere/HA/PLGA support, trypsin 21d Cumulative release amount are only 60.6%.
Claims (6)
1. one kind in conjunction with the prepared tissue engineering bracket with multiple somatomedin order release characteristics of the method for emulsifying-solvent evaporates technology and supercritical carbon dioxide foaming technology, it is characterized in that, adopt emulsifying-solvent evaporation method that multiple somatomedin is embedded in respectively in biodegradable macromolecular material, be prepared into different year growth factor slow-release microspheres, recycling supercritical foaming technology is written into different microspheres in porous support, builds the tissue engineering bracket with the controlled order release characteristics of multiple somatomedin.
2. a kind of method of utilizing emulsifying-solvent evaporation method to prepare multiple growth factor slow-release microsphere described according to claim 1, it is characterized in that, the somatomedin that is written into is respectively bone morphogenetic protein (BMP-2), vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF).
3. a kind of method of utilizing emulsifying-solvent evaporation method to prepare multiple growth factor slow-release microsphere described according to claim 1, it is characterized in that, pharmaceutical carrier is biodegradable polylactic acid (PLLA) and Polyethylene Glycol (PEG), wherein the PLLA molecular weight is 10,000～100,000, the PEG molecular weight is that the mass ratio of 400～10000, PLLA and PEG is 1:2～2:1.
4. a kind of method of utilizing emulsifying-solvent evaporation method to prepare multiple growth factor slow-release microsphere described according to claim 1, it is characterized in that, prepared growth factor slow-release microsphere presents smooth spherical, bone morphogenetic protein, the sustained-release micro-spheres mean diameter of three kinds of somatomedin such as vascular endothelial cell growth factor and basic fibroblast growth factor is respectively 32.2 μ m, 4.8 μ m and 2.2 μ m, the drug loading of microsphere is 0.10%～0.14%, envelop rate is 57.9%～80.1%, according to different PLLA molecular weight and different PLLA/PEG proportioning, obtain respectively having the sustained-release micro-spheres of different release characteristics.
5. a kind of supercritical carbon dioxide (sc-CO that utilizes described according to claim 1
2) foaming technique prepares the method for somatomedin composite tissue engineering support, it is characterized in that system's supercritical carbon dioxide pressure is 8MPa, temperature is 39 ℃, saturation time 8h.
6. according to the employing sc-CO described in right 1
2Foaming technique prepares somatomedin composite tissue engineering support, it is characterized in that, the backing substrate material is biodegradable poly lactic-co-glycolic acid (PLGA, molecular weight 50,000～150,000), the compound rest pore-size distribution is at 150 ~ 300 μ m, the connectedness in hole better, porosity is 76.84%, comprcssive strength is 5.11MPa, 21 days Cumulative release amounts of medicine are only 60.6%, the growth factor release initial stage, middle and late stage was take bone morphogenetic protein as main take vascular endothelial cell growth factor and basic fibroblast growth factor as main.
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| CN106902397A (en) * | 2017-01-06 | 2017-06-30 | 南京市六合区人民医院 | BMP 2/PLLA/nHA sustained-release micro-spheres and preparation method thereof |
| CN107019642A (en) * | 2017-03-31 | 2017-08-08 | 华东理工大学 | A kind of sustained-release administration type embolism and preparation method thereof |
| CN107412859A (en) * | 2017-04-26 | 2017-12-01 | 温州医科大学附属口腔医院 | A kind of preparation method of the tissue engineering bracket material of dual-gene timing sustained release |
| CN108159490A (en) * | 2018-01-16 | 2018-06-15 | 重庆医科大学 | It is a kind of to promote the bone tissue engineering scaffold that blood vessel quickly generates |
| CN108939136A (en) * | 2018-08-20 | 2018-12-07 | 重庆医科大学附属永川医院 | A kind of dressing and preparation method thereof for nose filling hemostasis |
| CN109833509A (en) * | 2019-01-18 | 2019-06-04 | 太阳雨林（厦门）生物医药有限公司 | A kind of multiple sustained release blood vessel embolism load drug composition |
| CN112812355A (en) * | 2020-12-31 | 2021-05-18 | 厦门天生爱科技有限公司 | Functional polymer foaming material with slow-release volatile Chinese herbal medicine effective components, preparation method and application |
| CN115414533A (en) * | 2022-09-20 | 2022-12-02 | 中国人民解放军总医院第一医学中心 | Tissue engineering scaffold for simulating physiological structure of bladder wall and preparation method thereof |
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| CN108939136A (en) * | 2018-08-20 | 2018-12-07 | 重庆医科大学附属永川医院 | A kind of dressing and preparation method thereof for nose filling hemostasis |
| CN109833509A (en) * | 2019-01-18 | 2019-06-04 | 太阳雨林（厦门）生物医药有限公司 | A kind of multiple sustained release blood vessel embolism load drug composition |
| CN109833509B (en) * | 2019-01-18 | 2021-10-15 | 太阳雨林（厦门）生物医药有限公司 | Multiple sustained-release vascular embolism drug-loading composition |
| CN112812355A (en) * | 2020-12-31 | 2021-05-18 | 厦门天生爱科技有限公司 | Functional polymer foaming material with slow-release volatile Chinese herbal medicine effective components, preparation method and application |
| CN115414533A (en) * | 2022-09-20 | 2022-12-02 | 中国人民解放军总医院第一医学中心 | Tissue engineering scaffold for simulating physiological structure of bladder wall and preparation method thereof |
| CN115414533B (en) * | 2022-09-20 | 2024-02-23 | 中国人民解放军总医院第一医学中心 | Tissue engineering scaffold simulating physiological structure of bladder wall and preparation method thereof |
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