CN106902397A - BMP 2/PLLA/nHA sustained-release micro-spheres and preparation method thereof - Google Patents
BMP 2/PLLA/nHA sustained-release micro-spheres and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L31/148—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- 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
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- 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
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- 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
Abstract
The invention discloses a kind of BMP 2/PLLA/nHA sustained-release micro-spheres and preparation method thereof, preparation method is comprised the following steps：(1) BMP 2 is dissolved in polyvinyl alcohol water solution, and adds nanometer hydroxyapatite, form the polyvinyl alcohol water solution of BMP 2/nHA；(2) polyethylene levorotatory lactide is dissolved in dichloromethane, and adds oil phase emulsifier, obtain PLLA dichloromethane emulsions；(3) polyvinyl alcohol water solution of BMP 2/nHA and PLLA dichloromethane emulsion are mixed, ultrasonic emulsification adds polyvinyl alcohol water solution, and magnetic agitation obtains double emulsion；(4) double emulsion is carried out into magnetic agitation, makes organic solvent evaporation, obtain aqueous microballoon, suction filtration obtains sustained-release micro-spheres.The BMP 2/PLLA/nHA sustained-release micro-spheres of gained have the advantages that good biocompatibility, absorbability are good, mechanical strength is high, degradability good, good stability.
Description
Technical field
The present invention relates to the preparing technical field of bone renovating material, more particularly to a kind of BMP-2/PLLA/nHA sustained-release micro-spheres
And preparation method thereof.
Background technology
Anterior cruciate ligament of knee joint (anterior cruciate ligament, ACL) be the important static(al) of knee joint and
One of dynamic property rock-steady structure, can prevent shin bone reach, hyperextension and excessively rotation, prevent the correlation after knee joint unstability concurrent
Disease.It is common disease, frequently-occurring disease that ACL is damaged, the numerous teenagers of major concern, is one of most common disease in population of adolescent.
There is instability of knee in ACL after damaging, increase joint other structures and damage probability, accelerate the regression of meniscus and articular cartilage,
Cause serious chronic ache and joint function disturbance, have a strong impact on daily routines and the quality of life of patient, suffer to teenager
Person brings huge pain and mental burden.ACL Reconstructions are fixed in bone road using transplanting tendon, substitute it is normal before hand over
The function of ligament is pitched, is that treatment ACL damages most efficient method.Between the healing of transplanting tendon and osseous tunnel inwall is tendon-bone interface
Fibr tissue forms connection, new bone formation, bone to the process for being grown into tendon, partial mold is transformed.BMP-2 is to have now been found that
It is unique a kind of can be as the protein factor of the adequate condition of induction bon e formation, i.e., under the condition that only independent BMP-2 is present
The formation of cartilage and bone tissue is can induce, and is all played an important role in each stage of skeletonization.In addition, BMP-2 can be bright
The isolated pluripotent stem cell from marrow of aobvious induction synthesizes the protein such as BGP to cartilage cell, bone cell differentiation,
Generation entochondrostosis, osteocyte is formed, and bone mineralization forms new bone.But simple BMP-2 spreads too fast, also easy quilt in vivo
Protein acid is decomposed, and easily occurs to be lost in, degrade and absorb, thus more target cells can not be acted within effective time, therefore
It is mainly used in basis and clinical research with other carrier material Application of composite in the reparation of tissue.Microballoon (microsphere)
Refer to that medicine dissolves or be dispersed in the microscopic, spherical entity formed in the matrix of macromolecular material, belong to matrix type skeleton micro-
Grain.Because of the slow release of insoluble drug release in its targeting and particulate to certain organs and tissue, have become and delay controlled release in recent years
The focus of dosage form research.But in existing BMP-2 sustained-release micro-spheres system, majority uses artificial synthesized lipophilic polymeric poly
Thing material as BMP-2 slow-released carrier, its poor biocompatibility, the shortcomings of cell absorption affinity is weaker, mechanical strength is not enough, from
And causing existing BMP-2 sustained-release micro-spheres system absorptance low, insoluble drug release is unstable, ultimately results in macromolecular material/BMP-2
Slow-released system influences Bone Defect Repari during knitting.
The content of the invention
The technical problem to be solved in the present invention is to overcome the deficiencies in the prior art, there is provided a kind of good biocompatibility, absorption
Good, mechanical strength is high, degradability is good for property, good stability BMP-2/PLLA/nHA sustained-release micro-spheres and preparation method thereof.
In order to solve the above technical problems, the present invention uses following technical scheme：
A kind of preparation method of BMP-2/PLLA/nHA sustained-release micro-spheres, comprises the following steps：
(1) BMP-2 is dissolved in polyvinyl alcohol water solution, and adds nanometer hydroxyapatite, form the poly- of BMP-2/nHA
Vinyl alcohol aqueous solution；
(2) polyethylene levorotatory lactide is dissolved in dichloromethane, and adds oil phase emulsifier, obtain PLLA- dichloromethanes
Alkane emulsion；
(3) by the PLLA- dichloromethanes obtained by the polyvinyl alcohol water solution of the BMP-2/nHA obtained by step (1) and step (2)
Alkane emulsion mixes, and ultrasonic emulsification obtains colostric fluid；Polyvinyl alcohol water solution is added, magnetic agitation obtains double emulsion；
(4) double emulsion obtained by step (3) is carried out into magnetic agitation, makes organic solvent evaporation, obtain aqueous microballoon, by institute
Obtaining aqueous microballoon carries out suction filtration, obtains BMP-2/PLLA/nHA sustained-release micro-spheres.
The preparation method of above-mentioned BMP-2/PLLA/nHA sustained-release micro-spheres, it is preferred that the BMP-2, nano-hydroxy-apatite
Stone is=10~20: 10~20: 150~250 with the mass ratio of polyethylene levorotatory lactide.
The preparation method of above-mentioned BMP-2/PLLA/nHA sustained-release micro-spheres, it is preferred that in the step (2), the oil phase
Emulsifying agent is oil phase emulsifier SPAN-80.
The preparation method of above-mentioned BMP-2/PLLA/nHA sustained-release micro-spheres, it is preferred that in the step (3), magnetic agitation
Rotating speed be 750r/min~850r/min, the time be 5min~10min.
The preparation method of above-mentioned BMP-2/PLLA/nHA sustained-release micro-spheres, it is preferred that in the step (4), magnetic agitation
Rotating speed be 350r/min~450r/min, the time be 3.5h~4h.
The preparation method of above-mentioned BMP-2/PLLA/nHA sustained-release micro-spheres, it is preferred that in the step (4), the suction filtration
The filter membrane for using is for miillpore filter that aperture is 0.4 μm~0.5 μm.
Used as a total inventive concept, the present invention also provides a kind of BMP-2/PLLA/nHA sustained-release micro-spheres, using above-mentioned
Method prepare.
Compared with prior art, the advantage of the invention is that：
1st, BMP-2 is passed through absorption process and nanometer hydroxyapatite (nano-Hydroxyapatite, abbreviation by the present invention
NHA) carrier combine and use multi-emulsion method composite polyethylene levorotatory lactide (Poly-L-lactide, PLLA) be prepared into sustained release it is micro-
Ball, PLLA is plant origin, and entirely without toxic action, slow release BMP-2/ hydroxyapatites are micro- during gradually degrading
Grain, and it is finally decomposed to water and carbon dioxide；With good degradability, absorbability, mechanical strength and biological safety,
The microsphere sustained-release system that PLLA is combined with nanometer hydroxyapatite, can increase substantially the encapsulating effect of medicine and protein, prolong
The release time of medicine long, the degradation speed of material, good stability can be adjusted by controlling component content.By nHA with
PLLA is combined, and on the one hand can make to greatly improve the encapsulating effect of sustained-release micro-spheres, the slow-release time of extension medicine, is reduced as far as possible
Burst release is unstable with protein, greatly improves the utilization rate of microglobulin matter, it is to avoid a large amount of protein are dashed forward
The too high phenomenon of the local acid concentration of generation is released, so as to avoid influenceing the generation of bone tissue.On the one hand the acid of PLA can be made
Property catabolite can be buffered by HA, while the osteoconductive of HA can provide good osteocyte adhesion growing environment, compound
Loose structure is then cell growth, regeneration and adhesion provide condition, meets the biological requirement of bone tissue engineer.Slow
BMP-2/ nanometer hydroxyapatite microballoons are sustained during degraded, certain BMP-2 concentration is maintained in tendon-bone interface, sustained release
BMP-2 can promote tendon bone intersection Derived from Mesenchymal Stem Cells, and can promote the cartilaginous tissue of new life to bone tissue knot
Structure is reinvented, and ultimately forms natural fabric, so as to reappear original tendon-bone interface biological function.To can be sustained by special process micro-
Ball be combined with each other and is made expansion bolt, and prepared BMP-2 is sustained absorbable expansion bolt just can be with the auxiliary of arthroscope
Clinical manipulation is carried out, it is convenient succinct.
Brief description of the drawings
Fig. 1 is the SEM figures (amplifying 1000 times) of BMP-2/PLLA/nHA sustained-release micro-spheres prepared by the embodiment of the present invention 1.
Fig. 2 is the drug release patterns in vitro of BMP-2/PLLA/nHA sustained-release micro-spheres prepared by the embodiment of the present invention 1.
Specific embodiment
Below in conjunction with Figure of description and specific preferred embodiment, the invention will be further described, and following examples are retouched
Specific embodiments of the invention is stated, so that the present invention is further illustrated, these embodiments are explanation without table
Show all of possibility of the invention, the material being not limited only in these embodiments of the invention, reaction condition or parameter.Appoint
Where association area experienced person, this can be realized using other materials or reaction condition according to the principle of this patent
The described biotin-avidin labelling technique combination immunochromatography technique of invention prepares stigmata analyte detection card.These are simultaneously
The basic conception of present invention description, therefore these change or different scopes that all should be covered in the present invention are not departed from
It is interior.
Embodiment 1：
(1) BMP-2 of 15mg is dissolved in polyvinyl alcohol (PVA) aqueous solution, and adds 15mg nanometer hydroxyapatites, shape
Into the polyvinyl alcohol water solution of BMP-2/nHA；
(2) 200mg polyethylene levorotatory lactides are dissolved in dichloromethane, and add oil phase emulsifier SPAN-80, obtained
PLLA- dichloromethane emulsions；
(3) by the PLLA- dichloromethanes obtained by the polyvinyl alcohol water solution of the BMP-2/nHA obtained by step (1) and step (2)
Alkane emulsion mixes, and ultrasonic emulsification obtains colostric fluid；Polyvinyl alcohol water solution, magnetic agitation are added, rotating speed is 800r/min, when
Between be 10min, obtain double emulsion；
(4) double emulsion obtained by step (3) is carried out into magnetic agitation, rotating speed is 400r/min, and the time is 4h, is made organic molten
Agent is evaporated, and obtains aqueous microballoon, uses the aperture to carry out suction filtration for 0.45 μm of miillpore filter the aqueous microballoon of gained, obtains BMP-
2/PLLA/nHA sustained-release micro-spheres.
Fig. 1 is the SEM figures of BMP-2/PLLA/nHA sustained-release micro-spheres manufactured in the present embodiment, it is seen that microballoon form is regular
It is even, it is approximate circle, without adhesion.
Sustained-release micro-spheres are be combined with each other by technique are made expansion bolt, the environment similar to articular cavity is prepared in vitro,
It is slow after expansion bolt is fixed in the environment to degrade and be sustained BMP-2/ nanometer hydroxyapatite microballoons.Determined by Shu Jiafa
BMP-2 sustained concentrations.Shu Jiafa measuring principles are using absorbance change of the spectrophotometric determination solution under certain wavelength
To determine this reaction.F.T.P.BMP-2 units are defined first, and it makes equivalent to per minute at 450nm under prescribed conditions
BMP-2 amounts required during absorbance reduction by 0.001.In practical operation, using the active as measure of original natural activity BMP-2
Benchmark, applies flexibly natural activity BMP-2 correction F.T.P.BMP-2 units, so as to return out the drop of absorbance in measurement BMP-2 every time
Low value.The buffer system for using is Na2HPO4-NaH2PO4PBS.Substrate solution uses PBS
The BMP-2 solution of dissolving, with PBS as reference, regulation substrate solution absorbance is used after 1.30.Due to
BMP-2 itself can be decomposed, and the substrate solution should be used in a hour upon configuration.In test process, phosphoric acid is typically used
BMP-2 is diluted to the change that 0.01mg/mL measures absorbance by salt buffer solution, ensures to change 0.01 per 15s absorbances as far as possible
~0.04.2.5mL substrate solutions are instilled into a 1cm cuvette, plus 0.5mL enzyme solutions with liquid getting device, both solution are filled
Divide mixing, it is reference mensuration absorbance to sentence phosphate buffer in 450nm with spectrophotometer.In about 3min every
15s reads an absorbance.BMP-2 activity computing formula are as follows：
In formula：
Ew --- the weight containing enzyme in enzyme solutions used by per 0.5mL；
0.001 --- a unit it is per minute it is interior make absorbance decline 0.001；
Δ E450 --- the change of absorbance per minute at 450nm；
Every crowd of BMP-2 uses certain density BMP-2 standard liquids as BMP-2 in measure benchmark, then determination sample
Enzymatic activity, contrast obtain BMP-2 concentration in sample.Finally calculate the release rate of BMP-2.
Fig. 2 is that BMP-2/PLLA/nHA sustained-release microspheres of the invention prepare the song of the vitro drug release after expansion bolt
Line, as seen from the figure, in microballoon in the release rate 24h of BMP-2 release rate more than 15%, 7d more than 35%, this mainly due to
Caused by the BMP-2 dissolutions of microsphere surface, it is prominent release after enter slow acquisition time, about 90% BMP-2 is measured in being released in 43d
Entirely, the release behavior in this period is that the slow degraded of PLLA materials and drug diffusion cause.This absolutely proves the BMP-2/
PLLA/nHA sustained-release micro-spheres can more smoothly discharge BMP-2, be lived again with bone more consistent with the knitting cycle.
The above is only the preferred embodiment of the present invention, and protection scope of the present invention is not limited merely to above-mentioned implementation
Example.All technical schemes belonged under thinking of the present invention belong to protection scope of the present invention.It is noted that for the art
Those of ordinary skill for, improvements and modifications under the premise without departing from the principles of the invention, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (7)
1. a kind of preparation method of BMP-2/PLLA/nHA sustained-release micro-spheres, comprises the following steps：
(1) BMP-2 is dissolved in polyvinyl alcohol water solution, and adds nanometer hydroxyapatite, form the polyethylene of BMP-2/nHA
Alcohol solution；
(2) polyethylene levorotatory lactide is dissolved in dichloromethane, and adds oil phase emulsifier, obtain PLLA- dichloromethane breast
Liquid；
(3) by the PLLA- dichloromethane breast obtained by the polyvinyl alcohol water solution of the BMP-2/nHA obtained by step (1) and step (2)
Liquid mixes, and ultrasonic emulsification obtains colostric fluid；Polyvinyl alcohol water solution is added, magnetic agitation obtains double emulsion；
(4) double emulsion obtained by step (3) is carried out into magnetic agitation, makes organic solvent evaporation, obtain aqueous microballoon, gained is contained
Water microballoon carries out suction filtration, obtains BMP-2/PLLA/nHA sustained-release micro-spheres.
2. the preparation method of BMP-2/PLLA/nHA sustained-release micro-spheres according to claim 1, it is characterised in that the BMP-
2nd, the mass ratio of nanometer hydroxyapatite and polyethylene levorotatory lactide is=10~20: 10~20: 150~250.
3. the preparation method of BMP-2/PLLA/nHA sustained-release micro-spheres according to claim 1, it is characterised in that the step
(2) in, the oil phase emulsifier is oil phase emulsifier SPAN-80.
4. the preparation method of BMP-2/PLLA/nHA sustained-release micro-spheres according to claim 1, it is characterised in that the step
(3) in, the rotating speed of magnetic agitation is 750r/min~850r/min, and the time is 5min~10min.
5. the preparation method of BMP-2/PLLA/nHA sustained-release micro-spheres according to claim 1, it is characterised in that the step
(4) in, the rotating speed of magnetic agitation is 350r/min~450r/min, and the time is 3.5h~4h.
6. the preparation method of BMP-2/PLLA/nHA sustained-release micro-spheres according to claim 1, it is characterised in that the step
(4) in, the filter membrane that the suction filtration is used is for miillpore filter that aperture is 0.4 μm~0.5 μm.
7. a kind of BMP-2/PLLA/nHA sustained-release micro-spheres, it is characterised in that using the method described in any one of claim 1~6
Prepare.
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| CN201710009319.4A CN106902397A (en) | 2017-01-06 | 2017-01-06 | BMP 2/PLLA/nHA sustained-release micro-spheres and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107485434A (en) * | 2017-08-18 | 2017-12-19 | 南京市六合区人民医院 | A kind of spinal vertebral booster and its manufacture method |
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| CN101461786A (en) * | 2009-01-08 | 2009-06-24 | 上海交通大学 | PLA/PLGA shell-core microballoons prepared by oil in water-solid in oil method, and preparation method thereof |
| CN101579539A (en) * | 2009-06-18 | 2009-11-18 | 重庆文理学院 | Preparation method of cohesive composite microsphere porous scaffolds |
| CN103143065A (en) * | 2013-03-19 | 2013-06-12 | 四川大学 | Tissue engineering scaffold with multi-growth-factor sequential release characteristic |
| CN103599074A (en) * | 2013-11-26 | 2014-02-26 | 重庆医药工业研究院有限责任公司 | Iloperidone sustained release microsphere and preparation method thereof |
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| CN107485434A (en) * | 2017-08-18 | 2017-12-19 | 南京市六合区人民医院 | A kind of spinal vertebral booster and its manufacture method |
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