CN105013005B - A kind of complex microsphere - Google Patents
A kind of complex microsphere Download PDFInfo
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- CN105013005B CN105013005B CN201510514803.3A CN201510514803A CN105013005B CN 105013005 B CN105013005 B CN 105013005B CN 201510514803 A CN201510514803 A CN 201510514803A CN 105013005 B CN105013005 B CN 105013005B
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Abstract
The invention discloses a kind of complex microsphere, including big ball, bead, the bead is loaded in the surface of big ball, and formation is similar to Raspberry-like structure.Used big ball, the surface of bead are loose structure, and two kinds of spheroids can carry two kinds of different medicines simultaneously, and big ball surface mainly carries medicine by suction-operated, and release is very fast；Bead carries medicine by emulsifying to wrap up, and release is slower.The big ball is loaded with anti-inflammatory medicaments, and the bead is loaded with the growth factor of angiogenic growth factor or stem cell Osteoblast Differentiation.It can be played by the different rate of release of two kinds of spheroid medicines while discharge the purpose of two kinds of medicines.
Description
Technical field
The present invention relates to bioceramic material technical field, more specifically, is related to a kind of complex microsphere.
Background technology
Large segmental bone defect caused by the reasons such as wound, tumour and infection is the problem that orthopaedics faces.Fast development in recent years
Bone tissue engineer and regenerative medicine be the bright outlook that brings of bone defect healing first meeting clue.The research of this area is more at present
Focus on the improvement of sclerotin alternative materials, the selection of good seed cell and exploitation of corresponding complex technique etc., but from bone
The mechanism of wound healing is set out, caused host response after being implanted by analysis of material, so as to targetedly build energy
The material of cell Osteoblast Differentiation is stimulated, it is less as the research of point of penetration using it.Bone renovating material is inquired into from knitting mechanism
Prepare and be applied to constructing for tissue engineered bone, it is possible to bring new thinking for the treatment of Cranial defect.
After implantation material enters in vivo as foreign matter, the inflammatory reaction of tissue can be caused first, and inflammatory reaction is persistently deposited
The time of knitting can extended.With the degraded of material and the regeneration of bone tissue, blood vessel can gradually form in cambium, energy
Enough the material of vascularization is promoted also to play good facilitation to osteanagenesis.Surrounding materials meeting concentrating portions are free to be done
Cell, if the medicine that material carries can stimulate stem cell Osteoblast Differentiation, it equally can also promote the formation of freshman bone tissue, and then
Accelerate bone wound healing.
Therefore, controlled release anti-inflammatory medicaments and angiogenic growth factor or bone on the material that can promote into osteanagenesis
Growth factor will be to there is important meaning into osteanagenesis.
The content of the invention
It is an object of the invention to overcome the deficiencies of the prior art and provide a kind of complex microsphere, on the big ball of complex microsphere
Be loaded with anti-inflammatory medicaments, bead is loaded with angiogenic growth factor or bone growth factor, can effectively facilitate vascularization and
Bone tissue regeneration, shorten the time of knitting.
The object of the present invention is achieved like this：
A kind of complex microsphere, including big ball made of bioceramic, bead made of high polymer material, the bead are loaded in
The surface of big ball, big ball, the surface of bead are loose structure, and the big ball is loaded with anti-inflammatory medicaments, and the bead is uploaded
There are angiogenic growth factor or bone growth factor.
In order that anti-inflammatory, the effect of angiogenic growth are more preferable, it is preferable that the anti-inflammatory medicaments are DEX, the rush blood
Pipe growth factor is VEGF.
In order that there is suitable drug concentration in body, anti-inflammatory effectively is carried out to body, promotes blood vessel to recover, preferably
Ground, the drug concentration of the DEX is 5-15mgmL-1；The drug concentration of the VEGF is 50-200ngmL-1。
In order that big ball can adsorb more anti-inflammatory medicaments, and preferably play the work of tissue engineering bracket material
With, it is preferable that the big ball is the hollow ball with open-celled structure.
In order to realize suitable release amount of medicine and release time, it is preferable that a diameter of 400-600 μ of the big ball
M, a diameter of 20-40 μm of the bead.
It is further preferred that a diameter of 500 μm of the big ball, a diameter of 30 μm of the bead.
Preferably, the material of the big ball is used in calcium silicates, hydroxyapatite, tricalcium phosphate, and hydroxyapatite/
The one of which of sour DFP biphase ceramics.Calcium silicates, hydroxyapatite, calcium phosphate ceramics and hydroxyapatite/acid acid three
Calcium biphase ceramics have good osteoconductive in itself, after it is degraded the composition such as caused silicon, calcium, phosphorus can stimulate stem cell to
Gegenbaur's cell converts.Therefore, by the calcium silicates with open-celled structure, hydroxyapatite, calcium phosphate ceramics, hydroxyapatite/
Sour DFP biphase ceramics tiny balloon can also play a part of tissue engineering bracket material as medicine controlled release carrier.
Preferably, the material of the bead uses PLGA.PLGA is polymerize at random by two kinds of monomer-lactic acid and hydroxyacetic acid
Form, be a kind of degradable functional polymer organic compound, there is good biocompatibility, nontoxic, good encystation
With the performance of film forming, it is widely used in pharmacy, medical engineering material and modernization industry field.In the U.S., PLGA passes through FDA
Certification, formally included as pharmaceutic adjuvant into American Pharmacopeia.
By adopting the above-described technical solution, the present invention has the advantages that：
By the big ball medicine different from bead combination load, in the DEX of big ball surface controlled release anti-inflammatory, can suppress to be implanted into
During inflammatory reaction, by grafting big ball surface bead controlled release promote role of Vasculogenesis VEGF.Big ball release DEX
Speed is very fast, can quickly play a part of anti-inflammatory early stage repairing；And PLGA degradeds are slower, the later stage constantly discharges VEGF,
The generation of new vessels, the dual controlled release of two kinds of medicines can be promoted, big ball can play the work of bone tissue engineering stent material simultaneously
With will collectively promote bone tissue regeneration, new thinking provided for large segmental bone defect reparation.
The complex microsphere of the present invention has the following advantages that relative to prior art：
1. as the application method of common micro-ball, use is very convenient；
2. big ball can play the material of tissue engineering bracket while as drug release carrier；
3. by the dual controlled release of two kinds of medicines, normal blood concentration can be maintained, does not cause drug accumulation to be poisoned, aligns
Normal cell, the toxic side effect of tissue are small；
4. blood concentration is stable, curative effect, safety quick is improved.
Brief description of the drawings
Fig. 1 is the complex microsphere SEM pictures of the present invention.
Embodiment
It is a kind of complex microsphere referring to Fig. 1, including big ball made of bioceramic, bead made of high polymer material, institute
The material for stating big ball is preferably in calcium silicates, hydroxyapatite, tricalcium phosphate, the sour DFP biphase ceramics of hydroxyapatite/acid
One of which, the material of the bead is preferably Poly(D,L-lactide-co-glycolide (poly (lactic-co-glycolic
Acid), PLGA).A diameter of 400-600 μm of the big ball, preferably 500 μm, it is a diameter of 20-40 μm of the bead, excellent
Elect 30 μm as.The bead is loaded in the surface of big ball, and formation is similar to Raspberry-like structure.The big ball is hollow ball, big ball, bead
Surface be loose structure, the big ball is loaded with anti-inflammatory medicaments, preferably dexamethasone (Dexamethasone,
DEX), the drug concentration of the DEX is 5-15mgmL-1.The bead is loaded with angiogenic growth factor, preferably intravascular
Skin growth factor (Vascular endothelial growth factor, VEGF), the drug concentration of the VEGF is 50-
200ng·mL-1。
The structure of big balloon borne bead can discharge two kinds of medicines simultaneously, with reference to ceramic microsphere as tissue engineering bracket, profit
With its good biocompatibility, can play a part of promoting bone tissue regeneration jointly.Ceramic microsphere and polymer microsphere
The effectively above-mentioned performance of the complex microsphere of the big balloon borne bead of assembling structure, the complex microsphere of big balloon borne bead provided by the invention
Cranial defect packing material can be used as, the ability of bone wound and defect healing can be significantly increased, be that a kind of new bone is repaiied
Multiple material.
The preparation method of complex microsphere is as follows：
Step 1) prepares big ball, prepares bead by double emulsion method, big ball carries anti-inflammatory medicaments by adsorption, small
Ball is wrapped up by double emulsions and carries angiogenic growth factor；Then bead surface is used into PEI
(Polyetherimide, PEI) is modified, and PEI concentration is 0.01-0.5%, and bead is stirred into 7-17 hours in PEI solution.
For step 2) by modified bead and big ball Hybrid assembling, the time that bead mixes with big ball is 2-6 hours, is produced
To the complex microsphere of big balloon borne bead.
Embodiment one
The present embodiment takes following technical scheme：Preparing adsorption has DEX calcium silicates tiny balloon as compound micro-
The big ball of ball.Weigh 5-15mg and be loaded with bead of the VEGF porous PLGA microballoons as complex microsphere, and add 5ml 0.01-
0.5%PEI solution, 4h is vibrated on the shaking table that speed is 120rpm, is well mixed, makes PLGA microsphere surface uniform adsorptions PEI.
Then mixture is centrifuged with secondary water, control centrifugal speed 7000rpm, centrifugation time 10min, is centrifuged repeatedly 3 times, removes not
The PEI firmly adsorbed.The PLGA microballoons of washes clean are moved into centrifuge tube, add about 1ml secondary waters, 50-120mg is added and inhales
Calcium silicates tiny balloon with DEX, is subsequently placed on shaking table and vibrates 4h, be freeze-dried after centrifugation, you can be grafted onto PLGA
Calcium silicates microsphere surface.The multistage composite microballoon of the big balloon borne bead prepared can slowly discharge DEX and the promotion of anti-inflammatory
The VEGF of angiogenic growth.
Embodiment two
Preparing adsorption has the big ball of Hydroxyapatite hollow microsphere complex microsphere of aspirin.Weigh 5-15mg loads
There is bead of the BMP2 porous PLGA microballoons as complex microsphere, and add 5ml 0.01-0.5%PEI solution, be in speed
4h is vibrated on 120rpm shaking table, is well mixed, makes PLGA microsphere surface uniform adsorptions PEI.Then by mixture secondary water
Centrifugation, control centrifugal speed 7000rpm, centrifugation time 10min, is centrifuged repeatedly 3 times, removes the PEI not adsorbed firmly.Will washing
Clean PLGA microballoons are moved into centrifuge tube, are added about 1ml secondary waters and 50-120mg Hydroxyapatite hollow microspheres, are then put
In vibrating 4h on shaking table, it is freeze-dried after centrifugation, you can PLGA is transferred into knot and arrives hydroxyapatite micro-sphere surface.What is prepared is big balloon borne
The multistage composite microballoon of bead can slowly discharge the aspirin of anti-inflammatory and promote the BMP2 of stem cell Osteoblast Differentiation.
Embodiment three
Preparing adsorption has big ball of the tricalcium phosphate tiny balloon as complex microsphere of brufen.Weigh 5-15mg loads
There is beads of the porous PLGA microballoons 5-15mg of TGF-β as complex microsphere, and add 5ml 0.01-0.5%PEI solution,
Speed is to vibrate 4h on 120rpm shaking table, is well mixed, makes PLGA microsphere surface uniform adsorptions PEI.Then mixture is used
Secondary water centrifuges, and control centrifugal speed 7000rpm, centrifugation time 10min, is centrifuged repeatedly 3 times, removes the PEI not adsorbed firmly.
The PLGA microballoons of washes clean are moved into centrifuge tube, add about 1ml secondary waters and 50-120mg Hydroxyapatite hollow microspheres,
It is subsequently placed on shaking table and vibrates 4h, be freeze-dried after centrifugation, you can PLGA microballoons is transferred into knot and arrive tricalcium phosphate microsphere surface.Prepare
The multistage composite microballoon of big balloon borne bead can slowly discharge the brufen of anti-inflammatory and promote stem cell Osteoblast Differentiation
TGF-β。
Example IV
Preparing adsorption has the sour DFP biphase ceramics tiny balloon of DEX hydroxyapatite/acid as complex microsphere
Big ball.Weigh 5-15mg and be loaded with bead of the VEGF porous PLGA microballoons as complex microsphere, and add 5ml 0.01-0.5%
PEI solution, 4h is vibrated on the shaking table that speed is 120rpm, is well mixed, is PLGA microsphere surface uniform adsorptions PEI.Then
Mixture is centrifuged with secondary water, control centrifugal speed 7000rpm, centrifugation time 10min, is centrifuged repeatedly 3 times, removes infirm
The PEI of absorption.The PLGA microballoons of washes clean are moved into centrifuge tube, add about 1ml secondary waters and 50-120mg hydroxy-apatites
Stone tiny balloon, is subsequently placed on shaking table and vibrates 4h, is freeze-dried after centrifugation, you can it is micro- to tricalcium phosphate that PLGA microballoons are transferred into knot
Ball surface.The multistage composite microballoon of the big balloon borne bead prepared can slowly discharge the DEX of anti-inflammatory and promote angiogenic growth
VEGF.
Describe the complex microsphere according to big balloon borne bead proposed by the present invention in an illustrative manner above with reference to accompanying drawing.But
It is, can also be it will be appreciated by those skilled in the art that the complex microsphere of the big balloon borne bead proposed for the invention described above
Do not depart from and make various improvement on the basis of present invention, therefore, protection scope of the present invention should will by appended right
The content of book is asked to determine.
Claims (7)
- A kind of 1. complex microsphere, it is characterised in that：Including small made of big ball made of bioceramic, high polymer material PLGA Ball, the bead are loaded in the surface of big ball, and big ball, the surface of bead are loose structure, and the big ball is loaded with anti-inflammatory agent Thing, the bead are loaded with angiogenic growth factor and/or promote the growth factor of stem cell Osteoblast Differentiation；The preparation method of complex microsphere is as follows：Step 1) prepares big ball, prepares bead by double emulsion method, big ball carries anti-inflammatory medicaments by adsorption, and bead leads to Cross double emulsions parcel angiogenic growth factor and/or promote the growth factor of stem cell Osteoblast Differentiation；Then bead surface is made With polyetherimide modified, PEI concentration is 0.01-0.5%, and bead is stirred into 7-17 hours in PEI solution；For step 2) by modified bead and big ball Hybrid assembling, the time that bead mixes with big ball is 2-6 hours, that is, is obtained big The complex microsphere of balloon borne bead.
- 2. complex microsphere according to claim 1, it is characterised in that：The anti-inflammatory medicaments are DEX, aspirin, cloth At least one of ibuprofen, the angiogenic growth factor are VEGF, and the growth factor of the rush stem cell Osteoblast Differentiation is At least one of BMP2, TGF-β.
- 3. complex microsphere according to claim 2, it is characterised in that：The drug concentration of the anti-inflammatory is 5-15mgmL-1；The drug concentration of the growth factor is 50-200ngmL-1。
- 4. complex microsphere according to any one of claims 1 to 3, it is characterised in that：The big ball is empty with open-celled structure Bulbus cordis, bead are that surface has loose structure porous ball.
- 5. complex microsphere according to any one of claims 1 to 3, it is characterised in that：A diameter of 400-600 μ of the big ball M, a diameter of 20-40 μm of the bead.
- 6. complex microsphere according to claim 5, it is characterised in that：A diameter of 500 μm of the big ball, the bead A diameter of 30 μm.
- 7. complex microsphere according to any one of claims 1 to 3, it is characterised in that：The material of the big ball using calcium silicates, One kind in hydroxyapatite, tricalcium phosphate and hydroxyapatite/tricalcium phosphate biphase ceramics.
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| CN105963773A (en) * | 2016-04-28 | 2016-09-28 | 南京凤源新材料科技有限公司 | Preparation method of polylactide acid glycolic acid copolymer-hydroxylapatite composite microspheres |
| CN107823703A (en) * | 2017-11-17 | 2018-03-23 | 河北点云生物科技有限公司 | A kind of method of 3D printing artificial bone manufacture injection-type preparation |
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| WO2002071985A1 (en) * | 2001-03-14 | 2002-09-19 | Drexel University | Polymeric bioresorbable composites containing an amorphous calcium phosphate polymer ceramic for bone repair and replacement |
| CN100396340C (en) * | 2006-09-05 | 2008-06-25 | 四川大学 | Composite nanometer hydroxy apatitel medical polymer material tissue engineering stent material and preparation method |
| CN101455863A (en) * | 2007-12-12 | 2009-06-17 | 龙脉医疗器械(北京)有限公司 | Medicine eluting coronary stent |
| CN101249284B (en) * | 2008-03-18 | 2013-06-19 | 中国科学院上海硅酸盐研究所 | Biological medical nano hollow ellipsoid and preparation method and application thereof |
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