CN105013005A - Composite microsphere - Google Patents
Composite microsphere Download PDFInfo
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- CN105013005A CN105013005A CN201510514803.3A CN201510514803A CN105013005A CN 105013005 A CN105013005 A CN 105013005A CN 201510514803 A CN201510514803 A CN 201510514803A CN 105013005 A CN105013005 A CN 105013005A
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Abstract
The invention discloses a composite microsphere comprising a large sphere and a small sphere, wherein the small sphere is loaded on the surface of the large sphere and a strawberry-like structure is formed. Surfaces of the used large and small spheres adopt porous structures, the two spheres can be loaded with two different drugs simultaneously, the large sphere is mainly loaded with one drug on the surface through adsorption and releases the drug more quickly, and the small sphere is loaded with the other drug through emulsification coating and releases the drug more slowly. The large sphere is loaded with an anti-inflammatory drug and the small sphere is loaded with angiogenic growth factors or stem cell osteogenic differentiation growth factors. The two drugs can be released simultaneously due to different release rates of the drugs of the two spheres.
Description
Technical field
The present invention relates to bioceramic material technical field, more specifically, relate to a kind of complex microsphere.
Background technology
The large segmental bone defect caused by reason such as wound, tumor and infection is the difficult problem that orthopaedics faces.The bone tissue engineer of fast development in recent years and regenerative medicine are the bright outlook first meeting clue that bone defect healing brings.The research multi-focus of current this area is in the improvement of sclerotin substitution material, the selection of good seed cell and the exploitation etc. of corresponding complex technique, but from the mechanism of bone wound healing, the host response caused after being implanted by analysis of material, thus build targetedly can the material of irritation cell Osteoblast Differentiation, with the research for point of penetration less.Inquire into the preparation of bone renovating material from knitting mechanism and be applied to constructing of tissue engineered bone, likely for the treatment of Cranial defect brings new thinking.
Embedded material enters after in body as foreign body, first can cause the inflammatory reaction of tissue, and inflammatory reaction sustainable existence can extend the time of knitting.Along with the degraded of material and the regeneration of osseous tissue, in cambium, blood vessel can be formed gradually, can promote that angiopoietic material also can play good facilitation to osteanagenesis.The stem cell that surrounding materials meeting concentrating portions is free, if the medicine that material carries can stimulate stem cell Osteoblast Differentiation, equally also can promote the formation of freshman bone tissue, and then accelerated bone wound healing.
Therefore, important meaning will be had to becoming osteanagenesis with angiogenic growth factor or skeletal growth factor having controlled release anti-inflammatory medicaments on the material that can promote into osteanagenesis.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of complex microsphere is provided, the large ball of complex microsphere is loaded with anti-inflammatory medicaments, bead is loaded with angiogenic growth factor or skeletal growth factor, can effectively promote vascularization and osteanagenesis, shorten the time of knitting.
The object of the present invention is achieved like this:
A kind of complex microsphere, comprise large ball that bioceramic makes, bead that macromolecular material is made, described bead is loaded in the surface of large ball, and the surface of large ball, bead is loose structure, described large ball is loaded with anti-inflammatory medicaments, described bead is loaded with angiogenic growth factor or skeletal growth factor.
In order to make the better effects if of anti-inflammatory, angiogenic growth, preferably, described anti-inflammatory medicaments is DEX, and described angiogenic growth factor is VEGF.
In order to make to have suitable drug level in body, effectively carry out antiinflammatory to body, promote that blood vessel recovers, preferably, the drug level of described DEX is 5-15mgmL
-1; The drug level of described VEGF is 50-200ngmL
-1.
In order to make large ball can adsorb more anti-inflammatory medicaments, and play the effect of tissue engineering bracket material better, preferably, described large ball is the hollow ball with open-celled structure.
In order to realize suitable release amount of medicine and release time, preferably, the diameter of described large ball is 400-600 μm, and the diameter of described bead is 20-40 μm.
Further preferably, the diameter of described large ball is 500 μm, and the diameter of described bead is 30 μm.
Preferably, the material of described large ball adopts in calcium silicates, hydroxyapatite, tricalcium phosphate, and hydroxyapatite/sour DFP biphase ceramics is wherein a kind of.Calcium silicates, hydroxyapatite, calcium phosphate ceramics and hydroxyapatite/sour DFP biphase ceramics itself has good bone conductibility, and the composition such as silicon, calcium, phosphorus produced after its degraded can stimulate stem cell to osteoblast to transform.Therefore, using there is the calcium silicates of open-celled structure, hydroxyapatite, calcium phosphate ceramics, hydroxyapatite/sour DFP biphase ceramics tiny balloon as medicine controlled release carrier, also can play the effect of tissue engineering bracket material simultaneously.
Preferably, the material of described bead adopts PLGA.PLGA is polymerized at random by two kinds of monomer-lactic acid and hydroxyacetic acid, it is a kind of degradable functional polymer organic compound, there is the performance of good biocompatibility, nontoxic, good encystation and film forming, be widely used in pharmacy, medical engineering material and modernization industrial circle.At U.S. PLGA by FDA certification, formally included into American Pharmacopeia as pharmaceutic adjuvant.
Owing to have employed technique scheme, the present invention has following beneficial effect:
Combined by large ball and bead and carry different medicines, at the DEX of large ball surface controlled release anti-inflammatory, the inflammatory reaction in implantation process can be suppressed, urged the VEGF of role of Vasculogenesis by grafting at the bead controlled release on large ball surface.Large ball release DEX speed is very fast, is repairing the effect in earlier stage playing anti-inflammatory fast; And PLGA degraded is comparatively slow, the later stage discharges VEGF constantly, can promote the generation of new vessels, the dual controlled release of two kinds of medicines, large ball can play the effect of bone tissue engineering stent material simultaneously, jointly will promote osteanagenesis, for large segmental bone defect reparation provides new thinking.
Complex microsphere of the present invention has the following advantages relative to prior art tool:
1. the same with the using method of common micro-ball, it is very convenient to use;
2. large 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, can normal blood drug level be maintained, not cause drug accumulation poisoning, little to the toxic and side effects of normal cell, tissue;
4. blood drug level is stablized, and improves curative effect, safety quick.
Accompanying drawing explanation
Fig. 1 is complex microsphere SEM picture of the present invention.
Detailed description of the invention
See Fig. 1, for a kind of complex microsphere, comprise large ball that bioceramic makes, bead that macromolecular material is made, the material of described large ball is preferably the wherein one in calcium silicates, hydroxyapatite, tricalcium phosphate, hydroxyapatite/sour DFP biphase ceramics, the material of described bead is preferably Poly(D,L-lactide-co-glycolide (poly (lactic-co-glycolic acid), PLGA).The diameter of described large ball is 400-600 μm, and be preferably 500 μm, the diameter of described bead is 20-40 μm, is preferably 30 μm.Described bead is loaded in the surface of large ball, is formed and is similar to Raspberry-like structure.Described large ball is hollow ball, and the surface of large ball, bead is loose structure, and described large ball is loaded with anti-inflammatory medicaments, and be preferably dexamethasone (Dexamethasone, DEX), the drug level of described DEX is 5-15mgmL
-1.Described bead is loaded with angiogenic growth factor, and be preferably VEGF (Vascular endothelial growth factor, VEGF), the drug level of described VEGF is 50-200ngmL
-1.
The structure that large ball carries bead can discharge two kinds of medicines simultaneously, in conjunction with ceramic microsphere as tissue engineering bracket, utilizes the biocompatibility that it is good, jointly can play the effect promoting osteanagenesis.Ceramic microsphere and the effective of polymer microsphere assemble the above-mentioned performance that the large ball built carries the complex microsphere of bead, large ball provided by the invention carries the complex microsphere of bead can as Cranial defect packing material, can improve the ability of bone wound and defect healing significantly, be a kind of novel bone renovating material.
The preparation method of complex microsphere is as follows:
Step 1) prepare large ball, by double emulsion legal system for bead, large ball carries anti-inflammatory medicaments by surface adsorption, and bead carries angiogenic growth factor by double emulsions parcel; Then bead surface is used Polyetherimide (Polyetherimide, PEI) modification, the concentration of PEI is 0.01-0.5%, and bead is stirred 7-17 hour in PEI solution.
Step 2) by modified bead and large ball Hybrid assembling, the time that bead mixes with large ball is 2-6 hour, namely obtains the complex microsphere that large ball carries bead.
Embodiment one
The present embodiment takes following technical scheme: preparation surface is adsorbed with the large ball of calcium silicates tiny balloon as complex microsphere of DEX.Take the bead of porous PLGA microsphere as complex microsphere that 5-15mg is loaded with VEGF, and add the 0.01-0.5%PEI solution of 5ml, in speed be 120rpm shaking table on to vibrate 4h, mix homogeneously, makes PLGA microsphere surface uniform adsorption PEI.Then by centrifugal for mixture intermediate water, centrifugal speed 7000rpm, centrifugation time 10min is controlled, centrifugal 3 times repeatedly, the PEI that removing is not firmly adsorbed.Moved in centrifuge tube by the PLGA microsphere of washes clean, add about 1ml intermediate water, add the calcium silicates tiny balloon that 50-120mg is adsorbed with DEX, be then placed in 4h that shaking table vibrates, centrifugal postlyophilization, can by PLGA grafting to calcium silicates microsphere surface.The multistage composite microsphere that the large ball prepared carries bead can discharge the DEX of anti-inflammatory lentamente and promote the VEGF of angiogenic growth.
Embodiment two
Preparation surface is adsorbed with the large ball of the Hydroxyapatite hollow microsphere complex microsphere of aspirin.Take the bead of porous PLGA microsphere as complex microsphere that 5-15mg is loaded with BMP2, and add the 0.01-0.5%PEI solution of 5ml, in speed be 120rpm shaking table on to vibrate 4h, mix homogeneously, makes PLGA microsphere surface uniform adsorption PEI.Then by centrifugal for mixture intermediate water, centrifugal speed 7000rpm, centrifugation time 10min is controlled, centrifugal 3 times repeatedly, the PEI that removing is not firmly adsorbed.Moved in centrifuge tube by the PLGA microsphere of washes clean, add about 1ml intermediate water and 50-120mg Hydroxyapatite hollow microsphere, be then placed in 4h that shaking table vibrates, centrifugal postlyophilization, can transfer knot to hydroxyapatite micro-sphere surface by PLGA.The multistage composite microsphere that the large ball prepared carries bead can discharge the aspirin of anti-inflammatory lentamente and promote the BMP2 of stem cell Osteoblast Differentiation.
Embodiment three
Preparation surface is adsorbed with the large ball of tricalcium phosphate tiny balloon as complex microsphere of ibuprofen.Take the bead of porous PLGA microsphere 5-15mg as complex microsphere that 5-15mg is loaded with TGF-β, and add the 0.01-0.5%PEI solution of 5ml, in speed be 120rpm shaking table on to vibrate 4h, mix homogeneously, makes PLGA microsphere surface uniform adsorption PEI.Then by centrifugal for mixture intermediate water, centrifugal speed 7000rpm, centrifugation time 10min is controlled, centrifugal 3 times repeatedly, the PEI that removing is not firmly adsorbed.Moved in centrifuge tube by the PLGA microsphere of washes clean, add about 1ml intermediate water and 50-120mg Hydroxyapatite hollow microsphere, be then placed in 4h that shaking table vibrates, centrifugal postlyophilization, can transfer knot to tricalcium phosphate microsphere surface by PLGA microsphere.The multistage composite microsphere that the large ball prepared carries bead can discharge the ibuprofen of anti-inflammatory lentamente and promote the TGF-β of stem cell Osteoblast Differentiation.
Embodiment four
Preparation surface is adsorbed with the large ball of hydroxyapatite/sour DFP biphase ceramics tiny balloon as complex microsphere of DEX.Take the bead of porous PLGA microsphere as complex microsphere that 5-15mg is loaded with VEGF, and add the 0.01-0.5%PEI solution of 5ml, in speed be 120rpm shaking table on to vibrate 4h, mix homogeneously is PLGA microsphere surface uniform adsorption PEI.Then by centrifugal for mixture intermediate water, centrifugal speed 7000rpm, centrifugation time 10min is controlled, centrifugal 3 times repeatedly, the PEI that removing is not firmly adsorbed.Moved in centrifuge tube by the PLGA microsphere of washes clean, add about 1ml intermediate water and 50-120mg Hydroxyapatite hollow microsphere, be then placed in 4h that shaking table vibrates, centrifugal postlyophilization, can transfer knot to tricalcium phosphate microsphere surface by PLGA microsphere.The multistage composite microsphere that the large ball prepared carries bead can discharge the DEX of anti-inflammatory lentamente and promote the VEGF of angiogenic growth.
The complex microsphere that the large ball proposed according to the present invention carries bead is described in an illustrative manner above with reference to accompanying drawing.But; it will be appreciated by those skilled in the art that the large ball proposed for the invention described above carries the complex microsphere of bead, various improvement can also be made on the basis not departing from content of the present invention; therefore, protection scope of the present invention should be determined by the content of appending claims.
Claims (8)
1. a complex microsphere, it is characterized in that: comprise large ball that bioceramic makes, bead that macromolecular material is made, described bead is loaded in the surface of large ball, the surface of large ball, bead is loose structure, described large ball is loaded with anti-inflammatory medicaments, described bead is loaded with the somatomedin of angiogenic growth factor and/or short stem cell Osteoblast Differentiation.
2. complex microsphere according to claim 1, it is characterized in that: described anti-inflammatory medicaments is at least one in DEX, aspirin, ibuprofen, described angiogenic growth factor is VEGF, and the somatomedin of described short stem cell Osteoblast Differentiation is at least one in BMP2, TGF-β.
3. complex microsphere according to claim 2, is characterized in that: the drug level of described anti-inflammatory is 5-15mgmL
-1; The drug level of described somatomedin is 50-200ngmL
-1.
4., according to the arbitrary described complex microsphere of claims 1 to 3, it is characterized in that: described large ball is for having open-celled structure hollow ball, and bead is that surface has loose structure porous ball.
5., according to the arbitrary described complex microsphere of claims 1 to 3, it is characterized in that: the diameter of described large ball is 400-600 μm, the diameter of described bead is 20-40 μm.
6. complex microsphere according to claim 5, is characterized in that: the diameter of described large ball is 500 μm, and the diameter of described bead is 30 μm.
7. according to the arbitrary described complex microsphere of claims 1 to 3, it is characterized in that: the material of described large ball adopts the one in calcium silicates, hydroxyapatite, tricalcium phosphate and hydroxyapatite/tricalcium phosphate biphase ceramics.
8. according to the arbitrary described complex microsphere of claims 1 to 3, it is characterized in that: the material of described bead adopts PLGA.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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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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2015
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| US20100197823A1 (en) * | 2001-03-14 | 2010-08-05 | Drexel University | Polymeric Resorbable Composites Containing an Amorphous Calcium Phosphate Polymer Ceramic for Bone Repair and Replacement |
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Cited By (2)
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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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