CN101695584B - Injectable composite material capable of promoting bone regeneration and repair and preparation method thereof - Google Patents
Injectable composite material capable of promoting bone regeneration and repair and preparation method thereof Download PDFInfo
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- 239000002131 composite material Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 230000008439 repair process Effects 0.000 title claims abstract description 13
- 230000001737 promoting effect Effects 0.000 title claims abstract description 8
- 230000010478 bone regeneration Effects 0.000 title claims abstract description 7
- 239000004005 microsphere Substances 0.000 claims abstract description 35
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 34
- 239000011573 trace mineral Substances 0.000 claims abstract description 34
- 235000013619 trace mineral Nutrition 0.000 claims abstract description 34
- 239000011575 calcium Substances 0.000 claims abstract description 21
- 229920001661 Chitosan Polymers 0.000 claims abstract description 19
- 239000000017 hydrogel Substances 0.000 claims abstract description 19
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 18
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 18
- 239000000661 sodium alginate Substances 0.000 claims abstract description 18
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000008367 deionised water Substances 0.000 claims abstract description 11
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 11
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims abstract description 11
- 239000011521 glass Substances 0.000 claims abstract description 10
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- 239000000725 suspension Substances 0.000 claims description 8
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 6
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- 101100496858 Mus musculus Colec12 gene Proteins 0.000 claims description 4
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Abstract
本发明公开的促骨再生修复的可注射复合材料是由海藻酸钠、壳聚糖、多元微量元素协同掺杂磷酸钙多孔微球、生物活性玻璃纳米颗粒为组元经去离子水和细胞培养液调制复合制备而成，其组分的质量百分数含量为：海藻酸钠0.10～0.50％；壳聚糖0.01～0.20％；多元微量元素协同掺杂磷酸钙多孔微球5～30％；生物活性玻璃0.05～0.50％；细胞培养液25～55％；去离子水30～45％。本发明制备工艺简单，制得的复合材料具有优良的可注射性和快速降解特性，水凝胶网络能富集由无机微粒降解释放的钙、磷离子和微量元素，能促进成骨性细胞迁移、生长、增殖和分化，对骨内微损伤、骨折或骨缺损具有快速诱导骨再生并促进骨修复的功效。The injectable composite material for promoting bone regeneration and repair disclosed by the present invention is composed of sodium alginate, chitosan, multivariate trace elements synergistically doped with calcium phosphate porous microspheres, and bioactive glass nanoparticles as components through deionized water and cell culture. It is prepared by compounding and compounding liquid, and the mass percentage content of its components is: sodium alginate 0.10-0.50%; chitosan 0.01-0.20%; multivariate trace elements synergistically doped calcium phosphate porous microspheres 5-30%; biological activity Glass 0.05-0.50%; cell culture medium 25-55%; deionized water 30-45%. The preparation process of the invention is simple, and the prepared composite material has excellent injectability and rapid degradation characteristics, and the hydrogel network can enrich the calcium, phosphorus ions and trace elements released by the degradation of inorganic particles, and can promote the migration of osteoblast cells , growth, proliferation and differentiation, and has the effect of rapidly inducing bone regeneration and promoting bone repair for intraosseous micro-injury, fracture or bone defect.
Description
Technical field
The present invention relates to a kind of hydrogel-biological activity inorganic particles injectable complex bone renovating material, Preparation method and use, belong to bio-medical material and regeneration medicine technology field.
Background technology
Along with increasingly serious population expansion and the arriving in aging epoch, the bone injury treatment that osteoporosis causes becomes the important issue of every country.Osteoporotic basic feature is that bone density descends and bone fragility significantly improves, and micro-damage, fracture and the damaged risk of large tracts of land bone increase greatly in the position bones such as spinal column, femur, carpal bone.
At present, there is no especially effectively development of drugs in treating primary osteoporosis both at home and abroad, mainly to put prevention first.For a long time, the damaged treatment of osteoporotic fracture and bone is fixing in the metal or alloy material, joint replacement etc. is as main, and patient that should not replacement adopts the expectant treatments such as reduction by traction.But fracture delayed union or bone does not connect, interior fixing unsuccessfully wait FAQs to cause patient's long-term bed, and cause a large amount of complication, thereby its disability rate and mortality rate are always high.
In recent years, the advantages such as Wicresoft's internal fixation operation is little because of its wound, minimizing is lost blood come into one's own clinically gradually, but the design of the biological activity of internal fixation material still rests on interior fixing and displacement metal species material surface modifying, promotes that the effect of fracture plane of disruption healing is also not obvious.Therefore, accelerating the new model that development can promote the new material of union of fracture and explore osteoporotic fracture, bone defect healing, shorten treatment time, avoid the generation of complication, is the effective way that reduces mortality rate and thoroughly cure osteoporotic fracture.
Promote union of osteoportic fracture and defect repair that physical chemistry and the biological characteristics of biomaterial have been proposed very high requirement, on the one hand, require embedded material to have fast degradability, with satisfy area of new bone open into; On the other hand, require material to have superior biological activity, the osteanagenesis of energy rapid induction promotes the fracture face knitting; In addition, the specification requirement that embedded material is delivered to the fracture plane of disruption and damaged place is higher, requires material to have the height rheological characteristic, can enter damaged interior any narrow and small vacancy position by material by approach such as injections, forms even filling.At present, the damaged filling reparation of bone is poor with the biological activity of conventional material, the material of constructing with the compactness micro-nano granules also exists osteanagenesis and the difficult coupling of material degradation speed, the calcium phosphate self-curing material injects problems such as causing thrombosis behind the fracture face, therefore at present clinically simple calcium phosphate ceramic and self-curing material, bio-vitric bulky grain packing material etc. the requirement that all can't satisfy the treatment of osteoporotic fracture and defect repair.
Porous calcium phosphate eight calcium (Ca
8(HPO
4)
2(PO
4)
45H
2O) be steady type synthos of a kind of Jie in widespread attention gradually in recent years, studies show that this synthos are presoma materials that the human bone tooth is organized apatite, degradability is all more better than tricalcium phosphate and hydroxyapatite in physiological environment.A large amount of animal models of recent years and experiment in vitro result of study show, the OCP embedded material not only has more superior biodegradability and biological activity (O.Suzuki than tricalcium phosphate and hydroxyapatite, et al.Curr.Med.Chem.2008,15,305-313), and have induced activity potentiality (P.Habibovic, et al.J Mater Sci Mater Med.2004 15, a 373-80 that promotes the bone mesenchymal stem cell to osteoblast differentiation; T.Anada, et al.Tissue Eng.Part A.2008, Jun, 965-978.).Mix the biological activity, biological degradability and the bone defect repair effect that are expected to improve material behind the trace element such as silicon, strontium, zinc, magnesium in OCP, they are being regulated bone metabolism, are promoting the irreplaceable biological effect of performance in the bone strength.
Sodium alginate is the very high water-soluble polyelectrolyte polysaccharide of a kind of electronegative density, has good degradability and biocompatibility, is used in a large number tissue engineering bracket and medicine embedded material.Chitosan is a kind of natural polycation polysaccharide, easily degrades and the product avirulence, and its degraded can be again growing into of cell and tissue provides the space, thereby can promote the generation of new bone.The high-moisture percentage hydrogel that these two kinds of materials mediations form has superior rheological characteristic and structural stability.
Up-to-date knowledge according to existing clinical practice bibliographical information and biomaterial progress, in the urgent need to exploring the composite system by high bioactivity constituent element and similar extracellular matrix, development all can be satisfied clinically micro-damage in the sufferers of osteoporosis face human bone on chemical composition and biology performance, fracture and the damaged quickly-healing of large tracts of land bone, repair more preferably active material fully, such material possesses the porous gel state extracellular matrix of similar osseous tissue and the chemical constituent of inorganic mineral, especially various trace elements is compound, thereby possess at cell and molecular level and realize active control to relevant (doing) cell proliferation of skeletonization and differentiation, activating the gene relevant with osteanagenesis expresses fast, be implemented in host's molecule, the active substance that cell and tissue acceptance picked-up or implantation provide is accurately regulated and control and is replied, and various trace elements energy coordinated regulation material degradation is to reach the optimum efficiency of the collaborative coupling of the damaged Regeneration and Repair of bone.
Summary of the invention
The purpose of this invention is to provide a kind of have extracellular matrix gel porous network micro structure and contain various trace elements obviously promote minimally-invasive treatment type Injectable composite material of osteoporotic fracture quickly-healing and the damaged Regeneration and Repair of bone and preparation method thereof.
The Injectable composite material that promoting bone regeneration of the present invention is repaired, be by the collaborative doping phosphoric acid calcium porous microsphere of sodium alginate, chitosan, more trace elements, bioactivity glass nano-particle be constituent element through deionized water and compound being prepared from of cell culture fluid modulation, the mass percent content of its component is:
Sodium alginate 0.10～0.50%;
Chitosan 0.01～0.20%;
More trace elements is worked in coordination with doping phosphoric acid calcium porous microsphere 5～30%;
Bioactivity glass 0.05～0.50%;
Cell culture fluid 25～55%;
Deionized water 30～45%, said components sum are 100%.
The collaborative doping phosphoric acid calcium of above-mentioned more trace elements is zinc, strontium, magnesium and at least two kinds of collaborative OCP, hydroxyapatite or both complex that mix of silicon, the mass percent content that calcium phosphate porous microsphere represents take oxide form as:
P
2O
5 38～44％
H
2O 3～8%, and the said components sum is 100%, and SiO
2, ZnO, MgO and at least two kinds of materials of SrO are not 0 simultaneously.
The mole percent content that above-mentioned bioactivity glass represents take oxide form as:
CaO 32～50％
P
2O
5 0～12％
B
2O
3 0～12％
Na
2O 3～8％
The particle diameter of the collaborative doping phosphoric acid calcium porous microsphere of said more trace elements is 5～600 μ m; Said bioactive glass particle particle diameter is 50～800nm.
The preparation method of the Injectable composite material that promoting bone regeneration of the present invention is repaired may further comprise the steps:
1) will contain SiO
3 2-, PO
4 3-Inorganic salt 1: 10 in molar ratio add in poly (sodium aspartate) or the sodium polyacrylate aqueous solution, control sodium phosphate concentration is 1～10%, and this sodium phosphate mixed solution is maintained 37～60 ℃, and the pH value of regulating mixed solution is 4.8～7.0,, will contain Ca again
2+, Sr
2+, Zn
2+And Mg
2+The solution of at least two kinds of ions is added drop-wise in the sodium phosphate mixed solution, drips total mole number and the SiO of ion
3 2-And PO
4 3-The ratio of total mole number be 8: 6, keep solution temperature and continuous stirring ageing 0～1000 minute after dropwising, then filter the collaborative doping phosphoric acid calcium microsphere of the more trace elements of separating out, and wash successively with deionized water and dehydrated alcohol, then filtration, vacuum drying are for subsequent use;
2) by product CaO: P
2O
5: SiO
2: B
2O
3: Na
2The ratio 32～50: 0～12: 40～56: 0～12 of O mole: an amount of lime nitrate of 3～8 weighings, triethyl phosphate, ethyl orthosilicate, boric acid and Chile saltpeter, add successively fully reaction in the ethanol, and 60 ℃ of lower ageings, then 550～700 ℃ of lower calcinings, obtain bioactive glass nano powder, make suspension in weighing 0.05～0.15g bioactivity glass nanoparticulate dispersed to 2～6g cell culture fluid, for subsequent use;
3) the abundant stirring and dissolving of an amount of sodium alginate powder of room temperature lower-weighing is in containing 500ppm Ca
2+And 50ppmSr
2+Aqueous solution in, make it become the Sodium Alginate Hydrogel Films that concentration is 5g/L, for subsequent use;
4) an amount of chitosan powder of room temperature lower-weighing and adding in the 5g/L acetic acid solution fully stirs and makes it become concentration to be the 20g/L chitosan solution, and is for subsequent use;
5) weighing 1～3g is by step 1) the collaborative doping phosphoric acid calcium microsphere of more trace elements of preparation, and join 6g by step 3) preparation Sodium Alginate Hydrogel Films in, after stirring, with step 4) preparation chitosan solution 0.5～1.0g slowly splash in this hydrogel, stir, add again step 2) suspension that makes, stir, obtain the Injectable bone repair material of hydrogel-biological activity inorganic particles complex.
Among the present invention, all there are not strict kind restriction in doped silicon, zinc, strontium and the employed soluble inorganic salt of magnesium active element, generally contain Ca
2+Inorganic salt be Ca (CH
3COO)
2H
2O, Ca (NO
3)
2And CaCl
2In a kind of or triangular combination in any; Contain PO
4 3-Inorganic salt be Na
3PO
4, Na
2HPO
42H
2O and NaH
2PO
412H
2A kind of or triangular combination in any among the O; The said SiO that contains
3 2-Inorganic salt adopt Na
2SiO
3Contain Sr
2+Inorganic salt adopts SrCl
2And Sr (NO
3)
2In a kind of or combination in any between the two, contain Zn
2+Inorganic salt adopts ZnCl
2And Zn (NO
3)
2In a kind of or combination in any between the two; Contain Mg
2+Inorganic salt adopts MgCl
2And Mg (NO
3)
2In a kind of or combination in any between the two.
Beneficial effect of the present invention is:
Injectable bone repair material of the present invention, processing technology is simple, and each component ratio makes it be suitable for Wicresoft's injection through optimal design and uses, and good rheological characteristic can adapt to difform fracture face and the damaged secretion of bone simultaneously.According to said method the organic and inorganic composite repairing material of preparation not only possesses the high-moisture percentage gel network of similar extracellular aquagel state substrate, and contain strontium, zinc, magnesium and silicon more trace elements biological activity ion, Acidity of Aikalinity is regulated by the alkalescence ion of bioactivity glass stripping in its gel network, has satisfied the microenvironment of osteogenic cell migration, adhesion, growth and proliferation and differentiation; Secondly, the hydrogel porous network structure of high degree of water is conducive to growth in nutrient substance transmission and the area of new bone, especially the composite that is compounded to form by the collaborative doping phosphoric acid calcium porous microsphere of low content sodium alginate, chitosan component and more trace elements, high-ratio surface bio-vitric nanoparticle has the fast degradation characteristic, can be rapid healing of fracture and area of new bone and grows into the space is provided.In addition, the yin, yang ionic group produces adsorption to the inorganic ions of calcium phosphate microsphere and bio-vitric stripping in the interior sodium alginate of hydrogel matrix network, the chitosan, promote the active ion dosage of cell proliferation, differentiation for Intracellular growth provides optimum, thereby optimized the biological activity of new osteanagenesis.The inorganic micro-nano grain of rice of biodegradable injection-type of the present invention-hydrogel composites bone renovating material has the prospect of extensive use in the damaged Regeneration and Repair of micro-damage, fracture and bone in the various bones in the osteoporosis human body.
Description of drawings
Fig. 1 is the collaborative doping phosphoric acid calcium X ray diffracting spectrum of more trace elements of the present invention, and (a) is for containing Mg, Zn, the material of Sr and Si trace element, ageing 10 minutes among the figure; (b) for containing Mg, the material of Zn and Sr trace element, ageing 240 minutes; (c) for containing the material of Mg and Zn trace element material, ageing 360 minutes; (d) for containing the material of Mg and Zn trace element material, ageing 1000 minutes.
Fig. 2 is the collaborative doping phosphoric acid calcium stereoscan photograph of more trace elements of the present invention, and (a) is for containing Mg, Zn, the material of Sr and Si trace element, ageing 10 minutes among the figure; (b) for containing Mg, the material of Zn and Sr trace element, ageing 240 minutes; (c) for containing the material of Mg and Zn trace element material, ageing 360 minutes.
Fig. 3 is the stereoscan photograph of composite, and (a) is for containing Mg, Zn, the composite photo of Sr and Si doping microsphere among the figure; (b) for containing Mg, the composite photo of Zn and Sr doping microsphere; (c) for containing Mg, Zn, and the composite photo of Sr doping microsphere.
Fig. 4 is the X-ray photograph that composite is expelled to rat femur medullary cavity model.
Fig. 5 is the bone density test pattern that composite is expelled to rat femur medullary cavity model.
Fig. 6 is the two and three dimensions micro-CT photo that composite is expelled to rat femur medullary cavity model.
Fig. 7 is the tissue specimen HE dyeing optical photograph that composite is expelled to rat femur medullary cavity model.
The specific embodiment
Further illustrate the present invention below in conjunction with example, but these examples do not limit the scope of the invention, all technology that realizes based on foregoing of the present invention and the material of preparation all belong to protection scope of the present invention.Reagent purity that embodiment uses all is not less than analytical reagent purity index.
1) will contain SiO
3 2-, PO
4 3-Na
2SiO
3And Na
3PO
4Inorganic salt be to add in sodium polyaspartate aqueous solution at 1: 10 in molar ratio, control sodium phosphate concentration is 10%, this mixed solution is maintained 37 ℃, and the pH value with hydrochloric acid conditioning solution is 7.0 under the condition of continuity, continuous stirring forms homogeneous solution, will contain Ca again
2+, Sr
2+, Zn
2+And Mg
2+Ca (the CH of ion
3COO)
2H
2O, SrCl
2, ZnCl
2And MgCl
2Solution is added drop-wise in the sodium phosphate mixed solution, Ca
2+, Sr
2+, Zn
2+And Mg
2+Total mole number and SiO
3 2-And PO
4 3-The ratio of total mole number be 8: 6, keep solution temperature and continuous stirring ageing 10 minutes after dropwising, then stop stirring and filtration and separate out the collaborative doping phosphoric acid calcium microsphere of more trace elements, and wash successively 3 times with deionized water and dehydrated alcohol, then filter, vacuum drying, shown in Fig. 1 (a) and Fig. 2 (a), synthetic trace element doping phosphoric acid calcium is the OCP microsphere respectively for X ray diffracting spectrum and stereoscan photograph.
2) by product CaO: P
2O
5: SiO
2: B
2O
3: Na
2The ratio of O mole 36: 4: 52: an amount of lime nitrate of weighing in 4: 4, triethyl phosphate, ethyl orthosilicate, boric acid and Chile saltpeter, add successively in the ethanol in stirring and reacted 2 hours, then 60 ℃ of lower ageings 24 hours, again 700 ℃ of lower calcinings 1.5 hours, obtain bioactive glass nano powder, the 0.15g bioactive glass nano powder is distributed among the 2g cell culture fluid DMEM makes suspension, for subsequent use;
3) the abundant stirring and dissolving of an amount of sodium alginate powder of room temperature lower-weighing is in containing 500ppm Ca
2+And 50ppmSr
2+Aqueous solution in, make it become the hydrogel that concentration is 50g/L;
4) an amount of chitosan powder of room temperature lower-weighing and adding in the 5g/L acetic acid solution fully stirs and makes it become concentration to be the 20g/L chitosan solution, and is for subsequent use;
5) weighing 3g step 1) the collaborative doping phosphoric acid calcium microsphere of the more trace elements of preparation, and adding 6g step 3) in the Sodium Alginate Hydrogel Films of preparation, after stirring, with step 4) preparation chitosan solution 1.0g slowly splash in this hydrogel, stir; Add again step 2) suspension that makes, stir, obtain hydrogel-biological activity inorganic particles complex injectable materials.The pH value that records composite is 7.6, and the section structure pattern stereoscan photograph of the composite of this example preparation is shown in Fig. 3 (a), and microsphere particle is uniformly distributed in the hydrogel network.
Preparation method is with embodiment 1, and difference is: step 1) will contain PO
4 3-Na
2HPO
42H
2The O inorganic salt is to add in sodium polyacrylate aqueous solution at 1: 10 in molar ratio, and control sodium phosphate concentration is 10%, this mixed solution is maintained 60 ℃, and the pH value with hydrochloric acid conditioning solution is 4.8 under the condition of continuity, and continuous stirring formation homogeneous solution will contain Ca again
2+, Sr
2+, Zn
2+And Mg
2+The CaCl of ion
2, SrCl
2, ZnCl
2And MgCl
2Solution is added drop-wise in the sodium phosphate mixed solution, Ca
2+, Sr
2+, Zn
2+And Mg
2+Total mole number and PO
4 3-The ratio of molal quantity be 8: 6, keep solution temperature and continuous stirring ageing 240 minutes after dropwising, OCP microsphere particle generation Partial Conversion, obtain the slower hydroxyapatite of degradation rate and OCP complex microsphere, wash successively 3 times with deionized water and dehydrated alcohol, then filtration, vacuum drying.Microsphere particle X ray diffracting spectrum and pattern stereoscan photograph are respectively shown in Fig. 1 (b) and Fig. 2 (b).
The composite pattern photo of this example preparation is shown in Fig. 3 (b), and microsphere is uniformly distributed in the hydrogel network.
Embodiment 3
Preparation method is with embodiment 1, and difference is: step 1) will contain PO
4 3-Na
3PO
4Be to add in sodium polyacrylate aqueous solution at 1: 10 in molar ratio, control sodium phosphate concentration is 10%, this mixed solution is maintained 40 ℃, and the pH value with hydrochloric acid conditioning solution is 6.8 under the condition of continuity, and continuous stirring formation homogeneous solution will contain Ca again
2+, Zn
2+And Mg
2+The CaCl of ion
2, Zn (NO3)
2And MgCl
2Solution is added drop-wise in the sodium phosphate mixed solution, Ca
2+, Zn
2+And Mg
2+Total mole number and PO
4 3-The ratio of molal quantity be 8: 6, keep solution temperature and continuous stirring ageing 360 minutes after dropwising, the OCP microsphere particle transforms, and obtains the slower hydroxyapatite micro-sphere of degradation rate, wash successively 3 times with deionized water and dehydrated alcohol, then filtration, vacuum drying.Microsphere particle X ray diffracting spectrum and pattern stereoscan photograph are respectively shown in Fig. 1 (c) and Fig. 2 (c).
The composite pattern photo of this example preparation is shown in Fig. 3 (c), and microsphere is uniformly distributed in the hydrogel network.
With embodiment 1 preparation method, difference is:
Step 1) digestion time is controlled to be 1000 minutes in, makes the collaborative doped hydroxyapatite microsphere of more trace elements, and the microsphere particle X ray diffracting spectrum is shown in Fig. 1 (d);
Step 2) by product CaO: P
2O
5: SiO
2: B
2O
3: Na
2The ratio of O mole 38: 6: 52: an amount of lime nitrate of weighing in 0: 4, triethyl phosphate, ethyl orthosilicate and Chile saltpeter, add successively in the ethanol in stirring and reacted 2 hours, then 60 ℃ of lower ageings 48 hours, again 600 ℃ of lower calcinings 1.5 hours, obtain bioactive glass nano powder, the 0.10g bioactive glass nano powder is distributed among the 2g cell culture fluid DMEM makes suspension;
Then, weighing 3g is by step 1) microsphere of preparation, and add 6g step 3) in the Sodium Alginate Hydrogel Films of preparation, after stirring, with step 4) the chitosan solution 1.0g of preparation slowly splashes in this hydrogel, stirs; Again with step 2) preparation suspension join in the composite aquogel, stir, obtain hydrogel-biological activity inorganic particles composite materials.The pH value that records composite is 7.2.
The composite of Application Example 1 preparation carries out Osteoporosis Rats marrow cavity of femur osteanagenesis efficient and material degradation property testing, concrete grammar and result are as follows: sample is carried out the gamma Rays sterilization, to 30 12 the week age SD female rats, wherein extract ovary for 15, be the OVXed experimental group; All the other 15 only go out to extract a small amount of fatty tissue at ovary, are the Sham Sham-operated control group.Treat that 30 rats normally clean when raising for 24 age in week, it is 0.11 ± 0.03 and 0.19 ± 0.02 that live body test experiments group and matched group femoral bmd are respectively, and has statistical significant difference, shows that the experimental group rat has suffered from osteoporosis.By gamma Rays material sample is sterilized, inject respectively sterile sampling 1.5g to two groups of rats, two back leg femoral cavities under aseptic and anesthesia, then bone wax envelope sample introduction pin hole is sewed up cortex.After continuation raised for 1～8 week, put to death rat by the excessive anesthetis method of injection, take whole femur, carry out respectively X-ray, bone density, the reconstruction of micro-CT two and three dimensions piece cutting structure and histology HE dyeing and characterize, respectively shown in Fig. 4～7.The experimental group femur is found the new bone mineralising of injection material (seeing Fig. 4) during interior the 8th week; The experimental group femoral bmd is fast rise in time, the 8th when week and matched group there was no significant difference (seeing Fig. 5); Although experimental group porous bone deterioration is obvious, injection material generation mineralising is obvious, and the matched group material does not have mineralising skeletonization (seeing Fig. 6) because of fast degradation; Tissue staining confirms the 4th week to begin to occur the mineralising bone, and the 8th all mineralisings are remarkable, and the microsphere particle material degradation disintegrates and still has residual pieces, and matched group 8 rear material degradations do not have new bone (seeing Fig. 7).
Claims (7)
1. the Injectable composite material repaired of a promoting bone regeneration, it is characterized in that it be by the collaborative doping phosphoric acid calcium porous microsphere of sodium alginate, chitosan, more trace elements, bioactivity glass nano-particle be constituent element through deionized water and compound being prepared from of cell culture fluid modulation, the mass percent content of its component is:
Sodium alginate 0.10～0.50%;
Chitosan 0.01～0.20%;
More trace elements is worked in coordination with doping phosphoric acid calcium porous microsphere 5～30%;
Bioactivity glass 0.05～0.50%;
Cell culture fluid 25～55%;
Deionized water 30～45%, said components sum are 100%.
2. Injectable composite material according to claim 1, it is characterized in that the collaborative doping phosphoric acid calcium of said more trace elements is zinc, strontium, magnesium and at least two kinds of collaborative OCP, hydroxyapatite or both complex that mix of silicon, the mass percent content that calcium phosphate porous microsphere represents take oxide form as:
CaO 40～55％
P
2O
5 38～44％
SiO
2 0～0.3％
SrO 0～5.5％
ZnO 0～3.5％
MgO 0～4.5％
H
2O 3～8%, and the said components sum is 100%, and SiO
2, ZnO, MgO and at least two kinds of materials of SrO are not 0 simultaneously.
3. Injectable composite material according to claim 1, it is characterized in that mole percent content that said bioactivity glass represents take oxide form as:
CaO 32～50％
P
2O
5 0～12％
SiO
2 40～56％
B
2O
3 0～12％
Na
2O 3～8％
4. Injectable composite material according to claim 1 and 2 is characterized in that the particle diameter of the collaborative doping phosphoric acid calcium porous microsphere of said more trace elements is 5～600 μ m.
5. according to claim 1 or 3 described Injectable composite materials, it is characterized in that said bioactive glass particle particle diameter is 50～800nm.
6. the preparation method of Injectable composite material according to claim 1 is characterized in that may further comprise the steps:
1) will contain SiO
3 2-, PO
4 3-Inorganic salt 1: 10 in molar ratio add in poly (sodium aspartate) or the sodium polyacrylate aqueous solution, control sodium phosphate concentration is 1～10%, and this sodium phosphate mixed solution is maintained 37～60 ℃, and the pH value of regulating mixed solution is 4.8～7.0,, will contain Ca again
2+, Sr
2+, Zn
2+And Mg
2+The solution of at least two kinds of ions is added drop-wise in the sodium phosphate mixed solution, drips total mole number and the SiO of ion
3 2-And PO
4 3-The ratio of total mole number be 8: 6, keep solution temperature and continuous stirring ageing 0～1000 minute after dropwising, then filter the collaborative doping phosphoric acid calcium microsphere of the more trace elements of separating out, and wash successively with deionized water and dehydrated alcohol, then filtration, vacuum drying are for subsequent use;
2) by product CaO: P
2O
5: SiO
2: B
2O
3: Na
2The ratio 32～50: 0～12: 40～56: 0～12 of O mole: an amount of lime nitrate of 3～8 weighings, triethyl phosphate, ethyl orthosilicate, boric acid and Chile saltpeter, add successively fully reaction in the ethanol, and 60 ℃ of lower ageings, then 550～700 ℃ of lower calcinings, obtain bioactive glass nano powder, make suspension in weighing 0.05～0.15g bioactivity glass nanoparticulate dispersed to 2～6g cell culture fluid, for subsequent use;
3) the abundant stirring and dissolving of an amount of sodium alginate powder of room temperature lower-weighing is in containing 500ppm Ca
2+And 50ppmSr
2+Aqueous solution in, make it become the Sodium Alginate Hydrogel Films that concentration is 5g/L, for subsequent use;
4) an amount of chitosan powder of room temperature lower-weighing and adding in the 5g/L acetic acid solution fully stirs and makes it become concentration to be the 20g/L chitosan solution, and is for subsequent use;
5) weighing 1～3g is by step 1) the collaborative doping phosphoric acid calcium microsphere of more trace elements of preparation, and join 6g by step 3) preparation Sodium Alginate Hydrogel Films in, after stirring, with step 4) preparation chitosan solution 0.5～1.0g slowly splash in this hydrogel, stir, add again step 2) suspension that makes, stir, obtain the Injectable bone repair material of hydrogel-biological activity inorganic particles complex.
7. the preparation method of Injectable composite material according to claim 6 is characterized in that the said Ca of containing
2+Inorganic salt be Ca (CH
3COO)
2H
2O, Ca (NO
3)
2And CaCl
2In a kind of or triangular combination in any; Contain PO
4 3-Inorganic salt be Na
3PO
4, Na
2HPO
42H
2O and NaH
2PO
412H
2A kind of or triangular combination in any among the O; The said SiO that contains
3 2-Inorganic salt adopt Na
2SiO
3Contain Sr
2+Inorganic salt adopts SrCl
2And Sr (NO
3)
2In a kind of or combination in any between the two, contain Zn
2+Inorganic salt adopts ZnCl
2And Zn (NO
3)
2In a kind of or combination in any between the two; Contain Mg
2+Inorganic salt adopts MgCl
2And Mg (NO
3)
2In a kind of or combination in any between the two.
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| CN102432694A (en) * | 2011-09-28 | 2012-05-02 | 郭宏昌 | Medicine for promoting bone cell growth |
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