CN101721751B - Human tissue engineering support loaded with controlled-release cell growth factor and provided with hollow silicon dioxide ball with kernel and preparation method and applications thereof - Google Patents
Human tissue engineering support loaded with controlled-release cell growth factor and provided with hollow silicon dioxide ball with kernel and preparation method and applications thereof Download PDFInfo
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- CN101721751B CN101721751B CN2008102240131A CN200810224013A CN101721751B CN 101721751 B CN101721751 B CN 101721751B CN 2008102240131 A CN2008102240131 A CN 2008102240131A CN 200810224013 A CN200810224013 A CN 200810224013A CN 101721751 B CN101721751 B CN 101721751B
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Abstract
The invention belongs to the technical field of bomedical material preparation, in particular relates to human tissue engineering support loaded with controlled-release cell growth factor and provided with hollow silicon dioxide ball with kernel and a preparation method and applications thereofThe human tissue engineering support is prepared in the following steps: the hollow silicon dioxide submicron ball loaded with cell growth factors and provided with kernel is self-assembled with gelatin to form a compound ball which is composed of the hollow silicon dioxide submicron ball loaded with cell growth factors and provided with kernel and the gelatin; then the compound ball is loaded to macromolecule polymer fiber base material obtained by the electric spinning method, thus obtaining the human tissue engineering support.With hollow silicon dioxide submicron ball with kernel as a slow release carrier of the cell growth factors, cell proliferation and differentiation is promoted by loading and slowly releasing the cell growth factors.The human tissue engineering support of the invention is an all-round imitation of the cell growth microenvironment, thus enjoying broad application prospect in the field of tissue engineering support covering tissue repair and tissue reconstruction.
Description
Technical field
The invention belongs to the biomedical material preparing technical field, particularly load the human tissue engineering support and its production and use of the hollow silica ball with kernel of controlled-release cell growth factor.
Background technology
Tissue, the particularly source of the great organ of human body are deficient, are large obstacles of gentrify human body disease damage tissue or human organ tissue transplantation always; Be used for the exploitation of human tissue engineering product of biological activity substitute of structure, the function of gentrify human body disease damage tissue or human organ, will help greatly to improve level of human health.The human tissue engineering product loads on a kind of good cell compatibility and can be by on the biomaterial of people's body degraded and absorbed of having with the normal tissue cell of people's cultured and amplified in vitro, then with load the disease damage position of biomaterial composites implant into body tissue of normal tissue cell or the disease damage position of organ, as the biomaterial of Growth of Cells support gradually by people's body degraded and absorbed in, cell is propagation and differentiation constantly, and be formed on the consistent new tissue of tissue at the disease damage position of the disease damage position of form and function aspect and tissue or organ, thereby reach the purpose of repairing wound and Reconstruction of The Function.
Human tissue engineering support is conducive to adhesion, propagation and the differentiation of cell, for Growth of Cells provides suitable external environment for the cell that makes up tissue provides three-dimensional rack.Desirable human tissue engineering support should possess following features: 1) possess good biocompatibility, can not affect because of the rejection of adjacent tissue neoblastic function; 2) have degradability and suitable degradation rate, when the new human tissue cell of transplanting or tissue were survived in receptor, timbering material can be degraded voluntarily; 3) has the biomechanical strength that meets human body cell, human tissue organ's requirement; 4) have good human body cell interface relation, can interact to preserve and promote the human body cell function; 5) be convenient to be processed into desirable two dimension or three dimensional structure, and can keep original shape after being transplanted in the human body.
Except human tissue engineering support, cell growth factor is moved promoting the division growth of cell, and gene expression and differentiation play vital effect.Add cell growth factor in cultivating system, the analog cell microenvironment can prolong the cell survival time, makes up the tissue with 26S Proteasome Structure and Function.Cell growth factor is compound to the focus that becomes in recent years research in the human tissue engineering support.
At present, developed the human tissue engineering support that several different methods prepares various structures, but the human tissue engineering support General Mechanics intensity difference that obtains, the function that do not possess controlled-release cell growth factor.Patent of invention " a kind of preparation method of chitosan tubular bracket " (publication number: disclose a kind of preparation method of the chitosan tubular bracket with Weaving method preparation CN1568904), but this support does not have the function of controlled-release cell growth factor; Patent of invention " a kind of construction method that contains the skin tissue engineering scaffold of epidermal growth factor " (publication number: obtain containing the skin tissue engineering scaffold of epidermal growth factor CN1511592) by freeze-drying, but the tissue engineering bracket intensity that obtains is relatively poor.
The present invention is directed to the demand of the outer cell culture of human body, prepared human tissue engineering support by simple preparation method design.This human tissue engineering support adopts the hollow silica sub-micron ball controlled-release cell growth factor with kernel, then self assembly is silicon dioxide/gelatin-compounded ball, load on the polymer fiber of electrical spinning method preparation, obtain human tissue engineering support.This human tissue engineering support comprehensive simulated human body cell microenvironment comprises micron and the nanostructured, controlled-release cell growth factor of the extracellular matrix of cell, possesses the ideal conditions of the high vigor cultivation of human body cell.This human tissue engineering support has good mechanical performance and cell compatibility, and is applied widely, can be used for the reparation of the histoorgans such as bone, cartilage, nerve, blood vessel, bladder, kidney, liver.
Summary of the invention
One of purpose of the present invention the has provided load human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor.
The preparation method of human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor that two of purpose of the present invention has provided load.
The purposes of the human tissue engineering support of the hollow silica ball with kernel of three of purpose of the present invention is loads controlled-release cell growth factor.
Load of the present invention the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, be that the hollow silica sub-micron ball with kernel by having loaded cell growth factor and gelatin self assembly are to have loaded the composite balls that the hollow silica sub-micron ball with kernel of cell growth factor and gelatin form, then it loaded on the high polymer fiber as the human tissue engineering support base material that is prepared by electrical spinning method and obtain.
Load of the present invention the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor be: on as the high polymer fiber of human tissue engineering support base material load the hollow silica sub-micron ball with kernel of controlled-release cell growth factor and the composite balls that gelatin forms.The particle diameter of composite balls is 1 μ m～1000 μ m.
Also loaded nutrient substance in the composite balls that described hollow silica sub-micron ball with kernel and gelatin form, the composite balls of the hollow silica sub-micron ball with kernel with the gelatin composition of obtained on as the high polymer fiber of human tissue engineering support base material load controlled-release cell growth factor and nutrient substance.The particle diameter of composite balls is 1 μ m～1000 μ m.
Load of the present invention the preparation method of human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor may further comprise the steps:
The hollow silica sub-micron ball that 1) will have a kernel is immersed in the cell growth factor aqueous solution, under being 4 ℃, temperature stirs, then be centrifugal under 4 ℃ in temperature, with washed with de-ionized water gained solid product, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of cell growth factor;
2) with step 1) loading that obtains the hollow silica sub-micron ball ultra-sonic dispersion with kernel of cell growth factor in aqueous gelatin solution, then lyophilization has obtained loading the hollow silica sub-micron ball with kernel of cell growth factor and the composite balls that gelatin forms;
3) with step 2) loading that obtains the hollow silica sub-micron ball with kernel of cell growth factor and the composite balls that gelatin forms be dispersed in the alcohol solvent, add N-hydroxy-succinamide (NHS) and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides (EDC), fully reaction under the room temperature, use afterwards phosphate buffer (PBS) washing, obtain on the surface of composite balls can with the activated carboxylic group as the amino covalence coupling on the high molecular polymer of human tissue engineering support base material; The composite balls of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid as the high polymer fiber of human tissue engineering support base material for preparing by electrical spinning method, 4 ℃ of lower reactions, take out the high polymer fiber after soaking, with phosphate buffer washing, the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor that obtained load.
Step 1) be with 10 in
-3It is 10 that the hollow silica sub-micron ball that～10g has a kernel is immersed in concentration
-3In the cell growth factor aqueous solution of～10mmol/L; In the cell growth factor aqueous solution, also further contain nutrient substance.
Step 2) final concentration of hollow silica sub-micron ball in aqueous gelatin solution with kernel that has loaded cell growth factor is 10
-3～100mg/mL, the mass concentration of aqueous gelatin solution is 0.05～10%; Perhaps step 2) final concentration of hollow silica sub-micron ball in aqueous gelatin solution with kernel that has loaded cell growth factor and nutrient substance is 10
-3～100mg/mL, the mass concentration of aqueous gelatin solution is 0.05～10%.
Step 3) the hollow silica sub-micron ball with kernel of cell growth factor and the composite balls that gelatin forms have been loaded in, perhaps loaded the hollow silica sub-micron ball with kernel of cell growth factor and nutrient substance and the composite balls that gelatin forms, the concentration in alcohol solvent is 10
-2～10
2Mg/mL; N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in alcohol solvent is respectively 10
-7～10
-3Mol/L.
Step 3) contain in the phosphate-buffered dispersion liquid in to pass through the high polymer fiber as the human tissue engineering support base material that electrical spinning method prepares be 10
-2～10
2Mg/ml.
Described nutrient substance is selected from vitamin A, vitamin B (comprises B1, B2, B6, B12, PP, inositol, M etc.), vitamin C, vitamin D, vitamin E, vitamin K, tryptophan, threonine, methionine, valine, lysine, leucine, isoleucine, phenylalanine, L-glutaminate, purine, pyrimidine, glucose, fructose, galactose, lactose, sucrose, maltose, cholic acid, choline, sterin, creatine, prostaglandin, epinephrine, insulin, cholesterol, phospholipid, glycolipid, hemoglobin, ribose, a kind of in the deoxyribose etc. or greater than more than one.
Step 1) the times of stirring under temperature is 4 ℃ are 12～72 hours.
Step 3) fully the time of reaction is 15～60 minutes under the room temperature; Time 4 ℃ of lower reactions is 4～72 hours.
Described hollow silica sub-micron ball with kernel has the hollow meso-hole structure, as slow-released carrier, by loading, slowly Growth of Cells, propagation and the differentiation of release cells factors stimulated growth human body.
The preparation of described hollow silica sub-micron ball with kernel and can be referring to number of patent application CN200610089184.9 and number of patent application CN200610113976.5 as slow-released carrier.
The particle diameter of described hollow silica sub-micron ball with kernel is between 100～1000nm, and outer casing thickness is between 20～200nm; It is the movably preparing spherical SiO 2 kernel of 50～500nm that one particle diameter is arranged in the cavity of this hollow silica sub-micron ball; This hollow silica sub-micron ball has meso-hole structure, and mesoporous aperture is 3～50nm; The specific surface area of this hollow silica sub-micron ball is 100～1000m
2/ g.
Wherein, be the described method of CN200610089184.9 according to number of patent application, be that the Fluohydric acid. molar concentration described in the CN200610089184.9 is from 1 * 10 with number of patent application
-3～5 * 10
-1Mol/L expands to 1 * 10
-4～10 * 10
-1Mol/L, the mesoporous average pore size that can obtain having the hollow silica sub-micron ball of kernel expands to 3～50nm by 3～10nm, and reference area is by 140～500m
2/ g expands to 140～1000m
2/ g.
Described cell growth factor is selected from transforming growth factor, epidermal growth factor, VEGF, basic fibroblast growth factor, nerve growth factor, chondromodulin, glial growth factor, platelet derived growth factor, hepatocyte growth factor, people's Keratinocytes factor, insulin like growth factor, a kind of in the bone morphogenetic protein etc. or greater than more than one.
The diameter of described high polymer fiber as the human tissue engineering support base material is 10nm～1000 μ m, and the compound human tissue engineering support diameter that has after the hollow silica sub-micron ball of kernel and the composite balls that gelatin forms is 1010nm～2000 μ m.
Described high polymer fiber is different with molecular weight according to selected type of polymer, and the degradation time in human body is about 1 day～1 year.High molecular polymer is amino polyvinyl alcohol, hold amino polylactic acid, the statistic copolymer of end aminopropan lactide and Acetic acid, hydroxy-, bimol. cyclic ester, random or the block copolymer of end aminopropan lactide-ethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester, polymine, PPI, polyethyene diamine, polyamide, PVOH amine, hold amino Polyethylene Glycol, polylysine, poly-gamma-glutamic acid, poly-aspartate, poly arginine, poly-asparagine, chitin, chitosan, poly-amino-beta--cyclodextrin, gelatin, collagen, aminoglycan, fibroin, spider silk fibroin, aminocellulose or amino starch etc.
The processing of electricity consumption spinning equipment can be as the technique of the high polymer fiber of human tissue engineering support base material: the high molecular polymer spinning liquid that configures is joined in the reservoir of electric spinning device, adopt No. 9 the tack spinning head, the spinning liquid flow velocity is 0.01ml/h～100ml/h, apply voltage 1～50kV and carry out Electrospun, the receptor at 0.1cm above spinning nozzle～100cm place obtains high polymer fiber.
Load of the present invention controlled-release cell growth factor or further to contain the preparation cost of human tissue engineering support of the hollow silica ball with kernel of nutrient substance low, be fit to large-scale production, can be used as the support of reparation or the reconstruction of various human soma or organ; Described tissue or organ comprise liver, nerve, bone, cartilage, kidney, bladder, blood vessel, skin or heart.
Load of the present invention the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor compare with existing human tissue engineering support, have the following advantages and outstanding effect: 1) human tissue engineering support of the present invention's preparation adopts the good material of biocompatibility, has hierarchy, specific surface area is large, is conducive to cell adhesion and growth; 2) cell growth factor etc. is loaded in the hollow silica sub-micron ball with kernel, has greatly saved the consumption of expensive cell growth factor; 3) cell growth factor is contained in the hollow silica sub-micron ball with kernel, increases cell to tropism and the adhesive force of support, promote cell to the support internal breeding, thereby promote the release with extracellular matrix components of converging between the cell; 4) high polymer fiber becomes tissue with cell proliferation, can be had the hollow silica of kernel with urine and defecate by degradable, can not cause organism immune response and inflammatory reaction; 5) further contain nutrient substance and can play auxiliary curative effect to the healing of wound.
The specific embodiment
Embodiment 1.
1.0.001g (particle diameter is 100nm, and outer casing thickness is 22nm, and mesoporous aperture is 3nm, and specific surface area is 100m to have the hollow silica sub-micron ball of kernel (kernel size for 50nm)
2/ g) be immersed in the 0.001mmol/L nerve growth factor aqueous solution, be 4 ℃ of lower stirrings 12 hours in temperature.Temperature be 4 ℃ lower centrifugal, 3 times gained solid products of washed with de-ionized water, lyophilization obtains loading the hollow silica ball with kernel of nerve growth factor.
2. the hollow silica ball ultra-sonic dispersion with kernel of the loading nerve growth factor that will obtain is in mass concentration is 1% aqueous gelatin solution, and the final concentration of hollow silica ball in aqueous gelatin solution with kernel that loads nerve growth factor is 10
-3Mg/mL, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of nerve growth factor and the composite balls that gelatin forms.The particle diameter of composite balls is 1 μ m.
3. the 1g chitosan is dissolved in the 10ml water, makes Electrospun liquid.The spinning liquid that configures is joined in the reservoir of electric spinning device, adopt No. 9 the tack spinning head, the spinning liquid flow velocity is 0.1ml/h, applies voltage 5kV and carries out Electrospun.The receptor at 15cm place obtains chitin fiber above spinning nozzle.Approximately 950 microns of average fibre diameters.
4. the loading that step 2 is obtained the composite balls that forms of the hollow silica ball with kernel of nerve growth factor and gelatin be dispersed in the alcohol solvent, the hollow silica sub-micron ball with kernel that has loaded nerve growth factor is 1mg/mL with the concentration of composite balls in alcohol solvent of gelatin composition; Add N-hydroxy-succinamide and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, make N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in above-mentioned alcohol solvent be respectively 10
-7Mol/L, mix homogeneously, room temperature was fully reacted 15 minutes, washed 2 times with phosphate buffer afterwards, obtain on the surface of composite balls can with the activated carboxylic group as the amino covalence coupling on the chitin fiber of human tissue engineering support base material.The composite balls 1mg/ml of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid that passes through the chitin fiber that step 3 prepares that concentration is 1mg/ml, 4 ℃ of lower reactions 4 hours, take out the chitin fiber after soaking, wash about 3 times with phosphate buffer, but obtain the chitin fiber human tissue engineering support that load has the hollow silica ball with kernel that has loaded the slow release nerve growth factor.
When this human tissue engineering support can sustain damage at people's nerve, when nerve is repaired, its recovery support as nerve is used.
Embodiment 2.
1.10g (particle diameter is 980nm, and outer casing thickness is 20nm, and mesoporous aperture is 10nm, and specific surface area is 400m to have the hollow silica sub-micron ball of kernel (kernel size for 500nm)
2/ g) be immersed in the 10mmol/L epidermal growth factor aqueous solution, be 4 ℃ of lower stirrings 72 hours in temperature.Temperature be 4 ℃ lower centrifugal, 3 times gained solid products of washed with de-ionized water, lyophilization obtains the hollow silica ball with kernel of load table skin growth factor.
With the hollow silica ball ultra-sonic dispersion with kernel of the load table skin growth factor that obtains in mass concentration is 0.1% aqueous gelatin solution, the final concentration of hollow silica ball in aqueous gelatin solution with kernel of load table skin growth factor is 100mg/mL, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of epidermal growth factor and the composite balls that gelatin forms.The particle diameter of composite balls is 1000 μ m.
3. the 1g amino polyvinyl alcohol is dissolved in the 10ml water, makes Electrospun liquid.The spinning liquid that configures is joined in the reservoir of electric spinning device, adopt No. 9 the tack spinning head, the spinning liquid flow velocity is 100ml/h, applies voltage 50kV and carries out Electrospun.The receptor at 85cm place obtains the amino polyvinyl alcohol fiber above spinning nozzle.Average fibre diameter is 300nm approximately.
4. the loading that step 2 is obtained the composite balls that forms of the hollow silica ball with kernel of epidermal growth factor and gelatin be dispersed in the alcohol solvent, the hollow silica sub-micron ball with kernel that has loaded epidermal growth factor is 100mg/mL with the concentration of composite balls in alcohol solvent of gelatin composition; Add N-hydroxy-succinamide and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, make N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in above-mentioned alcohol solvent be respectively 10
-3Mol/L, mix homogeneously, room temperature was fully reacted 60 minutes, washed 2 times with phosphate buffer afterwards, obtain on the surface of composite balls can with the activated carboxylic group as the amino covalence coupling on the amino polyvinyl alcohol fiber of human tissue engineering support base material.The composite balls 100mg/ml of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid that passes through the amino polyvinyl alcohol fiber that step 3 prepares that concentration is 100mg/ml, 4 ℃ of lower reactions 4 hours, take out the amino polyvinyl alcohol fiber after soaking, wash about 3 times with phosphate buffer, but obtain the amino polyvinyl alcohol fiber human tissue engineering support that load has the hollow silica ball with kernel that has loaded the slow release epidermal growth factor.
When this human tissue engineering support can sustain damage at people's blood vessel, when blood vessel is repaired, its recovery support as blood vessel is used.
Embodiment 3.
1.0.1g (particle diameter is 700nm, and outer casing thickness is 50nm, and mesoporous aperture is 20nm, and specific surface area is 1000m to have the hollow silica sub-micron ball of kernel (kernel size for 250nm)
2/ g) be immersed in the 0.1mmol/L bone morphogenetic protein aqueous solution, be 4 ℃ of lower stirrings 48 hours in temperature.Temperature be 4 ℃ lower centrifugal, 3 times gained solid products of washed with de-ionized water, lyophilization obtains loading the hollow silica ball with kernel of bone morphogenetic protein.
2. the hollow silica ball ultra-sonic dispersion with kernel of the loading bone morphogenetic protein that will obtain is in mass concentration is 9.8% aqueous gelatin solution, the final concentration of hollow silica ball in aqueous gelatin solution with kernel that loads bone morphogenetic protein is 1mg/mL, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of bone morphogenetic protein and the composite balls that gelatin forms.The particle diameter of composite balls is 180 μ m.
3. the 0.2g gelatin is dissolved in the 10ml water, makes Electrospun liquid.The spinning liquid that configures is joined in the reservoir of electric spinning device, adopt No. 9 the tack spinning head, the spinning liquid flow velocity is 1ml/h, applies voltage 5kV and carries out Electrospun.The receptor at 0.1cm place obtains gelatin fiber above spinning nozzle.Approximately 40 microns of average fibre diameters.
4. the loading that step 2 is obtained the composite balls that forms of the hollow silica ball with kernel of bone morphogenetic protein and gelatin be dispersed in the alcohol solvent, the hollow silica sub-micron ball with kernel that has loaded bone morphogenetic protein is 0.05mg/mL with the concentration of composite balls in alcohol solvent of gelatin composition; Add N-hydroxy-succinamide and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, make N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in above-mentioned alcohol solvent be respectively 5 * 10
-6Mol/L, mix homogeneously, room temperature was fully reacted 30 minutes, washed 2 times with phosphate buffer afterwards, obtain on the surface of composite balls can with the activated carboxylic group as the amino covalence coupling on the gelatin fiber of human tissue engineering support base material.The composite balls 0.05mg/ml of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid that passes through the gelatin fiber that step 3 prepares that concentration is 0.05mg/ml, 4 ℃ of lower reactions 24 hours, take out the gelatin fiber after soaking, wash about 3 times with phosphate buffer, but obtain the gelatin fiber human tissue engineering support that load has the hollow silica ball with kernel that has loaded the slow release bone morphogenetic protein.
When this human tissue engineering support can sustain damage at people's cartilage, when cartilage is repaired, its recovery support as cartilage is used.
Embodiment 4.
1.1g (particle diameter is 500nm to have the hollow silica sub-micron ball of kernel (kernel size for 230nm), outer casing thickness is 50nm, mesoporous aperture is 45nm, specific surface area is 650m2/g) be immersed in the 1mmol/L hepatocyte growth factor aqueous solution, be 4 ℃ of lower stirrings 50 hours in temperature.Temperature be 4 ℃ lower centrifugal, 3 times gained solid products of washed with de-ionized water, lyophilization obtains loading the hollow silica ball with kernel of hepatocyte growth factor.
2. the hollow silica ball ultra-sonic dispersion with kernel of the loading hepatocyte growth factor that will obtain is in mass concentration is 5% aqueous gelatin solution, the final concentration of hollow silica ball in aqueous gelatin solution with kernel that loads hepatocyte growth factor is 10mg/mL, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of hepatocyte growth factor and the composite balls that gelatin forms.The particle diameter of composite balls is 50 μ m.
3. the 1g fibroin is dissolved in the 10ml water, makes Electrospun liquid.The spinning liquid that configures is joined in the reservoir of electric spinning device, adopt No. 9 the tack spinning head, the spinning liquid flow velocity is 10ml/h, applies voltage 15kV and carries out Electrospun.The receptor at 10cm place obtains fibroin fiber above spinning nozzle.Approximately 90 microns of average fibre diameters.
4. the loading that step 2 is obtained the composite balls that forms of the hollow silica ball with kernel of hepatocyte growth factor and gelatin be dispersed in the alcohol solvent, the hollow silica sub-micron ball with kernel that has loaded hepatocyte growth factor is 0.01mg/mL with the concentration of composite balls in alcohol solvent of gelatin composition; Add N-hydroxy-succinamide and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, make N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in above-mentioned alcohol solvent be respectively 10
-5Mol/L, mix homogeneously, room temperature was fully reacted 30 minutes, washed 2 times with phosphate buffer afterwards, obtain on the surface of composite balls can with the activated carboxylic group as the amino covalence coupling on the fibroin fiber of human tissue engineering support base material.The composite balls 0.01mg/ml of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid that passes through the fibroin fiber that step 3 prepares that concentration is 0.01mg/ml, 4 ℃ of lower reactions 48 hours, take out the fibroin fiber after soaking, wash about 3 times with phosphate buffer, but obtain the fibroin fiber human tissue engineering support that load has the hollow silica ball with kernel that has loaded the slow release hepatocyte growth factor.
When this human tissue engineering support can sustain damage at people's liver, when liver is repaired, its recovery support as liver is used.
Embodiment 5.
1.0.01g (particle diameter is 700nm, and outer casing thickness is 40nm, and mesoporous aperture is 25nm, and specific surface area is 800m to have the hollow silica sub-micron ball of kernel (kernel size for 250nm)
2/ g) be immersed in the 5mmol/L hepatocyte growth factor aqueous solution, be 4 ℃ of lower stirrings 12 hours in temperature.Temperature be 4 ℃ lower centrifugal, 3 times gained solid products of washed with de-ionized water, lyophilization obtains loading the hollow silica ball with kernel of hepatocyte growth factor.
2. the hollow silica ball ultra-sonic dispersion with kernel of the loading hepatocyte growth factor that will obtain is in mass concentration is 2% aqueous gelatin solution, the final concentration of hollow silica ball in aqueous gelatin solution with kernel that loads hepatocyte growth factor is 0.1mg/mL, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of hepatocyte growth factor and the composite balls that gelatin forms.The particle diameter of composite balls is 160 μ m.
3. the 0.5g polylactic acid is dissolved in the 10ml water, makes Electrospun liquid.The spinning liquid that configures is joined in the reservoir of electric spinning device, adopt No. 9 the tack spinning head, the spinning liquid flow velocity is 0.1ml/h, applies voltage 10kV and carries out Electrospun.The receptor at 20cm place obtains acid fiber by polylactic above spinning nozzle.Approximately 100 microns of average fibre diameters.
4. the loading that step 2 is obtained the composite balls that forms of the hollow silica ball with kernel of hepatocyte growth factor and gelatin be dispersed in the alcohol solvent, the hollow silica sub-micron ball with kernel that has loaded hepatocyte growth factor is 10mg/mL with the concentration of composite balls in alcohol solvent of gelatin composition; Add N-hydroxy-succinamide and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, make N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in above-mentioned alcohol solvent be respectively 10
-5Mol/L, mix homogeneously, room temperature was fully reacted 45 minutes, washed 2 times with phosphate buffer afterwards, obtain on the surface of composite balls can with the activated carboxylic group as the amino covalence coupling on the acid fiber by polylactic of human tissue engineering support base material.The composite balls 10mg/ml of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid that passes through the acid fiber by polylactic that step 3 prepares that concentration is 10mg/ml, 4 ℃ of lower reactions 24 hours, take out the acid fiber by polylactic after soaking, wash about 3 times with phosphate buffer, but obtain the acid fiber by polylactic human tissue engineering support that load has the hollow silica ball with kernel that has loaded the slow release hepatocyte growth factor.
When this human tissue engineering support can sustain damage at people's liver, when liver is repaired, its recovery support as liver is used.
Embodiment 6.
1.0.5g (particle diameter is 220nm, and outer casing thickness is 40nm, and mesoporous aperture is 25nm, and specific surface area is 800m to have the hollow silica sub-micron ball of kernel (kernel size for 80nm)
2/ g) be immersed in the 1mmol/L transforming growth factor β aqueous solution, be 4 ℃ of lower stirrings 36 hours in temperature.Temperature be 4 ℃ lower centrifugal, 3 times gained solid products of washed with de-ionized water, lyophilization obtains loading the hollow silica ball with kernel of transforming growth factor β.
2. the hollow silica ball ultra-sonic dispersion with kernel of the loading transforming growth factor β that will obtain is in mass concentration is 0.05% aqueous gelatin solution, the final concentration of hollow silica ball in aqueous gelatin solution with kernel that loads transforming growth factor β is 0.05mg/mL, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of transforming growth factor β and the composite balls that gelatin forms.The particle diameter of composite balls is 250 μ m.
With the 0.5g starch dissolution in 10ml water, make Electrospun liquid.The spinning liquid that configures is joined in the reservoir of electric spinning device, adopt No. 9 the tack spinning head, the spinning liquid flow velocity is 0.5ml/h, applies voltage 20kV and carries out Electrospun.The receptor at 5cm place obtains starch fiber above spinning nozzle.Approximately 460 microns of average fibre diameters.
4. the loading that step 2 is obtained the composite balls that forms of the hollow silica ball with kernel of transforming growth factor β and gelatin be dispersed in the alcohol solvent, the hollow silica sub-micron ball with kernel that has loaded the transforming growth factor β factor is 1mg/mL with the concentration of composite balls in alcohol solvent of gelatin composition; Add N-hydroxy-succinamide and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, make N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in above-mentioned alcohol solvent be respectively 5 * 10
-5Mol/L, mix homogeneously, room temperature was fully reacted 50 minutes, washed 2 times with phosphate buffer afterwards, obtain on the surface of composite balls can with the activated carboxylic group as the amino covalence coupling on the starch fiber of human tissue engineering support base material.The composite balls 1mg/ml of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid that passes through the starch fiber that step 3 prepares that concentration is 1mg/ml, 4 ℃ of lower reactions 50 hours, take out the starch fiber after soaking, wash about 3 times with phosphate buffer, but obtain the starch fiber human tissue engineering support that load has the hollow silica ball with kernel that has loaded the slow release transforming growth factor β.
When this human tissue engineering support can sustain damage at people's kidney, when kidney is repaired, its recovery support as kidney is used.
Embodiment 7.
1.0.2g (particle diameter is 600nm, and outer casing thickness is 30nm, and mesoporous aperture is 50nm, and specific surface area is 600m to have the hollow silica sub-micron ball of kernel (kernel size for 200nm)
2/ g) be immersed in the 1mmol/L platelet derived growth factor aqueous solution, be 4 ℃ of lower stirrings 60 hours in temperature.Temperature be 4 ℃ lower centrifugal, 3 times gained solid products of washed with de-ionized water, lyophilization obtains loading the hollow silica ball with kernel of platelet derived growth factor.
2. the hollow silica ball ultra-sonic dispersion with kernel of the loading platelet derived growth factor that will obtain is in mass concentration is 0.5% aqueous gelatin solution, the final concentration of hollow silica ball in aqueous gelatin solution with kernel that loads platelet derived growth factor is 0.2mg/mL, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of platelet derived growth factor and the composite balls that gelatin forms.The particle diameter of composite balls is 150 μ m.
With the 1g collagenolysis in 10ml water, make Electrospun liquid.The spinning liquid that configures is joined in the reservoir of electric spinning device, adopt No. 9 the tack spinning head, the spinning liquid flow velocity is 10ml/h, applies voltage 30kV and carries out Electrospun.The receptor at 55cm place obtains collagen fiber above spinning nozzle.Approximately 180 microns of average fibre diameters.
4. the loading that step 2 is obtained the composite balls that forms of the hollow silica ball with kernel of platelet derived growth factor and gelatin be dispersed in the alcohol solvent, the hollow silica sub-micron ball with kernel that has loaded platelet derived growth factor is 0.2mg/mL with the concentration of composite balls in alcohol solvent of gelatin composition; Add N-hydroxy-succinamide and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, make N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in above-mentioned alcohol solvent be respectively 2 * 10
-4Mol/L, mix homogeneously, room temperature was fully reacted 30 minutes, washed 2 times with phosphate buffer afterwards, obtain on the surface of composite balls can with the activated carboxylic group as the amino covalence coupling on the collagen fiber of human tissue engineering support base material.The composite balls 0.2mg/ml of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid that passes through the collagen fiber that step 3 prepares that concentration is 0.2mg/ml, 4 ℃ of lower reactions 48 hours, take out the collagen fiber after soaking, wash about 3 times with phosphate buffer, but obtain the collagen fiber human tissue engineering support that load has the hollow silica ball with kernel that has loaded the slow release platelet derived growth factor.
This human tissue engineering support can when Person's skin sustains damage, use its recovery support as skin when skin is repaired.
Embodiment 8.
1.0.05g (particle diameter is 300nm, and outer casing thickness is 30nm, and mesoporous aperture is 20nm, and specific surface area is 850m to have the hollow silica sub-micron ball of kernel (kernel size for 100nm)
2/ g) be immersed in the 0.1mmol/L chondromodulin aqueous solution, be 4 ℃ of lower stirrings 40 hours in temperature.Temperature be 4 ℃ lower centrifugal, 3 times gained solid products of washed with de-ionized water, lyophilization obtains loading the hollow silica ball with kernel of chondromodulin.
2. the hollow silica ball ultra-sonic dispersion with kernel of the loading chondromodulin that will obtain is in mass concentration is 1% aqueous gelatin solution, the final concentration of hollow silica ball in aqueous gelatin solution with kernel that loads chondromodulin is 0.02mg/mL, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of chondromodulin and the composite balls that gelatin forms.The particle diameter of composite balls is 40 μ m.
With 1g PVOH amine solvent in 10ml water, make Electrospun liquid.The spinning liquid that configures is joined in the reservoir of electric spinning device, adopt No. 9 the tack spinning head, the spinning liquid flow velocity is 1ml/h, applies voltage 15kV and carries out Electrospun.The receptor at 20cm place obtains PVOH amine fiber above spinning nozzle.Approximately 100 microns of average fibre diameters.
4. the loading that step 2 is obtained the composite balls that forms of the hollow silica ball with kernel of chondromodulin and gelatin be dispersed in the alcohol solvent, the hollow silica sub-micron ball with kernel that has loaded chondromodulin is 0.05mg/mL with the concentration of composite balls in alcohol solvent of gelatin composition; Add N-hydroxy-succinamide and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, make N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in above-mentioned alcohol solvent be respectively 1 * 10
-4Mol/L, mix homogeneously, room temperature was fully reacted 20 minutes, washed 2 times with phosphate buffer afterwards, obtain on the surface of composite balls can with the activated carboxylic group as the amino covalence coupling on the PVOH amine fiber of human tissue engineering support base material.The composite balls 0.05mg/ml of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid that passes through the PVOH amine fiber that step 3 prepares that concentration is 0.05mg/ml, 4 ℃ of lower reactions 40 hours, take out the PVOH amine fiber after soaking, wash about 3 times with phosphate buffer, but obtain the PVOH amine fiber human tissue engineering support that load has the hollow silica ball with kernel that has loaded the slow release chondromodulin.
When this human tissue engineering support can sustain damage at people's cartilage, when skin is repaired, its recovery support as cartilage is used.
Embodiment 9
1.0.4g (particle diameter is 260nm, and outer casing thickness is 30nm, and mesoporous aperture is 10nm, and specific surface area is 600m to have the hollow silica sub-micron ball of kernel (kernel size for 90nm)
2/ g) be immersed in (L-glutaminate that contains 0.01mol/L) in the 0.01mmol/L epidermal growth factor aqueous solution, be 4 ℃ of lower stirrings 52 hours in temperature.Temperature be 4 ℃ lower centrifugal, 3 times gained solid products of washed with de-ionized water, lyophilization obtains the hollow silica ball with kernel of load table skin growth factor and L-glutaminate.
With the hollow silica ball ultra-sonic dispersion with kernel of the load table skin growth factor that obtains and L-glutaminate in mass concentration is 0.5% aqueous gelatin solution, the final concentration of hollow silica ball in aqueous gelatin solution with kernel of load table skin growth factor and L-glutaminate is 0.2mg/mL, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of epidermal growth factor and L-glutaminate and the composite balls that gelatin forms.The particle diameter of composite balls is 15 μ m.
3. the 1g polylysine is dissolved in the 10ml water, makes Electrospun liquid.The spinning liquid that configures is joined in the reservoir of electric spinning device, adopt No. 9 the tack spinning head, the spinning liquid flow velocity is 0.5ml/h, applies voltage 5kV and carries out Electrospun.The receptor at 15cm place obtains the polylysine fiber above spinning nozzle.Approximately 600 microns of average fibre diameters.
4. the loading that step 2 is obtained the hollow silica ball with kernel of epidermal growth factor and L-glutaminate and the composite balls that gelatin forms be dispersed in the alcohol solvent, the hollow silica sub-micron ball with kernel that has loaded epidermal growth factor and L-glutaminate is 0.4mg/mL with the concentration of composite balls in alcohol solvent of gelatin composition; Add N-hydroxy-succinamide and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, make N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in above-mentioned alcohol solvent be respectively 1 * 10
-3Mol/L, mix homogeneously, room temperature was fully reacted 30 minutes, washed 2 times with phosphate buffer afterwards, obtain on the surface of composite balls can with the activated carboxylic group as the amino covalence coupling on the collagen of human tissue engineering support base material.The composite balls 0.4mg/ml of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid that passes through the polylysine fiber that step 3 prepares that concentration is 0.4mg/ml, 4 ℃ of lower reactions 24 hours, take out the polylysine after soaking, wash about 3 times with phosphate buffer, but obtain the polylysine fiber human tissue engineering support that load has the hollow silica ball with kernel that has loaded slow release epidermal growth factor and L-glutaminate.
This human tissue engineering support can when Person's skin sustains damage, use its recovery support as skin when skin is repaired.
Claims (18)
- A load human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, be that the hollow silica sub-micron ball with kernel by having loaded cell growth factor and gelatin self assembly are to have loaded the composite balls that the hollow silica sub-micron ball with kernel of cell growth factor and gelatin form, then it loaded on the high polymer fiber base material that is prepared by electrical spinning method and obtain; It is characterized in that:On as the high polymer fiber of human tissue engineering support base material load the hollow silica sub-micron ball with kernel of controlled-release cell growth factor and the composite balls that gelatin forms;Described high molecular polymer is amino polyvinyl alcohol, hold amino polylactic acid, the statistic copolymer of end aminopropan lactide and Acetic acid, hydroxy-, bimol. cyclic ester, random or the block copolymer of end aminopropan lactide-ethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester, polymine, PPI, polyethyene diamine, polyamide, PVOH amine, hold amino Polyethylene Glycol, polylysine, poly-gamma-glutamic acid, poly-aspartate, poly arginine, poly-asparagine, chitin, chitosan, poly-amino-beta--cyclodextrin, gelatin, collagen, aminoglycan, fibroin, spider silk fibroin, aminocellulose or amino starch.
- Load according to claim 1 the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, it is characterized in that: described have in the hollow silica sub-micron ball of kernel and the composite balls that gelatin forms also loaded nutrient substance.
- Load according to claim 1 and 2 the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, it is characterized in that: described have the hollow silica sub-micron ball of kernel and the particle diameter of the composite balls that gelatin forms is 1 μ m～1000 μ m.
- Load according to claim 1 and 2 the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, it is characterized in that: the particle diameter of described hollow silica sub-micron ball with kernel is between 100～1000nm, and outer casing thickness is between 20～200nm; It is the movably preparing spherical SiO 2 kernel of 50～500nm that one particle diameter is arranged in the cavity of this hollow silica sub-micron ball; This hollow silica sub-micron ball has meso-hole structure, and mesoporous aperture is 3～50nm; The specific surface area of this hollow silica sub-micron ball is 100～1000m 2/ g.
- Load according to claim 3 the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, it is characterized in that: the particle diameter of described hollow silica sub-micron ball with kernel is between 100～1000nm, and outer casing thickness is between 20～200nm; It is the movably preparing spherical SiO 2 kernel of 50～500nm that one particle diameter is arranged in the cavity of this hollow silica sub-micron ball; This hollow silica sub-micron ball has meso-hole structure, and mesoporous aperture is 3～50nm; The specific surface area of this hollow silica sub-micron ball is 100～1000m 2/ g.
- Load according to claim 1 the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, it is characterized in that: described cell growth factor is selected from transforming growth factor, epidermal growth factor, VEGF, basic fibroblast growth factor, nerve growth factor, chondromodulin, glial growth factor, platelet derived growth factor, hepatocyte growth factor, people's Keratinocytes factor, insulin like growth factor, a kind of in the bone morphogenetic protein or greater than more than one.
- Load according to claim 2 the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, it is characterized in that: described nutrient substance is selected from vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, tryptophan, threonine, methionine, valine, lysine, leucine, isoleucine, phenylalanine, L-glutaminate, purine, pyrimidine, glucose, fructose, galactose, lactose, sucrose, maltose, cholic acid, choline, sterin, creatine, prostaglandin, epinephrine, insulin, cholesterol, phospholipid, glycolipid, hemoglobin, ribose, a kind of in the deoxyribose or greater than more than one.
- Load according to claim 1 the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, it is characterized in that: the diameter of described high polymer fiber as the human tissue engineering support base material is 10nm～1000 μ m.
- One kind according to claim 1～8 each described load the preparation method of human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, it is characterized in that, the method may further comprise the steps:The hollow silica sub-micron ball that 1) will have a kernel is immersed in the cell growth factor aqueous solution, under being 4 ℃, temperature stirs, then be centrifugal under 4 ℃ in temperature, with washed with de-ionized water gained solid product, lyophilization has obtained loading the hollow silica sub-micron ball with kernel of cell growth factor;2) with step 1) loading that obtains the hollow silica sub-micron ball ultra-sonic dispersion with kernel of cell growth factor in aqueous gelatin solution, then lyophilization has obtained loading the hollow silica sub-micron ball with kernel of cell growth factor and the composite balls that gelatin forms;3) with step 2) loading that obtains the hollow silica sub-micron ball with kernel of cell growth factor and the composite balls that gelatin forms be dispersed in the alcohol solvent, add N-hydroxy-succinamide and 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides, mix homogeneously, fully reaction under the room temperature, afterwards with phosphate buffer washing, obtain on the surface of composite balls and activated carboxylic group as the amino covalence coupling on the high molecular polymer of human tissue engineering support base material; The composite balls of the activated carboxylic that obtains is distributed to contains in the phosphate-buffered dispersion liquid as the high polymer fiber of human tissue engineering support base material for preparing by electrical spinning method, 4 ℃ of lower reactions, take out the high polymer fiber after soaking, with phosphate buffer washing, the human tissue engineering support of the hollow silica sub-micron ball with kernel of controlled-release cell growth factor that obtained load;Described high molecular polymer is amino polyvinyl alcohol, hold amino polylactic acid, the statistic copolymer of end aminopropan lactide and Acetic acid, hydroxy-, bimol. cyclic ester, random or the block copolymer of end aminopropan lactide-ethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester, polymine, PPI, polyethyene diamine, polyamide, PVOH amine, hold amino Polyethylene Glycol, polylysine, poly-gamma-glutamic acid, poly-aspartate, poly arginine, poly-asparagine, chitin, chitosan, poly-amino-beta--cyclodextrin, gelatin, collagen, aminoglycan, fibroin, spider silk fibroin, aminocellulose or amino starch.
- 10. method according to claim 9 is characterized in that: step 1) in be with 10 -3It is 10 that the hollow silica sub-micron ball that～10g has a kernel is immersed in concentration -3In the cell growth factor aqueous solution of～10mmol/L.
- 11. according to claim 9 or 10 described methods, it is characterized in that: also contain nutrient substance in the cell growth factor aqueous solution.
- 12. method according to claim 9 is characterized in that: the final concentration of hollow silica sub-micron ball in aqueous gelatin solution with kernel that has loaded cell growth factor is 10 -3～100mg/mL.
- 13. method according to claim 11 is characterized in that: the final concentration of hollow silica sub-micron ball in aqueous gelatin solution with kernel that has loaded cell growth factor and nutrient substance is 10 -3～100mg/mL.
- 14. according to claim 12 or 13 described methods, it is characterized in that: the mass concentration of aqueous gelatin solution is 0.05～10%.
- 15. method according to claim 9 is characterized in that: step 3) in to have loaded the concentration of composite balls in alcohol solvent that the hollow silica sub-micron ball with kernel of cell growth factor and gelatin form be 10 -2～10 2Mg/mL; N-hydroxy-succinamide and 1-ethyl-3-(3-the dimethyl aminopropyl)-concentration of carbodiimides in alcohol solvent is respectively 10 -7～10 -3Mol/L.
- 16. method according to claim 9 is characterized in that: step 3) in contain in the phosphate-buffered dispersion liquid to pass through the high polymer fiber as the human tissue engineering support base material that electrical spinning method prepares be 10 -2～10 2Mg/mL.
- 17. one kind according to claim 1～8 each described load the purposes of human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor, it is characterized in that: described load the human tissue engineering support of the hollow silica ball with kernel of controlled-release cell growth factor for the preparation of the support as reparation or the reconstruction of tissue or organ.
- 18. purposes according to claim 17 is characterized in that: described tissue or organ comprise liver, nerve, bone, cartilage, kidney, bladder, blood vessel, skin or heart.
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| CN101953797B (en) * | 2010-09-06 | 2012-05-23 | 中华人民共和国卫生部肝胆肠外科研究中心 | Method for preparing medicament carrying controlled-release nanometer material and application |
| CN102091331B (en) * | 2011-01-19 | 2012-11-21 | 浙江大学 | Carboxyl mesoporous silica nanoparticle carrier material and preparation method thereof |
| CN102671244B (en) * | 2012-06-04 | 2015-01-21 | 广州迈普再生医学科技有限公司 | Micro/nano-fiber bone repairing scaffold and production method thereof |
| CN103990177A (en) * | 2014-04-29 | 2014-08-20 | 东华大学 | Preparation method for mesoporous-silicon medicine-carrying system modified by bone-morphogenetic-protein active polypeptide |
| CN105288749A (en) * | 2015-05-20 | 2016-02-03 | 北京航空航天大学 | Preparation method of slow-release polypeptide growth factor biological material scaffold |
| CN106344966A (en) * | 2015-07-13 | 2017-01-25 | 中南大学 | Method for improving cell adhesion of polyglycolic acid stent by using mesoporous silica |
| CN106706524B (en) * | 2017-02-22 | 2019-04-19 | 大连大学 | A method of using oxygen content in the quick detection gas of fibroin film |
| CN106806939B (en) * | 2017-03-29 | 2020-03-31 | 中国人民解放军国防科学技术大学 | Bone repair material and preparation method and application thereof |
| WO2020125806A1 (en) | 2018-12-17 | 2020-06-25 | Shanghai United Imaging Intelligence Co., Ltd. | Systems and methods for image segmentation |
| CN109754394B (en) * | 2018-12-28 | 2021-02-23 | 上海联影智能医疗科技有限公司 | Three-dimensional medical image processing device and method |
| CN109825194B (en) * | 2019-01-24 | 2020-12-18 | 首都医科大学宣武医院 | Heat-insulating coating material for medical catheter and preparation method and application thereof |
| CN113750294B (en) * | 2021-08-31 | 2022-08-16 | 四川大学 | Nerve repair stent loaded with multiple gene vector microspheres and preparation method thereof |
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