CN101791439B - Construction method of medical titanium alloy implant surface growth factor delivery system - Google Patents
Construction method of medical titanium alloy implant surface growth factor delivery system Download PDFInfo
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- CN101791439B CN101791439B CN 201010142543 CN201010142543A CN101791439B CN 101791439 B CN101791439 B CN 101791439B CN 201010142543 CN201010142543 CN 201010142543 CN 201010142543 A CN201010142543 A CN 201010142543A CN 101791439 B CN101791439 B CN 101791439B
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Abstract
The invention relates to a construction method of a medical titanium alloy implant surface growth factor delivery system, which comprises the following steps that: micro-groove ridges are prepared on the surface of a medical low-elastic Beta titanium alloy; gelatin is dissolved into deionized water, and then 2-imine hydrogen chloride mercaptan is added to be dialyzed and dried, to prepare SH gelatin; the SH gelatin is dissolved in double-distilled water to be ultrasonically homogenized to prepare B liquid, emulsifier is added into liquid paraffin, and then the B liquid is dripped into the liquid paraffin which is added with the emulsifier, isopropyl alcohol and ether are cleaned, added with glutaraldehyde and cured, ether elutes, dries and sieves out the cured substance, and 60Co irradiates and sterilizes, to prepare SH gelatin microspheres; and the microspheres are soaked into rhBMP2 guanidine hydrochloride saturated solution and freeze dried under a vacuum condition, to prepare the SH gelatin microspheres loaded with growth factors. Medical low-elastic Beta titanium alloy implant material is soaked into dopamine solution, and a layer of adhered polymer thin film is generated on the surface of the titanium alloy; and the implant material which decorates the surface is put into the growth factor SH gelatin microsphere solution, vacuum is pumped, and the medical titanium alloy implant surface growth factor delivery system is prepared.
Description
Technical field
The present invention relates to a kind of medical bone and induce the preparation method of metal implant material, be specifically related to a kind of construction method of medical titanium alloy implant surface growth factor delivery system.
Background technology
The good bioactivity surface with bone inducibility is a difficult problem of puzzlement metal material implant always.Metal current material surface active modification has several different methods, but up to now, is applied to clinical porous surface and the calcium phosphate coating of also only limiting to, and still there is a big difference from desirable bioactivity surface.In order to make metal implant material have good bioactivity surface, the inventor has carried out a series of research.In the research in early days, use first RGD decorative material micropore surface, the method that again medicine carrying microballoons is compound to RGD makes up the growth factor slow-release system of material surface.Yet the technique of titanium pearl sintering defectiveness still on the one hand, sintering strength does not reach requirement, and RGD is as polypeptide on the other hand, is difficult to all the time guarantee with the bond strength of inorganic metal material surface.Therefore, seek a kind of more effective, more firmly in conjunction with just becoming a new difficult problem.
Summary of the invention
The object of the invention is to overcome the shortcoming of above-mentioned prior art, provide and to have improved the microsphere sustained-release Systems balanth, prepare stable spacetabs type somatomedin biological coating at medical titanium alloy implant surface, make internal fixation material have when keeping good mechanical characteristic that good bone is induced, the bone integration ability, with reduce implant after the construction method of the medical titanium alloy implant surface growth factor delivery system that occurs of the complication such as prosthetic loosening.
For achieving the above object, the technical solution used in the present invention is:
1) preparation of the little ditch ridge of medical titanium alloy implant surface form:
Adopt the solid-state laser marking machine at the little ditch ridge of medical low-elastic beta-titanium alloy surface preparation;
2) preparation of sulfhydrylation gelatin control-release microsphere
2.1 the preparation of sulfhydrylation gelatin
Getting the 1g gelatin is dissolved in the 100mL deionized water, and then the 2 Iminothiolane hydrochloride of adding 20mg, at room temperature react 15h, the 2 Iminothiolane hydrochloride that then will react remaining is removed with the hydrochloric acid solution dialysis, preserves to get the sulfhydrylation gelatin in-80 ℃ behind the vacuum drying;
2.2 the preparation of SH gelatin microsphere
Getting the sulfhydrylation gelatin is dissolved in and is made into the A liquid that mass concentration is 20%-30% in 50 ℃ of distilled waters, 50 ℃ of lower ultrasonic homogenize, the 20ml liquid paraffin is preheated to 40 ℃ and add the emulsifying agent span-80 of 0.8ml, then the volume ratio by 1:5 at the uniform velocity splashes into A liquid in the liquid paraffin that is added with emulsifying agent with 30/min, stir to get suspension and it is transferred to rapidly in 0～4 ℃ the water-bath while dripping, then add isopropanol dehydration and continue stirred for several minute, clean for several times with isopropyl alcohol and ether respectively, wash that to add the 20ml mass concentration behind emulsifying agent and the paraffin be that 5% glutaraldehyde places 4 ℃ of refrigerators to solidify 24h again off, adopt ether to the material eluting after solidifying, wash residual glutaraldehyde off, vacuum drying sieves under the room temperature, packing
60Sealing lucifuge cryopreservation gets SH gelatin microsphere behind the Co radiation sterilization;
2.3 the preparation of somatomedin SH gelatin microsphere
Get blank SH gelatin microsphere, be soaked in the rhBMP2 guanidine hydrochloride saturated solution 24h of 4mol/L, get the SH gelatin microsphere of loaded with growth behind the vacuum freeze-drying;
3) somatomedin sulfhydrylation gelatin control-release microsphere and implantation material surface are compound
3.1 the coating modifying of implantation material surface
Medical low-elastic beta-titanium alloy embedded material after will processing through step 1 is first through ultrasonic cleaning, then it is immersed in the dopamine solution, be adjusted to typical marine environment, air exposure, the dopamine spontaneous deposition generates the thin polymer film that one deck adheres at titanium alloy surface;
3.2 microsphere and embedded material is compound
The somatomedin SH gelatin microsphere is mixed with the solution of 0.2mg/ml, then the embedded material that will modify with the dopamine coating surface is positioned in the somatomedin SH gelatin microsphere solution, evacuation is placed 30min, takes out to obtain medical titanium alloy implant surface growth factor delivery system.
Described solid-state laser marking machine is F-DPC-50A type solid-state laser marking machine, laser power 50W (max), optical maser wavelength 1064um, focal length 175cm, scanning speed 2000mm/s, rate of scanning 5.5kHz.
Described little ditch ridge surface grooves width is cell rank 50 μ m, and the degree of depth is 20 μ m.
Described typical marine environment is the tris buffer that every 2mg dopamine adds 1 milliliter of 10mmol/L, pH=8.5.
The present invention on original medical low-elastic beta-titanium alloy titanium alloy implant surface antibiotic sustained release system basis, the introducing of novelty the bionical poly dopamine coating in ocean.Thereby the stimulation that research report osmotic pressure signal is arranged can make dopamine generation space conformation change object is produced strongly adherent.This coating also is quite stable under mechanical grinding, the strong physical action such as ultrasonic.SH gelatin microsphere by with the covalent bond of the poly dopamine coating of metal surface, make microsphere be incorporated into securely metal material surface.The method is compared with the RGD method of modifying, and preparation technology of coating is simpler, adheres to more powerful reliable.Utilize this poly dopamine coating to the little form finishing of metal, both satisfied the strongly adherent to the metal surface, again can with SH gelatin microsphere generation covalent bond, can reach theoretically the stable bond of microsphere-coating-metal surface fully.
Description of drawings
Figure 1A is regular little ditch ridge surface enlarged drawing, and Figure 1B is irregular matte surface enlarged drawing;
Fig. 2 is Oesteoblast growth figure; Wherein Fig. 2 A is that the surface osteoblast pseudopodium stretching, extension of regular little ditch ridge is many, and cellular morphology is good; Fig. 2 B is that matte surface osteoblast pseudopodium negligible amounts cellular morphology is bad;
Fig. 3 is the chemical reaction figure of sulfhydrylation gelatin;
Fig. 4 is the coating modifying figure of implantation material surface;
Fig. 5 is microsphere and embedded material recombination process figure.
The specific embodiment
Below in conjunction with drawings and Examples the present invention is described in further detail.But the present invention is not limited to following examples.
Through early-stage Study, little ditch ridge surface ratio smooth surface and irregular matte surface all are more suitable for osteoblastic adhesion and growth (is seen Fig. 1,2), and its preparation technology is simple, quality is easily controlled, be more suitable for suitability for industrialized production, the correlational study result delivers (Jun Fu, Zheng Guo, Yunyu Hu, Yongquan Zhang, Yulin Hao, Shujun Li.Effect of surface micro-topography of titanium material on the behaviors of rabbit osteoblast in vitro.Applied Surface Science.2008; 255:286-289).Therefore, the application adopts little ditch ridge surface to substitute previous titanium pearl sintered surface, to overcome the difficult problems such as sintering strength deficiency, sintering process complexity.
At occurring in nature, the bioenergy such as barnacle, mussel secrete a kind of special very strong protein of viscosity by the byssus dish, i.e. barnacle binding proteins is with surface of solids strong bonded such as rock, hulls.Barnacle binding proteins to multiple separate sources is analyzed discovery, these albumen all contain the tyrosine residue of high component without exception, in conglutination reaction, tyrosine generates dopamine under the effect of tryrosinase, and then under oxidizing condition, be polymerized to the poly dopamine, thereby form good bond.After this mechanism is illustrated, Lee etc. find that the use dopamine can be at alkalescence oxidation (10mmol/L Tris-HCl as raw material, pH 8.5, air exposure) forms poly dopamine coating in surfaces of various materials under the condition, and this coating is very stable, even can stand the destruction of mechanical grinding, ultrasonic and strong acid.On this basis, also having a key property is exactly can be by carrying out Mike's additive reaction or schiff base reaction adding new coating with the Organic substance that contains sulfydryl and amino, and this connects multi-medicament so that this coating can be used as the bridge of the modification of material surface.
Through after the groping and test repeatedly, the application has finally found a kind of better solution, namely uses the little ditch ridge of poly dopamine coating modifying metal material surface, and then connects with the sulfhydrylation gelatin of medicine carrying.
Its preparation process is as follows:
1) preparation of the little ditch ridge of medical titanium alloy implant surface form:
Adopting the solid-state laser marking machine is cell rank 50 μ m at the surperficial groove width of medical low-elastic beta-titanium alloy surface preparation, and the degree of depth is little ditch ridge of 20 μ m; Prepared regular little ditch ridge surface should be conducive to the embedding of microsphere, satisfying simultaneously new bone grows into to the requirement of little groove, the solid-state laser marking machine that adopts is F-DPC-50A type solid-state laser marking machine, laser power 50W (max), optical maser wavelength 1064um, focal length 175cm, scanning speed 2000mm/s, rate of scanning 5.5kHz;
2) preparation of sulfhydrylation gelatin control-release microsphere
2.1 the preparation of sulfhydrylation gelatin
Sulfhydrylation gelatin preparation method (Preparation and Evaluation of Thiol-Modified Gelatin Nanoparticles for Intracellular DNA Delivery in Response to Glutathione.Bioconjugate Chem.2005 with reference to Sushma Kommareddy and Mansoor Amiji, 16,1423-1432).Carry out covalent reaction by the amino of introducing sulfydryl part and gelatin and obtain sulfhydrylation gelatin (chemical reaction is seen Fig. 3).Detailed process is as follows: get the 1g gelatin and be dissolved in the 100mL deionized water, and then the 2 Iminothiolane hydrochloride of adding 20mg, at room temperature react 15h, the 2 Iminothiolane hydrochloride that then will react remaining is removed with the hydrochloric acid solution dialysis, preserves to get the sulfhydrylation gelatin in-80 ℃ behind the vacuum drying; The degree of gelatin sulfhydrylation can be calculated by colorimetry.Sulfhydrylation gelatin and common gelatin are dissolved in respectively containing in the phosphatic buffer of 1mmol/L edetic acid (EDTA) 0.1mol/L (PH=8.0) of equivalent, then getting 500 these solution of μ L and 100 μ L ellman's reagents (ELLman ' s reagent) and the buffer of 5mL mixes, chrominance response can occur under the room temperature, behind the reaction 15min, survey light absorption value at the 412nm wavelength.Then extrapolate to contain how many mmol sulfydryls in every gram gelatin according to the cysteine standard curve.
2.2 the preparation of SH gelatin microsphere
Emulsifying condensation method (Effects of intra-aterally biodegradable microsphere containing Mitomycin C.Cance r, 1985 with reference to Fujimoto S; 55:522) also improved;
Detailed process is as follows: get the sulfhydrylation gelatin and be dissolved in and be made into the A liquid that mass concentration is 20%-30% in 50 ℃ of distilled waters, the 20ml liquid paraffin is preheated to 40 ℃ and add the emulsifying agent span-80 of 0.8ml, then the volume ratio by 1:5 at the uniform velocity splashes into A liquid in the liquid paraffin that is added with emulsifying agent with 30/min, stir to get suspension and it is transferred to rapidly in 0～4 ℃ the water-bath while dripping, then add isopropanol dehydration and continue stirred for several minute, clean for several times with isopropyl alcohol and ether respectively, wash that to add the 20ml mass concentration behind emulsifying agent and the paraffin be that 5% glutaraldehyde places 4 ℃ of refrigerators to solidify 24h again off, adopt ether to the material eluting after solidifying, wash residual glutaraldehyde off, vacuum drying sieves under the room temperature, packing
60Sealing lucifuge cryopreservation gets SH gelatin microsphere behind the Co radiation sterilization;
2.3 the preparation of somatomedin SH gelatin microsphere
Take by weighing blank SH gelatin microsphere, be soaked in the rhBMP2 guanidine hydrochloride saturated solution 24h of 4mol/L, get the SH gelatin microsphere of loaded with growth behind the vacuum freeze-drying.
3) somatomedin base gelatin control-release microsphere and implantation material surface are compound
3.1 the coating modifying (see figure 4) of implantation material surface
Medical low-elastic beta-titanium alloy embedded material after will processing through step 1 is first through ultrasonic cleaning, then it is immersed in the dopamine solution, (every 2mg dopamine adds the tris of 1 milliliter of 10mmol/L to be adjusted to typical marine environment, pH=8.5), air exposure, the dopamine spontaneous deposition generates the thin polymer film that one deck adheres at titanium alloy surface; There are functional relationship in thickness and the response time of coating, and such as reaction 24h, coating layer thickness can reach 50nm, and coating layer thickness can be measured with atomic force microscope.
3.2 the compound (see figure 5) of microsphere and embedded material
The somatomedin SH gelatin microsphere is mixed with the solution of 0.2mg/ml, then the embedded material that will modify with the dopamine coating surface is positioned in the SH gelatin microsphere solution of somatomedin, evacuation is placed 30min, takes out to obtain medical titanium alloy implant surface growth factor delivery system.By measuring the surplus of SH gelatin microsphere in the mixed liquor, draw the binding capacity of gelatine microsphere and implantation material surface.Finally obtain medical titanium alloy implant surface growth slow-released system.
Claims (2)
1. the construction method of medical titanium alloy implant surface growth factor delivery system is characterized in that:
1) preparation of the little ditch ridge of medical titanium alloy implant surface form:
Adopt the solid-state laser marking machine at the little ditch ridge of medical low-elastic beta-titanium alloy surface preparation;
2) preparation of sulfhydrylation gelatin control-release microsphere
2.1 the preparation of sulfhydrylation gelatin
Getting the 1g gelatin is dissolved in the 100mL deionized water, and then the 2 Iminothiolane hydrochloride of adding 20mg, at room temperature react 15h, the 2 Iminothiolane hydrochloride that then will react remaining is removed with the hydrochloric acid solution dialysis, preserves to get the sulfhydrylation gelatin in-80 ℃ behind the vacuum drying;
2.2 the preparation of SH gelatin microsphere
Getting the sulfhydrylation gelatin is dissolved in and is made into the A liquid that mass concentration is 20%-30% in 50 ℃ of distilled waters, 50 ℃ of lower ultrasonic homogenize, the 20ml liquid paraffin is preheated to 40 ℃ and add the emulsifying agent span-80 of 0.8ml, then the volume ratio by 1:5 at the uniform velocity splashes into A liquid in the liquid paraffin that is added with emulsifying agent with 30/min, stir to get suspension and it is transferred to rapidly in 0 ~ 4 ℃ the water-bath while dripping, then add isopropanol dehydration and continue stirred for several minute, clean for several times with isopropyl alcohol and ether respectively, wash that to add the 20ml mass concentration behind emulsifying agent and the paraffin be that 5% glutaraldehyde places 4 ℃ of refrigerators to solidify 24h again off, adopt ether to the material eluting after solidifying, wash residual glutaraldehyde off, vacuum drying sieves under the room temperature, packing
60Sealing lucifuge cryopreservation gets SH gelatin microsphere behind the Co radiation sterilization;
2.3 the preparation of somatomedin SH gelatin microsphere
Get blank SH gelatin microsphere, be soaked in the rhBMP2 guanidine hydrochloride saturated solution 24h of 4mol/L, get the SH gelatin microsphere of loaded with growth behind the vacuum freeze-drying;
3) somatomedin sulfhydrylation gelatin control-release microsphere and implantation material surface are compound
3.1 the coating modifying of implantation material surface
Medical low-elastic beta-titanium alloy embedded material after will processing through step 1 is first through ultrasonic cleaning, then it is immersed in the dopamine solution, be adjusted to typical marine environment, air exposure, the dopamine spontaneous deposition generates the thin polymer film that one deck adheres at titanium alloy surface;
3.2 microsphere and embedded material is compound
The somatomedin SH gelatin microsphere is mixed with the solution of 0.2mg/ml, then the embedded material that will modify with the dopamine coating surface is positioned in the somatomedin SH gelatin microsphere solution, evacuation is placed 30min, takes out to obtain medical titanium alloy implant surface growth factor delivery system.
2. the construction method of medical titanium alloy implant surface growth factor delivery system according to claim 1, it is characterized in that: described little ditch ridge surface grooves width is cell rank 50 μ m, and the degree of depth is 20 μ m.
3. the construction method of medical titanium alloy implant surface growth factor delivery system according to claim 1 is characterized in that: described typical marine environment is the tris buffer that every 2mg dopamine adds 1 milliliter of 10mmol/L, pH=8.5.
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| CN102293693B (en) * | 2011-06-01 | 2013-06-26 | 中国人民解放军第四军医大学 | Porous titanium alloy human cervical interbody fusion cage with bioactivity and preparation method thereof |
| CN104224301A (en) * | 2013-06-24 | 2014-12-24 | 南京市鼓楼医院 | Orthopedic implant with surface micro-textures |
| CN104436313A (en) * | 2013-09-12 | 2015-03-25 | 上海交通大学医学院附属第九人民医院 | Growth factor nanotube slow-release system used for osseointegration and preparation method and application thereof |
| CN103725740A (en) * | 2013-12-06 | 2014-04-16 | 山东好当家海洋发展股份有限公司 | Method for extracting glycoprotein by using scollop blanching liquid |
| CN103837523B (en) * | 2014-02-28 | 2016-08-17 | 华中科技大学 | A kind of method detecting orthene and test kit |
| CN107441555B (en) * | 2017-07-27 | 2020-10-30 | 中山大学附属第一医院 | Preparation method of artificial skin capable of controllably releasing medicine |
| CN113476658A (en) * | 2021-07-16 | 2021-10-08 | 北京理工大学重庆创新中心 | Bessel beam-based bone joint implant surface treatment method |
| CN114699553B (en) * | 2022-02-24 | 2023-05-16 | 武汉亚洲生物材料有限公司 | Preparation method of 3D printed surface composite coating titanium mesh |
| CN114848895A (en) * | 2022-04-20 | 2022-08-05 | 湖南省儿童医院(湖南省红十字会医院) | 3D printing titanium alloy porous support loaded double-factor shell-core microsphere slow release system |
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| CN101091804A (en) * | 2007-07-18 | 2007-12-26 | 戴江华 | Method for constructing tissue-engineering bone by pouring stem cell of inducing bone marrow ground substance into vivo |
| CN101224314A (en) * | 2008-01-15 | 2008-07-23 | 郭征 | Antibiotic sustained release system building method of medical titanium alloy implant surface |
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| CN101091804A (en) * | 2007-07-18 | 2007-12-26 | 戴江华 | Method for constructing tissue-engineering bone by pouring stem cell of inducing bone marrow ground substance into vivo |
| CN101224314A (en) * | 2008-01-15 | 2008-07-23 | 郭征 | Antibiotic sustained release system building method of medical titanium alloy implant surface |
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