CN107661544A - Antibacterial facilitates porous orthopaedics implant of bone complex function and preparation method thereof - Google Patents

Antibacterial facilitates porous orthopaedics implant of bone complex function and preparation method thereof Download PDF

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CN107661544A
CN107661544A CN201710902781.7A CN201710902781A CN107661544A CN 107661544 A CN107661544 A CN 107661544A CN 201710902781 A CN201710902781 A CN 201710902781A CN 107661544 A CN107661544 A CN 107661544A
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porous
implant
arc oxidation
preparation
orthopaedics
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CN107661544B (en
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张腾
刘忠军
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Peking University Third Hospital
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Peking University Third Hospital
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    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
    • C25D11/00—Electrolytic coating by surface reaction, i.e. forming conversion layers
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    • C25D11/026—Anodisation with spark discharge
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
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    • C25D11/00—Electrolytic coating by surface reaction, i.e. forming conversion layers
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    • C25D11/26—Anodisation of refractory metals or alloys based thereon
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    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
    • C25D11/00—Electrolytic coating by surface reaction, i.e. forming conversion layers
    • C25D11/02—Anodisation
    • C25D11/30—Anodisation of magnesium or alloys based thereon
    • A—HUMAN NECESSITIES
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract

The present invention relates to antibacterial to promote the porous orthopaedics implant of Integrated implant function, preparation method, and porous orthopaedics implant is made using 3D printing technique including (1) in this method；(2) porous orthopaedics implant is surface-treated using micro-arc oxidation, the differential arc oxidation coating containing calcium P elements is covered on porous orthopaedics implant surface；(3) will be immersed through the implant after step (2) processing in 2~5mg/mL Dopamine hydrochloride solution, isothermal vibration 20~24 hours at 30~45 DEG C；(4) using deionized water or distilled water as solvent, add liquaemin and be configured to the heparin sodium aqua that concentration is 1~5mg/mL, then using heparin sodium aqua as solvent, add gentamicin and be configured to the gentamycin solution that concentration is 1~5mg/mL；It will be immersed through the implant after step (3) processing in gentamycin solution, and isothermal vibration 4~10 hours at 30~45 DEG C, the implant be made.

Description

Antibacterial facilitates porous orthopaedics implant of bone complex function and preparation method thereof
Technical field
The present invention relates to medical instruments field, more particularly to a kind of antibacterial facilitate the porous orthopaedics implant of bone complex function and Its preparation method.
Background technology
Metal implant is clinically widely used, but metal implant shows obvious biologically inert.At present, The surface-active that metal implant is improved using process for modifying surface is further to improve the effective way of its application effect.
At present, the method that the porous surface disclosed in the prior art in metal implant prepares calcium phosphor coating, Ke Yiti Its high osseointegration character.But osteocyte can be promoted to stick, the biomaterial surface that grows into equally also is adapted for colonizing for bacterium, especially It is 3D printing porous metals orthopaedics implant, although by force and can adapt to complicated shape with individuation with Integrated implant ability The characteristics of position, but the porous feature of 3D printing implant causes bone to be greatly increased with prosthesis integration surface area, this is in itself Infection probability can be increased.And orthopedic implant infections relating is bone surgery common complication, bone delay in healing is often led to very Loosened to bone nonunion, implants, in turn result in antibiotic and extend using even operative failure.So we are necessary in calcium phosphorus Coating further assigns its antibacterial functions on the basis of facilitating Integrated implant, it is effectively avoided the hair of orthopedic implant infections relating It is raw, it is preferably applied for clinic.
The content of the invention
(1) technical problems to be solved
It is several there is can also increase bacterium infection while Integrated implant is promoted for metal implant of the prior art The problem of rate, the invention provides it is a kind of can promote Integrated implant again with excellent antibacterial effect porous orthopaedics implant and its Preparation method.
(2) technical scheme
In order to solve the above-mentioned technical problem, the invention provides the system that antibacterial facilitates the porous orthopaedics implant of bone complex function Preparation Method, comprise the following steps：
(1) porous orthopaedics implant is made using 3D printing technique；
(2) the porous orthopaedics implant is surface-treated using micro-arc oxidation, be implanted into the porous orthopaedics Thing surface covers the differential arc oxidation coating containing calcium P elements；
(3) will be immersed through the porous orthopaedics implant after step (2) processing in 2~5mg/mL Dopamine hydrochloride solution, Isothermal vibration 20~24 hours at 30~45 DEG C；
(4) using deionized water or distilled water as solvent, liquaemin dissolving is added, it is 1~5mg/mL's to be configured to concentration Heparin sodium aqua, then using the heparin sodium aqua as solvent, add gentamicin and dissolved, be configured to concentration for 1~ 5mg/mL gentamycin solution；
It will be immersed through the metal implant after step (3) processing in the gentamycin solution, the constant temperature at 30~45 DEG C Concussion 4~10 hours, antibacterial is made and promotes the porous orthopaedics implant of Integrated implant function.
Preferably, in step (1), the metal implant is selected from porous titanium implant, porous titanium alloy implant, more Any of hole magnesium implant, porous magnesium alloy implant, and aperture is 600~700 μm.
Preferably, in step (4), the concentration of the gentamicin is 3~5mg/mL.
It is highly preferred that in step (4), the temperature of the isothermal vibration is 37~38 DEG C, and the time is 4~6 hours, rotating speed For 50~150rmp, preferably 100rmp.
Preferably, in step (3), the concentration of the Dopamine hydrochloride solution is 2~3mg/mL, and pH is 8~10, preferably For 8.5；And/or
The temperature of the isothermal vibration is 37~38 DEG C, and rotating speed is 50~150rmp, preferably 100rmp.
Preferably, in the step (2), the outer surface of the porous metal implants and inner surface are covered containing calcium phosphorus The differential arc oxidation coating of element.It is further preferred that in step (2), the differential of the arc of the outer surface covering of porous orthopaedics implant Oxide covering thickness is 1.5~2.2 μm, and the differential arc oxidation coating thickness of inner surface covering is 0.8~1.3 μm.
Preferably, the step (2) is carried out as follows：
(21) porous orthopaedics implant is cleaned by ultrasonic 15~20min with acetone, absolute ethyl alcohol and deionized water successively, so After dry；
(22) using deionized water as solvent prepare alkaline electrolyte, including concentration be 0.01~0.4mol/L calcium ion, The sodium hydroxide of 0.01~0.2mol/L phosphate anion, 0.02~0.2mol/L EDTA-2Na and 0.25~1mol/L, The mol ratio of wherein EDTA-2Na and calcium ion is more than 0.5；
(23) the porous orthopaedics implant after being handled using step (21) as anode, using stainless steel plate or stainless steel electrolytic groove as Negative electrode, using magnetic stirrer alkaline electrolyte, mixing speed is 40~60 beats/min, sets the pulse of differential arc oxidation Voltage is 250v, and working frequency 600Hz, dutycycle 10%, the differential arc oxidation time is 2~4min；
(24) by through step (23) processing after porous orthopaedics implant take out, using deionized water be cleaned by ultrasonic 15~ 20min, drying, surface treatment is completed, finally cover the differential arc oxidation containing calcium P elements on the surface of porous orthopaedics implant Coating.
It is highly preferred that in step (22), the alkaline electrolyte also includes 0.01~0.1mol/L strontium salt.
Present invention also offers the porous orthopaedics implant that a kind of antibacterial promotes Integrated implant function, using above-mentioned preparation method It is made.
The surface of the implant not only has differential arc oxidation coating, so that the implant can promote Integrated implant, and And surface modification also is carried out by covering poly-dopamine layer on the surface of differential arc oxidation coating, then using the poly-dopamine layer as load Body is loaded into medication coat, so that the implant also has excellent bactericidal property.In addition, the medicine being loaded into the implant Coating also has slow releasing function, can have lasting killing ability to the bacterium in implant surrounding tissue blood, is applicable very much In autoimmunity it is poor, with the easy infection crowd such as diabetes, and due to infection overhaul or surgical procedure in body other The patient of infection be present in position.
(3) beneficial effect
The above-mentioned technical proposal of the present invention has the following advantages that：
(1), the present invention is loaded into gentamicin, liquaemin on the surface of the metal implant with differential arc oxidation coating and gathered DOPA amine layer, triple combinations occurring between this several material, gentamicin is absorbed and fixed at implant surface securely, So that porous orthopaedics implant provided by the invention shows stronger Drug loading capacity.For porous metal implants, when When its inner surface and outer surface are loaded into gentamicin, liquaemin and poly-dopamine layer, by multiple combination, celebrating is big mould Element is absorbed and fixed at inner surface and the outer surface of porous orthopaedics implant securely, shows stronger Drug loading capacity, 1mg/ ML load concentration can effectively kills bacterium, and then to need higher load concentration can be only achieved identical for traditional implants Bactericidal effect.
(2), the present invention is loaded into medicine by the porous orthopaedics implant calcium phosphor coating surface after being handled through differential arc oxidation, So that porous orthopaedics implant can not only promote Integrated implant, but also the bacterium of implant surface and surrounding can be killed, compared with Prevent bacterial adhesion from forming biomembrane in implant surface in long-time.Interplantation can be increased by being loaded into the liquaemin on implants surface The blood compatibility of thing, and cell propagation and angiogenesis can be promoted.In addition, the present invention passes through micron made from differential arc oxidation Level hole considerably increases drugloading rate, can have to the bacterium in implant surrounding tissue blood and preferably kill ability.
(3) it is, low to cytotoxicity using porous orthopaedics implant made from preparation method provided by the invention, facilitate bone to imitate Fruit is good.
Brief description of the drawings
Fig. 1 a to 1c are that sample made from embodiment 1 and two groups of comparative samples and the culture medium co-cultivation 24 containing S. aureus L-forms are small When after bacterium anyway dyeing testing result, green representative viable bacteria, the dead bacterium of red representative；Wherein, Fig. 1 a are the first group pair Than the testing result of sample, Fig. 1 b are the testing result of second group of comparative sample, and Fig. 1 c are the 3rd group (i.e. made from embodiment 1 Sample) testing result；
After culture mediums of the Fig. 2 for sample made from embodiment 1 and two groups of comparative samples and containing S. aureus L-forms co-cultures 24 hours Sterilizing rate testing result；Wherein, first group represents blank sample, and second group represents differential arc oxidation sample, the 3rd group of generation Table laboratory sample, i.e., sample made from embodiment 1；
Fig. 3 is the cell proliferation activity testing result figure of sample made from embodiment 1 and two groups of comparative samples；Wherein, One group represents blank sample, and second group represents differential arc oxidation comparative sample, and the 3rd group represents laboratory sample, i.e. embodiment 1 Obtained sample；
Fig. 4 is the cell induction skeletonization alkaline phosphatase activities detection of sample made from embodiment 1 and two groups of comparative samples Result figure；Wherein, first group represents first group of comparative sample, and second group represents second group of comparative sample, the 3rd group of representative experiment Sample, i.e., sample made from embodiment 1；
Fig. 5 a to 5c are respectively the ESEM of different amplification of the cell after first group of comparative sample grows 14 days Figure；
Fig. 6 a to 6c are respectively the ESEM of different amplification of the cell after second group of comparative sample grows 14 days Figure；
Fig. 7 a to 7c are respectively different amplifications of the cell after laboratory sample (i.e. sample made from embodiment 1) grows 14 days The scanning electron microscope (SEM) photograph of multiple；
Fig. 8 a to 8b are respectively that the cell of the different amplification after cell grows 14 days in first group of comparative sample is dead Vital staining figure；
Fig. 9 a to 9b are respectively that the cell of the different amplification after cell grows 14 days in second group of comparative sample is dead Vital staining figure；
Figure 10 a to 10b are respectively the difference after cell grows 14 days on laboratory sample (i.e. sample made from embodiment 1) The cell life or death colored graph of multiplication factor；
Figure 11 is the gentamicin release profiles in sample made from embodiment 1.
Embodiment
To make the object, technical solutions and advantages of the present invention clearer, below in conjunction with the embodiment of the present invention, to this hair Bright technical scheme is clearly and completely described.Obviously, described embodiment is the part of the embodiment of the present invention, and The embodiment being not all of.Based on the embodiment in the present invention, those of ordinary skill in the art are not making creative work On the premise of the every other embodiment that is obtained, belong to the scope of protection of the invention.
Preparation method provided by the invention comprises the following steps：
In order to solve the above-mentioned technical problem, the porous orthopaedics implant of Integrated implant function is promoted the invention provides antibacterial Preparation method, comprise the following steps：
(1) porous orthopaedics implant is made using 3D printing technique；
(2) the porous orthopaedics implant is surface-treated using micro-arc oxidation, be implanted into the porous orthopaedics Differential arc oxidation coating of the surface covering containing calcium P elements of thing；
(3) will be immersed through the porous orthopaedics implant after step (2) processing in 2~5mg/mL Dopamine hydrochloride solution, Isothermal vibration 20~24 hours at 30~45 DEG C；
(4) using deionized water or distilled water as solvent, liquaemin dissolving is added, it is 1~5mg/mL's to be configured to concentration Heparin sodium aqua, then using the heparin sodium aqua as solvent, add gentamicin and dissolved, be configured to concentration for 1~ 5mg/mL gentamycin solution；
It will be immersed through the porous orthopaedics implant after step (3) processing in the gentamycin solution, at 35~45 DEG C Isothermal vibration 4~10 hours, antibacterial is made and promotes the porous orthopaedics implant of Integrated implant function.
For some embodiments, in the step (2), the inner surface of the porous orthopaedics implant and outer surface cover Differential arc oxidation coating containing calcium P elements.
For some embodiments, in step (1), the porous orthopaedics implant is selected from porous titanium implant, POROUS TITANIUM Any of alloy implants, porous magnesium implant, porous magnesium alloy implant, and aperture is 600~700 μm.
In preparation method provided by the invention, perseverance is carried out in Dopamine hydrochloride solution by the way that porous orthopaedics implant is immersed Temperature concussion, there is the poly-dopamine layer of superpower stickiness in the covering of the surface of porous orthopaedics implant.Then, will be covered with poly- more The porous orthopaedics implant of bar amine layer is immersed in the mixed solution of liquaemin and gentamicin, and isothermal vibration for a period of time, will be celebrated Big mycin is firmly adsorbed on the surface of porous orthopaedics implant.
By foregoing description, preparation method provided by the invention is not only loaded into micro- on the surface of porous orthopaedics implant Arc oxide covering, but also medication coat is loaded with, so that porous orthopaedics implant can not only promote Integrated implant, but also The bacterium of implant surface can be killed, prevents bacterial adhesion from forming biology on porous orthopaedics implant surface in a long time Film.In addition, the present invention also achieves the sustained release of medicine by the above method, can be in porous orthopaedics implant surrounding tissue blood Bacterium there is lasting killing ability.
Specifically, it is as follows to be loaded into the principle of medication coat for it：
First combination：Gentamicin directly acts on dopamine, so as to be fixed on porous orthopaedics implant surface.
Gentamicin is absorbed and fixed at dopamine by the primary amino radical of gentamicin by the way that schiff base reaction occurs with dopamine On.
Second combination：Liquaemin is fixed on dopamine by covalent bond first, and secondly liquaemin surface band is born The group (carboxyl and sulfenyl) of electric charge is due to there is stronger protein binding capacity, so can also couple with gentamicin, plays solid Determine the effect of gentamicin.
3rd combination：Because differential arc oxidation is negatively charged in the hydroxyapatite that material surface is formed, so also may be used To adsorb the gentamicin molecule of positively charged, and the micropore formed can increase drugloading rate.
Under the guarantee of above-mentioned triple combinations, gentamicin is absorbed and fixed at porous orthopaedics implant securely Surface, so that porous orthopaedics implant provided by the invention shows stronger Drug loading capacity.Work as porous metal implants Inner surface and outer surface when being loaded into gentamicin, liquaemin and poly-dopamine layer, pass through multiple combination, gentamicin Inner surface and the outer surface of porous orthopaedics implant are absorbed and fixed at securely, show stronger Drug loading capacity, 1mg/mL Load concentration can effectively kill bacterium, and traditional implants then need bigger load concentration to can be only achieved identical Bactericidal effect.
In order to ensure being loaded into the medication coat being evenly distributed on porous orthopaedics implant surface, control liquaemin and celebrating are big mould The dosage of element is extremely important.Due to the loose structure of porous orthopaedics implant, differential arc oxidation coating and poly- DOPA have been gone up in covering again Amine layer, so that medicine reduces in the intrapore mobility of metal implant, and poly-dopamine layer also has superpower stickiness, This causes medicine to be less susceptible to be uniformly distributed in hole.Therefore, in preparation method provided by the invention, the gentamicin is molten Liquid is prepared as follows：Using deionized water or distilled water as solvent, liquaemin dissolving is added, it is molten to be configured to liquaemin Liquid, then, using heparin sodium aqua as solvent, add gentamicin and dissolved, wherein, the concentration of the heparin sodium aqua is 1~5mg/mL (for example, can be 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL), it is described in the mixed solution The concentration of gentamicin is 1~5mg/mL (for example, can be 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL).Pass through The inner surface and appearance of the dosage of strict control liquaemin and gentamicin, liquaemin and gentamicin in porous orthopaedics implant Face is uniformly distributed.
In addition, in order to further ensure that medication coat being uniformly distributed in porous orthopaedics implant inner surface and outer surface, In certain embodiments, the temperature of the isothermal vibration in step (4) is 37~38 DEG C, and the time is 4~6 hours, and rotating speed is 50~150rmp, preferably 100rmp.
In order in the uniformly covering poly-dopamine layer of porous orthopaedics implant, in certain embodiments, step (3) In the concentration of the Dopamine hydrochloride solution be preferably 2~3mg/mL, pH is 8~10, preferably 8.5；And/or
The temperature of the isothermal vibration is 37~38 DEG C, and rotating speed is 50~150rmp, preferably 100rmp.
In certain embodiments, in step (2), the differential arc oxidation coating of the outer surface covering of porous orthopaedics implant is thick Spend for 1.5~2.2 μm, the differential arc oxidation coating thickness of inner surface covering is 0.8~1.3 μm.
The present invention is surface-treated using micro-arc oxidation to the porous orthopaedics implant, so as to be planted in porous orthopaedics Enter the differential arc oxidation coating of inner surface and outer surface covering containing calcium P elements of thing.This method can promote porous orthopaedics to plant Enter osteogenic activity, the increase Bone Ingrowth inside and outside thing, improve the overall Integrated implant ability of porous orthopaedics implant.
In certain embodiments, the step (2) is carried out as follows：
(21) porous orthopaedics implant is cleaned by ultrasonic 15~20min with acetone, absolute ethyl alcohol and deionized water successively, so After dry；
(22) using deionized water as solvent prepare alkaline electrolyte, including concentration be 0.01~0.4mol/L calcium ion, The sodium hydroxide of 0.01~0.2mol/L phosphate anion, 0.02~0.2mol/L EDTA-2Na and 0.25~1mol/L, The mol ratio of wherein EDTA-2Na and calcium ion is more than 0.5；
(23) the porous orthopaedics implant after being handled using step (21) as anode, using stainless steel plate or stainless steel electrolytic groove as Negative electrode, using magnetic stirrer alkaline electrolyte, mixing speed is 40~60 beats/min, sets the pulse of differential arc oxidation Voltage is 250v, and working frequency 600Hz, dutycycle 10%, the differential arc oxidation time is 2~4min；
(24) by through step (23) processing after porous orthopaedics implant take out, using deionized water be cleaned by ultrasonic 15~ 20min, drying, surface treatment is completed, finally cover the differential arc oxidation containing calcium P elements on the surface of porous orthopaedics implant Coating.
In preparation method provided by the invention, differential arc oxidation layer is located at implant surface and poly- DOPA as inter coat Between amine layer.On the one hand the porous orthopaedics implant of biologically inert is transformed into the porous orthopaedics with bioactivity and is implanted into by it Thing, promote the Integrated implant of porous orthopaedics implant and host bone；On the other hand, it also needs to participate in follow-up preparation process, as load Body contacts with dopamine.Therefore, how to ensure the validity of differential arc oxidation coating is also the problem that the present invention considers.At this In invention, not only micro-arc oxidation electrolyte is studied, but also the technological parameter of differential arc oxidation has been carried out accordingly Research, determines electrolyte using deionized water as solvent, the phosphorus of calcium ion, 0.01~0.2mol/L containing 0.01~0.4mol/L The sodium hydroxide of acid ion, 0.02~0.2mol/L EDTA-2Na and 0.25~1mol/L, and cause EDTA-2Na and calcium The mol ratio of ion is more than 0.5, in certain embodiments, the strontium salt that 0.01-0.1mol/L can also be added according to being actually needed Prepare the differential arc oxidation coating for mixing strontium；Micro-arc oxidation process parameter is：Using magnetic stirrer alkaline electrolyte, stirring speed Spend that for 40~60 beats/min, to set the pulse voltage of differential arc oxidation be 250v, working frequency 600Hz, dutycycle 10%, The differential arc oxidation time is 3min, obtained homogeneous calcic, the differential arc oxidation coating of phosphorus.As a result show, using made from this method The differential arc oxidation coating thickness of the outer surface covering of porous orthopaedics implant is 1.5~2.2 μm, the differential arc oxidation of inner surface covering Coating layer thickness is 0.8~1.3 μm.
In above-mentioned alkaline electrolyte, calcium ion in the calcium salts such as calcium acetate, calcium nitrate, calcium oxalate or calcium chloride one Kind, preferably calcium acetate.The one kind of phosphate anion in sodium dihydrogen phosphate, calcium dihydrogen phosphate, potassium dihydrogen phosphate, it is preferably Sodium dihydrogen phosphate.
Present invention also offers the porous orthopaedics implant that a kind of antibacterial promotes Integrated implant function, it uses above-mentioned preparation side Method is made.
Technical solution of the present invention is described further with reference to specific embodiment.
Embodiment 1
(1) the porous orthopaedics implant with the hole that is interconnected is made using 3D printing technique.
Individuation adaptation is printed using the model EBM S12 of ARCAM companies of Sweden production electron beam melting equipment Porous Ti-6Al-4V implants, aperture be 640 μm, strut diameter be 400 μm, there is diamond lattice pore structure.
(2) the porous Ti-6Al-4V implants are surface-treated using micro-arc oxidation, in the outer of the implant Surface is covered with 2.1 μm of differential arc oxidation coating, and inner surface is covered with 1.1 μm of differential arc oxidation coating.
(21) 0.065mol/L containing calcium acetate, sodium dihydrogen phosphate 0.03mol/L, EDTA-2Na are prepared using deionized water 0.04mol/L, sodium hydroxide 0.5mol/L alkaline electrolyte；
(22) using porous Ti-6Al-4V implants made from step (1), as anode, stainless steel is negative electrode, is stirred using magnetic force Device stirring alkaline electrolyte is mixed, mixing speed is 40 beats/min；Differential arc oxidation is carried out using direct current pulse power source.Voltage is set For 250V, dutycycle 10%, frequency 600Hz；Electrolyte temperature is kept to be not higher than 50 DEG C using circulating water cooling system, differential arc oxidation Time is 3min；
(23) the reacted porous Ti-6Al-4V implants of differential arc oxidation are cleaned by ultrasonic 20min with deionized water, in 40 DEG C oven for drying, i.e., 2.1 μm of the micro-nano differential arc oxidation containing calcium, phosphorus is generated in the outer surface of porous titanium alloy implant and is applied Layer, inner surface generate 1.1 μm of the micro-nano differential arc oxidation coating containing calcium, phosphorus.
(3) Dopamine hydrochloride is dissolved in Tris-HCl buffer solutions (10mM, pH=8.5), it is 2mg/mL to be configured to concentration Dopamine hydrochloride solution, then, the porous Ti-6Al-4V implants after differential arc oxidation is handled are immersed in the solution, profit With isothermal vibration device isothermal vibration 24 hours, wherein, the temperature setting of isothermal vibration is 37 DEG C, rotating speed 100rpm.
(4) using distilled water as solvent, add liquaemin and dissolved, it is molten to be configured to the liquaemin that concentration is 1mg/mL Liquid, then using the heparin sodium aqua of the concentration as solvent, add gentamicin and dissolved, it is 1mg/mL's to prepare and obtain concentration Gentamycin solution；
Then, the porous orthopaedics implant after step (3) processing is immersed into the solution, shaken using isothermal vibration device constant temperature Swing 6 hours, wherein, the temperature setting of isothermal vibration is 37 DEG C, rotating speed 100rpm, and antibacterial is made and promotes the more of Integrated implant function Hole Ti-6Al-4V implants.
Porous metal implants are as laboratory sample made from the embodiment.
Present invention also offers the two of embodiment 1 group comparative sample.This two groups of comparative samples equally use electron beam melting The porous metals support that technology is prepared using titanium alloy as raw material, difference are：First group of comparative sample is without differential arc oxidation, institute Obtained metal implant does not contain differential arc oxidation coating, i.e. the preparation method of first group of comparative sample do not include step (2), Step (3) and step (4)；Second group of comparative sample carries out differential arc oxidation, but without the operation of drug-carried coat, i.e. second group The preparation method of comparative sample does not include step (3) and step (4).
First, anti-microbial property detects
Detected respectively after three groups of samples are co-cultured 24 hours with the culture medium containing staphylococcus aureus (i.e. S. aureus L-forms) Implant contact sterilization performance.
Qualitative detection result：Bacterium is carried out using BacLightTM decoration methods to dye anyway come detection bacterium vigor, its Green represents viable bacteria, and red represents dead bacterium.As shown in Figure 1 a to 1c, wherein Fig. 1 a are first group of comparative sample to testing result Testing result, Fig. 1 b are the testing result of second group of comparative sample, and Fig. 1 c are the testing result of laboratory sample.
Quantitative testing result：Microbial activity detection is carried out using Kit-WST, testing result is as shown in Figure 2.
It is consistent that the data from qualitative detection and quantitatively detected can be seen that above-mentioned two testing result, laboratory sample Anti-microbial property is substantially better than two groups of comparative samples.
2nd, cell proliferation activity detects
By mesenchymal stem cells MSCs (hMSCs) 2 × 106It (is respectively first group of control sample that/mL, which is inoculated with compound 3 groups of samples, Product, second group of comparative sample and laboratory sample), 22h changes liquid, cultivates 1d, 7d and 14d respectively (d represents number of days).
CCK-8 cytoactive detections：PBS is washed 2 times, adds 900 μ L basal mediums 100 μ LCCK-8 (cumulative volume 10%), and 37 DEG C culture 1.5h, inhales 100 μ L, and 450nm surveys OD values, and as a result as shown in figure 3, wherein A groups are first group of comparative sample, B groups are the Two groups of comparative samples, C groups are laboratory sample.
It is repeated 3 times per 1 sample of time point, every group shares 9 samples.
It can be seen that from Fig. 3 data and cultivate 1d, 7d and 14d, hMSCs can be good at breeding on experiment sample.
3rd, cell induction skeletonization alkaline phosphatase activities detects
By mesenchymal stem cells MSCs (hMSCs) 2 × 106(A is first group of comparative sample to the compound 3 groups of samples of/ml；B is Two groups of comparative samples；C is laboratory sample).Observing time point：Induced osteogenesis culture 7d.Vitellophag, portion count, a Kit buffer is added with adding developer 1500ul after matrix liquid each 500ul, 37 DEG C of 15min, while prepares standard pipe. For 200ul into 96 orifice plates, ELIASA 405nm surveys light absorption value, and enzymatic activity is obtained by standard curve.Unit is pg/cell.Every time 2 samples (1 counting, 1 detection), are repeated 3 times, 6 samples totally.
Testing result is as shown in Figure 4.
Although the ALP levels of laboratory sample slightly reduce compared with second group of comparative sample it can be seen from Fig. 4 data, It is still higher than first group of comparative sample.And it can see laboratory sample to have no adverse effects to cell Osteoblast Differentiation.
4th, compound criteria scanning electron microscopic observation
By mesenchymal stem cells MSCs (hMSCs) 2 × 106It (is respectively first group of control sample that/mL, which is inoculated with compound 3 groups of samples, Product, second group of comparative sample and laboratory sample), 22h changes liquid, cultivates 14 days, is scanned electron microscopic observation and cell dyes anyway Observation (carrying out cell with Laser Scanning Confocal Microscope, dyeing is observed anyway).
Scanning electron microscopic observation result is shown in Fig. 5 a to 5c, Fig. 6 a to 6c and Fig. 7 a to 7c.In three figures, black arrow meaning Locate to be compounded in the cell on sample.It can be seen that when being co-cultured with cell, cell can be in implantation provided by the invention Thing surface growth.
Anyway dyeing observation result is shown in Fig. 8 a, Fig. 8 b, Fig. 9 a, Fig. 9 b, Figure 10 a and Figure 10 b, figure Green part generation to cell Table living cells.It can be seen that cell can be good on three groups of samples survival.Wherein, the cell on laboratory sample Upgrowth situation is more preferable, and cell quantity is more.
5th, gentamicin release profiles detect
Laboratory sample：Sample made from embodiment 1；Control sample：Preparation method is substantially the same with embodiment 1, different Part is：Not comprising differential arc oxidation step.
Laboratory sample and control sample are dipped into 2mL pbs solution (pH 7.4) respectively, use high performance liquid chromatograph The concentration of gentamicin in pbs solution is surveyed under 236nm wavelength, the measurement of equivalent pbs solution is changed after being spaced specific duration, according to inspection The release profiles that data draw out gentamicin are surveyed, monitor its release dynamics.
Testing result is as shown in figure 11, it can be seen that utilizing implantation made from medicine-carrying method provided by the invention For thing when discharging gentamicin, early stage, burst release was weaker, was advantageous to long duration antibacterial；And the sustainable gentamicin that discharges is up to 19 My god.And the sample (namely control sample) without differential arc oxidation, its burst size are less.
Embodiment 2
(1) the porous titanium implant of individuation adaptation is printed using EBM S12 electron beam melting equipment, aperture is 600 μ M, strut diameter are 500 μm, have dodecahedral pore structure.
(2) the porous titanium implant is surface-treated using micro-arc oxidation, covered in the outer surface of the implant 1.5 μm of differential arc oxidation coating is stamped, inner surface is covered with 0.8 μm of differential arc oxidation coating.
(21) using deionized water or preparation 0.01mol/L containing calcium acetate, sodium dihydrogen phosphate 0.01mol/L, EDTA-2Na 0.02mol/L, sodium hydroxide 0.25mol/L alkaline electrolyte；
(22) so that porous titanium implant is anode made from step (1), stainless steel is negative electrode, using magnetic stirrer Alkaline electrolyte, mixing speed are 60 beats/min；Differential arc oxidation is carried out using direct current pulse power source.Setting voltage is 250V, is accounted for Empty ratio 10%, frequency 600Hz；Using circulating water cooling system holding electrolyte temperature not higher than 50 DEG C, the differential arc oxidation time is 2min；
(23) the reacted porous metals support of differential arc oxidation is cleaned by ultrasonic 15min with deionized water, in 40 DEG C of baking ovens Drying, i.e., 1.5 μm of the micro-nano differential arc oxidation coating containing calcium, phosphorus is generated in the outer surface of porous titanium implant, in interior table Face generates 0.8 μm of the micro-nano differential arc oxidation coating containing calcium, phosphorus.
(3) Dopamine hydrochloride is dissolved in Tris-HCl buffer solutions (10mM, pH=8), it is 2.5mg/mL to be configured to concentration Dopamine hydrochloride solution, then, the implant after differential arc oxidation is handled is immersed in the solution, utilizes isothermal vibration device permanent Temperature concussion 24 hours, wherein, the temperature setting of isothermal vibration is 38 DEG C, rotating speed 150rpm.
(4) using deionized water as solvent, add liquaemin and dissolved, it is molten to be configured to the liquaemin that concentration is 2mg/mL Liquid, then using the heparin sodium aqua of the concentration as solvent, add gentamicin and dissolved, it is 2mg/mL's to prepare and obtain concentration Gentamycin solution；
Then, the porous orthopaedics implant after step (3) processing is immersed into the solution, shaken using isothermal vibration device constant temperature Swing 6 hours, wherein, the temperature setting of isothermal vibration is 38 DEG C, rotating speed 150rpm, and being made, there is antibacterial to promote Integrated implant function Porous titanium implant.
Embodiment 3
(1) the porous titanium alloy implant of individuation adaptation is printed using EBM S12 electron beam melting equipment, aperture is 700 μm, strut diameter is 450 μm, has honeycomb-like pore structure.
(2) metal implant is surface-treated using micro-arc oxidation, covered in the outer surface of the implant There is 2.2 μm of differential arc oxidation coating, inner surface is covered with 1.3 μm of differential arc oxidation coating.
(21) 0.35mol/L containing calcium acetate, sodium dihydrogen phosphate 0.2mol/L, EDTA-2Na are prepared using deionized water 0.2mol/L, sodium hydroxide 1mol/L alkaline electrolyte；
(22) so that porous titanium alloy implant is anode made from step (1), stainless steel is negative electrode, using magnetic stirring apparatus Alkaline electrolyte is stirred, mixing speed is 45 beats/min；Differential arc oxidation is carried out using direct current pulse power source.Set voltage be 250V, dutycycle 10%, frequency 600Hz；Electrolyte temperature is kept to be not higher than 50 DEG C, during differential arc oxidation using circulating water cooling system Between be 4min；
(23) the reacted porous metals support of differential arc oxidation is cleaned by ultrasonic 20min with deionized water, in 40 DEG C of baking ovens Drying, i.e., 2.2 μm of the micro-nano differential arc oxidation coating containing calcium, phosphorus is generated in the outer surface of porous titanium alloy implant, it is interior The micro-nano differential arc oxidation coating containing calcium, phosphorus of 1.3 μm of Surface Creation.
(3) Dopamine hydrochloride is dissolved in Tris-HCl buffer solutions (10mM, pH=10), it is 3mg/mL's to be configured to concentration Dopamine hydrochloride solution, then, the implant after differential arc oxidation is handled is immersed in the solution, utilize isothermal vibration device constant temperature Concussion 21 hours, wherein, the temperature setting of isothermal vibration is 38 DEG C, rotating speed 50rpm.
(4) using distilled water as solvent, add liquaemin and dissolved, it is molten to be configured to the liquaemin that concentration is 3mg/mL Liquid, then using the heparin sodium aqua of the concentration as solvent, add gentamicin and dissolved, it is 3mg/mL's to prepare and obtain concentration Gentamycin solution；
Then, the porous metal implants after step (3) processing are immersed into the solution, shaken using isothermal vibration device constant temperature Swing 5 hours, wherein, the temperature setting of isothermal vibration is 38 DEG C, rotating speed 50rpm, and being made, there is antibacterial to promote Integrated implant function Porous titanium alloy implant.
Embodiment 4
The step of embodiment 4, is substantially the same manner as Example 1, and difference is：
In step (3), the concentration of Dopamine hydrochloride solution is 4mg/mL；The temperature of isothermal vibration is 38 DEG C, and the time is 20h；
In step (4), the concentration of heparin sodium aqua is 3mg/mL, and the concentration of gentamycin solution is 4mg/mL, constant temperature The temperature of concussion is 38 DEG C, time 4h.
Embodiment 5
The step of embodiment 5, is substantially the same manner as Example 1, and difference is：
In step (3), the concentration of Dopamine hydrochloride solution is 3mg/mL；
In step (4), the concentration of heparin sodium aqua is 5mg/mL, and the concentration of gentamycin solution is 5mg/mL, constant temperature The time of concussion is 7h.
Embodiment 6
The step of embodiment 6, is substantially the same manner as Example 1, and difference is：
In step (1), the non-porous magnesium implant of individuation adaptation is prepared using EBM S12 electron beam melting equipment.
In step (21), chloride containing calcium 0.05mol/L, potassium dihydrogen phosphate 0.02mol/L are prepared using deionized water, EDTA-2Na 0.04mol/L, sodium hydroxide 0.4mol/L alkaline electrolyte.
In step (3), the concentration of Dopamine hydrochloride solution is 3mg/mL, and the temperature of isothermal vibration is 45 DEG C, the time 20 Hour.
In step (4), the concentration of liquaemin is 2mg/mL, and the concentration of gentamicin is 4.5mg/mL, the temperature of isothermal vibration Spend for 45 DEG C, time 12h.
Embodiment 7
The step of embodiment 7, is substantially the same manner as Example 1, and difference is：
In step (1), the non-porous magnesium alloy implant of individuation adaptation is gone out using EBM S12 electron beam melting equipment.
In step (21), chloride containing calcium 0.09mol/L, potassium dihydrogen phosphate are prepared using deionized water or distilled water 0.1mol/L, EDTA-2Na 0.09mol/L, sodium hydroxide 1mol/L alkaline electrolyte.
In step (3), the concentration of Dopamine hydrochloride is 4mg/mL, and the temperature of isothermal vibration is 30 DEG C, time 20h.
In step (4), the concentration of liquaemin is 3mg/mL, and the concentration of gentamicin is 3.5mg/mL, the temperature of isothermal vibration Spend for 35 DEG C, time 8h.
Embodiment 8
The step of embodiment 8, is substantially the same manner as Example 1, and difference is：
In step (1), the non-porous titanium alloy that individuation adaptation is prepared using EBM S12 electron beam melting equipment is implanted into Thing.In step (21), 0.065mol/L containing calcium acetate, sodium dihydrogen phosphate 0.03mol/L are prepared using deionized water or distilled water, EDTA-2Na 0.04mol/L, sodium hydroxide 0.5mol/L, strontium acetate 0.01-0.1mol/L alkaline electrolyte.
In step (3), the concentration of Dopamine hydrochloride is 5mg/mL, and the temperature of isothermal vibration is 40 DEG C, time 20h.
In step (4), the concentration of liquaemin is 5mg/mL, and the concentration of gentamicin is 5mg/mL, the temperature of isothermal vibration For 40 DEG C, time 6h.
The preparation condition of above-mentioned each embodiment is as shown in table 1 below, and wherein embodiment 9 is first group of comparative sample, implements Example 10 is second group of comparative sample.
Each embodiment preparation condition of table 1
In a word, it is notable using porous orthopaedics implant antibacterial effect made from preparation method provided by the invention, to cell Toxicity is low, also facilitates bone effect with good.
Finally it should be noted that：The above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations；Although The present invention is described in detail with reference to the foregoing embodiments, it will be understood by those within the art that：It still may be used To be modified to the technical scheme described in foregoing embodiments, or equivalent substitution is carried out to which part technical characteristic； And these modification or replace, do not make appropriate technical solution essence depart from various embodiments of the present invention technical scheme spirit and Scope.

Claims (10)

1. antibacterial facilitates the preparation method of the porous orthopaedics implant of bone complex function, it is characterised in that comprises the following steps：
(1) porous orthopaedics implant is made using 3D printing technique；
(2) the porous orthopaedics implant is surface-treated using micro-arc oxidation, in the porous orthopaedics implant table Face covers the differential arc oxidation coating containing calcium P elements；
(3) will be immersed through the porous orthopaedics implant after step (2) processing in 2~5mg/mL Dopamine hydrochloride solution, 30 Isothermal vibration 20~24 hours at~45 DEG C；
(4) using deionized water or distilled water as solvent, it is molten that addition liquaemin is configured to the liquaemin that concentration is 1~5mg/mL Liquid, then using the heparin sodium aqua as solvent, gentamicin is added, it is molten to be configured to the gentamicin that concentration is 1~5mg/mL Liquid；
It will be immersed through the metal implant after step (3) processing in the gentamycin solution, the isothermal vibration 4 at 30~45 DEG C ~10 hours, obtained antibacterial facilitated the porous orthopaedics implant of bone complex function.
2. preparation method according to claim 1, it is characterised in that in step (1), the porous orthopaedics implant choosing From any of porous titanium implant, porous titanium alloy implant, porous magnesium implant, porous magnesium alloy implant, and hole Footpath is 600~700 μm.
3. preparation method according to claim 1 or 2, it is characterised in that in step (4), the gentamicin it is dense Spend for 3~5mg/mL.
4. preparation method according to claim 3, it is characterised in that in step (4), the temperature of the isothermal vibration is 37~38 DEG C, the time is 4~6 hours, and rotating speed is 50~150rmp, preferably 100rmp.
5. preparation method according to claim 1 or 2, it is characterised in that in step (3), the Dopamine hydrochloride is molten The concentration of liquid is 2~3mg/mL, and pH is 8~10, preferably 8.5；And/or
The temperature of the isothermal vibration is 37~38 DEG C, and rotating speed is 50~150rmp, preferably 100rmp.
6. preparation method according to claim 1 or 2, it is characterised in that in step (2), the porous metals implantation The outer surface of thing and inner surface cover the differential arc oxidation coating containing calcium P elements.
7. preparation method according to claim 6, it is characterised in that in step (2), the porous orthopaedics implant The differential arc oxidation coating thickness of outer surface covering is 1.5~2.2 μm, the differential arc oxidation coating thickness of inner surface covering for 0.8~ 1.3μm。
8. according to the preparation method described in any one of claim 1~7, it is characterised in that the step (2) is as follows Carry out：
(21) porous orthopaedics implant is cleaned by ultrasonic 15~20min with acetone, absolute ethyl alcohol and deionized water successively, then dried It is dry；
(22) alkaline electrolyte is prepared by solvent of deionized water, including concentration is 0.01~0.4mol/L calcium ion, 0.01 The sodium hydroxide of~0.2mol/L phosphate anion, 0.02~0.2mol/L EDTA-2Na and 0.25~1mol/L, wherein The mol ratio of EDTA-2Na and calcium ion is more than 0.5；
(23) the porous orthopaedics implant after being handled using step (21) is anode, using stainless steel plate or stainless steel electrolytic groove as the moon Pole, using magnetic stirrer alkaline electrolyte, mixing speed is 40~60 beats/min, sets the pulse electricity of differential arc oxidation It is 2~4min to press as 250v, working frequency 600Hz, dutycycle 10%, differential arc oxidation time；
(24) it will be taken out through the porous orthopaedics implant after step (23) processing, 15~20min is cleaned by ultrasonic using deionized water, Drying, surface treatment is completed, finally cover the differential arc oxidation coating containing calcium P elements on the surface of porous orthopaedics implant.
9. preparation method according to claim 8, it is characterised in that in step (22), the alkaline electrolyte also wraps Include 0.01~0.1mol/L strontium salt.
10. a kind of antibacterial facilitates the porous orthopaedics implant of bone complex function, it is characterised in that using any one of claim 1~9 Preparation method be made.
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