CN110433330A - A kind of titanium-based activity bone implant and preparation method thereof - Google Patents
A kind of titanium-based activity bone implant and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of titanium-based activity bone implants and preparation method thereof, belong to medical material tech field, its method is as follows: after pure titanium area load dopamine, successively spin coating gelatin solution, dextran amine solution, gelatin solution, alpha-melanocyte stimulating hormone solution, to successively spin coating gelatin solution, dextran amine solution, gelatin solution, alpha-melanocyte stimulating hormone solution is known as primary complete spin coating, subsequent basis determines the number of the complete spin coating to the actual demand burst size of alpha-melanocyte stimulating hormone, one layer of gelatin solution of spin coating again after the last time complete spin coating to be done, then it is soaked in 2h or more in the solution of the graft polymers generated after eight arm polyethylene glycol amino grafting boric acid ester bond, titanium-based activity bone implant is made.The bone implant can largely discharge α-MSH in a short time, reach its effective concentration, and have the ability for promoting bone relevant cell Osteoblast Differentiation.The titanium-based activity bone implant preparation method is simple to operation, is suitble to expanded production.
Description
Technical field
The invention belongs to medical material tech fields, and in particular to a kind of titanium-based activity bone implant and preparation method thereof.
Background technique
Titanium implants have been widely used in clinical orthopaedics implantation due to its good mechanical performance and biocompatibility
In operation.However, since some defects of titanium implants itself make its clinical application be difficult to obtain perfect therapeutic effect, such as
The defects of surface metal ion extravasation, elasticity modulus mismatch, osteoinductive lacks, these defects make it to osteoporotic bone
The reparation difficulty of folding increases.
In order to enable implant quickly to integrate with bone tissue, acid and alkali corrosion, differential arc oxidation, plasma spraying, layer
During the surface that the technologies such as layer self assembly are introduced in bone implant is modified, in physiological conditions due to most of bioactive molecules
With positive charge or negative electrical charge and there is good biological function, therefore assembled and given birth to by charge interaction on titanium surface
Object bioactive molecule is the modified ideal method in titanium surface, and this mode can be in implant site delivery of biologically active steady in a long-term point
Son improves the local concentration of effector molecule, reduces side effect.
Alpha-melanocyte stimulating hormone (α-MSH) is a kind of bioactive molecule that cAMP can be promoted to express, and has portion at present
Research is divided to have shown that it can promote the Osteoblast Differentiation of osteoblast (MC3T3-E11), but dense required for it plays a role
Degree is higher, therefore the use on material is very limited.
Summary of the invention
In view of this, one of the objects of the present invention is to provide a kind of preparation methods of titanium-based activity bone implant；Purpose
Two be to provide a kind of titanium-based activity bone implant.
In order to achieve the above objectives, the invention provides the following technical scheme:
1, a kind of preparation method of titanium-based activity bone implant, the method are as follows:
After pure titanium area load dopamine, successively spin coating gelatin solution, dextran amine solution, gelatin solution, α-melanocyte
Cytositimulation element solution, will successively spin coating gelatin solution, dextran amine solution, gelatin solution, alpha-melanocyte stimulating hormone solution
Referred to as primary complete spin coating, subsequent basis determine the complete spin coating to the actual demand burst size of alpha-melanocyte stimulating hormone
Number, one layer of gelatin solution of spin coating again after the last time complete spin coating to be done, is then soaked in eight arm polyethylene glycol ammonia
2h or more in the solution of the graft polymers generated after base grafting boric acid ester bond, is made titanium-based activity bone implant.
Preferably, the method for the pure titanium area load dopamine is as follows: pure titanium is soaked in the Tris- containing dopamine
10-16h in HCl buffer；The concentration of the Tris-HCl buffer is 10mM, pH value 8.5, the Tris-HCl
The concentration of dopamine is 2mg/mL in buffer.
Preferably, when spin coating institute gelatine solution, dextran amine solution and alpha-melanocyte stimulating hormone solution, by as follows
Method spin coating: first with the speed spin coating 6-10s of 500-900r/min after, then with the speed spin coating 20- of 2000-2500r/min
25s, spin coating amount are 5-10 μ L/cm2。
Preferably, the dextran amine and alpha-melanocyte stimulating hormone of the gelatin in institute's gelatine solution, dextran amine solution
The mass ratio of alpha-melanocyte stimulating hormone three in solution is 2-10:2-10:1.
Preferably, the concentration of graft polymers is 5-10mg/mL in the solution of the graft polymers.
Preferably, the graft polymers is prepared as follows:
(1) p-nitrophenyl chloroformate is dissolved in tetrahydrofuran, inflated with nitrogen at 0 DEG C, obtains solution I；
(2) 4- (methylol) phenyl boric acid pinacol ester, 4-dimethylaminopyridine and triethylamine are dissolved in tetrahydrofuran,
Obtain solution II；
(3) under condition of ice bath, solution I is added dropwise in solution II under stiring by 10-20min, then in room
3-4h is stirred to react with the speed of 300-800r/min under temperature, the product after being spin-dried for after being spin-dried for methylene chloride dissolution obtains yellow
Color solution, again with NaHCO after successively being washed with the HCl of 1M, saturation NaCl solution3Solution is washed to the color of the yellow solution
Become light yellow, finally cross silicagel column, gradient elution is carried out using the mixed liquor of petroleum ether and methylene chloride as eluent, is spin-dried for
Boric acid ester bond is made afterwards；
(4) boric acid ester bond obtained in step (3) and eight arm polyethylene glycol amino are added in organic solvent with 800-
The speed of 1200r/min removes the organic solvent after being stirred to react 10-16h.
Preferably, the p-nitrophenyl chloroformate, 4- (methylol) phenyl boric acid pinacol ester, 4-dimethylaminopyridine and
The mass volume ratio of triethylamine is 0.47:0.5:0.04:0.6, and the unit of the mass volume ratio is g:g:g:mL；The boric acid
The molar ratio of ester bond and eight arm polyethylene glycol amino is 6-9:1.
Preferably, in step (3), the gradient elution specifically: first with petroleum ether and methylene chloride 1:4 by volume
The mixed liquor of formation is eluted, and is then eluted with petroleum ether and the methylene chloride mixed liquor that 3:7 is formed by volume, most
It is eluted afterwards with petroleum ether and the methylene chloride mixed liquor that 2:3 is formed by volume.
Preferably, in step (4), the organic solvent is one of methylene chloride, tetrahydrofuran or dimethyl sulfoxide.
2, the titanium-based activity bone implant prepared by the method.
The beneficial effects of the present invention are: the present invention provides a kind of titanium-based activity bone implants and preparation method thereof, should
The graft polymers that generates is as connector across different layers handle after eight arm polyethylene glycol amino are grafted boric acid ester bond in method
Dextran amine crosslinking is got up, while the alpha-melanocyte stimulating hormone (α-MSH) with osteoporosis therapy effect is clipped to centre,
Since boric acid ester bond has responsiveness to ROS, when ROS concentration is higher, boric acid ester bond is broken under ROS continuous action,
To release α-MSH, realizes the promotion to α-MSH local concentration, reach its effective concentration, make the titanium-based activity bone implant
With intelligence.The titanium-based active bone implant surfaces are smooth, good hydrophilic property, have more preferably biocompatibility, and traditional
The bone implant of layer-by-layer preparation is compared, which can sufficiently discharge life in a relatively short period of time
Object active factors, 7 days burst sizes are 2 times of traditional LBL self-assembly, have reached α-MSH and have promoted the best dense of Osteoblast Differentiation
Degree.Pass through experiment in vivo and experiment in vitro, it was demonstrated that the titanium-based activity bone implant have good promotion bone relevant cell at
The ability of bone differentiation.The titanium-based activity bone implant preparation method is simple to operation, is suitble to expanded production.
Other advantages, target and feature of the invention will be illustrated in the following description to a certain extent, and
And to a certain extent, based on will be apparent to those skilled in the art to investigating hereafter, Huo Zheke
To be instructed from the practice of the present invention.Target of the invention and other advantages can be realized by following specification and
It obtains.
Detailed description of the invention
To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention is made below in conjunction with attached drawing excellent
The detailed description of choosing, in which:
Fig. 1 is that each coat contact angle test result figure during titanium-based activity bone implant is prepared in embodiment 1；
Fig. 2 is the titanium prepared in pure titanium rod, comparative example 1, comparative example 2 and embodiment 1 without any modification
The SEM of base bone implant schemes；(a is that the SEM of the pure titanium rod without any modification schemes in Fig. 2, and b is in comparative example 1 in Fig. 2
The SEM of the titanium-based bone implant (Ti/LBL) of preparation schemes, and c is the titanium-based bone implant (Ti/ prepared in comparative example 2 in Fig. 2
LBLPEG-NBC) SEM figure, d is the titanium-based bone implant (Ti/LBL prepared in embodiment 1 in Fig. 2PEG-NBC- MSH) SEM figure)
Fig. 3 is Ti/LBL in embodiment 4PEG-NBCTwo kinds of titanium-based bone implants of-FITC-MSH and Ti/LBL-FITC-MSH exist
The releasing curve diagram of FITC-MSH under different condition；
Fig. 4 is the differentiation capability test result figure that different titanium-based bone implants regulate and control stem cell in embodiment 5；
Fig. 5 is that different titanium-based bone implants are implanted into Osteoporotic Model around different titanium-based implants in embodiment 5
The situation test result figure of ostosis；
Fig. 6 is that different titanium-based bone implants are implanted into Osteoporotic Model around different titanium-based implants in embodiment 5
The Osteoblast Differentiation aptitude tests result figure of bone relevant cell.
Specific embodiment
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this specification
Other advantages and efficacy of the present invention can be easily understood for disclosed content.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints and application, without departing from
Various modifications or alterations are carried out under spirit of the invention.
Embodiment 1
Prepare titanium-based activity bone implant
(1) 0.47g p-nitrophenyl chloroformate is dissolved in 15mL tetrahydrofuran, inflated with nitrogen at 0 DEG C, obtains solution I；
(2) by 0.5g 4- (methylol) phenyl boric acid pinacol ester, 0.04g 4-dimethylaminopyridine and 0.6mL triethylamine
It is dissolved in 5mL tetrahydrofuran, obtains solution II；
(3) under condition of ice bath, solution I in step (1) is added dropwise under stiring by 10min molten in step (2)
In liquid II, 3h is then stirred to react with the speed of 600r/min at room temperature, the production after being spin-dried for after being spin-dried for methylene chloride dissolution
Object obtains yellow solution, again with NaHCO after successively being washed with the HCl of 1M, saturation NaCl solution3Solution washs molten to the yellow
The color of liquid becomes light yellow, finally crosses silicagel column, successively with the mixing that 1:4 is formed by volume of petroleum ether and methylene chloride
The 2:3 formation by volume of liquid, petroleum ether and the methylene chloride mixed liquor that 3:7 is formed by volume, petroleum ether and methylene chloride
Mixed liquor carries out gradient elution, and boric acid ester bond is made after being spin-dried for；
(4) dichloromethane is added in boric acid ester bond obtained in step (3) and eight arm polyethylene glycol amino for 8:1 in molar ratio
Speed in alkane with 1000r/min removes methylene chloride after being stirred to react 12h, is made graft polymers (PEG-NBC)；
(5) it is 1mm by diameter, is highly soaked in the Tris-HCl buffer containing dopamine for the pure titanium rod of 10mm
12h makes pure titanium rod area load dopamine, wherein the concentration of Tris-HCl buffer is 10mM, pH value 8.5, Tris-HCl
The concentration of dopamine is 2mg/mL in buffer；
(6) the pure titanium rod surface for having loaded dopamine obtained in the step (5) successively spin coating gelatin solution, dextran amine
Solution, gelatin solution, alpha-melanocyte stimulating hormone solution, will successively spin coating gelatin solution (L), dextran amine solution (B), gelatin
Solution (L), alpha-melanocyte stimulating hormone solution (α-MSH) are known as primary complete spin coating, it is subsequent carry out complete spin coating twice again after
One layer of gelatin solution (L) of spin coating again is then soaked in and generates after the grafting boric acid ester bond of eight arm polyethylene glycol amino in step (4)
Titanium-based activity bone implant (Ti/LBL is made in 2h in the solution of graft polymers (PEG-NBC)PEG-NBC-MSH)；Wherein, gelatin
Gelatin in solution, the alpha-melanocyte stimulating hormone in the dextran amine and alpha-melanocyte stimulating hormone solution of dextran amine solution
The mass ratio of three is 10:10:1；When spin coating gelatin solution, dextran amine solution and alpha-melanocyte stimulating hormone solution, press
Following method spin coating: first with the speed spin coating 6s of 500r/min after, then with the speed spin coating 20s of 2000r/min, spin coating amount is
5μL/cm2；The concentration of graft polymers is 5mg/mL in the solution of graft polymers.
During preparing above-mentioned titanium-based activity bone implant, contact angle detection monitoring pure titanium rod surface multi-layer film is utilized
Building, as a result as shown in Figure 1, as shown in Figure 1, since the 1st layer of coating, material surface contact angle is respectively 61 °, and 52 °, 62 °,
It is gelatin, dextran amine, gelatin, the size of contact angle, subsequent pure titanium surface multi-layer when α-MSH is outermost layer that 45 ° corresponding
The contact angle that the deposition of film is formed also produces similar rule, and contact angle becomes 15 ° after being finally crosslinked with PEG-NBC, table
The drug-loading system of bright ROS response is formed on pure titanium rod surface.
Embodiment 2
Prepare titanium-based activity bone implant
(1) 0.47g p-nitrophenyl chloroformate is dissolved in 15mL tetrahydrofuran, inflated with nitrogen at 0 DEG C, obtains solution I；
(2) by 0.5g 4- (methylol) phenyl boric acid pinacol ester, 0.04g 4-dimethylaminopyridine and 0.6mL triethylamine
It is dissolved in 5mL tetrahydrofuran, obtains solution II；
(3) under condition of ice bath, solution I in step (1) is added dropwise under stiring by 20min molten in step (2)
In liquid II, 4h is then stirred to react with the speed of 300r/min at room temperature, the production after being spin-dried for after being spin-dried for methylene chloride dissolution
Object obtains yellow solution, again with NaHCO after successively being washed with the HCl of 1M, saturation NaCl solution3Solution washs molten to the yellow
The color of liquid becomes light yellow, finally crosses silicagel column, successively with the mixing that 1:4 is formed by volume of petroleum ether and methylene chloride
The 2:3 formation by volume of liquid, petroleum ether and the methylene chloride mixed liquor that 3:7 is formed by volume, petroleum ether and methylene chloride
Mixed liquor carries out gradient elution, and boric acid ester bond is made after being spin-dried for；
(4) tetrahydro furan is added in boric acid ester bond obtained in step (3) and eight arm polyethylene glycol amino for 9:1 in molar ratio
It mutters and removes tetrahydrofuran after being stirred to react 14h with the speed of 800r/min, graft polymers is made；
(5) it is 1mm by diameter, is highly soaked in the Tris-HCl buffer containing dopamine for the pure titanium rod of 10mm
14h makes pure titanium rod area load dopamine, wherein the concentration of Tris-HCl buffer is 10mM, pH value 8.5, Tris-HCl
The concentration of dopamine is 2mg/mL in buffer；
(6) the pure titanium rod surface for having loaded dopamine obtained in the step (5) successively spin coating gelatin solution, dextran amine
Solution, gelatin solution, alpha-melanocyte stimulating hormone solution, will successively spin coating gelatin solution, dextran amine solution, gelatin solution,
Alpha-melanocyte stimulating hormone solution is known as primary complete spin coating, subsequent to carry out after complete spin coating three times that one layer of gelatin of spin coating is molten again again
Liquid is then soaked in the solution of the graft polymers generated after eight arm polyethylene glycol amino grafting boric acid ester bond in step (4)
Titanium-based activity bone implant is made in 4h；Wherein, the dextran amine and α-melanocyte of the gelatin in gelatin solution, dextran amine solution
The mass ratio of alpha-melanocyte stimulating hormone three in cytositimulation element solution is 5:5:1；Spin coating gelatin solution, dextran amine are molten
When liquid and alpha-melanocyte stimulating hormone solution, spin coating as follows: first with the speed spin coating 10s of 700r/min after, then
With the speed spin coating 25s of 2200r/min, spin coating amount is 7 μ L/cm2；The concentration of graft polymers is in the solution of graft polymers
8mg/mL。
Embodiment 3
Prepare titanium-based activity bone implant
(1) 0.47g p-nitrophenyl chloroformate is dissolved in 15mL tetrahydrofuran, inflated with nitrogen at 0 DEG C, obtains solution I；
(2) by 0.5g 4- (methylol) phenyl boric acid pinacol ester, 0.04g 4-dimethylaminopyridine and 0.6mL triethylamine
It is dissolved in 5mL tetrahydrofuran, obtains solution II；
(3) under condition of ice bath, solution I in step (1) is added dropwise under stiring by 15min molten in step (2)
In liquid II, 3h is then stirred to react with the speed of 800r/min at room temperature, the production after being spin-dried for after being spin-dried for methylene chloride dissolution
Object obtains yellow solution, again with NaHCO after successively being washed with the HCl of 1M, saturation NaCl solution3Solution washs molten to the yellow
The color of liquid becomes light yellow, finally crosses silicagel column, successively with the mixing that 1:4 is formed by volume of petroleum ether and methylene chloride
The 2:3 formation by volume of liquid, petroleum ether and the methylene chloride mixed liquor that 3:7 is formed by volume, petroleum ether and methylene chloride
Mixed liquor carries out gradient elution, and boric acid ester bond is made after being spin-dried for；
(4) dimethyl is added in boric acid ester bond obtained in step (3) and eight arm polyethylene glycol amino for 6:1 in molar ratio
Speed in sulfoxide with 1200r/min removes dimethyl sulfoxide after being stirred to react 16h, and graft polymers is made；
(5) it is 1mm by diameter, is highly soaked in the Tris-HCl buffer containing dopamine for the pure titanium rod of 10mm
16h makes pure titanium rod area load dopamine, wherein the concentration of Tris-HCl buffer is 10mM, pH value 8.5, Tris-HCl
The concentration of dopamine is 2mg/mL in buffer；
(6) the pure titanium rod surface for having loaded dopamine obtained in the step (5) successively spin coating gelatin solution, dextran amine
Solution, gelatin solution, alpha-melanocyte stimulating hormone solution, will successively spin coating gelatin solution, dextran amine solution, gelatin solution,
Alpha-melanocyte stimulating hormone solution is known as primary complete spin coating, subsequent to carry out after four complete spin coatings that one layer of gelatin of spin coating is molten again again
Liquid is then soaked in the solution of the graft polymers generated after eight arm polyethylene glycol amino grafting boric acid ester bond in step (4)
Titanium-based activity bone implant is made in 5h；Wherein, the dextran amine and α-melanocyte of the gelatin in gelatin solution, dextran amine solution
The mass ratio of alpha-melanocyte stimulating hormone three in cytositimulation element solution is 2:2:1；Spin coating gelatin solution, dextran amine are molten
When liquid and alpha-melanocyte stimulating hormone solution, spin coating as follows: first with the speed spin coating 8s of 900r/min after, then with
The speed spin coating 23s of 2500r/min, spin coating amount are 10 μ L/cm2；The concentration of graft polymers is in the solution of graft polymers
10mg/mL。
Comparative example 1
(1) it is 1mm by diameter, is highly soaked in the Tris-HCl buffer containing dopamine for the pure titanium rod of 10mm
12h makes pure titanium rod area load dopamine, wherein the concentration of Tris-HCl buffer is 10mM, pH value 8.5, Tris-HCl
The concentration of dopamine is 2mg/mL in buffer；
(2) the pure titanium rod surface for having loaded dopamine obtained in the step (1) successively spin coating gelatin solution, dextran amine
Solution successively spin coating gelatin solution (L), dextran amine solution (B) will be known as primary complete spin coating, subsequent to carry out five times again completely
One layer of gelatin solution (L) of spin coating again after spin coating is made titanium-based bone implant (Ti/LBL)；Wherein, the gelatin in gelatin solution, Portugal
The mass ratio of both dextran amines of glycan amine aqueous solution is 1:1；When spin coating gelatin solution and dextran amine solution, by such as lower section
Method spin coating: first with the speed spin coating 6s of 500r/min after, then with the speed spin coating 20s of 2000r/min, spin coating amount is 5 μ L/
cm2。
Comparative example 2
(1) it is 1mm by diameter, is highly soaked in the Tris-HCl buffer containing dopamine for the pure titanium rod of 10mm
12h makes pure titanium rod area load dopamine, wherein the concentration of Tris-HCl buffer is 10mM, pH value 8.5, Tris-HCl
The concentration of dopamine is 2mg/mL in buffer；
(2) the pure titanium rod surface for having loaded dopamine obtained in the step (1) successively spin coating gelatin solution, dextran amine
Solution successively spin coating gelatin solution (L), dextran amine solution (B) will be known as primary complete spin coating, subsequent to carry out five times again completely
One layer of gelatin solution (L) of spin coating again after spin coating is then soaked in embodiment 1 eight arm polyethylene glycol amino in step (4) and is grafted
Titanium-based bone implant (Ti/LBL is made in 2h in the solution of the graft polymers (PEG-NBC) generated after boric acid ester bondPEG-NBC)；
Wherein, the mass ratio of both dextran amines of the gelatin in gelatin solution and dextran amine solution is 1:1；Spin coating gelatin solution and
When dextran amine solution, spin coating as follows: first with the speed spin coating 6s of 500r/min after, then with 2000r/min's
Speed spin coating 20s, spin coating amount are 5 μ L/cm2；The concentration of graft polymers is 5mg/mL in the solution of graft polymers.
Using scanning electron microscope respectively to pure titanium rod, comparative example 1, comparative example 2 and implementation without any modification
The titanium-based bone implant prepared in example 1 is tested, and test results are shown in figure 2, wherein a is without any modification in Fig. 2
The SEM of pure titanium rod schemes, and b is the SEM figure of the titanium-based bone implant (Ti/LBL) prepared in comparative example 1 in Fig. 2, and c is in Fig. 2
Titanium-based bone implant (the Ti/LBL prepared in comparative example 2PEG-NBC) SEM figure, d is the titanium prepared in embodiment 1 in Fig. 2
Base bone implant (Ti/LBLPEG-NBC- MSH) SEM figure, as shown in Figure 1, the pure titanium rod surface without any modification is more thick
It is rough, there is a little scratch, the surface Ti/LBL prepared in comparative example 1 is relatively smooth, the Ti/ prepared in comparative example 2
LBLPEG-NBCWith the Ti/LBL prepared in embodiment 1PEG-NBCThe surface-MSH is smooth, no significant difference, but compared with Ti/LBL, Ti/
LBLPEG-NBC- MSH seems even closer because of the multilayer film that surface covers.
Embodiment 4
Titanium-based bone implant (Ti/LBL in the present inventionPEG-NBC- MSH) α-MSH bioactie agent releasability test
(1) the titanium-based activity bone implant (Ti/LBL of α-MSH is marked containing FITC for preparationPEG-NBC-FITC-MSH)
The difference from embodiment 1 is that the alpha-melanocyte stimulating hormone solution in step (6) is replaced with FITC label α-
The titanium-based activity bone implant (Ti/ that α-MSH is marked containing FITC is made in melanophorin solution (FITC-MSH)
LBLPEG-NBC-FITC-MSH)；
(2) the titanium-based bone implant (Ti/LBL-FITC-MSH) containing FITC-MSH is prepared
1) it is 1mm by diameter, is highly soaked in the Tris-HCl buffer containing dopamine for the pure titanium rod of 10mm
12h makes pure titanium rod area load dopamine, wherein the concentration of Tris-HCl buffer is 10mM, pH value 8.5, Tris-HCl
The concentration of dopamine is 2mg/mL in buffer；
2) successively spin coating gelatin solution, dextran amine are molten on the pure titanium rod surface for having loaded dopamine obtained in step 1)
Liquid, gelatin solution, FITC label alpha-melanocyte stimulating hormone solution (FITC-MSH) will successively gather in spin coating gelatin solution (L), Portugal
Osamine solution (B), gelatin solution (L), FITC label alpha-melanocyte stimulating hormone solution (FITC-MSH) are known as primary complete rotation
It applies, it is subsequent to carry out after complete spin coating twice one layer of gelatin solution (L) of spin coating again again, the titanium-based bone implant containing FITC-MSH is made
(Ti/LBL-FITC-MSH)；Wherein, the gelatin in gelatin solution, the dextran amine of dextran amine solution and FITC label α-are black
The mass ratio of FITC label alpha-melanocyte stimulating hormone three in plain cytositimulation element solution is 10:10:1；Spin coating gelatin is molten
When liquid, dextran amine solution and FITC label alpha-melanocyte stimulating hormone solution, spin coating as follows: first with 500r/
After the speed spin coating 6s of min, then with the speed spin coating 20s of 2000r/min, spin coating amount is 5 μ L/cm2；The solution of graft polymers
The concentration of middle graft polymers is 5mg/mL.
(3) Ti/LBL that will be prepared in step (1)PEG-NBC- the FITC-MSH and middle Ti/LBL-FITC- prepared of step (2)
MSH is respectively placed in the PBS buffer solution that pH is 7.4 and neutralizes containing 500 μM of H2O2PBS buffer solution in, be incubated at 37 DEG C, In
Corresponding time point takes out all solution and carries out fluorescence intensity detection, and deposition according to release fluorescence intensity and before is made
The release profiles for stating two kinds of titanium-based bone implants FITC-MSH at different conditions, as a result as shown in figure 3, from the figure 3, it may be seen that having
H2O2Under the conditions of existing, in 36h and 72h, Ti/LBLPEG-NBCThe burst size of FITC-MSH respectively reaches 60% in-FITC-MSH
With 80%, and FITC-MSH burst size about reaches 25% and 40% respectively in Ti/LBL-FITC-MSH；In no H2O2Condition
Under, in 36h and 72h, Ti/LBLPEG-NBCThe burst size of FITC-MSH respectively reaches 15% and 23% in-FITC-MSH, and Ti/
FITC-MSH burst size about reaches 25% and 40%, subsequent FITC-MSH sustained release respectively in LBL-FITC-MSH；There is H2O2
Under conditions of be incubated for 7 days after, Ti/LBLPEG-NBCThe surface-FITC-MSH is almost without remaining FITC-MSH, and Ti/LBL-
Still there is about 50% FITC-MSH residual on the surface FITC-MSH；In no H2O2Under conditions of be incubated for 7 days after Ti/LBLPEG-NBC-
There are about 70% FITC-MSH residuals on the surface FITC-MSH, and there are about 50% FITC-MSH is residual on the surface Ti/LBL-FITC-MSH
It stays.The result shows that there is H2O2Under conditions of Ti/LBLPEG-NBCThe surface-FITC-MSH FITC-MSH shows to discharge speed faster
Rate, but in no H2O2When, since the crosslinked action of PEG-NBC leads to Ti/LBLPEG-NBCFITC-MSH is difficult in-FITC-MSH
It is released from titanium implants surface.
Embodiment 5
Titanium-based bone implant (Ti/LBL in the present inventionPEG-NBC- MSH) regulation stem cell differentiation capability test
The originally culture for carrying out mesenchymal stem cell first connects the inoculation of forth generation mesenchymal stem cell respectively
Kind prepares titanium-based bone implant in polystyrene board (TCPS), the pure titanium rod (Ti) without any modification, comparative example 1
(Ti/LBL), the titanium-based bone implant (Ti/LBL prepared in comparative example 2PEG-NBC) and embodiment 1 in the titanium-based bone for preparing
Implant (Ti/LBLPEG-NBC- MSH) surface, cell-seeding-density is 2 × 104A/cm2, after culture 7 days, collect cell and be used in combination
Trizol kit extracts total serum IgE, by total serum IgE reverse transcription at cDNA, detects for subsequent quantitative PCR (qPCR), purpose base
The expression of cause carries out normalizing with GAPDH gene, and passes through 2(-DD CT)Method is calculated, as a result as shown in figure 4, can by Fig. 4
Know, Ti/LBLPEG-NBCThe surface-MSH MSCs shows the expression of high-caliber Bone formation-related gene, including core Transcription Associated Factors
2, alkaline phosphatase, osteoprotegerin, osteopontin, type i collagen, osteocalcin.Wherein, Ti/LBLPEG-NBCIn the MSCs of-MSH group
The genes such as core Transcription Associated Factors 2, alkaline phosphatase, osteoprotegerin, osteopontin, type i collagen, osteocalcin divide compared with Ti group
1.3 times, 1.5 times, 1.6 times, 1.6 times, 1.8 times and 1.8 times have not been raised.Show that the ROS responsiveness constructed on pure titanium surface is released
The function interface for putting α-MSH is conducive to induce the differentiation of stem cell to osteoblast, promotes ostosis.
Embodiment 6
Titanium-based bone implant (Ti/LBL in the present inventionPEG-NBC- MSH) induce ostosis in osteoporosis animal models body
Aptitude tests construct the Osteoporotic Model of SD rat using ovary excision method, respectively by the pure titanium rod without any modification
(Ti), the titanium-based bone implant for preparing titanium-based bone implant (Ti/LBL) in comparative example 1, preparing in comparative example 2
(Ti/LBLPEG-NBC) and embodiment 1 in the titanium-based bone implant (Ti/LBL for preparingPEG-NBC- MSH) it is implanted into the osteoporosis of building
The femoral head epiphysis end of disease model, specifically: with intraperitoneal injection chloral hydrate anesthesia rat, sterilized to rat operation position shaving
Afterwards, using operation electricity turn (diameter 1.2cm) along the parallel direction of femoral head in rat femur skull epiphysis end turn hole, will be above-mentioned
Different titanium-based bone implants insert in the hole, after implantation 4 weeks, with the femoral head epiphysis of micro-CT observation Osteoporotic Model
The situation of ostosis around different titanium-based bone implants is held, as shown in figure 5, intermediate red area is titanium-based bone implant in Fig. 5
Implantation position, as shown in Figure 5, Ti/LBLPEG-NBCThere is more New born formation in the region 1mm around-MSH, from the longitudinal sectional of femoral head
Figure is it can be seen that Ti/LBLPEG-NBCBon e formation situation around-MSH is best.
Meanwhile masson and H&E is done to different titanium-based bone implant bone tissues and is dyed, observation titanium-based bone implant week
The Osteoblast Differentiation ability for enclosing bone relevant cell, as shown in fig. 6, Ti/LBLPEG-NBCThere are more new bones raw around-MSH implant
At showing titanium function interface (LBLPEG-NBC- MSH) it can more promote to be implanted into body interface for untreated pure titanium rod
Bone remoulding, this may be because of LBLPEG-NBC- MSH contains on surface this bioactive molecule of α-MSH, and this molecule can be positive and negative
Feedback adjusts the Osteoblast Differentiation of mescenchymal stem cell, finally promotes ostosis.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with
Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of the technical program, should all be covered in the present invention
Scope of the claims in.
Claims (10)
1. a kind of preparation method of titanium-based activity bone implant, which is characterized in that the method is as follows:
After pure titanium area load dopamine, successively spin coating gelatin solution, dextran amine solution, gelatin solution, alpha-melanophore
Stimulin solution will successively spin coating gelatin solution, dextran amine solution, gelatin solution, alpha-melanocyte stimulating hormone solution be known as
Primary complete spin coating, subsequent basis determine time of the complete spin coating to the actual demand burst size of alpha-melanocyte stimulating hormone
Number, one layer of gelatin solution of spin coating again after the last time complete spin coating to be done, is then soaked in eight arm polyethylene glycol amino
2h or more in the solution of the graft polymers generated after grafting boric acid ester bond, is made titanium-based activity bone implant.
2. the method as described in claim 1, which is characterized in that the method for the pure titanium area load dopamine is as follows: will be pure
Titanium is soaked in 10-16h in the Tris-HCl buffer containing dopamine；The concentration of the Tris-HCl buffer is
10mM, pH value 8.5, the concentration of dopamine is 2mg/mL in the Tris-HCl buffer.
3. the method as described in claim 1, which is characterized in that spin coating institute gelatine solution, dextran amine solution and α-melanocyte
When cytositimulation element solution, spin coating as follows: first with the speed spin coating 6-10s of 500-900r/min after, then with
The speed spin coating 20-25s of 2000-2500r/min, spin coating amount are 5-10 μ L/cm2。
4. the method as described in claim 1, which is characterized in that the Portugal of gelatin, dextran amine solution in institute's gelatine solution
The mass ratio of alpha-melanocyte stimulating hormone three in polidexide and alpha-melanocyte stimulating hormone solution is 2-10:2-10:1.
5. the method as described in claim 1, which is characterized in that the concentration of graft polymers in the solution of the graft polymers
For 5-10mg/mL.
6. the method as described in claim 1, which is characterized in that the graft polymers is prepared as follows:
(1) p-nitrophenyl chloroformate is dissolved in tetrahydrofuran, inflated with nitrogen at 0 DEG C, obtains solution I；
(2) 4- (methylol) phenyl boric acid pinacol ester, 4-dimethylaminopyridine and triethylamine are dissolved in tetrahydrofuran, are obtained
Solution II；
(3) under condition of ice bath, solution I is added dropwise in solution II under stiring by 10-20min, then at room temperature
It is stirred to react 3-4h with the speed of 300-800r/min, it is molten to obtain yellow for the product after being spin-dried for after being spin-dried for methylene chloride dissolution
Liquid, again with NaHCO after successively being washed with the HCl of 1M, saturation NaCl solution3Solution, which is washed to the color of the yellow solution, to be become
It is light yellow, silicagel column is finally crossed, gradient elution is carried out using the mixed liquor of petroleum ether and methylene chloride as eluent, is made after being spin-dried for
Obtain boric acid ester bond；
(4) boric acid ester bond obtained in step (3) and eight arm polyethylene glycol amino are added in organic solvent with 800-1200r/
The speed of min removes the organic solvent after being stirred to react 10-16h.
7. method as claimed in claim 6, which is characterized in that the p-nitrophenyl chloroformate, 4- (methylol) phenyl boric acid
The mass volume ratio of pinacol ester, 4-dimethylaminopyridine and triethylamine is 0.47:0.5:0.04:0.6, the mass volume ratio
Unit be g:g:g:mL；The molar ratio of the boric acid ester bond and eight arm polyethylene glycol amino is 6-9:1.
8. method as claimed in claim 6, which is characterized in that in step (3), the gradient elution specifically: first with stone
Oily ether and the methylene chloride mixed liquor that 1:4 is formed by volume are eluted, then by volume with petroleum ether and methylene chloride
The mixed liquor that 3:7 is formed is eluted, and is finally washed with petroleum ether and the methylene chloride mixed liquor that 2:3 is formed by volume
It is de-.
9. method as claimed in claim 6, which is characterized in that in step (4), the organic solvent is methylene chloride, tetrahydro
One of furans or dimethyl sulfoxide.
10. by the titanium-based activity bone implant of the described in any item method preparations of claim 1-9.
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