CN104028434A - Method for building laminin/heparin/SDF-1alpha anticoagulation and endothelialization induction multifunctional layer on titanium surface - Google Patents
Method for building laminin/heparin/SDF-1alpha anticoagulation and endothelialization induction multifunctional layer on titanium surface Download PDFInfo
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Abstract
The invention discloses a method for building a laminin/heparin/SDF-1alpha anticoagulation and endothelialization induction multifunctional layer on a titanium surface. The method comprises the steps that first, the amino Ti surface is built on the basis of the characteristic that electrostatic binding can happen between polylysine (PLL) and the Ti surface activated through alkali; second, on the basis of the specific binding action between Ln and Hep, an Ln/Hep compound is prepared, the Ln/Hep compound is fixed to the amino Ti surface in a covalence mode through an EDC/NHS/MES coupling agent; third, the SDF-1alpha is loaded on the surface modified by the Ln/Hep on the basis of the characteristic that specific binding can happen between SDF-1alpha and the Hep. Therefore, the biologically functional microenvironment for anticoagulation and endothelium regeneration induction is built. According to the method, because the multifunctional layer with the anticoagulation and endothelium regeneration induction function is built on the Ti surface, blood compatibility of materials and the injured endothelium repair capacity are remarkably improved.
Description
Affiliated technical field
The present invention relates to inorganic material surface modification technology, particularly the bioid method of modifying on artificial organs material titanium surface.
Background technology
Titanium (Ti) and titanium alloy material have been widely used in medical instruments field because of its good biocompatibility, as bone material, tooth implant, peripheral vascular support etc.But for the field of some special applications, as the treatment for coronary heart disease as cardiovascular embedded material, its security and biocompatibility also reach far away clinical requirement.Wherein, Ti material blood compatibility is poor, cell compatibility is not enough and there is no for vascellum endometrial hyperplasia and inflammatory reaction etc. the main aspect that remarkable inhibitory action is its application of restriction.
By material surface is carried out to bioid modification, build rational biological microenvironment, giving anticoagulation ability and the induction endothelial regeneration ability that material is good is to improve the effective ways of its biocompatibility.Laminin (Ln) is peculiar non-collagen sugar albumen in blood vessel endothelium basilar memebrane, can effectively promote adhesion, migration and the propagation of vascular endothelial cell.Interstitial cell derivative factor-1 α (SDF-1 α) is a kind of chemotactic factor (CF) marrow CXCR4+ stem cell and endothelial progenitor cells (EPCs) to strong chemotaxis, also have stimulating endothelial cell growth, induction endothelial progenitor cells is to the function of endothelial cell differentiation simultaneously.Heparin (Hep) is a kind of widely used anticoagulation medicine, clinical prevention and the treatment that is also usually used in immune inflammation reaction.In addition, Hep can be in conjunction with several functions albumen, and as Ln and SDF-1 α, the BA that the interaction of heparin and protein can Enhancin matter, extends its action time.
Poly-D-lysine (PLL) is a kind of amino amino acid polymer that is rich in, and is strong electropositive under neutral environment, can strong bonded after alkali thermal activation, be electronegative Ti surface, and on surface, introduce the amino in a large number with reactivity by electrostatic interaction.By the effect of EDC/NHSMES coupling agent, Ln/Hep compound covalency can be fixed on to amidized Ti surface.Utilize the feature of Hep specific binding SDF-1 α, can further introduce SDF-1 α on the surface of common fixed L n/Hep.
This Ln/Hep/SDF-1 α Multifunctional layered can significantly improve the blood compatibility at material surface, induces the endothelial progenitor cells in marrow and blood source to adhere to propagation at material surface simultaneously, promotes the regeneration of vascular endothelial cell, stimulates wound repair.And there is no at present the relevant report for the modification of Ti material surface bioid by the biological microenvironment of Ln/Hep/SDF-1 α.
Summary of the invention
The object of the present invention is to provide a kind of method that builds Ln/Hep/SDF-1 α anti-freezing and induction endothelialization Multifunctional layered at Ti material surface, by the method, Ti material surface is carried out to blood compatibility and the induction endothelial regeneration ability that bioid modification can effectively improve material.
The present invention realizes the technical scheme that above object adopts, a kind of method in the biological microenvironment of titanium surface construction Ln/Hep/SDF-1 α, and its step comprises:
A, the pure titanium of alkali thermal activation are after surface finish and cleaning treatment, in the NaOH solution that immersion concentration is 1～5mol/L, under 60～90 ℃ of conditions, react 8～16 hours, single steaming after water ultrasonic cleaning, immerse in distilled water, under 60～90 ℃ of conditions, react 8～16 hours single steaming after water ultrasonic cleaning, 37 ℃ of oven dry;
B, surface amination are soaked in the sample of alkali thermal activation in A step the poly-D-lysine (PLL of 0.5～3mg/ml, MW150～300KDa) in solution, under 4 ℃ of conditions, standing reaction is 8～24 hours, then uses phosphate buffer (PBS) to clean sample, preserves stand-by;
First the fixing altogether of C, laminin/heparin be the laminin solution of 30～300 μ g/ml and the heparin sodium aqua equal-volume blend that concentration is 3～10mg/ml by concentration, standing hatching 1～3 hour under 37 ℃ of conditions; Configuration mol ratio EDC/NHS/MES (0.05mol) buffer solution that is 2:1:1, is added in the mixed liquor of laminin/heparin with the volume ratio of 1:10, under room temperature standing 1～5 minute; Then the titanium sheet that is coated with PLL in B step is soaked in above-mentioned laminin/liquaemin mixed liquor, under 37 ℃ of conditions, standing reaction is 3～6 hours; Finally use PBS rinsing sample, preserve stand-by;
The sample that the loading of D, SDF-1 α obtains C step immerses in the SDF-1 α solution of 50～500ng/ml, and under 4 ℃ of conditions, standing reaction is 8～24 hours, obtains object after PBS rinsing.
Referring to Figure of description 1, course of reaction of the present invention and mechanism are divided into two parts, and first is the acquisition on amination Ti surface.First by alkali thermal activation, on Ti surface, introduce a large amount of hydroxyls, make surface be strong elecrtonegativity; Secondly in the PBS of pH=7.4 system, electropositive PLL molecule is firmly adsorbed in alkali activation Ti surface by electrostatic interaction, thereby on surface, introduces abundant amino fixing for follow-up biomolecule.Second portion is Ln/Hep/SDF-1 α fixing on Ti surface.First by Ln and Hep solution blending, utilize the interactional characteristic of Hep and Ln to make two kinds of abundant combinations of biomolecule, then use the carboxyl in EDC/NHS/MES coupling agent activation Ln/Hep compound, and in the primary amino radical generation dehydration condensation on amination Ti surface, thereby make Ln/Hep covalency be fixed on Ti surface, finally utilize the characteristic of the combination on Hep and SDF-1 α energy recurring structure territory, SDF-1 α is loaded into the Ti surface of fixed L n/Hep.
Compared with prior art, the invention has the beneficial effects as follows:
One, the creationary building mode of selecting Multifunctional layered, and under certain biomolecule concentration ratio, utilize the specific binding effect of Hep and Ln and SDF-1 α, and the crosslinked action of EDC/NHS/MES coupling agent, at Ti surface construction, go out the biological microenvironment of Ln/Hep/SDF-1 α.By this kind of method, can effectively suppress the loss of activity of biomolecule in covalency fixation procedure.In addition, after alkali thermal activation, the fixing mode of the special microporous pattern of sample surfaces and covalency can effectively improve Ln and Hep in the stability of material surface, extends the release time of SDF-1 α, strengthens the effect that its induction damage endothelium is repaired.
Two, the structure technique of biological microenvironment and fixing means are all simple to operation, and without expensive complicated equipment, process costs is lower, and controllability is strong, and effect is remarkable.
Three, the fixing of the activation on Ti surface and all biomolecule all adopts immersion way to carry out, can guarantee that material various piece can fix biomolecule uniformly, be conducive to realize various baroque cardiovascular implantation instruments as anti-freezing/induction endothelial regeneration functional modification on the surfaces such as intravascular stent, thrombus filter, applied widely.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, method of the present invention is described in further detail.
Fig. 1 is each step schematic diagram that in the inventive method, the biological microenvironment of Ti Surface L n/Hep/SDF-1 α builds.
Fig. 2 is the scanning electron microscope (SEM) photograph of sample surfaces platelet adhesion reaction.(A) Ti; (B) Ti of fixed L n/Hep/SDF-1 α.
Fig. 3 is sample surfaces Endothelial cell culture fluorescent staining result after 3 days.(A) Ti; (B) Ti of fixed L n/Hep/SDF-1 α.
Fig. 4 is that sample surfaces endothelial progenitor cells is cultivated fluorescent staining result after 2 hours and 3 days.(A1) Ti-2 hour; (A2) Ti-3 days; (B1) Ln/Hep/SDF-1 α-2 hour; (B2) Ln/Hep/SDF-1 α-3 day
Fig. 5 is sample surface morphology scanning electron microscope (SEM) photograph after the heat treatment of (A) alkali; (B) QCM characterizes the stability of the fixing Ln/Hep functional layer of covalency; (C) the release dynamics testing result of SDF-1 α.
The specific embodiment
Embodiment mono-
Referring to Fig. 1, the first specific embodiment of the present invention is that a kind of method at titanium surface construction Ln/Hep/SDF-1 α anti-freezing and induction endothelialization Multifunctional layered, the steps include:
A, the pure titanium of alkali thermal activation, after surface finish and cleaning treatment, in the NaOH solution that immersion concentration is 5mol/L, react 8 hours under 60 ℃ of conditions, single steaming after water ultrasonic cleaning, immerses in distilled water, under 90 ℃ of conditions, reacts 16 hours, single steaming after water ultrasonic cleaning, 37 ℃ of oven dry;
B, surface amination are soaked in the sample of alkali thermal activation in A step the poly-D-lysine (PLL of 3mg/ml, MW150～300KDa) in solution, under 4 ℃ of conditions, standing reaction is 8 hours, then uses phosphate buffer (PBS) to clean sample, preserves stand-by;
First the fixing altogether of C, laminin/heparin be the laminin solution of 300 μ g/ml and the heparin sodium aqua equal-volume blend that concentration is 10mg/ml by concentration, standing hatching 3 hours under 37 ℃ of conditions; Configuration mol ratio EDC/NHS/MES (0.05mol) buffer solution that is 2:1:1, is added in the mixed liquor of laminin/heparin with the volume ratio of 1:10, under room temperature standing 5 minutes; Then the titanium sheet that is coated with PLL in B step is soaked in above-mentioned laminin/liquaemin mixed liquor, under 37 ℃ of conditions, standing reaction is 3 hours; Finally use PBS rinsing sample, preserve stand-by;
The sample that the loading of D, SDF-1 α obtains C step immerses in the SDF-1 α solution of 500ng/ml, and under 4 ℃ of conditions, standing reaction is 24 hours, after PBS rinsing and get final product.
Embodiment bis-
A method in the biological microenvironment of titanium surface construction Ln/Hep/SDF-1 α, the steps include:
A, the pure titanium of alkali thermal activation, after surface finish and cleaning treatment, in the NaOH solution that immersion concentration is 1mol/L, react 16 hours under 90 ℃ of conditions, single steaming after water ultrasonic cleaning, immerses in distilled water, under 60 ℃ of conditions, reacts 8 hours, single steaming after water ultrasonic cleaning, 37 ℃ of oven dry;
B, surface amination are soaked in the sample of alkali thermal activation in A step the poly-D-lysine (PLL of 0.5mg/ml, MW150～300KDa) in solution, under 4 ℃ of conditions, standing reaction is 24 hours, then uses phosphate buffer (PBS) to clean sample, preserves stand-by;
First the fixing altogether of C, laminin/heparin be the laminin solution of 30 μ g/ml and the heparin sodium aqua equal-volume blend that concentration is 3mg/ml by concentration, standing hatching 1 hour under 37 ℃ of conditions; Configuration mol ratio EDC/NHS/MES (0.05mol) buffer solution that is 2:1:1, is added in the mixed liquor of laminin/heparin with the volume ratio of 1:10, under room temperature standing 1 minute; Then the titanium sheet that is coated with PLL in B step is soaked in above-mentioned laminin/liquaemin mixed liquor, under 37 ℃ of conditions, standing reaction is 6 hours; Finally use PBS rinsing sample, preserve stand-by;
The sample that the loading of D, SDF-1 α obtains C step immerses in the SDF-1 α solution of 50ng/ml, and under 4 ℃ of conditions, standing reaction is 8 hours, after PBS rinsing and get final product.
Embodiment tri-
A method in the biological microenvironment of titanium surface construction Ln/Hep/SDF-1 α, the steps include:
A, the pure titanium of alkali thermal activation, after surface finish and cleaning treatment, in the NaOH solution that immersion concentration is 3mol/L, react 12 hours under 80 ℃ of conditions, single steaming after water ultrasonic cleaning, immerses in distilled water, under 80 ℃ of conditions, reacts 12 hours, single steaming after water ultrasonic cleaning, 37 ℃ of oven dry;
B, surface amination are soaked in the sample of alkali thermal activation in A step the poly-D-lysine (PLL of 2.5mg/ml, MW150～300KDa) in solution, under 4 ℃ of conditions, standing reaction is 12 hours, then uses phosphate buffer (PBS) to clean sample, preserves stand-by;
The altogether fixing laminin solution that is first 200mg/ml by concentration of C, laminin/heparin and the heparin sodium aqua equal-volume blend that concentration is 5mg/ml, standing hatching 2 hours under 37 ℃ of conditions; Configuration mol ratio EDC/NHS/MES (0.05mol) buffer solution that is 2:1:1, is added in the mixed liquor of laminin/heparin with the volume ratio of 1:10, under room temperature standing 3 minutes; Then the titanium sheet that is coated with PLL in B step is soaked in above-mentioned laminin/liquaemin mixed liquor, under 37 ℃ of conditions, standing reaction is 4 hours; Finally use PBS rinsing sample, preserve stand-by;
The sample that the loading of SDF-1 α obtains C step immerses in the SDF-1 α solution of 200ng/ml, and under 4 ℃ of conditions, standing reaction is 12 hours, after PBS rinsing and get final product.
Claims (2)
1. in a method for titanium surface construction laminin/heparin/SDF-1 α anti-freezing and induction endothelialization Multifunctional layered, its step comprises:
A, alkali thermal activation: pure titanium is after surface finish and cleaning treatment, in the NaOH solution that immersion concentration is 1～5mol/L, under 60～90 ℃ of conditions, react 8～16 hours, single steaming after water ultrasonic cleaning, immerse in distilled water, under 60～90 ℃ of conditions, react 8～12 hours single steaming after water ultrasonic cleaning, 37 ℃ of oven dry;
B, surface amination: the poly-D-lysine (PLL that the sample of alkali thermal activation in A step is soaked in to 0.5～3mg/ml, MW150～300KDa) in solution, under 4 ℃ of conditions, standing reaction is 8～24 hours, then uses phosphate buffer (PBS) to clean sample, preserves stand-by;
Fixing altogether of C, laminin/heparin: by concentration, be first the laminin solution of 30～300 μ g/ml and the heparin sodium aqua equal-volume blend that concentration is 3～10mg/ml, standing hatching 1～3 hour under 37 ℃ of conditions; Configuration mol ratio EDC/NHS/MES (0.05mol) buffer solution that is 2:1:1, is added in the mixed liquor of laminin/heparin with the volume ratio of 1:10, under room temperature standing 1～5 minute; Then the titanium sheet that is coated with PLL in B step is soaked in above-mentioned laminin/liquaemin mixed liquor, under 37 ℃ of conditions, standing reaction is 3～6 hours; Finally use PBS rinsing sample, preserve stand-by;
The loading of D, SDF-1 α: the sample that C step is obtained immerses in the SDF-1 α solution of 50～500ng/ml, and standing reaction is 8～24 hours under 4 ℃ of conditions, obtains object after PBS rinsing.
2. a kind of method at titanium surface construction laminin/heparin/SDF-1 α anti-freezing and induction endothelialization Multifunctional layered according to claim 1, it is characterized in that: the store method in described B, C, D step is under surface wettability condition, 4 ℃ stored refrigerated.
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| CN106983919A (en) * | 2017-03-06 | 2017-07-28 | 西南交通大学 | A kind of construction method of Sema 4D VEGF coatings and application |
| CN107320788A (en) * | 2017-06-09 | 2017-11-07 | 西南交通大学 | A kind of SEMA4D and CXCL12 bimoleculars collaboration promotees the preparation method and applications of endothelialization coating in situ |
| CN109925540A (en) * | 2019-03-14 | 2019-06-25 | 西南交通大学 | Albumin is mediated to form method, biomaterial and its application of albumin layer on the surface of the material |
| CN113304332A (en) * | 2021-05-12 | 2021-08-27 | 广东顺德工业设计研究院(广东顺德创新设计研究院) | Anticoagulation coating and preparation method thereof |
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2014
- 2014-05-28 CN CN201410230833.7A patent/CN104028434B/en not_active Expired - Fee Related
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Cited By (8)
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| CN106983919A (en) * | 2017-03-06 | 2017-07-28 | 西南交通大学 | A kind of construction method of Sema 4D VEGF coatings and application |
| CN106983919B (en) * | 2017-03-06 | 2019-07-12 | 西南交通大学 | A kind of construction method of Sema 4D-VEGF coating and application |
| CN107320788A (en) * | 2017-06-09 | 2017-11-07 | 西南交通大学 | A kind of SEMA4D and CXCL12 bimoleculars collaboration promotees the preparation method and applications of endothelialization coating in situ |
| CN109925540A (en) * | 2019-03-14 | 2019-06-25 | 西南交通大学 | Albumin is mediated to form method, biomaterial and its application of albumin layer on the surface of the material |
| CN113304332A (en) * | 2021-05-12 | 2021-08-27 | 广东顺德工业设计研究院(广东顺德创新设计研究院) | Anticoagulation coating and preparation method thereof |
| CN114652892A (en) * | 2022-05-20 | 2022-06-24 | 上海明悦医疗科技有限公司 | Medical membrane material and preparation method thereof, uterine cavity anti-adhesion equipment and medical device |
| CN115522207A (en) * | 2022-08-30 | 2022-12-27 | 南京医科大学附属口腔医院 | Preparation method for constructing PLL/CPP-ACP self-assembled multilayer film on sand-blasting acid-etching titanium surface |
| CN115522207B (en) * | 2022-08-30 | 2024-06-04 | 南京医科大学附属口腔医院 | Preparation method for constructing PLL/CPP-ACP self-assembled multilayer film on sandblasted acid etched titanium surface |
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