For improving the coating of titanium alloy biocompatibility
Technical field:
This utility model relates to a kind of appearance surface coatings of titanium alloy, for improving titanium alloy biocompatibility, belongs to medical instruments field, is specially adapted to the modification of implanted human assistance heart material.
Background technology:
Heart transplantation is the most effective treatment means of heart disease at final stage.But due to the famine of heart donor, the waiting period of having every year a large amount of heart disease at final stage people to die from donor in.The development of human assistance heart has solved this difficult problem, can replace or auxiliary normal heart work, maintains human body Efficient Cycle, so human assistance heart can be used as the important means of Patients with Cardiac Failure assist circulation or patients underwent heart transplantation transition treatment.
Because human assistance heart belongs to external source implant, body can produce immune rejection, and reaction and thrombosis cause inflammation.Rejection for fear of body to human assistance heart, produces a large amount of inflammatory tissues, affects the normal operation of human assistance heart pump, need to carry out respective handling to the material of human assistance heart.
Utility model content:
This utility model is research and develop for improving the biocompatibility of human assistance heart a kind of and has bioactive face coat.Meanwhile, this utility model coating can also alleviate the inflammatory reaction that cardiac incision goes out, and promotes disappearing of inflammatory cell, improves the ability of sticking of cell, improves the organization healing ability of heart wound.
An object of the present utility model is to provide a kind of coating that can improve titanium alloy histocompatibility; Preferably can also improve the inflammatory reaction of heart wound, improve the healing ability of cardiac muscular tissue.Be specially adapted to the material modification of implantable human assistance heart titanium alloy.
Because human assistance heart is in operation process, can produce larger myocardium wound, healing rate is slower, and easily causes the immunoreation of body.Titanium alloy surface is comparatively stable, not portable electric charge, the absorbability of extracellular matrix albumen is lower, cause cell and titanium alloy to stick degree lower, cannot produce the somatomedin of induction macrophage and migration of fibroblast cells, cause a large amount of inflammatory cells to be gathered in wound, cause inflammation, reduce speed of wound healing.In order to improve the biocompatibility of human assistance heart, reduce the identification ability of body to foreign body, can prepare a kind of bioactive titanium alloy surface coating that has.
For reaching utility model object, this utility model has adopted following coating:
1, for improving a coating for titanium alloy biocompatibility, it is characterized in that, it comprises from inside to outside successively:
I) oxide layer, is the innermost layer of coating, is directly connected, for activating titanium alloy with titanium alloy;
Ii) transition zone, it is connected with the oxide layer of activation.
Above-mentioned coating can be improved titanium alloy histocompatibility, is mainly used in the surface modification of titanium alloy material of the surfaces externally and internally of human assistance heart.
2, according to the coating described in project 1, wherein also comprise
Iii) biological activity protein layer, is connected with transition zone, for improving the ability of sticking of cell.
The intermediate layer that now transition zone is coating, for fixing of protein.Biological activity protein layer is the 3rd layer or outermost layer of coating, is connected, for improving the ability of sticking of cell with transition zone.
Contain two-layer coating and compare with above-mentioned, the coating that contains three layers has better biocompatibility.
3,, according to the coating described in project 1 or 2, wherein said oxide layer is mainly Ti-O coating.
4, according to the coating described in project 1 or 2, wherein said transition zone is mainly phospholipid molecule, comprises phosphoglyceride and/or sphingomyelins.
5, according to the coating described in project 2, wherein said biological activity protein layer is mainly extracellular matrix protein, preferably collagen protein, elastin laminin, viscous protein and/or layer fibronectin, or its hydrolyzate gelatin for example.
6, according to the coating described in project 1 or 2, wherein said titanium alloy be metal solid whole or its outer be the metal of titanium alloy, preferred titanium alloy artificial accessory heart.
7,, according to the coating described in project 1 or 2, within wherein said oxide layer, be titanium alloy layer.
On the other hand, also provide the method for preparing above-mentioned coating:
First metal ester compounds and bronsted lowry acids and bases bronsted lowry organic solvent are mixed in proportion, form uniform High-pH solution, form at a certain temperature gel, dried titanium alloy is made oxide-film.Described alkali organic solvent is organic complex, dehydrated alcohol and water.Organic complex comprises such as diethanolamine, EDTA, acetylacetone,2,4-pentanedione etc.Oxide-film, through highly basic activation processing, makes oxide layer produce free free radical; Interaction by between the group on free radical and phospholipid molecule surface, is fixed on titanium alloy surface by phospholipid molecule.Finally, extracellular matrix protein is fixed to the surface of phospholipid molecule by the method for covalence graft, forms and be beneficial to sticking of cell.Specifically,
8, a method that applies titanium alloy surface, is characterized in that, the method comprises step below:
I) metal ester compounds is mixed with bronsted lowry acids and bases bronsted lowry organic solvent, form uniform solution, form at a certain temperature gel, by described gel dip-coating titanium alloy surface, dried;
Ii) titanium alloy use highly basic activation processing step I), makes its surface produce free free radical; Then immerse the solution that contains phospholipid molecule.
9,, according to the method for project 8, wherein said method also comprises step below:
Iii) extracellular matrix protein solution is coated in through ii) titanium alloy processed; Described extracellular matrix protein is preferably collagen protein, elastin laminin, viscous protein or layer fibronectin, or its hydrolyzate gelatin for example.
10, according to the method for project 8 or 9, preferred below at least one feature wherein:
(1), described metal ester compounds is titanate ester compound, preferably butyl titanate or butyl titanate;
(2), first described metal ester compounds mixes with the preferred glacial acetic acid of acid organic solvent;
(3), the mixed proportion of metal ester compounds and acid organic solvent is 1:1~20:1, preferred 10:1;
(4) homogeneous solution, step I) forming is neutral or approaches neutral;
(5), step I) described alkali organic solvent is for example diethanolamine, dehydrated alcohol and water of organic complex, by 8:x:y(x=0.1-0.2, y=0.04-0.07) ratio mixes, preferably in 8:0.15:0.06 ratio;
(6), described phospholipid molecule is lecithin or cephalin;
(7) temperature, step I) is about 60 ℃ of about 40-.
The biomimetic material that the characteristic of this utility model by extracellular matrix protein designs, by interconnective microenvironment between analog cell, induction heart tissue cell (as myocardial cell, smooth muscle cell, heart endothelial cell etc.) is attached on titanium alloy surface, secrete a large amount of cell growth factor, promote clearing up and discharging of inflammatory cell (as neutrophilic granulocyte, macrophage etc.); By heart tissue cell migration, propagation and differentiation, finally form the new tissue that has function.
This utility model can improve the inflammatory reaction of body, promote the healing of impaired heart tissue, also can reduce the thrombosis of human assistance heart, alleviate the postoperative problems such as acute and chronic immunologic rejection of being brought by wound healing, improve patient's life quality simultaneously.
Accompanying drawing explanation:
Fig. 1 is the cross-sectional view of an embodiment coating of the application
1 is titanium alloy; 2 is oxide layer; 3 is phospholipid molecule layer; 4 is extracellular matrix protein layer.
The specific embodiment:
Below describe the specific embodiment of the present utility model in detail, in any case but can not be interpreted as restriction of the present utility model.
As shown in Figure 1, in a specific embodiments, described coating is comprised of 4 parts, and arranges from inside to outside by the order of 1-4.Wherein the 1st layer is titanium alloy body, is also innermost one deck; The 2nd layer is the oxide layer of titanium, is close to titanium alloy; The 3rd layer is phospholipid molecule layer, adjacent with oxide layer; The 4th layer of protein layer is outmost one deck.
Can prepare described coating according to method below:
Butyl titanate, glacial acetic acid are mixed in 10:1 ratio, and 50 ℃ of heating mix homogeneously, are designated as solution A.Organic complex, dehydrated alcohol and water are pressed 8:x:y(x=0.1-0.2, y=0.04-0.07) ratio mixing, stir, be designated as solution B.By solution A, B mix homogeneously, room temperature ageing 24-96h.Mixed liquor is coated in to material surface uniformly, and 150-400 ℃ of heating 1-4h, obtains uniform Ti-O coating.
To put into NaOH with the material of Ti-O coating, ambient temperature overnight, cleans up after taking-up.The solution that contains phospholipid molecule is added to material surface, makes liquid by material submergence, be more than 20-40 ℃ of placement 2h.Material surface is the colourless thin film of layer of transparent, therefore, and the basic and oxide layer solid colour of material color.But this coating is comparatively fragile, easily destroyed.This thin film need carry out manipulation under aseptic condition.
Taking-up scribbles the material of phospholipid molecule, cleans up, and dries.Material surface dropping concentration after drying is the collagen solution of 1-10 μ g/mL, makes it cover this material surface, more than 20-40 ℃ of polymerization 1h.Taking-up cleans up post-drying.The 3rd coating is also the colourless thin film of layer of transparent, can measure by contact angle detection.Therefore, after three layers of coating apply, material is still the color of oxide layer, in bright and clean degree, slightly declines.Three layers of coating are more fragile, easily destroyed.This thin film need carry out manipulation under aseptic condition.
Therefore, in the operations such as following process, preservation, transportation, want significant care, prevent that coating is destroyed.
Embodiment mono-:
Butyl titanate, glacial acetic acid are mixed in 10:1 ratio, and 50 ℃ of heating mix homogeneously, are designated as solution A.Diethanolamine, dehydrated alcohol and water mix in 8:0.15:0.06 ratio, stir, and are designated as solution B.By solution A, B mix homogeneously, room temperature ageing 72h.Mixed liquor is coated in to silvery white Titanium alloy Ti-6Al-4V material surface uniformly, and 400 ℃ of heating 2h, obtain uniform titanium oxide azury (being abbreviated as Ti-O) coating.
To put into NaOH with the material of Ti-O coating, ambient temperature overnight, cleans up with deionized water after taking-up.The solution that contains lecithin is added to material surface, makes liquid by material submergence, place 2h, obtain two layers of coatings for 20 ℃.Material surface is the colourless thin film of layer of transparent, therefore, and the basic and oxide layer solid colour of material color.But this coating is comparatively fragile, easily destroyed.This thin film need carry out manipulation under aseptic condition.
Taking-up scribbles the material of lecithin, cleans up, and dry with deionized water.Material surface dropping concentration after drying is the collagen solution of 5 μ g/mL, makes it cover this material surface, 20 ℃ of polymerization 1h.Taking-up cleans up post-drying, obtains three layers of coating.The 3rd coating is also the colourless thin film of layer of transparent, and therefore, after three layers of coating apply, material is still the color of oxide layer, in bright and clean degree, slightly declines.
Embodiment bis-:
Tetraethyl titanate, acetic acid are mixed in 10:1 ratio, and 40 ℃ of heating mix homogeneously, are designated as solution A.Diethanolamine, dehydrated alcohol and water mix in 8:0.10:0.04 ratio, stir, and are designated as solution B.By solution A, B mix homogeneously, room temperature ageing 48h.Mixed liquor is coated in to titanium alloy T i-6Al-7Nb material surface uniformly, and 400 ℃ of heating 2h, obtain uniform Ti-O coating.
To put into NaOH with the material of Ti-O coating, ambient temperature overnight, cleans up with deionized water after taking-up.The solution that contains DPPC is added to material surface, makes liquid by material submergence, place 5h for 20 ℃.Material surface is the colourless thin film of layer of transparent, therefore, and the basic and oxide layer solid colour of material color.But this coating is comparatively fragile, easily destroyed.This thin film need carry out manipulation under aseptic condition.
Taking-up scribbles the material of DPPC, cleans up, and dry with deionized water.Material surface dropping concentration after drying is the elastin laminin solution of 3 μ g/mL, makes it cover this material surface, 20 ℃ of polymerization 2h.Taking-up cleans up post-drying.The 3rd coating is also the colourless thin film of layer of transparent, and therefore, after three layers of coating apply, material is still the color of oxide layer, in bright and clean degree, slightly declines.
Embodiment tri-:
Butyl titanate, nitric acid are mixed in 20:1 ratio, and 55 ℃ of heating mix homogeneously, are designated as solution A.Acetylacetone,2,4-pentanedione, dehydrated alcohol and water mix in 8:0.20:0.06 ratio, stir, and are designated as solution B.By solution A, B mix homogeneously, room temperature ageing 48h.Mixed liquor is coated in to titanium alloy T i-5Al-2.5Fe material surface uniformly, and 400 ℃ of heating 2h, obtain uniform Ti-O coating.
To put into NaOH with the material of Ti-O coating, ambient temperature overnight, cleans up with deionized water after taking-up.The solution that contains choline glycerophosphatide is added to material surface, makes liquid by material submergence, room temperature is placed 5h.Material surface is the colourless thin film of layer of transparent, therefore, and the basic and oxide layer solid colour of material color.But this coating is comparatively fragile, easily destroyed.This thin film need carry out manipulation under aseptic condition.
Taking-up scribbles the material of choline glycerophosphatide, cleans up, and dry with deionized water.Material surface dropping concentration after drying is the viscous protein solution of 4 μ g/mL, makes it cover this material surface, polymerized at room temperature 2h.Taking-up cleans up post-drying.The 3rd coating is also the colourless thin film of layer of transparent, and therefore, after three layers of coating apply, material is still the color of oxide layer, in bright and clean degree, slightly declines.
Test example
Adopt the method for embodiment mono-that implanted human assistance heart titanium alloy surface is coated to coating of the present utility model.6 sheep are divided into two groups, 3 every group.Compare with the titanium that does not contain coating of the present utility model implanted human assistance processed heart, in the situation that other conditions are identical, the titanium implanted human assistance processed heart that contains this utility model coating is obtained successfully in animal experiment, test group sheep is on average survived 106 days, and there is no obvious inflammatory reaction, time-to-live and quality of life are apparently higher than the matched group test sheep (on average surviving 3 days) of not applying this utility model coating.
When dissect physiology, find, untreated experiment sheep wound produces a large amount of hard pannus and fibrous tissue pieces, not firm with the laminating of entrance outer wall, easily falls down.And the human assistance heart of processing is contained in experiment sheep body, can improve the inflammatory reaction of wound, wound is firmly combined with entrance outer wall, can not produce pannus, and grows at entrance outer wall the cardiac muscular tissue that one deck is new.
Above-mentioned specific embodiment is illustrative, based on these embodiment, can introduce multiple variation in the situation that do not deviate from spirit or the claims scope of disclosure.