One kind crosslinking bioprosthesis valve and preparation method thereof
Technical field
Bioprosthesis valve and preparation method thereof is crosslinked the present invention relates to medical instruments field, more particularly to one kind.
Background technology
With economic development and aging population, the incidence of disease of veteran form calcific aortic disease (CAVD) is presented
The trend of liter, as the angiocardiopathy for being only second to coronary heart disease and hypertension.The retrospective non-randomized studies analysis prompting of one, China
The incidence of disease of the middle-older patient calcific aortic valve (AVC) of more than 50 years old is up to 49.38%.With the aging of population, calcification
Property aortic stenosis (CAS) the incidence of disease increase, will turn into China's valvular heart disease the primary cause of disease.
Aorta petal plant, which is carried out, using artificial valve changes the gold mark that (AVR) is the various types of aortic valve diseases of processing
It is accurate.It is increasing that (TAVR, the or TAVI) application trend of art worldwide is inserted through conduit sustainer bioprosthetic valves.This can
Can be because compared with conventional surgical AVR excessive risk, the technology is reduced the death rate and the potentiality of the incidence of disease.Through conduit actively
Arteries and veins valve implantation is smaller as a kind of wound, and the relatively low treatment method of risk gives severe aortic stenosis in patients, particularly
The patient of open chest surgery is unable to, new hope is brought.With widely using for intervention artificial heart biological cardiac valve, how it is improved
Service life, the failure of reduction biovalve is the important problem that we face.
Existing biovalve is essentially all to be crosslinked using single glutaraldehyde solution, and reach makes under certain condition
With the mechanical property and durability of scope, and possess good biocompatibility, then sew biovalve in one kind memory
On metallic support, then it is stored in finite concentration glutaraldehyde and preserves in liquid.Before Cardiac valve replacement is carried out, by valve
Film is transported to hospital operating room, and valve is cleaned, and then valve is delivered in heart of patient by conveyer device.
During making, sewing, transport and the use of above-mentioned valve, valve must be maintained in specific preservation liquid and ensure that valve is
Wet state.
Biovalve after domestic and international existing crosslinking is during making, sewing, transport and use, it is necessary to be stored in spy
In fixed preservation liquid and ensure that valve is wet state so that valve needs extra condition so that preparing in preparation process
Process is cumbersome, in transportation must valve and conveyer separate, valve must be washed on valve when needing preoperative loading, loading
The preservation liquid of residual, easily loss cause calcification and inactivate and increase the risk of bacterial infection, while limiting its clinical practice popularization.
Add the cost that biovalve preserves, transports and use.And biovalve is after glutaraldehyde cross-linking, on valve usually
Can remain the carboxyl on the unpaired aldehyde radical from glutaraldehyde and valve proteinaceous tissue, aldehyde radical and carboxyl easily with calcium ion knot
Close, cause the presence of calcification sites in bioprosthetic valves, this is a major reason for causing bioprosthetic valves calcification.Simultaneously because wet film is loaded,
Valve compressed dimension can not further reduce, and reduce patient's accommodation, and limitation valve inserts path, adds blood vessel concurrent
Disease.
With the gradually accumulation of TAVR clinical experiences, its complication is gradually decreased, and idicatio has gradually suffers to younger
Person, in it is low danger patient extension trend.At present it is all it is commercialized through conduit aortic valve in application process, potential problems
Gradually highlight, mainly include as follows:
1. valve durability is inadequate, it is impossible to meet valvular heart disease people's rejuvenation trend;
2. valve compressed dimension can not further reduce, patient's accommodation is reduced, limitation valve is inserted path, increased
Vascular complication;
3. valve need it is preoperative load, easy calcification and inactivate, poor durability and the manufacture defect such as accumulating condition harshness limit it
Clinical practice is promoted;
4. the biocompatibility of existing artificial bio-prosthetic valve is still not enough;The biocompatibility of artificial bio-prosthetic valve is influence valve
One major reason of film service life, eliminates the immunogenicity of valve and can strengthen host ECs and climb and cover function, reduce
Perivalvular leakage Probability.
Therefore, prior art has yet to be improved and developed.
The content of the invention
In view of above-mentioned the deficiencies in the prior art, it is an object of the invention to provide one kind crosslinking bioprosthesis valve and its system
Preparation Method, it is intended to solve existing bioprosthesis valve durability not enough, valve compressed dimension can not further reduce, valve is needed
It is preoperative to load, easy calcification and inactivate, manufacture accumulating condition is harsh and the problem of poor biocompatibility.
Technical scheme is as follows:
A kind of preparation method for being crosslinked bioprosthesis valve, including step:Bioprosthesis valve is immersed into glutaraldehyde and contained
In the mixed solution of the polymer composition of specified chemical functional group, crosslinking fixation is carried out, obtains being crosslinked bioprosthesis valve;Its
In, the specified chemical functional group is hydroxyl, carboxyl, NCO or siloxy group.
The preparation method of described crosslinking bioprosthesis valve, wherein, the polymer bag of the functional group containing specified chemical
Include in polyethylene glycol, polyvinyl alcohol, polyether Glycols, chitin, polyglycolic acid, PLA, polyurethane, polysiloxanes extremely
Few one kind.
The preparation method of described crosslinking bioprosthesis valve, wherein, the concentration of the glutaraldehyde is 0.1%~5%.
The preparation method of described crosslinking bioprosthesis valve, wherein, the polymer of the functional group containing specified chemical
Concentration is 10%~50%.
The preparation method of described crosslinking bioprosthesis valve, wherein, the fixed temperature of crosslinking is 25~45 DEG C.
The preparation method of described crosslinking bioprosthesis valve, wherein, crosslinking regular time is 1~7 day.
The preparation method of described crosslinking bioprosthesis valve, wherein, the preparation method also includes:By artificial bio-prosthetic valve
Film is immersed in the mixed solution of glutaraldehyde and the polymer composition of the functional group containing specified chemical, after progress crosslinking is fixed, is taken
Go out and be completely dried at 5~45 DEG C.
One kind crosslinking bioprosthesis valve, it uses the preparation method described in any of the above to be made.
Beneficial effect:The preparation method of crosslinking bioprosthesis valve of the present invention, can strengthen the physicochemical property of valve
And biocompatibility, the service life of valve is improved, while making valve be maintained to flexible property in the state of drying
Matter, so as to reduce the production of valve, cost of transportation, simplifies the use flow of valve.
Brief description of the drawings
The side that Fig. 1 chemically reacts for the polymer of valve of the present invention and crosslinking agent and the functional group containing specified chemical
Formula schematic diagram (R group in figure on polymer represents hydroxyl, carboxyl, NCO or siloxy group).
Embodiment
The present invention provides a kind of crosslinking bioprosthesis valve and preparation method thereof, to make the purpose of the present invention, technical scheme
And effect is clearer, clear and definite, the present invention is described in more detail below.It should be appreciated that specific implementation described herein
Example is not intended to limit the present invention only to explain the present invention.
Bioprosthesis valve (abbreviation valve) is passed through glutaraldehyde and the functional group containing specified chemical by the invention
Mixed with polymers solution is crosslinked, and contained chemical functional group chemically reacts with the group in valve in mixed solution, valve
Film, also can be with the hydroxyl in polymer, carboxyl, NCO or siloxy group etc. while being crosslinked with glutaraldehyde
Specified chemical functional group produces stable chemical covalent bonds, improves the submissiveization performance of valve, makes valve in the dry state
Good physicochemical property can be still kept, the material restricted problem of prepackage valve is solved.
It should be noted that bioprosthesis valve of the present invention includes but is not limited to pig pericardium heart valve, bovine pericardium valve
Deng animal pericardium heart valve.
The preparation method of the crosslinking bioprosthesis valve of present pre-ferred embodiments, including step:By bioprosthesis valve
In the mixed solution for immersing glutaraldehyde and the polymer composition of the functional group containing specified chemical, crosslinking fixation is carried out, obtains being crosslinked people
Work biovalve;Wherein, the specified chemical functional group is hydroxyl, carboxyl, NCO or siloxy group.
It is preferred that, in present pre-ferred embodiments, the preparation method can also include:Bioprosthesis valve is immersed penta
In the mixed solution of dialdehyde and the polymer of the functional group containing specified chemical composition, after progress crosslinking is fixed, take out 5~45
It is completely dried at DEG C.
In other words, in the present embodiment, the preparation method of the crosslinking bioprosthesis valve can include two steps:1. it is biological
The crosslinking of valve;2. low temperature drying.The present invention takes out the valve after mixed solution described above processing, in low-temperature condition
Lower drying, obtain be completely dried after crosslinking bioprosthesis valve, still with good pliability and mechanical property.
The mixed solution of glutaraldehyde of the present invention and the polymer of the functional group containing specified chemical composition, be by glutaraldehyde and
The polymer blending of the functional group containing specified chemical, as a kind of new crosslinking agent prescription, the valve after being crosslinked through the formula
It is still soft and moist after processing, and valve drying can be dried;And traditional crosslinking valve can become fragile after drying, cause nothing
Method is used.
When the specified chemical functional group is hydroxyl, by taking pig pericardium heart valve as an example, Pigs Hearts coating when uncrosslinked is glue
Former albumen, containing a large amount of amino and carboxyl, by the crosslinking of glutaraldehyde and the polymer blend solution of the functional group containing specified chemical,
Amino and aldehyde radical, carboxyl and hydroxyl reaction, form covalent bond, and the valve so formed has more preferable pliability, while dry
It can still be kept under dry state.
Further, in the present embodiment, the polymer of the functional group containing specified chemical includes polyethylene glycol, polyethylene
At least one of alcohol, polyether Glycols, chitin, polyglycolic acid, PLA, polyurethane, polysiloxanes.It is of the present invention
The polymer solution of the functional group containing specified chemical is the liquid nontoxic to human body, and is excellent toughener.
In the present embodiment, when the specified chemical functional group is hydroxyl, the polymerization of the functional group containing specified chemical
Thing is polyethylene glycol, polyvinyl alcohol, polyether Glycols or chitin;It is described to contain when the specified chemical functional group is carboxyl
The polymer of specified chemical functional group is polyglycolic acid or PLA;When the specified chemical functional group is NCO
When, the polymer of the functional group containing specified chemical is polyurethane;It is described when the specified chemical functional group is siloxy group
The polymer of the functional group containing specified chemical is polysiloxanes.
The present invention using with toughening effect the functional group containing specified chemical polymer, can by chemical covalent bonds with
Valve surface is combined, and valve is also possessed good pliability, valve is remained in that in dry conditions excellent soft
Toughness, so that cross-linking method of the present invention is applicable to the preparation of dry valve, realizes the kept dry of valve.
The crosslinking fixing means of the present invention, chemistry is passed through by the polymer of the functional group containing specified chemical with submissive effect
Covalent bond is combined with valve, this polymer is covered in valve surface, is assigned valve by the pliability of polymer, is contained simultaneously
The polymer of specified chemical functional group also some be connected to the organization internal of valve so that further enhancing toughness reinforcing effect
Really.
The present invention is crosslinked using bioprosthesis valve through glutaraldehyde and hydroxyl polymer-containing mixed solution.In solution
Glutaraldehyde and the polymer of the functional group containing specified chemical are combined by chemical covalent bonds with valve surface, valve is possessed good thing
Also possess good pliability while reason is with chemical property, and can remain in that in dry conditions excellent flexible
Property, realize the kept dry of valve.This method reduces valve material thickness and possesses fold and deactivated from function, tissue is calmed down simultaneously
Change, reduce the immunogenicity of material, enhance host ECs and climb the ability of covering, reduce the incidence of perivalvular leakage at a specified future date,
Add the service life of biovalve.
As shown in figure 1, Fig. 1 shows bioprosthesis valve of the present invention and crosslinking agent and the functional group containing specified chemical
The equation that polymer chemically reacts.In the present invention, glutaraldehyde is crosslinked instead by the amino in aldehyde radical and valve
Should, strengthen the physics and chemical property of valve;The specialization official in charge of learning that the polymer of the functional group containing specified chemical passes through end
It can roll into a ball and be chemically reacted with the amino or hydroxyl in valve, valve surface is covered a layers of polymer while crosslinked action
Thing.The molecular weight of polymer is larger, then single polymer molecule is also larger in the scope that valve surface is covered, therefore described containing spy
The polymer for determining chemical functional group is easy to assign bioprosthesis valve by the Chemical Physics performance of itself.
More specifically, as shown in figure 1, glutaraldehyde crosslinks reaction by the amino in aldehyde radical and valve;Polymer leads to
Terminal hydroxyl is crossed to be chemically reacted with carboxyl in valve, or terminal carboxyl group is chemically reacted with amino in valve or hydroxyl,
Or terminal isocyanate group reacts with amino in valve or hydroxyl, or terminal siloxane base is carried out instead with amino in valve
Should, valve surface is covered one layer of polymeric while crosslinked action.
Further, in the present embodiment, the concentration of the glutaraldehyde is 0.1%~5%.Such as described glutaraldehyde it is dense
Degree can be 0.1%, 1%, 2%, 3%, 4% or 5%.
Further, in the present embodiment, the concentration of the polymer of the functional group containing specified chemical is 10%~50%.
For example, the concentration of the polymer of the functional group containing specified chemical can be 10%, 20%, 30%, 40% or 50%.
Further, in the present embodiment, it is 25~45 DEG C to be crosslinked fixed temperature.For example, the fixed temperature of crosslinking can
Think 25 DEG C, 30 DEG C, 35 DEG C, 40 DEG C or 45 DEG C.
Further, in the present embodiment, crosslinking regular time is 1~7 day.For example, crosslinking regular time can be with
For 1 day, 2 days, 3 days, 4 days or 5 days.
When it is implemented, the cross-linking step of bioprosthesis valve of the present invention can be:Bioprosthesis valve is immersed penta 2
It is crosslinked in aldehyde and the mixed with polymers solution of the functional group containing specified chemical, wherein glutaraldehyde concentration is 0.1%~5%, is contained
The polymer concentration of specified chemical functional group be 10%~50%, crosslinking time be 1 day~7 days, while control temperature be 25~
45 DEG C, and ensure the smooth expansion of valve.
Bioprosthesis valve is crosslinked present invention also offers one kind, it uses above-described crosslinking bioprosthesis valve
Preparation method is made.
By using the preparation method of crosslinking bioprosthesis valve of the present invention, make leaflet thinner, more firmly, more resistant to
Long, more preferably, character is more stable for biocompatibility.The reduction of leaflet thickness causes the appearance and size reduction by 80% after valve compression,
And this method may apply to the preparation of dry valve, realize valve and can be filled in advance in induction system and dispatch from the factory, can use at any time,
Installed without preoperative, shorten operating time, reduce the mortality risk for waiting and being caused during valve implantation in patient's art.With this
Method crosslinking valve, preserved without being positioned in the storing liquid containing glutaraldehyde can preloaded system, thoroughly solve valve
Endurance issues, improve the biocompatibility of valve, reduce endocarditis probability of happening caused by immunogene risk, enhancing
Host ECs, which are climbed, covers function, reduces perivalvular leakage probability of happening.
The present invention is elaborated with specific embodiment below:
Embodiment 1
By pig pericardium heart valve at a temperature of 45 DEG C, 5% glutaraldehyde and 10% polyethylene glycol, 20% it is PVA mixed
Crosslinking immersion 2 days in solution are closed, after taking-up is completely dried at 45 DEG C, obtain being crosslinked bioprosthesis valve;Find after testing, this
Crosslinking bioprosthesis valve prepared by embodiment still remains excellent pliability, the appearance and size after valve compression after drying
Reduction by 80%, and biocompatibility is good, character is stable.
Embodiment 2
By pig pericardium heart valve at a temperature of 40 DEG C, it is crosslinked in 4% glutaraldehyde and 20% polyether Glycols mixed solution
Immersion 5 days, after taking-up is completely dried at 35 DEG C, obtains being crosslinked bioprosthesis valve;Find after testing, it is manufactured in the present embodiment
Crosslinking bioprosthesis valve still remains excellent pliability after drying, the appearance and size reduction by 80% after valve compression, and
Biocompatibility is good, and character is stable.
Embodiment 3
By pig pericardium heart valve at a temperature of 35 DEG C, crosslinking immersion 3 in 3% glutaraldehyde and 30% chitin mixed solution
My god, after taking-up is completely dried at 35 DEG C, obtain being crosslinked bioprosthesis valve;Find after testing, crosslinking manufactured in the present embodiment
Bioprosthesis valve still remains excellent pliability after drying, the appearance and size reduction by 80% after valve compression, and biological
Compatibility is good, and character is stable.
Embodiment 4
By pig pericardium heart valve at a temperature of 30 DEG C, 2% glutaraldehyde and 10% polyglycolic acid, 20% PLA are mixed
Crosslinking immersion 1 day in solution is closed, after taking-up is completely dried at 25 DEG C, obtains being crosslinked bioprosthesis valve;Find after testing, this
Crosslinking bioprosthesis valve prepared by embodiment still remains excellent pliability, the appearance and size after valve compression after drying
Reduction by 80%, and biocompatibility is good, character is stable.
Embodiment 5
By pig pericardium heart valve at a temperature of 35 DEG C, crosslinking immersion 1 in 1% glutaraldehyde and 40% polyurethane mixed solution
My god, after taking-up is completely dried at 25 DEG C, obtain being crosslinked bioprosthesis valve;Find after testing, crosslinking manufactured in the present embodiment
Bioprosthesis valve still remains excellent pliability after drying, the appearance and size reduction by 80% after valve compression, and biological
Compatibility is good, and character is stable.
Embodiment 6
By pig pericardium heart valve at a temperature of 25 DEG C, it is crosslinked in 0.1% glutaraldehyde and 50% polysiloxanes mixed solution
Immersion 1 day, after taking-up is completely dried at 5 DEG C, obtains being crosslinked bioprosthesis valve;Find after testing, it is manufactured in the present embodiment
Crosslinking bioprosthesis valve still remains excellent pliability after drying, the appearance and size reduction by 80% after valve compression, and
Biocompatibility is good, and character is stable.
Embodiment 7
By pig pericardium heart valve at a temperature of 25 DEG C, it is crosslinked in 0.1% glutaraldehyde and 10% polysiloxanes mixed solution
Immersion 1 day, after taking-up is completely dried at 5 DEG C, obtains being crosslinked bioprosthesis valve;Find after testing, it is manufactured in the present embodiment
Crosslinking bioprosthesis valve still remains excellent pliability after drying, the appearance and size reduction by 80% after valve compression, and
Biocompatibility is good, and character is stable.
Embodiment 8
By pig pericardium heart valve at a temperature of 25 DEG C, leaching is crosslinked in 0.1% glutaraldehyde and 10% polyethylene glycol mixed solution
Bubble 7 days, after taking-up is completely dried at 5 DEG C, obtains being crosslinked bioprosthesis valve;Find after testing, it is manufactured in the present embodiment to hand over
Connection bioprosthesis valve still remains excellent pliability after drying, the appearance and size reduction by 80% after valve compression, and raw
Thing compatibility is good, and character is stable.
In summary, the invention provides a kind of bioprosthesis valve and preparation method thereof, the preparation method includes step
Suddenly:In the mixed solution that bioprosthesis valve is immersed to glutaraldehyde and the polymer composition of the functional group containing specified chemical, handed over
Connection is fixed, and obtains being crosslinked bioprosthesis valve;Wherein, the specified chemical functional group is hydroxyl, carboxyl, NCO or silicon
Oxyalkyl.The preparation method of crosslinking bioprosthesis valve of the present invention, can strengthen the physicochemical property and bio-compatible of valve
Property, the service life of valve is improved, while making valve be maintained to flexible property in the state of drying, so as to reduce
The production of valve, cost of transportation, simplify the use flow of valve.
It should be appreciated that the application of the present invention is not limited to above-mentioned citing, for those of ordinary skills, can
To be improved or converted according to the above description, all these modifications and variations should all belong to the guarantor of appended claims of the present invention
Protect scope.