CN106215239A - A kind of preparation method of crosslinked antimicrobial type acellular matrix material - Google Patents
A kind of preparation method of crosslinked antimicrobial type acellular matrix material Download PDFInfo
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Abstract
The invention discloses the preparation method of a kind of antimicrobial form acellular matrix material.The present invention uses oxidation chitosan quaternary ammonium salt crosslinking acellular matrix material, utilize and form crosslinking between multiple aldehyde radicals and the active group on acellular matrix on oxidation chitosan quaternary ammonium salt, improve the structural stability of material, chitosan quaternary ammonium salt is grafted in acellular matrix material simultaneously, thus gives acellular matrix material high antibacterial bacteriostatic performance.The crosslinking of material can be united two into one by this method with endowing antibacterial, is the preparation method of a kind of novel functional acellular matrix material, can be widely applied to technical field of biological material.
Description
Technical field
The present invention relates to the preparation method of a kind of antimicrobial form acellular matrix material, be applied to technical field of biological material.
Background technology
Acellular matrix material is to process host material by physics, chemical and biological method, carry out de-cell process,
The material obtained after removing relevant antigen.It eliminates the cell component in natural material, remains matrix components, effectively drops
The low immunogenicity of natural material, can keep the basic structure of host material and performance (such as macroscopic view braiding structure, micro-simultaneously
View hole gap structure, physical mechanical strength etc.).Common acellular matrix material has acellular dermal matrix, de-cell cornea base
Take off thin under matter, human acellular amniotic membrane matrix, porcine aorta acellular matrix, cattle (or pig) pericardium acellular matrix, intestinal mucosa
Cytoplasmic matrix, urethra acellular matrix, de-cellular cartilage, the reparation or the tissue that can be used for skin, blood vessel, valve, urinary tract etc. are filled out
Fill, be widely used to medical field (Zhang Chen, Wang Zhijun, Gao Jingheng. the progress of acellular tissue matrices. University Of Dalian
Journal, 2007,28(3): 57-60).
Can eliminate or reduce immunogenicity by crosslinking, improve physical and mechanical properties, raising degradation resistant ability, preferably
Meet the needs used.Physical crosslinking method (such as hot dehydrogenation) is low owing to being confined to material surface and degree of cross linking degree, fails extensively
Application.Synthetic cross-linking agent wide material sources, can obtain specific molecular structure by the method for MOLECULE DESIGN, introduce multiple chemistry
Active group is in cross-linker molecules, thus crosslinking height；But synthetic cross-linking agent (such as glutaraldehyde) is not enough due to by-product and purity
Etc. reason, it is easily caused the Biocompatibility after crosslinking poor.Natural product and derivant cross-linking agent (such as genipin), phase
To good biocompatibility, but the most of less types, prepare and purify cost of a relatively high, it is impossible to extensive commercial application.
In recent years, along with the progress of science, to aoxidize the natural polysaecharides natural product derivant cross-linking agent as representative, become
For study hotspot.Such cross-linking agent, with natural saccharide as parent, forms multiple aldehyde radicals by oxidation, so that saccharide has crosslinking
Performance.Due to polysaccharide good biocompatibility, after being incorporated in biomaterial, after still ensuring that crosslinking, material has good life
The thing compatibility.Such as, the oxidized sodium alginate that alginate oxidation prepares is used as bio-medical material cross-linking agent, takes
Obtained preferable effect (Hu, Y, Lju, L, Gu ZP, Dan, WH et al. Modification of collagen
With a natural derived cross-linker, alginate dialdehyde [J]. CARBOHYDRATE
POLYMERS, 2014,102:324-332.) this kind of cross-linking agent have the higher degree of cross linking, overcomes physical crosslinking degree low
Shortcoming；Have preferable biocompatibility, the shortcoming overcoming synthetic cross-linking agent poor biocompatibility.Owing to polysaccharide is relative to valency
Honest and clean being easy to get, preparation cost is relatively low, thus has broad application prospects, and is more satisfactory Biological cross-linker.
Biomaterial, while treatment disease, there is also some problems.It is found that either long-term or short-term is stayed
Put the biomaterial in human body, various antibacterial often can be caused to infect.It is reported, the catheter in blood vessel sense that the U.S. occurred in a year
Example of catching an illness just has 5 ten thousand to 20 ten thousand examples, and mortality rate is up to 20%.And, these infection once occur, even if on application normal dose
The medicine of Radix Achyranthis Bidentatae can not effectively be treated, and the immune system of human body self can not remove these antibacterials.According to statistics, the doctor of 45%
Institute infect relevant to the use of biomaterial (Luo Jianbin. the progress [J] of antibacterial biological material. macromolecule circular, 2009,
3:58-60).And for treatment body surface wound, the biomaterial of burn, infecting also is one of the most universal complication, its meeting
Cause wound that substantial amounts of transudate occurs, decompose extracellular matrix protein and multiple somatomedin, hinder promoting epidermization and wound
Guan Bi, thus the process of appreciable impact rehabilitation, it could even be possible to cause burning trauma patient dead (Zhou Ying, perhaps zero. antiseptic dressing grinds
Study carefully progress. China's damage and reparation magazine, 2012,7(3): 307-310).Visible, either it is applied to body surface or internal
Biomaterial, having antibacterial bacteriostatic function is the Premium Features that biomaterial needs to possess, the improvement of biomaterial anti-microbial property
Become one of key technology of guarantee biomaterial serviceability.
Now widely used anti-biotic material includes antibiotic, metal ion, quaternary ammonium salt, natural antibacterial material etc..Antibiosis
The use of element, easily develops immunity to drugs；Metal ion (such as silver) then there may be that cell is perishable, unstable properties, cost high
Etc. various problems；Common quaternary ammonium salt has good broad spectrum antibacterial, but often biocompatibility is the best；Natural antibacterial material
(such as chitosan) biocompatibility is excellent, and anti-microbial property is good, but dissolubility is poor, limits its application.
Chitosan quaternary ammonium salt is the amino of chitosan to be changed into quaternary ammonium salt group or grafting low molecule quaternary ammonium salt and obtains
The product arrived.It belongs to polycationic compounds, have good water solublity, flocculability, biocompatibility, moisture absorbability and moisture retentivity and
The features such as more preferable antibiotic property, therefore its range of application is the most extensive.(Zhong Jing, Hong Yan, Chen Yong. chitosan quaternary ammonium salt up-to-date
Progress. China's Tissue Engineering Study and clinical rehabilitation, 2008,12(6): 1115-1118).
Use physical blending method, chitosan quaternary ammonium salt is joined in biomaterial, it is possible to give biomaterial with
Antibacterial bacteriostatic function, is the most commonly used method.But, chitosan quaternary ammonium molecules of salt lacks there is chemical reactivity
Group, it is difficult to form firm covalent bond with biomaterial and be combined.The chitosan quaternary ammonium salt that physical blending adds is easily from life
Thing material produces migration, runs off, it is impossible to produce permanent antibacterial bacteriostatic performance, it is difficult to produce a desired effect.
Therefore, current biomaterial, on the one hand need the cross-linking agent using biocompatibility excellent to cross-link,
Simultaneously need to give biomaterial with good antibacterial bacteriostatic function.Current method often can only meet one of them.Can
Crosslinking is united two into one with antibacterial, while crosslinking, gives biomaterial with antibiotic property？We hand at long-term biomaterial
In connection research, it is proposed that the neodoxy of " crosslinking of functionalization yardstick ": i.e. while crosslinking, give biomaterial with other merit
Energy.This viewpoint be we find and prepare a new generation functional type cross-linking agent provide new approaches.Employing has bridging property and antibacterial concurrently
The cross-linking agent of property, both can meet the needs of crosslinking, can give again material with anti-microbial property.
Oxidation chitosan quaternary ammonium salt, its parent is chitosan, itself has good biocompatibility；Chitosan quaternary ammonium salt
After selective oxidation, produce the aldehyde radical that multiple chemistry is active, it is thus possible to and between biomaterial, form firm crosslinking,
Improve the degradation resistant ability of material；In biomaterial, access chitosan quaternary ammonium salt structure simultaneously, thus there is excellent resisting
Bacterium bacteriostasis property, owing to generating firm covalent bond in cross-linking process, thus effectively prevent migration and the loss of antibacterial,
The shortcoming overcoming previous methods.The crosslinking of biomaterial can be united two into one by this method with endowing antibacterial, reaches simultaneously
Produce the dual purpose of cross-linking effect and endowing antibacterial, be the preparation side of a kind of novel functional acellular matrix material
Method, can be widely applied to technical field of biological material.
Summary of the invention
It is an object of the invention to provide the preparation of a kind of antimicrobial form acellular matrix material for the deficiencies in the prior art
Method, it is realized by techniques below measure.
The preparation method of a kind of antimicrobial form acellular matrix material, is characterized in that: weigh the acellular matrix of 100 weight portions
Material, at 20～65 DEG C, adds the buffer that pH value is 3.0～10.5 of 100～1000 weight portions, processes 10～60min；
It is subsequently adding the oxidation chitosan quaternary ammonium salt that oxidizability is 1～98% of 1～20 weight portions, processes 0.5～24.0 hour；Discard
Waste reaction solution, adds the water of 200～1000 weight portions, cleans 10～30 minutes；Discard cleaning waste liquid, add 100～1000 weights
The buffer that pH value is 3.0～10.5 of amount part, adds the aminoacid of 0.5～2.0 weight portions, at 20～65 DEG C, processes 0.5
～4.0 hours；Discard waste liquid, add the water of 200～1000 weight portions, clean 20～60 minutes；Discard waste liquid, add 100～
The water of 300 weight portions, adds lactic acid or the sodium lactate of 0.1～1.0 weight portions, at 20～35 DEG C, processes 30～90 minutes, will
Body lotion pH regulator is to neutral；Discard waste liquid, the injection water of 30～42 DEG C of addition 200～1000 weight portions, clean 1～4h；Abandon
Remove waste liquid, the injection water of 30～42 DEG C of addition 200～1000 weight portions, clean 1～4h.
The preparation method of antimicrobial form acellular matrix material according to claim 1, wherein said oxidation shell gathers
The structure that sugar quaternary ammonium salt is formed after referring to the oxidation of chitosan quaternary ammonium salt chosen property contains the chitosan quaternary ammonium salt of multiple aldehyde radicals.
The preparation method of antimicrobial form acellular matrix material according to claim 1, wherein said aminoacid, be
Refer to glycine, arginine, lysine and histidine.
The preparation method of antimicrobial form acellular matrix material according to claim 1, wherein said pH value is 3.0
～the buffer of 10.5, this pH is by using acetate hydrochloride buffer solution, phosphate buffered solution, boric acid Borax to buffer
Solution, NaHCO3-NaOH buffer solution reaches.
The preparation method of a kind of antimicrobial form acellular matrix material described in claim 1, it is characterised in that the method can be used
Cell is taken off in acellular dermal matrix, cell-eliminating coanea matrix, human acellular amniotic membrane matrix, porcine aorta acellular matrix, pericardium
Under substrate, intestinal mucosa in the preparation of acellular matrix, urethra acellular matrix, de-cellular cartilage.
In the present invention, oxidation chitooligosaccharidequaternary quaternary ammonium salt used is pharmaceutical grade, and other material is analytical pure or biological reagent.
This cross-linking method has the advantage that
(1) crosslinking degree is high: owing to oxidation chitosan quaternary ammonium molecules of salt contains multiple aldehyde radical, can with in acellular matrix material
Amino etc. produce multiple spot and combine, form the crosslinking of higher degree.The antigenicity of acellular matrix material can be reduced, improvement
Physical and mechanical properties and degradation resistance；
(2) antibacterial bacteriostatic performance is good: due to the positive charge that chitosan quaternary ammonium salt is stronger, having broad spectrum antibacterial, anti-microbial property is excellent
Good, the acellular matrix material after crosslinking introduces chitosan quaternary ammonium salt, thus just imparts acellular matrix material with good
Good antibacterial bacteriostatic function；
(3) antibacterial bacteriostatic performance is lasting: by the aldehyde radical in oxidation chitosan quaternary ammonium salt and the amino in acellular matrix material
Deng the firm covalent bond of formation, bond energy is big, and stability is high, thus effectively prevent the chitosan quaternary ammonium that physical blending process is easily generated
Migrating and the defect run off of salt, can keep its antibacterial bacteriostatic performance for a long time；
(4) good biocompatibility: in oxidation chitosan quaternary ammonium salt after aldehyde radical reaction, remaining chitosan quaternary ammonium salt groups in structure,
And chitosan quaternary ammonium salt derives from chitosan, thus inherit the biocompatibility that chitosan is good.Use aminoacid post processing,
The aldehyde radical that will remain removes, it is ensured that the good biocompatibility of cross-linked material；
(5) Modulatory character is good: can pass through the kind of selective oxidation chitosan, control degree of oxidation, the consumption of control cross-linking agent,
Control crosslinking degree and anti-microbial property；
(6) biodegradable: owing to chitosan quaternary ammonium salt has biodegradability, after being linked into biomaterial, the most permissible
Keep the biological degradability of cross-linked material, its degradation property can be regulated by crosslinking degree；
(7) biomaterial is given with good hydrophilic performance of keeping humidity: in biomaterial, introduce chitosan quaternary ammonium salt, gathered by shell
The performance of keeping humidity of sugar quaternary ammonium salt is given to biomaterial, so that the material after Jiao Lian has good hydrophilic, performance of keeping humidity；
(8) color is light: the collagen of oxidized chitosan quaternary ammonium salt crosslinking, can keep white, deep without after glutaraldehyde cross-linking
Yellow, the navy blue after also cross-linking without genipin；
(9) low in raw material price, can industrialization on a large scale: compared with the excellent cross-linking agent such as oxidation chitosan quaternary ammonium salt and genipin,
Its cheaper, thus, this method can apply to industrialized great production, is widely used in technical field of biological material.
In sum, the present invention, with oxidation chitosan quaternary ammonium salt as raw material, is applied to the friendship of acellular matrix material
Connection, on the one hand can reduce the antigenicity of material, improves structural stability and the degradation resistant ability of material；Material can be given simultaneously
Material, with good antibacterial bacteriostatic function, is the preparation method of a kind of novel functional acellular matrix material, can answer widely
For technical field of biological material.
Detailed description of the invention
Below by example, the present invention is specifically described, it is necessary to it is pointed out here that, this example is served only for right
The present invention further illustrates, and it is not intended that limiting the scope of the invention, the person skilled in the art in this field can
Some nonessential improvement and adjustment are made with the content according to foregoing invention.
Embodiment 1
(1) weigh the acellular allodermis matrix of 100 weight portions, join in reactor；
(2) add the boric acid borax buffer solution that pH value is 8.5 of 130 weight portions, rotate 30 points of kinds；
(3) weigh oxidation N-hydroxypropyltrimethyl ammonium chloride chitosan 8 weight portion that oxidizability is 8%, be dissolved in 20 weight portions
In distilled water；
(4) aqueous solution of oxidation chitosan quaternary ammonium salt is joined in reactor, be warmed up to 37 DEG C, react 16 hours, go anti-
Answer waste liquid；
(5) add the pure water of 300 weight portions, clean 20 minutes, remove waste liquid；
(6) add the boric acid borax buffer solution that pH value is 8.5 of 37 DEG C of 100 weight portions, add the bad ammonia of 1.5 weight portions
Acid, rotates 2 hours, removes waste liquid；
(7) add the pure water of 1000 weight portions, clean 30 minutes, remove waste liquid；
(8) add the pure water of 200 weight portions, add the lactic acid of 0.5 weight portion, process 1.5 hours, discard waste liquid；
(9) add 500 weight portions the injection water of 37 DEG C, clean 1 hour；Remove cleanout fluid, add addition 1000 weight
Part the injection water of 37 DEG C, clean 3 hours.
Embodiment 2
(1) weigh the bovine pericardium acellular matrix of 100 weight portions, join in reactor；
(2) add the acetate hydrochloride buffer solution that pH value is 4.8 of 200 weight portions, rotate 60 points of kinds；
(3) weigh the oxidation N that oxidizability is 80%, N, N-N-trimethyl chitosan TMC quaternary ammonium salt 4 weight portion, be dissolved in 50 weight portions
PH value is in the acetate hydrochloride buffer solution of 4.8；
(4) joining in reactor by the solution of oxidation chitosan quaternary ammonium salt, be warmed up to 42 DEG C, rotate 8 hours, dereaction is given up
Liquid；
(5) add the pure water of 500 weight portions, rotate 20 minutes, remove waste liquid；
(6) add the acetate hydrochloride buffer solution that pH value is 4.8 of 150 weight portions, add the arginine of 0.5 weight portion,
At 42 DEG C, rotate 4 hours, remove waste liquid；
(7) add the pure water of 800 weight portions, rotate 20 minutes, remove waste liquid；
(8) add the pure water of 100 weight portions, add the sodium lactate of 1.0 weight portions, rotate 90 minutes, remove waste liquid；
(9) add 1000 weight portions the injection water of 42 DEG C, clean 2 hours；Remove cleanout fluid, add addition 500 weight
Part the injection water of 42 DEG C, clean 4 hours.
Embodiment 3
(1) weigh the human acellular amniotic membrane matrix of 100 weight portions, join in reactor；
(2) NaHCO that pH value is 9.4 of 100 weight portions is added3-NaOH buffer solution, rotates 20 points of kinds；
(3) weigh oxidation O-hydroxypropyl-trimethyl ammonium chloride N-N-trimethyl chitosan TMC 16 weight portion that oxidizability is 5%, be dissolved in
In the pure water of 50 weight portions；
(4) solution of oxidation chitosan quaternary ammonium salt is joined in reactor, be warmed up to 32 DEG C, rotate 24 hours, dereaction
Waste liquid；
(5) add the pure water of 800 weight portions, rotate 40 minutes, remove waste liquid；
(6) adding 150 weight portion pH value is the NaHCO of 9.43-NaOH buffer solution, adds the glycine of 2.0 weight portions, 32
React 1 hour at DEG C, remove waste liquid；
(7) add the pure water of 300 weight portions, rotate 15 minutes, discard waste liquid；
(8) add the pure water of 300 weight portions, add the lactic acid of 1.0 weight portions, rotate 40 minutes, discard waste liquid；
(9) add 600 weight portions the injection water of 37 DEG C, clean 2 hours；Remove cleanout fluid, add addition 1000 weight
Part the injection water of 32 DEG C, clean 4 hours；
(10) human acellular amniotic membrane matrix, lyophilization are taken out.
Claims (5)
1. a preparation method for antimicrobial form acellular matrix material, is characterized in that: weigh the acellular matrix material of 100 weight portions
Material, at 20～65 DEG C, adds the buffer that pH value is 3.0～10.5 of 100～1000 weight portions, processes 10～60min；So
The oxidation chitosan quaternary ammonium salt that oxidizability is 1～98% of rear addition 1～20 weight portion, processes 0.5～24.0 hour；Discard anti-
Answer waste liquid, add the water of 200～1000 weight portions, clean 10～30 minutes；Discard cleaning waste liquid, add 100～1000 weight
Part the buffer that pH value is 3.0～10.5, add 0.5～2.0 weight portions aminoacid, at 20～65 DEG C, process 0.5～
4.0 hour；Discard waste liquid, add the water of 200～1000 weight portions, clean 20～60 minutes；Discard waste liquid, add 100～300
The water of weight portion, adds lactic acid or the sodium lactate of 0.1～1.0 weight portions, at 20～35 DEG C, processes 30～90 minutes, will bath
Liquid pH regulator is to neutral；Discard waste liquid, the injection water of 30～42 DEG C of addition 200～1000 weight portions, clean 1～4h；Discard
Waste liquid, the injection water of 30～42 DEG C of addition 200～1000 weight portions, cleans 1～4h.
The preparation method of antimicrobial form acellular matrix material the most according to claim 1, wherein said oxidation chitosan
The structure that quaternary ammonium salt is formed after referring to the oxidation of chitosan quaternary ammonium salt chosen property contains the chitosan quaternary ammonium salt of multiple aldehyde radicals.
The preparation method of antimicrobial form acellular matrix material the most according to claim 1, wherein said aminoacid, refer to
Glycine, arginine, lysine and histidine.
The preparation method of antimicrobial form acellular matrix material the most according to claim 1, wherein said pH value be 3.0～
The buffer of 10.5, this pH is by using acetate hydrochloride buffer solution, phosphate buffered solution, boric acid Borax buffering molten
Liquid, NaHCO3-NaOH buffer solution reaches.
5. the preparation method of a kind of antimicrobial form acellular matrix material described in claim 1, it is characterised in that the method can be used for
Acellular dermal matrix, cell-eliminating coanea matrix, human acellular amniotic membrane matrix, porcine aorta acellular matrix, pericardium take off cell base
Under matter, intestinal mucosa in the preparation of acellular matrix, urethra acellular matrix, de-cellular cartilage.
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| CN107823717A (en) * | 2017-11-29 | 2018-03-23 | 四川大学 | A kind of preparation method of anticalcium biological sticking patch |
| CN109731124A (en) * | 2018-12-24 | 2019-05-10 | 山东朱氏药业集团有限公司 | A kind of nano silver composite hydrogel dressing patch and preparation method thereof |
| CN112569405A (en) * | 2020-12-07 | 2021-03-30 | 四川大学 | Preparation method of chitosan quaternary ammonium salt type acellular dermal matrix material |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107823717A (en) * | 2017-11-29 | 2018-03-23 | 四川大学 | A kind of preparation method of anticalcium biological sticking patch |
| CN109731124A (en) * | 2018-12-24 | 2019-05-10 | 山东朱氏药业集团有限公司 | A kind of nano silver composite hydrogel dressing patch and preparation method thereof |
| CN112569405A (en) * | 2020-12-07 | 2021-03-30 | 四川大学 | Preparation method of chitosan quaternary ammonium salt type acellular dermal matrix material |
| CN114681673A (en) * | 2020-12-31 | 2022-07-01 | 杭州启明医疗器械股份有限公司 | Crease-resistant dehydrated cross-linked biomaterial, and preparation method and application thereof |
| CN114272429A (en) * | 2021-12-16 | 2022-04-05 | 成都汉丁新材料科技有限公司 | Fetal bovine dermal matrix dressing and preparation method thereof |
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