CN105457085B - A kind of bionical adhesion hydrogel of collagen-based mussel and preparation method thereof - Google Patents

A kind of bionical adhesion hydrogel of collagen-based mussel and preparation method thereof Download PDF

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CN105457085B
CN105457085B CN201610050568.3A CN201610050568A CN105457085B CN 105457085 B CN105457085 B CN 105457085B CN 201610050568 A CN201610050568 A CN 201610050568A CN 105457085 B CN105457085 B CN 105457085B
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collagen
fresh water
solution
crosslinking agent
mussel
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胡杨
朱士臣
熊善柏
赵思明
刘友明
尹涛
尤娟
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Huazhong Agricultural University
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Abstract

Present invention relates particularly to bionical adhesion hydrogel of a kind of collagen-based mussel and preparation method thereof.Undenatured collagen is obtained as waste using freshwater fishskin or fish scale, undenatured collagen is dissolved in 0.1~0.5M/L acetic acid,diluted, obtain 5~20mg/mL collagen solutions, at not higher than 10 DEG C, adjust collagen solution pH, 1~20mg/mL dopamine solution is pressed into collagen dry weight 1~20% is added in collagen solution, react 1~4h and add crosslinking agent, crosslinking agent is the 1~10% of collagen dry weight, regulate and control gelation process, fully it is placed in after washing in the bag filter of 3800 molecular cut offs after dialysis 24h in 0.9% physiological saline packaging bag, sterilized in 10~30kGy radiated by gamma-ray.The gel pH value of the hydrogel material of the present invention is 6~8, and bonding action is 0.05~2.0MPa, and mean porosities are 60~90%, can be used as the biomimetic material of biomedicine.

Description

A kind of bionical adhesion hydrogel of collagen-based mussel and preparation method thereof
Technical field
The invention belongs to biomedical materials field, and in particular to a kind of bionical adhesion hydrogel of collagen-based mussel and its Preparation method.
Background technology
The bionical pasting material of mussel is because of its wide market application foreground, available for caused by wound, operation and shaping etc. Skin, muscle, cohering at bone equivalent damage and repair and pursued by numerous scientific workers.The bionical pasting material of mussel External form mainly include membranaceous, spongy and water-setting it is gluey, because aqueous gel-like material has hydrophilic polymer network, To cell residing for normal physiological context it is similar, quite by tissue and cell pro-gaze, therefore, the gluey bionical pasting material of mussel of water-setting Research concentrate the most it is also the most extensive.
Preferable bio-adhesive material should meet the Adhesion property requirement of general pasting material, again in face of biomedicine Specific demand in：Good biocompatibility, excellent biological inducing action and harsh use environment (such as dry/ Different interfaces under the conditions of wet).In recent years, people are all existing for current various synthesis high score subclass bio-adhesive materials to solve More problems (such as biocompatibility is inadequate, and Adhesion property is not ideal enough under wetting conditions, biological inducing action shortcoming etc.), progressively By research work focus on biology stick behavior, to realize this target from bionical angle, mussel is exactly this kind of life The Typical Representative of thing.Mussel is a kind of mollusk of raised growth in ocean and coastal area, sticks egg by secreting mussel (MAPs) can form very strong interaction with substrate material surface in a humid environment in vain, contain in its amino acid sequence Nearly 30% L-3,4 dihydroxyphenylalanine and 15% lysine residue.Although directly extracting MAPs from mussel or using gene recombination technology Carry out Prepare restructuring mussel adhesion protein and more good achievement is also achieved in scientific research, but it is numerous extraction process to be present Inherent limitation trivial, cost is higher, yield is insufficient, therefore, egg is sticked containing imitative mussel using the bionical method synthesis of macromolecule The bionical pasting material of mussel of white Functional Unit (3,4- dihydroxy benzenes propylamine, dopamine, Dopamine) turns into the heat of current research Point.Wang Yao etc. is host molecule using four arm polyethylene glycol, and dopamine and double sulphur are introduced by coupling reaction in its structure Key, the bionical adhesion hydrogel (Wang Yao of gelator (PEG- dopamines) mussel based on PEG of end group functional is synthesized Preparation Deng degradable hydrogels of the based on PEG-DOPA is circulated a notice of with property [J] macromolecules, and 2014,8：84-89)；Open peak etc. It is by 1- (3- dimethylaminopropyls) -3- ethylcarbodiimines (EDC) that the free amino group of dopamine is bonded by acid amides Branch is prepared for the bionical polyacrylate pasting material of mussel containing dopamine, the introducing of dopamine is significantly on polyacrylate Improve the adhesion and hydrophily (synthesis of the dopamine modified polyacrylates such as peak and performance study of acrylate [J] investigations of materials and application, 2010,4 (4)：711-715)；Also have been reported that, using EDC by dopamine and carboxylic poly- ammonia Ester, which combines, prepares the bionical polyurethane pasting material of mussel containing dopamine, and its adhesion strength to metal improves 30% or so, And (the bionical polyurethane of mussels of the such as Sun Peiyu containing dopamine [J] the high scores that can be compared favourably with expensive mussel adhesion protein Sub- journal, 2009,8：803-808)；More there are the PNIPAM and polyvinyl alcohol by dopamine and amination or carboxylated Only combined Deng high polymer by non-covalent bond, prepare based on synthesizing that high molecular mussel is bionical to stick membrane material, investigate it to each The Adhering capacity of proteinoid and cell (Zhang Y, et al.Assembly of poly (dopamine)/poly (N- isopropylacrylamide)mixed films and their temperature-dependent interaction with proteins,Liposomes,and Cells[J].Langmuir,2013,29(32):10213-10222).But this A little synthesis macromolecules are under the jurisdiction of biologically inert component, in terms of the biological inducing action and biocompatibility of end-product, still not to the utmost Such as people's will.
With the continuous development of the bionical pasting material of mussel, requirement no longer office of the people to the bionical bio-adhesive material of mussel It is limited to Adhesion property, progressively increases the attention to biological inducing action.Have been reported that and fibroin is passed through into carbodiimide hydrochloride It is coupled with L-3,4 dihydroxyphenylalanine by way of Covalent bonding together, has the mussel of biocompatibility and adhesion concurrently to obtain and imitate Membrane material is sticked in life, and (height moves the preparation of dynamic DOPA bionic adhesion materials and its applies [D] .2013, and Donghua University, master graduates Paper)；Bovine serum albumin has been incorporated into titanium alloy substrate material surface by Lee seminars by dopamine, be prepared for have compared with The quite bionical titanium alloy functional membrane pasting material of the mussel of thing mineralised surface (Ryu J.B., et al.Mussel-inspired polydopamine coating as a universal route to hydroxyapatite crystallization [J].Advanced Functional Materials,2010,20(13):2132-2139)；Chen etc. passes through chitosan etc. Naturally the mode coated has been incorporated into advance Poly(D,L-lactide-co-glycolide (PLGA) film table for having infiltrated dopamine solution Face, it is prepared for having the bionical PLGA of mussel of good osteogenic induction growth to stick membrane material, but the research is limited to membrane material Expect direction, and it is membrane material main body (Chen G, et al.Effects of surface to synthesize macromolecule PLGA functionalization of PLGA membranes for guided bone regeneration on proliferation and behavior of osteoblasts[J].Journal of Biomedical Materials Research Part A,2013,101(1):44-53)；The catabolite gelatin of dopamine and collagen is passed through coupling agent by Yang Qian Chemical bonding, is prepared for based on the amine-modified gelatin-based pasting material of DOPA, and it is used for into the thin of surface of metal material embedded Born of the same parents are sticked and grown, but the bioactivity of gelatin can not show a candle to collagen by a large amount of confirmations (Yang Qian DOPA structure is used for material surface Biomimetic modification and its Basic of Biology research [D] .2014, Jilin University, doctor's thesis).
In summary, Current patents document or non-patent literature are confined to synthesize the phase interaction of macromolecule and dopamine more With end-product biology inducing action is limited, not fully up to expectations in the high molecular mussel Bionic Design of biologically active native, especially It is not yet to be seen in report in terms of bionical adhesion hydrogel of collagen-based mussel and preparation method thereof.
The content of the invention
The purpose of the present invention is the problem of presence for prior art, there is provided a kind of bionical adhesion water-setting of collagen-based mussel Glue and preparation method thereof.This method not only makes the bionical adhesion hydrogel of prepared mussel be extracted relative to from mussel byssus Adhesion protein price it is lower, and have the excellent bioactivity of collagen concurrently.Not only develop new bionical adhesion hydrogel Material, and open new field for the high level conversion of fresh water collagen.Collagen-based mussel prepared by the present invention is bionical glutinous Attached property hydrogel, its chemical composition are mainly fresh water collagen, dopamine and crosslinking agent, and wherein fresh water collagen is 100 parts, more Bar amine is 1~20 part, and crosslinking agent is 1~10 part.Preferably, fresh water collagen is 100 parts, and dopamine is 2~12 parts, crosslinking agent For 5~9 parts.Further preferably fresh water collagen is 100 parts, and dopamine is 10 parts, and crosslinking agent is 8 parts.The hydrogel material Outward appearance is light grey or black gelinite, the impurity being visible by naked eyes, and gel pH value is 6~8, and bonding action is 0.05~ 2.0MPa, mean porosities are 60~90%, and cytotoxicity is not more than 0 grade.
Specifically, the preparation method of the bionical adhesion hydrogel of collagen-based mussel of the invention is as described below：
(1) undenatured fresh water collagen is extracted from freshwater fishskin or fish scale according to " acid-enzyme combined techniques " of routine, through salt Freeze-drying obtains spongy undenatured fresh water collagen after analysis, centrifugation, separation, sour molten, dialysis；
(2) carried undenatured collagen is dissolved in dilute acid soln, obtains certain density collagen solution, adjusted by low temperature After pH, then the dopamine solution prepared added in the collagen solution according to a certain percentage；
(3) select a good opportunity and add crosslinking agent, by that can be prepared after regulating and controlling gelation process, fully washing, dialysis, irradiation sterilization Go out the bionical adhesion hydrogel of collagen-based mussel.
The raw material fingerling class of fresh water collagen described in above-mentioned steps (1) cover seven common large Chinese carps (such as black carp, Grass carp, carp, crucian, silver carp, bighead, megalobrama amblycephala), but it is not excluded for the fresh-water fishes kind of other species.
In " acid-enzyme combined techniques " of the undenatured fresh water collagen of extraction described in above-mentioned steps (1), sour species includes Acetic acid, citric acid, sour concentration range are 0.1~0.5M/L, and enzyme is pepsin, and the dosage of enzyme is substrate butt quality 0.5~2.0%, for the temperature control of whole extraction process at 0~4 DEG C, the tropocollagen molecule amount for extracting to obtain is about 300,000 dalton, Typical α 1, α 2 and β, γ band can be observed through SDS-PAGE detections.
Dilute acid soln described in above-mentioned steps (2) is acetic acid, and concentration is 0.1~0.5M/L；The concentration of collagen solution is 5 ~20mg/mL；The temperature conditionss for adjusting pH are not higher than 10 DEG C, and it is 6~8 to adjust the collagen solution pH after pH；Dopamine solution Concentration is 1~20mg/mL, and wherein the mass percent of dopamine and collagen is 1~20%, and the reaction time is 1~4h.
Crosslinking agent described in above-mentioned steps (3) is any of oxidized sodium alginate, vegatable tannin, Geniposide, is handed over Join agent dosage be collagen butt weight 1~10%, crosslinking agent add opportunity can be gelation process before, gelation During or gelation process after either phase, it is preferable that the addition opportunity of crosslinking agent be gelation process in, gelation The regulation and control of process mainly realize that wherein pH value range is 7.0~8.0, temperature by controlling pH value, the temperature and time of solution For 35~42 DEG C, the time is 1~12h；Irradiation dose is 10~30kGy.
The concrete technical scheme for implementing the product of the present invention is as described below：
A kind of bionical adhesion hydrogel of collagen-based mussel prepared using fresh water collagen, is prepared into by following step Arrive：
Raw material proportioning by weight is as follows：
Undenatured 100 parts of fresh water collagen；
1~20 part of dopamine；
1~10 part of crosslinking agent；
Preparation process is：
(1) preparation of undenatured fresh water collagen：
Smashed to pieces after new fresh water fish skin or fish scale are cleaned up at 20 ± 1 DEG C, be 1 in solid-liquid ratio：25 0.01M's 24h is handled in NaOH solution, to remove non-collagen tissue；With 10% isopropanol stirring 4h removing fat constituents；0.5M's Pepsin hydrolysis is carried out in acetic acid solution, pepsin dosage is the 0.5% of substrate butt quality, is centrifuged in 10000r/min 10min, supernatant is taken, first adjust pH to be saltoutd to neutrality, then with (NH4) 2SO4 with NaOH, then in 0.1M/L Na2HPO4 solution Dialysis, freeze, whole extraction process is maintained at 4 DEG C and carried out, and produces unmodified freshwater fish collagen；Its molecular weight is 30 Ten thousand dalton, typical α 1, α 2 and β, γ band can be observed through SDS-PAGE detections；
(2) preparation of the bionical adhesion hydrogel of collagen-based mussel：
Unmodified fresh water collagen is dissolved in 0.1~0.5M/L acetic acid,diluted by formula ratio, obtain concentration for 5~ 20mg/mL collagen solution, then under conditions of not higher than 10 DEG C, the pH of collagen solution is adjusted to 6~8, then by formula ratio It is molten that dopamine solution that the concentration prepared is 1~20mg/mL according to the 1~20% of collagen dry weight is added to described collagen In liquid, after reacting 1~4h, add described crosslinking agent by formula ratio, the dosage of the crosslinking agent for collagen dry weight 1~ 10%, regulate and control gelation process, then fully washing, 0.9% is placed in after the 24h that dialysed in the bag filter of 3800 molecular cut offs Physiological saline packaging bag in, it is finally bionical glutinous to collagen-based mussel using 10~30kGy radiated by gamma-ray sterilizing, thus obtaining the product Attached property hydrogel.
The one kind of wherein described crosslinking agent in oxidized sodium alginate, vegatable tannin, Geniposide.
One of preferred scheme of the present invention is the bionical adhesion water-setting of collagen-based mussel prepared using fresh water collagen Glue, raw material proportioning by weight are as follows：
Undenatured 100 parts of fresh water collagen；
Dopamine 2~12 part；
5~9 parts of crosslinking agent.
The two of the preferred scheme of the present invention are the bionical adhesion water-settings of collagen-based mussel prepared using fresh water collagen Glue, raw material proportioning by weight are as follows：
Undenatured 100 parts of fresh water collagen；
10 parts of dopamine；
8 parts of crosslinking agent.
The crosslinking agent adds opportunity as before gelation process or in gelation process or after gelation process Either phase, opportunity is preferably added to as in gelation process.
A kind of method that the bionical adhesion hydrogel of collagen-based mussel is prepared using fresh water collagen is applicant provided, is wrapped Include the following steps：
Raw material proportioning by weight is as follows：
Undenatured 100 parts of fresh water collagen；
1~20 part of dopamine；
1~10 part of crosslinking agent；
Preparation process is as follows：
(1) preparation of undenatured fresh water collagen：
Smashed to pieces after new fresh water fish skin or fish scale are cleaned up at 20 ± 1 DEG C, be 1 in solid-liquid ratio：25 0.01M's 24h is handled in NaOH solution, to remove non-collagen tissue；With 10% isopropanol stirring 4h removing fat constituents；0.5M's Pepsin hydrolysis is carried out in acetic acid solution, pepsin dosage is the 0.5% of substrate butt quality, is centrifuged in 10000r/min 10min, supernatant is taken, first adjust pH to be saltoutd to neutrality, then with (NH4) 2SO4 with NaOH, then in 0.1M/L Na2HPO4 solution Dialysis, freeze, whole extraction process is maintained at 4 DEG C and carried out, and produces unmodified freshwater fish collagen；Its molecular weight is 30 Ten thousand dalton, typical α 1, α 2 and β, γ band can be observed through SDS-PAGE detections；
(2) preparation of the bionical adhesion hydrogel of collagen-based mussel：
Unmodified fresh water collagen is dissolved in 0.1~0.5M/L acetic acid,diluted by formula ratio, obtain concentration for 5~ 20mg/mL collagen solution, then under conditions of not higher than 10 DEG C, the pH of collagen solution is adjusted to 6~8, then by formula ratio It is molten that dopamine solution that the concentration prepared is 1~20mg/mL according to the 1~20% of collagen dry weight is added to described collagen In liquid, after reacting 1~4h, add described crosslinking agent by formula ratio, the dosage of the crosslinking agent for collagen dry weight 1~ 10%, regulate and control gelation process, then fully washing, 0.9% is placed in after the 24h that dialysed in the bag filter of 3800 molecular cut offs Physiological saline packaging bag in, it is finally bionical glutinous to collagen-based mussel using 10~30kGy radiated by gamma-ray sterilizing, thus obtaining the product Attached property hydrogel.
The one kind of crosslinking agent in oxidized sodium alginate, vegatable tannin, Geniposide described in above-mentioned preparation method.
It is before the addition opportunity of crosslinking agent described in above-mentioned preparation method is gelation process or in gelation process or solidifying Either phase after gel process.Preferably, the addition opportunity of crosslinking agent is in gelation process.
The bionical adhesion hydrogel of collagen-based mussel of the present invention can be as the application of biomedical sector biomimetic material.
The bionical adhesion hydrogel of collagen-based mussel prepared by the present invention is by collagen and DOPA by chemical bond What amine was combined, the phase separation of collagen and DOPA amine component is avoided in the gel rubber system of formation, end-product hydrogel sticks Knotting strength is 0.05~2.0MPa；Prepared hydrogel has the Adhering capacity of mussel protein uniqueness and the biology that collagen is excellent concurrently Activity, skin caused by wound, operation and shaping etc. can be widely used in various bodies, at muscle equivalent damage because of tool change Cohere and repair.
Compared with prior art, the invention has the advantages that：
1st, the bionical adhesion hydrogel of collagen-based mussel prepared by the present invention and traditional synthesis macromolecule adhesion water-setting Glue is compared, and has excellent Adhering capacity, biological inducing action and biodegradable.
2nd, the addition of crosslinking agent of the present invention improves the mechanical property of hydrogel, meanwhile, used with traditional collagen hydrogel Glutaraldehyde or carbodiimide cross-linker compare, the present invention used in crosslinking agent belong to bion crosslinking agent, avoid tradition The potential source biomolecule toxicity that chemical cross-linking agent (glutaraldehyde or carbodiimides) introduces from source.
3rd, compared with directly extracting mussel adhesion protein from natural mussel, the raw material sources used in the present invention are extensive, institute The cost for obtaining product is relatively lower.
4th, compared with using genetically engineered biological synthesis mussel adhesion protein, present invention process is relatively easy, it is ripe, be easy to Operational control and large-scale production.
5th, present invention process can make product have regulatable stick by regulating and controlling reactant dosage and gelation process Performance.
One group of performance characterization result of the bionical adhesion hydrogel of collagen-based mussel that the present invention of table 1 is prepared
Brief description of the drawings
Fig. 1：The bionical adhesion hydrogel material of one group of collagen-based mussel (column body) being prepared for the present invention.
Fig. 2：One group of elastic modulus detection knot of the bionical adhesion hydrogel of collagen-based mussel being prepared for the present invention Fruit.
Fig. 3：One group of loss moduli of the bionical adhesion hydrogel of collagen-based mussel being prepared for the present invention determines knot Fruit.
Fig. 4：One group of fissipation factor of the bionical adhesion hydrogel of collagen-based mussel being prepared for the present invention determines knot Fruit.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be that following examples are served only for The invention will be further described, it is impossible to is interpreted as limiting the scope of the invention, person skilled in the art's root in the field Some the nonessential modifications and adaptations made according to the content of the invention described above, still fall within the category that the present invention protects.
Embodiment 1
Smashed to pieces after fresh grass carp skin is cleaned up at 20 ± 1 DEG C, be 1 in solid-liquid ratio：25 0.01M NaOH solution Middle processing 24h, to remove non-collagen tissue.Then fat constituent is removed with 10% isopropanol stirring 4h.Then 0.5M's Pepsin hydrolysis is carried out in acetic acid solution, pepsin dosage centrifuges for 0.5%, 10000r/min of substrate butt quality 10min takes supernatant, first adjusts pH to neutrality with NaOH, then with (NH4)2SO4Saltout, then the Na in 0.1M/L2HPO4In solution thoroughly Analysis, freeze, whole extraction process is maintained at 4 DEG C and carried out, and produces unmodified grass carp collagen.
Using the unmodified grass carp collagen (5mg/mL) of 0.1M/L acetic acid, collagen solution pH is adjusted at 0 DEG C Value then adds 20mg/mL dopamine solution, wherein dopamine dosage is the 20% of collagen quality, is sufficiently stirred to 7.0 It is even, react 1h.
PH value is adjusted to 7.5 after adding the oxidized sodium alginate reaction 4h of collagen dry weight 10%, is placed in 37 DEG C of baking ovens permanent Warm 4h, then fully wash, 0.9% physiological saline packaging is placed in after the 24h that dialysed in the bag filter of 3800 molecular cut offs In bag, finally under 10kGy intensity radiated by gamma-ray sterilizing, thus obtaining the product to the bionical adhesion hydrogel of collagen-based mussel.
Embodiment 2
Fresh silver carp (such as variegated carp, be commonly called as big head or silver carp) skin is smashed to pieces after being cleaned up at 20 ± 1 DEG C, expected Liquor ratio is 1：24h is handled in 25 0.01M NaOH solution, to remove non-collagen tissue.Then 4h is stirred with 10% acetone Remove fat constituent.Then pepsin hydrolysis is carried out in 0.2M citric acid solution, pepsin dosage is substrate butt 1.0%, the 10000r/min centrifugations 10min of quality takes supernatant, first adjusts pH to neutrality with NaOH, then with (NH4)2SO4Saltout, Again in 0.1M/L Na2HPO4Dialyse, freeze, whole extraction process is maintained at 4 DEG C and carried out, and produces unmodified silver carp in solution Fish skin collagen.
Using the unmodified silver carp collagen (10mg/mL) of 0.2M/L acetic acid, collagen solution pH is adjusted at 4 DEG C Value then adds 10mg/mL dopamine solution, wherein dopamine dosage is the 10% of collagen quality, is sufficiently stirred to 6.0 It is even, react 3h.
Add after the vegatable tannin of collagen dry weight 8% and adjust pH value immediately to 7.0, be placed in constant temperature 4h in 37 DEG C of baking ovens, with Fully washing afterwards, it is placed in the bag filter of 3800 molecular cut offs after dialysis 24h in 0.9% physiological saline packaging bag, most Afterwards under 15kGy intensity radiated by gamma-ray sterilizing, thus obtaining the product to the bionical adhesion hydrogel of collagen-based mussel.
Embodiment 3
Smashed to pieces after fresh crucian skin is cleaned up at 20 ± 1 DEG C, be 1 in solid-liquid ratio：25 0.01M NaOH solution Middle processing 24h, to remove non-collagen tissue.Then fat constituent is removed with 10% acetone stirring 4h.Then in 0.2M second Pepsin hydrolysis is carried out in acid solution, pepsin dosage centrifuges for 1.5%, 10000r/min of substrate butt quality 10min takes supernatant, first adjusts pH to neutrality with NaOH, then with (NH4)2SO4Saltout, then the Na in 0.1M/L2HPO4In solution thoroughly Analysis, freeze, whole extraction process is maintained at 4 DEG C and carried out, and produces unmodified crucian collagen.
Using the unmodified crucian collagen (15mg/mL) of 0.5M/L acetic acid, collagen solution pH is adjusted at 4 DEG C Value then adds 15mg/mL dopamine solution, wherein dopamine dosage is the 15% of collagen quality, is sufficiently stirred to 7.5 It is even, react 3h.
Above-mentioned system pH is adjusted to 8.0, constant temperature 4h in 37 DEG C of baking ovens is placed in, is during which slowly added to collagen dry weight 10% Geniposide is crosslinked, then fully washing, and 0.9% life is placed in after the 24h that dialysed in the bag filter of 3800 molecular cut offs Manage in salt solution packaging bag, finally under 20kGy intensity radiated by gamma-ray sterilizing, thus obtaining the product to the bionical adhesion water of collagen-based mussel Gel.
Embodiment 4
Smashed to pieces after fresh bighead skin is cleaned up at 20 ± 1 DEG C, be 1 in solid-liquid ratio：25 0.01M NaOH solution Middle processing 24h, to remove non-collagen tissue.Then fat constituent is removed with 10% isopropanol stirring 4h.Then 0.5M's Pepsin hydrolysis is carried out in acetic acid solution, pepsin dosage centrifuges for 2.0%, 10000r/min of substrate butt quality 10min takes supernatant, first adjusts pH to neutrality with NaOH, then with (NH4)2SO4Saltout, then the Na in 0.1M/L2HPO4In solution thoroughly Analysis, freeze, whole extraction process is maintained at 4 DEG C and carried out, and produces unmodified bighead collagen.
Using the unmodified bighead collagen (5mg/mL) of 0.2M/L acetic acid, collagen solution pH is adjusted at 0 DEG C Value then adds 10mg/mL dopamine solution, wherein dopamine dosage is the 20% of collagen quality, is sufficiently stirred to 8.0 It is even, react 4h.
Above-mentioned system is placed in constant temperature 4h in 37 DEG C of baking ovens, is during which slowly added to the oxidized sodium alginate of collagen dry weight 8% It is crosslinked, then fully washing, 0.9% physiological saline is placed in after the 24h that dialysed in the bag filter of 3800 molecular cut offs In packaging bag, finally under 30kGy intensity radiated by gamma-ray sterilizing, thus obtaining the product to the bionical adhesion hydrogel of collagen-based mussel.
Embodiment 5
Fresh black carp scales are cleaned up, are 1 in solid-liquid ratio：20 0.05M Na2CO312h is handled in solution, with loose Fish scale structure；And in 0.2M HCl solution soak 12h decalcifications, in 0.05M NaOH solution soak 8h removing fat into Point；Then pepsin hydrolysis is carried out in 0.2M acetic acid solution, pepsin dosage is the 1.5% of substrate butt quality, 10000r/min centrifugations 10min takes supernatant, pH is adjusted to neutrality with NaOH, with (NH4)2SO4Saltout, then 0.1M/L's Na2HPO4Dialyse, freeze, whole extraction process is maintained at 4 DEG C and carried out, and produces unmodified black carp scales collagen in solution.
Using the unmodified black carp scales collagen (10mg/mL) of 0.5M/L acetic acid, collagen solution pH is adjusted at 4 DEG C Value then adds 15mg/mL dopamine solution, wherein dopamine dosage is the 10% of collagen quality, is sufficiently stirred to 7.0 It is even, react 4h.
Above-mentioned system is placed in constant temperature 1h in 42 DEG C of baking ovens, then adds the oxidized sodium alginate reaction of collagen dry weight 5% 4h, fully washing, it is placed in the bag filter of 3800 molecular cut offs after dialysis 24h in 0.9% physiological saline packaging bag, most Afterwards under 20kGy intensity radiated by gamma-ray sterilizing, thus obtaining the product to the bionical adhesion hydrogel of collagen-based mussel.
Embodiment 6
Fresh carp scales is cleaned up, is 1 in solid-liquid ratio：20 0.05M Na2CO312h is handled in solution, with loose Fish scale structure；And in 0.2M HCl solution soak 12h decalcifications, in 0.05M NaOH solution soak 8h removing fat into Point；Then pepsin hydrolysis is carried out in 0.1M citric acid solution, pepsin dosage is substrate butt quality 1.0%, 10000r/min centrifugation 10min take supernatant, pH are adjusted to neutrality with NaOH, with (NH4)2SO4Saltout, then in 0.1M/L Na2HPO4Dialyse, freeze, whole extraction process is maintained at 0 DEG C and carried out, and produces unmodified carp scales collagen in solution.
Using the unmodified carp scales collagen (15mg/mL) of 0.5M/L acetic acid, collagen solution pH is adjusted at 4 DEG C Value then adds 10mg/mL dopamine solution, wherein dopamine dosage is the 10% of collagen quality, is sufficiently stirred to 7.0 It is even, react 2h.
Above-mentioned system is placed in constant temperature 4h in 35 DEG C of baking ovens, then adds the Geniposide reaction 4h of collagen dry weight 8%, fully Washing, it is placed in 0.9% physiological saline packaging bag after dialysis 24h in the bag filter of 3800 molecular cut offs, finally exists Radiated by gamma-ray sterilizing, thus obtaining the product is to the bionical adhesion hydrogel of collagen-based mussel under 25kGy intensity.
Embodiment 7
Fresh gurnet squama is cleaned up, is 1 in solid-liquid ratio：20 0.05M Na2CO312h is handled in solution, with loose Fish scale structure；And in 0.2M HCl solution soak 12h decalcifications, in 0.05M NaOH solution soak 8h removing fat into Point；Then pepsin hydrolysis is carried out in 0.5M acetic acid solution, pepsin dosage is the 2.0% of substrate butt quality, 10000r/min centrifugations 10min takes supernatant, pH is adjusted to neutrality with NaOH, with (NH4)2SO4Saltout, then 0.1M/L's Na2HPO4Dialyse, freeze, whole extraction process is maintained at 4 DEG C and carried out, and produces unmodified triangular bream scale collagen in solution.
Using the unmodified triangular bream scale collagen (20mg/mL) of 0.5M/L acetic acid, collagen solution is adjusted at 10 DEG C PH value then adds 1mg/mL dopamine solution, wherein dopamine dosage is the 1% of collagen quality, is sufficiently stirred to 6.0 It is even, react 4h.
Above-mentioned system is adjusted into pH to 8.0, is placed in constant temperature 12h in 37 DEG C of baking ovens, then adds the capital Buddhist nun of collagen dry weight 1% Redress and answer 4h, fully washing, 0.9% physiological saline packaging is placed in after the 24h that dialysed in the bag filter of 3800 molecular cut offs In bag, finally under 30kGy intensity radiated by gamma-ray sterilizing, thus obtaining the product to the bionical adhesion hydrogel of collagen-based mussel.

Claims (10)

  1. A kind of 1. bionical adhesion hydrogel of collagen-based mussel prepared using fresh water collagen, it is characterised in that described collagen The bionical adhesion hydrogel of base mussel is prepared by following step：
    Raw material proportioning by weight is as follows：
    Undenatured 100 parts of fresh water collagen；
    1~20 part of dopamine；
    1~10 part of crosslinking agent；
    (1) preparation of undenatured fresh water collagen：
    Smashed to pieces after new fresh water fish skin is cleaned up at 20 ± 1 DEG C, be 1 in solid-liquid ratio：In 25 0.01M NaOH solution 24h is handled, to remove non-collagen tissue；With 10% isopropanol stirring 4h removing fat constituents；In 0.5M acetic acid solution Pepsin hydrolysis is carried out, pepsin dosage is the 0.5% of substrate butt quality, centrifuges 10min in 10000r/min, takes Clear liquid, pH first is adjusted to neutrality with NaOH, then with (NH4)2SO4Saltout, then the Na in 0.1M/L2HPO4Dialyse, freeze in solution, it is whole Individual extraction process is maintained at 4 DEG C and carried out, and produces unmodified freshwater fish collagen；Its molecular weight is 300,000 dalton, warp Typical α can be observed in SDS-PAGE detections1、α2With β, γ band；
    (2) preparation of the bionical adhesion hydrogel of collagen-based mussel：
    Unmodified fresh water collagen is dissolved in 0.1~0.5M/L acetic acid,diluted by formula ratio, it is 5~20mg/ to obtain concentration ML collagen solution, then under conditions of not higher than 10 DEG C, the pH of collagen solution is adjusted to 6~8, then will be prepared by formula ratio The dopamine solution that good concentration is 1~20mg/mL is added to according to the 1~20% of collagen dry weight in described collagen solution, After reacting 1~4h, described crosslinking agent is added by formula ratio, the dosage of the crosslinking agent is the 1~10% of collagen dry weight, regulation and control Gelation process, then fully wash, 0.9% physiology salt is placed in after the 24h that dialysed in the bag filter of 3800 molecular cut offs In water packaging bag, finally using 10~30kGy radiated by gamma-ray sterilizing, thus obtaining the product to the bionical adhesion water-setting of collagen-based mussel Glue.
  2. 2. the bionical adhesion hydrogel of collagen-based mussel prepared as claimed in claim 1 using fresh water collagen, its feature It is, the one kind of the crosslinking agent in oxidized sodium alginate, vegatable tannin, Geniposide.
  3. 3. the bionical adhesion hydrogel of collagen-based mussel prepared as claimed in claim 1 using fresh water collagen, its feature It is：Raw material proportioning by weight is as follows：
    Undenatured 100 parts of fresh water collagen；
    Dopamine 2~12 part；
    5~9 parts of crosslinking agent.
  4. 4. the bionical adhesion hydrogel of collagen-based mussel prepared as claimed in claim 1 using fresh water collagen, its feature It is：Raw material proportioning by weight is as follows：
    Undenatured 100 parts of fresh water collagen；
    10 parts of dopamine；
    8 parts of crosslinking agent.
  5. 5. a kind of bionical adhesion hydrogel of collagen-based mussel prepared using fresh water collagen as claimed in claim 1, its It is characterised by：The crosslinking agent adds opportunity as before gelation process or in gelation process or after gelation process Either phase.
  6. A kind of 6. method that the bionical adhesion hydrogel of collagen-based mussel is prepared using fresh water collagen, it is characterised in that：Including The following steps：
    Raw material proportioning by weight is as follows：
    Undenatured 100 parts of fresh water collagen；
    1~20 part of dopamine；
    1~10 part of crosslinking agent；
    (1) preparation of undenatured fresh water collagen：
    Smashed to pieces after new fresh water fish skin is cleaned up at 20 ± 1 DEG C, be 1 in solid-liquid ratio：In 25 0.01M NaOH solution 24h is handled, to remove non-collagen tissue；With 10% isopropanol stirring 4h removing fat constituents；In 0.5M acetic acid solution Pepsin hydrolysis is carried out, pepsin dosage is the 0.5% of substrate butt quality, centrifuges 10min in 10000r/min, takes Clear liquid, pH first is adjusted to neutrality with NaOH, then with (NH4)2SO4Saltout, then the Na in 0.1M/L2HPO4Dialyse, freeze in solution, it is whole Individual extraction process is maintained at 4 DEG C and carried out, and produces unmodified freshwater fish collagen；Its molecular weight is 300,000 dalton, warp Typical α can be observed in SDS-PAGE detections1、α2With β, γ band；
    (2) preparation of the bionical adhesion hydrogel of collagen-based mussel：
    Unmodified fresh water collagen is dissolved in 0.1~0.5M/L acetic acid,diluted by formula ratio, it is 5~20mg/ to obtain concentration ML collagen solution, then under conditions of not higher than 10 DEG C, the pH of collagen solution is adjusted to 6~8, then will be prepared by formula ratio The dopamine solution that good concentration is 1~20mg/mL is added to according to the 1~20% of collagen dry weight in described collagen solution, After reacting 1~4h, described crosslinking agent is added by formula ratio, the dosage of the crosslinking agent is the 1~10% of collagen dry weight, regulation and control Gelation process, then fully wash, 0.9% physiology salt is placed in after the 24h that dialysed in the bag filter of 3800 molecular cut offs In water packaging bag, finally using 10~30kGy radiated by gamma-ray sterilizing, thus obtaining the product to the bionical adhesion water-setting of collagen-based mussel Glue.
  7. A kind of 7. side that the bionical adhesion hydrogel of collagen-based mussel is prepared using fresh water collagen as claimed in claim 6 Method, it is characterised in that：The one kind of the crosslinking agent in oxidized sodium alginate, vegatable tannin, Geniposide.
  8. A kind of 8. side that the bionical adhesion hydrogel of collagen-based mussel is prepared using fresh water collagen as claimed in claim 6 Method, it is characterised in that：The addition opportunity of the crosslinking agent be gelation process before or gelation process in or gelation process Either phase afterwards.
  9. 9. a kind of as described in claim 6 or 8 prepares the bionical adhesion hydrogel of collagen-based mussel using fresh water collagen Method, it is characterised in that：The addition opportunity of the crosslinking agent is in gelation process.
  10. A kind of 10. bionical adhesion water of collagen-based mussel prepared using fresh water collagen described in any one of Claims 1 to 5 The purposes of gel, it is characterised in that：The bionical adhesion hydrogel of described collagen-based mussel is as biomedical biomimetic material Using.
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CN103638554A (en) * 2013-11-13 2014-03-19 浙江大学 Preparation method of composite material of silk fibroin and marine mussel adhesion protein

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