CN105457085A - Collagen-based mussel bionic adhesive hydrogel and preparation method thereof - Google Patents
Collagen-based mussel bionic adhesive hydrogel and preparation method thereof Download PDFInfo
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Abstract
The invention particularly relates to collagen-based mussel bionic adhesive hydrogel and a preparation method thereof. Fish skin or fish scale of freshwater fish serves as a raw material to prepare non-denatured collagen, the non-denatured collagen is dissolved in dilute acetic acid of 0.1-0.5 M/L to obtain a collagen solution with the concentration being 5-20 mg/ml, the pH of the collagen solution is adjusted at the temperature not higher than 10 DEG C, a dopamine solution which has the concentration being 1-20 mg/ml and accounts for 1-20% of the dry weight of the collagen is added into the collagen solution, reaction is conducted for 1-4 hours, a cross-linking agent is added, the cross-linking agent accounts for 1-20% of the dry weight of the collagen, the gelation process is regulated, and the mixture is fully washed with water, then dialyzed in a dialysis bag with the molecular weight cut-off being 3800 for 24 h, placed in a 0.9% normal saline packaging bag, irradiated in 10-30 kGy gamma rays and sterilized. The gel pH value of the hydrogel material is 6-8, adhesion strength is 0.05-2.0 MPa, the average porosity is 60-90%, and the hydrogel material can be used for a bionic material of biomedicine.
Description
Technical field
The invention belongs to biomedical materials field, be specifically related to bionical adhesion hydrogel of a kind of collagen-based mussel and preparation method thereof.
Background technology
The bionical pasting material of mussel, because of its wide market application foreground, can be used for skin that wound, operation and shaping etc. cause, muscle, cohering of skeleton equivalent damage place is subject to pursuing of numerous scientific workers with reparation.The external form of the bionical pasting material of mussel mainly comprises membranaceous, spongy and water-setting is gluey, because aqueous gel-like material has hydrophilic polymer network, similar to normal physiological context residing for cell, quite look at by tissue and cell parent, therefore, the research of the bionical pasting material of the mussel of water-setting glue is concentrated also extensive the most.
Desirable bio-adhesive material should meet the Adhesion property requirement of general pasting material, specific demand again in biomedical applications: good biocompatibility, excellent biotic induce effect and harsh environment for use (the different interfaces under such as dry/wet condition).In recent years, (such as biocompatibility is inadequate in order to solve the problems of current various synthesis high score subclass bio-adhesive material existence for people, under wetting conditions, Adhesion property is not ideal enough, biotic induce effect shortcoming etc.), what progressively research work is focused on biology sticks behavior, to realizing this goal from bionical angle, mussel is exactly the Typical Representative of this kind of biology.Mussel is a kind of raised growth at the Mollusca of ocean and coastal area, very strong interaction can be formed with substrate material surface in a humid environment, containing the L-3,4 dihydroxyphenylalanine of nearly 30% and the lysine residue of 15% in its aminoacid sequence by secretion mussel adhesion protein (MAPs).Although extracting directly MAPs or adopt gene recombination technology to prepare restructuring mussel adhesion protein also to achieve comparatively good achievement in scientific research from mussel, but there is the inherent limitation that leaching process is loaded down with trivial details, cost is higher, productive rate is not enough, therefore, the method synthesis adopting macromolecule bionical is containing imitative mussel adhesion protein Functional Unit (3,4-dihydroxy benzenes propylamine, dopamine, Dopamine) the bionical pasting material of mussel become the focus of current research.Wang Yao etc. utilize four arm Polyethylene Glycol to be host molecule, dopamine and cystine linkage is introduced by coupling reaction in its structure, synthesized end group functional the bionical adhesion hydrogel of (PEG-dopamine) mussel of the gelator based on PEG (Wang Yao etc. based on preparation and the character [J] of the degradable hydrogel of PEG-DOPA. macromolecule is circulated a notice of, 2014,8:84-89), the free amino group of dopamine is grafted on polyacrylate by amido link by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine (EDC) by Zhang Feng etc., prepare the bionical polyacrylate pasting material of mussel containing dopamine, the introducing of dopamine significantly improve the adhesion of acrylate and hydrophilic (Zhang Feng etc. synthesis and property research [J] of dopamine modified polyacrylate. investigation of materials and application, 2010,4 (4): 711-715), also report is had, EDC is adopted dopamine to be combined the bionical polyurethane pasting material of mussel prepared containing dopamine with carboxylic polyurethane, it improves about 30% to the adhesion strength of metal, and can compare favourably with expensive mussel adhesion protein (Sun Peiyu etc. the bionical polyurethane of the mussel containing dopamine [J]. macromolecule journal, 2009,8:803-808), more have and dopamine is combined by means of only non-covalent bond with amination or the high polymer such as carboxylated PNIPAM and polyvinyl alcohol, based on synthesizing, high molecular mussel is bionical sticks membrane material in preparation, investigate its Adhering capacity (ZhangY to different kinds of proteins and cell, etal.Assemblyofpoly (dopamine)/poly (N-isopropylacrylamide) mixedfilmsandtheirtemperature-dependentinteractionwithpr oteins, Liposomes, andCells [J] .Langmuir, 2013, 29 (32): 10213-10222).But these synthesis macromolecules are under the jurisdiction of biologically inert component, in the biotic induce effect and biocompatibility of end-product, still not fully up to expectations.
Along with the development of the bionical pasting material of mussel, the requirement of people to the bionical bio-adhesive material of mussel is no longer confined to Adhesion property, progressively increases the attention to biotic induce effect.There is the mode coupling reported and be combined by covalent bond by carbodiimide hydrochloride and L-3,4 dihydroxyphenylalanine by fibroin, to obtain have concurrently the mussel of biocompatibility and adhesion bionical stick membrane material (high dynamic. the preparation of DOPA bionic adhesion material and application [D] .2013 thereof, Donghua University, master's thesis), bovine serum albumin has been incorporated into titanium alloy substrate material surface by dopamine by Lee seminar, prepare the mussel bionical titanium alloy functional membrane pasting material (RyuJ.B. with better biomineralization surface, etal.Mussel-inspiredpolydopaminecoatingasauniversalroute tohydroxyapatitecrystallization [J] .AdvancedFunctionalMaterials, 2010,20 (13): 2132-2139), chitosan etc. has been incorporated into by the mode naturally applied Poly(D,L-lactide-co-glycolide (PLGA) the film surface having infiltrated dopamine solution in advance by Chen etc., prepare the bionical PLGA of mussel with good osteogenic induction growth and stick membrane material, but this research is limited to membrane material direction, and synthesis macromolecule PLGA is membrane material main body (ChenG, etal.EffectsofsurfacefunctionalizationofPLGAmembranesfor guidedboneregenerationonproliferationandbehaviorofosteob lasts [J] .JournalofBiomedicalMaterialsResearchPartA, 2013, 101 (1): 44-53), the catabolite gelatin of dopamine and collagen is passed through coupling agent chemical bonding by Yang Qian, prepare the gelatin-based pasting material modified based on dopamine, and it is used for cell adhesion and the growth of surface of metal material embedded, but the biological activity of gelatin by a large amount of confirm to can not show a candle to collagen (Yang Qian. DOPA structure is used for biomimetic modification and Basic of Biology research [D] .2014 thereof of material surface, Jilin University, doctor's thesis).
In sum, Current patents document or non-patent literature are confined to the interaction of synthesizing macromolecule and dopamine more, end-product biotic induce limited use, not fully up to expectations in biologically active native high molecular mussel Bionic Design, especially in bionical adhesion hydrogel of collagen-based mussel and preparation method thereof, be not yet seen in report.
Summary of the invention
The object of the invention is for prior art Problems existing, bionical adhesion hydrogel of a kind of collagen-based mussel and preparation method thereof is provided.The method not only makes prepared mussel bionical adhesion hydrogel lower relative to the adhesion protein price extracted from mussel byssus, and has the biological activity of collagen excellence concurrently.Not only develop new bionical adhesion hydrogel material, and for fresh-water fishes collagen high level transform open new field.The bionical adhesion hydrogel of collagen-based mussel prepared by the present invention, its chemical composition is mainly fresh-water fishes collagen, dopamine and cross-linking agent, and wherein fresh-water fishes collagen is 100 parts, and dopamine is 1 ~ 20 part, and cross-linking agent is 1 ~ 10 part.Preferably, fresh-water fishes collagen is 100 parts, and dopamine is 2 ~ 12 parts, and cross-linking agent is 5 ~ 9 parts.Further preferably, fresh-water fishes collagen is 100 parts, and dopamine is 10 parts, and cross-linking agent is 8 parts.This hydrogel material outward appearance is light grey or black gelinite, and without the impurity that naked eyes are visible, gel pH value is 6 ~ 8, and bonding action is 0.05 ~ 2.0MPa, and mean porosities is 60 ~ 90%, and cytotoxicity is not more than 0 grade.
Particularly, the preparation method of collagen-based mussel of the present invention bionical adhesion hydrogel is as described below:
(1) " acid-enzyme combined techniques " conveniently extracts non-degeneration fresh-water fishes collagen from freshwater fishskin or fish scale, through saltouing, centrifugal, be separated, acid-soluble, dialysis postlyophilization obtains spongy non-degeneration fresh-water fishes collagen;
(2) by put forward non-denatured collagen and be dissolved in dilute acid soln, obtain certain density collagen solution, after regulating pH by low temperature, then the dopamine solution prepared added in described collagen solution according to a certain percentage;
(3) select a good opportunity and add cross-linking agent, by the bionical adhesion hydrogel of collagen-based mussel can be prepared after regulation and control gelation process, fully washing, dialysis, irradiation sterilization.
The raw material fingerling class of the fresh-water fishes collagen described in above-mentioned steps (1) contains common seven large Chinese carps (such as Mylopharyngodon piceus, Ctenopharyngodon idellus, Cyprinus carpio, Carassius auratus, Hypophthalmichthys molitrix, Aristichthys nobilis, Megalobrama amblycephala), but does not get rid of the fresh-water fishes kind of other kind.
In " acid-enzyme combined techniques " of the extraction non-degeneration fresh-water fishes collagen described in above-mentioned steps (1), the kind of acid comprises acetic acid, citric acid, the concentration range of acid is 0.1 ~ 0.5M/L, enzyme is pepsin, the consumption of enzyme is 0.5 ~ 2.0% of substrate butt quality, the temperature of whole leaching process controls at 0 ~ 4 DEG C, extracts the tropocollagen molecule amount obtained and is about 300,000 dalton, detects can be observed typical α 1, α 2 and β, γ band through SDS-PAGE.
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; Regulate the temperature conditions of pH not higher than 10 DEG C, regulate the collagen solution pH after pH to be 6 ~ 8; The concentration of dopamine solution is 1 ~ 20mg/mL, and wherein the mass percent of dopamine and collagen is 1 ~ 20%, and the response time is 1 ~ 4h.
Cross-linking agent described in above-mentioned steps (3) is any one in oxidized sodium alginate, vegatable tannin, genipin, the consumption of cross-linking agent is 1 ~ 10% of collagen butt weight, the opportunity that cross-linking agent adds can for the either phase before gelation process, in gelation process or after gelation process, preferably, the opportunity that adds of cross-linking agent is in gelation process, the regulation and control of gelation process mainly through controlling the pH value of solution, temperature and time realizes, wherein pH value range is 7.0 ~ 8.0, temperature is 35 ~ 42 DEG C, and the time is 1 ~ 12h; Irradiation dose is 10 ~ 30kGy.
The concrete technical scheme implementing product of the present invention is as described below:
The bionical adhesion hydrogel of the collagen-based mussel utilizing fresh-water fishes collagen to prepare, is prepared by following step:
Proportioning raw materials is by weight as follows:
Non-degeneration fresh-water fishes collagen 100 parts;
Dopamine 1 ~ 20 part;
Cross-linking agent 1 ~ 10 part;
Preparation process is:
(1) preparation of non-degeneration fresh-water fishes collagen:
Smashing to pieces after new fresh water fish skin or fish scale being cleaned up at 20 ± 1 DEG C, is process 24h in the NaOH solution of the 0.01M of 1:25, to remove non-collagen tissue at solid-liquid ratio; Isopropyl alcohol with 10% stirs 4h and removes fat constituent; Pepsin hydrolysis is carried out in the acetic acid solution of 0.5M, pepsin consumption is 0.5% of substrate butt quality, at the centrifugal 10min of 10000r/min, get supernatant, first adjust pH to neutral with NaOH, then use (NH4) 2SO4 to saltout, dialyse in the Na2HPO4 solution of 0.1M/L again, lyophilizing, carries out at whole leaching process remains on 4 DEG C, obtains unmodified freshwater fish collagen; Its molecular weight is 300,000 dalton, detects can be observed typical α 1, α 2 and β, γ band through SDS-PAGE;
(2) preparation of the bionical adhesion hydrogel of collagen-based mussel:
By formula ratio, unmodified fresh-water fishes collagen is dissolved in the acetic acid,diluted of 0.1 ~ 0.5M/L, obtain the collagen solution that concentration is 5 ~ 20mg/mL, subsequently not higher than under the condition of 10 DEG C, regulate pH to 6 ~ 8 of collagen solution, the dopamine solution being 1 ~ 20mg/mL by the concentration prepared by formula ratio again joins in described collagen solution according to 1 ~ 20% of collagen dry weight, after reaction 1 ~ 4h, described cross-linking agent is added by formula ratio, the consumption of described cross-linking agent is 1 ~ 10% of collagen dry weight, regulation and control gelation process, fully wash subsequently, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, the radiated by gamma-ray sterilizing of 10 ~ 30kGy is finally utilized namely to obtain the bionical adhesion hydrogel of collagen-based mussel.
Wherein said cross-linking agent is selected from the one in oxidized sodium alginate, vegatable tannin, genipin.
One of preferred version of the present invention is, the bionical adhesion hydrogel of the collagen-based mussel utilizing fresh-water fishes collagen to prepare, and proportioning raw materials is by weight as follows:
Non-degeneration fresh-water fishes collagen 100 parts;
Dopamine 2 ~ 12 part;
Cross-linking agent 5 ~ 9 parts.
Two of preferred version of the present invention is, the bionical adhesion hydrogel of the collagen-based mussel utilizing fresh-water fishes collagen to prepare, and proportioning raw materials is by weight as follows:
Non-degeneration fresh-water fishes collagen 100 parts;
Dopamine 10 parts;
Cross-linking agent 8 parts.
Either phase before the adding of described cross-linking agent being gelation process opportunity or in gelation process or after gelation process, preferably adding opportunity is in gelation process.
Applicant provide a kind of method utilizing fresh-water fishes collagen to prepare the bionical adhesion hydrogel of collagen-based mussel, comprise the following steps:
Proportioning raw materials is by weight as follows:
Non-degeneration fresh-water fishes collagen 100 parts;
Dopamine 1 ~ 20 part;
Cross-linking agent 1 ~ 10 part;
Preparation process is as follows:
(1) preparation of non-degeneration fresh-water fishes collagen:
Smashing to pieces after new fresh water fish skin or fish scale being cleaned up at 20 ± 1 DEG C, is process 24h in the NaOH solution of the 0.01M of 1:25, to remove non-collagen tissue at solid-liquid ratio; Isopropyl alcohol with 10% stirs 4h and removes fat constituent; Pepsin hydrolysis is carried out in the acetic acid solution of 0.5M, pepsin consumption is 0.5% of substrate butt quality, at the centrifugal 10min of 10000r/min, get supernatant, first adjust pH to neutral with NaOH, then use (NH4) 2SO4 to saltout, dialyse in the Na2HPO4 solution of 0.1M/L again, lyophilizing, carries out at whole leaching process remains on 4 DEG C, obtains unmodified freshwater fish collagen; Its molecular weight is 300,000 dalton, detects can be observed typical α 1, α 2 and β, γ band through SDS-PAGE;
(2) preparation of the bionical adhesion hydrogel of collagen-based mussel:
By formula ratio, unmodified fresh-water fishes collagen is dissolved in the acetic acid,diluted of 0.1 ~ 0.5M/L, obtain the collagen solution that concentration is 5 ~ 20mg/mL, subsequently not higher than under the condition of 10 DEG C, regulate pH to 6 ~ 8 of collagen solution, the dopamine solution being 1 ~ 20mg/mL by the concentration prepared by formula ratio again joins in described collagen solution according to 1 ~ 20% of collagen dry weight, after reaction 1 ~ 4h, described cross-linking agent is added by formula ratio, the consumption of described cross-linking agent is 1 ~ 10% of collagen dry weight, regulation and control gelation process, fully wash subsequently, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, the radiated by gamma-ray sterilizing of 10 ~ 30kGy is finally utilized namely to obtain the bionical adhesion hydrogel of collagen-based mussel.
Described in above-mentioned preparation method, cross-linking agent is selected from the one in oxidized sodium alginate, vegatable tannin, genipin.
Either phase before the adding of cross-linking agent described in above-mentioned preparation method being gelation process opportunity or in gelation process or after gelation process.Preferably, the opportunity that adds of cross-linking agent is in gelation process.
The bionical adhesion hydrogel of collagen-based mussel of the present invention can be used as the application of biomedical sector biomimetic material.
Collagen and dopamine are combined by chemical bond by the bionical adhesion hydrogel of the collagen-based mussel prepared by the present invention, avoid being separated of collagen and dopamine component in the gel rubber system formed, the bond strength of end-product hydrogel is 0.05 ~ 2.0MPa; Prepared hydrogel has the Adhering capacity of mussel protein uniqueness and the biological activity of collagen excellence concurrently, can be widely used in skin that wound, operation and shaping etc. cause, the cohering and reparation of muscle equivalent damage place because of tool change with various body.
Compared with prior art, tool of the present invention has the following advantages:
1, the collagen-based mussel bionical adhesion hydrogel prepared of the present invention is compared with traditional synthesis macromolecule adhesion hydrogel, has excellent Adhering capacity, biotic induce effect and biodegradable.
2, cross-linking agent of the present invention add the mechanical property improving hydrogel, simultaneously, compared with the glutaraldehyde adopted with traditional collagen hydrogel or carbodiimide cross-linker, the present invention's cross-linking agent used belongs to biotype cross-linking agent, avoids the potential source biomolecule toxicity that traditional chemical cross-linking agent (glutaraldehyde or carbodiimides) is introduced from source.
3, compared with extracting directly mussel adhesion protein from natural mussel, the present invention's raw material sources used are extensive, and the cost of products obtained therefrom is relatively lower.
4, synthesize compared with mussel adhesion protein with employing genetically engineered biological, present invention process is relatively simple, ripe, be easy to operation control and large-scale production.
5, present invention process is by regulation and control reactant consumption and gelation process, makes product have regulatable Adhesion property.
One group of performance characterization result of the bionical adhesion hydrogel of the collagen-based mussel that table 1 the present invention prepares
Accompanying drawing explanation
Fig. 1: the bionical adhesion hydrogel material of one group of collagen-based mussel (column body) prepared for the present invention.
Fig. 2: be one group of elastic modulus detection result of the bionical adhesion hydrogel of collagen-based mussel that the present invention prepares.
Fig. 3: be one group of loss moduli measurement result of the bionical adhesion hydrogel of collagen-based mussel that the present invention prepares.
Fig. 4: be one group of fissipation factor measurement result of the bionical adhesion hydrogel of collagen-based mussel that the present invention prepares.
Detailed description of the invention
Below by embodiment, the present invention is specifically described; what be necessary to herein means out is that following examples are only for the invention will be further described; limiting the scope of the invention can not be interpreted as; some nonessential improvement and adjustment that the person skilled in the art in this field makes according to the content of the invention described above, still belong to the category of the present invention's protection.
Embodiment 1
Smashing to pieces after fresh grass carp skin being cleaned up at 20 ± 1 DEG C, is process 24h in the NaOH solution of the 0.01M of 1:25, to remove non-collagen tissue at solid-liquid ratio.Then fat constituent is removed with the isopropyl alcohol stirring 4h of 10%.Then in the acetic acid solution of 0.5M, carry out pepsin hydrolysis, pepsin consumption is that 0.5%, 10000r/min centrifugal 10min of substrate butt quality gets supernatant, first adjusts pH to neutral with NaOH, then uses (NH
4)
2sO
4saltout, then at the Na of 0.1M/L
2hPO
4dialyse in solution, lyophilizing, carries out at whole leaching process remains on 4 DEG C, obtains unmodified grass carp skin collagen.
Adopt the unmodified grass carp skin collagen (5mg/mL) of acetic acid of 0.1M/L, at 0 DEG C, regulate collagen solution pH value to 7.0, add the dopamine solution of 20mg/mL subsequently, wherein dopamine consumption is 20% of collagen quality, stir, reaction 1h.
Add collagen dry weight 10% oxidized sodium alginate reaction 4h after adjust ph to 7.5, be placed in 37 DEG C of baking oven constant temperature 4h, fully wash subsequently, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, and finally under 10kGy intensity, namely radiated by gamma-ray sterilizing obtains the bionical adhesion hydrogel of collagen-based mussel.
Embodiment 2
Being smashed to pieces after cleaning up at 20 ± 1 DEG C by fresh Hypophthalmichthys molitrix (such as Aristichthys nobilis is commonly called as big head or silver carp) skin, is process 24h in the NaOH solution of the 0.01M of 1:25, to remove non-collagen tissue at solid-liquid ratio.Then fat constituent is removed with the acetone stirring 4h of 10%.Then in the citric acid solution of 0.2M, carry out pepsin hydrolysis, pepsin consumption is that 1.0%, 10000r/min centrifugal 10min of substrate butt quality gets supernatant, first adjusts pH to neutral with NaOH, then uses (NH
4)
2sO
4saltout, then at the Na of 0.1M/L
2hPO
4dialyse in solution, lyophilizing, carries out at whole leaching process remains on 4 DEG C, obtains unmodified Hypophthalmichthys molitrix collagen.
Adopt the unmodified Hypophthalmichthys molitrix collagen (10mg/mL) of acetic acid of 0.2M/L, at 4 DEG C, regulate collagen solution pH value to 6.0, add the dopamine solution of 10mg/mL subsequently, wherein dopamine consumption is 10% of collagen quality, stir, reaction 3h.
To add after the vegatable tannin of collagen dry weight 8% adjust ph to 7.0 immediately, be placed in 37 DEG C of baking oven constant temperature 4h, fully wash subsequently, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, and finally under 15kGy intensity, namely radiated by gamma-ray sterilizing obtains the bionical adhesion hydrogel of collagen-based mussel.
Embodiment 3
Smashing to pieces after being cleaned up at 20 ± 1 DEG C by fresh Carassius auratus skin, is process 24h in the NaOH solution of the 0.01M of 1:25, to remove non-collagen tissue at solid-liquid ratio.Then fat constituent is removed with the acetone stirring 4h of 10%.Then in the acetic acid solution of 0.2M, carry out pepsin hydrolysis, pepsin consumption is that 1.5%, 10000r/min centrifugal 10min of substrate butt quality gets supernatant, first adjusts pH to neutral with NaOH, then uses (NH
4)
2sO
4saltout, then at the Na of 0.1M/L
2hPO
4dialyse in solution, lyophilizing, carries out at whole leaching process remains on 4 DEG C, obtains unmodified Carassius auratus collagen.
Adopt the unmodified Carassius auratus collagen (15mg/mL) of acetic acid of 0.5M/L, at 4 DEG C, regulate collagen solution pH value to 7.5, add the dopamine solution of 15mg/mL subsequently, wherein dopamine consumption is 15% of collagen quality, stir, reaction 3h.
Regulate above-mentioned system pH to 8.0, be placed in 37 DEG C of baking oven constant temperature 4h, the genipin that period slowly adds collagen dry weight 10% is cross-linked, fully wash subsequently, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, and finally under 20kGy intensity, namely radiated by gamma-ray sterilizing obtains the bionical adhesion hydrogel of collagen-based mussel.
Embodiment 4
Smashing to pieces after being cleaned up at 20 ± 1 DEG C by fresh Aristichthys nobilis skin, is process 24h in the NaOH solution of the 0.01M of 1:25, to remove non-collagen tissue at solid-liquid ratio.Then fat constituent is removed with the isopropyl alcohol stirring 4h of 10%.In the acetic acid solution of 0.5M, carry out pepsin hydrolysis subsequently, pepsin consumption is that 2.0%, 10000r/min centrifugal 10min of substrate butt quality gets supernatant, first adjusts pH to neutral with NaOH, then uses (NH
4)
2sO
4saltout, then at the Na of 0.1M/L
2hPO
4dialyse in solution, lyophilizing, carries out at whole leaching process remains on 4 DEG C, obtains unmodified Aristichthys nobilis collagen.
Adopt the unmodified Aristichthys nobilis collagen (5mg/mL) of acetic acid of 0.2M/L, at 0 DEG C, regulate collagen solution pH value to 8.0, add the dopamine solution of 10mg/mL subsequently, wherein dopamine consumption is 20% of collagen quality, stir, reaction 4h.
Above-mentioned system is placed in 37 DEG C of baking oven constant temperature 4h, the oxidized sodium alginate that period slowly adds collagen dry weight 8% is cross-linked, fully wash subsequently, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, and finally under 30kGy intensity, namely radiated by gamma-ray sterilizing obtains the bionical adhesion hydrogel of collagen-based mussel.
Embodiment 5
Being cleaned up by fresh black carp scales, is the Na of the 0.05M of 1:20 at solid-liquid ratio
2cO
312h is processed, with loose fish scale structure in solution; And 12h decalcification is soaked in the HCl solution of 0.2M, in the NaOH solution of 0.05M, soak 8h remove fat constituent; Then in the acetic acid solution of 0.2M, carry out pepsin hydrolysis, pepsin consumption is that 1.5%, 10000r/min centrifugal 10min of substrate butt quality gets supernatant, adjusts pH to neutral, with (NH with NaOH
4)
2sO
4saltout, then at the Na of 0.1M/L
2hPO
4dialyse in solution, lyophilizing, carries out at whole leaching process remains on 4 DEG C, obtains unmodified black carp scales collagen.
Adopt the unmodified black carp scales collagen (10mg/mL) of acetic acid of 0.5M/L, at 4 DEG C, regulate collagen solution pH value to 7.0, add the dopamine solution of 15mg/mL subsequently, wherein dopamine consumption is 10% of collagen quality, stir, reaction 4h.
Above-mentioned system is placed in 42 DEG C of baking oven constant temperature 1h, add the oxidized sodium alginate reaction 4h of collagen dry weight 5% subsequently, abundant washing, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, and finally under 20kGy intensity, namely radiated by gamma-ray sterilizing obtains the bionical adhesion hydrogel of collagen-based mussel.
Embodiment 6
Being cleaned up by fresh Squama Cyprinus carpio, is the Na of the 0.05M of 1:20 at solid-liquid ratio
2cO
312h is processed, with loose fish scale structure in solution; And 12h decalcification is soaked in the HCl solution of 0.2M, in the NaOH solution of 0.05M, soak 8h remove fat constituent; Then in the citric acid solution of 0.1M, carry out pepsin hydrolysis, pepsin consumption is that 1.0%, 10000r/min centrifugal 10min of substrate butt quality gets supernatant, adjusts pH to neutral, with (NH with NaOH
4)
2sO
4saltout, then at the Na of 0.1M/L
2hPO
4dialyse in solution, lyophilizing, carries out at whole leaching process remains on 0 DEG C, obtains unmodified Squama Cyprinus carpio collagen.
Adopt the unmodified Squama Cyprinus carpio collagen (15mg/mL) of acetic acid of 0.5M/L, at 4 DEG C, regulate collagen solution pH value to 7.0, add the dopamine solution of 10mg/mL subsequently, wherein dopamine consumption is 10% of collagen quality, stir, reaction 2h.
Above-mentioned system is placed in 35 DEG C of baking oven constant temperature 4h, add the genipin reaction 4h of collagen dry weight 8% subsequently, abundant washing, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, and finally under 25kGy intensity, namely radiated by gamma-ray sterilizing obtains the bionical adhesion hydrogel of collagen-based mussel.
Embodiment 7
Being cleaned up by fresh Carnis Megalobramae squama, is the Na of the 0.05M of 1:20 at solid-liquid ratio
2cO
312h is processed, with loose fish scale structure in solution; And 12h decalcification is soaked in the HCl solution of 0.2M, in the NaOH solution of 0.05M, soak 8h remove fat constituent; Then in the acetic acid solution of 0.5M, carry out pepsin hydrolysis, pepsin consumption is that 2.0%, 10000r/min centrifugal 10min of substrate butt quality gets supernatant, adjusts pH to neutral, with (NH with NaOH
4)
2sO
4saltout, then at the Na of 0.1M/L
2hPO
4dialyse in solution, lyophilizing, carries out at whole leaching process remains on 4 DEG C, obtains unmodified triangular bream scale collagen.
Adopt the unmodified triangular bream scale collagen (20mg/mL) of acetic acid of 0.5M/L, at 10 DEG C, regulate collagen solution pH value to 6.0, add the dopamine solution of 1mg/mL subsequently, wherein dopamine consumption is 1% of collagen quality, stir, reaction 4h.
Above-mentioned system is regulated pH to 8.0, be placed in 37 DEG C of baking oven constant temperature 12h, add the genipin reaction 4h of collagen dry weight 1% subsequently, abundant washing, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, and finally under 30kGy intensity, namely radiated by gamma-ray sterilizing obtains the bionical adhesion hydrogel of collagen-based mussel.
Claims (10)
1. the bionical adhesion hydrogel of the collagen-based mussel utilizing fresh-water fishes collagen to prepare, is characterized in that described collagen-based mussel bionical adhesion hydrogel is prepared by following step:
Proportioning raw materials is by weight as follows:
Non-degeneration fresh-water fishes collagen 100 parts;
Dopamine 1 ~ 20 part;
Cross-linking agent 1 ~ 10 part;
(1) preparation of non-degeneration fresh-water fishes collagen:
Smashing to pieces after new fresh water fish skin or fish scale being cleaned up at 20 ± 1 DEG C, is process 24h in the NaOH solution of the 0.01M of 1:25, to remove non-collagen tissue at solid-liquid ratio; Isopropyl alcohol with 10% stirs 4h and removes fat constituent; In the acetic acid solution of 0.5M, carry out pepsin hydrolysis, pepsin consumption is 0.5% of substrate butt quality, at the centrifugal 10min of 10000r/min, gets supernatant, first adjusts pH to neutral with NaOH, then uses (NH
4)
2sO
4saltout, then at the Na of 0.1M/L
2hPO
4dialyse in solution, lyophilizing, carries out at whole leaching process remains on 4 DEG C, obtains unmodified freshwater fish collagen; Its molecular weight is 300,000 dalton, detects can be observed typical α through SDS-PAGE
1, α
2with β, γ band;
(2) preparation of the bionical adhesion hydrogel of collagen-based mussel:
By formula ratio, unmodified fresh-water fishes collagen is dissolved in the acetic acid,diluted of 0.1 ~ 0.5M/L, obtain the collagen solution that concentration is 5 ~ 20mg/mL, subsequently not higher than under the condition of 10 DEG C, regulate pH to 6 ~ 8 of collagen solution, the dopamine solution being 1 ~ 20mg/mL by the concentration prepared by formula ratio again joins in described collagen solution according to 1 ~ 20% of collagen dry weight, after reaction 1 ~ 4h, described cross-linking agent is added by formula ratio, the consumption of described cross-linking agent is 1 ~ 10% of collagen dry weight, regulation and control gelation process, fully wash subsequently, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, the radiated by gamma-ray sterilizing of 10 ~ 30kGy is finally utilized namely to obtain the bionical adhesion hydrogel of collagen-based mussel.
2. the bionical adhesion hydrogel of the collagen-based mussel utilizing fresh-water fishes collagen to prepare as claimed in claim 1, it is characterized in that, described cross-linking agent is selected from the one in oxidized sodium alginate, vegatable tannin, genipin.
3. the bionical adhesion hydrogel of the collagen-based mussel utilizing fresh-water fishes collagen to prepare as claimed in claim 1, is characterized in that: proportioning raw materials is by weight as follows:
Non-degeneration fresh-water fishes collagen 100 parts;
Dopamine 2 ~ 12 part;
Cross-linking agent 5 ~ 9 parts.
4. the bionical adhesion hydrogel of the collagen-based mussel utilizing fresh-water fishes collagen to prepare as claimed in claim 1, is characterized in that: proportioning raw materials is by weight as follows:
Non-degeneration fresh-water fishes collagen 100 parts;
Dopamine 10 parts;
Cross-linking agent 8 parts.
5. the bionical adhesion hydrogel of a kind of collagen-based mussel utilizing fresh-water fishes collagen to prepare as claimed in claim 1, it is characterized in that: the either phase before the adding of described cross-linking agent being gelation process opportunity or in gelation process or after gelation process, preferably adding opportunity is in gelation process.
6. utilize fresh-water fishes collagen to prepare a method for the bionical adhesion hydrogel of collagen-based mussel, it is characterized in that: comprise the following steps:
Proportioning raw materials is by weight as follows:
Non-degeneration fresh-water fishes collagen 100 parts;
Dopamine 1 ~ 20 part;
Cross-linking agent 1 ~ 10 part;
(1) preparation of non-degeneration fresh-water fishes collagen:
Smashing to pieces after new fresh water fish skin or fish scale being cleaned up at 20 ± 1 DEG C, is process 24h in the NaOH solution of the 0.01M of 1:25, to remove non-collagen tissue at solid-liquid ratio; Isopropyl alcohol with 10% stirs 4h and removes fat constituent; In the acetic acid solution of 0.5M, carry out pepsin hydrolysis, pepsin consumption is 0.5% of substrate butt quality, at the centrifugal 10min of 10000r/min, gets supernatant, first adjusts pH to neutral with NaOH, then uses (NH
4)
2sO
4saltout, then at the Na of 0.1M/L
2hPO
4dialyse in solution, lyophilizing, carries out at whole leaching process remains on 4 DEG C, obtains unmodified freshwater fish collagen; Its molecular weight is 300,000 dalton, detects can be observed typical α through SDS-PAGE
1, α
2with β, γ band;
(2) preparation of the bionical adhesion hydrogel of collagen-based mussel:
By formula ratio, unmodified fresh-water fishes collagen is dissolved in the acetic acid,diluted of 0.1 ~ 0.5M/L, obtain the collagen solution that concentration is 5 ~ 20mg/mL, subsequently not higher than under the condition of 10 DEG C, regulate pH to 6 ~ 8 of collagen solution, the dopamine solution being 1 ~ 20mg/mL by the concentration prepared by formula ratio again joins in described collagen solution according to 1 ~ 20% of collagen dry weight, after reaction 1 ~ 4h, described cross-linking agent is added by formula ratio, the consumption of described cross-linking agent is 1 ~ 10% of collagen dry weight, regulation and control gelation process, fully wash subsequently, the 24h that dialyses in the bag filter of 3800 molecular cut offs is placed in the normal saline packaging bag of 0.9%, the radiated by gamma-ray sterilizing of 10 ~ 30kGy is finally utilized namely to obtain the bionical adhesion hydrogel of collagen-based mussel.
7. a kind of method utilizing fresh-water fishes collagen to prepare the bionical adhesion hydrogel of collagen-based mussel as claimed in claim 6, is characterized in that: described cross-linking agent is selected from the one in oxidized sodium alginate, vegatable tannin, genipin.
8. a kind of method utilizing fresh-water fishes collagen to prepare the bionical adhesion hydrogel of collagen-based mussel as claimed in claim 6, is characterized in that: the either phase before the adding of described cross-linking agent being gelation process opportunity or in gelation process or after gelation process.
9. a kind of method utilizing fresh-water fishes collagen to prepare the bionical adhesion hydrogel of collagen-based mussel as described in claim 6 or 8, is characterized in that: the opportunity that adds of described cross-linking agent is in gelation process.
10. the purposes of the bionical adhesion hydrogel of a kind of collagen-based mussel utilizing fresh-water fishes collagen to prepare described in any one of Claims 1 to 5, is characterized in that: described collagen-based mussel bionical adhesion hydrogel is as the application of biomedical biomimetic material.
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| CN108543115A (en) * | 2018-04-02 | 2018-09-18 | 华中农业大学 | A kind of osteoinductive collagen-based composite hydrogel and preparation method thereof |
| CN110054683A (en) * | 2019-04-24 | 2019-07-26 | 青岛科技大学 | A kind of extraction pre-treating method of Java tilapia skin macromolecular collagen |
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| CN110054683A (en) * | 2019-04-24 | 2019-07-26 | 青岛科技大学 | A kind of extraction pre-treating method of Java tilapia skin macromolecular collagen |
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