CN110408057A - Suitable for biomedical DHPMC blended cross linking modified collagen and preparation method thereof - Google Patents
Suitable for biomedical DHPMC blended cross linking modified collagen and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of suitable for biomedical DHPMC blended cross linking modified collagen and preparation method thereof, its raw material specifically includes that 100 parts of collagen, 40~200 parts of dialdehyde hydroxypropyl methyl cellulose, wherein, the dialdehyde hydroxypropyl methyl cellulose be by hydroxypropyl methyl cellulose as obtained by sodium metaperiodate selective oxidation, its oxidizability is 19~35%, and relative viscosity reduces 23.57~70.47% when T is 25 ± 0.01 DEG C.By DHPMC blended cross linking modified collagen, there is obtained modified collagen product the present invention chemical crosslinking to form the higher thermal stability of covalent bond bring and the stronger degradation property of resistance to enzyme simultaneously, and retain the higher biocompatibility of physical blending bring.
Description
Technical field
The present invention relates to collagen base biological medical material technical fields, and in particular to a kind of suitable for biomedical
More specifically DHPMC blended cross linking modified collagen and preparation method thereof is to utilize modified dialdehyde hydroxypropyl methyl fiber
Plain (DHPMC) and collagen carry out cross-linking modified prepared modified collagen and preparation method thereof.
Background technique
Collagen is the most fibrous structure albumen of animal in-vivo content, is the important composition ingredient of cellular matrix, is one
The excellent natural high molecular substance of kind.Its three strands of helical structures can make it have a good biocompatibility, biodegradable,
Film forming and mechanical property are widely used in the fields such as food industry, the biomedicine, cosmetics (biology of Li Guoying collagen
Learn property [J] Chinese leather, 2002,31 (21): 20-21).But since collagen thermal stability and mechanical strength are lower, Yi Beisheng
Object is degraded, and viscosity is larger, and film forming ability is not strong etc. limits it in the application of biological medicine Material Field.Therefore, usually
It needs to be modified the collagen-based materials used by the method for physics or chemistry, to enhance the service performance of collagen-based materials.
The common method of modifying of collagen has: (1) cross-linking modified using physical crosslinking or using chemical cross-linking agent；(2) pass through
With the blending and modifyings such as other natural or synthetic polymer.
Firstly, cross-linked modification method, which refers to by forming covalent key connection collagen molecules, improves the power of collagenous fibres
The method for learning performance and thermal stability.Wherein, being physical crosslinking and be chemically crosslinked is common cross-linked modification method.Physical crosslinking method
Such as ultraviolet irradiation, radiation exposure method etc., the performance of collagen film can be enhanced, and avoid addition noxious material.
But the disadvantage is that the collagen degree of cross linking obtained is low, uniformity is poor.Chemical crosslink technique such as carbodiimide, glutaraldehyde
Deng, the crosslinked of stable homogeneous can be obtained, and be conducive to adjust, control the degree of cross linking, mechanical property and biocompatibility,
But also has and introduce external source toxic agent, the deficiency that remaining reagent difficulty is removed.It is documented using glutaraldehyde steam to collagen fibre
Dimension carries out crosslinking Treatment, enhances the thermal stability of collagenous fibres, and tensile strength and breaking strength (Zhang Jicai, Ding Changkun, penta 2
The structure and performance study [J] research and development of the cross-linking modified rat-tail type i collagen fiber of aldehyde, 2016,39 (02): 26-29).But
Glutaraldehyde has certain cytotoxicity and calcification and is easy to hydrolyze to form free small molecule aldehyde (Zhang Yun phoenix, Du Guo
Graceful, the method for modifying of collagen summarizes [J] Chemical Engineering Technology and exploitation, 2015,44 (06): 46-50).Therefore, usually will not
It will use only physical crosslinking or chemical crosslinking gained modified collagen product be widely used in field of biomedical materials.
Secondly, being also to improve the common method of collagen performance using collagen and natural polymer blended modification.It needs
Illustrate, blending and modifying refers to that by two or more polymer, through mixing, each component accommodates macroscopic view is made each other
The process of homogeneous substance.The factor for influencing blending and modifying is mainly compatibility, poor compatibility, and interfacial adhesion is bad；Compatibility is good,
Interfacial adhesion is close, can integrate the excellent performance of each component.In general, blend each group polarity, composition, viscosity, point
Son amount, surface tension are more close, and finally formed blend compatibility is better.Therefore, it to be capable of forming with collagen good
Compatibility, the most representational mainly natural polysaecharides, such as starch of used natural polymer, carboxymethyl cellulose
With sodium alginate etc..According to published document, (Cuicui is blended with type i collagen using hydroxypropyl methyl cellulose
Ding, Min Zhang,Guoying Li.Preparation and characterization of collagen/
hydroxypropyl methylcellulose(HPMC)blend film[J].Carbohydrate Polymers.119
(2015) 194-201), by the secondary keys such as intermolecular hydrogen bond and effect entangled to each other, so that cross-linking modified collagen
Thermal stability, mechanism and hydrophilicity improve.And natural macromolecule modification agent used in such method will not usually draw
Enter external source toxicity and maintain the original activity of collagen substantially, is more suitable for using resulting modified collagen product as biomedical material
Material application.
Collagen can be made to enhance its correlated performance although above-mentioned document, which discloses blending, forms intermolecular hydrogen bonding, usually be increased
Strong performance is not sufficient to fully meet the field of biomedical materials requirement of current fast development, such as organizes in biomedicine
The related fieldss such as engineering rack require collagen to have higher thermal stability and resistance to enzyme degradability.
The advantages of in summary all kinds of collagen modification modes, will be formed covalent between collagen and natural polymer in recent years
Crosslinking is more popular collagen modification method, and dialdehyde cellulose is mixed with collagen, passes through intermolecular formation schiff bases key, crosslinking
Form dialdehyde cellulose/collagen composite membrane.The composite membrane has good thermal stability, the degradation property of resistance to enzyme and bio-compatible
Property, will not introduce external source toxicity, can be used as in organizational project timbering material (Yongmei Cheng, Jinting Lu,
Shilin Liu,et al.The preparation,characterization and evaluation of
regenerated cellulose/collagen composite hydrogel films[J].107(2014)57-64).This
Outside, intermolecular in addition to covalent bond, there are also the formation of the secondary keys such as hydrogen bond, are conducive to the raising of collagen thermal stability.(Bai Zhongxiang,
But time, but Wei Hua, dialdehyde carboxymethyl cellulose-collagen composite hemostatic material development [J] .2018,32 (10): 3628-
3633)。
But the present inventor has found in the course of the research, in the collagen modification method of above-mentioned formation covalent cross-linking, In
It is usually to select cellulose oxidation being modified as the dialdehyde cellulose of high aldehyde as crosslinking agent pair in disclosed technical literature
Collagen progress is cross-linking modified, achievees the purpose that cross-linked effect enhances by improving aldehyde.Pertinent literature shows cellulose oxidation
The process of reaction is usually along with its degradation reaction.It is bound to by improving degree of oxidation to reach the high aldehyde group content of cellulose
It will lead to the violent degradation of cellulose, molecular weight, viscosity significantly reduce.And cellulose oxidation is modified as high aldehyde group content fiber
Plain modified collagen product is formed by blended cross linking, although blend is intermolecular to be capable of forming schiff bases key covalent cross-linking,
The compatibility of modified high aldehyde group content cellulose and collagen compared to under the compatibility of cellulose and collagen before modified
Many has been dropped, aforementioned collagen has been had lost with natural polymer physics and bring feature performance benefit is blended, be mainly reflected in modified height
Aldehyde group content cellulose viscosity differs larger with the viscosity of collagen.So significantly limiting modified adhesive obtained by such method
The application and popularization of original product.
Therefore, it needs a kind of while there is chemical crosslinking to form the higher thermal stability of covalent bond bring and stronger resistance to
Enzyme degradation property, and retain the modified collagen and preparation method thereof of the higher biocompatibility of physical blending bring, it will very
Be conducive to modified collagen product in the application and development of field of biomedicine.
Summary of the invention
The present invention provides a kind of DHPMC blended cross linking modified collagen and preparation method thereof suitable for biomedicine, passes through
Hydroxypropyl methyl cellulose (HMPC) local selective oxidation is controlled, so that modified dialdehyde hydroxypropyl methyl cellulose
(DHPMC) possess aldehyde and relative molecular mass appropriate, obtained as crosslinking agent a kind of while there is chemistry
Be cross-linked to form the higher thermal stability of covalent bond bring and the stronger degradation property of resistance to enzyme, but retain physical blending bring compared with
The modified collagen of high biocompatibility.To achieve the above object, the present invention is using the technology being made of following technical measures
Scheme is realized.
A kind of DHPMC blended cross linking modified collagen suitable for biomedicine, its raw material specifically includes that according to parts by weight
100 parts of collagen,
40~200 parts of dialdehyde hydroxypropyl methyl cellulose；
Wherein, the dialdehyde hydroxypropyl methyl cellulose is that hydroxypropyl methyl cellulose is passed through sodium metaperiodate selectivity oxygen
Change gained, oxidizability is 19~35%, and relative viscosity reduces 23.57~70.47% at 25 ± 0.01 DEG C.Due to opposite point
Protonatomic mass can be characterized indirectly by relative viscosity, therefore the relative molecular mass in the present invention is all made of relative viscosity characterizes.
Wherein, the collagen would generally select solid-state according to cross-linking modified preparation purpose or be configured to the liquid of solution
State, therefore, for the ease of collagen and dialdehyde hydroxypropyl methyl cellulose carry out it is cross-linking modified react, those skilled in the art can root
Solution is configured by dialdehyde hydroxypropyl methyl cellulose according to common sense in the field selection is appropriate, and is in selected collage raw material
When non-solid, collagen solution concentration appropriate is selected, in order to being normally carried out for cross-linking modified reaction.In addition, the glue in raw material
Former and dialdehyde hydroxypropyl methyl cellulose parts by weight all refer in particular to dry weight.
It is worth noting that the hydroxypropyl methyl cellulose is by sodium metaperiodate when being selectively oxidized, mainly
The key for all having hydroxyl on 2,3 carbon of its saccharide ring by being broken, forms two aldehyde radical substituent groups.In order to which this hair is better described
It is bright, and providing a kind of control hydroxypropyl methyl cellulose selective oxidation to obtain oxidizability is 19~35%, relative viscosity
The preparation method of 23.57~70.47% dialdehyde hydroxypropyl methyl cellulose, specific steps are reduced at 25 ± 0.01 DEG C
Are as follows:
Configuration quality concentration is 1~3% Gonak, with hydroxypropyl methyl cellulose and sodium metaperiodate
In the ratio between amount of substance 1:(0.04~0.20) ratio be added in the above solution sodium metaperiodate mixing, then adjust pH be 2~6,
Reaction temperature is 30~50 DEG C, is stirred to react 3~5h under conditions of shading；After reaction time reaches, purify and it is dry to get
Dialdehyde hydroxypropyl methyl cellulose.
The reaction principle that above-mentioned hydroxypropyl methyl cellulose is selectively oxidized by sodium metaperiodate is schematically as follows:
Wherein, group R is CH3、CH2CHOHCH3Or H.
Further, the purifying and drying are specially rotated 3~5 times with dehydrated alcohol and deionized water respectively, and
Place it in oven drying.
Wherein, the oxidizability is as obtained by hydroxyamine hydrochloride measurement.Specifically:
It takes 0.1g oxidation product to be dissolved in 30ml deionized water, adjusts pH to 4.5, be configured to solution first.It weighs
0.43g hydroxylamine hydrochloride is dissolved in 20ml deionized water, is adjusted pH to 4.5, is configured to solution second.Solution first and solution second are mixed
It closes, at 40 DEG C of temperature, is stirred to react 4h.It is titrated again with 0.1mol/l NaOH, records volume used, be then calculated as follows
Oxidizability OD (formula 1).
In formula:
C: the concentration of NaOH used, mol/L when titration；
V: the volume of NaOH used, ml when titration；
M: the quality of weighed oxidation product, g.
Wherein, relative viscosity is measured using Ubbelohde viscosimetry.Specifically:
Configure the oxidation product weak solution under the different oxidizing conditions of 5mg/ml.Pure solvent is placed on 25 ± 0.01 first
DEG C water bath with thermostatic control in after constant temperature 30min, delivery time of the pure solvent in capillary is accurately measured using stopwatch, is denoted as t0；
The collagen weak solution of above-mentioned various concentration is measured in the same way again in the delivery time of capillary, is denoted as t1.Pure solvent and
The delivery time replication of the collagen weak solution of each concentration five times, takes its average value.It is (public that relative viscosity is calculated according to the following formula
Formula 2):
Wherein, the collagen is animal derived collagen, and normally, those skilled in the art can select according to practical application
Suitable collagenous source has excellent technical effect, measured obtained skill in the present invention in order to better illustrate the present invention
Art effect data is all using the collagen extracted from ox-hide according to the obtained modified collagen product of the content of present invention.
Normally, those skilled in the art can also add other poly- second known in the art according to practical application request
Glycol, other auxiliary agents such as glycerol.But on condition that these processing aids realize the purpose of the present invention and to the excellent effects of the present invention
The acquirement of fruit must not adversely affect.
Preferably, in order to make gained it is cross-linking modified after collagen in thermal stability, the degradation property of resistance to enzyme, bio-compatible
Property three aspect all have excellent properties, the raw material specifically includes that in parts by weight
100 parts of collagen,
100~140 parts of dialdehyde hydroxypropyl methyl cellulose；
Wherein, the dialdehyde hydroxypropyl methyl cellulose is that hydroxypropyl methyl cellulose is passed through sodium metaperiodate selectivity oxygen
Change gained, oxidizability is 20~30%, and relative viscosity reduces 23.57~45.66% at 25 ± 0.01 DEG C.
The above-mentioned preparation method for being suitable for biomedical DHPMC blended cross linking modified collagen, comprising the following steps:
(1) it stocks up
Its raw material specifically includes that according to parts by weight
100 parts of collagen,
40~200 parts of dialdehyde hydroxypropyl methyl cellulose；
Wherein, the dialdehyde hydroxypropyl methyl cellulose is that hydroxypropyl methyl cellulose is passed through sodium metaperiodate selectivity oxygen
Change gained, oxidizability is 19~35%, and relative viscosity reduces 23.57~70.47% at 25 ± 0.01 DEG C.
(2) cross-linking modified
Configure the dialdehyde hydroxypropyl methyl cellulose stocked up in step (1) to the dialdehyde hydroxypropyl methyl of pH value 3~7
Cellulose solution, then addition collagen is mixed in the solution, adjusting pH is 3~7, and temperature is reacted under the conditions of being 0~35 DEG C
24-72h is to get DHPMC blended cross linking modified collagen product.
Preferably, described in order to enable more efficiently between dialdehyde hydroxypropyl methyl cellulose and collagen be crosslinked
Dialdehyde hydroxypropyl methyl cellulose is configured to the dialdehyde Gonak of pH value 3~7, wherein dialdehyde hydroxypropyl first
The mass concentration of base cellulose solution is 5~20%, and according to the technical knowledge in the field, generally selecting will not be with dialdehyde hydroxypropyl
Reaction is generated between ylmethyl cellulose or influence the weak acidic buffer of dialdehyde hydroxypropyl methyl cellulose and collagen reaction into
Row configuration, such as the NaAc_HAc buffer solution of pH value 4.
Typically, the collagen of addition in the solution is mixed, and those skilled in the art can select according to different collagens
Addition manner appropriate is selected, such as is added after configuring solution or dissolution for collagen, or solid collagem membrane is straight
It connects to be put into dialdehyde Gonak and impregnate, above-mentioned addition manner is the conventional treatment mode of the art.
Secondly, if it is described in the solution addition collagen solution state mixed after, those skilled in the art can use according to final products
Way correspondingly changes blended cross linking condition, such as pH, temperature, concentration, and making product form finally can be gel, film etc..
By above-mentioned preparation step, the collagen after final gained is cross-linking modified has good biological degradability, raw
Object compatibility and low cytotoxicity compare unmodified collagen sponge, and thermal stability is improved up to 68.9 DEG C, in the pancreatin degradation item of 6h
Under part, resistance to enzymatic hydrolysis performance enhancement is up to 39%；And according to dialdehyde hydroxypropyl methyl fiber obtained by optimal technical scheme of the present invention
The plain more unmodified preceding minimum loss of cellulose of relative viscosity is 23.57%.
Collagen after gained of the invention is cross-linking modified can be used as biomedical material, for medicine controlled releasing, biology branch
The fields such as frame, hemostatic material.Such as modified collagen can be used as styptic sponge, the alternative materials of extracellular matrix, slow releasing medicinal
Object carrier etc..
Technical principle of the invention is as follows:
The present invention selects hydroxypropyl methyl cellulose oxidation modification to be dialdehyde hydroxypropyl methyl cellulose as crosslinking agent,
Firstly because HPMC is cheap, degradability is good, and has good dispersibility, film forming, with natural polymer chemical combination
Object compatibility is good.Although in addition, making inhomogeneity since HPMC saccharide ring 2,3 above with different substituents and degree of substitution difference
The related physical performance of the HPMC of type has difference, but contains great amount of hydroxy group, and hydroxyl reactive group is primarily directed to its sugar
For 2,3 bit substituent of ring.It is easy to learn, is mainly exactly to be broken on 2,3 carbon to have when sodium metaperiodate is selectively oxidized
There is the key of hydroxyl, forms two aldehyde radicals.For different type HPMC, if the sodium periodate oxidation condition used is identical,
The physicochemical properties of oxidation product DHPMC, such as the trend range of aldehyde group content, relative viscosity variation are similar.If using it
His oxidant, the content of aldehyde radical and position have uncertainty in the product for being easy to cause oxidation HPMC final, and react more difficult
Control, generates more side reaction, the poor repeatability of experiment.
Secondly, modified dialdehyde hydroxypropyl methyl cellulose has hydroxyl and aldehyde radical active group, therefore and glue simultaneously
When carrying out crosslinking blending between original, forms respectively the Hydrogenbond for belonging to physical bond and belong to chemically combined schiff bases
Key, so that cross-linked modification method of the present invention is no longer limited to single crosslinking method physically or chemically, the cross-linking modified glue of gained
Original product has more preferably functional.
In addition, being blended to form physical bond and chemically combined premise guaranteeing that modified HPMC be crosslinked with collagen
Under, possessed advantage function when in order to retain the good characteristic of unmodified preceding HPMC as far as possible and be blended with collagen, the present invention
Technical solution overcomes the technology prejudice that high aldehyde is pursued in existing open source literature, has appropriate aldehyde and phase by selection
To the dialdehyde hydroxypropyl methyl cellulose of molecular mass as crosslinking agent, it is blended to enhance HPMC after oxidation modification with collagen
The compatibility of crosslinking enhances the filming performance of modified collagen, so that properties of product meet biomedical material standard, answers extensively
For related fields.
The present invention has advantageous effects below:
1, the present invention has chemical friendship simultaneously by DHPMC blended cross linking modified collagen, obtained modified collagen product
Connection forms the higher thermal stability of covalent bond bring and the stronger degradation property of resistance to enzyme, and it is higher to retain physical blending bring
Biocompatibility, also have the characteristics that external source toxicity will not be introduced and maintain the original activity of collagen substantially, and having can
Regeneration, biodegradability, low cytotoxicity, the speciality such as good water solubility, applicable pH range is wider, meets biology doctor
Material standard is learned, and can be widely applied to related fields.
2, the collagen after present invention gained is cross-linking modified has a good biological degradability, biocompatibility and low thin
Cellular toxicity compares unmodified collagen sponge, and thermal stability is improved up to 68.9 DEG C, under the pancreatin degradation condition of 6h, resistance to enzymatic hydrolysis
It can enhance up to 39%, the more unmodified preceding cellulose loss range of relative viscosity is 23.57~70.47%.
3, in the preferred technical solution of the present invention, when hydroxypropyl methyl cellulose is selectively oxidized, oxidation side
What formula was selected is sodium metaperiodate selective local limited oxidation, and side reaction is few in the selective oxidation reaction, makes the product obtained
With a certain amount of aldehyde radical but itself again will not cause significantly to degrade because of oxidation, keep the excellent performance of itself.
Detailed description of the invention
Fig. 1 is that different sodium metaperiodates and hydroxypropyl methyl cellulose match synthesized dialdehyde in 1-2 of the embodiment of the present invention
The infrared spectrogram of hydroxypropyl methyl cellulose.In figure, the ratio that each spectral line is identified is different periodic acid in embodiment 1-2
Sodium and hydroxypropyl methyl cellulose match, and HPMC spectral line is the infrared spectroscopy of hydroxypropyl methyl cellulose.
Fig. 2 is collagen sponge obtained by the cross-linking modified collagen of dialdehyde hydroxypropyl methyl cellulose in 1-2 of the embodiment of the present invention
DSC figure.In figure, the temperature that each spectral line is identified is the thermostability temperature (Td) of cross-linking modified product in embodiment 1-2, pure glue
It originally was the spring collagen sponge blank sample modified without dialdehyde hydroxypropyl methyl cellulose.
Specific embodiment
The invention will be further described by way of example and in conjunction with the accompanying drawings.It is worth noting that the implementation provided
Example should not be understood as limiting the scope of the invention, and person skilled in art's content according to the present invention makees the present invention
Some nonessential modifications and adaptations out still should belong to the scope of the present invention.
It is worth noting that 1) oxidizability of dialdehyde hydroxypropyl methyl cellulose prepared by following embodiments and comparative example
It is to be measured using hydroxyamine hydrochloride.It takes 0.1g oxidation product to be dissolved in 30ml deionized water, adjusts pH to 4.5.It weighs
0.43g hydroxylamine hydrochloride is dissolved in 20ml deionized water, adjusts pH to 4.5.Two solution are mixed, at 40 DEG C of temperature, stirring
React 4h.It is titrated again with 0.1mol/l NaOH, records volume used, oxidizability OD (formula 1) is then calculated as follows.
In formula:
C: the concentration of NaOH used, mol/L when titration；
V: the volume of NaOH used, ml when titration；
M: the quality of weighed oxidation product, g.
The relative viscosity of dialdehyde hydroxypropyl methyl cellulose prepared by following embodiments and comparative example is viscous using Ubbelohde
Degree method measures.Configure the oxidation product weak solution under the different oxidizing conditions of 5mg/ml.Pure solvent is placed on 25 ± 0.01 first
DEG C water bath with thermostatic control in after constant temperature 30min, delivery time of the pure solvent in capillary is accurately measured using stopwatch, is denoted as t0；
The collagen weak solution of above-mentioned various concentration is measured in the same way again in the delivery time of capillary, is denoted as t1.Pure solvent and
The delivery time replication of the collagen weak solution of each concentration five times, takes its average value.It is (public that relative viscosity is calculated according to the following formula
Formula 2):
2) the cross-linking modified collagen of dialdehyde hydroxypropyl methyl cellulose prepared by following embodiments and comparative example, thermal denaturation
Temperature, the degree of cross linking, enzyme degradation property are to be tested to obtain by the following method and using existing equipment.
The thermal denaturation temperature of cross-linking modified rear collagen sponge is measured using differential scanning calorimeter.
It measures the degree of cross linking of the cross-linking modified collagen of dialdehyde hydroxypropyl methyl cellulose: weighing the modified collagen of 0.15g
The 2,4,6- tri- for 0.1% (V/V) that 2ml is newly configured is added in solution immediately after mixing with the borate buffer solution that the pH value of 2ml is 10
Nitrobenzene-sulfonic acid (TNBS) solution, vortex oscillation are protected from light 60min in 50 DEG C of thermostat water bath after being stirred.Reaction
After, the hydrochloric acid solution for being immediately 6 M to the concentration that 4ml is added in above-mentioned solution shakes up and is placed on 60 DEG C of thermostat water bath
In the reaction was continued 90min, until solution is clarified.It is measured at 340nm after cooling down at room temperature using ultraviolet-visible spectrophotometer
The crosslinking angle value of solution.Replication 3 times, it is averaged (formula 2).
In formula:
A0: the absorbance of natural collagen；
A1: the absorbance of collagen after dialdehyde hydroxypropyl methyl cellulose is cross-linking modified.
Measure the resistance to enzymic degradation ability of the cross-linking modified collagen of dialdehyde hydroxypropyl methyl cellulose: by the crosslinking after freeze-drying
Modified collagen (quality m0) be soaked in the phosphate buffer containing 0.02% pancreatin (pH=7.4), it is vibrated at 37 DEG C.Point
Not Mei Xie 6h, by after enzymatic treatment remaining collagen sponge sample take out, deionized water flushing be put into afterwards in 70 DEG C of baking oven for several times
It is dry, it is put into cooling in drier after 3h, is weighed as m1, by calculate can acquire it is cross-linking modified after collagen enzyme degradation rate
(formula 3).
In formula:
m0: the sample quality before enzymatic hydrolysis, g；
m1: the sample quality after enzymatic hydrolysis, g.
Collagen specimens used in following embodiment 1-2 and comparative example 1 are the collagen extracted in ox-hide.
Embodiment 1
(1) dialdehyde hydroxypropyl methyl cellulose is prepared
Configuration quality concentration is 2% Gonak, is pressed with hydroxypropyl methyl cellulose and sodium metaperiodate
Sodium metaperiodate mixing is added in the ratio between amount of substance 1:0.04 ratio in the above solution, and then adjusting pH is 3, reaction temperature 35
DEG C, it is stirred to react 4h in dark conditions；After reaction time reaches, purifying and dry to get oxidizability is 19.18%, phase
23.57% dialdehyde hydroxypropyl methyl cellulose is reduced when T is 25 ± 0.01 DEG C to viscosity.
(2) cross-linking modified
According to parts by weight, by dialdehyde hydroxypropyl methyl cellulose and 800 parts of acetic acid-obtained in 40 parts of steps (1)
Sodium acetate (pH=3.98) mixing, is configured to dialdehyde Gonak, then weigh 100 parts of Collagen specimens and be used in combination
8000 parts of Acetic acid-sodium acetate (pH=3.98) dissolutions are configured to collagen solution, above two solution are mixed, temperature 4
It is stirred to react and is freeze-dried for 24 hours to get the collagen cross-linking modified using modified HPMC under the conditions of DEG C.
After measured, the obtained collagen cross-linking modified using modified HPMC, thermal denaturation temperature are 59.2 DEG C；It hands over
Connection degree is 42.16%；The 6h degradation rate of resistance to pancreatin is 46.41%.
Embodiment 2
(1) dialdehyde hydroxypropyl methyl cellulose is prepared
Configuration quality concentration is 2% Gonak, is pressed with hydroxypropyl methyl cellulose and sodium metaperiodate
Sodium metaperiodate mixing is added in the ratio between amount of substance 1:0.20 ratio in the above solution, and then adjusting pH is 4, reaction temperature 35
DEG C, it is stirred to react 4h in dark conditions；After reaction time reaches, purifying and dry to get oxidizability is 31.05%, phase
70.47% dialdehyde hydroxypropyl methyl cellulose is reduced when T is 25 ± 0.01 DEG C to viscosity.
(2) cross-linking modified
According to parts by weight, by dialdehyde hydroxypropyl methyl cellulose and 8000 portions of vinegar obtained in 200 parts of steps (1)
The mixing of acid-sodium acetate (pH=3.98) buffer solution, is configured to dialdehyde Gonak, then weigh 100 parts of glue
Raw sample is simultaneously configured to collagen solution with 8000 parts of Acetic acid-sodium acetate (pH=3.98) buffer solution dissolutions, will be above two molten
Liquid is mixed, and temperature is stirred to react under the conditions of being 4 DEG C to be freeze-dried for 24 hours to get the collagen cross-linking modified using modified HPMC
Product.
After measured, the obtained collagen cross-linking modified using modified HPMC, thermal denaturation temperature are 60.4 DEG C；It hands over
Connection degree is 56.37%；The 6h degradation rate of resistance to pancreatin is 38.76%.
As shown in Fig. 1 in Figure of description, as seen from the figure, in 1732cm-1And 780cm-1There is aldehyde radical (- CHO) in place
Characteristic absorption peak.The former belongs to the stretching vibration of free aldehyde radical, and the latter belongs to the vibration of hemiacetal.With sodium metaperiodate dosage
Increase, aldehyde radical peak is gradually increased, and illustrates that the content of aldehyde radical gradually increases.Fig. 2 it is found that with dialdehyde hydroxypropyl methyl cellulose with
When collagen blending and modifying, the thermal stability of collagen can be improved.
In conclusion the aldehyde group content of dialdehyde hydroxypropyl methyl cellulose is higher, relative viscosity is lower, carries out with collagen
Biocompatibility is poorer when cross-linking modified；But opposite, aldehyde group content is lower, and the degree of cross linking is got over when carrying out cross-linking modified with collagen
Low, thermal denaturation and the degradation property of resistance to enzyme are lower.Therefore, it is necessary to select so that modified dialdehyde hydroxypropyl methyl cellulose possesses
Aldehyde and relative molecular mass appropriate, to obtain thermal stability with higher and the stronger degradation property of resistance to enzyme, again
Retain the modified collagen compared with high-biocompatibility.
Embodiment 3
(1) dialdehyde hydroxypropyl methyl cellulose is prepared
Configuration quality concentration is 2% Gonak, is pressed with hydroxypropyl methyl cellulose and sodium metaperiodate
Sodium metaperiodate mixing is added in the ratio between amount of substance 1:0.08 ratio in the above solution, and then adjusting pH is 3, reaction temperature 35
DEG C, it is stirred to react 4h in dark conditions；After reaction time reaches, purifying and dry to get oxidizability is 21.67%, phase
27.05% dialdehyde hydroxypropyl methyl cellulose is reduced when T is 25 ± 0.01 DEG C to viscosity.
(2) cross-linking modified
According to parts by weight, dialdehyde hydroxypropyl methyl cellulose obtained in 120 parts of steps (1) is gone with 2892 parts
Ionized water mixing, is configured to dialdehyde Gonak, then weigh 100 parts of Collagen specimens and with 8000 parts
The acetate dissolution of 0.5mol/L is configured to collagen solution, and above two solution is mixed, and the pH for adjusting mixed liquor is 5, In
Temperature is stirred to react under the conditions of being 4 DEG C to be freeze-dried for 24 hours to get the collagen cross-linking modified using modified HPMC.
After measured, the obtained collagen cross-linking modified using modified HPMC, thermal denaturation temperature are 68.9 DEG C；It hands over
Connection degree is 65.54%；The 6h degradation rate of resistance to pancreatin is 32.15%.
Embodiment 4
(1) dialdehyde hydroxypropyl methyl cellulose is prepared
Configuration quality concentration is 3% Gonak, is pressed with hydroxypropyl methyl cellulose and sodium metaperiodate
Sodium metaperiodate mixing is added in the ratio between amount of substance 1:0.08 ratio in the above solution, and then adjusting pH is 4, reaction temperature 40
DEG C, it is stirred to react 4h in dark conditions；After reaction time reaches, purifying and dry to get oxidizability is 19.97%, phase
26.31% dialdehyde hydroxypropyl methyl cellulose is reduced when T is 25 ± 0.01 DEG C to viscosity.
(2) cross-linking modified
According to parts by weight, by dialdehyde hydroxypropyl methyl cellulose and 4480 portions of vinegar obtained in 140 parts of steps (1)
Acid-sodium acetate (pH=3.98) mixing, is configured to dialdehyde Gonak, then weigh 100 parts of Collagen specimens simultaneously
It is configured to collagen solution with 8000 parts of Acetic acid-sodium acetate (pH=3.98) dissolutions, above two solution is mixed, temperature is
It is stirred to react and is freeze-dried for 24 hours to get the collagen cross-linking modified using modified HPMC under the conditions of 4 DEG C.
After measured, the obtained collagen cross-linking modified using modified HPMC, thermal denaturation temperature are 67.6 DEG C；It hands over
Connection degree is 63.21%；The 6h degradation rate of resistance to pancreatin is 35.44%.
Embodiment 5
(1) dialdehyde hydroxypropyl methyl cellulose is prepared
Configuration quality concentration is 3% Gonak, is pressed with hydroxypropyl methyl cellulose and sodium metaperiodate
Sodium metaperiodate mixing is added in the ratio between amount of substance 1:0.12 ratio in the above solution, and then adjusting pH is 5, reaction temperature 35
DEG C, it is stirred to react 4h in dark conditions；After reaction time reaches, purifying and dry to get oxidizability is 25.39%, phase
44.47% dialdehyde hydroxypropyl methyl cellulose is reduced when T is 25 ± 0.01 DEG C to viscosity.
(2) cross-linking modified
According to parts by weight, dialdehyde hydroxypropyl methyl cellulose obtained in 100 parts of steps (1) is gone with 20000 parts
Ionized water mixing, is configured to dialdehyde Gonak, then weigh 100 parts of Collagen specimens and with 8000 parts
The acetate dissolution of 0.5mol/L is configured to collagen solution, and above two solution is mixed, and is 4 DEG C of conditions in pH=7 temperature
Under be stirred to react 2h, be freeze-dried to get the collagen cross-linking modified using modified HPMC.
After measured, the obtained collagen cross-linking modified using modified HPMC, thermal denaturation temperature are 61.05 DEG C；It hands over
Connection degree is 60.24%；The 6h degradation rate of resistance to pancreatin is 36.64%.By pertinent literature it is found that glutaraldehyde and collagen it is best anti-
Answering pH value is 6~8.With this condition, the amino being more advantageous in the aldehyde radical and collagen in dialdehyde cellulose forms schiff bases key
Cross-linking reaction, increase the degree of cross linking.
Embodiment 6
(1) dialdehyde hydroxypropyl methyl cellulose is prepared
Configuration quality concentration is 1% Gonak, is pressed with hydroxypropyl methyl cellulose and sodium metaperiodate
Sodium metaperiodate mixing is added in the ratio between amount of substance 1:0.10 ratio in the above solution, and then adjusting pH is 2, reaction temperature 30
DEG C, it is stirred to react 5h in dark conditions；After reaction time reaches, purifying and dry to get oxidizability is 23.53%, phase
35.24% dialdehyde hydroxypropyl methyl cellulose is reduced when T is 25 ± 0.01 DEG C to viscosity.
(2) cross-linking modified
According to parts by weight, by dialdehyde hydroxypropyl methyl cellulose and 400 parts of phosphoric acid obtained in 80 parts of steps (1)
Salt buffer solution (PBS, 10mmol/L NaH2Pa/Na2HPa, 100mmol/L NaCl, pH=7.4) mixing, it is configured to dialdehyde
Gonak.100 parts of collagen sponges are weighed again, are dissolved in 8000 parts of phosphate after being shredded at low temperature
Buffer solution (PBS, 10mmol/L NaH2Pa/Na2HPa, 100mmol/L NaCl, pH=7.4).Collagen solution is placed in 37
3h is cultivated at DEG C and obtains pure collagen gel, and collagen gel is then soaked in dialdehyde Gonak.In temperature
It is reacted under the conditions of being 30 DEG C for 24 hours to get the collagen cross-linking modified using modified HPMC.
After measured, the obtained collagen cross-linking modified using modified HPMC, thermal denaturation temperature are 51.3 DEG C；It hands over
Connection degree is 32.16%；The 6h degradation rate of resistance to pancreatin is 54.39%.
Embodiment 7
(1) dialdehyde hydroxypropyl methyl cellulose is prepared
Configuration quality concentration is 3% Gonak, is pressed with hydroxypropyl methyl cellulose and sodium metaperiodate
Sodium metaperiodate mixing is added in the ratio between amount of substance 1:0.15 ratio in the above solution, and then adjusting pH is 6, reaction temperature 50
DEG C, it is stirred to react 3h in dark conditions；After reaction time reaches, purifying and dry to get oxidizability is 26.74%, phase
25.81% dialdehyde hydroxypropyl methyl cellulose is reduced when T is 25 ± 0.01 DEG C to viscosity.
(2) cross-linking modified
According to parts by weight, by dialdehyde hydroxypropyl methyl cellulose and 820 parts of phosphoric acid obtained in 180 parts of steps (1)
Salt buffer solution (PBS, 10mmol/L NaH2Pa/Na2HPa, 100mmol/L NaCl, pH=7.4) mixing, be configured to it is double again
100 parts of collagen sponges are weighed, are dissolved in 8000 parts of phosphate buffer solutions (PBS, 10mmol/L after being shredded at low temperature
NaH2Pa/Na2HPa, 100mmol/L NaCl, pH=7.4).Collagen solution is placed at 37 DEG C and cultivates 3h and obtains pure collagen and coagulate
Collagen gel is then soaked in dialdehyde Gonak by glue.Temperature be 37 DEG C under the conditions of react for 24 hours to get
Utilize the cross-linking modified collagen of modified HPMC.
After measured, the obtained collagen cross-linking modified using modified HPMC, thermal denaturation temperature are 63.9 DEG C；It hands over
Connection degree is 53.60%；The 6h degradation rate of resistance to pancreatin is 35.87%.
Comparative example 1
Collagen sponge sample is directly tested, thermal denaturation temperature is 52.1 DEG C；The degree of cross linking is 0；The 6h degradation rate of resistance to pancreatin is
98.66%.
Hydroxypropyl methyl cellulose sample is directly tested, not according to methoxyl group and hydroxypropoxy content in the structure of HPMC
It is four kinds of substituted types, i.e., 1828,2208,2906,2910 types with HPMC can be divided.Different HPMC models is corresponding with different
Viscosity, and the viscosity fluctuation range of every kind of model is larger, and in-between value is generally taken to indicate.Such as when HPMC methoxyl content is 27
~30%, hydroxypropoxy content is 4.0~7.5%, and relative viscosity is 403% at 25 ± 0.01 DEG C
Comparative example 2
100 parts of collagen sponges and 100 parts of HPMC powder are weighed, are dissolved respectively with 667 parts of 0.1mol/L acetums.
Configured collagen and HPMC solution are taken, is blended with the mass ratio that collagen/HPMC is 7/3, is stirred at 4 DEG C altogether
It is mixed, evacuation and centrifugal degassing is carried out after mixing evenly, is stood for 24 hours.
After measured, after HPMC is mixed with collagen solution, thermal denaturation temperature is 41.2 DEG C；The degree of cross linking is 0, the test of this degree of cross linking
The Method And Principle of use be had neither part nor lot in collagen reaction epsilon-amino reacted with TNBS generate substance that show color.Due to not having in HPMC
There are-CHO either other active groups to react with the epsilon-amino in collagen, therefore it reacts final absorbance and pure glue with TNBS
Original with TNBS be it is identical, by formula 2 it is found that the degree of cross linking is 0.
Claims (10)
1. a kind of suitable for biomedical DHPMC blended cross linking modified collagen, it is characterised in that its raw material according to parts by weight
It specifically includes that
100 parts of collagen,
40~200 parts of dialdehyde hydroxypropyl methyl cellulose；
Wherein, the dialdehyde hydroxypropyl methyl cellulose is that hydroxypropyl methyl cellulose is passed through sodium metaperiodate selective oxidation institute
, oxidizability is 19~35%, and relative viscosity, which is 25 ± 0.01 DEG C in T, reduces 23.57~70.47%.
2. being suitable for biomedical DHPMC blended cross linking modified collagen according to claim 1, it is characterised in that described double
The preparation method of aldehyde hydroxypropyl methyl cellulose, the steps include:
Configuration quality concentration is 1~3% Gonak, presses object with hydroxypropyl methyl cellulose and sodium metaperiodate
Mass ratio 1:(0.04~0.20) ratio be added in the above solution sodium metaperiodate mixing, then adjust pH be 2~6, reaction
Temperature is 30~50 DEG C, is stirred to react 3~5h under conditions of shading；After reaction time reaches, purify and dry to get dialdehyde
Hydroxypropyl methyl cellulose.
3. being suitable for biomedical DHPMC blended cross linking modified collagen according to claim 2, it is characterised in that: described
It purifies and dries, to be rotated respectively 3~5 times with dehydrated alcohol and deionized water, and place it in oven drying.
4. being suitable for biomedical DHPMC blended cross linking modified collagen according to claim 1, it is characterised in that the original
Material specifically includes that in parts by weight
100 parts of collagen,
100~140 parts of dialdehyde hydroxypropyl methyl cellulose；
Wherein, the dialdehyde hydroxypropyl methyl cellulose is that hydroxypropyl methyl cellulose is passed through sodium metaperiodate selective oxidation institute
, oxidizability is 20~30%, and relative viscosity, which is 25 ± 0.01 DEG C in T, reduces 23.57~45.66%.
5. a kind of preparation method suitable for biomedical DHPMC blended cross linking modified collagen, it is characterised in that including following
Step:
(1) it stocks up
Its raw material specifically includes that according to parts by weight
100 parts of collagen,
40~200 parts of dialdehyde hydroxypropyl methyl cellulose；
Wherein, the dialdehyde hydroxypropyl methyl cellulose is that hydroxypropyl methyl cellulose is passed through sodium metaperiodate selective oxidation institute
, oxidizability is 19~35%, and relative viscosity, which is 25 ± 0.01 DEG C in T, reduces 23.57~70.47%；
(2) cross-linking modified
Configure the dialdehyde hydroxypropyl methyl cellulose stocked up in step (1) to the dialdehyde hydroxypropyl methyl fiber of pH value 3~7
Plain solution, then addition collagen is mixed in the solution, adjusting pH is 3~7, and temperature reacts 24-72h under the conditions of being 0~35 DEG C,
Up to DHPMC blended cross linking modified collagen product.
6. being suitable for the preparation method of biomedical DHPMC blended cross linking modified collagen, feature according to claim 5
Be: the dialdehyde hydroxypropyl methyl cellulose is configured to the dialdehyde Gonak of pH value 3~7, wherein double
The mass concentration of aldehyde Gonak is 5~20%.
7. being suitable for the preparation method of biomedical DHPMC blended cross linking modified collagen, feature according to claim 5
It is the preparation method of the dialdehyde hydroxypropyl methyl cellulose, the steps include:
Configuration quality concentration is 1~3% Gonak, presses object with hydroxypropyl methyl cellulose and sodium metaperiodate
Mass ratio 1:(0.04~0.20) ratio be added in the above solution sodium metaperiodate mixing, then adjust pH be 2~6, reaction
Temperature is 30~50 DEG C, is stirred to react 3~5h under conditions of shading；After reaction time reaches, purify and dry to get dialdehyde
Hydroxypropyl methyl cellulose.
8. being suitable for the preparation method of biomedical DHPMC blended cross linking modified collagen, feature according to claim 7
Be: the purifying and drying to be rotated respectively 3~5 times with dehydrated alcohol and deionized water, and place it in oven drying.
9. being suitable for the preparation method of biomedical DHPMC blended cross linking modified collagen, feature according to claim 5
It is that the raw material specifically includes that in parts by weight
100 parts of collagen,
100~140 parts of dialdehyde hydroxypropyl methyl cellulose；
Wherein, the dialdehyde hydroxypropyl methyl cellulose is that hydroxypropyl methyl cellulose is passed through sodium metaperiodate selective oxidation institute
, oxidizability is 20~30%, and relative viscosity, which is 25 ± 0.01 DEG C in T, reduces 23.57~45.66%.
10. being suitable for biomedical DHPMC blended cross linking modified collagen as described in claim 1, it is applied to medicine controlled releasing, life
Object bracket, hemostatic material field.
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| CN115282349A (en) * | 2022-07-05 | 2022-11-04 | 复旦大学附属眼耳鼻喉科医院 | Corneal crosslinking reagent beneficial to improving CCT reduction in rose bengal-green light corneal collagen crosslinking technology |
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| CN111471193A (en) * | 2020-06-15 | 2020-07-31 | 四川大学 | Dialdehyde polysaccharide nanoparticle crosslinked collagen hydrogel and preparation method thereof |
| CN111471193B (en) * | 2020-06-15 | 2021-03-16 | 四川大学 | Dialdehyde polysaccharide nanoparticle crosslinked collagen hydrogel and preparation method thereof |
| CN113350567A (en) * | 2020-12-31 | 2021-09-07 | 孛朗孚(杭州)生物科技有限公司 | Biocompatible polymer dressing based on collagen |
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| CN113943441A (en) * | 2021-09-28 | 2022-01-18 | 陕西科技大学 | Hydrophobic dialdehyde carboxymethyl cellulose-collagen aerogel composite phase-change temperature-regulating material and preparation method thereof |
| CN113943441B (en) * | 2021-09-28 | 2022-11-29 | 陕西科技大学 | Hydrophobic dialdehyde carboxymethyl cellulose-collagen aerogel composite phase-change temperature-adjusting material and preparation method thereof |
| CN115282349A (en) * | 2022-07-05 | 2022-11-04 | 复旦大学附属眼耳鼻喉科医院 | Corneal crosslinking reagent beneficial to improving CCT reduction in rose bengal-green light corneal collagen crosslinking technology |
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