CN104147632B - The chitosan Wound-protection liquid body dressing of specific cell adhesion - Google Patents
The chitosan Wound-protection liquid body dressing of specific cell adhesion Download PDFInfo
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- 229920001661 Chitosan Polymers 0.000 title claims abstract description 112
- 239000007788 liquid Substances 0.000 title claims abstract description 36
- 230000021164 cell adhesion Effects 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 18
- 229920001184 polypeptide Polymers 0.000 claims abstract description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 9
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 9
- 238000006731 degradation reaction Methods 0.000 claims abstract description 8
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- 238000002360 preparation method Methods 0.000 claims abstract description 6
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- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical group NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims description 50
- 239000000243 solution Substances 0.000 claims description 23
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- 239000004471 Glycine Chemical group 0.000 abstract 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical group NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 abstract 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
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- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
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- Materials For Medical Uses (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides chitosan Wound-protection liquid body dressing of a kind of specific cell adhesion and preparation method thereof, the present invention has the chitosan graft of high relative molecular mass (more than 100,000) the polypeptide RGD (arginine, glycine and aspartic acid sequence) that cell-specific is adhered to, and a kind of low-molecular weight chitoglycan Wound-protection liquid body dressing of specific cell adhesion is prepared in the presence of molecular weight regulator by gamma-ray irradiation degradation technique.The present invention is used for clinically wound sterilization, hemostasis and pain-relieving, antipruritic, promotion healing.There is the present invention cell-specific to recognize adhesion, it is to avoid allosome rejection, biocompatibility are good, have wide range of applications, preparation technology is simply controllable, the characteristics of reproducible.
Description
The invention belongs to medical use liquid dressing technical field.
Background technology
Chitosan is a kind of natural polysaccharide, and substantial amounts of research and application are obtained on clinical medicine.Chitosan enzyme
It can be absorbed after solution by tissue, there is good biocompatibility and good degradability to human body, to the nontoxic nothing of human body
Accumulation.The performance of chitosan corresponding thereto molecular mass magnitude relationship closely, such as Gram-negative bacteria, with relative
The reduction of molecular mass, the anti-microbial property of chitosan gradually strengthens, for gram-positive bacteria, with subtracting for relative molecular mass
Small, the anti-microbial property of chitosan gradually weakens.Research show the chitosan of relative molecular mass more than 100,000 have it is good into
Film and stop blooding, relieve the pain, anti-microbial property, relative molecular mass be less than 10,000 chitosan, with much high relative molecular mass shells
The function that glycan does not have, such as moisture retention, immunological regulation, anti-cancer, exclude in vivo toxic material, antibacterial, prevent wound
Infection, promotes many effects such as granulation growth and skin regeneration.Adjust function of intestines and stomach microcirculation etc..
Arginine-glycine-aspartic acid（Arg-Gly-Asp, RGD）Tripeptides be a kind of important cell recognition site with
Signal enabling molecule, is present in a variety of biological cell epimatrixs and plasma protein structure, while being also iuntercellular identifying system
Base unit.RGD is played as a kind of important cell recognition site and signal enabling molecule in many vital movements
Important regulatory function, with important medical value, be included in effect in terms of tumor diagnosis and treatment, treatment acute renal failure anti-inflammatory,
Inducing tissue regeneration, treatment osteoporosis and skin regeneration, wound healing etc..
Chitosan is unique active polysaccharide containing amino in nature, by the catalytic reaction of amino, carboxyl, will contain RGD
Sequences polypeptide small molecule grafts on chitosan molecule, can effectively improve chitosan and cell, the adhering to of extracellular matrix, compatible
Performance, promotes the specific binding of chitosan and body, preferably plays the positive work of chitosan and RGD sequence to wound healing
With.
But relative molecular weight of chitosan is general all more than 100,000 in natural chitosan crude product, poorly water-soluble should
Use and be restricted.Therefore select appropriate method to degrade chitosan, the performance applications of chitosan can be improved.Shell gathers
The biodegrading process of sugar mainly has chemical method, enzyme process, physical method.Wherein chemical method degraded molecular weight distribution is wide, but technique bar
Part is poor, and degradation process is difficult to control to, poor repeatability；Enzyme degradation conditions are gentle, but the structure to chitosan has selection
Property；Physical method degraded has reaction fast, pollution-free, reproducible, but reaction mechanism is more complicated.
The content of the invention
In view of the above-mentioned problems, being applied it is an object of the invention to provide a kind of chitosan Wound-protection liquid body of specific cell adhesion
Material and preparation method thereof.A kind of chitosan Wound-protection liquid body dressing of specific cell adhesion of the present invention has good film forming
With stop blooding, relieve the pain, antibacterial, prevent wound infection, promote the performances such as granulation growth and skin regeneration, reduction forms scar, to wound
Face healing has good therapeutic effect.A kind of preparation side of the chitosan Wound-protection liquid body dressing of specific cell adhesion of the present invention
Method, it is fast with reaction, it is pollution-free, the characteristics of reproducible.
In order to solve the above technical problems, the technical scheme that the present invention is provided is：
A kind of chitosan Wound-protection liquid body dressing of specific cell adhesion of the present invention and preparation method thereof, it is characterised in that
Grafting micromolecule polypeptide RGD chitosan and molecular-weight adjusting agent solution is prepared with pure water, mixed aqueous solution is passed through into gamma-rays
Irradiative degradation process is prepared.
Chitosan graft polypeptide RGD of the present invention is characterised by, dissolves chitosan in MES
（MES, pH 4.0-6.0 cushioning liquid）In, add 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides（EDC）, N- hydroxyls
Succinimide（NHS）And RGD, it is stirred at room temperature 12 hours, dialyses 3 days, freeze-drying, the shell for obtaining product RGD grafting gathers
Sugar.Wherein chitosan（Molecular weight 100,000 and more than）Concentration is 0.1%-5%, and chitosan is 1 with RGD mol ratios:10-1:1, shell gathers
Sugar is 1 with EDC mol ratios:10-10:1, EDC is 1 with NHS mol ratios:1-10:1.Dialyzate composition is selected from lactic acid, acetic acid, richness
Horse acid and hydrochloric acid.Composition described above, composition example include but is not limited to this.
RGD containing peptides of the present invention are to contain arginine-glycine-aspartic acid（Arg-Gly-Asp）Sequence
Micromolecule polypeptide, with cell specially recognition capability.
Chitosan graft RGD grafting rates of the present invention are chitosan in 10%-60%, the aqueous solution of molecular weight regulator
Mass concentration be 0.2-3%, the mass concentration of molecular weight regulator is 0.04-0.2%.
Gamma-ray irradiation degradation technique of the present invention is penetrated for the γ of cobalt -60 of irradiation intensity 10-25kGy under oxygen free condition
Line is irradiated.
Molecular weight regulator of the present invention is the one or more in iodine, amino acid, polypeptide, protein.Described group
Non-limitative example into composition includes but is not limited to iodine, glutamic acid, aspartic acid lysine, histidine, cecropin D, α-breast
Albumin, ovalbumin or serum albumin.
Compared with prior art, the technical scheme that the present invention is provided, in the presence of molecular weight regulator, it is suppressed that shell gathers
The rapid irradiance degraded of sugar, than the chitosan containing high relative molecular mass in more in conventional irradiation catabolite, shell gathers
The architectural features such as the deacetylation of sugar do not change.The technical scheme that the present invention is provided is so that chitosan has specificity thin
Born of the same parents, tissue adhension effect, with good biocompatibility, catabolite has very wide molecular weight distribution, has concurrently high relative
Molecular weight chitosan, low relative molecular mass chitosan and chitosan oligosaccharide various ingredients, with good film forming and hemostasis, stop
Pain, antibacterial, prevent wound infection, promote granulation growth and the performance such as skin regeneration.Chitosan Wound-protection liquid body dressing is sprayed at skin
Skin surface, adhesion is good, forms the antibacterial film with breathable properties, with broad-spectrum antiseptic, reduces cicatrization, promotes the surface of a wound
Healing.
It is verified by experiments, chitosan Wound-protection liquid body dressing of the present invention is to the various traumatic surface of a wound, and body surface ulcer surface of a wound etc. is all
With significant curative effect.
Embodiment
With reference to embodiment, the claim to the present invention is described in further detail, but is not constituted pair
Any limitation of the present invention, the modification of anyone limited number of time made within the scope of the invention as claimed, still the present invention's
In claims.
Embodiment 1
Chitosan is dissolved in MES, is added EDC, NHS and RGD, is stirred at room temperature 12 hours, is dialysed 3 days, freeze-drying.
Wherein chitosan concentration is 1%, and chitosan is 1 with RGD mol ratios:10, chitosan is 1 with EDC mol ratios:10, EDC rub with NHS
You are than being 10:1.Dialyzate composition is watery hydrochloric acid.RGD grafting rates are 58%.
At room temperature, solution is prepared according to formula as below：
RGD- chitosans（Percentage by weight, relative molecular mass more than 400,000）1%；
Ovalbumin（Percentage by weight）0.2%；
Surplus is purified water.
By the solution left standstill that has configured 24 hours, filtering removed insoluble matter, under anaerobic, 10kGy cobalt-60γrays
Irradiation 20 minutes, is made faint yellow clear liquid, as product.
Embodiment 2
Chitosan is dissolved in MES, is added EDC, NHS and RGD, is stirred at room temperature 12 hours, is dialysed 3 days, and freezing is dry
It is dry.Wherein chitosan concentration is 4%, and chitosan is 1 with RGD mol ratios:10, chitosan is 1 with EDC mol ratios:5, EDC and NHS
Mol ratio is 5:1.Dialyzate composition is lactic acid.RGD grafting rates are 32%.
At room temperature, solution is prepared according to formula as below：
RGD- chitosans（Percentage by weight, relative molecular mass more than 100,000）3%；
Iodine（Percentage by weight）0.05%；
Surplus is purified water.
By the solution left standstill that has configured 24 hours, filtering removed insoluble matter, under anaerobic, 15kGy cobalt-60γrays
Irradiation 20 minutes, is made faint yellow clear liquid, as product.
Embodiment 3
Chitosan is dissolved in MES, is added EDC, NHS and RGD, is stirred at room temperature 12 hours, is dialysed 3 days, freeze-drying.
Wherein chitosan concentration is 5%, and chitosan is 1 with RGD mol ratios:10, chitosan is 1 with EDC mol ratios:10, EDC rub with NHS
You are than being 5:1.Dialyzate composition is fumaric acid.RGD grafting rates are 40%.
At room temperature, solution is prepared according to formula as below：
RGD- chitosans（Percentage by weight, relative molecular mass more than 400,000）2%；
Alpha lactalbumin（Percentage by weight）0.08%；
Surplus is purified water.
By the solution left standstill that has configured 24 hours, filtering removed insoluble matter, under anaerobic, 25kGy cobalt-60γrays
Irradiation 20 minutes, is made faint yellow clear liquid, as product.
Embodiment 4
Chitosan is dissolved in MES, is added EDC, NHS and RGD, is stirred at room temperature 12 hours, is dialysed 3 days, freeze-drying.
Wherein chitosan concentration is 0.5%, and chitosan is 1 with RGD mol ratios:5, chitosan is 5 with EDC mol ratios:1, EDC rubs with NHS
You are than being 10:1.Dialyzate composition is citric acid.RGD grafting rates are 26%.
At room temperature, solution is prepared according to formula as below：
RGD- chitosans（Percentage by weight, relative molecular mass more than 600,000）0.8%；
Histidine（Percentage by weight）0.05%；
Surplus is purified water.
By the solution left standstill that has configured 24 hours, filtering removed insoluble matter, under anaerobic, 50kGy cobalt-60γrays
Irradiation 20 minutes, is made faint yellow clear liquid, as product.
Embodiment 5
Chitosan is dissolved in MES, is added EDC, NHS and RGD, is stirred at room temperature 12 hours, is dialysed 3 days, freeze-drying.
Wherein chitosan concentration is 2.5%, and chitosan is 1 with RGD mol ratios:10, chitosan is 1 with EDC mol ratios:10, EDC and NHS
Mol ratio is 10:1.Dialyzate composition is acetic acid.RGD grafting rates are 60%.
At room temperature, solution is prepared according to formula as below：
RGD- chitosans（Percentage by weight, relative molecular mass more than 100,000）1%；
Aspartic acid（Percentage by weight）0.04%；
Surplus is purified water.
By the solution left standstill that has configured 24 hours, filtering removed insoluble matter, under anaerobic, 10kGy cobalt-60γrays
Irradiation 20 minutes, is made faint yellow clear liquid, as product.
Embodiment 6
Chitosan is dissolved in MES, is added EDC, NHS and RGD, is stirred at room temperature 12 hours, is dialysed 3 days, and freezing is dry
It is dry.Wherein chitosan concentration is 0.1%, and chitosan is 1 with RGD mol ratios:10, chitosan is 1 with EDC mol ratios:5, EDC with
NHS mol ratios are 5:1.Dialyzate composition is malic acid.RGD grafting rates are 37%.
At room temperature, solution is prepared according to formula as below：
RGD- chitosans（Percentage by weight, relative molecular mass more than 400,000）0.3%；
Cecropin D（Percentage by weight）0.1%；
Surplus is purified water.
By the solution left standstill that has configured 24 hours, filtering removed insoluble matter, under anaerobic, 15kGy cobalt-60γrays
Irradiation 20 minutes, is made faint yellow clear liquid, as product.
Embodiment 7
Chitosan is dissolved in MES, is added EDC, NHS and RGD, is stirred at room temperature 12 hours, is dialysed 3 days, and freezing is dry
It is dry.Wherein chitosan concentration is 1%, and chitosan is 1 with RGD mol ratios:5, chitosan is 10 with EDC mol ratios:1, EDC and NHS
Mol ratio is 10:1.Dialyzate composition is tartaric acid.RGD grafting rates are 28%.
At room temperature, solution is prepared according to formula as below：
RGD- chitosans（Percentage by weight, relative molecular mass more than 400,000）0.5%；
Histidine（Percentage by weight）0.2%；
Surplus is purified water.
By the solution left standstill that has configured 24 hours, filtering removed insoluble matter, under anaerobic, 25kGy cobalt-60γrays
Irradiation 20 minutes, is made faint yellow clear liquid, as product.
Embodiment 8
Chitosan is dissolved in MES, is added EDC, NHS and RGD, is stirred at room temperature 12 hours, is dialysed 3 days, and freezing is dry
It is dry.Wherein chitosan concentration is 1%, and chitosan is 1 with RGD mol ratios:5, chitosan is 1 with EDC mol ratios:5, EDC and NHS
Mol ratio is 10:1.Dialyzate composition is hydrochloric acid.RGD grafting rates are 34%.
At room temperature, solution is prepared according to formula as below：
RGD- chitosans（Percentage by weight, relative molecular mass more than 600,000）1.2%；
Iodine（Percentage by weight）0.06%；
Surplus is purified water.
By the solution left standstill that has configured 24 hours, filtering removed insoluble matter, under anaerobic, 15kGy cobalt-60γrays
Irradiation 20 minutes, is made faint yellow clear liquid, as product.
Embodiment 9
Chitosan is dissolved in MES, is added EDC, NHS and RGD, is stirred at room temperature 12 hours, is dialysed 3 days, and freezing is dry
It is dry.Wherein chitosan concentration is 1%, and chitosan is 1 with RGD mol ratios:1, chitosan is 1 with EDC mol ratios:1, EDC and NHS
Mol ratio is 10:1.Dialyzate composition is watery hydrochloric acid.RGD grafting rates are 10%.
At room temperature, solution is prepared according to formula as below：
RGD- chitosans（Percentage by weight, relative molecular mass more than 400,000）1.5%；
Serum albumin（Percentage by weight）0.3%；
Surplus is purified water.
By the solution left standstill that has configured 24 hours, filtering removed insoluble matter, under anaerobic, 25kGy cobalt-60γrays
Irradiation 20 minutes, is made faint yellow clear liquid, as product.
Embodiment 10
Chitosan is dissolved in MES, is added EDC, NHS and RGD, is stirred at room temperature 12 hours, is dialysed 3 days, and freezing is dry
It is dry.Wherein chitosan concentration is 0.1%, and chitosan is 1 with RGD mol ratios:10, chitosan is 1 with EDC mol ratios:5, EDC with
NHS mol ratios are 1:1.Dialyzate composition is watery hydrochloric acid.RGD grafting rates are 35%.
At room temperature, solution is prepared according to formula as below：
RGD- chitosans（Percentage by weight, relative molecular mass more than 400,000）0.2%；
Lysine（Percentage by weight）0.5%；
Surplus is purified water.
By the solution left standstill that has configured 24 hours, filtering removed insoluble matter, under anaerobic, 15kGy cobalt-60γrays
Irradiation 20 minutes, is made faint yellow clear liquid, as product.
Antibacterial experiment in vitro and clinical effectiveness
Chitosan Wound-protection liquid body dressing obtained by embodiment 1-10 is subjected to inhibitory effect checkout facility using suspension method,
Test organisms is Candida albicans, Escherichia coli and staphylococcus aureus, takes its 3-14 for ordinary nutrient agar fresh cultured thing,
It is 1 × 10 that bacteria containing amount is made of the PBS of the peptone containing 10g/L6-2×106Cfu/mL bacteria suspension.When bacteria suspension and shell
The dressing of glycan Wound-protection liquid body is 2:When 1, act on 10 minutes, Candida albicans, Escherichia coli and staphylococcus aureus it is antibacterial
Rate reaches 99.99%, when bacteria suspension and the dressing of chitosan Wound-protection liquid body are 4:When 1, act on 10 minutes, Candida albicans, large intestine
The bacteriostasis rate of bacillus and staphylococcus aureus reaches 98.00%.When bacteria suspension and the dressing of chitosan Wound-protection liquid body are 8:When 1,
Effect 10 minutes, Candida albicans, Escherichia coli and the bacteriostasis rate of staphylococcus aureus reach 95.00%.（It is shown in Table 1）
Table 1
*：Control group uses the chitosan of commercialized product shield wound biological dressing (non-grafted RGD) progress pair under the same terms
Than.
Chitosan Wound-protection liquid body dressing obtained by embodiment 1-10 is applied to skin and frustrates scratch clinical care.At random will
120 skins frustrate scratch patient and are randomly divided into three groups：Chitosan Wound-protection liquid body dressing treatment group, Iodophor control group, mupirocin
Ointment control group, compares clinical efficacy.Clinical observation result is that Iodophor control group is better than mupirocin ointment control group, chitosan
Wound-protection liquid body dressing treatment group is sprayed at the surface of a wound, and the surface of a wound is dried, and oedema is light, and pain substantially mitigates, and has comfort, general 2-4
Its wound healing, without cicatrization, non-pigment is calm.
Claims (8)
1. the chitosan Wound-protection liquid body dressing of a kind of specific cell adhesion, it is characterised in that prepare molecular-weight adjusting with pure water
Agent and the solution of chitosan, wherein the molecular weight of the chitosan is more than 100,000, are obtained by gamma-ray irradiation degradation technique
Chitosan Wound-protection liquid body dressing, the chitosan graft has the polypeptide containing RGD sequence, and the RGD grafting rates of graft product are
10%-60%；The mass concentration of chitosan described in the chitosan of grafting and the aqueous solution of molecular weight regulator is 0.2-3%,
The mass concentration of the molecular weight regulator is 0.04-0.2%, and described molecular weight regulator is iodine, amino acid or protein
In one or more.
2. the chitosan Wound-protection liquid body dressing of the specific cell adhesion of claim 1, it is characterised in that the gamma-ray irradiation
Degradation technique is the cobalt-60γray irradiation of irradiation intensity 10-25kGy under oxygen free condition.
3. the preparation method of the chitosan Wound-protection liquid body dressing of any one of claim 1-2 specific cell adhesion：It is special
Levy and be, grafting micromolecule polypeptide RGD chitosan and the mixed solution of molecular weight regulator are prepared with pure water, will be mixed water-soluble
Liquid prepares the chitosan Wound-protection liquid body dressing of the specific cell adhesion by gamma-ray irradiation degradation technique.
4. the method for claim 3, it is characterised in that dissolve chitosan in MES, adds 1- (3- diformazan ammonia
Base propyl group) -3- ethyl carbodiimides（EDC）, n-hydroxysuccinimide（NHS）And RGD, it is stirred at room temperature 12 hours, dialyses
3 days, dialyzate was lactic acid, acetic acid, fumaric acid, the dilute aqueous solution of hydrochloric acid, and freeze-drying obtains product and is grafted with containing RGD sequence
The chitosan of polypeptide.
5. the concentration of the method for claim 4, wherein chitosan in MES is 0.1%-5%, chitosan rubs with RGD
You are than being 1:10-1:1, chitosan is 1 with EDC mol ratios:10-10:1, EDC is 1 with NHS mol ratios:1-10:1.
6. the method for claim 5, wherein chitosan are 1 with EDC mol ratios:5-5:1.
7. the method for claim 4, wherein MES are the form of pH 4.0-6.0 cushioning liquid.
8. the method for claim 4, wherein dialyzate composition are selected from lactic acid, acetic acid, fumaric acid and hydrochloric acid.
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| In vitro evaluation of an RGD-functionalized chitosan derivative for enhanced cell adhesion;Annasara Hansson等;《Carbohydrate Polymers》;20120714;第90卷;摘要、第1495页"2.Materials and methods"部分、第1499页右栏末段至第1500页左栏第1段 * |
| 壳聚糖在水溶液中的辐射降解反应;张志亮等;《高分子学报》;20061031(第7期);第841页左栏第1段至末段 * |
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