CN103893813A - Polymer composition and polymer material - Google Patents
Polymer composition and polymer material Download PDFInfo
- Publication number
- CN103893813A CN103893813A CN201210586655.2A CN201210586655A CN103893813A CN 103893813 A CN103893813 A CN 103893813A CN 201210586655 A CN201210586655 A CN 201210586655A CN 103893813 A CN103893813 A CN 103893813A
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- histidine
- macromolecule
- polymeric composition
- hydroxyl
- matrix metalloproteinase
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- 102000004196 processed proteins & peptides Human genes 0.000 description 1
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- NHDHVHZZCFYRSB-UHFFFAOYSA-N pyriproxyfen Chemical compound C=1C=CC=NC=1OC(C)COC(C=C1)=CC=C1OC1=CC=CC=C1 NHDHVHZZCFYRSB-UHFFFAOYSA-N 0.000 description 1
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- Materials For Medical Uses (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供高分子组合物与高分子材料。一种高分子组合物，包括：具有羟基的高分子；以及组氨酸或组氨酸之衍生物接枝于该具有羟基的高分子上。
The present invention provides a polymer composition and a polymer material. A polymer composition comprises: a polymer having a hydroxyl group; and histidine or a histidine derivative grafted onto the polymer having a hydroxyl group.
Description
Technical field
The present invention is about a kind of polymeric composition, and there is the polymeric composition of zinc ion affinity especially in regard to one, and this polymeric composition has matrix metalloproteinase (matrixmetallopoateinases, MMPs) suppress effect, can be directly using bulk form as chronic wounds dressing or can be in order to process the surface of medical device can improve tissue inflammation's symptom and/or promote wound healing so that sufferer is used in this chronic wounds dressing or medical device.
Background technology
The matrix metalloproteinase (matrixmetallopoateinases, MMPs) of current known high activity and concentration is the main cause that causes chronic wounds slowly not heal.The infection of wound and inflammation meeting cause organizes a large amount of secretion of MMPs to decompose and the cell and the antibacterial that remove wound bed death, but matrix metal proteinase activity is too high also can the decomposition of cambium and the damage of somatomedin, make wound get back to once again the inflammation phase, cannot heal and form vicious cycle.Said circumstances is very common in the wound of patient of diabetes or the chronic sufferer of other pathogenic, and even causes the even amputation of wound deterioration of sufferer.The dressing now with matrix metalloproteinase inhibition can reduce local host metal proteinase activity, promotes wound healing.
Again, in various inflammatory reaction, as rheumatoid arthritis (rheumatoid arthritis) and osteoarthritis (osteoarthritis) also equal situations of a large amount of secretion of MMPs in a organized way.The matrix metalloproteinase performance of high activity often starts multiple biochemical mechanism, for the machine that causes a disease one of turns, causes cartilage destruction.In addition in the time of coronary artery disease (as coronary heart disease) and myocardial damage, produce there is activity matrix metalloproteinase often again further degradation of cell epimatrix cause speckle and blood vessel wall attenuation and even break.The material now with matrix metalloproteinase inhibition can be used as effect of alleviating disease.
In addition, conventionally in the time of angiogenesis, cell migration, the newborn reconstruction of tissue, must there is the generation of matrix metalloproteinase with the degraded of helper cell extracellular matrix materials.But in the time that tumor generates, the activity performance of excessive matrix metalloproteinase can cause extracellular basement membrane degradation, and therefore promotes the infringement ability of tumor and transfer ability to rise thereupon, causes the diffusion of tumor cell.Now there is the inhibitor of matrix metal proteinase activity of inhibition and the exploitation of material and can contribute to reduce neonate tumour blood vessel and transfer.
Matrix metalloproteinase is that a group contains zinc ion, can decompose the endopeptidease of most cells epimatrix.In its structure, form in conjunction with albumen (hemopexin) effect section and four effect sections of cross-film (transmembrane) (domain) containing proparea (prodomain), catalytic center, erythrocruorin.Have been found that now the matrix metalloproteinase that exceedes 25 kinds, it can roughly be divided into four types, comprises (1) Collagenase; (2) gelatinase; (3) stromelysin; With (4) membranous type matrix metalloproteinase.Can effectively decompose the gelatin that is rich in tissue, collagen protein, with proteoglycan etc., and form, organize metabolism and inflammatory response relevant with tissue.Matrix metalloproteinase is secretion generation period, and now the zinc atom of its activated positions is combined with cystine, is the state of disactivation, after polypeptide is cut, opens, and matrix metalloproteinase becomes the form that has activity.
Research at present mainly contains three kinds of methods for the inhibition method of matrix metalloproteinase: the tissue inhibiting (tissue inhibitor ofmetalloproteinase) of (1) use metalloproteases forms the complex reversible, non-covalent bond is combined with matrix metalloproteinase Hemopexin loses activity it; (2) directly suppress the activity performance of matrix metalloproteinase with peptide or antibody mode; And the molecule between (3) use and zinc ion with high-affinity makes enzyme deactivation with bond.Its chelated zinc ion and then make the deactivated mechanism of matrix metalloproteinase is the atom of (lone pairelectrons) to be very easy to form coordination (coordination) form with transition metal with bonding electron not by phosphorus, nitrogen, sulfur, oxygen etc.
By document and in recent years Related product R&D direction show, the advanced dressing of chronic wounds starts demand and suppresses matrix metal proteinase activity to promote wound bed to rebuild healing.This series products contacts raw doctor's material that can suppress matrix metal proteinase activity as the third inhibition method take exploitation with wound bed.Take the Promogran chronic wounds dressing of Systagenix company as example, the combination base material of its oxidized cellulose and collagen protein can effectively absorb wound bed transudate, and by the affinity inhibitory enzyme activity of oxidized cellulose acid group and zinc ion.It is in base material, to add the EDTA with chelated zinc ionization that Smith & Nephew company also releases its inhibition mechanism of chronic wounds dressing Biostep, because matrix metalloproteinase must be by maintaining the state of its activation with the combination of zinc ion, therefore in base material, free EDTA can effectively reduce zinc ion concentration, even absorption makes it inactivation containing the matrix metalloproteinase of zinc.Exist but this chelating molecule is free state, therefore action time and usefulness are easily restricted.
Therefore need at present a kind of new material badly, the activity that it can long-acting inhibition matrix metalloproteinase.
Summary of the invention
The invention provides a kind of polymeric composition, comprising: the macromolecule with hydroxyl; And the derivatives graft of histidine or histidine has on the macromolecule of hydroxyl in this.
The present invention also provides a kind of macromolecular material, comprising: polymeric composition, and it comprises: the macromolecule with hydroxyl; And the derivatives graft of histidine or histidine has on the macromolecule of hydroxyl in this.
The present invention further provides a kind of medical device, comprising: polymeric composition, it comprises: the macromolecule with hydroxyl; And the derivatives graft of histidine or histidine has on the macromolecule of hydroxyl in this.
To state with other object, feature and advantage and can become apparent in order to allow on the present invention, preferred embodiment cited below particularly, and coordinate appended diagram, be described in detail below:
Accompanying drawing explanation
Fig. 1 shows one of formation polymeric composition of the present invention embodiment;
Fig. 2 shows the application mode of polymeric composition of the present invention;
The suppression ratio of the Boc histidine that Fig. 3 shows variable concentrations to Matrix Metalloproteinase-9;
The suppression ratio of the polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " (Lot1 of embodiment 1) that Fig. 4 shows variable concentrations to Matrix Metalloproteinase-9;
Fig. 5 shows thin film that polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " (Lot1 of embodiment 1) the formed suppression ratio to Matrix Metalloproteinase-9;
Fig. 6 shows thin film that polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " (Lot2 of embodiment 1) the formed suppression ratio to Matrix Metalloproteinase-9;
Fig. 7 shows thin film Lot1-1 and the suppression ratio of Lot1-2 to Matrix Metalloproteinase-9 that polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " (Lot2 of embodiment 1) is formed;
Fig. 8 shows thin film that poly ethylene vinyl alcohol grafting histidine derivative " EVOH-g-BocHis " (Lot3 of embodiment 2 and Lot4) the formed suppression ratio to Matrix Metalloproteinase-9;
Fig. 9 shows thin film that hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis " (Lot5 of embodiment 3) the formed suppression ratio to Matrix Metalloproteinase-9;
Figure 10 shows thin film that hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis " (Lot6 of embodiment 3) the formed suppression ratio to Matrix Metalloproteinase-9;
Figure 11 shows thin film that hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis " (Lot6 of embodiment 3 and Lot7) the formed suppression ratio to Matrix Metalloproteinase-9;
Figure 12 shows the result of the long-acting inhibition measures of effectiveness of poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot 3) to Matrix Metalloproteinase-9;
Figure 13 shows the result through the base material (EVOH-c-BocHis) of histidine impregnation processing and the long-acting inhibition measures of effectiveness of poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot 4).
Figure 14 shows the active assessment result of grafting histidine derivative film sample to zoopery diabetic mice wound fluid matrix metalloproteinase-9.
[primary clustering symbol description]
101～there is the macromolecule of hydroxyl;
The derivant of 103～histidine or histidine;
105～base material;
S1～mixing, coating, impregnation processing procedure.
The specific embodiment
In an embodiment of the present invention, the invention provides polymeric composition, it has zinc ion affinity, and has effect of the activity of inhibition matrix metalloproteinase (matrix metallopoateinases, MMPs).Referring to Fig. 1.Fig. 1 shows one of formation polymeric composition of the present invention embodiment.In Fig. 1, show, the derivant 103 of histidine or histidine is grafted on the macromolecule 101 with hydroxyl and is formed polymeric composition of the present invention.
As shown in Figure 1, the present invention's polymeric composition can comprise that the macromolecule 101 with hydroxyl grafts on the macromolecule 101 with hydroxyl with the derivant 103 of histidine or histidine.Polymeric composition of the present invention has zinc ion affinity, and has effect of the activity that suppresses matrix metalloproteinase.In one embodiment, can can be included, but are not limited to Fibroblast collagenase, MMP-2, Matrix metalloproteinase-8, Matrix Metalloproteinase-9 and/or MMP-13 by the matrix metalloproteinase that polymeric composition of the present invention suppressed.
In the present invention's polymeric composition, the derivant of histidine or histidine is about 0.1 ~ 99wt%.
In the present invention's polymeric composition, the macromolecule of hydroxyl can comprise synthetic macromolecule or natural polymer, and above-mentioned synthetic macromolecule or natural polymer can comprise linear polymeric or have the macromolecule of side chain.
In one embodiment, above-mentioned synthetic macromolecule can be linear synthetic macromolecule.The example of the synthetic macromolecule of above-mentioned linearity can comprise polyolefin-based glycol (polyalkylene glycol), polyvinyl alcohol (polyvinyl alcohol, PVA), polyvinyl acetate (polyvinyl acetate, PVAc), vinyl alcohol-vinyl acetate copolymerized compound (poly (vinyl alcohol-co-vinylacetate)), ethylene-vinyl alcohol copolymer (poly (ethylene vinyl-co-alcohol, EVOH)) its derivant and above-mentioned combination etc., but be not limited to this.
Again, in one embodiment, in polymeric composition of the present invention, the macromolecule of above-mentioned hydroxyl can be natural polymer, and natural polymer can comprise polysaccharide polymer.Be applicable to sugar high molecular more than polymeric composition of the present invention and can include, but not limited to hyaluronic acid (hyaluronic acid), starch (starch), cellulose (cellulose), methylcellulose (methylcellulose), hydroxypropyl cellulose (hydroxypropyl cellulose), hydroxypropyl emthylcellulose (hydroxypropyl methylcellulose), oxidized cellulose (oxidizedcellulose), glucosan (dextran), scleroglucan (scleroglucan), chitin (chitin), spherical chitosan (chitosan), card Derain glue (crudlan), Algin (alginate), carrageenin (carrageenan), pectin (pectin), Radix Acaciae senegalis (gum Arabic), close magnificent locust beam gum (guar gum), tie blue glue (gellan), Pu Lulan (pullulan), chrondroitin (chondroitin sulfate), heparin (heparin) or keratin sulfate (keratin sulfate) or derivatives thereof etc.
And in polymeric composition of the present invention, histidine and histidine derivative thereof have the nitrogen of the lone electron pair of possessing (lone pair) because of it, so can carry out the effect of chelated zinc ion.The derivant of above-mentioned histidine can comprise N
α-protection group threonine derivative, but be not limited to this.Above-mentioned N
αthe example of-protection group threonine derivative can include, but are not limited to N
α-Boc-histidine (N
α-Boc-histidine), N
α-Cbz-histidine (N
α-Cbz-histidine), N
α-Fmoc-histidine (N
α-Fmoc-histidine) and N
α-Ac-histidine (N
α-Ac-histidine) etc.
In polymeric composition of the present invention, the derivant of this above-mentioned histidine or histidine can directly graft on the macromolecule with hydroxyl, or can graft on the macromolecule with hydroxyl by connecting agent.
In one embodiment, the derivant of histidine or histidine is directly to graft on the macromolecule with hydroxyl.In this embodiment, the derivant of above-mentioned histidine or histidine can chemical covalency bond directly graft on the macromolecule with hydroxyl, and above-mentioned chemical covalency bond can comprise ester bond or amido Ethyl formate, but is not limited to this.Ester bond bond can be replaced in the high molecular hydroxyl with hydroxyl by protonated functional group by histidine or histidine.
In a specific embodiment, polymeric composition of the present invention comprises having the macromolecule of hydroxyl and the derivant of histidine directly grafts on the above-mentioned macromolecule with hydroxyl, wherein the above-mentioned macromolecule with hydroxyl comprises polyvinyl alcohol, ethylene-vinyl alcohol copolymer, hyaluronic acid, cellulose or hydroxypropyl emthylcellulose, and the derivant of above-mentioned histidine is N
α-Boc-histidine.
In another embodiment, the derivant of above-mentioned histidine or histidine can graft on the macromolecule with hydroxyl by connecting agent (spacer), and be applicable to connect between the present invention the example of agent, can comprise polyethylene glycol class, alkanes carbochain etc., but be not limited to this.
The matrix metalloproteinase suppression ratio of polymeric composition of the present invention can reach 10-100%.In one embodiment, polymeric composition of the present invention can reach about 20.39%-62.15% to the suppression ratio of Matrix Metalloproteinase-9.
The application mode of polymeric composition of the present invention can be referring to Fig. 2, but is not limited to this.Fig. 2 shows, comprise the macromolecule 101 with hydroxyl with graft on have the histidine of macromolecule 101 of hydroxyl or the polymeric composition of the present invention of the derivant of histidine 103 by mixing, coating, impregnation processing procedure S1 and be combined with base material 105.
Polymeric composition of the present invention can be distributed in base material or the surface of medical device and/or inner by promiscuous mode.
Or polymeric composition of the present invention can form solution.In one embodiment, above-mentioned solution can be machined directly to bulk, and this bulk can be used for medical application, but is not limited to this.
In another embodiment, above-mentioned solution can be used to process base material or medical device with physical absorption in the surface of this base material or medical device.In this embodiment, the material of base material can comprise, but be not limited to, polysaccharide (for example, cellulose and derivant thereof, hyaluronic acid and derivant thereof etc.), polyurethanes, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polypropylene type etc., or above-mentioned combination, and the example of medical device can comprise, such as wound dressing, tissue substituent, tissue engineering bracket, blood contact device and conduit etc., but be not limited to this.
In another embodiment of the present invention, the present invention also provides a kind of macromolecular material, it comprises the polymeric composition of the invention described above, and the polymeric composition of the invention described above has zinc ion affinity, and has effect of the activity that suppresses matrix metalloproteinase.Because the present invention's macromolecular material includes the polymeric composition of effect with activity that suppresses matrix metalloproteinase, therefore it can be used for medical treatment with the symptom in order to improve sufferer tissue inflammation and/or promotion wound healing, but is not limited to this.
In one embodiment, macromolecular material macromolecular material of the present invention can more comprise base material.In this embodiment, in macromolecular material of the present invention, polymeric composition can mix with base material or polymeric composition physical absorption in the surface of base material or interior to form medical device.
The example of the material of above-mentioned base material, (for example can be polysaccharide, cellulose and derivant thereof, hyaluronic acid and derivant thereof etc.), polyurethanes, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polypropylene type etc., or above-mentioned combination, but be not limited to this.In addition, above-mentioned medical device can include, but are not limited to wound dressing, tissue substituent, tissue engineering bracket, blood contact device or conduit etc.
[embodiment]
Synthesizing of polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis "
Shown in the following mode of structure (I) of polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis ":
Boc-His-OH (4.48g, 17.57mmol) and DMAP (1.95g, 15.97mmol) are placed in to the two-neck bottle that Magnetitum is housed.Two-neck bottle evacuation is also filled afterwards to drying nitrogen to remove bottle interior air in 3 minutes.Then adding DMAc (35ml) in two-neck bottle and stirring evenly suspends content in 10 minutes.Get EDC solid (3.06g, 15.97mmol) and pour into fast in two-neck bottle, with 30 ℃ of water-baths 3 hours with activated b oc-His-OH.By PVA
10k(molecular weight is 10000) (2.79g, 53.24mmol, 80% hydrolysis (hydrolyzed)) adds in DMAc (28ml) and in 80 ℃ and is stirred to and dissolves to form PVA solution completely, and be cooled to afterwards 45 ℃ for subsequent use.To activate rear Boc-His-LG solution (LG=Leaving Group(leaving group)) add fast above-mentioned PVA solution, and in 45 ℃ of sustained responses 24 hours to form a reaction solution.Naturally after cooling, above-mentioned reaction solution is loaded on to bag filter (MWCO:6-8,000), with DMAc (1.5L, 20X) dialysis 40 hours (changing dialysis solution once in the 16th hour), again with DIW (7.5L, 100X) dialysis 48 hours (changing dialysis solution in the 3rd, 6,9,12,24,27,30,33 and 36 hours).Collect solid, lyophilization and obtain product P VA-g-BocHis.
According to the experimental technique of the above, obtain the macromolecular material PVA-g-BocHis of the different B ocHis grafting degree of different batches by adjusting the reaction equivalent between PVA and Boc-His-OH, and determine its percent grafting with nuclear magnetic resonance spectrometer (Nuclear Magnetic ResonanceSpectroscopy).Result is as shown in table 1.
Table 1, PVA-g-BocHis material specification
Synthesizing of poly ethylene vinyl alcohol grafting histidine derivative " EVOH-g-BocHis "
Shown in the following mode of structure (II) of poly ethylene vinyl alcohol grafting histidine derivative " EVOH-g-BocHis ":
formula (II).
Boc-His-OH (11.46g, 44.88mmol) and DMAP (4.98g, 40.8mmol) are placed in to the two-neck bottle that Magnetitum is housed.Two-neck bottle evacuation is also filled afterwards to drying nitrogen to remove bottle interior air in 3 minutes.Then adding DMAc (90ml) in two-neck bottle and stirring evenly suspends content in 10 minutes.Get EDC solid (7.82g, 40.8mmol) and pour into fast in two-neck bottle, with 30 ℃ of water-baths 3 hours with activated b oc-His-OH.EVOH (5.84g, 150mmol, 32mol%ethylene unit) is added in DMAc (58ml) and in 80 ℃ and is stirred to and dissolves to form EVOH solution completely, and be cooled to afterwards 45 ℃ for subsequent use.To activate rear Boc-His-LG solution (LG=Leaving Group(leaving group)) add fast above-mentioned EVOH solution, and in 45 ℃ of sustained responses 24 hours to form a reaction solution.Naturally after cooling, above-mentioned reaction solution is loaded on to bag filter (MWCO:6-8,000), with DMAc (3.0L, 20X) dialysis 40 hours (changing dialysis solution once in the 16th hour).Afterwards, pouring liquid in bag filter into DIW (5.0L, 25X) precipitates for the first time again.Collect solid with MeOH back dissolving (10%w/v), then pour DIW (7.0L, 35X) into and precipitate again for the second time.Collect solid and solid is launched to clean three times with DIW.Lyophilization and obtain product EVOH-g-BocHis.
According to the experimental technique of the above, obtain the macromolecular material EVOH-g-BocHis of different B ocHis grafting degree by adjusting the reaction equivalent between EVOH and Boc-His-OH, and determine its percent grafting with nuclear magnetic resonance spectrometer.Result is as shown in table 2.
Table 2, EVOH-g-BocHis material specification
Synthesizing of hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis "
Shown in the following mode of structure (III) of hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis ":
Boc-His-OH (2.92g, 11.44mmol) and DMAP (1.27g, 10.4mmol) are placed in to the two-neck bottle that Magnetitum is housed.Two-neck bottle evacuation is also filled afterwards to drying nitrogen to remove bottle interior air in 3 minutes.Then adding DMAc (22.9ml) in two-neck bottle and stirring evenly suspends content in 10 minutes.Get EDC solid (1.99g, 10.4mmol) and pour into fast in two-neck bottle, with 30 ℃ of water-baths 3 hours with activated b oc-His-OH.By HPMC(2.0g, 10.4mmol, Mn120,000, replacement degree (the degree of substitution of methoxyl group (methoxy), DS): 1.1-1.6mol, mole replacement degree (the molar degree of substitution of expoxy propane (propyleneoxide), MS): 0.1-0.3mol) add in DMAc (40ml) and in 80 ℃ and be stirred to and dissolve to form HPMC solution completely, and be cooled to afterwards 50 ℃ for subsequent use.To activate rear Boc-His-LG solution (LG=Leaving Group(leaving group)) add fast above-mentioned HPMC solution, and in 50 ℃ of sustained responses 24 hours to form a reaction solution.Naturally after cooling, above-mentioned reaction solution is loaded on to bag filter (MWCO:6-8,000), with DMAc (1.4L, 20X) dialysis 40 hours (changing dialysis solution once in the 16th hour), again with DIW (7.0L, 100X) dialysis 72 hours (changing dialysis solution in the 3rd, 6,9,12,24,27,30,33,36,48,52 and 56 hours).Collect solid, lyophilization and obtain product HPMC-g-BocHis.
According to the experimental technique of the above, obtain the macromolecular material HPMC-g-BocHis of different B ocHis grafting degree by adjusting the reaction equivalent between HPMC and Boc-His-OH, and determine its percent grafting with nuclear magnetic resonance spectrometer.Result is as shown in table 3.
Table 3, HPMC-g-BocHis material specification
Synthesizing of hyaluronic acid grafting histidine derivative " HA-g-BocHis "
Shown in the following mode of structure (IV) of hyaluronic acid grafting histidine derivative " HA-g-BocHis ":
Boc-His-OH (8.42g, 33.0mmol) and DMAP (3.67g, 30.0mmol) are placed in to the two-neck bottle that Magnetitum is housed.Two-neck bottle evacuation is also filled afterwards to drying nitrogen to remove bottle interior air in 3 minutes.Then adding DMAc (66ml) in two-neck bottle and stirring evenly suspends content in 10 minutes.Get EDC solid (5.75g, 30.0mmol) and pour into fast in two-neck bottle, with 30 ℃ of water-baths 3 hours with activated b oc-His-OH.HATBA (18.6g, 30.0mmol) is poured in glass reaction groove.Glass reaction truss is established after mechanical stirring device to evacuation 10 minutes to remove a bottle interior air, afterwards and with drying nitrogen backfill.The DMAc (186ml) that will dewater with molecular sieve adds in glass reaction groove, and is placed in 45 ℃ of circulator baths and with rotating speed 250rpm mechanical agitation more than 2 hours, so that HA
16000tBA(molecular weight is 16000) or HA
350000tBA(molecular weight is 350,000) uniform dissolution to be to form HA solution.To activate rear Boc-His-LG solution (LG=Leaving Group(leaving group)) add fast containing in the glass reaction groove of above-mentioned HATBA solution.After 30 minutes, improve mechanical agitation rotating speed in glass reaction groove to 300rpm, and make in reactive tank solution in 45 ℃ of sustained responses 24 hours to form reaction solution.Naturally after cooling, reaction solution is transferred to bag filter (MWCO:12-14,000), with DMAc (6.0L, 20X) dialysis 40 hours (changing dialysis solution on the 16th hour once), again with DIW (18.0L, 100X) dialysis 72 hours (within the 3rd, 6,9,12,24,27,30,33,36,48,52 and 56 hours, changing dialysis solution).Then, collecting aqueous solution in bag filter, by sodium ion exchange resin (ROHM HAAS, food stage, 520g), is replaced into sodium ion by TBA, and its vacuum concentration to concentration of aqueous solution is about to 1-1.5wt%.Afterwards, adjust pH to 7.6 ± 0.2 with 0.1M NaOH, utilize the dry product HA-g-BocHis that obtains of freeze-drying.
According to the experimental technique of the above, obtain the macromolecular material HA-g-BocHis of different B ocHis grafting degree by adjusting the reaction equivalent between HA and Boc-His-OH, and determine its percent grafting with nuclear magnetic resonance spectrometer.Result is as shown in table 4.
Table 4, HA-g-BocHis material specification
Synthesizing of cellulose graft histidine derivative " Cellulose-g-BocHis "
Shown in the following side's formula V of structure of cellulose graft histidine derivative " Cellulose-g-BocHis ":
Boc-His-OH (1.39g, 5.34mmol) and DMAP (0.6g, 4.94mmol) are placed in to the two-neck bottle that Magnetitum is housed.Two-neck bottle evacuation is also filled afterwards to drying nitrogen to remove bottle interior air in 3 minutes.Then adding DMAc (10.9ml) in two-neck bottle and stirring evenly suspends content in 10 minutes.Get EDC solid (0.95g, 4.94mmol) and pour into fast in two-neck bottle, with 30 ℃ of water-baths 3 hours with activated b oc-His-OH.Cellulose cloth (2.00g, 12.34mmol) is put into 150ml glass reaction groove, be impregnated in the DMAc (20ml) that molecular sieve dewatered, and stir more than 2 hours with rotating speed 100rpm in 45 ℃.To activate rear Boc-His-LG solution (LG=Leaving Group(leaving group)) add fast in glass reaction groove, make cloth and Boc-His-LG solution in 45 ℃ of sustained responses 24 hours.Naturally after cooling, will react rear cellulose cloth, immerse DMAc (0.5L, 20X) and stir 0.5 hour, then put into DIW (1.0L, 100X) and stir 1 hour, re-use afterwards DIW and clean three times, to remove the rear impurity of reaction.Finally Cellulos-g-BocHis is drying to obtain.
Different samples are to activity of matrix metalloproteinase-9 inhibition test
Analytical method
Step 1: front (pro)-Matrix Metalloproteinase-9 activation
Before 10 μ g/ml-Matrix Metalloproteinase-9 (R & D) solution adds 100mMAPMA(final concentration 1mM), and act on 2 hours in 37 ℃ of incubators before-Matrix Metalloproteinase-9 is transformed into Matrix Metalloproteinase-9 (activatedpro-matrix metallopoateinases) before activation
Step 2: test sample
Matrix Metalloproteinase-9 before activation is analyzed to buffer solution (50mM Tris, 10mM CaCl with activity of matrix metalloproteinase-9
2, 150mM NaCl, 0.05%Brij-35 (w/v), pH7.5) and to be diluted to concentration be 100ng/ml.Each test sample adds respectively activation Matrix Metalloproteinase-9 before, is placed in 37 ℃ of incubators and reacts 2 or 24 hours.Negative control group is not containing Matrix Metalloproteinase-9 solution before the activation of test example reaction, positive controls added activity of matrix metalloproteinase-9 inhibitor 1 in Matrix Metalloproteinase-9 solution before activation, 10-phenanthroline (1,10-Phenanthroline, 1,10-PT) (final concentration 0.1mM).
Step 3: activity of matrix metalloproteinase-9 analysis
Before taking-up and the reacted activation of material, Matrix Metalloproteinase-9 solution is in the black dish in 96-hole (black plate).Add equal-volume Matrix Metalloproteinase-9 substrate (final concentration 10uM) to react 0.5-1 hour in 37 ℃ of incubators, measure fluorescence value of reading (Ex/Em=320/405nm) in high sensitivity fluor tester (Flexstation3).
Experimental result
The impact of A.Boc-histidine concentrations on activity of matrix metalloproteinase-9 inhibition
By the Boc histidine of known variable concentrations and activated Matrix Metalloproteinase-9 effect 2 hours, measure the impact that activity of matrix metalloproteinase-9 is subject to variable concentrations histidine and change.Result as shown in Figure 3.In the time that histidine concentrations reaches 2.64mg/ml, Matrix Metalloproteinase-9 is had to more than 50% inhibition.y=21.83ln(x)+28.06。
B. polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " powder concn suppresses the assessment of usefulness to activity of matrix metalloproteinase-9
The polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " that is 13.3% by percent grafting (Lot1 of embodiment 1) powder is made into the test sample book into variable concentrations, and tests its impact on activity of matrix metalloproteinase-9.Result is if table 5 is with as shown in the 4th figure.
The polyvinyl alcohol graft copolymerized histidine derivative of table 5, variable concentrations inhibition effect to Matrix Metalloproteinase-9
Result shows, PVA-g-His percent grafting be 13.3%, PVA-g-His concentration while being 2% ~ 10% to the suppression ratio of Matrix Metalloproteinase-9 for having 47.78%; PVA-g-His concentration is that 20% Matrix Metalloproteinase-9 has 62.15% inhibition.
C. the thin film of the polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " of the Lot1 of embodiment 1 suppresses measures of effectiveness to activity of matrix metalloproteinase-9
Polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " powder (percent grafting 13.3%) that Lot1 obtained of embodiment 1 is added in DMAC, and dissolve (500rpm in stirring at room temperature, 6 hours), after dissolving, insert mould and dry 72 hours to become diaphragm with 60 ℃.The film sample that is diameter 1cm by membrane cutting carries out the test of 24 hours activity of matrix metalloproteinase-9s, and respectively take BocHis and PVA thin film as matched group.The results are shown in table 6 and Fig. 5.
Table 6, thin film that polyvinyl alcohol graft copolymerized histidine derivative formed inhibition effect to Matrix Metalloproteinase-9
Result shows, the thin film of Lots1 can reach 33.27% suppression ratio to the suppression ratio of Matrix Metalloproteinase-9 and in comparison PVA thin film (matched group) slowly dissolving only have 16.89% decay of activity situation.
D. the thin film of the polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " of the Lot2 of embodiment 1 suppresses measures of effectiveness to activity of matrix metalloproteinase-9
Polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " powder (percent grafting 19.0%) that Lot2 obtained of embodiment 1 is added in DMAC, and dissolve (500rpm in stirring at room temperature, 6 hours), after dissolving, insert mould and dry 72 hours to become diaphragm with 60 ℃.The film sample that is diameter 1cm by membrane cutting carries out activity of matrix metalloproteinase-9 test in 24 hours, and to be cross-linked PVA (cPVA) thin film as matched group.The results are shown in table 7 and Fig. 6.
Table 7, polyvinyl alcohol graft copolymerized histidine derivative thin film inhibition effect to Matrix Metalloproteinase-9
-: not containing histidine
Because film size is fixed, therefore be about 19.4mg/ml according to the histidine of its grafting of Lot2 of film weight and the known embodiment 1 of percent grafting with respect to the concentration of matrix metal proteinase activity analytical solution, this Lots2 thin film can reach 41.04% suppression ratio to Matrix Metalloproteinase-9.Crosslinked PVA (cPVA) thin film is to the not active inhibition of tool of Matrix Metalloproteinase-9 in comparison.
E. the thin film of the polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " of the Lot1 of embodiment 1 suppresses measures of effectiveness to activity of matrix metalloproteinase-9
Polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " powder (percent grafting 13.3%) that Lot1 obtained of embodiment 1 is added in DMAC, and dissolve (500rpm in stirring at room temperature, 6 hours), after dissolving, insert mould and dry 72 hours to become diaphragm with 60 ℃.The film sample that is diameter 1cm by membrane cutting carries out activity of matrix metalloproteinase-9 test in 24 hours, and to be cross-linked PVA thin film (cPVA) as matched group.The results are shown in table 8 and Fig. 7.
Table 8, polyvinyl alcohol graft copolymerized histidine derivative thin film inhibition effect to Matrix Metalloproteinase-9
-: not containing histidine
Because film size is fixed, and batch difference causes the difference in thickness between PVA-g-BocHis sample Lot1-1 and Lot1-2 batch, therefore PVA-g-BocHis thin film is respectively 21.64mg/ml and 12.4mg/ml according to the histidine of weight and percent grafting known PVA-g-BocHis thin film Lot1-1 and its grafting of Lot1-2 with respect to the concentration of matrix metal proteinase activity analytical solution.From result, Lots1-1 and 1-2 thin film have respectively 29.26% and 44.97% maximum inhibition to Matrix Metalloproteinase-9.The not active inhibition of tool of crosslinked PVA thin film (cPVA) in comparison.
F. the thin film of the poly ethylene vinyl alcohol grafting histidine derivative " EVOH-g-BocHis " of the Lot3 of embodiment 2 and Lot4 suppresses measures of effectiveness to activity of matrix metalloproteinase-9
Poly ethylene vinyl alcohol grafting histidine derivative " EVOH-g-BocHis " powder that Lot3 and Lot4 obtained of embodiment 2 is added in DMAC, and dissolve (500rpm in stirring at room temperature, 6 hours), after dissolving, insert mould and dry 72 hours to become diaphragm with 60 ℃.The film sample that is diameter 1cm by membrane cutting carries out activity of matrix metalloproteinase-9 test in 24 hours, and take EVOH thin film as matched group.The results are shown in table 9 and Fig. 8.
Table 9, poly ethylene vinyl alcohol grafting histidine derivative thin film inhibition effect to Matrix Metalloproteinase-9
-not containing histidine
Because film size is fixed but difference in thickness between sample Lot1-1 and Lot1-2 batch, be therefore respectively 17.7mg/ml and 24.03mg/ml according to the histidine of weight and percent grafting known EVOH-g-BocHis thin film Lot3 and its grafting of Lot4 with respect to the concentration of matrix metal proteinase activity analytical solution.From result, the activity of Lots3 and 4 thin film suppresses usefulness has respectively 43.68% and 38.25% maximum inhibition Lots3 and 4 thin film Matrix Metalloproteinase-9 to be had respectively to 43.68% and 38.25% maximum inhibition because its histidine weight percent rises.The not active inhibition of tool of EVOH thin film in comparison.
G. the thin film of the hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis " of the Lot5 of embodiment 3 suppresses measures of effectiveness to activity of matrix metalloproteinase-9
Poly-hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis " powder dissolution that Lot5 obtained of embodiment 3 is inserted to mould after DMAC and dry 72 hours to become diaphragm with 60 ℃.The film sample that is diameter 1cm by membrane cutting carries out activity of matrix metalloproteinase-9 test in 3 hours, and take HPMC thin film as matched group.The results are shown in table 10 and Fig. 9.
Table 10, hydroxypropyl emthylcellulose grafting histidine derivative thin film inhibition effect to Matrix Metalloproteinase-9
-: not containing histidine
Be 2.4mg/ml according to the histidine of weight and its grafting of the known HPMC-g-BocHis Lot5 of percent grafting thin film with respect to the concentration of matrix metal proteinase activity analytical solution.From result, Lot5 thin film has 33.2% maximum inhibition to Matrix Metalloproteinase-9.The not active inhibition of tool of HPMC thin film in comparison.
H. the thin film of the hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis " of the Lot6 of embodiment 3 suppresses measures of effectiveness to activity of matrix metalloproteinase-9
Poly-hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis " powder dissolution that Lot6 obtained of embodiment 3 is inserted to mould after DMAC and dry 72 hours to become diaphragm with 60 ℃.The film sample that is diameter 1cm by membrane cutting carries out the test of 24 hours activity of matrix metalloproteinase-9s, and take HPMC (cHPMC) thin film that is cross-linked as matched group.The results are shown in table 11 and Figure 10.
Table 11, hydroxypropyl emthylcellulose grafting histidine derivative thin film inhibition effect to Matrix Metalloproteinase-9
-: not containing histidine
Be 10.15mg/ml according to the histidine of weight and its grafting of the known HPMC-g-BocHis Lot6 of percent grafting thin film with respect to the concentration of matrix metal proteinase activity analytical solution.From result, Lot6 thin film has 42.41% maximum inhibition to Matrix Metalloproteinase-9, in comparison the not active inhibition of tool of cHPMC thin film.
I. the thin film of the hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis " of the Lot6 of embodiment 3 and Lot7 suppresses measures of effectiveness to activity of matrix metalloproteinase-9
Hydroxypropyl emthylcellulose grafting histidine derivative " HPMC-g-BocHis " powder that Lot6 and Lot7 obtained of embodiment 3 is added in DMAC, and dissolve (500rpm in stirring at room temperature, 6 hours), after dissolving, insert mould and dry 72 hours to become diaphragm with 60 ℃.The film sample that is diameter 1cm by membrane cutting carries out the test of 2 hours activity of matrix metalloproteinase-9s, and take HPMC (cHPMC) thin film that is cross-linked as matched group.The results are shown in table 12 and Figure 11.
Table 12, hydroxypropyl emthylcellulose grafting histidine derivative thin film inhibition effect to Matrix Metalloproteinase-9
-: not containing histidine
Because film size is fixed but difference in thickness between Lot6 and Lot7 batch, be therefore respectively 5.52mg/ml and 8.71mg/ml according to the histidine of weight and percent grafting known HPMC-g-BocHis thin film Lot6 and its grafting of Lot7 with respect to the concentration of matrix metal proteinase activity analytical solution.From result, Lots6 and 7 thin film on Matrix Metalloproteinase-9 because being subject to the maximum inhibition that has respectively 37.26% and 36.37% that affects of its hydrophilic nmature change.The not active inhibition of tool of cHPMC thin film in comparison.
Long-acting inhibition measures of effectiveness experiment
Laboratory sample preparation
A. poly ethylene vinyl alcohol grafting histidine derivative film sample preparation (EVOH-g-BocHis):
The poly ethylene vinyl alcohol grafting histidine derivative powder of Lot3 and Lot4 is added in DMAC, and dissolve in stirring at room temperature, after dissolving, insert mould and dry 72 hours to become diaphragm with 60 ℃.
B. impregnation film sample preparation (applying the EVOH thin film (BocHiscoated EVOH Film, EVOH-c-Bochis) of Boc histidine):
Get appropriate Boc histidine concussion and be dissolved in the common solution (co-solvent) of 10ml (DMAc/MeOH5:95) so that its dissolving.After poly ethylene vinyl alcohol thin film being immersed after dissolving completes to this Boc histidine (Boc-Histidine) solution, take out, afterwards thin film is positioned in 60 ℃ of baking ovens to 24 hours, completes the EVOH thin film that applies Boc histidine after removing the solvent in solution.EVOH thin film coated Boc histidine content is take nuclear magnetic resonance spectrometer and determination of elemental analysis as approximately 9.18%.
Experimental technique and result
A. the long-acting inhibition measures of effectiveness experiment of poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot3) to Matrix Metalloproteinase-9
Poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot3) is positioned in PBS buffer solution in 37 ℃ and is shaken with 150rpm, and the fresh PBS buffer solution of displacement in every 2 hours is with simulated body fluid physiology situation.Activity of matrix metalloproteinase-9 test is carried out in sampling in every 4,8 and 24 hours.With poly ethylene vinyl alcohol thin film as matched group.Result is if table 13 is with as shown in Figure 12.
The result of table 13, the long-acting inhibition measures of effectiveness of poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot3) to Matrix Metalloproteinase-9
From table 13 and Figure 12, poly ethylene vinyl alcohol grafting histidine derivative film sample is all effectively maintained at 20.39% to 27.84% to the inhibition of Matrix Metalloproteinase-9.
B. only through the base material (EVOH-c-BocHis) of histidine impregnation processing and the long-acting inhibition measures of effectiveness of poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot4)
Respectively will be through the base material of histidine impregnation processing (EVOH-c-BocHis) and poly ethylene vinyl alcohol grafting histidine derivative film sample (EVOH-g-His, Lot4) sample is positioned in PBS buffer solution in 37 ℃ and shakes with 150rpm, and the fresh PBS buffer solution of displacement in every 2 hours is with simulated body fluid physiology situation.In initial and the 24th hour respectively sampling carry out activity of matrix metalloproteinase-9 test.Result is if table 14 is with as shown in Figure 13.
Table 14, through the result of the base material (EVOH-c-BocHis) of histidine impregnation processing and the long-acting inhibition measures of effectiveness of poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot4)
Result shows poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot4), not only Matrix Metalloproteinase-9 is had to inhibition, more can long-actingly maintain this inhibit feature.Otherwise coating histidine derivative solution weight percentage rate reaches 9.18% EVOH-c-BocHis, though Matrix Metalloproteinase-9 is had to good inhibition usefulness when initial, after 24 hours, be close to forfeiture inhibit feature.
Embodiment 8
Diabetic mice wound fluid matrix metalloproteinase is active to be detected
Laboratory sample preparation
A. poly ethylene vinyl alcohol grafting histidine derivative film sample (EVOH-g-BocHis) preparation:
Poly ethylene vinyl alcohol grafting histidine derivative (EVOH-g-BocHis) powder of embodiment 2 is added in DMAC with the ratio of solid composition 15%, and dissolve in stirring at room temperature, after dissolving, insert mould and dry 72 hours to become diaphragm with 60 ℃.
B. poly-hydroxypropyl emthylcellulose grafting histidine derivative film sample preparation (HPMC-g-BocHis):
Poly-hydroxypropyl emthylcellulose grafting histidine derivative (HPMC-g-BocHis) powder that embodiment 3 is obtained is dissolved in and inserts mould after DMAC and dry 72 hours to become diaphragm with 60 ℃ with solid composition 15% ratio.
C. diabetic mice; Inject continuously rat (strain: Sprague-Dawley (SD)) 4 weeks with streptozocin (streptozotocin, STZ), make to produce the zootype of similar Second-Type diabetes.
Experimental technique and result
A. will be numbered respectively six diabetes rats behinds of 1 to 6, output the wound that 5cm X6cm is large.Numbering 1 is that EVOH processed group, numbering 3 are poly ethylene vinyl alcohol grafting histidine derivative thin film (EVOH-g-BocHis) processed group with the rat of numbering 4 with the mice of numbering 2, and numbering 5 is poly-hydroxypropyl emthylcellulose grafting histidine derivative thin film (HPMC-g-BocHis) processed group with the rat of numbering 6.
B. by sample thin film mulching in wound surface, then on thin film, add the dressing of last layer waterproof and breathable, and with sutures, dressing be fixed on to wound surrounding.Operation latter the 1st day and the 3rd day, extracts respectively wound fluid, carries out the active detection of wound fluid matrix metalloproteinase.
C. matrix metal proteinase activity analysis: wound fluid is to analyze buffer solution (50mM Tris, 10mM CaCl
2, 150mM NaCl, 0.05%Brij-35 (w/v), pH7.5) and dilute 50 times.After getting dilution, wound fluid adds equal-volume Matrix Metalloproteinase-9 substrate (final concentration 10uM) to react 0.5-1 hour in 37 ℃ of incubators, measures fluorescence value of reading (Ex/Em=320/405nm) in high sensitivity fluor tester (Flexstation3).
Table 15, the active assessment result of grafting histidine derivative film sample to zoopery diabetic mice wound fluid matrix metalloproteinase-9
From table 15 and Figure 14, after operation the 3rd day, grafting histidine derivative film dressing (poly ethylene vinyl alcohol grafting histidine derivative thin film (EVOH-g-BocHis) and poly-hydroxypropyl emthylcellulose grafting histidine derivative thin film (HPMC-g-BocHis)), its wound fluid matrix metalloproteinase activity reduces during obviously compared with the 1st day, wherein again to gather hydroxypropyl emthylcellulose grafting histidine derivative material result as good.
Although the present invention discloses as above with preferred embodiment; so it is not in order to limit the present invention; anyly have the knack of this skill person; without departing from the spirit and scope of the invention; when doing a little change and retouching, therefore the present invention's protection domain when depending on after the attached claim person of defining be as the criterion.
Claims (27)
1. a polymeric composition, comprising:
There is the macromolecule of hydroxyl; And
The derivatives graft of histidine or histidine has on the macromolecule of hydroxyl in this.
2. polymeric composition as claimed in claim 1, and the derivant of this histidine or this histidine is about 0.1 ~ 99wt%.
3. polymeric composition as claimed in claim 1, wherein this macromolecule with hydroxyl comprises synthetic macromolecule or natural polymer.
4. polymeric composition as claimed in claim 3, the macromolecule that wherein this synthetic macromolecule or this natural polymer comprise linear polymeric or have side chain.
5. polymeric composition as claimed in claim 3, wherein this synthetic macromolecule is linear synthetic macromolecule.
6. polymeric composition as claimed in claim 5, wherein the synthetic macromolecule of this linearity comprises polyolefin-based glycol (polyalkylene glycol), polyvinyl alcohol (polyvinylalcohol, PVA), polyvinyl acetate (polyvinyl acetate, PVAc), vinyl alcohol-vinyl acetate copolymerized compound (poly (vinyl alcohol-co-vinyl acetate)), ethylene-vinyl alcohol copolymer (poly (ethylene vinyl-co-alcohol, EVOH)) or its combination.
7. polymeric composition as claimed in claim 3, wherein this natural polymer comprises polysaccharide polymer.
8. polymeric composition as claimed in claim 7, wherein this polysaccharide polymer comprises hyaluronic acid (hyaluronic acid), starch (starch), cellulose (cellulose), methylcellulose (methylcellulose), hydroxypropyl cellulose (hydroxypropyl cellulose), hydroxypropyl emthylcellulose (hydroxypropyl methylcellulose), oxidized cellulose (oxidized cellulose), glucosan (dextran), scleroglucan (scleroglucan), chitin (chitin), spherical chitosan (chitosan), card Derain glue (crudlan), Algin (alginate), carrageenin (carrageenan), pectin (pectin), Radix Acaciae senegalis (gum Arabic), close magnificent locust beam gum (guar gum), tie blue glue (gellan), Pu Lulan (pullulan), chrondroitin (chondroitin sulfate), heparin (heparin) or keratin sulfate (keratin sulfate).
9. polymeric composition as claimed in claim 1, wherein the derivant of this histidine is N
α-protection group threonine derivative.
10. polymeric composition as claimed in claim 9, wherein this N
α-protection group threonine derivative comprises N
α-Boc-histidine (N
α-Boc-histidine), N
α-Cbz-histidine (N
α-Cbz-histidine), N
α-Fmoc-histidine (N
α-Fmoc-histidine) or N
α-Ac-histidine (N
α-Ac-histidine).
11. polymeric compositions as claimed in claim 1, wherein the derivant of this histidine or this histidine is directly to graft on this macromolecule with hydroxyl, or grafts on this macromolecule with hydroxyl by connecting agent.
12. polymeric compositions as claimed in claim 11, wherein the derivant of this histidine or this histidine is directly to graft on this macromolecule with hydroxyl.
13. polymeric compositions as claimed in claim 12, wherein the derivant of this histidine or this histidine is directly to graft on this macromolecule with hydroxyl with chemical covalency bond.
14. polymeric compositions as claimed in claim 13, wherein this chemistry covalency bond comprises ester bond or amido Ethyl formate.
15. polymeric compositions as claimed in claim 12, wherein this macromolecule with hydroxyl is polyvinyl alcohol, ethylene-vinyl alcohol copolymer, hyaluronic acid, cellulose or hydroxypropyl emthylcellulose, and the derivant N of this histidine
α-Boc-histidine.
16. polymeric compositions as claimed in claim 11, wherein the derivant of this histidine or this histidine be by this even agent graft on this macromolecule with hydroxyl.
17. polymeric compositions as claimed in claim 16, wherein this even agent comprise polyethylene glycol class or alkanes carbochain.
18. polymeric compositions as claimed in claim 1, wherein this polymeric composition is distributed in base material with promiscuous mode or the surface of medical device and/or inner.
19. polymeric compositions as claimed in claim 1, wherein this polymeric composition forms solution.
20. polymeric compositions as claimed in claim 19, wherein this solution is machined directly to bulk.
21. polymeric compositions as claimed in claim 19, wherein this solution be used to process base material or medical device with physical absorption in the surface of this base material or medical device.
22. polymeric compositions as claimed in claim 21, wherein the material of this base material is polysaccharide, polyurethanes, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polypropylene type or above-mentioned combination.
23. polymeric compositions as claimed in claim 21, wherein this medical device comprises wound dressing, tissue substituent, tissue engineering bracket, blood contact device or conduit.
24. 1 kinds of macromolecular materials, comprising:
Polymeric composition, it comprises:
There is the macromolecule of hydroxyl; And
The derivatives graft of histidine or histidine has on the macromolecule of hydroxyl in this.
25. macromolecular materials as claimed in claim 24, more comprise base material, wherein this polymeric composition and this base material mixes or this polymeric composition physical absorption in the surface of this base material or interior to form medical device.
26. macromolecular materials as claimed in claim 25, wherein the material of this base material comprises polysaccharide, polyurethanes, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polypropylene type or above-mentioned combination.
27. macromolecular materials as claimed in claim 25, wherein this medical device comprises wound dressing, tissue substituent, tissue engineering bracket, blood contact device or conduit.
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