CN104877087A - Temperature-sensitive hydrogel having bioactivity and preparation method of temperature-sensitive hydrogel - Google Patents
Temperature-sensitive hydrogel having bioactivity and preparation method of temperature-sensitive hydrogel Download PDFInfo
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Abstract
The invention relates to a temperature-sensitive hydrogel having bioactivity and a preparation method of the temperature-sensitive hydrogel. The preparation method comprises the following steps: 1) preparing HO-PEG-COOH; 2) preparing Ac-PEG-COOH; 3) preparing Ac-PEG-Ac; 4) preparing Ac-PEG-g-IKVAV; 5) preparing a PNIPAM-b-PEG-g-IKVAV precursor; and 6) preparing the temperature-sensitive hydrogel having the bioactivity, namely dissolving the PNIPAM-b-PEG-g-IKVAV precursor into DMF, and then adding PNIPAM, a micromolecular cross-linking agent, Ac-PEG-Ac and AIBN, sealing and vacuumizing and then reacting at 70 DEG C for 12 hours. The preparation method is simple in process; the obtained hydrogel is quick in response to temperature change response to temperature change, has bioactivity and is capable of promoting the adhesion and proliferation of nerve cells; as a result, a support materials is provided for central nervous restoration.
Description
Technical field
The present invention relates to one and there is bioactive temperature-sensitive hydrogel and preparation method thereof.
Background technology
For a long time, still undesirable to the reparation of peripheral nerve injury clinically, to thick, long section neurologic defect and multiple nerve injury at one's wit's end especially.People are exploring and are finding the bridge material that effectively can replace autotransplantation nerve always, along with the development of organizational engineering and neuroscience, application organizational engineering principle prepares neural graft's thing, autologous nerve bridge joint long segment injured nerve is replaced to obtain good therapeutic effect with it, therefore neural tissue engineering graft receives increasing concern, is expected to utilize organizational engineering to solve a difficult problem for nervous tissue reparation.In recent years, people recognize that body material occupies critical role in organizational project gradually, along with going deep into of studying material and organism interaction mechanism, require that body material has biological activity, the favourable reaction of host can be induced, such as can the regeneration etc. of inducing host tissue.
Hydrogel be a kind of can swelling in water while material internal retain large quantity of moisture and don't the macromolecular material that can be dissolved in water, general in electric neutrality or ionic, it forms multicomponent system by the three-dimensional net structure be cross-linked and medium, its mechanical property is similar to soft tissue, as a kind of soft material, without fixed geometry, interior three-dimensional vesicular structure, thus can not cause the strong immunological rejection of body and reduce the disadvantageous effect of immune factor and immunocyte.Hydrogel is used to have the following advantages as neural tissue engineering timbering material tool: (1) hydrogel inside, containing a large amount of water, contributes to gel inside and carries out effective substance exchange with outside atmosphere, maintain the balance of tissue microenvironment; (2) vesicular structure is conducive to cell adhesion and cell and grows into internal stent; (3) can be modified by the extracellular matrix of short cell adhesion polypeptide and promoting growth of cell, can be used as the carrier of bioactive molecules, and then promote cell adhesion and tissue growth; (4) biocompatibility is good, and tissue irritation is lower; (5) cell migration and axon growth can effectively be promoted; (6) generally have biological degradability, after can avoiding tissue regeneration, second operation takes out; (7) can gelatinizing-in-situ or the cavity by injection fillers arbitrary shape.
But the disadvantage of synthetic macromolecule hydrogel lacks biological activity exactly at present, be unfavorable for neurocyte selective adsorption and activate some specific genes, therefore synthesis macromolecule hydrogel is needed to carry out biological activity modification, based on the Bionic Design of neurocyte extracellular matrix materials, utilize the polycomponent compounding technology of material, some had the surface that bioactive molecule is incorporated into synthesis macromolecule hydrogel, to changing synthesis macromolecule hydrogel to the selective adsorption of neurocyte and short neural axon growth.
Summary of the invention
Technical problem to be solved by this invention is for above shortcomings in prior art, one is provided to have bioactive temperature-sensitive hydrogel and preparation method thereof, the PNIPAM-b-(PEG-g-IKVAV) of chain transfer activity group is connected to as presoma using end, using Ac-PEG-Ac as macromolecules cross-linking agent, using BISAM as small molecules linking agent, prepare one by the radical polymerization of initiator initiating activity and have bioactive temperature-sensitive hydrogel, this hydrogel can be used as the hydrogel scaffold material promoting neural cell adhesion and propagation.
For solving the problems of the technologies described above, technical scheme provided by the invention is:
There is provided one to have bioactive temperature-sensitive hydrogel, it is prepared by following methods:
1) prepare HO-PEG-COOH: be dissolved in tetrahydrofuran (THF) by polyoxyethylene glycol (PEG), obtain the polyglycol solution that concentration is 0.01 ~ 0.07g/mL, in polyglycol solution, add CaH
2, add ethyl bromoacetate after stirring under room temperature, wherein polyoxyethylene glycol, CaH
2be 1:0.85:1.7 with ethyl bromoacetate mol ratio, filter after abundant stirring, normal hexane is added in filtrate, filter out gained throw out, by water-soluble after throw out vacuum-drying, obtain the aqueous solution that concentration is 0.2 ~ 0.6g/mL, the NaOH aqueous solution is added in the described aqueous solution, polyoxyethylene glycol and NaOH mol ratio is made to be 1:1.7, hydrochloric acid soln adjust ph to 12.5 is used after abundant stirring, add methylene dichloride and carry out initial extraction, pH value is also adjusted to 3 by water intaking phase, in aqueous phase, add methylene dichloride again carry out reextraction, get organic phase and add normal hexane, separation obtains HO-PEG-COOH,
2) Ac-PEG-COOH is prepared: by step 1) gained HO-PEG-COOH is dissolved in tetrahydrofuran (THF) and obtains the HO-PEG-COOH solution that concentration is 0.01 ~ 0.1g/mL, and add acrylate chloride and triethylamine, HO-PEG-COOH and acrylate chloride, triethylamine mol ratio is made to be 1:2.3:2.5, room temperature reaction filtered after 3 ~ 6 hours, in gained filtrate, add normal hexane, throw out separation, drying obtain Ac-PEG-COOH;
3) Ac-PEG-Ac is prepared: be dissolved in by polyoxyethylene glycol in tetrahydrofuran (THF), obtain the polyglycol solution that concentration is 0.01 ~ 0.07g/mL, acrylate chloride and triethylamine is added in polyglycol solution, make polyoxyethylene glycol and acrylate chloride, the mol ratio of triethylamine is 1:3:3.5, room temperature reaction filtered after 1 ~ 4 hour, in gained filtrate, add normal hexane, throw out separation, drying obtain Ac-PEG-Ac;
4) Ac-PEG-g-IKVAV is prepared: by step 2) Ac-PEG-COOH for preparing is dissolved in tetrahydrofuran (THF), add dicyclohexylcarbodiimide (DCC) and N-hydroxy-succinamide (NHS), make Ac-PEG-COOH and dicyclohexylcarbodiimide, N-hydroxy-succinamide mol ratio is 1:2.5:2.5, activate and add IKVAV polypeptide and N after 0.5 ~ 2 hour, N-diisopropylethylamine (DIPEA), wherein Ac-PEG-COOH and IKVAV polypeptide, N, the mol ratio of N-diisopropylethylamine is 1:1.5:1.5, normal hexane is added after reacting 2 ~ 6h under room temperature, throw out is separated, drying obtains Ac-PEG-g-IKVAV,
5) PNIPAM-b-PEG-g-IKVAV presoma is prepared: take NIPA as reaction monomers, 4-cyanopentanoic acid dithiobenzoic acid ester is RAFT agent, Diisopropyl azodicarboxylate (AIBN) is initiator, 1, 4-dioxane is solvent, each component molar ratio is: NIPA: 4-cyanopentanoic acid dithiobenzoic acid ester: Diisopropyl azodicarboxylate=100 ~ 40:1:0.01 ~ 0.03, vacuum-pumping density isolates PNIPAM (NIPA) with ether sedimentation after being honored as a queen and reacting 5 ~ 8h in 60 ~ 80 DEG C, PNIPAM is dissolved in tetrahydrofuran (THF) and obtains the aqueous solution that concentration is 0.1 ~ 0.6g/mL, add step 4 again) gained Ac-PEG-g-IKVAV and Diisopropyl azodicarboxylate, wherein PNIPAM and Ac-PEG-g-IKVAV mol ratio is 1:1, PNIPAM and Diisopropyl azodicarboxylate mol ratio are 9.5 ~ 23:1, in 60 ~ 80 DEG C of reaction 6 ~ 12h after sealing vacuumizes, normal hexane is added after reaction terminates, throw out is separated, drying obtains PNIPAM-b-PEG-g-IKVAV presoma,
6) preparation has bioactive temperature-sensitive hydrogel: by step 5) gained PNIPAM-b-PEG-g-IKVAV presoma is dissolved in DMF (dimethyl formamide), add step 5 again) gained PNIPAM, small molecules linking agent, step 3) gained Ac-PEG-Ac and AIBN, each component molar ratio is: PNIPAM-b-PEG-g-IKVAV presoma: PNIPAM: small molecules linking agent: Ac-PEG-Ac:AIBN=1:280 ~ 700:3000 ~ 5000:100 ~ 300:200 ~ 500, vacuum-pumping density is honored as a queen in 60 ~ 80 DEG C of reaction 6 ~ 24h, obtain that there is bioactive temperature-sensitive hydrogel after gained gel washed with de-ionized water.
By such scheme, step 1) described molecular weight polyethylene glycol is 2000; Step 3) described molecular weight polyethylene glycol is 4000.
By such scheme, step 1) described vacuum-drying condition is vacuum-drying 12 ~ 48 hours under room temperature condition.
Preferably, step 4) described IKVAV polypeptide is that the biochemical (Shanghai) Co., Ltd. of gill produces, product type is No:P110124-WY061697.
By such scheme, step 6) described small molecules linking agent is one in N,N methylene bis acrylamide (BISAM), Vinylstyrene, Ethylene glycol dimethacrylate.
Preparation method's step that the present invention has bioactive temperature-sensitive hydrogel is as follows:
1) prepare HO-PEG-COOH: be dissolved in by polyoxyethylene glycol in tetrahydrofuran (THF), obtain the polyglycol solution that concentration is 0.01 ~ 0.07g/mL, in polyglycol solution, add CaH
2, add ethyl bromoacetate after stirring under room temperature, wherein polyoxyethylene glycol, CaH
2be 1:0.85:1.7 with ethyl bromoacetate mol ratio, filter after abundant stirring, normal hexane is added in filtrate, filter out gained throw out, by water-soluble after throw out vacuum-drying, obtain the aqueous solution that concentration is 0.2 ~ 0.6g/mL, the NaOH aqueous solution is added in the described aqueous solution, polyoxyethylene glycol and NaOH mol ratio is made to be 1:1.7, hydrochloric acid soln adjust ph to 12.5 is used after abundant stirring, add methylene dichloride and carry out initial extraction, pH value is also adjusted to 3 by water intaking phase, in aqueous phase, add methylene dichloride again carry out reextraction, get organic phase and add normal hexane, separation obtains HO-PEG-COOH,
2) Ac-PEG-COOH is prepared: by step 1) gained HO-PEG-COOH is dissolved in tetrahydrofuran (THF) and obtains the HO-PEG-COOH solution that concentration is 0.01 ~ 0.1g/mL, and add acrylate chloride and triethylamine, HO-PEG-COOH and acrylate chloride, triethylamine mol ratio is made to be 1:2.3:2.5, room temperature reaction filtered after 3 ~ 6 hours, in gained filtrate, add normal hexane, throw out separation, drying obtain Ac-PEG-COOH;
3) Ac-PEG-Ac is prepared: be dissolved in by polyoxyethylene glycol in tetrahydrofuran (THF), obtain the polyglycol solution that concentration is 0.01 ~ 0.07g/mL, acrylate chloride and triethylamine is added in polyglycol solution, make polyoxyethylene glycol and acrylate chloride, the mol ratio of triethylamine is 1:3:3.5, room temperature reaction filtered after 1 ~ 4 hour, in gained filtrate, add normal hexane, throw out separation, drying obtain Ac-PEG-Ac;
4) Ac-PEG-g-IKVAV is prepared: by step 2) Ac-PEG-COOH for preparing is dissolved in tetrahydrofuran (THF), add dicyclohexylcarbodiimide and N-hydroxy-succinamide, make Ac-PEG-COOH and dicyclohexylcarbodiimide, N-hydroxy-succinamide mol ratio is 1:2.5:2.5, activate and add IKVAV polypeptide and N after 0.5 ~ 2 hour, N-diisopropylethylamine, wherein Ac-PEG-COOH and IKVAV polypeptide, N, the mol ratio of N-diisopropylethylamine is 1:1.5:1.5, normal hexane is added after reacting 2 ~ 6h under room temperature, throw out is separated, drying obtains Ac-PEG-g-IKVAV,
5) PNIPAM-b-PEG-g-IKVAV presoma is prepared: take NIPA as reaction monomers, 4-cyanopentanoic acid dithiobenzoic acid ester is RAFT agent, Diisopropyl azodicarboxylate is initiator, 1, 4-dioxane is solvent, each component molar ratio is: NIPA: 4-cyanopentanoic acid dithiobenzoic acid ester: Diisopropyl azodicarboxylate=100 ~ 40:1:0.01 ~ 0.03, vacuum-pumping density isolates PNIPAM with ether sedimentation after being honored as a queen and reacting 5 ~ 8h in 60 ~ 80 DEG C, PNIPAM is dissolved in tetrahydrofuran (THF) and obtains the aqueous solution that concentration is 0.1 ~ 0.6g/mL, add step 4 again) gained Ac-PEG-g-IKVAV and Diisopropyl azodicarboxylate, wherein PNIPAM and Ac-PEG-g-IKVAV mol ratio is 1:1, PNIPAM and Diisopropyl azodicarboxylate mol ratio are 9.5 ~ 23:1, in 60 ~ 80 DEG C of reaction 6 ~ 12h after sealing vacuumizes, normal hexane is added after reaction terminates, throw out is separated, drying obtains PNIPAM-b-PEG-g-IKVAV presoma,
6) preparation has bioactive temperature-sensitive hydrogel: by step 5) gained PNIPAM-b-PEG-g-IKVAV presoma is dissolved in DMF, add step 5 again) gained PNIPAM, small molecules linking agent, step 3) gained Ac-PEG-Ac and AIBN, each component molar ratio is: PNIPAM-b-PEG-g-IKVAV presoma: PNIPAM: small molecules linking agent: Ac-PEG-Ac:AIBN=1:280 ~ 700:3000 ~ 5000:100 ~ 300:200 ~ 500, vacuum-pumping density is honored as a queen in 60 ~ 80 DEG C of reaction 6 ~ 24h, obtain that there is bioactive temperature-sensitive hydrogel after gained gel washed with de-ionized water.
By such scheme, step 1) described molecular weight polyethylene glycol is 2000; Step 3) described molecular weight polyethylene glycol is 4000.
By such scheme, step 4) described IKVAV polypeptide is that the biochemical (Shanghai) Co., Ltd. of gill produces, product type is No:P110124-WY061697.
By such scheme, step 6) described small molecules linking agent is one in N,N methylene bis acrylamide, Vinylstyrene, Ethylene glycol dimethacrylate.
The present invention also comprises and above-mentionedly has the application of bioactive temperature-sensitive hydrogel as neural tissue engineering timbering material.
NIPA PNIPAM is a kind of typical temperature-sensitive macromolecular intelligent gel rubber material, the research of people to it is long-standing, because molecular chain being connected with hydrophilic amide group (-CONH-) and hydrophobic sec.-propyl [-CH (CH simultaneously
3)
2], PNIPAM demonstrate vary with temperature and dissolve (precipitation), distinct temperature susceptibility that swelling (contraction) changes, PNIPAM also has that no cytotoxicity, biocompatibility are good, polymkeric substance is easy to the good characteristics such as modification, makes it be used widely in organizational project.PNIPAM inwardly grows as neural tissue engineering timbering material energy sustenticular cell, and form the cell paste that polymkeric substance holds, utilize the temperature dependent properties of material, do not need enzymic digestion can obtain complete cellular layer, overcome the problem of organizational project by Biodegradable scaffold restriction.The transformation temperature of PNIPAM is near the physiological temp of people and a little more than envrionment temperature, and being made into injection aquagel can the gelation in position of appendix cell, reduces the wound of operation.In addition, it controlled and stably can discharge each proteinoid and somatomedin, and this is conducive to promoting tissue growth and vasculogenesis in Various Tissues engineering.PEG (polyoxyethylene glycol) is as a kind of amphipathic nature polyalcohol, both water-soluble, is dissolved in again most organic solvent, and its good biocompatibility, there is the features such as nontoxic, immunogenicity is low, excrete by kidney, can not accumulate in vivo.Be with a wide range of applications at biomedicine field.IKVAV polypeptide is the pentapeptide sequence on ln chain, can be combined with neurocyte and promote nerve growth.
Beneficial effect of the present invention is: 1, the present invention is using NIPAAm (NIPA) as principal monomer and CH
2=CHCO-PEG-IKVAV (Ac-PEG-g-IKVAV) realizes RAFT polymerization, and passes through CH
2=CHCO-PEG-OCCH=CH
2(Ac-PEG-Ac) be cross-linked to form and have bioactive temperature-sensitive hydrogel, preparation technology is simple; 2, to have bioactive temperature-sensitive hydrogel security high for gained of the present invention, cell-free immunoreactive, quick response can be made to the change of temperature, this hydrogel not only overcomes the shortcoming of natural polymer hydrogel mechanical property deficiency, still there is biological activity simultaneously, neural cell adhesion and propagation can be promoted, for nervus centralis reparation provides a kind of timbering material, also can add the biomimetic scaffolds that substratum is cultivated as neural tissue cell as required.
Embodiment
For making those skilled in the art understand technical scheme of the present invention better, below in conjunction with embodiment, the present invention is described in further detail.
In embodiment, IKVAV polypeptide used is that the biochemical (Shanghai) Co., Ltd. of gill produces, and product type is No:P110124-WY061697.
Embodiment 1
Have a preparation method for bioactive temperature-sensitive hydrogel, step is as follows:
1) HO-PEG-COOH is prepared: be dissolved in the tetrahydrofuran (THF) of 50L drying by 500gPEG (Mn=2000), add 8.9025gCaH
2, stirred at ambient temperature 1 hour, then add 47.3mL ethyl bromoacetate, stirred at ambient temperature 2 hours, filters, adds normal hexane and be settled out PEG mixture in filtrate, filter out gained throw out, by throw out vacuum-drying 12 hours at ambient temperature, obtain PEG mixture.PEG mixture is mixed with the 0.2g/mL aqueous solution, add 1mol/L NaOH aqueous solution 425mL, stir after 2 hours, with the hydrochloric acid soln of 1mol/L, system pH value is adjusted to 12.5, add methylene dichloride and carry out initial extraction, water intaking phase, pH value is adjusted to 3 by the HCl solution dripping 1mol/L, again add methylene dichloride and carry out reextraction, get organic phase, add normal hexane, filter, obtain HO-PEG-COOH;
2) Ac-PEG-COOH is prepared: get 50g step 1) gained HO-PEG-COOH is dissolved in the tetrahydrofuran (THF) of 5L drying, add 4.54mL acrylate chloride and 8.47mL triethylamine, stirring at room temperature 3 hours, filter, normal hexane is added in filtrate, filter to obtain throw out, vacuum-drying obtains Ac-PEG-COOH;
3) Ac-PEG-Ac is prepared: take 100gPEG (Mn=4000) and be dissolved in the tetrahydrofuran (THF) of 10L drying, add 6.09mL acrylate chloride and 12.20mL triethylamine, stirred at ambient temperature reacts 1 hour, filter, normal hexane is added in filtrate, filter, collecting precipitation, vacuum-drying obtains Ac-PEG-Ac (Mn=4108);
4) Ac-PEG-g-IKVAV is prepared: get 1g step 2) gained Ac-PEG-COOH (Mn=2112) is dissolved in 20mL tetrahydrofuran (THF), add 0.2448g DCC (dicyclohexylcarbodiimide) and 0.1362gNHS, activate and add 0.3755gIKVAV polypeptide and 0.0918g DIPEA after 0.5 hour, 2h is reacted under room temperature, add normal hexane, filter, collecting precipitation, vacuum-drying obtains Ac-PEG-g-IKVAV (Mn=2622.75);
5) PNIPAM-b-PEG-g-IKVAV presoma is prepared: take N-isopropylacrylamide 20g, RAFT agent (4-cyanopentanoic acid dithiobenzoic acid ester) 0.4807g, Diisopropyl azodicarboxylate 0.0029g, add solvent 1, 4-dioxane 40mL, airtight vacuumize after in 80 DEG C reaction 5h after go out PNIPAM (Mn=2840) with ether sedimentation, taking 2gPNIPAM is dissolved in 20mL tetrahydrofuran (THF), add 1.8470g step 4) gained Ac-PEG-g-IKVAV, 0.005g AIBN, vacuumize sealing, in 60 DEG C of reaction 12h, add normal hexane, filter to obtain precipitation, vacuum-drying obtains PNIPAM-b-PEG-g-IKVAV presoma (Mn=5462.75),
6) preparation has bioactive temperature-sensitive hydrogel: take 0.0546g step 5) gained PNIPAM-b-PEG-g-IKVAV presoma, 14.2g step 5) gained PNIPAM, 4.63g BISAM, 4.11g step 3) gained Ac-PEG-Ac, 0.33g AIBN, adds 100mL DMF (dimethyl formamide) as solvent, vacuumizes, in 80 DEG C of reaction 6h, after gained gel washed with de-ionized water, obtain that there is bioactive temperature-sensitive hydrogel.
Prepared by the present embodiment have bioactive temperature-sensitive hydrogel can be used as neural tissue engineering timbering material.
Embodiment 2
Have a preparation method for bioactive temperature-sensitive hydrogel, step is as follows:
1) HO-PEG-COOH is prepared: be dissolved in the tetrahydrofuran (THF) of 7L drying by 500gPEG (Mn=2000), add 8.9025gCaH
2, stirred at ambient temperature 1 hour, then add 47.3mL ethyl bromoacetate, stirred at ambient temperature 2 hours, filters, adds normal hexane and be settled out PEG mixture in filtrate, filter out gained throw out, by throw out vacuum-drying 48 hours at ambient temperature, obtain PEG mixture.PEG mixture is mixed with the 0.2g/mL aqueous solution, add 1mol/L NaOH aqueous solution 425mL, stir after 2 hours, with the hydrochloric acid soln of 1mol/L, system pH value is adjusted to 12.5, add methylene dichloride and carry out initial extraction, water intaking phase, drip 1mol/L HCl solution and pH value is adjusted to 3, again add methylene dichloride and carry out reextraction, get organic phase, add normal hexane, filter, obtain HO-PEG-COOH;
2) Ac-PEG-COOH is prepared: get 50g step 1) gained HO-PEG-COOH is dissolved in the tetrahydrofuran (THF) of 0.7L drying, add 4.54mL acrylate chloride and 8.47mL triethylamine, stirring at room temperature 6 hours, filter, normal hexane is added in filtrate, filter to obtain throw out, vacuum-drying obtains Ac-PEG-COOH;
3) Ac-PEG-Ac is prepared: take 100gPEG (Mn=4000) and be dissolved in the tetrahydrofuran (THF) of 1.43L drying, add 6.09mL acrylate chloride and 12.20mL triethylamine, stirred at ambient temperature reacts 4 hours, filter, normal hexane is added in filtrate, filter, collecting precipitation, vacuum-drying obtains Ac-PEG-Ac;
4) Ac-PEG-g-IKVAV is prepared: get 1g step 2) gained Ac-PEG-COOH is dissolved in 20mL tetrahydrofuran (THF), add 0.2448g DCC and 0.1362gNHS, activate and add 0.3755gIKVAV polypeptide and 0.0918g DIPEA after 0.5 hour, 6h is reacted under room temperature, add normal hexane, filter, collecting precipitation, vacuum-drying obtains Ac-PEG-g-IKVAV;
5) PNIPAM-b-PEG-g-IKVAV presoma is prepared: take N-isopropylacrylamide 20g, RAFT agent (4-cyanopentanoic acid dithiobenzoic acid ester) 1.2018g, Diisopropyl azodicarboxylate 0.0087g, add solvent 1, 4-dioxane 70mL, airtightly to vacuumize, PNIPAM (Mn=2840) is gone out with ether sedimentation after reaction 8h, taking 2gPNIPAM is dissolved in 3.5mL tetrahydrofuran (THF), add 1.8470g step 4) gained Ac-PEG-g-IKVAV, 0.008g AIBN, vacuum-pumping density is honored as a queen in 80 DEG C of reaction 6h, add normal hexane, filter to obtain precipitation, vacuum-drying obtains PNIPAM-b-PEG-g-IKVAV presoma (Mn=5462.75),
6) preparation has bioactive temperature-sensitive hydrogel: take 0.0546g step 5) gained PNIPAM-b-PEG-g-IKVAV presoma, 19.88g step 5) gained PNIPAM, 7.71g BISAM, 12.32g step 3) gained Ac-PEG-Ac, 0.82g AIBN, adds 100mL DMF as solvent, vacuumizes, in 60 DEG C of reaction 24h, after gained gel washed with de-ionized water, obtain that there is bioactive temperature-sensitive hydrogel.
Prepared by the present embodiment have bioactive temperature-sensitive hydrogel can be used as neural tissue engineering timbering material.
Embodiment 3
Have a preparation method for bioactive temperature-sensitive hydrogel, step is as follows:
1) HO-PEG-COOH is prepared: be dissolved in the tetrahydrofuran (THF) of 10L drying by 500gPEG (Mn=2000), add 8.9025gCaH
2, stirred at ambient temperature 1 hour, then add 47.3mL ethyl bromoacetate, stirred at ambient temperature 2 hours, filters, adds normal hexane and be settled out PEG mixture in filtrate, filter out gained throw out, by throw out vacuum-drying 48 hours at ambient temperature, obtain PEG mixture.PEG mixture is mixed with the aqueous solution of 0.6g/mL, add 1mol/L NaOH aqueous solution 425mL, stir after 2 hours, with the hydrochloric acid soln of 1mol/L, system pH value is adjusted to 12.5, add methylene dichloride and carry out initial extraction, water intaking phase, drip 1mol/L HCl solution and pH value is adjusted to 3, again add methylene dichloride and carry out reextraction, get organic phase, add normal hexane, filter, obtain HO-PEG-COOH;
2) Ac-PEG-COOH is prepared: get 50g step 1) gained HO-PEG-COOH is dissolved in the tetrahydrofuran (THF) of 0.5L drying, add 4.54mL acrylate chloride and 8.47mL triethylamine, stirring at room temperature 4 hours, filter, normal hexane is added in filtrate, filter to obtain throw out, vacuum-drying obtains Ac-PEG-COOH;
3) Ac-PEG-Ac is prepared: take 100gPEG (Mn=4000) and be dissolved in the tetrahydrofuran (THF) of 2L drying, add 6.09mL acrylate chloride and 12.20mL triethylamine, stirred at ambient temperature reacts 2 hours, filter, normal hexane is added in filtrate, filter, collecting precipitation, vacuum-drying obtains Ac-PEG-Ac;
4) Ac-PEG-g-IKVAV is prepared: get 1g step 2) gained Ac-PEG-COOH is dissolved in 20mL tetrahydrofuran (THF), add 0.2448g DCC and 0.1362gNHS, activate and add 0.3755gIKVAV polypeptide and 0.0918g DIPEA after 1 hour, 2h is reacted under room temperature, add normal hexane, filter, collecting precipitation, vacuum-drying obtains Ac-PEG-g-IKVAV (Mn=2622.75);
5) PNIPAM-b-PEG-g-IKVAV presoma is prepared: take N-isopropylacrylamide 20g, RAFT agent (4-cyanopentanoic acid dithiobenzoic acid ester) 1.2018g, Diisopropyl azodicarboxylate 0.0073g, add solvent 1, 4-dioxane 60mL, airtightly to vacuumize, PNIPAM (Mn=2840) is gone out with ether sedimentation after reaction 8h, taking 2gPNIPAM is dissolved in 4mL tetrahydrofuran (THF), add 1.8470g step 4) gained Ac-PEG-g-IKVAV, 0.005g AIBN, vacuum-pumping density is honored as a queen in 60 DEG C of reaction 8h, add normal hexane, filter to obtain precipitation, vacuum-drying obtains PNIPAM-b-PEG-g-IKVAV presoma (Mn=5462.75),
6) preparation has bioactive temperature-sensitive hydrogel: take 0.0546g step 5) gained PNIPAM-b-PEG-g-IKVAV presoma, 19.72g step 5) gained PNIPAM, 5g BISAM, 5.58g step 3) gained Ac-PEG-Ac, 0.5g AIBN, adds 100mL DMF as solvent, vacuumizes, in 70 DEG C of reaction 12h, after gained gel washed with de-ionized water, obtain that there is bioactive temperature-sensitive hydrogel.
Prepared by the present embodiment have bioactive temperature-sensitive hydrogel can be used as neural tissue engineering timbering material.
Embodiment 4
Have a preparation method for bioactive temperature-sensitive hydrogel, step is as follows:
1) HO-PEG-COOH is prepared: be dissolved in the tetrahydrofuran (THF) of 10L drying by 500gPEG (Mn=2000), add 8.9025gCaH
2, stirred at ambient temperature 1 hour, then add 47.3mL ethyl bromoacetate, stirred at ambient temperature 2 hours, filters, adds normal hexane and be settled out PEG mixture in filtrate, filter out gained throw out, by throw out vacuum-drying 48 hours at ambient temperature, obtain PEG mixture.PEG mixture is mixed with the aqueous solution of 0.6g/mL, add 1mol/L NaOH aqueous solution 425mL, stir after 2 hours, with the hydrochloric acid soln of 1mol/L, system pH value is adjusted to 12.5, add methylene dichloride and carry out initial extraction, water intaking phase, drip 1mol/L HCl solution and pH value is adjusted to 3, again add methylene dichloride and carry out reextraction, get organic phase, add normal hexane, filter, obtain HO-PEG-COOH;
2) Ac-PEG-COOH is prepared: get 50g step 1) gained HO-PEG-COOH is dissolved in the tetrahydrofuran (THF) of 0.5L drying, add 4.54mL acrylate chloride and 8.47mL triethylamine, stirring at room temperature 4 hours, filter, normal hexane is added in filtrate, filter to obtain throw out, vacuum-drying obtains Ac-PEG-COOH;
3) Ac-PEG-Ac is prepared: take 100gPEG (Mn=4000) and be dissolved in the tetrahydrofuran (THF) of 2L drying, add 6.09mL acrylate chloride and 12.20mL triethylamine, stirred at ambient temperature reacts 2 hours, filter, normal hexane is added in filtrate, filter, collecting precipitation, vacuum-drying obtains Ac-PEG-Ac;
4) Ac-PEG-g-IKVAV is prepared: get 1g step 2) gained Ac-PEG-COOH is dissolved in 20mL tetrahydrofuran (THF), add 0.2448g DCC and 0.1362gNHS, activate and add 0.3755gIKVAV polypeptide and 0.0918g DIPEA after 2 hours, 2h is reacted under room temperature, add normal hexane, filter, collecting precipitation, the dry 12h of ambient temperature in vacuum obtains Ac-PEG-g-IKVAV;
5) PNIPAM-b-PEG-g-IKVAV presoma is prepared: take N-isopropylacrylamide 20g, RAFT agent (4-cyanopentanoic acid dithiobenzoic acid ester) 1.2018g, Diisopropyl azodicarboxylate 0.0216g, add solvent 1, 4-dioxane 40mL, airtightly to vacuumize, PNIPAM is gone out with ether sedimentation after reaction 8h, taking 2gPNIPAM (Mn=6980) is dissolved in 4mL tetrahydrofuran (THF), add 0.7613g step 4) gained Ac-PEG-g-IKVAV, 0.005g AIBN, vacuum-pumping density is honored as a queen in 80 DEG C of reaction 6h, add normal hexane, filter to obtain precipitation, the dry 24h of ambient temperature in vacuum obtains PNIPAM-b-PEG-g-IKVAV presoma (Mn=9512.75),
6) preparation has bioactive temperature-sensitive hydrogel: take 0.0951g step 5) gained PNIPAM-b-PEG-g-IKVAV presoma, 19.31g step 5) gained PNIPAM, 5g BISAM, 5.58g step 3) gained Ac-PEG-Ac, 0.5g AIBN, adds 100mL DMF as solvent, vacuumizes, in 70 DEG C of reaction 12h, after gained gel washed with de-ionized water, obtain that there is bioactive temperature-sensitive hydrogel.
Prepared by the present embodiment have bioactive temperature-sensitive hydrogel can be used as neural tissue engineering timbering material.
Claims (9)
1. have a bioactive temperature-sensitive hydrogel, it is characterized in that, it is prepared by following methods:
1) prepare HO-PEG-COOH: be dissolved in by polyoxyethylene glycol in tetrahydrofuran (THF), obtain the polyglycol solution that concentration is 0.01 ~ 0.07g/mL, in polyglycol solution, add CaH
2, add ethyl bromoacetate after stirring under room temperature, wherein polyoxyethylene glycol, CaH
2be 1:0.85:1.7 with ethyl bromoacetate mol ratio, filter after abundant stirring, normal hexane is added in filtrate, filter out gained throw out, by water-soluble after throw out vacuum-drying, obtain the aqueous solution that concentration is 0.2 ~ 0.6g/mL, the NaOH aqueous solution is added in the described aqueous solution, polyoxyethylene glycol and NaOH mol ratio is made to be 1:1.7, hydrochloric acid soln adjust ph to 12.5 is used after abundant stirring, add methylene dichloride and carry out initial extraction, pH value is also adjusted to 3 by water intaking phase, in aqueous phase, add methylene dichloride again carry out reextraction, get organic phase and add normal hexane, separation obtains HO-PEG-COOH,
2) Ac-PEG-COOH is prepared: by step 1) gained HO-PEG-COOH is dissolved in tetrahydrofuran (THF) and obtains the HO-PEG-COOH solution that concentration is 0.01 ~ 0.1g/mL, and add acrylate chloride and triethylamine, HO-PEG-COOH and acrylate chloride, triethylamine mol ratio is made to be 1:2.3:2.5, room temperature reaction filtered after 3 ~ 6 hours, in gained filtrate, add normal hexane, throw out separation, drying obtain Ac-PEG-COOH;
3) Ac-PEG-Ac is prepared: be dissolved in by polyoxyethylene glycol in tetrahydrofuran (THF), obtain the polyglycol solution that concentration is 0.01 ~ 0.07g/mL, acrylate chloride and triethylamine is added in polyglycol solution, make polyoxyethylene glycol and acrylate chloride, the mol ratio of triethylamine is 1:3:3.5, room temperature reaction filtered after 1 ~ 4 hour, in gained filtrate, add normal hexane, throw out separation, drying obtain Ac-PEG-Ac;
4) Ac-PEG-g-IKVAV is prepared: by step 2) Ac-PEG-COOH for preparing is dissolved in tetrahydrofuran (THF), add dicyclohexylcarbodiimide and N-hydroxy-succinamide, make Ac-PEG-COOH and dicyclohexylcarbodiimide, N-hydroxy-succinamide mol ratio is 1:2.5:2.5, activate and add IKVAV polypeptide and N after 0.5 ~ 2 hour, N-diisopropylethylamine, wherein Ac-PEG-COOH and IKVAV polypeptide, N, the mol ratio of N-diisopropylethylamine is 1:1.5:1.5, normal hexane is added after reacting 2 ~ 6h under room temperature, throw out is separated, drying obtains Ac-PEG-g-IKVAV,
5) PNIPAM-b-PEG-g-IKVAV presoma is prepared: take NIPA as reaction monomers, 4-cyanopentanoic acid dithiobenzoic acid ester is RAFT agent, Diisopropyl azodicarboxylate is initiator, 1, 4-dioxane is solvent, each component molar ratio is: NIPA: 4-cyanopentanoic acid dithiobenzoic acid ester: Diisopropyl azodicarboxylate=100 ~ 40:1:0.01 ~ 0.03, vacuum-pumping density isolates PNIPAM with ether sedimentation after being honored as a queen and reacting 5 ~ 8h in 60 ~ 80 DEG C, PNIPAM is dissolved in tetrahydrofuran (THF) and obtains the aqueous solution that concentration is 0.1 ~ 0.6g/mL, add step 4 again) gained Ac-PEG-g-IKVAV and Diisopropyl azodicarboxylate, wherein PNIPAM and Ac-PEG-g-IKVAV mol ratio is 1:1, PNIPAM and Diisopropyl azodicarboxylate mol ratio are 9.5 ~ 23:1, in 60 ~ 80 DEG C of reaction 6 ~ 12h after sealing vacuumizes, normal hexane is added after reaction terminates, throw out is separated, drying obtains PNIPAM-b-PEG-g-IKVAV presoma,
6) preparation has bioactive temperature-sensitive hydrogel: by step 5) gained PNIPAM-b-PEG-g-IKVAV presoma is dissolved in DMF, add step 5 again) gained PNIPAM, small molecules linking agent, step 3) gained Ac-PEG-Ac and AIBN, each component molar ratio is: PNIPAM-b-PEG-g-IKVAV presoma: PNIPAM: small molecules linking agent: Ac-PEG-Ac:AIBN=1:280 ~ 700:3000 ~ 5000:100 ~ 300:200 ~ 500, vacuum-pumping density is honored as a queen in 60 ~ 80 DEG C of reaction 6 ~ 24h, obtain that there is bioactive temperature-sensitive hydrogel after gained gel washed with de-ionized water.
2. according to claim 1 have bioactive temperature-sensitive hydrogel, it is characterized in that step 1) described molecular weight polyethylene glycol is 2000; Step 3) described molecular weight polyethylene glycol is 4000.
3. according to claim 1 have bioactive temperature-sensitive hydrogel, it is characterized in that step 4) described IKVAV polypeptide is that the biochemical (Shanghai) Co., Ltd. of gill produces, product type is No:P110124-WY061697.
4. according to claim 1 have bioactive temperature-sensitive hydrogel, it is characterized in that step 6) described small molecules linking agent is one in N,N methylene bis acrylamide, Vinylstyrene, Ethylene glycol dimethacrylate.
5. there is a preparation method for bioactive temperature-sensitive hydrogel, it is characterized in that step is as follows:
1) prepare HO-PEG-COOH: be dissolved in by polyoxyethylene glycol in tetrahydrofuran (THF), obtain the polyglycol solution that concentration is 0.01 ~ 0.07g/mL, in polyglycol solution, add CaH
2, add ethyl bromoacetate after stirring under room temperature, wherein polyoxyethylene glycol, CaH
2be 1:0.85:1.7 with ethyl bromoacetate mol ratio, filter after abundant stirring, normal hexane is added in filtrate, filter out gained throw out, by water-soluble after throw out vacuum-drying, obtain the aqueous solution that concentration is 0.2 ~ 0.6g/mL, the NaOH aqueous solution is added in the described aqueous solution, polyoxyethylene glycol and NaOH mol ratio is made to be 1:1.7, hydrochloric acid soln adjust ph to 12.5 is used after abundant stirring, add methylene dichloride and carry out initial extraction, pH value is also adjusted to 3 by water intaking phase, in aqueous phase, add methylene dichloride again carry out reextraction, get organic phase and add normal hexane, separation obtains HO-PEG-COOH,
2) Ac-PEG-COOH is prepared: by step 1) gained HO-PEG-COOH is dissolved in tetrahydrofuran (THF) and obtains the HO-PEG-COOH solution that concentration is 0.01 ~ 0.1g/mL, and add acrylate chloride and triethylamine, HO-PEG-COOH and acrylate chloride, triethylamine mol ratio is made to be 1:2.3:2.5, room temperature reaction filtered after 3 ~ 6 hours, in gained filtrate, add normal hexane, throw out separation, drying obtain Ac-PEG-COOH;
3) Ac-PEG-Ac is prepared: be dissolved in by polyoxyethylene glycol in tetrahydrofuran (THF), obtain the polyglycol solution that concentration is 0.01 ~ 0.07g/mL, acrylate chloride and triethylamine is added in polyglycol solution, make polyoxyethylene glycol and acrylate chloride, the mol ratio of triethylamine is 1:3:3.5, room temperature reaction filtered after 1 ~ 4 hour, in gained filtrate, add normal hexane, throw out separation, drying obtain Ac-PEG-Ac;
4) Ac-PEG-g-IKVAV is prepared: by step 2) Ac-PEG-COOH for preparing is dissolved in tetrahydrofuran (THF), add dicyclohexylcarbodiimide and N-hydroxy-succinamide, make Ac-PEG-COOH and dicyclohexylcarbodiimide, N-hydroxy-succinamide mol ratio is 1:2.5:2.5, activate and add IKVAV polypeptide and N after 0.5 ~ 2 hour, N-diisopropylethylamine, wherein Ac-PEG-COOH and IKVAV polypeptide, N, the mol ratio of N-diisopropylethylamine is 1:1.5:1.5, normal hexane is added after reacting 2 ~ 6h under room temperature, throw out is separated, drying obtains Ac-PEG-g-IKVAV,
5) PNIPAM-b-PEG-g-IKVAV presoma is prepared: take NIPA as reaction monomers, 4-cyanopentanoic acid dithiobenzoic acid ester is RAFT agent, Diisopropyl azodicarboxylate is initiator, 1, 4-dioxane is solvent, each component molar ratio is: NIPA: 4-cyanopentanoic acid dithiobenzoic acid ester: Diisopropyl azodicarboxylate=100 ~ 40:1:0.01 ~ 0.03, vacuum-pumping density isolates PNIPAM with ether sedimentation after being honored as a queen and reacting 5 ~ 8h in 60 ~ 80 DEG C, PNIPAM is dissolved in tetrahydrofuran (THF) and obtains the aqueous solution that concentration is 0.1 ~ 0.6g/mL, add step 4 again) gained Ac-PEG-g-IKVAV and Diisopropyl azodicarboxylate, wherein PNIPAM and Ac-PEG-g-IKVAV mol ratio is 1:1, PNIPAM and Diisopropyl azodicarboxylate mol ratio are 9.5 ~ 23:1, in 60 ~ 80 DEG C of reaction 6 ~ 12h after sealing vacuumizes, normal hexane is added after reaction terminates, throw out is separated, drying obtains PNIPAM-b-PEG-g-IKVAV presoma,
6) preparation has bioactive temperature-sensitive hydrogel: by step 5) gained PNIPAM-b-PEG-g-IKVAV presoma is dissolved in DMF, add step 5 again) gained PNIPAM, small molecules linking agent, step 3) gained Ac-PEG-Ac and AIBN, each component molar ratio is: PNIPAM-b-PEG-g-IKVAV presoma: PNIPAM: small molecules linking agent: Ac-PEG-Ac:AIBN=1:280 ~ 700:3000 ~ 5000:100 ~ 300:200 ~ 500, vacuum-pumping density is honored as a queen in 60 ~ 80 DEG C of reaction 6 ~ 24h, obtain that there is bioactive temperature-sensitive hydrogel after gained gel washed with de-ionized water.
6. the preparation method with bioactive temperature-sensitive hydrogel according to claim 5, is characterized in that step 1) described molecular weight polyethylene glycol is 2000; Step 3) described molecular weight polyethylene glycol is 4000.
7. the preparation method with bioactive temperature-sensitive hydrogel according to claim 5, it is characterized in that step 4) described IKVAV polypeptide is that the biochemical (Shanghai) Co., Ltd. of gill produces, product type is No:P110124-WY061697.
8. the preparation method with bioactive temperature-sensitive hydrogel according to claim 5, it is characterized in that step 6) described small molecules linking agent is one in N,N methylene bis acrylamide, Vinylstyrene, Ethylene glycol dimethacrylate.
9. a claim 1-4 arbitrary described in there is the application of bioactive temperature-sensitive hydrogel as neural tissue engineering timbering material.
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