CN108359054A - A kind of full interpenetration network hydrogel of glucose-sensitive type and preparation method thereof - Google Patents
A kind of full interpenetration network hydrogel of glucose-sensitive type and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of full interpenetration network hydrogel of glucose-sensitive type and preparation method thereof, which includes two kinds of mutually interspersed networks, and one is the polymer network of acrylamido phenyl boric acid AAPBA, another kind is chitosan CS cross-linked networks.The hydrogel can reduce the pKa of PBA, have good response intensity and the speed of response to glucose at physiological ph, and relative to the gel of no CS cross-linked networks, swelling time shortens, and swellbility improves, and inierpeneirating network structure improves the mechanical strength of hydrogel.The preparation method of the hydrogel is simple, and reaction condition is mild, is suitable for industrialized production.
Description
【Technical field】
The invention belongs to medical macromolecular materials fields, and in particular to arrive a kind of glucose-sensitive type hydrogel and its preparation
Method.
【Background technology】
Diabetes are a kind of common chronic metabolic disorders, need accurately to monitor human body level to adjust
Whole insulin dosage, to control the blood sugar concentration of patient.Only continuously measuring blood glucose just can effectively control the use of insulin
Amount, avoids the generation of hypoglycemia.Continuous real time blood sugar detector and the insulin releasing system of self-control are control blood
The sharp weapon of sugar fluctuation.Glucose responding type hydrogel all plays the role of core in the research of this two technologies, can be right
The concentration of glucose of system is monitored and provides automatically response, discharges the insulin of load, realizes to blood sugar in diabetic patients
Concentration intelligent control.
Glucose responding type hydrogel using phenyl boric acid group (PBA) as recognition element, have stability is good, toxicity is low,
There is no the advantages that immunological rejection.There is unionized hydrophobic boronate in PBA and its derivative and the hydrophilic boron of ionization is negative in water
Ion, the boron anion after ionization is easy to combine by reversible covalent bonds with substances containing vicinal diamines such as glucose, and shape
At more hydrophilic borate, gel inner ion intensity is made to increase, the inside and outside permeable pressure head that generates of system causes gel swelling, water
The swelling character of gel provided with the variation of concentration of glucose easily detect it is corresponding.But the pKa of PBA (8.6) compares physiology
Major part PBA is in unionized state when pH high, pH7.4, and very weak with the binding force of glucose, response is very low.It solves at present
This problem is mainly by PBA derivative of (1) synthesis with relatively low pKa, but building-up process often complex and expensive, yield compared with
It is low.(2) amino is introduced on PBA polymer chains, neighbouring amino can be coordinated with boron atom, reduce the pKa of PBA, but
Amino in side group can not be completely exposed, and reproducibility is not high.
Chitosan (CS) is the unique alkaline polysaccharide of nature, and a large amount of amino is contained on strand, can and boron atom
It is combined into complex.Using ipn technology, PBA copolymers will be contained and form inierpeneirating network structure (IPN) hydrogel with CS.CS
Amino and copolymer strand on boric acid be coordinated, boron anion is formed, to improve hydrogel containing PBA under physiological environment
To the response of glucose.
【Invention content】
The present invention uses ipn technology, will be based on the copolymer and chitosan of acrylamido phenyl boric acid (AAPBA)
CS cross-linking agents form the full interpenetration network hydrogel of glucose-sensitive type based on PBA.The hydrogel is under a kind of physiological condition
To the hydrogel of glucose-sensitive, a kind of that the invention further relates to reaction conditions is mild, synthetic route is easy temperature-sensitive hydrogel system
Preparation Method.The invention is realized by the following technical scheme.
A kind of full interpenetration network hydrogel of glucose-sensitive type, including two kinds of mutually interspersed networks；One is based on third
The polymer network of acrylamide base phenyl boric acid, another kind are chitosan crosslinked networks；
Polymer network based on acrylamido phenyl boric acid polymerize under the action of the first crosslinking agent by three kinds of monomers and
At；Three kinds of monomers are respectively：Acrylamido phenyl boric acid, amides and Third monomer, acrylamido phenyl boric acid, amides and
The mole percent ratio of Third monomer is (5-20)：(0-30)：(50-95)；
Chitosan forms chitosan crosslinked network under the action of the second crosslinking agent.
Further improvement of the present invention is：
Amides select acrylamide or Methacrylamide；Third monomer selects dimethacrylamide, metering system
Sour dimethylaminoethyl or n-isopropyl acrylamide；First crosslinking agent selects diene class crosslinking agent；The quality of first crosslinking agent
For the 0.1%-1% of three kinds of monomer mass sums.
Second crosslinking agent selects glutaraldehyde, sodium tripolyphosphate, calgon, sodium β-glycerophosphate or epoxychloropropane.
A kind of preparation method of the full interpenetration network hydrogel of glucose-sensitive type, includes the following steps：
(1) it weighs Chitosan powder to be dissolved in water or acetic acid solution, forms chitosan solution；
(2) acrylamido phenyl boric acid, amides, Third monomer, the first crosslinking agent and accelerator are added to chitosan
In solution, magneton magnetic agitation 10min is then added；
(3) initiator and the second crosslinking agent are added into the solution obtained by step (2), then magnetic agitation 20min, takes
Go out magneton, room temperature stands solution, and the full interpenetration network hydrogel of glucose-sensitive type is made；
A kind of full interpenetration network hydrogel of glucose-sensitive type being obtained by this method, including two kinds of mutually interspersed nets
Network；One is the polymer network based on acrylamido phenyl boric acid, another kind is chitosan crosslinked network；
Polymer network based on acrylamido phenyl boric acid polymerize under the action of the first crosslinking agent by three kinds of monomers and
At；Three kinds of monomers are respectively：Acrylamido phenyl boric acid, amides and Third monomer, acrylamido phenyl boric acid, amides and
The mole percent ratio of Third monomer is (5-20)：(0-30)：(50-95)；
Chitosan forms chitosan crosslinked network under the action of the second crosslinking agent.
The molecular weight of chitosan is 100,000-40 ten thousand in step (1), and the mass concentration of chitosan solution is 2%-5%；Step
(1) if in chitosan is soluble in water, dissolving after directly use, if dissolving chitosan in acetic acid solution, dissolving it is laggard
Row magnetic agitation.
The mole percent ratio of acrylamide ylboronic acid, amides and Third monomer is (5-20) in step (2)：(0-
30)：(50-95)；The quality of first crosslinking agent is the 0.1%-1% of three kinds of monomer mass sums；
Amides select acrylamide or Methacrylamide；Third monomer selects dimethacrylamide, metering system
Sour dimethylaminoethyl or n-isopropyl acrylamide；First crosslinking agent selects diene class crosslinking agent；Accelerator selects tetramethyl
Diamines.
In step (3) quality of initiator be three kinds of monomer mass sums 0.03%-3%, initiator select ammonium persulfate,
Potassium peroxydisulfate, sodium peroxydisulfate, dibenzoyl peroxide or azodiisobutyronitrile；Second crosslinking agent selects glutaraldehyde, tripolyphosphate
Sodium, calgon, sodium β-glycerophosphate or epoxychloropropane；After taking out magneton, room temperature stands solution 24 hours.
A kind of full interpenetration network hydrogel of glucose-sensitive type detection glucose content in insulin releasing system
Using.
Compared with the existing technology, the present invention has following advantageous effect：
The invention discloses a kind of full interpenetration network hydrogels of glucose-sensitive type and preparation method thereof.The hydrogel packet
Two kinds of mutually interspersed networks are included, one is the polymer network based on acrylamido phenyl boric acid AAPBA, another kind is that shell is poly-
Sugared CS cross-linked networks.The hydrogel can reduce the pKa of PBA, have good response intensity and sound to glucose at physiological ph
Answer rate.It carries out maximum swelling degree with the gel for being not added with CS cross-linked networks by hydrogel made from CS cross-linked networks is added and reaches
Time measurement is spent to maximum swelling, as a result, it has been found that the hydrogel maximum swelling degree of addition CS cross-linked networks can reach 9.6%, is reached
The time of maximum swelling degree is 260min or so；And the gel maximum swelling degree for being not added with CS cross-linked networks is 3%, reaches maximum
The time of swellbility is 360min or so, therefore adds the shortening of swelling behavior time, swellbility made from CS cross-linked networks and carry
Height, and inierpeneirating network structure improves the mechanical strength of hydrogel.
Further, the present invention prepares the preparation method use of the full interpenetration network hydrogel of glucose-sensitive type while polymerizeing
Interpenetrating networks method, preparation method is simple, and reaction condition is mild, is suitable for industrialized production, and this method can be made by changing
The concentration of ratio and CS during standby between monomer changes responsiveness of the gel to glucose.
Further, subject hydrogel is applied to the insulin releasing system in glucose detection and self-control
In, the response intensity and the speed of response of hydrogel concentration of glucose can be improved so that the insulin releasing system of self-control is fast
Speed provides response, discharges the insulin of load, reduces the blood glucose in blood.
【Description of the drawings】
Fig. 1 is the Macroscopic single crystal figure (note based on AAPBA：R in figure1-R4Can be H, CH3, CH2CH3；X can be O or
N)；
Fig. 2 is the cross-linking reaction of CS and glutaraldehyde aldehyde radical (GA)；
Fig. 3 is based on AAPBA polymer and CS cross-linked network interpenetrating networks schematic diagrames；
Fig. 4 is schematic diagram of the full interpenetration network hydrogel to glucose responding；
Fig. 5 is the FTIR spectrograms of P (AAPBA-DMAA-AM)/CS-GA；
Fig. 6 is the FTIR spectrograms of P (AAPBA-DMAEMA-AM)/CS-GA；
Fig. 7 be different CS contents P (AAPBA-DMAEMA-AM)/CS-GA gels in pH=7.3, (20mmol/l's) is molten
Swollen curve；
Different glucose solutions of P (AAPBA-DMAEMA-AM)/CS-GA hydrogels of the Fig. 8 containing CS (2%) in pH=7.3
In swelling curve；
Different glucose solutions of P (AAPBA-DMAEMA-AM)/CS-GA hydrogels of the Fig. 9 containing CS (3%) in pH=7.3
In swelling curve.
【Specific implementation mode】
The present invention relates to a kind of a kind of mild to the hydrogel of glucose-sensitive and reaction condition under physiological condition, conjunctions
At the temperature-sensitive hydrogel preparation method of route simplicity.It is poly- by the polymer and shell that are based on acrylamido phenyl boric acid (AAPBA)
The network interpenetrating of sugared (CS) each self-forming has synthesized the full interpenetration network hydrogel of glucose-sensitive type based on PBA.AAPBA, acyl
Amine and Third monomer carry out free radical polymerization, while CS in the CS solution containing the first crosslinking agent, accelerator and initiator
It is crosslinked, is prepared under physiological condition to the hydrogel of concentration of glucose response type under the effect of the second crosslinking agent.
Wherein amides can be acrylamide (AM) or Methacrylamide (MAm)；Third monomer can be dimethyl
Acrylamide (DMAA), dimethylaminoethyl acrylate methyl base ethyl ester (DMAEMA) or n-isopropyl acrylamide (NIPAM)；First crosslinking
Agent is diene class crosslinking agent, such as N ' N- methylene-bisacrylamides (MBA), tetrabutyl ammonium bromide (BBE) and divinylbenzene
(DVB) etc.；The accelerator is tetramethylethylenediamine (TEMED)；The initiator can be ammonium persulfate (APS), persulfuric acid
Potassium (KPS), sodium peroxydisulfate, dibenzoyl peroxide (BPO) or azodiisobutyronitrile (AIBN)；Second crosslinking agent can be
Glutaraldehyde (GA), sodium tripolyphosphate (STPP), calgon (SHMP), sodium β-glycerophosphate (GP) or epoxychloropropane
(ECH)。
Fig. 1 is the reaction principle figure of monomer AAPBA, monomer AM and monomer DMAA, which also needs to be added the in the solution
One crosslinking agent, accelerator TEMED and initiator A PS.Three kinds of monomers polymerize under the action of initiator, and formation is based on
The polymer network of AAPBA.
Fig. 2 is the cross-linking reaction that CS occurs under the second crosslinking agent GA effects, forms CS cross-linked polymers.
As shown in figure 3, respectively being polymerize with CS cross-linked polymers based on the polymer of AAPBA or cross-linking reaction, with this
It is formed simultaneously synchronous making, the as full interpenetration network hydrogel of glucose-sensitive type based on PBA of the invention.
Fig. 4 be the present invention interpenetration network hydrogel in glucose solution with the response schematic diagram of glucose.
The preparation method of interpenetration network hydrogel provided by the invention is as follows：
(1) CS for weighing 0.2-0.5g is dissolved in the water or acetic acid solution of 10ml, forms the CS solution of 2%-5%.Such as use
CS is then directly dissolved in water by water dissolution；It is such as dissolved with acetic acid solution, then magnetic agitation is uniform after CS being dissolved in acetic acid.
Wherein, the molecular weight of CS is 100,000-40 ten thousand.
(2) pipette the CS solution of the 2-5% of 1ml or 2ml with pipette, be added monomer AAPBA, amides, Third monomer,
First crosslinking agent and accelerator TEMED, magnetic agitation 10min is to being uniformly dissolved；Wherein, AAPBA, amides and Third monomer
Mole percent ratio is (5-20)：(0-30)：(50-95), crosslinking agent are the 0.1%-1% of three kinds of monomer mass sums.
(3) continue to stir 20min after initiator and the second crosslinking agent are added in the solution obtained by step (2), take out magnetic
Son, room temperature stand 24 hours and carry out cross-linking reaction, form the full interpenetration network hydrogel of glucose-sensitive type based on PBA, wherein
The dosage of initiator is the 0.03%-3% of three kinds of monomer mass sums.
The detection of performance is carried out to the above-mentioned hydrogel being prepared, it is shown that steps are as follows：
(1) hydrogel being prepared is cut into block, is placed in constant temperature distilled water and impregnates, remove unreacted monomer, often
First water is changed every 6h, sample freeze-drying is used for the test of follow-up performance after 48h.
(2) fritter dry sample is placed in the phosphate buffer solution (PBS) of pH=7.3 and reaches balance；It is subsequently placed in pH=
In 7.3,20mmol/L glucose phosphate buffer solution, a hydrogel weight is weighed per 30min, repeats this process to hydrogel
Constant weight measures the swellbility of hydrogel.The calculation formula of hydrogel Swellability SD is as follows:
SD=(WtOne Wd)/Wd
In formula, WdIndicate the weight of the gel balanced in PBS, WtIt indicates to take gel from glucose solution in t moment
Go out, blots the weight weighed after surface moisture.
The meaning of data marks in detail in 1 bracket of embodiment, and meaning is indicated in each substance bracket of In remaining embodiment
It is same as Example 1.
Embodiment 1:The preparation of P (AAPBA-DMAA-AM)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 300,000,0.2g to be dissolved in 10ml water, is made into 2% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.096g (mole percents：6%), AM：0.156g (mole
Percentage：And DMAA 26%)：0.6ml (mole percent 68%), crosslinking agent MBA：4.14mg be (three kinds of monomer mass sums
0.5%) it is placed in solution, is pipetted with pipette and TEMED：10ul, magnetic agitation 10min is uniform to solution, while being added new
The APS solution 0.5ml (40mg/ml) (the 2.4% of three kinds of monomer mass sums) of fresh preparation, GA solution 10ul continue to stir
20min, takes out magneton, and room temperature standing carries out cross-linking reaction for 24 hours.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 270min, and maximum swelling degree is 5.3%.
Fig. 5 is the infrared spectrum of P (AAPBA-DMAA-AM)/full interpenetration network hydrogels of CS-GA.3216cm-1Place is formation
- the OH and-NH of hydrogen bond association2Stretching vibration absworption peak overlapping and broadening multi-absorption peak.1058cm-1Place is stretching for C-N
The superposition of contracting vibration absorption peak and C-O skeleton stretching vibration peaks, therefore peak shape is sharp herein.2902cm-1Place, which is that C-H is flexible, to shake
Dynamic Absorption Characteristics peak.1610cm-1It is the formation of imine linkage C=N, that is, the amino of chitosan and penta that the notable peak at place is corresponding
Condensation reaction occurs between the aldehyde radical of dialdehyde and forms schiff alkali structures.It is in conjunction with CS-GA reaction principles it is found that main after crosslinking
It is that primary amine becomes secondary amine.Polymer is in 1640-1680cm-1There is not double bond characteristic absorption peak, illustrate that monomer polymerize, with CS
Interpenetrating success.
Embodiment 2:The preparation of P (AAPBA-DMAA)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 300,000,0.2g to be dissolved in 10ml water, is made into 2% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.096g (5%) and DMAA：1.0ml (95%), crosslinking agent
MBA：0.0106mg (1%) is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation 10min is uniform to solution, together
When be added Fresh APS solution 0.2ml (40mg/ml) (0.75%), GA solution 10ul, continue stir 20min, take out magnetic
Son, room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 270min, and maximum swelling degree is 5.8%.
Embodiment 3:The preparation of P (AAPBA-DMAA-AM)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 400,000,0.2g to be dissolved in 10ml water, is made into 2% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.096g (20%), AM：0.054g (30%) and DMAA：
131ul (50%), crosslinking agent MBA：2.76mg (1%) is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation
10min is uniform to solution, while APS solution 0.1ml (40mg/ml) (1.5%), the GA solution 15ul of Fresh is added, after
Continuous stirring 20min takes out magneton, and room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 260min, and maximum swelling degree is 5.9%.
Embodiment 4：The preparation of P (AAPBA-DMAEMA-AM)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 400,000,0.2g to be dissolved in 10ml water, is made into 2% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.096g (5%), AM：0.156g (22%) and DMAEMA：
1.2ml (73%), crosslinking agent MBA：0.0156g (1%), TEMED is pipetted with pipette：10ul, magnetic agitation 10min to solution
Uniformly, while the APS solution 0.5ml (40mg/ml) (1.38%) of Fresh is added, GA solution 10ul continue to stir
20min takes out magneton, and room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 260min, and maximum swelling degree is 9.6%.
Fig. 6 is the infrared spectrum of P (AAPBA-DMAEMA-AM)/full interpenetration network hydrogels of CS-GA.Polymer exists
3284cm-1Absorption peak be-NH and-OH stretching vibration peaks overlap peak, 1663cm-1The absorption peak at place is the spy of amide C=O
Levy absorption peak；1427cm-1Absorption peak be amide-NH absorption peaks, 1151cm-1Absorption peak C-N characteristic absorption peak；980cm-1The weak peak of vicinity is the absorption peak of-OH on CS, above analysis shows generating P (AAPBA-DMAEMA-AM)/CS-GA water-settings
Glue.
Embodiment 5：The preparation of P (AAPBA-DMAEMA-AM)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 400,000,0.3g to be dissolved in 10ml water, is made into 3% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.096g (5%), AM：0.156g (22%) and DMAEMA：
1.2ml (73%), crosslinking agent MBA：0.0156g (1%) is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation
10min is uniform to solution, while APS solution 0.5ml (40mg/ml) (1.38%), the GA solution 15ul of Fresh is added, after
Continuous stirring 20min takes out magneton, and room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 265min, and maximum swelling degree is 7.2%.
Embodiment 6：The preparation of P (AAPBA-DMAEMA-AM)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 400,000,0.4g to be dissolved in 10ml water, is made into 4% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.096g (5%), AM：0.156g (22%) and DMAEMA：
1.2ml (73%), crosslinking agent MBA：0.0156g (1%) is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation
10min is uniform to solution, while APS solution 0.5ml (40mg/ml) (1.38%), the GA solution 15ul of Fresh is added, after
Continuous stirring 20min takes out magneton, and room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 268min, and maximum swelling degree is 7.0%.
Embodiment 7：The preparation of P (AAPBA-DMAEMA-AM)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 400,000,0.5g to be dissolved in 10ml water, is made into 5% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.096g (5%), AM：0.156g (22%) and DMAEMA：
1.2ml (73%), crosslinking agent MBA：0.0156g (1%) is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation
10min is uniform to solution, while APS solution 0.5ml (40mg/ml) (1.38%), the GA solution 15ul of Fresh is added, after
Continuous stirring 20min takes out magneton, and room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 270min, and maximum swelling degree is 5.3%.
Embodiment 8：The preparation of P (AAPBA-NIPAM-AM)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 350,000,0.4g to be dissolved in 10ml water, is made into 4% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.032g (8%), AM：8.3mg (6%) and NIPAM：0.2g
(86%) and BBE：2.33ul (1%), is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation 10min are to molten
Liquid is uniform, while APS solution 180ul (40mg/ml) (3%), the GA solution 20ul of Fresh is added, and continues to stir 20min,
Magneton is taken out, room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 260min, and maximum swelling degree is 8.2%.
Embodiment 9：The preparation of P (AAPBA-NIPAM-AM)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 350,000,0.5g to be dissolved in 10ml water, is made into 5% CS solution.
(2) 2mlCS solution is pipetted, AAPBA is accurately weighed：0.032g (10%), AM：18mg (15%) and NIPAM：
0.144g (75%), crosslinking agent DVB：2.11ul (1%), is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation
10min is uniform to solution, while APS solution 145.5ul (40mg/ml) (3%), the GA solution 40ul of Fresh is added, after
Continuous stirring 20min takes out magneton, and room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 260min, and maximum swelling degree is 8.7%.
Embodiment 10：The preparation of P (AAPBA-NIPAM-AM)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 100,000,0.4g to be dissolved in 10ml water, is made into 4% CS solution.
(2) 2mlCS solution is pipetted, AAPBA is accurately weighed：0.032g (8%), AM：8.3mg (6%) and NIPAM：0.2g
(86%), crosslinking agent MBA：2.4mg (1%), is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation 10min is extremely
Solution is uniform, while the APS solution 180ul (40mg/ml) (3%) of Fresh is added, and GA solution 40ul continue to stir
20min takes out magneton, and room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 270min, and maximum swelling degree is 7.3%.
Embodiment 11：The preparation of P (AAPBA-NIPAM-AM)/full interpenetration network hydrogels of CS-STPP
(1) it weighs the CS that molecular weight is 200,000,0.4g and is dissolved in 10ml, in 1% acetic acid solution, magnetic agitation is uniform, matches
At 4% CS solution.
(2) 2mlCS solution is pipetted, AAPBA is accurately weighed：0.032g (8%), AM：8.3mg (6%) and NIPAM：0.2g
(86%), crosslinking agent MBA：2.4mg (1%), is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation 10min is extremely
Solution is uniform, while the APS solution 180ul (40mg/ml) (3%) of Fresh is added, and 4% STPP solution 1ml continue to stir
20min is mixed, magneton is taken out, room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 265min, and maximum swelling degree is 6.9%.
Embodiment 12：The preparation of P (AAPBA-NIPAM-AM)/full interpenetration network hydrogels of CS-ECH
(1) it weighs the CS that molecular weight is 200,000,0.4g and is dissolved in 10ml, in 1% acetic acid solution, magnetic agitation is uniform, matches
At 4% CS solution.
(2) 2mlCS solution is pipetted, AAPBA is accurately weighed：0.032g (8%), AM：8.3mg (6%) and NIPAM：0.2g
(86%), crosslinking agent MBA：0.24mg (0.1%), is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation
10min is uniform to solution, while the epoxychloropropane of the APS solution 180ul (40mg/ml) (3%) and 4% of Fresh is added
ECH solution 2ml continue to stir 20min, take out magneton, and room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 260min, and maximum swelling degree is 7.4%.
Embodiment 13：The preparation of P (AAPBA-DMAA-MAm)/full interpenetration network hydrogels of CS-GA
(1) it weighs the CS that molecular weight is 300,000,0.2g to be dissolved in 10ml water, is made into 2% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.096g (6%), MAm：0.156g (22%) and DMAA：
0.6ml (72%), crosslinking agent MBA：0.0083g (1%) is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation
10min is uniform to solution, while KPS solution 6ul (40mg/ml) (0.03%), the GA solution 10ul of Fresh is added, and continues
20min is stirred, magneton is taken out, room temperature standing carries out cross-linking reaction for 24 hours.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 270min, and maximum swelling degree is 5.4%.
Embodiment 14：The preparation of P (AAPBA-DMAA-AM)/full interpenetration network hydrogels of CS-SHMP
(1) it weighs the CS that molecular weight is 400,000,0.2g to be dissolved in 10ml water, is made into 2% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.096g (20%), AM：0.054g (30%) and DMAA：
131ul (50%), crosslinking agent MBA：2.76mg (1%), is placed in solution, is pipetted with pipette and TEMED：10ul, magnetic force stir
It mixes that 10min is uniform to solution, while the sodium peroxydisulfate solution 0.2ml (40mg/ml) (3%) of Fresh, SHMP solution is added
1ml continues to stir 20min, takes out magneton, and room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 265min, and maximum swelling degree is 6.0%.
Embodiment 15：The preparation of P (AAPBA-NIPAM-AM)/full interpenetration network hydrogels of CS-GP
(1) it weighs the CS that molecular weight is 350,000,0.4g to be dissolved in 10ml water, is made into 4% CS solution.
(2) 1mlCS solution is pipetted, AAPBA is accurately weighed：0.032g (8%), AM：8.3mg (6%) and NIPAM：0.2g
(86%), MBA：2.4mg (1%), is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation 10min are equal to solution
It is even, while BPO solution 180ul (40mg/ml) (3%), the GP solution 1ml of Fresh is added, continue to stir 20min, take out
Magneton, room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 260min, and maximum swelling degree is 8.2%.
Embodiment 16：The preparation of P (AAPBA-NIPAM-AM)/full interpenetration network hydrogels of CS-STPP
(1) it weighs the CS that molecular weight is 200,000,0.4g and is dissolved in 10ml, in 1% acetic acid solution, magnetic agitation is uniform, matches
At 4% CS solution.
(2) 2mlCS solution is pipetted, AAPBA is accurately weighed：0.032g (8%), AM：8.3mg (6%) and NIPAM：0.2g
(86%), crosslinking agent MBA：2.4mg (1%), is placed in solution, and TEMED is pipetted with pipette：10ul, magnetic agitation 10min is extremely
Solution is uniform, while the AIBN solution 180ul (40mg/ml) (3%) of Fresh, 4% STPP solution 1ml is added, and continues
20min is stirred, magneton is taken out, room temperature, which is stood, carries out cross-linking reaction.
(3) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(4) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose phosphate
In buffer solution (pH=7.3,20mmol/l), the swelling time for reaching balance is 265min, and maximum swelling degree is 6.9%.
Comparative example 17：The preparation of P (AAPBA-DMAEMA-AM) hydrogel
(1) 1ml deionized waters are pipetted, AAPBA is accurately weighed：0.096g (5%), AM：0.156g (22%), MBA：
0.0156g (1%), is placed in solution, and DMAEMA is pipetted with pipette：1.2ml (73%) TEMED：In 10ul to solution, magnetic force
It is uniform to solution to stir 10min, while the APS solution 0.5ml (40mg/ml) (1.38%) of Fresh is added, continues to stir
20min takes out magneton, and room temperature, which is stood, carries out cross-linking reaction.
(2) hydrogel obtained is divided into fritter, be placed in distilled water, remove demonomerization, a water is changed every 6h, after 48h,
Test of the sample freeze-drying for follow-up correlated performance.
(3) a fritter dry sample is placed in PBS buffer solutions (pH=7.3) and reaches balance, be subsequently placed in glucose solution
In (pH=7.3,20mmol/l), the swelling time for reaching balance is 360min, and maximum swelling degree is 3.0%.
Embodiment 18：Swellbility contrast test
By hydrogel sheet of the embodiment 4,5,6,7,17 based on the serial difference CS contents of AAPBA DMAEMA containing monomer, in life
It is impregnated in reason pH buffer solutions and reaches balance, immersed in the glucose solution of concentration 20mM, pH=7.3 respectively, weighed per 30min
Hydrogel weight simultaneously records, and repeats this process to hydrogel constant weight, the swellbility of hydrogel is calculated according to swellbility formula.
As a result as shown in Fig. 7, embodiment 4,5,6,7 is that gel obtained, embodiment 17 are in the solution containing CS
The ordinary gel obtained in the solution for being not added with CS, under physiological pH (20mM), gel obtained reaches most in CS solution
The time of big swellbility in 260min or so, is not added with the time that ordinary gel obtained in the solution of CS reaches maximum swelling degree
In 330min or so, therefore shorten the response time.It is not added with maximum swelling degree under the ordinary gel physiological pH of CS and there was only 3% left side
The right side, gel SD obtained is significantly increased after adding CS, reaches 9.6%.Illustrate the amino of CS and phenyl boric acid group in gel network
In conjunction with phenyl boric acid salt is formed, for negatively charged phenyl boric acid salt groups easily with glucose bonding, the glucose for increasing hydrogel is quick
Perception.
Embodiment 19：The performance test of hydrogel obtained in glucose solution in various concentration CS
The hydrogel sheet of embodiment 4,5 is impregnated in physiological pH buffer solution and reaches balance, immerses various concentration respectively
Glucose solution (pH=7.3) in, per 30min weigh a hydrogel weight simultaneously record, repeat this process to hydrogel perseverance
Weight calculates the swellbility (attached drawing 8,9) of hydrogel according to swellbility formula.As seen from Figure 8, the hydrogel of CS (2%) reaches
To maximum swelling degree time in 260min or so, as seen from Figure 9, the hydrogel of CS (3%) reaches maximum swelling degree
Time is in 300min or so.The increase with CS contents is can be seen that in conjunction with Fig. 8 and Fig. 9, the time for reaching maximum swelling degree increases
Add, the reason is that as CS is containing increase is measured, double interpenetrating networks crosslinkings are close, are unfavorable for the swelling of hydrogel.
Conclusion
In conjunction with the hydrogel performance test obtained after CS is added, hydrogel performance test that CS is directly obtained is not added and not
Hydrogel obtained swellbility in glucose solution measures experiment in same CS contents, obtains to draw a conclusion：
(1) gel obtained reaches time of maximum swelling degree and makes significantly less than being not added in the solution of CS in CS solution
The ordinary gel obtained reaches the time of maximum swelling degree, that is, shortens the response time.Gel SD values obtained are apparent after adding CS
More than the ordinary gel SD values for being not added with CS.
(2) with the increase of CS contents, the time for reaching maximum swelling degree increases.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
With within principle, any modification, equivalent replacement, improvement and so on should all be included in the protection scope of the present invention god.
Claims (8)
1. a kind of full interpenetration network hydrogel of glucose-sensitive type, which is characterized in that including two kinds of mutually interspersed networks；It is a kind of
It is the polymer network based on acrylamido phenyl boric acid, another kind is chitosan crosslinked network；
Polymer network based on acrylamido phenyl boric acid is polymerized by three kinds of monomers under the action of the first crosslinking agent；Three
Planting monomer is respectively：Acrylamido phenyl boric acid, amides and Third monomer, acrylamido phenyl boric acid, amides and third
The mole percent ratio of monomer is (5-20)：(0-30)：(50-95)；
Chitosan forms chitosan crosslinked network under the action of the second crosslinking agent.
2. a kind of full interpenetration network hydrogel of glucose-sensitive type according to claim 1, which is characterized in that amides select
With acrylamide or Methacrylamide；Third monomer select dimethacrylamide, dimethylaminoethyl methacrylate or
N-isopropyl acrylamide；First crosslinking agent selects diene class crosslinking agent；The quality of first crosslinking agent be three kinds of monomer masses and
0.1%-1%.
3. a kind of full interpenetration network hydrogel of glucose-sensitive type according to claim 1, which is characterized in that the second crosslinking
Glutaraldehyde, sodium tripolyphosphate, calgon, sodium β-glycerophosphate or epoxychloropropane are selected in agent.
4. a kind of preparation method of the full interpenetration network hydrogel of glucose-sensitive type, which is characterized in that include the following steps：
(1) it weighs Chitosan powder to be dissolved in water or acetic acid solution, forms chitosan solution；
(2) acrylamido phenyl boric acid, amides, Third monomer, the first crosslinking agent and accelerator are added to chitosan solution
In, magneton magnetic agitation 10min is then added；
(3) initiator and the second crosslinking agent are added into the solution obtained by step (2), then magnetic agitation 20min, take out magnetic
Son, room temperature stand solution, and the full interpenetration network hydrogel of glucose-sensitive type is made；
A kind of full interpenetration network hydrogel of glucose-sensitive type being obtained by this method, including two kinds of mutually interspersed networks；One
Kind is the polymer network based on acrylamido phenyl boric acid, and another kind is chitosan crosslinked network；
Polymer network based on acrylamido phenyl boric acid is polymerized by three kinds of monomers under the action of the first crosslinking agent；Three
Planting monomer is respectively：Acrylamido phenyl boric acid, amides and Third monomer, acrylamido phenyl boric acid, amides and third
The mole percent ratio of monomer is (5-20)：(0-30)：(50-95)；
Chitosan forms chitosan crosslinked network under the action of the second crosslinking agent.
5. a kind of preparation method of full interpenetration network hydrogel of glucose-sensitive type according to claim 4, feature exist
In the molecular weight of chitosan is 100,000-40 ten thousand in step (1), and the mass concentration of chitosan solution is 2%-5%；In step (1)
If chitosan is soluble in water, directly used after dissolving, if dissolving chitosan in acetic acid solution, magnetic force is carried out after dissolving
Stirring.
6. a kind of preparation method of full interpenetration network hydrogel of glucose-sensitive type according to claim 4, feature exist
In the mole percent ratio of acrylamido phenyl boric acid, amides and Third monomer is (5-20) in step (2)：(0-30)：
(50-95)；The quality of first crosslinking agent is the 0.1%-1% of three kinds of monomer mass sums；
Amides select acrylamide or Methacrylamide；Third monomer selects dimethacrylamide, methacrylic acid two
Methylamino ethyl ester or n-isopropyl acrylamide；First crosslinking agent selects diene class crosslinking agent；Accelerator selects tetramethyl diamines.
7. a kind of preparation method of full interpenetration network hydrogel of glucose-sensitive type according to claim 4, feature exist
In the quality of initiator is the 0.03%-3% of three kinds of monomer mass sums in step (3), and initiator selects ammonium persulfate, over cure
Sour potassium, sodium peroxydisulfate, dibenzoyl peroxide or azodiisobutyronitrile；Second crosslinking agent selects glutaraldehyde, sodium tripolyphosphate, six
Sodium metaphosphate, sodium β-glycerophosphate or epoxychloropropane；After taking out magneton, room temperature stands solution 24 hours.
8. a kind of full interpenetration network hydrogel of glucose-sensitive type described in claim 1 is in detection glucose content and insulin
Application in release system.
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| CN110511322A (en) * | 2019-08-29 | 2019-11-29 | 西北大学 | A kind of interpenetrating net polymer microgel and preparation method thereof of rapid glucose response |
| CN110527023A (en) * | 2019-08-29 | 2019-12-03 | 西北大学 | A kind of glucose-sensitive interpenetrating net polymer hydrogel and preparation method thereof based on microgel |
| CN111116996A (en) * | 2020-01-08 | 2020-05-08 | 曲阜师范大学 | Cellulose aerogel modified by surfactant and preparation method thereof |
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Application publication date: 20180803 |
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