CN110627976A - Tussah silk fibroin hydrogel and preparation method and application thereof - Google Patents
Tussah silk fibroin hydrogel and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of biomedical materials, in particular to tussah silk fibroin hydrogel and a preparation method and application thereof. The invention provides a preparation method of tussah silk fibroin hydrogel, which comprises the following steps: (1) mixing tussah silk fibroin and quaternary ammonium salt, and carrying out ring-opening addition reaction to obtain quaternized tussah silk fibroin; (2) and mixing the quaternized tussah silk fibroin and N-isopropyl acrylamide, and carrying out in-situ polymerization reaction under the action of an initiator to obtain the tussah silk fibroin hydrogel. The tussah silk fibroin hydrogel prepared by the method has good biocompatibility and strong cell adhesion capability, can promote cell proliferation, and has good mechanical property, temperature responsiveness and antibacterial property.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to tussah silk fibroin hydrogel and a preparation method and application thereof.
Background
Biomedical materials need to have the following characteristics: (1) biocompatibility matched with biological tissues promotes tissue cell proliferation; (2) mechanical strength to match biological tissue; (3) the degradation product has no toxic or side effect; (4) with adjustable functionality.
At present, silk fibroin is widely applied to matrix materials of tissue engineering, biomedicine and cell engineering, has no toxicity, no stimulation, low or no immunogenicity, has good biocompatibility and can promote cell growth. Silk fibroin is a general name of silkworm silk fibroin and tussor silk fibroin, the silkworm silk fibroin is continuously developed in recent decades and has been widely applied, but the tussor silk fibroin is not fully researched and developed, the tussah silk fibroin is taken as a typical tussor silk protein which is mainly composed of amino acids and has no obvious difference with the silkworm silk fibroin, but the tussah silk protein contains a unique arginine-glycyl-aspartic acid (RGD) tripeptide sequence, the RGD tripeptide sequence is a binding site of a cell integrin receptor and can be specifically bound with mammalian cells, and the RGD tripeptide sequence can promote the interaction between the mammalian cells and extracellular matrix, so that the tussah silk fibroin can provide stronger cell adhesion capacity compared with the tussah silk fibroin.
However, the tussah silk fibroin contains a large number of poly-alanine sequences, has strong hydrophobicity, poor mechanical property after forming gel, is fragile, and cannot meet the requirements of modern biomaterials.
Disclosure of Invention
The invention aims to provide tussah silk fibroin hydrogel and a preparation method and application thereof. The tussah silk fibroin hydrogel prepared by the method has good biocompatibility and strong cell adhesion capability, can promote cell proliferation, and has good mechanical property, temperature responsiveness and antibacterial property.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of tussah silk fibroin hydrogel, which comprises the following steps:
(1) mixing tussah silk fibroin and quaternary ammonium salt, and carrying out ring-opening addition reaction to obtain quaternized tussah silk fibroin;
(2) and mixing the quaternized tussah silk fibroin and N-isopropyl acrylamide, and carrying out in-situ polymerization reaction under the action of an initiator to obtain the tussah silk fibroin hydrogel.
Preferably, the mass ratio of the tussah silk fibroin to the quaternary ammonium salt in the step (1) is (1-3): (3-5).
Preferably, the mixing in step (1) is carried out in a specific manner: and (3) dropwise adding the quaternary ammonium salt into the tussah silk fibroin in the form of a quaternary ammonium salt aqueous solution at the speed of 12 drops/min.
Preferably, the mixing in the step (1) is carried out under the condition that the pH value is 10-11.
Preferably, the temperature of the ring-opening addition reaction in the step (1) is 20-30 ℃, and the time of the ring-opening addition reaction is 2-3 h.
Preferably, the mass ratio of the quaternized tussah silk fibroin in the step (2) to the N-isopropylacrylamide is (1-3): (1-7).
Preferably, the initiator in the step (2) comprises ammonium persulfate and N, N, N ', N' -tetramethylethylenediamine.
Preferably, the temperature of the in-situ polymerization reaction is room temperature, and the time is 12-16 h.
The invention also provides the tussah silk fibroin hydrogel prepared by the preparation method of the technical scheme.
The invention also provides the application of the tussah silk fibroin hydrogel in the technical field of medical dressing, cell culture or drug sustained release.
The invention provides a preparation method of tussah silk fibroin hydrogel, which comprises the following steps: (1) mixing tussah silk fibroin and quaternary ammonium salt, and carrying out ring-opening addition reaction to obtain quaternized tussah silk fibroin; (2) and mixing the quaternized tussah silk fibroin and N-isopropyl acrylamide, and carrying out in-situ polymerization reaction under the action of an initiator to obtain the tussah silk fibroin hydrogel. In the invention, the unique RGD tripeptide sequence of the tussah silk fibroin is beneficial to cell growth, and the quaternary ammonium salt is subjected to ring-opening addition reaction to obtain the quaternized tussah silk fibroin with excellent antibacterial performance; the amino acid on the quaternized tussah silk fibroin is connected with the poly-N-isopropylacrylamide through a hydrogen bond, so that the tussah silk fibroin hydrogel with good mechanical property, temperature responsiveness and antibacterial property is obtained, and the quaternized tussah silk fibroin hydrogel has wide application prospects in the fields of medical dressings, cell culture or drug sustained release and the like. Compared with the prior art of preparing a gel material by adopting a cross-linking agent, the tussah silk fibroin hydrogel prepared by the method is non-toxic, has no residue, has excellent comprehensive performance, and has better economic and social benefits.
Drawings
FIG. 1 shows the conditions of 18h of the tussah silk fibroin hydrogel prepared in examples 1-3 and comparative example 1;
FIG. 2 shows the antibacterial effect of the samples prepared in examples 1 to 3 and comparative examples 1 to 3 on Escherichia coli;
FIG. 3 shows the antibacterial effect of the samples prepared in examples 1 to 3 and comparative examples 1 to 3 on Staphylococcus aureus;
FIG. 4 is a stress-strain curve of the tussah silk fibroin hydrogel prepared in examples 1-3;
FIG. 5 is a diagram of a tussah silk fibroin hydrogel prepared in examples 1-3;
FIG. 6 is a pictorial view of a sample prepared in comparative examples 1 to 3;
FIG. 7 is a curve of the equilibrium swelling ratios of the tussah silk fibroin hydrogel prepared in examples 1-3 at different temperatures;
FIG. 8 is a first derivative curve of the equilibrium swelling ratio of FIG. 7.
Detailed Description
The invention provides a preparation method of tussah silk fibroin hydrogel, which comprises the following steps:
(1) mixing tussah silk fibroin and quaternary ammonium salt, and carrying out ring-opening addition reaction to obtain quaternized tussah silk fibroin;
(2) and mixing the quaternized tussah silk fibroin and N-isopropyl acrylamide, and carrying out in-situ polymerization reaction under the action of an initiator to obtain the tussah silk fibroin hydrogel.
In the present invention, unless otherwise specified, the starting materials for the preparation are all commercially available products well known to those skilled in the art.
The invention mixes the tussah silk fibroin and quaternary ammonium salt to carry out ring-opening addition reaction to obtain the quaternized tussah silk fibroin. The preparation method of the tussah silk fibroin is not specially limited, and the preparation method of the tussah silk fibroin which is conventional in the field can be adopted. As an embodiment of the present invention, the preparation method of the tussah silk fibroin is preferably: (1) degumming tussah cocoons: cutting tussah cocoons, weighing, boiling in a sodium carbonate aqueous solution with the mass concentration of 0.5% for 30min, repeatedly washing with deionized water for three times, continuously repeating the boiling and washing steps for 2 times, and naturally drying degummed tussah silk; (2) tussah silk dissolution: dissolving degummed tussah silk in 12mol/L lithium thiocyanate solution for 5h to obtain crude tussah silk fibroin solution; then putting the crude tussah silk fibroin solution into a 8000-14000 kDa dialysis bag, and dialyzing for 3d with water; and finally, freeze-drying the dialyzed tussah silk fibroin to obtain the spongy tussah silk fibroin.
In the present invention, the quaternary ammonium salt is preferably an epoxy-based quaternary ammonium salt, and more preferably 2, 3-epoxypropyltrimethylammonium chloride.
In the invention, the mass ratio of the tussah silk fibroin to the quaternary ammonium salt is preferably (1-3): (3-5), more preferably (1.5-2.2): (3.1-5), most preferably (1.8-2.1): (4.5-5).
In the present invention, the specific manner of mixing is preferably: the quaternary ammonium salt is dripped into the tussah silk fibroin in the form of quaternary ammonium salt aqueous solution, and more preferably: the tussah silk fibroin is firstly dissolved in water to obtain tussah silk fibroin aqueous solution, and then the quaternary ammonium salt aqueous solution is dripped into the tussah silk fibroin aqueous solution. In the invention, the concentration of the quaternary ammonium salt aqueous solution is preferably 0.3-0.5 g/mL, more preferably 0.45-0.5 g/mL; the concentration of the tussah silk fibroin aqueous solution is preferably 20-30 mg/mL, and more preferably 25 mg/mL. In the present invention, magnetic stirring is preferably carried out simultaneously with the dropwise addition. In the present invention, the dropping speed is preferably 12 drops/min, specifically, one drop at every 5 seconds. The method adopts a dropwise adding mode for mixing, can ensure that the dropwise added quaternary ammonium salt and the tussah silk fibroin fully react, and simultaneously avoids the conformation transformation of the tussah silk fibroin.
In the present invention, the mixing is preferably performed at a pH of 10 to 11. The method preferably utilizes a sodium hydroxide solution to adjust the pH value of the tussah silk fibroin aqueous solution to 10-11, and then the tussah silk fibroin aqueous solution is mixed with a quaternary ammonium salt aqueous solution, wherein the concentration of the sodium hydroxide solution is preferably 1 mol/L. The invention limits the mixing under the condition of the pH value, and is beneficial to promoting the smooth operation of the ring-opening addition reaction of the quaternary ammonium salt and the tussah silk fibroin.
In the invention, the mixing is preferably carried out under the ice-water bath condition, and the mixing temperature is preferably 0-10 ℃, and more preferably 5 ℃. The invention limits the tussah silk fibroin to be mixed with the quaternary ammonium salt under the condition of low temperature, can prevent the tussah silk fibroin from being gelatinized, and if the tussah silk fibroin is changed into a stable structure after the gelatinization, the reaction with the quaternary ammonium salt becomes difficult.
In the invention, the temperature of the ring-opening addition reaction is preferably 20-30 ℃, and more preferably 25-30 ℃; the time of the ring-opening addition reaction is preferably 2-3 h, more preferably 2.5-3 h, and the timing is started when the system temperature reaches the temperature required by the ring-opening addition reaction.
In a specific embodiment of the present invention, when the quaternary ammonium salt is 2, 3-epoxypropyltrimethylammonium chloride, the formula of the ring-opening addition reaction is:
the epoxypropyl three-membered ring structure in the 2, 3-epoxypropyltrimethylammonium chloride is active, can perform a ring-opening reaction under the catalysis of alkali, and has an amino group (NH) on the tussah silk fibroin during the reaction with the tussah silk fibroin3) And (3) directly attacking the central carbon atom of the epoxy three-membered ring by the nucleophilic group and the amino group to break and open the C-O ring, and then carrying out ring opening addition reaction to generate the quaternized tussah silk fibroin.
After the ring-opening addition reaction is finished, preferably, the obtained system is dialyzed and freeze-dried in sequence to obtain the quaternized tussah silk fibroin. In the present invention, the specific method of dialysis is preferably: and (3) placing the system obtained by the ring-opening addition reaction in a 8000-14000 kDa dialysis bag, dialyzing for 24 hours in a refrigerator at 4 ℃, and changing water once every 4 hours. The invention removes the unreacted quaternary ammonium salt in the ring-opening addition reaction process through dialysis. In the present invention, the temperature of the freeze-drying is preferably-50 ℃, and the freeze-drying is preferably performed under vacuum conditions.
After the quaternary ammonium tussah silk fibroin is obtained, the quaternary ammonium tussah silk fibroin and N-isopropyl acrylamide are mixed, and in-situ polymerization reaction is carried out under the action of an initiator to obtain the tussah silk fibroin hydrogel. In the invention, the mass ratio of the quaternized tussah silk fibroin to the N-isopropyl acrylamide is preferably (1-3): (1-7), more preferably 2: 3. In the invention, the N-isopropyl acrylamide is a temperature-sensitive polymer monomer, so that the tussah silk fibroin hydrogel has temperature responsiveness.
In the present invention, the initiator preferably includes ammonium persulfate and N, N' -tetramethylethylenediamine. In the invention, the ammonium persulfate is an initiator for monomer polymerization, and the N, N, N ', N' -tetramethylethylenediamine is an auxiliary initiator, so that the ammonium persulfate can be promoted to generate free radicals at a lower temperature, and the free radicals attack double bonds of the N-isopropylacrylamide monomer to polymerize the N-isopropylacrylamide monomer into a polymer. The initiator adopted by the invention belongs to a mild initiator, and can initiate polymerization reaction at room temperature, so that the influence on the structure of quaternized tussah silk fibroin can be avoided, and the initiator is more energy-saving and environment-friendly.
In the invention, the mass ratio of the ammonium persulfate to the N-isopropylacrylamide is preferably 1 (30-80), and more preferably 1: 50; the N, N, N ', N' -tetramethyl ethylenediamine preferably takes part in the reaction in the form of an aqueous solution, the mass fraction of the N, N, N ', N' -tetramethyl ethylenediamine aqueous solution is preferably 5%, and the dosage ratio of the N, N, N ', N' -tetramethyl ethylenediamine aqueous solution to ammonium persulfate is preferably 40-100 μ L: 2mg, more preferably 60 to 100. mu.L: 2 mg.
Preferably, the ammonium persulfate and the N-isopropyl acrylamide are dissolved in water to obtain a mixed solution of the ammonium persulfate and the N-isopropyl acrylamide, and then the mixed solution of the ammonium persulfate and the N-isopropyl acrylamide is mixed with the quaternized tussah silk fibroin to obtain a quaternized tussah silk fibroin solution; and mixing the quaternized tussah silk fibroin solution with N, N, N ', N' -tetramethyl ethylenediamine, and carrying out in-situ polymerization reaction to obtain the tussah silk fibroin hydrogel.
In the invention, the water is preferably deionized water, and the mass ratio of the N-isopropylacrylamide to the water is preferably 500mg: 8-15 mL, more preferably 500mg: 10 mL.
In the invention, the temperature of the in-situ polymerization reaction is preferably room temperature, specifically 20-30 ℃, and the time is preferably 12-16 h, and more preferably 12-14 h.
In a specific embodiment of the present invention, the ring-opening addition reaction has the formula:
after the in-situ polymerization reaction is finished, the system obtained by the in-situ polymerization reaction is preferably dialyzed to obtain the tussah silk fibroin hydrogel. In the present invention, the specific method of dialysis is preferably: putting the system obtained by the in-situ polymerization reaction into a 8000-14000 kDa dialysis bag, dialyzing for 8 hours, and changing water every 2 hours in the dialysis bag; the temperature of the dialysis is preferably 4 ℃. The invention removes unreacted substances in the in-situ polymerization reaction process through dialysis, and improves the purity of the tussah silk fibroin hydrogel.
The invention also provides the tussah silk fibroin hydrogel prepared by the preparation method of the technical scheme. The tussah silk fibroin hydrogel provided by the invention has good biocompatibility, antibacterial property, mechanical strength and temperature response characteristics, and in addition, the tussah silk fibroin hydrogel provided by the invention has no toxic or side effect, and is suitable for being used as a biomedical material.
The invention also provides the application of the tussah silk fibroin hydrogel in the technical field of medical dressing, cell culture or drug sustained release. In particular can be used as cell culture base material, cartilage, scaffold, medical antibacterial dressing, drug carrier and the like.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
1.543g of tussah silk fibroin is put into a three-mouth flask, deionized water is added for dissolution, 25mg/mL of tussah silk fibroin aqueous solution is prepared, and 1mol/L of sodium hydroxide solution is used for adjusting the pH value of the tussah silk fibroin aqueous solution to 10; immersing the three-neck flask in an ice-water bath, and keeping the temperature at 5 ℃; then dissolving 3.086g of 2, 3-epoxypropyltrimethylammonium chloride in 10mL of deionized water, dropwise adding the 2, 3-epoxypropyltrimethylammonium chloride solution into a three-neck flask by using a constant-pressure dropping funnel under magnetic stirring, wherein the dropping speed is 1 drop/5 seconds, adjusting the temperature of a water bath kettle to 20 ℃ after the dropping is finished, and carrying out ring-opening addition reaction for 2 hours; putting the obtained solution into a 8000-14000 kDa dialysis bag, dialyzing in a refrigerator at 4 ℃ for 24 hours, and changing water every 4 hours during the dialysis for removing unreacted quaternary ammonium salt; freeze-drying the dialyzed solution to finally obtain quaternized tussah silk fibroin;
weighing 500mg of N-isopropyl acrylamide monomer and 10mg of ammonium persulfate initiator, and dissolving with 10mL of deionized water; weighing 42.8mg of quaternized tussah silk fibroin, and placing in a 5mL glass test tube; firstly, a liquid transfer gun is used for measuring a mixed solution of 2 mLN-isopropyl acrylamide and ammonium persulfate, the mixed solution is injected into a test tube containing quaternized tussah silk fibroin, and the test tube is slightly shaken to dissolve the quaternized tussah silk fibroin; then adding 40 mu L of 5% N, N, N ', N' -tetramethylethylenediamine aqueous solution into the test tube, fully and uniformly mixing, and carrying out in-situ polymerization reaction for 16h at room temperature to form gel; and taking out the gel from the test tube, putting the gel into a dialysis bag with 8000-14000 kDa, dialyzing for 8h, changing water every 2h in the dialysis period, and removing unreacted substances to obtain the tussah silk fibroin hydrogel.
Example 2
1.809g of tussah silk fibroin is put into a three-mouth flask, deionized water is added for dissolution, 25mg/mL of tussah silk fibroin aqueous solution is prepared, and 1mol/L of sodium hydroxide solution is used for adjusting the pH value of the tussah silk fibroin aqueous solution to 10; immersing the three-neck flask in an ice-water bath, and keeping the temperature at 5 ℃; then 4.523g of 2, 3-epoxypropyltrimethylammonium chloride is dissolved in 10mL of deionized water, under the condition of magnetic stirring, a constant-pressure dropping funnel is adopted to dropwise add the 2, 3-epoxypropyltrimethylammonium chloride solution into a three-neck flask at the dropping speed of 1 drop/5 seconds, after the dropping is finished, the temperature of a water bath is adjusted to 25 ℃, and the ring-opening addition reaction is carried out for 2.5 hours; putting the obtained solution into a 8000-14000 kDa dialysis bag, dialyzing in a refrigerator at 4 ℃ for 24 hours, and changing water every 4 hours during the dialysis for removing unreacted quaternary ammonium salt; freeze-drying the dialyzed solution to finally obtain quaternized tussah silk fibroin;
weighing 500mg of N-isopropyl acrylamide monomer and 10mg of ammonium persulfate initiator, and dissolving with 10mL of deionized water; weighing 64.3mg of quaternized tussah silk fibroin, and placing the quaternized tussah silk fibroin in a 5mL glass test tube; firstly, a liquid transfer gun is used for measuring a mixed solution of 3 mLN-isopropyl acrylamide and ammonium persulfate, the mixed solution is injected into a test tube containing quaternized tussah silk fibroin, and the test tube is slightly shaken to dissolve the quaternized tussah silk fibroin; then adding 60 mu L of 5% N, N, N ', N' -tetramethylethylenediamine aqueous solution into the test tube, fully and uniformly mixing, and carrying out in-situ polymerization reaction for 14h at room temperature to form gel; and taking out the gel from the test tube, putting the gel into a dialysis bag with 8000-14000 kDa, dialyzing for 8h, changing water every 2h in the dialysis period, and removing unreacted substances to obtain the tussah silk fibroin hydrogel.
Example 3
2.137g of tussah silk fibroin is put into a three-mouth flask, deionized water is added for dissolution, 25mg/mL of tussah silk fibroin aqueous solution is prepared, and 1mol/L of sodium hydroxide solution is used for adjusting the pH value of the tussah silk fibroin aqueous solution to 10; immersing the three-neck flask in an ice-water bath, and keeping the temperature at 5 ℃; then 4.986g of 2, 3-epoxypropyltrimethylammonium chloride is dissolved in 10mL of deionized water, under the condition of magnetic stirring, a constant-pressure dropping funnel is adopted to dropwise add the 2, 3-epoxypropyltrimethylammonium chloride solution into a three-neck flask at the dropping speed of 1 drop/5 seconds, after the dropping is finished, the temperature of a water bath is adjusted to 30 ℃, and ring-opening addition reaction is carried out for 3 hours; putting the obtained solution into a 8000-14000 kDa dialysis bag, dialyzing in a refrigerator at 4 ℃ for 24 hours, and changing water every 4 hours during the dialysis for removing unreacted quaternary ammonium salt; freeze-drying the dialyzed solution to finally obtain quaternized tussah silk fibroin;
weighing 500mg of N-isopropyl acrylamide monomer and 10mg of ammonium persulfate initiator, and dissolving with 10mL of deionized water; weighing 107.1mg of quaternized tussah silk fibroin, and placing in a 5mL glass test tube; firstly, a liquid transfer gun is used for measuring a mixed solution of 5 mLN-isopropyl acrylamide and ammonium persulfate, the mixed solution is injected into a test tube containing quaternized tussah silk fibroin, and the test tube is slightly shaken to dissolve the quaternized tussah silk fibroin; then adding 100 mu L of 5% N, N, N ', N' -tetramethylethylenediamine aqueous solution into the test tube, fully and uniformly mixing, and carrying out in-situ polymerization reaction for 12h at room temperature to form gel; and taking out the gel from the test tube, putting the gel into a dialysis bag with 8000-14000 kDa, dialyzing for 8h, changing water every 2h in the dialysis period, and removing unreacted substances to obtain the tussah silk fibroin hydrogel.
Comparative example 1
Weighing 500mg of N-isopropyl acrylamide monomer and 10mg of ammonium persulfate initiator, and dissolving with 10mL of deionized water; weighing 42.8mg of tussah silk fibroin, and placing in a 5mL glass test tube; firstly, a liquid transfer gun is used for measuring a mixed solution of 2 mLN-isopropyl acrylamide and ammonium persulfate, the mixed solution is injected into a test tube containing tussah silk fibroin, and the test tube is slightly shaken to dissolve the tussah silk fibroin; then, adding 40 mu L of 5% N, N, N ', N' -tetramethylethylenediamine aqueous solution into the test tube, fully and uniformly mixing, and carrying out in-situ polymerization reaction for 12h at room temperature to form gel; and taking out the gel from the test tube, putting the gel into a dialysis bag with 8000-14000 kDa, dialyzing for 8 hours, and removing unreacted substances to obtain the non-quaternized tussah silk fibroin hydrogel.
Comparative example 2
Weighing 500mg of N-isopropylacrylamide monomer and 10mg of ammonium persulfate initiator, dissolving the N-isopropylacrylamide monomer and the ammonium persulfate initiator by using 10mL of deionized water, taking a mixed solution of 2 mLN-isopropylacrylamide and ammonium persulfate by using a liquid-transferring gun, injecting the mixed solution into a 5mL glass bottle, adding 40 mu L of 5% N, N, N ', N' -tetramethylethylenediamine aqueous solution into the bottle, fully and uniformly mixing, carrying out in-situ polymerization reaction for 12h at room temperature, placing the bottle in a 8000-4000 kDa dialysis bag, dialyzing for 8h, and removing unreacted substances, wherein the finally obtained product does not form a gel material with a geometric shape, but is a viscous flowable liquid which has temperature sensitivity but cannot become gel, and cannot detect mechanical properties, and has no mechanical properties.
Comparative example 3
1.543g of tussah silk fibroin is put into a three-neck flask, deionized water is added for dissolution, 25mg/mL of tussah silk fibroin aqueous solution is prepared, and 1mol/L of NaOH solution is used for adjusting the pH value of the tussah silk fibroin aqueous solution to 10-11; immersing the three-neck flask in an ice-water bath, and keeping the temperature at 5 ℃; then dissolving 3.086g of 2, 3-epoxypropyltrimethylammonium chloride in 10mL of deionized water, dropwise adding the 2, 3-epoxypropyltrimethylammonium chloride solution into a three-necked bottle by using a constant-pressure dropping funnel under magnetic stirring, wherein the dropping speed is 1 drop/5 seconds, the dropping time is 10min, adjusting the temperature of a water bath to 20 ℃ after the dropping is finished, and carrying out ring-opening addition reaction for 2 h; putting the obtained solution into a 8000-14000 kDa dialysis bag, dialyzing in a refrigerator at 4 ℃ for 24 hours, and changing water every 4 hours during the dialysis for removing unreacted quaternary ammonium salt; freeze-drying the dialyzed solution to finally obtain quaternized tussah silk fibroin;
weighing 42.8mg of quaternized tussah silk fibroin, placing the quaternized tussah silk fibroin in a 5mL glass bottle, adding 2mL of deionized water into the glass bottle, uniformly dissolving, standing for 12h, changing the quaternized tussah silk fibroin from original light yellow transparent liquid into white gel, enabling the gel to still flow when the glass bottle is inverted or shaken, and enabling the gel to be fragile, so that the mechanical property cannot be detected.
Test example 1
The antibacterial performance of the tussah silk fibroin hydrogel prepared in the examples 1-3 and the comparative example 1 is detected according to the GB15979-2002 standard: the tussah silk fibroin hydrogel prepared in examples 1-3 and comparative example 1 was infected with bacteria, cultured on agar medium patch, and cultured at 37 ℃ for 18h, and the infection is shown in fig. 1. As can be clearly seen from fig. 1, after the tussah silk fibroin hydrogel patches prepared in examples 1 to 3 were cultured, no obvious colonies were observed on the agar medium, whereas after the tussah silk fibroin hydrogel patches prepared in comparative example 1 were cultured, many colonies grew on the agar medium.
And (3) calculating the bacteriostasis rate of the tussah silk fibroin hydrogel prepared in the examples 1-3 by taking the comparative example 1 as a control group, wherein the calculation formula of the bacteriostasis rate is as follows: bacteriostasis rate X4(A-B)/A × 100%, wherein A is the average colony number of the control sample, and B is the average colony number of the tested sample; knotIf as shown in table 1:
TABLE 1 inhibition ratio of tussah silk fibroin hydrogel prepared in examples 1-3
| Bacterial strain | Example 1 | Example 2 | Example 3 |
| Escherichia coli ATCC25922 | 76.5％ | 92.7％ | 98.6％ |
| Staphylococcus aureus ATCC6538 | 81.9％ | 94.6％ | 99.7％ |
As can be seen from Table 1, compared with the gel prepared by non-quaternized modified tussah silk fibroin in comparative example 1, the bacteriostatic rate of example 1 is not less than 75%, and the gel has bacteriostatic action, and the bacteriostatic rates of examples 2-3 are not less than 90%, and has stronger bacteriostatic action.
Test example 2
And (3) carrying out antibacterial effect detection on the samples prepared in the examples 1-3 and the comparative examples 1-3 by adopting a turbidity measurement method: the number of microorganisms in the culture solution was measured by using the absorbance on an ultraviolet spectrophotometer, each sample of examples 1 to 3 and comparative examples 1 to 3 was cultured in a liquid medium containing a bacterial solution at 37 ℃ for 18 hours, the absorbance at 600nm of the experiment was used as an index to evaluate the growth of the microorganisms, and the OD of each sample was measured to be 600nm, and the bacterial growth of each sample was reflected, as shown in FIG. 2 and FIG. 3.
As can be seen from the graphs in FIGS. 2 to 3, the tussah silk fibroin hydrogel prepared in the examples 1 to 3 has a good antibacterial effect on Escherichia coli and Staphylococcus aureus, and the number of bacteria in 18h is low; in comparison examples 1-2, the bacteria have a large number of bacteria in 18h and no antibacterial property; the comparative example 3 has a good antibacterial effect on escherichia coli and staphylococcus aureus, but does not have mechanical properties due to in-situ polymerization with N-isopropylacrylamide, which can show that the antibacterial effect of the tussah silk fibroin hydrogel prepared by the invention has a direct relation with quaternization of the tussah silk fibroin.
Test example 3
The compression mode is adopted to detect the compression mechanical properties of the tussah silk fibroin hydrogel prepared in the embodiment 1-3, the stress-strain curve is shown in fig. 4, the tussah silk fibroin hydrogel is not crushed within 50% of deformation, and the bearable stress is gradually increased along with the increase of the deformation, so that the tussah silk fibroin hydrogel prepared in the embodiment 1-3 can meet the mechanical property requirements of some tissues and can be used as a biomedical material.
Test example 4
Fig. 5 shows a real object diagram of the tussah silk fibroin hydrogel prepared in examples 1 to 3, and fig. 6 shows a real object diagram of the sample prepared in comparative examples 1 to 3, and it can be seen from fig. 5 that the tussah silk fibroin hydrogel prepared in examples 1 to 3 can be made into gel materials with different shapes; as can be seen from fig. 6, the samples prepared in comparative examples 2 and 3 did not become gel, and were still flowable when inverted and shaken, and had no mechanical properties. Although the sample prepared in the comparative example 1 can form gel, the antibacterial performance test of the test examples 1-2 finds that the sample in the comparative example 1 has no antibacterial effect, which indicates that the higher mechanical strength and the high antibacterial property of the tussah silk fibroin hydrogel prepared by the invention are brought by the quaternization of the tussah silk fibroin and the in-situ polymerization of N-isopropyl, and the defect is that the quaternary ammonium tussah silk fibroin and the N-isopropyl have no compatibility.
Test example 5
The results of testing the equilibrium swelling properties of the tussah silk fibroin hydrogel prepared in examples 1-3 at different temperatures are shown in fig. 7 and 8. As can be seen from fig. 7, as the temperature increases, the equilibrium swelling ratio of the tussah silk fibroin hydrogel prepared in examples 1 to 3 gradually decreases, fig. 8 is obtained by first-order derivation of the swelling ratio curve, the first-order derivation is performed on the deswelling curve of the gel, that is, the first-order derivative of the equilibrium swelling ratio with respect to the temperature, the LCST of the gel can be determined according to the peak temperature corresponding to the absolute value, meanwhile, the response sensitivity of the gel can be determined according to the peak area of the curve, and fig. 8 shows that the tussah silk fibroin hydrogel prepared in examples 1 to 3 has a temperature response characteristic at 32 ℃, which indicates that the tussah silk fibroin hydrogel prepared by the present invention has a temperature-sensitive characteristic.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The preparation method of the tussah silk fibroin hydrogel is characterized by comprising the following steps:
(1) mixing tussah silk fibroin and quaternary ammonium salt, and carrying out ring-opening addition reaction to obtain quaternized tussah silk fibroin;
(2) and mixing the quaternized tussah silk fibroin and N-isopropyl acrylamide, and carrying out in-situ polymerization reaction under the action of an initiator to obtain the tussah silk fibroin hydrogel.
2. The preparation method of claim 1, wherein the mass ratio of the tussah silk fibroin to the quaternary ammonium salt in the step (1) is (1-3): (3-5).
3. The method according to claim 1 or 2, wherein the mixing in step (1) is carried out in a specific manner: and (3) dropwise adding the quaternary ammonium salt into the tussah silk fibroin in the form of a quaternary ammonium salt aqueous solution at the speed of 12 drops/min.
4. The method according to claim 3, wherein the mixing in step (1) is carried out at a pH of 10 to 11.
5. The preparation method according to claim 1, wherein the temperature of the ring-opening addition reaction in the step (1) is 20 to 30 ℃, and the time of the ring-opening addition reaction is 2 to 3 hours.
6. The preparation method according to claim 1, wherein the mass ratio of the quaternized tussah silk fibroin in the step (2) to the N-isopropylacrylamide is (1-3): (1-7).
7. The method according to claim 1, wherein the initiator in the step (2) comprises ammonium persulfate and N, N, N ', N' -tetramethylethylenediamine.
8. The preparation method according to claim 1, wherein the in-situ polymerization reaction is carried out at room temperature for 12-16 h.
9. The tussah silk fibroin hydrogel prepared by the preparation method of any one of claims 1-8.
10. The tussah silk fibroin hydrogel of claim 9, wherein the tussah silk fibroin hydrogel is used in the technical fields of medical dressing, cell culture or drug sustained release.
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| CN111317869A (en) * | 2020-02-29 | 2020-06-23 | 福建医科大学附属第二医院 | Novel injectable hydrogel for treating bronchial pleural fistula |
| CN113072717A (en) * | 2021-03-23 | 2021-07-06 | 北京理工大学 | Silk fibroin-NIPAM photonic crystal hydrogel and preparation method thereof |
| CN114392728A (en) * | 2021-12-29 | 2022-04-26 | 重庆大学 | Magnetic hydrogel capable of efficiently adsorbing cationic dye and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111317869A (en) * | 2020-02-29 | 2020-06-23 | 福建医科大学附属第二医院 | Novel injectable hydrogel for treating bronchial pleural fistula |
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| CN114392728A (en) * | 2021-12-29 | 2022-04-26 | 重庆大学 | Magnetic hydrogel capable of efficiently adsorbing cationic dye and preparation method and application thereof |
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