CN113813440B - Bioadhesive adjustable hydrogel material and preparation method and application thereof - Google Patents
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Abstract
The invention provides a bioadhesive adjustable hydrogel material, a preparation method and application thereof, and belongs to the technical field of medical hydrogels. The hydrogel material at least comprises polyethylene glycol dopamine and polyethylene glycol activated ester. The mass ratio of the polyethylene glycol dopamine to the polyethylene glycol activating ester is 0.1-1: 1 to 10. The hydrogel prepared by the invention has low swelling rate and bioadhesion, so that the hydrogel is particularly suitable for being used as a surgical sealant; meanwhile, the preparation method is used for obtaining the hydrogel under the normal temperature condition by mixing the components, and has the advantages of simple and convenient steps, simple operation, easy industrialized mass production and the like, so that the preparation method has wide application prospect.
Description
Technical Field
The invention belongs to the technical field of medical hydrogels, and particularly relates to a bioadhesive adjustable hydrogel material, a preparation method and application thereof.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
The surgical sealant can be used for sealing operation wounds in human bodies, has the functions of adhesion and sealing on the wounds after the gluing, and is degraded along with the healing of the wounds. It has been used in various surgical operations such as respiratory surgery, digestive surgery, cardiovascular surgery, oral surgery, neurosurgery, etc. The suture is applied to clinical operation, so that the use of suture lines and the occurrence of postoperative anastomotic stoma leakage can be reduced, and the operation time can be obviously shortened.
The hydrogel is used as a biocompatible material and is mainly used for postoperative anti-adhesion, hemostatic, filling of defective tissues, prevention of tissue fluid leakage, slow release of drugs and the like in medicine. And thus can be used as a surgical sealant. The prior art CN201911014682.0 discloses a polyethylene glycol activated ester, and the hydrogel material prepared by the polyethylene glycol activated ester has lower swelling rate, so that the problem of injury to human bodies is reduced. However, the inventor further researches and found that the bioadhesion of the hydrogel prepared by the method is deficient, so that the further preparation of the medical hydrogel with good bioadhesion and bioadhesion adjustability is of great significance.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a bioadhesive adjustable hydrogel material, a preparation method and application thereof. According to the research of the invention, after polyethylene glycol dopamine is added, the bioadhesion of the prepared hydrogel can be effectively improved, and the swelling rate of the hydrogel can be further reduced, so that the hydrogel has good practical application value.
In particular, in a first aspect of the present invention, there is provided a bioadhesive tunable hydrogel material comprising at least polyethylene glycol dopamine and polyethylene glycol-like activated esters.
The mass ratio of the polyethylene glycol dopamine to the polyethylene glycol activating ester is 0.1-1: 1 to 10, preferably 1:3.
wherein the polyethylene glycol dopamine comprises one or more of four-arm polyethylene glycol dopamine, six-arm polyethylene glycol dopamine and eight-arm polyethylene glycol dopamine;
the weight average molecular weight (Mw) of the four-arm polyethylene glycol dopamine, the six-arm polyethylene glycol dopamine and the eight-arm polyethylene glycol dopamine is 0.1-4 ten thousand daltons.
The weight average molecular weight of the quadrifilar polyethylene glycol dopamine can be 1000, 2000, 5000, 10000, 20000 and 40000 daltons.
The weight average molecular weight of the six-arm polyethylene glycol dopamine can be 1000, 2000, 5000, 10000, 20000 and 40000 daltons.
The weight average molecular weight of the eight-arm polyethylene glycol dopamine can be 1000, 2000, 5000, 10000, 20000 and 40000 daltons.
Experiments prove that under the condition of the same molecular weight, the eight-arm polyethylene glycol dopamine can provide more crosslinking points than the four-arm polyethylene glycol dopamine and the six-arm polyethylene glycol dopamine, but the contained dopamine is relatively less, so that the adhesion effect is relatively reduced, and the bioadhesion of the final hydrogel is regulated by controlling the type and the dosage of the specific polyethylene glycol dopamine.
The polyethylene glycol activating ester comprises one or more of polyethylene glycol succinimide glutarate, polyethylene glycol succinimide adipic acid ester, polyethylene glycol succinimide suberate and polyethylene glycol succinimide sebacic acid ester.
Preferably, the polyethylene glycol activating ester comprises at least two of polyethylene glycol succinimide glutarate, polyethylene glycol succinimide adipate, polyethylene glycol succinimide suberate and polyethylene glycol succinimide sebacate.
Preferably, the polyethylene glycol activating ester is a combination of polyethylene glycol succinimidyl glutarate and polyethylene glycol succinimidyl sebacate.
More preferably, the polyethylene glycol succinimidyl glutarate is a four-arm polyethylene glycol succinimidyl glutarate, a six-arm polyethylene glycol succinimidyl glutarate or an eight-arm polyethylene glycol succinimidyl glutarate, and the weight average molecular weight (Mw) is 2000-40000 daltons, preferably 10000-20000 daltons;
the polyethylene glycol succinimide sebacate is four-arm polyethylene glycol succinimide sebacate, six-arm polyethylene glycol succinimide sebacate or eight-arm polyethylene glycol succinimide sebacate, and the weight average molecular weight (Mw) is 2000-40000 daltons, preferably 10000-20000 daltons.
More preferably, the mass ratio of the polyethylene glycol succinimidyl glutarate to the polyethylene glycol succinimidyl sebacate is 0.1-1: 1 to 10, preferably 1:2.
preferably, the bioadhesive tunable hydrogel material further comprises a cross-linking agent comprising at least one of polylysine, polyethylenimine and aminopolyethylene glycol;
more preferably, the crosslinking agent includes polylysine and polyethyleneimine;
further preferably, the mass ratio of polylysine to polyethyleneimine is 5-95: 95-5.
Preferably, the bioadhesive tunable hydrogel material may further comprise a coloring agent, a drug and/or an antioxidant.
In a second aspect of the present invention, there is provided a method for preparing the above bioadhesive tunable hydrogel material, the method comprising:
and uniformly mixing polyethylene glycol dopamine, polyethylene glycol activating ester and a cross-linking agent.
The mass ratio of the polyethylene glycol dopamine to the polyethylene glycol activating ester to the cross-linking agent is as follows: 0.1 to 1:1 to 10:0.1 to 0.5.
The reaction is carried out under the condition of a solution, and a solvent in the solution can be a buffer solution.
Specifically, the polyethylene glycol dopamine and polyethylene glycol activating ester are dissolved in a buffer solution A to obtain a solution A;
the cross-linking agent is dissolved in the buffer solution B to obtain a solution B; thus, in one embodiment of the invention, the method of preparation comprises:
mixing the solution A and the solution B and extruding; or alternatively, the process may be performed,
mixing solution A, solution B, and coloring agent, medicine and/or antioxidant, and extruding.
Wherein, the liquid crystal display device comprises a liquid crystal display device,
the buffer solution A can be an acidic phosphate solution (0.5-1.5 mM, pH 3.5-6.5);
the buffer B may be an alkaline borate solution (50-80 mM, pH 7.5-10.5).
In a third aspect of the invention, there is provided the use of the above-described hydrogel material with adjustable bioadhesion in the preparation of biomedical materials;
the beneficial effects of the above technical scheme are that:
1) The hydrogel prepared by the technical scheme has low swelling rate and bioadhesion, and the bioadhesion of the final hydrogel is adjusted by controlling the type and the amount of specific polyethylene glycol dopamine added, so that the hydrogel is particularly suitable for being used as a surgical sealant.
2) The preparation method of the hydrogel provided by the technical scheme comprises the steps of mixing the components, and obtaining the hydrogel under the normal temperature condition; the method has the advantages of simple and convenient steps, simple operation, easy industrialized mass production and the like, and has wide application prospect.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
In one exemplary embodiment of the present invention, a bioadhesive tunable hydrogel material is provided comprising at least polyethylene glycol dopamine and polyethylene glycol-based activated esters.
In another specific embodiment of the invention, the mass ratio of the polyethylene glycol dopamine to the polyethylene glycol activating ester is 0.1-1: 1 to 10, preferably 1:3.
wherein the polyethylene glycol dopamine comprises one or more of four-arm polyethylene glycol dopamine, six-arm polyethylene glycol dopamine and eight-arm polyethylene glycol dopamine;
the molecular weight of the four-arm polyethylene glycol dopamine, the six-arm polyethylene glycol dopamine and the eight-arm polyethylene glycol dopamine is 0.1-4 ten thousand daltons.
The molecular weight of the quadrifilar polyethylene glycol dopamine can be 1000, 2000, 5000, 10000, 20000 and 40000 daltons.
The molecular weight of the six-arm polyethylene glycol dopamine can be 1000, 2000, 5000, 10000, 20000 and 40000 daltons.
The molecular weight of the eight-arm polyethylene glycol dopamine can be 1000, 2000, 5000, 10000, 20000 and 40000 daltons.
Experiments prove that under the condition of the same molecular weight, the eight-arm polyethylene glycol dopamine can provide more crosslinking points than the four-arm polyethylene glycol dopamine and the six-arm polyethylene glycol dopamine, but the contained dopamine is relatively less, so that the adhesion effect is relatively reduced, and the bioadhesion of the final hydrogel is regulated by controlling the type and the dosage of the specific polyethylene glycol dopamine.
In yet another embodiment of the present invention, the polyethylene glycol-based activating esters include one or more of polyethylene glycol succinimide glutarate, polyethylene glycol succinimide adipate, polyethylene glycol succinimide suberate, polyethylene glycol succinimide sebacate.
In yet another embodiment of the present invention, the polyethylene glycol-based activating esters include at least two of polyethylene glycol succinimide glutarate, polyethylene glycol succinimide adipate, polyethylene glycol succinimide suberate, polyethylene glycol succinimide sebacate.
In yet another embodiment of the present invention, the polyethylene glycol succinimidyl glutarate is a four-arm polyethylene glycol succinimidyl glutarate, a six-arm polyethylene glycol succinimidyl glutarate or an eight-arm polyethylene glycol succinimidyl glutarate, and the weight average molecular weight (Mw) is 2000 to 40000 daltons, preferably 10000 to 20000 daltons.
In yet another embodiment of the present invention, the polyethylene glycol succinimide sebacate is a four-arm polyethylene glycol succinimide sebacate, a six-arm polyethylene glycol succinimide sebacate, or an eight-arm polyethylene glycol succinimide sebacate, and the weight average molecular weight (Mw) is 2000 to 40000 daltons, preferably 10000 to 20000 daltons.
In another specific embodiment of the invention, the mass ratio of the polyethylene glycol succinimidyl glutarate to the polyethylene glycol succinimidyl sebacate is 0.1-1: 1 to 10, preferably 1:2.
in yet another embodiment of the present invention, the bioadhesive tunable hydrogel material further comprises a cross-linking agent comprising at least one of polylysine, polyethylenimine and aminopolyethylene glycol.
In yet another embodiment of the present invention, the crosslinking agent comprises polylysine and polyethylenimine.
In yet another embodiment of the present invention, the ratio of polylysine to polyethyleneimine is 5 to 95: 95-5.
In yet another embodiment of the present invention, the polylysine has a molecular weight of 100 to 3000 daltons; further comprises: trilysine (molecular weight 402 daltons), tetralysine (molecular weight 530 daltons), pentalysine (molecular weight 658 daltons), decalysine (molecular weight 1298 daltons).
In yet another embodiment of the present invention, the polyethyleneimine has a molecular weight of 1000 to 500000 daltons; including 1000 daltons, 1800 daltons, 2000 daltons, 5000 daltons, 10000 daltons, 15000 daltons, 200000 daltons, 250000 daltons, 300000 daltons, 400000 daltons, and 500000 daltons.
In yet another embodiment of the present invention, the aminopolyethylene glycol has a molecular weight of 1000 to 500000 daltons; including 1000 daltons, 5000 daltons, 10000 daltons, 15000 daltons, 200000 daltons, 250000 daltons, 300000 daltons, 400000 daltons, and 500000 daltons.
In yet another embodiment of the present invention, the bioadhesive tunable hydrogel material may further comprise a coloring agent, a drug and/or an antioxidant.
In still another embodiment of the present invention, there is provided a method for preparing the above bioadhesive tunable hydrogel material, the method comprising:
and uniformly mixing polyethylene glycol dopamine, polyethylene glycol activating ester and a cross-linking agent.
The mass ratio of the polyethylene glycol dopamine to the polyethylene glycol activating ester to the cross-linking agent is as follows: 0.1 to 1:1 to 10:0.1 to 0.5.
The reaction is carried out under the condition of a solution, and a solvent in the solution can be a buffer solution.
Specifically, the polyethylene glycol dopamine and polyethylene glycol activating ester are dissolved in a buffer solution A to obtain a solution A.
The cross-linking agent is dissolved in the buffer solution B to obtain a solution B; thus, in one embodiment of the invention, the method of preparation comprises:
mixing the solution A and the solution B and extruding; or alternatively, the process may be performed,
mixing solution A, solution B, and coloring agent, medicine and/or antioxidant, and extruding.
In yet another embodiment of the present invention, the buffer A may be an acidic phosphate solution (0.5-1.5 mM, pH 3.5-6.5).
The buffer B may be an alkaline borate solution (50-80 mM, pH 7.5-10.5).
In a further embodiment of the present invention, there is provided the use of the above-described bioadhesive tunable hydrogel material for the preparation of biomedical materials;
in yet another embodiment of the present invention, the biomedical material may be a surgical sealant.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail below with reference to specific examples and comparative examples.
Example 1
A bioadhesive tunable hydrogel material, the method of making the hydrogel material comprising:
according to the gel preparation amount, 0.1g of four-arm polyethylene glycol dopamine (weight average molecular weight 2000 Da), 0.2g of four-arm polyethylene glycol succinimidyl glutarate (weight average molecular weight 10000 Da) and 0.2g of four-arm polyethylene glycol succinimidyl sebacate (weight average molecular weight 20000 Da) are added into 2.5mL of PBS (1.5 mM, pH=4.0) solution to obtain solution A, 2.5mL (pH=9.8) of trilysine (10 g/L) -borate buffer (65 mM) and 0.1mL of polyethylene imine (molecular weight 1800) mass fraction 10% aqueous solution are mixed to obtain solution B, and the solution A and the solution B are fully mixed to obtain the hydrogel material.
Example 2
A bioadhesive tunable hydrogel material, the method of making the hydrogel material comprising:
according to the gel preparation amount, 0.1g of hexa-arm polyethylene glycol dopamine (weight average molecular weight 5000 Da), 0.3g of tetra-arm polyethylene glycol succinimidyl glutarate (weight average molecular weight 10000 Da) and 0.2g of tetra-arm polyethylene glycol succinimidyl sebacate (weight average molecular weight 10000 Da) are added into 2.5mL of PBS (1.5 mM, pH=5.0) solution to obtain solution A, 2.5mL (pH=10.1) of trilysine (10 g/L) -borate buffer (65 mM) and 0.1mL of polyethylene imine (molecular weight 1800) mass fraction 10% aqueous solution are mixed to obtain solution B, and the solution A and the solution B are fully mixed to obtain the hydrogel material.
Example 3
A bioadhesive tunable hydrogel material, the method of making the hydrogel material comprising:
according to the gel preparation amount, 0.1g of eight-arm polyethylene glycol dopamine (weight average molecular weight 10000 Da), 0.1g of four-arm polyethylene glycol succinimidyl glutarate (weight average molecular weight 10000 Da) and 0.2g of four-arm polyethylene glycol succinimidyl sebacate (weight average molecular weight 20000 Da) are added into 2.5mL of PBS (1.5 mM, pH=6.0) solution to obtain solution A, 2.5mL (pH=9.8) of trilysine (15 g/L) -borate buffer (65 mM) and 0.1mL of polyethylene imine (molecular weight 1800) mass fraction 10% aqueous solution are mixed to obtain solution B, and the solution A and the solution B are fully mixed to obtain the hydrogel material.
Comparative example 1
A bioadhesive tunable hydrogel material, the method of making the hydrogel material comprising:
according to the gel preparation amount, 0.2g of quadrifilar polyethylene glycol succinimidyl glutarate (weight average molecular weight 20000 Da) and 0.2g of quadrifilar polyethylene glycol succinimidyl sebacate (weight average molecular weight 10000 Da) are added into 2.5mL of PBS (1.5 mM, pH=4.5) solution to obtain solution A, 2.5mL (pH=10.5) of trilysine (15 g/L) -borate buffer (65 mM) and 0.1mL of 10% aqueous solution of polyethyleneimine (molecular weight 2000) are mixed to obtain solution B, and the solution A and the solution B are fully mixed to obtain the hydrogel material.
Comparative example 2
A bioadhesive tunable hydrogel material, the method of making the hydrogel material comprising:
according to the gel preparation amount, 0.4g of quadrifilar polyethylene glycol succinimidyl glutarate (weight average molecular weight 10000 Da) is added into 2.5mL of PBS (1.5 mM, pH=5.5) solution to obtain solution A, 2.5mL (pH=9.5) of trilysine (15 g/L) -borate buffer (65 mM) and 0.1mL of 10% aqueous solution of polyethyleneimine (molecular weight 1800) are mixed to obtain solution B, and the solution A and the solution B are fully and uniformly mixed to obtain the hydrogel material.
Comparative example 3
A bioadhesive tunable hydrogel material, the method of making the hydrogel material comprising:
according to the gel preparation amount, 0.5g of quadrifilar polyethylene glycol succinimide sebacate (weight average molecular weight 10000 Da) is added into 2.5mL of PBS (1.5 mM, pH=4.0) solution to obtain solution A, 2.5mL (pH=9.8) of trilysine (15 g/L) -borate buffer (65 mM) and 0.1mL of 10% aqueous solution of polyethylenimine (molecular weight 2000) are mixed to obtain solution B, and the solution A and the solution B are fully mixed to obtain the hydrogel material.
Verification of swelling Rate and biosorption Performance Effect
1) The swelling ratio was measured for examples 1 to 3 and comparative examples 1 to 3 as follows: the hydrogel prepared above is weighed and moved into a grinding triangular flask, added into 7.4 phosphate buffer solution (the formula of the phosphate buffer solution is that 1.36g of monopotassium phosphate is weighed, 79mL of 0.1mol/mL of sodium hydroxide solution is added, and the solution is diluted to 200mL of water to obtain the phosphate buffer solution with the pH of 7.4) which is preheated to 37+/-1 ℃, the grinding triangular flask is placed into a 37+/-1 ℃ incubator, samples are taken out every few hours, surface moisture is absorbed by filter paper, and the weighing is finished until the weight is no longer increased. The gel swell ratio was calculated as follows:
swelling ratio= (mass of sample after swelling-sampling amount) ×100%/sampling amount.
2) The hydrogel adhesion properties of examples 1-3 and comparative examples 1-3 were examined. The specific method comprises the following steps: the pigskin was cut into pieces of 2.5 cm. Times.3 cm, and soaked in PBS at 37℃for 1 hour. The pigskin is adhered to a glass plate by using cyanoacrylate adhesive, curing is carried out for 1h, 0.6g of the prepared medical hydrogel is weighed and attached to the tail end of the pigskin, the glass plate which is also adhered with the pigskin is covered, a complete model is formed, and the overlapping area is recorded by using a digital caliper. After that, the mixture was pressed with a 100g weight for 30 minutes. The maximum force was recorded by stretching at a speed of 5mm/min with a universal tensile machine. Each sample was averaged 5 times. The adhesion of the hydrogel to the pigskin was used as the test result. The specific results are shown in the following table:
| sample of | Swelling Rate (%) | Bonding strength (Kpa) |
| Example 1 | 1.7 | 3.5 |
| Example 2 | 5.2 | 2.8 |
| Example 3 | 12.6 | 2.5 |
| Comparative example 1 | 28.6 | 1.2 |
| Comparative example 2 | 76.5 | 0.8 |
| Comparative example 3 | 94.3 | 1.0 |
The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the same, but rather, various modifications and variations may be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.
Claims (5)
1. A bioadhesive adjustable hydrogel material, wherein the hydrogel material comprises at least polyethylene glycol dopamine and polyethylene glycol-like activated esters;
the polyethylene glycol dopamine is quadrifilar polyethylene glycol dopamine;
the weight average molecular weight of the quadrifilar polyethylene glycol dopamine is 2000 daltons;
the polyethylene glycol activating ester comprises four-arm polyethylene glycol succinimide glutarate and four-arm polyethylene glycol succinimide sebacate;
the weight average molecular weight of the four-arm polyethylene glycol succinimidyl glutarate is 10000 daltons;
the weight average molecular weight of the four-arm polyethylene glycol succinimide sebacate is 20000 daltons;
the mass ratio of the four-arm polyethylene glycol succinimidyl glutarate to the four-arm polyethylene glycol succinimidyl sebacate is 1:2;
the bioadhesive tunable hydrogel material further comprises a cross-linking agent comprising polylysine, polyethylenimine;
the ratio of polylysine to polyethyleneimine is 5-95: 95-5;
the preparation method of the bioadhesive adjustable hydrogel material comprises the following steps:
according to the gel preparation amount, adding 0.1g of quadrifilar polyethylene glycol dopamine with weight average molecular weight of 2000Da, 0.2g of quadrifilar polyethylene glycol succinimidyl glutarate with weight average molecular weight of 10000Da and 0.2g of quadrifilar polyethylene glycol succinimidyl sebacate with weight average molecular weight of 20000Da into PBS solution with concentration of 2.5mL of 1.5mM and pH of 4.0 to obtain solution A, mixing 2.5mL of a borate buffer solution with concentration of 10g/L and pH of 65mM and weight of 9.8 with 0.1mL of a polyethyleneimine mass fraction of 10% aqueous solution with molecular weight of 1800 to obtain solution B, and fully and uniformly mixing the solution A and the solution B to obtain a hydrogel material;
the hydrogel material has both low swelling ratio and bioadhesion.
2. The hydrogel material of claim 1, wherein the bioadhesive tunable hydrogel material further comprises a coloring agent, a drug, or an antioxidant.
3. A method of preparing the bioadhesive tunable hydrogel material according to any one of claims 1-2, said method comprising:
according to the gel preparation amount, adding 0.1g of quadrifilar polyethylene glycol dopamine with weight average molecular weight of 2000Da, 0.2g of quadrifilar polyethylene glycol succinimidyl glutarate with weight average molecular weight of 10000Da and 0.2g of quadrifilar polyethylene glycol succinimidyl sebacate with weight average molecular weight of 20000Da into PBS solution with concentration of 2.5M and pH of 4.0 to obtain solution A, mixing 2.5mL of a trilysine-concentration of 65mM with pH of 9.8 with 0.1mL of a polyethyleneimine mass fraction of 10% aqueous solution with molecular weight of 1800 to obtain solution B, and fully mixing the solution A and the solution B to obtain the hydrogel material.
4. Use of a bioadhesive tunable hydrogel material according to any one of claims 1-2 for the preparation of a biomedical material.
5. The use of claim 4, wherein the biomedical material is a surgical sealant.
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| CN202111015584.6A CN113813440B (en) | 2021-08-31 | 2021-08-31 | Bioadhesive adjustable hydrogel material and preparation method and application thereof |
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