CN110643057A - Application of polyethylene glycol activated ester in preparation of low-swelling hydrogel and low-swelling hydrogel comprising same - Google Patents
Application of polyethylene glycol activated ester in preparation of low-swelling hydrogel and low-swelling hydrogel comprising same Download PDFInfo
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Abstract
The invention provides application of polyethylene glycol activated ester in preparation of low-swelling hydrogel and low-swelling hydrogel comprising the same, and relates to the technical field of new medical materials. The low-swelling hydrogel is hydrogel with a swelling rate of less than 50%, and the hydrogel has a very good low-swelling effect by using hydrogel with a longer degradable carbon chain (m is a positive integer of 3-10 in a structural formula) and the molecular weight of the polyethylene glycol part of the polyethylene glycol activated ester is 3000-10000 daltons, so that the problem that the existing hydrogel is generally high in swelling rate, cannot be applied to nerves in a limited space and is prone to causing human body injury is effectively solved. The low-swelling hydrogel can be widely applied to the preparation process of biomedical material products, in particular to the preparation of tissue sealants of skull and/or spinal parts.
Description
Technical Field
The invention relates to the technical field of new medical materials, in particular to application of polyethylene glycol activated ester in preparation of low-swelling hydrogel and the low-swelling hydrogel comprising the same.
Background
The hydrogel is used as a biocompatible material and is mainly used for postoperative adhesion prevention, hemostat, defect tissue filling, tissue fluid leakage prevention, drug slow release and the like. The existing biodegradable material hydrogel has a high swelling ratio which is generally 50-600%. When the hydrogel is used as a human tissue sealant, because the swelling rate is generally high, the hydrogel cannot be applied to nerves in a limited space, adverse events of human body injury are often caused easily, for example, nerve compression is generated when the swelling rate of spine sealant is too high, pain is caused to patients, and numbness and even loss of sensation of lower limbs are caused seriously; in addition, swelling of the sealant in the confined space of the brain can cause persistent headaches in the patient.
Therefore, it is necessary and urgent to develop a hydrogel with a low swelling ratio (< 50%) to alleviate the problem that the existing hydrogel has a generally high swelling ratio and is prone to causing injury to human body.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a new application of polyethylene glycol activated ester, which is an application of the polyethylene glycol activated ester in preparing low-swelling hydrogel.
The second purpose of the invention is to provide a low-swelling hydrogel, which comprises the polyethylene glycol activated ester, and the hydrogel effectively solves the problems that the existing hydrogel has a generally high swelling rate, cannot be applied to nerves in a limited space and is prone to causing human body injury.
The third purpose of the invention is to provide a preparation method of the low-swelling hydrogel, which has the advantages of simple and convenient steps, simple operation and easy industrial mass production.
The fourth purpose of the invention is to provide an application of the low-swelling hydrogel, and the low-swelling hydrogel can be widely applied to the preparation process of biomedical material products.
The invention provides an application of polyethylene glycol activated ester in preparing low-swelling hydrogel;
the low-swelling hydrogel is a hydrogel with a swelling ratio of-20% to less than 50%.
Further, the polyethylene glycol activated ester is selected from at least one of the structures shown in the formula (A);
a structure represented by formula (a):
in the formula (A), m is a positive integer of 3-10, preferably, m is 3, 4, 5, 6, 7, 8, 9 or 10, more preferably 10;
n is a positive integer of 20-300;
p is a positive integer of 1-4, preferably, p is 1, 2, 3 or 4;
r is core of polyethylene glycol activated ester, and is selected from C, C-C, CH-CH or CH2CH2O；
And the molecular weight of the polyethylene glycol part in the polyethylene glycol activated ester is 3000-10000 dalton;
preferably, the molecular weight of the polyethylene glycol part of the polyethylene glycol activated ester is 3000-5000 daltons;
more preferably, the polyethylene glycol moiety of the polyethylene glycol activated ester has a molecular weight of 3350 daltons.
Further, the polyethylene glycol activated ester comprises one of polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl adipate, polyethylene glycol succinimidyl suberate and polyethylene glycol succinimidyl sebacate;
preferably, the polyethylene glycol moiety of the polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl adipate, polyethylene glycol succinimidyl suberate and polyethylene glycol succinimidyl sebacate has a molecular weight of 3350 daltons;
preferably, the polyethylene glycol activated ester is polyethylene glycol succinimide sebacate;
more preferably, the polyethylene glycol moiety of the polyethylene glycol succinimide sebacate has a molecular weight of 3350 daltons.
Further, the polyethylene glycol activated ester comprises at least two of polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl adipate, polyethylene glycol succinimidyl suberate and polyethylene glycol succinimidyl sebacate;
preferably, the polyethylene glycol activated ester is a combination of polyethylene glycol succinimide glutarate and polyethylene glycol succinimide sebacate;
more preferably, the polyethylene glycol moiety of the polyethylene glycol succinimidyl glutarate and polyethylene glycol succinimidyl sebacate has a molecular weight of 3350 daltons;
more preferably, the mass ratio of the polyethylene glycol succinimide glutarate to the polyethylene glycol succinimide sebacate is 0.5: 1.5.
The invention provides a low-swelling hydrogel which comprises the polyethylene glycol activated ester.
Further, based on the mass of the hydrogel, the content of the polyethylene glycol activated ester in the hydrogel is 0.075-0.25 g/ml;
preferably, the hydrogel further comprises a cross-linking agent;
preferably, the cross-linking agent comprises at least one of polylysine, polyethyleneimine and aminopolyethylene glycol;
more preferably, the cross-linking agent comprises polylysine and polyethyleneimine;
further preferably, the ratio of polylysine to polyethyleneimine is 5-95: 95 to 5 percent;
more preferably, the polylysine has a molecular weight of 100-3000 daltons;
more preferably, the molecular weight of the polyethyleneimine is 1000-500000 daltons;
more preferably, the molecular weight of the amino polyethylene glycol is 1000-500000 daltons;
preferably, the hydrogel also comprises a buffer solution for dissolving the polyethylene glycol activated ester and/or the cross-linking agent;
more preferably, the buffer solution for dissolving the polyethylene glycol activated ester comprises a phosphate solution with the pH value of 3.5-5.0;
more preferably, the buffer solution for dissolving the crosslinking agent comprises a borate solution or pure water with the pH value of 9.0-10.5;
preferably, the hydrogel further comprises at least one of a coloring agent, a drug and an antioxidant.
Further, the low-swelling hydrogel comprises:
(a) 7.5-25% of polyethylene glycol activated ester;
(b) 1.5-3% of a cross-linking agent;
(c) 65-91% of a buffer solution;
(d) 0-0.1% of a coloring agent;
(e) 0-5% of a drug;
(f) 0-0.5% of antioxidant.
The invention provides a preparation method of the low-swelling hydrogel, which comprises the following steps:
the components were mixed and then extruded to give a hydrogel.
Further, the preparation method comprises the following steps:
dissolving polyethylene glycol activated ester in a buffer solution to obtain a solution A;
dissolving a cross-linking agent in a buffer solution or pure water, and uniformly mixing to obtain a solution B;
(III) then uniformly mixing the solution A, the solution B, an optional coloring agent, an optional medicament and an optional antioxidant, and extruding to obtain the low-swelling hydrogel;
the sequence of the step (I) and the step (II) can be exchanged;
preferably, the preparation method further comprises the step of performing radiation sterilization on the polyethylene glycol activated ester, the solution A and the solution B before dissolution;
more preferably, the irradiation dose is 5-25 kGy.
The invention provides an application of the low-swelling hydrogel in preparation of biomedical material products;
preferably, the biomedical material comprises a tissue sealant for use in the skull and/or spinal site.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a new application of polyethylene glycol activated ester, which is an application of the polyethylene glycol activated ester in preparation of low-swelling hydrogel (-20% < swelling ratio < 50%).
The low-swelling hydrogel provided by the invention comprises the polyethylene glycol activated ester, has a very good low-swelling effect, and effectively solves the problem that the existing hydrogel has a generally high swelling rate, cannot be applied to nerves in a limited space and is prone to causing human body injury.
The preparation method of the low-swelling hydrogel provided by the invention mixes the components and then extrudes the mixture to obtain the hydrogel. The method has the advantages of simple and convenient steps, simple operation and easy industrialized large-scale production.
The low-swelling hydrogel provided by the invention can be widely applied to the preparation process of biomedical material products.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a pathological diagram of 7d acute inflammation and chronic inflammation cell coexistence after animal subcutaneous implantation provided by application example 5 of the invention;
FIG. 2 is a pathological diagram of a 14d reduction in inflammatory response after subcutaneous implantation in an animal according to application example 5 of the present invention;
FIG. 3 is a pathological diagram showing the substantial elimination of the residual inflammation of the test article at 56d after the animal subcutaneous implantation provided by application example 5 of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present 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.
According to one aspect of the invention, the application of polyethylene glycol activated ester in preparing low-swelling hydrogel;
the low-swelling hydrogel is hydrogel with a swelling ratio of less than 50%.
The invention provides a new application of polyethylene glycol activated ester, which is an application of the polyethylene glycol activated ester in preparation of low-swelling hydrogel (-20% < swelling ratio < 50%).
The swelling ratio of the low-swelling hydrogel is typically, but not limited to, measured by a buffer test.
In a preferred embodiment of the present invention, the polyethylene glycol-based activated ester is selected from at least one of those having a structure represented by formula (a);
a structure represented by formula (a):
in the formula (A), m is a positive integer of 3-10, preferably, m is 3, 4, 5, 6, 7, 8, 9 or 10, more preferably 10;
n is a positive integer of 20-300;
p is a positive integer of 1-4, preferably, p is 1, 2, 3 or 4;
r is core of polyethylene glycol activated ester, and is selected from C, C-C, CH-CH or CH2CH2O；
And the molecular weight of the polyethylene glycol part of the polyethylene glycol activated ester is 3000-10000 daltons.
As a preferable embodiment, the structure of the polyethylene glycol activated ester has a longer degradable carbon chain (m is a positive integer of 3-10 in the structural formula), and the increase of the degradable carbon chain increases the hydrophobicity of the polyethylene glycol activated ester, so that the polyethylene glycol activated ester has stronger hydrophobicity. The swelling rate of the hydrogel can be effectively reduced by using the polyethylene glycol activated ester to prepare the hydrogel, which is determined by the characteristic that the polyethylene glycol activated ester has stronger hydrophobicity. Meanwhile, the molecular weight of the polyethylene glycol part of the polyethylene glycol activated ester is 3000-10000 daltons, and the lower molecular weight is also beneficial to reducing the swelling rate of the hydrogel prepared in the later period.
In the preferred embodiment, the polyethylene glycol moiety of the polyethylene glycol activated ester has a molecular weight of 3000 to 5000 daltons;
in a preferred embodiment, the polyethylene glycol moiety of the polyethylene glycol activated ester has a molecular weight of 3000 to 5000 daltons, which has a better effect of reducing the swelling ratio of the hydrogel. Preferably, the hydrogel swelling ratio is lowest when the polyethylene glycol moiety of the polyethylene glycol activated ester has a molecular weight of 3350 daltons.
Typical but non-limiting preferred embodiments of the molecular weight of the polyethylene glycol moiety of the above-described polyethylene glycol activated esters are: molecular weight 3000 dalton, molecular weight 3350 dalton, molecular weight 4000 dalton, molecular weight 5000 dalton, molecular weight 6000 dalton, molecular weight 7000 dalton, molecular weight 8000 dalton, molecular weight 9000 dalton and molecular weight 10000 dalton.
In a preferred embodiment of the present invention, the polyethylene glycol activated ester includes one of polyethylene glycol succinimidyl glutarate (PEG-SG), polyethylene glycol succinimidyl adipate (PEG-SA), polyethylene glycol succinimidyl suberate (PEG-SSub), and polyethylene glycol succinimidyl sebacate (PEG-SSeb);
wherein m in the structural formula of the polyethylene glycol succinimide glutarate is 3;
polyethylene glycol succinimide adipate, wherein m in the structural formula is 4;
the polyethylene glycol succinimide suberate has a structural formula, wherein m is 6;
the polyethylene glycol succinimide sebacate has a structural formula in which m is 8.
As a preferred embodiment, the larger the value of m in the structural formula is, the longer the degradable carbon chain in the structure of the polyethylene glycol activated ester is, so that the polyethylene glycol activated ester has better hydrophobic property, which is determined by the characteristic that the polyethylene glycol activated ester has stronger hydrophobicity.
As a preferred embodiment, typical but non-limiting preferred embodiments of the above mentioned polyethylene glycol activated esters are: polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl adipate, polyethylene glycol succinimidyl suberate, polyethylene glycol succinimidyl sebacate.
In the preferred embodiment described above, the polyethylene glycol moiety of the polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl adipate, polyethylene glycol succinimidyl suberate and polyethylene glycol succinimidyl sebacate has a molecular weight of 3350 daltons;
as a preferred embodiment, when the molecular weight of the polyethylene glycol moiety of the polyethylene glycol succinimidyl glutarate, the polyethylene glycol succinimidyl adipate, the polyethylene glycol succinimidyl suberate and the polyethylene glycol succinimidyl sebacate is 3350 daltons, the hydrogel prepared by the method has better swelling rate effect.
In the preferred embodiment, the polyethylene glycol-based activated ester is polyethylene glycol succinimide sebacate, and the hydrogel obtained therefrom has a higher swelling ratio. Preferably, the polyethylene glycol activated ester is polyethylene glycol succinimide sebacate with the molecular weight of 3350 daltons of polyethylene glycol part, and the hydrogel swelling rate effect is the best.
In a preferred embodiment of the present invention, the polyethylene glycol-based activated ester comprises at least two of polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl adipate, polyethylene glycol succinimidyl suberate, polyethylene glycol succinimidyl sebacate;
in the above preferred embodiment, the polyethylene glycol-based activated ester is a combination of polyethylene glycol succinimide adipate and polyethylene glycol succinimide sebacate;
as a preferred embodiment, the hydrogel prepared from the polyethylene glycol activated ester obtained by combining polyethylene glycol succinimidyl glutarate and polyethylene glycol succinimidyl sebacate has better effect.
More preferably, the polyethylene glycol activated ester is polyethylene glycol succinimide glutarate and polyethylene glycol succinimide sebacate, and the molecular weight of the polyethylene glycol part of the polyethylene glycol activated ester is 3350 daltons, so that the prepared hydrogel has better effect.
In the above preferred embodiment, the mass ratio of the polyethylene glycol succinimide glutarate to the polyethylene glycol succinimide sebacate is 0.5: 1.5.
In a preferred embodiment, when the two are compounded, the swelling rate of the hydrogel obtained by compounding the polyethylene glycol succinimidyl glutarate and the polyethylene glycol succinimidyl sebacate with the molecular weight of 3350 daltons of the polyethylene glycol part is the lowest when the two are compounded in a mass ratio of 0.5: 1.5.
According to one aspect of the present invention, a low-swelling hydrogel includes the above polyethylene glycol-based activated ester.
The low-swelling hydrogel provided by the invention comprises the polyethylene glycol activated ester, has a very good low-swelling effect, and effectively solves the problem that the existing hydrogel has a generally high swelling rate, cannot be applied to nerves in a limited space and is prone to causing human body injury.
In a preferred embodiment of the invention, based on the mass of the hydrogel, the content of the polyethylene glycol activated ester in the hydrogel is 0.075-0.25 g/ml;
in a preferred embodiment, the content of the polyethylene glycol activated ester in the hydrogel is 0.5-1.0 g/3-5 ml. The hydrogel prepared within the content range has a low swelling ratio, and the swelling ratio of the prepared hydrogel is below 50%.
In a preferred embodiment of the present invention, the hydrogel further comprises a crosslinking agent;
in a preferred embodiment, the hydrogel further comprises a crosslinking agent which reacts with the polyethylene glycol-based activated ester to form a network gel structure having a steric structure, thereby producing the hydrogel.
Preferably, the cross-linking agent comprises polylysine and polyethyleneimine;
in the preferred embodiment, the polylysine has a molecular weight of 100 to 3000 daltons; typical but non-limiting preferred embodiments of the molecular weight of the polylysine described above are: trilysine (molecular weight 402 daltons), tetralysine (molecular weight 530 daltons), pentalysine (molecular weight 658 daltons), decalysine (molecular weight 1298 daltons).
In the preferred embodiment, the molecular weight of the polyethyleneimine is 1000 to 500000 daltons. Typical but non-limiting preferred embodiments of the molecular weight of the above-mentioned polyethyleneimines are: 1000 daltons, 1800 daltons, 2000 daltons, 5000 daltons, 10000 daltons, 15000 daltons, 200000 daltons, 250000 daltons, 300000 daltons, 400000 daltons and 500000 daltons.
In the preferred embodiment, the aminopolyethylene glycol has a molecular weight of 1000 to 500000 daltons. Typical but non-limiting preferred embodiments of the molecular weight of the aminopolyethylene glycols described above are: 1000 daltons, 5000 daltons, 10000 daltons, 15000 daltons, 200000 daltons, 250000 daltons, 300000 daltons, 400000 daltons and 500000 daltons.
In a preferred embodiment of the present invention, the hydrogel further comprises a buffer solution for dissolving the polyethylene glycol type activated ester and/or the crosslinking agent;
in the preferred embodiment, the buffer solution for dissolving the polyethylene glycol activated ester comprises a phosphate solution with a pH value of 3.5-5.0;
in a preferred embodiment, the polyethylene glycol activated ester is stable in the pH range, the crosslinking agent is stable in the alkaline range, and the crosslinking reaction speed is high under alkaline conditions. In addition, the acid-base solution is neutral after being mixed in the pH value range and has no irritation to human bodies.
In the above preferred embodiment, the buffer solution for dissolving the crosslinking agent includes a borate solution having a pH of 9.0 to 10.5;
in a preferred embodiment of the present invention, the hydrogel further comprises at least one of a coloring agent, a drug and an antioxidant.
As a preferred embodiment, the hydrogel further comprises at least one of a coloring agent, a drug and an antioxidant.
In a preferred embodiment, the staining agent is used for increasing visualization, so that a doctor can judge the use amount and the effect of the hydrogel in clinical use. The addition of the drug can reduce infection and inflammation and promote wound healing. The addition of antioxidant to the powder can prolong the shelf life and resist the effect of radiation sterilization on the activity of the powder. The addition of the antioxidant in the solution can reduce the occurrence of side reactions when the active primary amine in the crosslinking agent is subjected to radiation sterilization.
In a preferred embodiment of the present invention, the low-swelling hydrogel comprises:
(a) 7.5-25% of polyethylene glycol activated ester;
(b) 1.5-3% of a cross-linking agent;
(c) 65-91% of a buffer solution;
(d) 0-0.1% of a coloring agent;
(e) 0-5% of a drug;
(f) 0-0.5% of antioxidant.
According to an aspect of the present invention, a method for preparing the low-swelling hydrogel comprises the following steps:
the components were mixed and then extruded to give a hydrogel.
The preparation method of the low-swelling hydrogel provided by the invention mixes the components and then extrudes the mixture to obtain the hydrogel. The method has the advantages of simple and convenient steps, simple operation and easy industrialized large-scale production.
In a preferred embodiment of the present invention, the preparation method comprises the steps of:
dissolving polyethylene glycol activated ester in a buffer solution to obtain a solution A;
dissolving a cross-linking agent in a buffer solution or pure water, and uniformly mixing to obtain a solution B;
(III) then uniformly mixing the solution A, the solution B, an optional coloring agent, an optional medicament and an optional antioxidant, and extruding to obtain the low-swelling hydrogel;
the sequence of the step (I) and the step (II) can be exchanged;
in a preferred embodiment of the present invention, the preparation method further comprises the step of subjecting the polyethylene glycol activated ester, the solution a and the solution B to radiation sterilization before dissolution;
preferably, the irradiation dose is 5-25 kGy.
According to one aspect of the invention, the use of the low-swelling hydrogel for preparing biomedical material products;
the low-swelling hydrogel provided by the invention can be widely applied to the preparation process of biomedical material products.
In a preferred embodiment of the invention, the biomedical material comprises a tissue sealant for the skull and/or spinal site.
The technical solution of the present invention will be further described with reference to the following examples.
Examples 1 to 7
A hydrogel, wherein the selection of the polyethylene glycol activated ester in the hydrogel of the examples 1-4 is shown in the following table:
the selection of the polyethylene glycol activated ester in the hydrogel of examples 5-7 is shown in the following table:
| group of | Polyethylene glycol activated ester species | Ratio of |
| Example 5 | PEG3350-SG:PEG3350-SA | 0.5:1.5 |
| Example 6 | PEG3350-SG:PEG3350-SSeb | 1:1 |
| Example 7 | PEG3350-SG:PEG3350-SSeb | 0.5:1.5 |
The hydrogel of the embodiment 1-7 consists of the following components:
(a) 0.5g of polyethylene glycol activated ester;
(b) trilysine (15g/L) -borate buffer (65mM)2.5mL, pH 9.8;
(c) 0.1mL of 10% aqueous solution of polyethyleneimine (molecular weight of 1800) in mass fraction;
(d) phosphate buffer (1.5mM)2.4mL, pH 4.0;
the preparation method of the hydrogel of the embodiment 1-7 comprises the following steps:
dissolving polyethylene glycol activated ester (a) in phosphate buffer solution (d) to obtain solution A, then uniformly mixing trilysine-borate buffer solution (B) with the aqueous solution of polyethyleneimine (c) to obtain solution B, spraying solution A and solution B into a special silica gel tube through a double-linkage liquid mixer, and preparing hydrogel with the diameter of 0.74cm and the length of 0.5cm in the silica gel tube.
Experimental example 1
In order to show that the hydrogel prepared by the present application has a relatively low swelling ratio, the inventors have performed swelling ratio detection on the hydrogels prepared by the above examples 1 to 7, and the specific detection method is as follows:
weighing the prepared hydrogel, transferring the hydrogel into a ground triangular flask, adding a phosphate buffer solution (the formula of the phosphate buffer solution is that 1.36g of monopotassium phosphate is weighed, 79mL of 0.1mol/mL sodium hydroxide solution is added, and water is used for diluting the solution to 200mL, wherein the pH value of the phosphate buffer solution is 7.4) which is preheated to 37 +/-1 ℃, putting the ground triangular flask into an incubator at 37 +/-1 ℃, taking out a sample every few hours, absorbing surface moisture by using filter paper, weighing the sample until the weight is not increased any more, and finishing weighing. The gel swelling ratio was calculated as follows.
Swelling ratio (mass of sample after swelling-sample amount) × 100%/sample amount.
The detection by the method obtains:
the hydrogel of example 1 had a swelling ratio of 30.56%;
the hydrogel of example 2 had a swelling ratio of 24.33%;
the swelling ratio of the hydrogel of example 3 was 13.57%;
the hydrogel of example 4 had a swelling ratio of-7.91%;
the swelling ratio of the hydrogel of example 5 was 26.84%;
the swelling ratio of the hydrogel of example 6 was 14.63%;
the swelling ratio of the hydrogel of example 7 was 1.32%.
From the above experimental results, it can be seen that, as the carbon chain of the degradable part in the polyethylene glycol activated ester increases (m value in the structural formula increases), the swelling ratio of the formed hydrogel gradually decreases, which is caused by the increase of hydrophobicity due to the increase of the carbon chain, so that the swelling ratio of the gel decreases.
Wherein, when used alone, the hydrogel prepared by using polyethylene glycol succinimide sebacate (PEG3350-SSeb) in example 4 has better effect; when the two are compounded and used, the PEG3350-SG and the PEG3350-SSeb in example 7 are mixed according to the proportion of 0.5:1.5, the effect is best when the components are compounded and used.
Example 8
A hydrogel, consisting of:
(a) 1.0g of polyethylene glycol succinimide sebacate (PEG 3350-SSeb);
(b) trilysine (15g/L) -borate buffer (65mM)2.5mL, pH 9.8;
(c) 0.1375mL of 10% polyethyleneimine (molecular weight 2000) water solution, wherein the concentration of the mixed polyethyleneimine of (b) and (c) is about 5.5 g/L;
(d) phosphate buffer (1.5mM)2.4mL, pH 4.0;
the preparation method of the hydrogel is the same as that of examples 1 to 4.
Example 9
A hydrogel, consisting of:
(a) 1.0g of polyethylene glycol succinimide sebacate (PEG 3350-SSeb);
(b) trilysine (10g/L) -borate buffer (65mM)2.5mL, pH 9.8;
(c) 0.1375mL of 20% polyethyleneimine (molecular weight 2000) water solution, wherein the concentration of the polyethyleneimine obtained after mixing (b) and (c) is about 11 g/L;
(d) phosphate buffer (1.5mM)2.4mL, pH 4.0;
the preparation method of the hydrogel is the same as that of examples 1 to 4.
Example 10
A hydrogel, consisting of:
(a) 1.0g of polyethylene glycol succinimide sebacate (PEG 3350-SSeb);
(b) trilysine (5g/L) -borate buffer (65mM)2.5mL, pH 9.8;
(c) 0.1375mL of 30% polyethyleneimine (molecular weight 2000) water solution, wherein the concentration of the polyethyleneimine obtained after mixing (b) and (c) is about 16.5 g/L;
(d) phosphate buffer (1.5mM)2.4mL, pH 4.0;
the preparation method of the hydrogel is the same as that of examples 1 to 4.
Example 11
A hydrogel, consisting of:
(a) 1.0g of polyethylene glycol succinimide sebacate (PEG 3350-SSeb);
(b) trilysine (20g/L) -borate buffer (65mM)2.5mL, pH 9.8;
(d) phosphate buffer (1.5mM)2.4mL, pH 4.0;
the preparation method of the hydrogel comprises the following steps:
dissolving polyethylene glycol activated ester (a) in phosphate buffer solution (d) to obtain solution A, spraying the solution A and the trilysine-borate buffer solution (b) into a special silica gel tube through a duplex liquid mixer, and preparing hydrogel with the diameter of 0.74cm and the length of 0.5cm in the silica gel tube.
Example 12
A hydrogel, consisting of:
(a) 1.0g of polyethylene glycol succinimide sebacate (PEG 3350-SSeb);
(c) polyethyleneimine (22g/L, molecular weight 2000) -borate buffer (65mM)2.5mL, pH 9.8;
(d) phosphate buffer (1.5mM)2.3mL, pH 4.0;
the preparation method of the hydrogel comprises the following steps:
dissolving polyethylene glycol activated ester (a) in phosphate buffer solution (d) to obtain solution A, spraying the solution A and the aqueous solution of polyethyleneimine (c) into a special silica gel tube through a double-liquid mixer, and preparing hydrogel with the diameter of 0.74cm and the length of 0.5cm in the silica gel tube.
Experimental example 2
PEI having a molecular weight of 2000 contains 18 primary amines which can participate in the reaction, and trilysine contains 4 primary amines which can participate in the reaction, so that (b) and (c) are mixed and calculated according to the following formula for the PEI content (molar ratio of primary amines):
in order to show that the hydrogel prepared by the method has a low swelling ratio, the inventor performs swelling ratio detection on the hydrogel prepared by the above examples 8-12, and the specific detection method is the same as that of the experimental examples 1-4.
The detection by the method obtains:
the swelling ratio of the hydrogel of example 8 was 5.08%;
the hydrogel of example 9 had a swelling ratio of-1.68%;
the hydrogel of example 10 had a swelling ratio of-6.24%;
the hydrogel of example 11 had a swelling ratio of 19.91%;
the hydrogel of example 12 had a swelling ratio of-17.44%;
from the above experimental results, it can be seen that the swelling ratio of the formed hydrogel gradually decreases with the increase of the content of PEI, probably because polyethyleneimine contains more primary amine, provides more crosslinking sites, and has higher crosslinking density; the cost of polyethyleneimine is lower when the same amount of primary ammonia is provided.
Examples 13 to 20
A hydrogel, the choice of the polyethylene glycol activated ester in the hydrogel of the examples 13-20 is shown in the following table:
the hydrogel of the embodiment 13-20 consists of the following components:
(a) 1.0g of polyethylene glycol activated ester;
(b) pentalysine (15g/L) -borate buffer (50mM)2.5mL, pH 9.5;
(c) 0.1mL of polyethyleneimine (molecular weight is 1800) aqueous solution with the mass fraction of 1.5%;
(d) phosphate buffer (2.0mM)2.4mL, pH 4.3;
the preparation method of the hydrogel is the same as that of examples 1 to 4.
Experimental example 3
In order to show that the hydrogel prepared by the method has a low swelling ratio, the inventor performs swelling ratio detection on the hydrogel prepared by the above examples 13-20, and the specific detection method is the same as that of the experimental examples 1-4.
The detection by the method obtains:
the swelling ratio of the hydrogel of example 13 was 23.75%;
the hydrogel of example 14 had a swelling ratio of 13.72%;
the swelling ratio of the hydrogel of example 15 was 2.16%;
the hydrogel of example 16 had a swelling ratio of-10.78%;
the swelling ratio of the hydrogel of example 17 was 35.62%;
the swelling ratio of the hydrogel of example 18 was 30.71%;
the hydrogel of example 19 had a swelling ratio of 16.67%;
the swelling ratio of the hydrogel of example 20 was 12.18%.
From the above experimental results, it is known that the swelling ratio of the hydrogel increases with the increase of the molecular weight of PEG, which is probably caused by the change of the steric structure and hydrophobicity of the hydrogel due to the molecular weight, and the steric structure is looser and the proportion of the hydrophobic segment is reduced.
Example 21
A hydrogel, consisting of:
(a) polyethylene glycol succinimidyl glutarate (PEG5000-SG)1.0g, containing 0.01% carotene;
(b) pentalysine (7.5g/L) -borate buffer (65mM)2.5mL, pH 9.8;
(c) 0.1mL of 10% polyethyleneimine (molecular weight 2000) aqueous solution;
(d) phosphate buffer (2.0mM)2.5mL, pH 4.3;
the preparation method of the hydrogel is the same as that of examples 1 to 4. The swelling ratio was found to be 17.63%.
Example 22
A hydrogel, consisting of:
(a) 0.8g of polyethylene glycol succinimidyl suberate (PEG3350-SSub) containing 0.005% brilliant blue;
(b) tetra-lysine (8g/L) -borate buffer (65mM)2.5mL, pH 9.8;
(c) 0.2mL of a 10% polyethyleneimine (MW 1800) -borate buffer (70mM) solution;
(d) phosphate buffer (2.0mM)2.5mL, pH 4.3;
the preparation method of the hydrogel is the same as that of examples 1 to 4. The swelling ratio was found to be 16.49%.
Example 23
A hydrogel, consisting of:
(a) 0.8g of four-arm polyethylene glycol succinimide adipate (4-arm-PEG10000-SA) containing 0.01% brilliant blue;
(b) tetra-lysine (5g/L) -borate buffer (65mM)2.5mL, pH 9.8;
(c) 0.2mL of 50% aminopolyethylene glycol (molecular weight 1800) aqueous solution;
(d) phosphate buffer (2.0mM)2.4mL (pH 4.3) with 0.1g dexamethasone dissolved;
the preparation method of the hydrogel is the same as that of examples 1 to 4. The swelling ratio was found to be 43.32%.
Example 24
A hydrogel, consisting of:
(a) polyethylene glycol succinimidyl glutarate (PEG3350-SG)0.5g, containing 0.01% brilliant blue;
(b) decalysine (5g/L) -borate buffer (70mM)1.5mL, pH 10.0;
(c) 0.2mL of 50% aminopolyethylene glycol (molecular weight 1800) aqueous solution;
(d) phosphate buffer (2.5mM)1.4mL (pH 4.5) with 0.05g acyclovir dissolved therein;
the preparation method of the hydrogel is the same as that of examples 1 to 4. The swelling ratio was found to be 14.81%.
Example 25
A hydrogel, consisting of:
(a) 0.5g of polyethylene glycol succinimidyl propionate (PEG 3350-SPA);
m in the structural formula of the polyethylene glycol succinimide propionate is 1;
(b) trilysine (8g/L) -borate buffer (65mM)1.5mL, pH 9.8;
(c) 0.05mL of 10% aqueous solution of polyethyleneimine (molecular weight of 1800);
(d) phosphate buffer (1.5mM)1.4mL, pH 4.0;
the preparation method of the hydrogel comprises the following steps:
dissolving polyethylene glycol activated ester (a) in phosphate buffer solution (d) to obtain solution A, then uniformly mixing trilysine-borate buffer solution (B) with the aqueous solution of polyethyleneimine (c) to obtain solution B, spraying solution A and solution B into a special silica gel tube through a double-linkage liquid mixer, and preparing hydrogel with the diameter of 0.74cm and the length of 0.5cm in the silica gel tube. The swelling ratio was found to be 162.34%.
Example 26
A hydrogel, consisting of:
(a) four-arm polyethylene glycol succinimide glutarate (4-arm-PEG2w-SG)0.5 g;
the molecular weight of the four-arm polyethylene glycol succinimide glutarate is more than 1 w;
(b) trilysine (5g/L) -borate buffer (65mM)2.5mL, pH 9.8;
(c) 0.05mL of 10% aqueous solution of polyethyleneimine (molecular weight of 1800);
(d) phosphate buffer (1.5mM)2.4mL, pH 4.0;
the preparation method of the hydrogel comprises the following steps:
dissolving polyethylene glycol activated ester (a) in phosphate buffer solution (d) to obtain solution A, then uniformly mixing trilysine-borate buffer solution (B) with the aqueous solution of polyethyleneimine (c) to obtain solution B, spraying solution A and solution B into a special silica gel tube through a double-linkage liquid mixer, and preparing hydrogel with the diameter of 0.74cm and the length of 0.5cm in the silica gel tube. The swelling ratio was found to be 131.87%.
Application example 1
The medical hydrogel with low swelling ratio is obtained by the following forms:
1) a first component: 0.6g of polyethylene glycol activated ester (PEG 3350-SSub).
2) A second component: pentalysine (4g/L) -borate buffer (50mM)2.5mL, pH 9.5.
3) A third component: 0.1mL of 10% polyethyleneimine (MW 1800) borate buffer (30 mM).
4) Buffer solution: phosphate buffer (2.0mM)2.5mL, pH 4.3.
After irradiation sterilization, the first component is dissolved by buffer solution to obtain a first solution, the second component and the third component are mixed to obtain a second solution, and the first solution and the second solution are sprayed on the subcranial dura mater of the New Zealand white rabbit through a double-combined liquid mixer.
Application example 2
The medical hydrogel with low swelling ratio is obtained by the following forms:
1) a first component: 0.6g of polyethylene glycol activated ester (PEG 5000-SA).
2) A second component: decalysine (8g/L) -borate buffer (55mM)2.5mL, pH 10.1.
3) A third component: 0.15mL of a 20% aqueous solution of polyethyleneimine (molecular weight 1800).
4) Buffer solution: phosphate buffer (3.0mM)2.5mL, pH 4.5.
After irradiation sterilization, the first component is dissolved by buffer solution to obtain a first solution, the second component and the third component are mixed to obtain a second solution, and the first solution and the second solution are sprayed on the spinal column lower dura mater of the back of the New Zealand white rabbit through a double-liquid mixer.
Application example 3
The medical hydrogel with low swelling ratio is obtained by the following forms:
1) a first component: 1.0g of polyethylene glycol activated ester (PEG 3350-SSeb).
2) A second component: trilysine (5g/L) -borate buffer (55mM)2.5mL, pH 9.9.
3) A third component: 0.3mL of borate buffer (40mM) containing 15% polyethyleneimine (molecular weight 2000).
4) Buffer solution: phosphate buffer (2.0mM)2.5mL, pH 4.3.
After irradiation sterilization, the first component is dissolved by using a buffer solution to obtain a first solution, the second component and the third component are mixed to obtain a second solution, and the first solution and the second solution are sprayed on the dura mater under the skull of the beagle dog through a double-connection liquid mixer.
Application example 4
The medical hydrogel with low swelling ratio is obtained by the following forms:
1) a first component: 1.0g of polyethylene glycol activated ester (PEG 1W-SSub).
2) A second component: trilysine (5g/L) -borate buffer (55mM)2.5mL, pH 9.8.
3) A third component: 0.4mL of a 10% aqueous solution of polyethyleneimine (MW 1800) and 10% aminopolyethylene glycol (MW 2000).
4) Buffer solution: phosphate buffer (2.0mM)2.5mL, pH 4.3.
After irradiation sterilization, the first component is dissolved by using a buffer solution to obtain a first solution, the second component and the third component are mixed to obtain a second solution, and the first solution and the second solution are sprayed on the lower spinal dura mater of the back of the beagle dog through a double-liquid mixer.
And (3) detecting gel forming time: the gel curing time is used for reacting the speed of in-situ forming of hydrogel, so that the operation of the next step after clinical gel use is directly influenced, and the detection method comprises the following steps: the nucleophilic component (first component) and the electrophilic component (second component) are mixed by a two-component liquid mixer, injected into a gel curing tester (MDGT-II, Toyobo electronics Co., Ltd.) preheated to 37 ℃ and immediately timed after the gel is injected until the gel is formed (the gel is picked up by a toothpick), and the time for forming the gel is recorded.
Burst strength (mmHg) test: in addition to gel formation time and swelling ratio, the breaking strength of the hydrogel, which reflects the mechanical properties of the hydrogel during use, is also important, and in some embodiments, is generally not less than 50 mmHg. The detection method comprises the following steps: a hole of about 0.16cm (+ -0.02 cm) in diameter is punched in fresh pig casing, the gel product of the invention is applied to the hole to form a hydrogel of a predetermined thickness, phosphate buffer solution with pH 7.4 (the formulation method is the same as that mentioned above for swelling ratio) is used, the casing is pressurized under the casing until the gel breaks, and the maximum pressure is recorded by a digital readout connected to a sensor.
In vitro degradation time detection: the cylindrical gel prepared in the same way as in the measurement of the gel swelling ratio is put into a phosphate buffer solution (the preparation method is the same as the preparation method mentioned in the swelling ratio) which is isotonic with blood and has the pH value of 7.4 at the temperature of 37 +/-1 ℃, and the time for in-vitro degradation of the gel is recorded when the cylindrical gel is observed daily until the cylindrical gel is invisible.
The performance of the hydrogels in the application examples one to four was tested, and the results are shown in the following table, and it can be seen that the hydrogels all meet the following criteria: 1) the gel forming time is less than 5 seconds; 2) swelling ratio < 50%; 3) The rupture strength is not less than 100 mmHg. The hydrogel has better performance, can be used in nerve parts in limited space such as skull, spine and the like, and has wide application prospect.
Application example 5 animals were implanted with medical sealant samples subcutaneously:
healthy adult New Zealand white rabbits were selected and implanted subcutaneously in 3 sample spots (hydrogel formulation same as in application example 4) 0.5 mL/spot on both sides of the rabbit spine, with the implant incision parallel to the spine, 25-50mm from the midline, approximately 25mm apart for each implant, with an implantation period of 7 days, 14 days and 56 days, and the sample implantation method was evaluated in reference to GBT16886.6-1997, part 6 of the medical device biology evaluation: the operation process specified in the local reaction test after implantation is carried out, and the animals are observed every day after the operation without any abnormal phenomenon, local, general and behavioral abnormalities.
Killing the animals at each sampling time point, and taking the implanted parts for histopathological evaluation;
as shown in figure 1, postoperative 7d acute and chronic inflammatory cells co-exist.
As shown in fig. 2, the post-operative 14d inflammatory response decreased.
As shown in FIG. 3, no test substance remained at 56d after the operation, and the inflammation was substantially eliminated.
The animal experiment results show that the low-swelling hydrogel is completely degraded at a subcutaneous implantation part within 56 days, has no subcutaneous abnormal lesion at the implantation part, and has higher biological safety. The hydrogels formed from other similar materials of the present invention are believed to have similar biological safety.
In summary, the polyethylene glycol activated ester has a longer degradable carbon chain, and the increase of the degradable carbon chain increases the hydrophobicity of the polyethylene glycol activated ester, so that the polyethylene glycol activated ester has stronger hydrophobicity. The swelling rate of the hydrogel can be effectively reduced by using the polyethylene glycol activated ester to prepare the hydrogel, which is determined by the characteristic that the polyethylene glycol activated ester has stronger hydrophobicity.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. The application of polyethylene glycol activated ester in preparing low-swelling hydrogel;
the low-swelling hydrogel is a hydrogel with a swelling ratio of-20% to less than 50%.
2. The use according to claim 1, wherein the polyethylene glycol-based activated ester is selected from at least one of those having a structure represented by formula (A);
a structure represented by formula (a):
in the formula (A), the compound (A),
m is a positive integer of 3 to 10, preferably, m is 3, 4, 5, 6, 7, 8, 9 or 10, more preferably 10;
n is a positive integer of 20-300;
p is a positive integer of 1-4, preferably, p is 1, 2, 3 or 4;
r is core of polyethylene glycol activated ester, and is selected from C, C-C, CH-CH or CH2CH2O；
And the molecular weight of the polyethylene glycol part of the polyethylene glycol activated ester is 3000-10000 dalton;
preferably, the molecular weight of the polyethylene glycol part of the polyethylene glycol activated ester is 3000-5000 daltons;
more preferably, the polyethylene glycol moiety of the polyethylene glycol activated ester has a molecular weight of 3350 daltons.
3. The use of claim 1 or 2, wherein the polyethylene glycol activated ester comprises one of polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl adipate, polyethylene glycol succinimidyl suberate, polyethylene glycol succinimidyl sebacate;
preferably, the polyethylene glycol moiety of the polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl adipate, polyethylene glycol succinimidyl suberate and polyethylene glycol succinimidyl sebacate has a molecular weight of 3350 daltons;
preferably, the polyethylene glycol activated ester is polyethylene glycol succinimide sebacate;
more preferably, the polyethylene glycol moiety of the polyethylene glycol succinimide sebacate has a molecular weight of 3350 daltons.
4. The use according to claim 1 or 2, wherein the polyethylene glycol-based activated ester comprises at least two of polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl adipate, polyethylene glycol succinimidyl suberate, polyethylene glycol succinimidyl sebacate;
preferably, the polyethylene glycol activated ester is a combination of polyethylene glycol succinimide glutarate and polyethylene glycol succinimide sebacate;
more preferably, the polyethylene glycol moiety of the polyethylene glycol succinimidyl glutarate and polyethylene glycol succinimidyl sebacate has a molecular weight of 3350 daltons;
more preferably, the mass ratio of the polyethylene glycol succinimide glutarate to the polyethylene glycol succinimide sebacate is 0.5: 1.5.
5. A low-swelling hydrogel, comprising the activated polyethylene glycol ester according to any one of claims 1 to 4.
6. The low-swelling hydrogel according to claim 5, wherein the amount of the polyethylene glycol-based activated ester in the hydrogel is 0.075-0.25 g/ml based on the mass of the hydrogel;
preferably, the hydrogel further comprises a cross-linking agent;
preferably, the cross-linking agent comprises at least one of polylysine, polyethyleneimine and aminopolyethylene glycol;
more preferably, the cross-linking agent comprises polylysine and polyethyleneimine;
more preferably, the ratio of polylysine to polyethyleneimine is 5-95: 95-5;
more preferably, the polylysine has a molecular weight of 100-3000 daltons;
more preferably, the molecular weight of the polyethyleneimine is 1000-500000 daltons;
more preferably, the molecular weight of the amino polyethylene glycol is 1000-500000 daltons;
preferably, the hydrogel also comprises a buffer solution for dissolving the polyethylene glycol activated ester and/or the cross-linking agent;
more preferably, the buffer solution for dissolving the polyethylene glycol activated ester comprises a phosphate solution with the pH value of 3.5-5.0;
more preferably, the buffer solution for dissolving the cross-linking agent comprises a borate solution or pure water with the pH value of 9.0-10.5;
preferably, the hydrogel further comprises at least one of a coloring agent, a drug and an antioxidant.
7. The low-swelling hydrogel according to claim 5 or 6, wherein the low-swelling hydrogel comprises:
(a) 7.5-25% of polyethylene glycol activated ester;
(b) 1.5-3% of a cross-linking agent;
(c) 65-91% of a buffer solution;
(d) 0-0.1% of a coloring agent;
(e) 0-5% of a drug;
(f) 0-0.5% of antioxidant.
8. A method for preparing the low-swelling hydrogel according to any one of claims 5 to 7, wherein the method comprises the following steps:
the components were mixed and then extruded to give a hydrogel.
9. The method for preparing a low-swelling hydrogel according to claim 8, wherein the method comprises the steps of:
dissolving polyethylene glycol activated ester in a buffer solution to obtain a solution A;
dissolving a cross-linking agent in a buffer solution, and uniformly mixing to obtain a solution B;
(III) then uniformly mixing the solution A, the solution B, an optional coloring agent, an optional medicament and an optional antioxidant, and extruding to obtain the low-swelling hydrogel;
the sequence of the step (I) and the step (II) can be exchanged;
preferably, the preparation method further comprises the step of performing radiation sterilization on the polyethylene glycol activated ester, the solution A and the solution B before dissolution;
more preferably, the irradiation dose is 5-25 kGy.
10. Use of a low-swelling hydrogel according to any one of claims 5 to 7 for the preparation of a biomedical material product;
preferably, the biomedical material comprises a tissue sealant for use in the skull and/or spinal site.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111905155A (en) * | 2020-07-23 | 2020-11-10 | 北京诺康达医药科技股份有限公司 | Closed hydrogel and preparation method and application thereof |
| CN112999419A (en) * | 2021-04-23 | 2021-06-22 | 江苏地韵医疗科技有限公司 | Gel and preparation method thereof |
| CN113813440A (en) * | 2021-08-31 | 2021-12-21 | 赛克赛斯生物科技股份有限公司 | Hydrogel material with adjustable biological adhesion and preparation method and application thereof |
| CN113827766A (en) * | 2021-10-11 | 2021-12-24 | 赛克赛斯生物科技股份有限公司 | Drug-loaded surgical sealant and preparation method and application thereof |
| CN114149544A (en) * | 2021-12-16 | 2022-03-08 | 北京理工大学 | Adhesive photonic crystal hydrogel sensor and preparation method and application thereof |
| CN114907558A (en) * | 2021-02-09 | 2022-08-16 | 上海瓴就医疗科技有限公司 | Low-swelling injectable hydrogel and preparation method and application thereof |
| CN115837093A (en) * | 2021-12-13 | 2023-03-24 | 北京博辉瑞进生物科技有限公司 | Medical tissue glue and preparation method and application thereof |
| CN116421744A (en) * | 2023-04-17 | 2023-07-14 | 杭州融华再生医学科技有限公司 | Absorbable medical hydrogel and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843925A (en) * | 2009-03-27 | 2010-09-29 | 综合性外科公司 | Low-swelling biocompatible hydrogels |
| US20100261652A1 (en) * | 2009-04-08 | 2010-10-14 | California Institute Of Technology | Tissue Adhesive Using Engineered Proteins |
| CN102911493A (en) * | 2012-09-28 | 2013-02-06 | 山东赛克赛斯药业科技有限公司 | Biodegradable medical hydrogel and preparation method and application thereof |
| CN105963792A (en) * | 2016-04-29 | 2016-09-28 | 深圳迈普再生医学科技有限公司 | Medical hydrogel composition, medical hydrogel as well as preparation method and application of medical hydrogel |
| CN108014365A (en) * | 2017-12-14 | 2018-05-11 | 沈伟 | A kind of sealer hydrogel and its kit and preparation method |
-
2019
- 2019-10-23 CN CN201911014682.0A patent/CN110643057B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843925A (en) * | 2009-03-27 | 2010-09-29 | 综合性外科公司 | Low-swelling biocompatible hydrogels |
| US20100261652A1 (en) * | 2009-04-08 | 2010-10-14 | California Institute Of Technology | Tissue Adhesive Using Engineered Proteins |
| CN102911493A (en) * | 2012-09-28 | 2013-02-06 | 山东赛克赛斯药业科技有限公司 | Biodegradable medical hydrogel and preparation method and application thereof |
| CN105963792A (en) * | 2016-04-29 | 2016-09-28 | 深圳迈普再生医学科技有限公司 | Medical hydrogel composition, medical hydrogel as well as preparation method and application of medical hydrogel |
| CN108014365A (en) * | 2017-12-14 | 2018-05-11 | 沈伟 | A kind of sealer hydrogel and its kit and preparation method |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111905155B (en) * | 2020-07-23 | 2021-10-15 | 北京诺康达医药科技股份有限公司 | Closed hydrogel and preparation method and application thereof |
| CN111905155A (en) * | 2020-07-23 | 2020-11-10 | 北京诺康达医药科技股份有限公司 | Closed hydrogel and preparation method and application thereof |
| WO2022016664A1 (en) * | 2020-07-23 | 2022-01-27 | 北京诺康达医药科技股份有限公司 | Sealing hydrogel, preparation method therefor and application thereof |
| CN114907558B (en) * | 2021-02-09 | 2024-05-07 | 上海瓴就医疗科技有限公司 | Low-swelling injectable hydrogel and preparation method and application thereof |
| CN114907558A (en) * | 2021-02-09 | 2022-08-16 | 上海瓴就医疗科技有限公司 | Low-swelling injectable hydrogel and preparation method and application thereof |
| CN112999419A (en) * | 2021-04-23 | 2021-06-22 | 江苏地韵医疗科技有限公司 | Gel and preparation method thereof |
| CN112999419B (en) * | 2021-04-23 | 2022-05-27 | 江苏地韵医疗科技有限公司 | Gel and preparation method thereof |
| CN113813440B (en) * | 2021-08-31 | 2023-08-04 | 赛克赛斯生物科技股份有限公司 | Bioadhesive adjustable hydrogel material and preparation method and application thereof |
| CN113813440A (en) * | 2021-08-31 | 2021-12-21 | 赛克赛斯生物科技股份有限公司 | Hydrogel material with adjustable biological adhesion and preparation method and application thereof |
| CN113827766A (en) * | 2021-10-11 | 2021-12-24 | 赛克赛斯生物科技股份有限公司 | Drug-loaded surgical sealant and preparation method and application thereof |
| CN115837093A (en) * | 2021-12-13 | 2023-03-24 | 北京博辉瑞进生物科技有限公司 | Medical tissue glue and preparation method and application thereof |
| WO2023109329A1 (en) * | 2021-12-13 | 2023-06-22 | 北京博辉瑞进生物科技有限公司 | Medical tissue adhesive, and preparation method therefor and use thereof |
| CN115837093B (en) * | 2021-12-13 | 2023-08-04 | 北京博辉瑞进生物科技有限公司 | Medical tissue glue and preparation method and application thereof |
| CN114149544B (en) * | 2021-12-16 | 2022-11-04 | 北京理工大学 | Adhesive photonic crystal hydrogel sensor and preparation method and application thereof |
| CN114149544A (en) * | 2021-12-16 | 2022-03-08 | 北京理工大学 | Adhesive photonic crystal hydrogel sensor and preparation method and application thereof |
| CN116421744A (en) * | 2023-04-17 | 2023-07-14 | 杭州融华再生医学科技有限公司 | Absorbable medical hydrogel and preparation method thereof |
| CN116421744B (en) * | 2023-04-17 | 2024-02-09 | 杭州融华再生医学科技有限公司 | Absorbable medical hydrogel and preparation method thereof |
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