CN111437444B - Preparation method of intestinal adhesion-resistant double-layer biogel and double-layer biogel - Google Patents
Preparation method of intestinal adhesion-resistant double-layer biogel and double-layer biogel Download PDFInfo
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Abstract
本发明提供的一种抗肠粘连双层生物凝胶的制备方法，包括以下步骤：S1：预先制备壳聚糖溶液；S2：制备甲基丙烯酸酯化壳聚糖纯品；S3：制备甲基丙烯酸酯化壳聚糖溶液；S4：制备HA‑DA‑AEMA纯品；S5：HA‑DA‑AEMA溶液制备；S6：将HA‑DA‑AEMA溶液和甲基丙烯酸酯化壳聚糖溶液分别固化成与组织粘附的内层生物凝胶和抗粘连的外层生物凝胶。与组织粘附的内层生物凝胶可以和肠道表面紧密结合，能够起到固定肠道伤口的作用，防止炎性渗出和出血，抗粘连外层生物凝胶可以避免与组织粘附的内层生物凝胶粘性面和腹腔或者和其它肠道粘连，避免了肠粘连给患者带来的痛苦。
The method for preparing an anti-intestinal adhesion bilayer biogel provided by the present invention includes the following steps: S1: pre-preparing a chitosan solution; S2: preparing pure methacrylated chitosan; S3: preparing methyl methacrylate Acrylate chitosan solution; S4: prepare pure HA-DA-AEMA; S5: prepare HA-DA-AEMA solution; S6: solidify HA-DA-AEMA solution and methacrylated chitosan solution respectively into an inner biogel that adheres to the tissue and an outer biogel that resists adhesion. The inner biogel adhered to the tissue can be closely combined with the intestinal surface, which can fix the intestinal wound and prevent inflammatory exudation and bleeding. The viscous surface of the inner biogel adheres to the abdominal cavity or to other intestinal tracts, avoiding the pain caused by intestinal adhesions to patients.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to a preparation method of an anti-intestinal adhesion double-layer biogel and the double-layer biogel.
Background
Intestinal adhesion is a common surgical system disease, and abnormal adhesion occurs between intestinal tubes or between intestinal tubes and organs in abdominal cavity.
After the intestinal adhesion is formed, partial adhesion may restrict the peristalsis of the intestinal tube or pull the intestinal tube, resulting in slight abdominal pain or abdominal distension of the patient in long-term paroxysmal; when intestinal adhesion causes incomplete intestinal obstruction, although food can pass through the intestinal canal, the adhesion can cause slow speed of food passing through the intestinal canal, and nausea and paroxysmal abdominal pain and abdominal distension can occur after a patient eats; when intestinal adhesion causes complete intestinal obstruction, patients can suffer from symptoms of abdominal pain, nausea, and cessation of exsufflation.
The main cause of intestinal adhesion is abdominal surgery. In the prior art, two solutions for intestinal adhesion exist, one is conservative treatment, namely diet control, medicine taking and exercise strengthening, and can relieve pain caused by the intestinal adhesion but cannot relieve the intestinal adhesion; the other is a secondary operation capable of relieving intestinal adhesions, but the secondary operation may produce new intestinal adhesions. The problem of intestinal adhesion is not solved in the medical field at present.
Therefore, it is necessary to provide a preparation method of double-layer biogel for resisting intestinal adhesion and a double-layer biogel for overcoming the defects of the prior art.
Disclosure of Invention
The invention aims to avoid the defects of the prior art and provide a preparation method of an anti-intestinal adhesion double-layer biological gel, which can be used for preparing the anti-intestinal adhesion double-layer biological gel, and the gel can act between an abdominal cavity and an intestinal tract and between the intestinal tract and the intestinal tract to form a physical barrier and block intestinal adhesion.
The above object of the present invention is achieved by the following technical measures:
provides a preparation method of double-layer biological gel for resisting intestinal adhesion, which comprises the following steps:
s1: preparing a chitosan solution in advance;
s2: preparing a pure product of the methacrylated chitosan;
specifically, dripping a methacrylic anhydride solution into a chitosan solution, dialyzing and freeze-drying a mixture formed by reaction to obtain a pure product of the methacrylated chitosan;
s3: preparing a methacrylated chitosan solution;
specifically, a pure product of the methacrylated chitosan is prepared into 5-50 ml of solution with the mass volume concentration of 2-10% w/v, a photoinitiator is added, the solution is uniformly stirred, and then the solution is stored at 4 ℃;
s4: preparing a HA-DA-AEMA pure product;
specifically, 4-5 mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-5 mmol of N-hydroxysuccinimide, 2-5 mmol of dopamine and 2-3 mmol of methacrylic acid-2-aminoethyl ester acid are respectively weighed and placed in a light-resistant centrifugal tube;
placing 5-50 ml of a sodium hyaluronate solution with a mass volume ratio of 1-20% w/v into a container, adjusting the pH value of the sodium hyaluronate solution to 5.0-6.0 by using 0.1-0.3 mol/L hydrochloric acid, adding weighed 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, stirring for 20-30 min, sequentially adding weighed N-hydroxysuccinimide, dopamine and methacrylic acid-2-aminoethyl ester acid to obtain a mixed solution, dialyzing and freeze-drying to obtain an HA-DA-AEMA pure product;
s5: preparing an HA-DA-AEMA solution;
specifically, preparing 5-50 ml of a solution with the mass volume concentration of 2-10% w/v from a HA-DA-AEMA pure product, adding a photoinitiator, uniformly stirring, and then storing at 4 ℃;
s6: respectively solidifying the HA-DA-AEMA solution and the methacrylated chitosan solution into an inner-layer biogel adhered to the tissues and an anti-adhesion outer-layer biogel;
specifically, an HA-DA-AEMA solution is spread on a flat dish, a photoinitiator is added, and the HA-DA-AEMA solution is irradiated by a 365nm ultraviolet lamp for 30-90 s;
and after the HA-DA-AEMA solution is changed from a liquid state to a solid state, spreading the methacrylated chitosan solution on the HA-DA-AEMA liquid-solid state, adding a photoinitiator, and then irradiating by using a 365nm ultraviolet lamp for 30-150 seconds until the two solutions are completely changed into the solid state, wherein the anti-intestinal adhesion double-layer biogel is formed by the inner-layer biogel adhered to the tissues and the anti-adhesion outer-layer biogel.
Preferably, the preparation of the chitosan solution in advance in S1 is specifically: dissolving chitosan with the mass volume fraction of 3-10% w/v in 50-200 ml of 1-5% acetic acid, stirring by using a magnetic stirrer, adjusting the rotating speed of the stirrer to 1000r/min, and stirring for 24-48 h.
Preferably, the mass volume concentration of the methacrylated chitosan solution in S3 is 4-7% w/v, the mass volume ratio of the S4 sodium hyaluronate solution is 7-15% w/v, and the mass volume concentration of the HA-DA-AEMA solution in S5 is 4-7% w/v.
Preferably, the dropwise addition of methacrylic anhydride in S2 is specifically: heating the chitosan solution to 50-60 ℃ in an oil bath kettle by stirring, dripping methacrylic anhydride with the concentration of 94-95% into the chitosan solution at the speed of 0.5-1 ml/min, stirring by using a magnetic stirrer at the rotating speed of 1000r/min, and stirring for 4-6 h.
Preferably, the dialysis lyophilization in S2 is specifically: and (3) placing the mixture into a dialysis bag at room temperature, dialyzing the mixture for 5-6 days by using distilled water, and freeze-drying the mixture for 24-48 hours at the temperature of-40-80 ℃ and under the pressure of 5-100 mbar after dialysis is finished.
Preferably, the dialysis lyophilization in S2 is specifically: at normal temperature, placing the container bearing the mixed solution on a magnetic stirrer, adjusting the rotating speed of the stirrer to 850-1000 r/min, and stirring for 24-48 h;
and after stirring, putting the mixed solution into a dialysis bag, dialyzing for 3-5 days by using PBS, and after dialysis, freeze-drying the mixture for 24-48 h at the temperature of-80 ℃ and under the pressure of 300-400 mbar.
Preferably, the photoinitiator is Irgacure 2959 or LAP, and the mass volume fractions of the Irgacure 2959 and the LAP are both 0.1-20% w/v.
Preferably, the deacetylation degree of the chitosan in S1 is 75-90%, the molecular weight is 310000-375000 g & mol < -1 >, and the viscosity is 800-.
Preferably, the molecular weight of the sodium hyaluronate in S4 is 9-10 ten thousand, the molecular weight of the dopamine is 189.64, and the molecular weight of the methacrylic acid-2-aminoethyl ester acid is 165.62.
The invention provides a preparation method of an anti-intestinal adhesion double-layer biological gel, which comprises the following steps: s1: preparing a chitosan solution in advance; s2: preparing a pure product of the methacrylated chitosan; s3: preparing a methacrylated chitosan solution; s4: preparing a HA-DA-AEMA pure product; s5: preparing an HA-DA-AEMA solution; s6: the HA-DA-AEMA solution and the methacrylated chitosan solution are respectively solidified into an inner biogel which is adhered to the tissues and an anti-adhesion outer biogel. The inner layer biological gel adhered to the tissue can be tightly combined with the surface of the intestinal tract, the effect of fixing the wound of the intestinal tract can be achieved, inflammatory exudation and bleeding are prevented, the adhesion-resistant outer layer biological gel can avoid the adhesion of the adhesive surface of the inner layer biological gel adhered to the tissue and the abdominal cavity or other intestinal tracts, and the pain of patients caused by intestinal adhesion is avoided.
The invention also aims to avoid the defects of the prior art and provide a double-layer biological gel which can act between the abdominal cavity and the intestinal tract and between the intestinal tract and the intestinal tract to form a physical barrier and block intestinal adhesion.
The above object of the present invention is achieved by the following technical measures:
a double-layer biological gel is prepared by adopting a preparation method of the double-layer biological gel for resisting intestinal adhesion.
The invention provides a double-layer biogel which is prepared by adopting a preparation method of the double-layer biogel for resisting intestinal adhesion. The preparation method of the double-layer biological gel for resisting intestinal adhesion comprises the following steps: s1: preparing a chitosan solution in advance; s2: preparing a pure product of the methacrylated chitosan; s3: preparing a methacrylated chitosan solution; s4: preparing a HA-DA-AEMA pure product; s5: preparing an HA-DA-AEMA solution; s6: the HA-DA-AEMA solution and the methacrylated chitosan solution are respectively solidified into an inner biogel which is adhered to the tissues and an anti-adhesion outer biogel. The inner layer biological gel adhered to the tissue can be tightly combined with the surface of the intestinal tract, the effect of fixing the wound of the intestinal tract can be achieved, inflammatory exudation and bleeding are prevented, the adhesion-resistant outer layer biological gel can avoid the adhesion of the adhesive surface of the inner layer biological gel adhered to the tissue and the abdominal cavity or other intestinal tracts, and the pain of patients caused by intestinal adhesion is avoided.
Drawings
The invention is further illustrated by means of the attached drawings, the content of which is not in any way limiting.
FIG. 1 is a schematic diagram of the synthesis mechanism of the anti-blocking outer gel of the present invention.
FIG. 2 is a schematic diagram of the mechanism of synthesis of the inner layer gel for tissue adhesion according to the present invention.
FIG. 3 is a schematic view of the combination of an outer layer biogel and an inner layer biogel into a double-layer structure biogel according to the present invention.
Detailed Description
The invention is further illustrated by the following examples.
Example 1.
A preparation method of an anti-intestinal adhesion bilayer biogel comprises the following steps:
s1: preparing a chitosan solution in advance;
the chitosan solution prepared in advance in S1 specifically comprises: dissolving chitosan with the mass volume fraction of 3% w/v in acetic acid with the concentration of 1%, stirring by using a magnetic stirrer, adjusting the rotating speed of the stirrer to be 1000r/min, and stirring for 24 h. It should be noted that the chitosan and acetic acid mixed solution should be uniformly shaken at room temperature before being stirred by a magnetic stirrer, and in addition, the volume of the chitosan can be calculated according to the mass-to-volume ratio of 3% w/v, which is a well-known process of the person skilled in the art and is not described herein again.
The deacetylation degree of the chitosan in S1 is 75%, the molecular weight is 310000g & mol < -1 >, and the viscosity is 800. The higher the degree of deacetylation of chitosan, the more favorable the chitosan is to be dissolved.
S2: preparing a pure product of the methacrylated chitosan;
specifically, dripping a methacrylic anhydride solution into a chitosan solution, dialyzing and freeze-drying a mixture formed by reaction to obtain a pure product of the methacrylated chitosan;
the dropwise adding of methacrylic anhydride in the S2 is specifically as follows: heating the chitosan solution to 50 ℃ in an oil bath kettle under stirring, dripping methacrylic anhydride with the concentration of 94 percent into the chitosan solution at the speed of 0.5, stirring by a magnetic stirrer at the rotating speed of 1000r/min for 4 hours. It should be noted that the mass volume of methacrylic anhydride can be calculated according to the mass volume of chitosan in S1 and the mass volume concentration of the methacrylated chitosan solution in S3, which are well known to those skilled in the art and will not be described herein again.
The dialysis freeze-drying in the S2 step is specifically as follows: the mixture was dialyzed against distilled water at room temperature for 5d in a dialysis bag, and after dialysis was completed, the mixture was lyophilized at-40 ℃ under a pressure of 5mbar for 24 h. The dialysis bag used in this example was a dialysis bag from Sigma, U.S. with a molecular weight of 12-14 kDa.
It should be noted that, when a methacrylic anhydride solution is added dropwise to the chitosan solution, as shown in fig. 1, chitosan reacts with methacrylic anhydride to form methacrylated chitosan. The mixture formed after the chitosan is completely reacted should be the methacrylated chitosan and the residual methacrylic anhydride, so the residual methacrylic anhydride is filtered by a dialysis bag to obtain the pure product of the methacrylated chitosan.
S3: preparing a methacrylated chitosan solution;
specifically, preparing a pure product of the methacrylated chitosan into 5-50 ml of a solution with the mass volume concentration of 2% w/v, adding a photoinitiator, uniformly stirring, and then storing at 4 ℃; in this example, after stirring for 2 hours, the methacrylated chitosan solution was mixed with the initiator uniformly. It should be noted that the amount of the pure methacrylated chitosan can be calculated according to the mass volume concentration of the methacrylated chitosan solution, and this process is well known to those skilled in the art and will not be described herein. .
S4: preparing a HA-DA-AEMA pure product;
specifically, 4mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4mmol of N-hydroxysuccinimide, 2mmol of dopamine and 2mmol of methacrylic acid-2-aminoethyl ester acid are respectively weighed and placed in a light-resistant centrifuge tube;
placing 5-50 ml of a sodium hyaluronate solution with a mass volume ratio of 1% w/v into a double-mouth flask, then adjusting the pH value of the sodium hyaluronate solution to 5.0 by using 0.1mol/L hydrochloric acid, then adding weighed 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, stirring for 20min, then sequentially adding weighed N-hydroxysuccinimide, dopamine and methacrylic acid-2-aminoethyl ester acid to obtain a mixed solution, dialyzing and freeze-drying to obtain an HA-DA-AEMA pure product; in this embodiment, the process of adjusting PH is: putting a probe of a PH meter into a double-mouth flask, after the reading of the PH meter is stable, beginning to dropwise add 0.1mol/L hydrochloric acid into the beaker by using a dropper, and stopping adding the hydrochloric acid solution when the reading of the PH meter reaches 5.0. The mechanism for synthesizing HA-DA-AEMA from sodium hyaluronate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, dopamine and methacrylic acid-2-aminoethyl ester acid is shown in FIG. 2.
The dialysis freeze-drying in the S4 step is specifically as follows: at normal temperature, placing the container bearing the mixed solution on a magnetic stirrer, adjusting the rotating speed of the stirrer to 850r/min, and stirring for 24 hours;
after stirring, the mixture was placed in a dialysis bag and dialyzed against PBS for 3 days, and after dialysis, the mixture was lyophilized at-80 ℃ under a pressure of 300mbar for 24 hours.
The molecular weight of the sodium hyaluronate in S4 is 9 ten thousand, the molecular weight of the dopamine is 189.64, and the molecular weight of the methacrylic acid-2-aminoethyl ester acid is 165.62.
S5: preparing an HA-DA-AEMA solution;
specifically, preparing 5-50 ml of a solution with the mass volume concentration of 2% w/v from a HA-DA-AEMA pure product, adding a photoinitiator, uniformly stirring, and storing at 4 ℃;
s6: respectively solidifying the HA-DA-AEMA solution and the methacrylated chitosan solution into an inner-layer biogel adhered to the tissues and an anti-adhesion outer-layer biogel;
specifically, an HA-DA-AEMA solution is spread on a flat dish, a photoinitiator is added, and the HA-DA-AEMA solution is irradiated by a 365nm ultraviolet lamp for 30-90 s;
and after the HA-DA-AEMA solution is changed from a liquid state to a solid state, spreading the methacrylated chitosan solution on the HA-DA-AEMA liquid-solid state, adding a photoinitiator, and then irradiating by using a 365nm ultraviolet lamp for 30-150 seconds until the two solutions are completely changed into the solid state, wherein the anti-intestinal adhesion double-layer biogel is formed by the inner-layer biogel adhered to the tissues and the anti-adhesion outer-layer biogel. The conditions of the anti-intestinal adhesion bilayer biogel consisting of the inner biogel adhered to the tissue and the anti-adhesion outer biogel on the damaged intestinal tract are shown in fig. 3.
In the embodiment, the photoinitiator is Irgacure 2959 or LAP, and the mass volume fractions of the Irgacure 2959 and the LAP are both 0.1% w/v.
In this example, the raw material sources used are not particularly limited, and commercially available products known to those skilled in the art may be used.
The preparation method of the anti-intestinal adhesion double-layer biological gel utilizes an ultraviolet light crosslinking mode to enable chemical crosslinking to occur between an anti-adhesion outer-layer biological gel formed by the methacrylate-esterified chitosan and an inner-layer biological gel formed by HA-DA-AEMA and adhered to tissues, and the two layers of biological gels are tightly combined into a whole, so that the formed double-layer biological gel can play a role in fixing intestinal wounds, prevent inflammatory exudation and bleeding, avoid the combination of an adhesive surface and the abdominal wall surface or the intestinal tract, and prevent unnecessary adhesion.
Example 2.
A method for preparing an anti-intestinal adhesion bilayer biogel, the other characteristics of which are the same as those of example 1, except that: the chitosan solution prepared in advance in S1 specifically comprises: dissolving chitosan with the mass volume fraction of 10% w/v in acetic acid with the concentration of 5%, stirring by using a magnetic stirrer at the rotating speed of 1000r/min for 48 h.
The deacetylation degree of the chitosan in S1 is 90%, the molecular weight is 375000g & mol < -1 >, and the viscosity is 2000.
The dropwise adding of methacrylic anhydride in the S2 is specifically as follows: heating the chitosan solution to 60 ℃ in an oil bath kettle under stirring, dripping 95% methacrylic anhydride into the chitosan solution at the speed of 1ml/min, stirring by a magnetic stirrer at the rotating speed of 1000r/min, and stirring for 6 h.
The mass volume concentration of the methacrylated chitosan solution in S3 was 10% w/v.
Weighing 5mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 5mmol of N-hydroxysuccinimide, 5mmol of dopamine and 3mmol of methacrylic acid-2-aminoethyl ester acid in S4, and placing the obtained mixture into a light-resistant centrifugal tube;
putting a sodium hyaluronate solution with the mass volume ratio of 20% w/v into a container, adjusting the pH value of the sodium hyaluronate solution to 6.0 by using 0.3mol/L hydrochloric acid, then adding weighed 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, stirring for 30min, then sequentially adding weighed N-hydroxysuccinimide, dopamine and methacrylic acid-2-aminoethyl ester acid to obtain a mixed solution, dialyzing and freeze-drying to obtain an HA-DA-AEMA pure product;
the dialysis freeze-drying in the S4 step is specifically as follows: at normal temperature, placing the container bearing the mixed solution on a magnetic stirrer, adjusting the rotating speed of the stirrer to 1000r/min, and stirring for 48 hours;
after stirring, the mixture was placed in a dialysis bag and dialyzed against PBS for 5 days, and after dialysis, the mixture was lyophilized at-80 ℃ for 48h at 400 mbar.
The molecular weight of the sodium hyaluronate in S4 is 10 ten thousand, the molecular weight of dopamine is 189.64, and the molecular weight of methacrylic acid-2-aminoethyl ester acid is 165.62.
The mass volume concentration of the HA-DA-AEMA solution in S5 is 10% w/v.
Irgacure 2959 and LAP were both 20% w/v by weight volume.
The preparation method of the anti-intestinal adhesion double-layer biological gel utilizes an ultraviolet light crosslinking mode to enable chemical crosslinking to occur between an anti-adhesion outer-layer biological gel formed by the methacrylate-esterified chitosan and an inner-layer biological gel formed by HA-DA-AEMA and adhered to tissues, and the two layers of biological gels are tightly combined into a whole, so that the formed double-layer biological gel can play a role in fixing intestinal wounds, prevent inflammatory exudation and bleeding, avoid the combination of an adhesive surface and the abdominal wall surface or the intestinal tract, and prevent unnecessary adhesion.
Example 3.
A method for preparing an anti-intestinal adhesion bilayer biogel, the other characteristics of which are the same as those of example 1, except that: the chitosan solution prepared in advance in S1 specifically comprises: dissolving chitosan with the mass volume fraction of 5% w/v in acetic acid with the concentration of 3%, stirring by using a magnetic stirrer, adjusting the rotating speed of the stirrer to be 1000r/min, and stirring for 36 h.
The deacetylation degree of the chitosan in S1 is 83%, the molecular mass is 350000g & mol-1, and the viscosity is 1500.
The dropwise adding of methacrylic anhydride in the S2 is specifically as follows: heating the chitosan solution to 55 ℃ in an oil bath kettle under stirring, dripping methacrylic anhydride with the concentration of 94.5 percent into the chitosan solution at the speed of 0.75ml/min, stirring by a magnetic stirrer at the rotating speed of 1000r/min for 5 hours.
The mass volume concentration of the methacrylated chitosan solution in S3 was 6% w/v.
Weighing 4.5mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4.5mmol of N-hydroxysuccinimide, 3mmol of dopamine and 2.5mmol of methacrylic acid-2-aminoethyl ester acid in S4 respectively, and placing the obtained product into a light-resistant centrifugal tube;
putting a sodium hyaluronate solution with the mass volume ratio of 10% w/v into a container, adjusting the pH value of the sodium hyaluronate solution to 5.5 by using 0.2mol/L hydrochloric acid, then adding weighed 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, stirring for 25min, then sequentially adding weighed N-hydroxysuccinimide, dopamine and methacrylic acid-2-aminoethyl ester acid to obtain a mixed solution, dialyzing and freeze-drying to obtain an HA-DA-AEMA pure product;
the dialysis freeze-drying in the S4 step is specifically as follows: at normal temperature, placing the container bearing the mixed solution on a magnetic stirrer, adjusting the rotating speed of the stirrer to 920r/min, and stirring for 36 hours;
after stirring, the mixture was placed in a dialysis bag and dialyzed against PBS for 4 days, and after dialysis, the mixture was lyophilized at-80 ℃ for 36h at a pressure of 350 mbar.
The molecular weight of the sodium hyaluronate in S4 is 9.5 ten thousand, the molecular weight of the dopamine is 189.64, and the molecular weight of the methacrylic acid-2-aminoethyl ester acid is 165.62.
The mass volume concentration of the HA-DA-AEMA solution in S5 is 6% w/v.
The mass volume fraction of Irgacure 2959 and LAP is 0.1-20% w/v.
The preparation method of the anti-intestinal adhesion double-layer biological gel utilizes an ultraviolet light crosslinking mode to enable chemical crosslinking to occur between an anti-adhesion outer-layer biological gel formed by the methacrylate-esterified chitosan and an inner-layer biological gel formed by HA-DA-AEMA and adhered to tissues, and the two layers of biological gels are tightly combined into a whole, so that the formed double-layer biological gel can play a role in fixing intestinal wounds, prevent inflammatory exudation and bleeding, avoid the combination of an adhesive surface and the abdominal wall surface or the intestinal tract, and prevent unnecessary adhesion.
Example 4.
A method for preparing an anti-intestinal adhesion bilayer biogel, the other characteristics of which are the same as those of example 1, except that: the mass volume concentration of the methacrylated chitosan solution in S3 is 4-7% w/v, the mass volume ratio of the S4 sodium hyaluronate solution is 7-15% w/v, and the mass volume concentration of the HA-DA-AEMA solution in S5 is 4-7% w/v. The preparation method of the anti-intestinal adhesion double-layer biological gel utilizes an ultraviolet light crosslinking mode to enable chemical crosslinking to occur between an anti-adhesion outer-layer biological gel formed by the methacrylate-esterified chitosan and an inner-layer biological gel formed by HA-DA-AEMA and adhered to tissues, and the two layers of biological gels are tightly combined into a whole, so that the formed double-layer biological gel can play a role in fixing intestinal wounds, prevent inflammatory exudation and bleeding, avoid the combination of an adhesive surface and the abdominal wall surface or the intestinal tract, and prevent unnecessary adhesion.
Example 5.
A method for preparing an anti-intestinal adhesion bilayer biogel, the other characteristics of which are the same as those of example 1, except that: the mass volume concentration of the methacrylated chitosan solution in S3 is 5-76% w/v, the mass volume ratio of the S4 sodium hyaluronate solution is 9-12% w/v, and the mass volume concentration of the HA-DA-AEMA solution in S5 is 5-6% w/v. The preparation method of the anti-intestinal adhesion double-layer biological gel utilizes an ultraviolet light crosslinking mode to enable chemical crosslinking to occur between an anti-adhesion outer-layer biological gel formed by the methacrylate-esterified chitosan and an inner-layer biological gel formed by HA-DA-AEMA and adhered to tissues, and the two layers of biological gels are tightly combined into a whole, so that the formed double-layer biological gel can play a role in fixing intestinal wounds, prevent inflammatory exudation and bleeding, avoid the combination of an adhesive surface and the abdominal wall surface or the intestinal tract, and prevent unnecessary adhesion.
Example 6.
A double-layer biological gel is prepared by adopting a preparation method of the double-layer biological gel for resisting intestinal adhesion. The preparation method of the double-layer biological gel for resisting intestinal adhesion comprises the following steps: s1: preparing a chitosan solution in advance; s2: preparing a pure product of the methacrylated chitosan; s3: preparing a methacrylated chitosan solution; s4: preparing a HA-DA-AEMA pure product; s5: preparing an HA-DA-AEMA solution; s6: the HA-DA-AEMA solution and the methacrylated chitosan solution are respectively solidified into an inner biogel which is adhered to the tissues and an anti-adhesion outer biogel.
The application method of the double-layer biological gel is illustrated by taking the double-layer biological gel used after abdominal cavity surgery as an example: before abdominal cavity operation is finished but a wound is not sutured, coating HA-DA-AEMA solution on an operation incision, an operation exposed intestinal surface, a gastrointestinal anastomosis stoma and the like, irradiating the operation incision, the operation exposed intestinal surface, the gastrointestinal anastomosis stoma and the like with 365nm ultraviolet lamp for 30s, converting the liquid state into a liquid-solid state to form an inner layer biogel adhered to a tissue, then coating methacrylated chitosan solution on the inner layer biogel adhered to the tissue, irradiating the inner layer biogel with 365nm ultraviolet lamp for 60s, forming a double-layer gel after the HA-DA-AEMA solution and the methacrylated chitosan solution are solidified, and suturing the wound. Wherein the methacrylated chitosan solution solidifies into an anti-adherent outer layer biogel.
The double-layer biological gel can be tightly combined with the inner-layer biological gel adhered to the tissue and the surface of the intestinal tract, can play a role in fixing the wound of the intestinal tract and prevent inflammatory exudation and bleeding, and the anti-adhesion outer-layer biological gel can avoid the adhesion of the adhesive surface of the inner-layer biological gel adhered to the tissue and the abdominal cavity or other intestinal tracts, thereby avoiding the pain of patients caused by intestinal adhesion.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The preparation method of the double-layer biological gel for resisting the intestinal adhesion is characterized by comprising the following steps:
s1: preparing a chitosan solution in advance;
s2: preparing a pure product of the methacrylated chitosan;
specifically, dripping a methacrylic anhydride solution into a chitosan acetic acid solution, dialyzing and freeze-drying a mixture formed by reaction to obtain a pure product of the methacrylated chitosan;
s3: preparing a methacrylated chitosan solution;
specifically, a pure product of the methacrylated chitosan is prepared into 5-50 ml of solution with the mass volume concentration of 2-10% w/v, a photoinitiator is added, the solution is uniformly stirred, and then the solution is stored at 4 ℃;
s4: preparing a HA-DA-AEMA pure product;
specifically, 4-5 mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-5 mmol of N-hydroxysuccinimide, 2-5 mmol of dopamine and 2-3 mmol of methacrylic acid-2-aminoethyl ester acid are respectively weighed and placed in a light-resistant centrifugal tube;
placing 5-50 ml of a sodium hyaluronate solution with a mass volume ratio of 1-20% w/v into a container, adjusting the pH value of the sodium hyaluronate solution to 5.0-6.0 by using 0.1-0.3 mol/L hydrochloric acid, adding weighed 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, stirring for 20-30 min, sequentially adding weighed N-hydroxysuccinimide, dopamine and methacrylic acid-2-aminoethyl ester acid to obtain a mixed solution, dialyzing and freeze-drying to obtain an HA-DA-AEMA pure product;
s5: preparing an HA-DA-AEMA solution;
specifically, preparing 5-50 ml of a solution with the mass volume concentration of 2-10% w/v from a HA-DA-AEMA pure product, adding a photoinitiator, uniformly stirring, and then storing at 4 ℃;
s6: respectively solidifying the HA-DA-AEMA solution and the methacrylated chitosan solution into an inner-layer biogel adhered to the tissues and an anti-adhesion outer-layer biogel;
specifically, an HA-DA-AEMA solution is spread on a flat dish, a photoinitiator is added, and the HA-DA-AEMA solution is irradiated by a 365nm ultraviolet lamp for 30-90 s;
and after the HA-DA-AEMA solution is changed from a liquid state to a solid state, spreading the methacrylated chitosan solution on the HA-DA-AEMA liquid-solid state, adding a photoinitiator, and then irradiating by using a 365nm ultraviolet lamp for 30-150 seconds until the two solutions are completely changed into the solid state, wherein the anti-intestinal adhesion double-layer biogel is formed by the inner-layer biogel adhered to the tissues and the anti-adhesion outer-layer biogel.
2. The method for preparing the anti-intestinal adhesion bilayer bio-gel according to claim 1, wherein the chitosan solution prepared in advance in S1 is specifically: dissolving chitosan with the mass volume ratio of 3-10% w/v in 50-200 ml of 1-5% acetic acid, stirring by using a magnetic stirrer, adjusting the rotating speed of the stirrer to 1000r/min, and stirring for 24-48 h.
3. The preparation method of the anti-intestinal adhesion bilayer biogel as claimed in claim 1, wherein the mass volume concentration of the methacrylated chitosan solution in S3 is 4-7% w/v, the mass volume ratio of the S4 sodium hyaluronate solution is 7-15% w/v, and the mass volume concentration of the HA-DA-AEMA solution in S5 is 4-7% w/v.
4. The preparation method of the anti-intestinal adhesion bilayer biogel according to claim 1, wherein the dropwise addition of methacrylic anhydride in S2 specifically comprises the following steps: heating the chitosan solution to 50-60 ℃ in an oil bath kettle by stirring, dripping methacrylic anhydride with the concentration of 94-95% into the chitosan solution at the speed of 0.5-1 ml/min, stirring by using a magnetic stirrer at the rotating speed of 1000r/min, and stirring for 4-6 h.
5. The method for preparing the anti-intestinal adhesion bilayer bio-gel according to claim 1, wherein the lyophilization in S2 comprises: and (3) placing the mixture into a dialysis bag at room temperature, dialyzing the mixture for 5-6 days by using distilled water, and freeze-drying the mixture for 24-48 hours at the temperature of-40-80 ℃ and under the pressure of 5-100 mbar after dialysis is finished.
6. The method for preparing the anti-intestinal adhesion bilayer bio-gel according to claim 1, wherein the lyophilization in S4 comprises: at normal temperature, placing the container bearing the mixed solution on a magnetic stirrer, adjusting the rotating speed of the stirrer to 850-1000 r/min, and stirring for 24-48 h;
and after stirring, putting the mixed solution into a dialysis bag, dialyzing for 3-5 days by using PBS, and after dialysis, freeze-drying the mixture for 24-48 h at the temperature of-80 ℃ and under the pressure of 300-400 mbar.
7. The preparation method of the double-layer biological gel for resisting the intestinal adhesion according to any one of claims 1 to 6, wherein the photoinitiator is Irgacure 2959 or LAP, and the mass volume fractions of the Irgacure 2959 and the LAP are both 0.1-20% w/v.
8. The method for preparing the double-layered biogel for resisting intestinal adhesion according to claim 1, wherein the deacetylation degree of the chitosan in S1 is 75-90%, and the molecular mass is 310000-375000 g-mol-1The viscosity is 800-.
9. The method for preparing the double-layered bio-gel for resisting the intestinal adhesion according to claim 1, wherein the molecular weight of the sodium hyaluronate is 9 to 10 ten thousand, the molecular weight of the dopamine is 189.64, and the molecular weight of the methacrylic acid-2-aminoethyl ester acid is 165.62 in S4.
10. A bilayer biogel which is prepared by a process for preparing an anti-intestinal adhesion bilayer biogel according to any one of claims 1 to 9.
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| CN111939315B (en) * | 2020-08-12 | 2021-10-19 | 山东百多安医疗器械股份有限公司 | Adherable healing-promoting hemostatic membrane and preparation method thereof |
| CN115282325B (en) * | 2022-07-08 | 2023-07-28 | 海雅美生物技术(珠海)有限公司 | Gel dressing for wound repair and preparation process thereof |
| CN115998906B (en) * | 2022-12-30 | 2024-11-26 | 厦门大学附属心血管病医院 | In situ probe gel and preparation method and administration method thereof |
| CN116328020B (en) * | 2023-03-07 | 2024-12-31 | 北京化工大学 | Biological adhesive and preparation method and application thereof |
| CN116510093A (en) * | 2023-05-31 | 2023-08-01 | 西安交通大学 | Preparation method of medical anti-adhesion material |
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