CN105194740B - A kind of post-operation adhesion preventing hydrogel and preparation method thereof - Google Patents

Abstract

The invention discloses a postoperative anti-adhesion hydrogel and a preparation method thereof. The hydrogel is composed of sodium alginate powder, chitosan powder, acrylamide monomer, N,N'-methylenebisacrylamide , calcium sulfate, ammonium persulfate and N,N,N'N'-tetramethylethylenediamine. The invention provides a preparation method of a high-strength, high-toughness chitosan and sodium alginate composite hydrogel, the preparation method is easy to operate, the parameters are controllable, the material is easy to obtain, the solvent is non-toxic or low-toxic, and it is safe to handle and use ; This method combines the advantages of two natural biological materials, which can well meet the requirements of preventing postoperative anti-adhesion of patients and the nursing and treatment needs of medical staff. The hydrogel is soft and easy to adhere to the skin, has good flexibility, can effectively prevent wound adhesion, and can be degraded and absorbed to avoid secondary trauma. It is expected to become a new type of postoperative anti-adhesion material.

Description

Postoperative anti-adhesion hydrogel and preparation method thereof

technical field

The invention belongs to the technical field of biomedical materials, and relates to a medical hydrogel with postoperative anti-adhesion, antibacterial, hemostatic and healing functions and a preparation method thereof.

Background technique

Postoperative adhesion is one of the important medical problems to be solved urgently at home and abroad since the history of surgery. Most of the operations in the surgical field involve the prevention of adhesion between tissues. The occurrence of adhesion will not only bring pain to patients but also face high surgical expenses. Therefore, it is urgent to develop adhesion prevention materials. Under normal circumstances, the fibrous bands of connective tissue will not stick together with adjacent organs or tissues, but after surgery, due to surgical trauma, wound ischemia, foreign body presence, bleeding and exposed wound surface and bacterial infection Abnormal structures in which fibrous bands of connective tissue stick together with adjacent tissues or organs are also common clinical phenomena in the field of surgery—adhesions. Postoperative adhesions can cause serious complications, such as adhesive ileus in the abdomen and pelvis, recurrent laryngeal nerve injury after thyroid surgery, and female infertility caused by pelvic tissue adhesions. Among them, about 93% of patients who have undergone abdominal surgery will have adhesions, and the incidence of adhesions in patients who have undergone gynecological surgery is as high as 97% (40% of infertile women are caused by adhesions). Therefore, how to effectively prevent postoperative adhesions to reduce the incidence of clinical complications is an important issue to be solved in clinical treatment.

At present, there are mainly two types of postoperative adhesion prevention materials used clinically: gel and polylactic acid: gel (sodium hyaluronate and chitosan gel) can biodegrade in vivo, but the degradation rate is too fast , the retention time in the body is too short and the gel is easy to lose, which makes the anti-adhesion effect poor; polylactic acid (L-polylactic acid, racemic polylactic acid, etc.) is currently the most widely used material in biomedical engineering, and it is also certified by the US FDA It is one of the few biological materials, but it will produce acidic degradation products during the degradation process. On the one hand, acidic substances play an autocatalytic role, accelerate the degradation of the matrix, reduce the retention time in the body, and reduce the anti-adhesion effect. On the other hand, the accumulation of a large amount of acidic products may cause non-infectious inflammation and cause certain irritation to tissues and organs. Sodium alginate has good biocompatibility, biodegradability, hemostasis and other biological properties, and there are few reports on it as an anti-adhesion material. An ideal anti-adhesion material should have good biocompatibility, suitable tissue adhesion (no sutures required), be able to completely cover the wound surface and have sufficient retention time in the body; it can be degraded and absorbed without secondary surgery. Take it out; it can effectively prevent the formation of adhesions without affecting the normal healing process of the wound; at the same time, it also has the functions of hemostasis, antibacterial, and healing promotion, and has certain mechanical strength and toughness, so that the material can be implanted during the operation.

Among the existing patents, CN 103224679A discloses a chitosan polyacrylamide hydrogel base material, which is composed of acrylamide, methylene bisacrylamide, ammonium persulfate, tetramethylethylenediamine, chitosan and other solutions Composition, to obtain hydrogels with different hardness and non-toxic effects, which reduces the complexity of studying cell mechanics. CN 104558420A discloses a temperature- and pH-sensitive carboxymethyl chitosan hydrogel, which is composed of ammonium persulfate, N,N,N',N'-tetramethylethylenediamine and N,N'-methylene The base bisacrylamide is used as an initiator, an accelerator and a crosslinking agent, and is prepared through a crosslinking reaction, which improves its biocompatibility and expands its application range. CN 103396562A discloses a preparation method based on sodium alginate-acrylamide hydrogel, using acrylamide monomer and methylenebisacrylamide as crosslinking agent, ammonium persulfate and N,N,N',N'- Tetramethylethylenediamine is used as a catalyst to obtain sodium alginate hydrogel with high strength and high toughness. The alginate-polyacrylamide hydrogel prepared by Li et al. can have high strength and toughness at the same time, using acrylamide, N,N'-methylenebisacrylamide, CaSO ₄ 2H ₂ O and CaCl ₂ as crosslinks agent, ammonium persulfate and N,N,N',N'-tetramethylethylenediamine as catalysts, the hydrogel has a good application prospect in the field of biomedicine.

Contents of the invention

The present invention integrates the existing materials and the preparation method for improving the performance of the hydrogel, and provides a postoperative anti-adhesion hydrogel and a preparation method thereof. Chitosan and sodium alginate are compounded to prepare a water gel with high strength and high toughness. Gel is expected to become a postoperative anti-adhesion material with antibacterial, hemostasis, absorption of tissue exudate, maintenance of wound surface moisture and effective promotion of wound healing.

The purpose of the present invention is achieved through the following technical solutions:

A postoperative anti-adhesion hydrogel composed of sodium alginate powder, chitosan powder, acrylamide monomer, N,N'-methylenebisacrylamide, calcium sulfate, ammonium persulfate and N,N,N 'N'-tetramethylethylenediamine, wherein the mass ratio of chitosan powder to sodium alginate powder is 8-10:1-3, chitosan and sodium alginate mixed powder and acrylamide mono The mass ratio of the body is 1:3-20, the mass ratio of N,N'-methylenebisacryloyl to acrylamide monomer is 0.0006-0.0025, the mass ratio of calcium sulfate to acrylamide monomer is 0.016, persulfate The mass ratio of ammonium to acrylamide monomer is 0.006-0.03, and the mass ratio of N,N,N',N'-tetramethylethylenediamine to acrylamide monomer is 0.0025-0.0055.

A preparation method of the above-mentioned postoperative anti-adhesion hydrogel, the specific steps are as follows:

Step 1: Dissolve chitosan and sodium alginate mixed powder in 0.5-2w/v% acetic acid aqueous solution at room temperature, stir with a magnetic stirrer to fully dissolve, and obtain a uniform and stable mixed solution;

The second step: add acrylamide monomer to the mixed solution obtained in the first step in sequence, and stir the mixed solution at room temperature for 10-48 hours until the solution is uniformly dissolved; then gradually add N,N'-methylenebisacrylamide, Calcium sulfate is used as a crosslinking agent, ammonium persulfate and N,N,N' N'-tetramethylethylenediamine are used as catalysts, and stirring is continued at room temperature for 0.5-3h, and the prepared solution is left to stand at room temperature for 0.5- Degassing for 2 hours; Pour the static solution into a glass mold, and let it stand at room temperature for 6-10 hours to ensure its complete reaction to obtain a hydrogel.

The third step: The hydrogel prepared in the second step is completely soaked in the CaCl ₂ solution with a concentration of 0.05-1.5M for 3-36h, the cations diffuse into the hydrogel network structure, and induce chitosan and sodium alginate Cross-linking to prepare a high-strength and high-toughness composite hydrogel anti-adhesion material.

Preferably, the concentration of chitosan and sodium alginate mixed powder in the first step solution is 0.5-2% (w/w).

Preferably, in the first step, chitosan is a milky white powder with a degree of deacetylation>70%, and its grade is medical grade, and sodium alginate is a white powder, and its grade is medical grade.

Compared with prior art, the beneficial effect of the present invention is:

1. The present invention provides a preparation method of high-strength, high-toughness chitosan and sodium alginate composite hydrogel, the preparation method is easy to operate, the parameters are controllable, the material is easy to obtain, the solvent is non-toxic or low-toxic, and the treatment and It is safe to use; this method integrates the advantages of two natural biological materials, and can well meet the requirements of preventing postoperative anti-adhesion of patients and the nursing and treatment needs of medical staff.

2. The chitosan and sodium alginate composite hydrogel prepared by this method has the characteristics of high strength and high toughness, which makes up for the shortcomings of previous hydrogels. Chitosan itself has broad-spectrum antibacterial, hemostasis, absorption of exudate, healing , as well as good biocompatibility and biodegradability, when sodium alginate is in contact with wound exudate, soluble sodium alginate can be prepared by ion exchange, and at the same time release calcium ions into the wound to induce platelet activation, which can Accelerates wound healing.

3. The hydrogel is soft and easy to adhere to the skin, has good flexibility, can effectively prevent wound adhesion, and can be degraded and absorbed to avoid secondary trauma. It is expected to become a new type of postoperative anti-adhesion material.

Detailed ways

The technical solution of the present invention will be further described below in conjunction with the examples, but it is not limited thereto. Any modification or equivalent replacement of the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention should be covered by the present invention within the scope of protection.

Example 1

(1) Weigh a certain amount of glacial acetic acid with an electronic balance to make an acetic acid aqueous solution with a mass fraction of 0.5w/v%, weigh a certain mass of CS/SA (9/1) powder and add it to the acetic acid aqueous solution to prepare The mixed solution of 0.5w/v% was stirred with a magnetic stirrer to fully dissolve it to obtain a uniform and stable solution.

(2) Add acrylamide monomers to the above mixed solution in sequence, and stir the mixed solution at room temperature for 2 days until the solution is uniformly dissolved; then gradually add N,N'-methylenebisacryloyl and calcium sulfate as cross-linking agents, Use ammonium persulfate and N,N,N' N'-tetramethylethylenediamine as a catalyst, continue to stir at room temperature for 1h, and leave the prepared solution at room temperature for 0.5-2h to defoam; The solution was poured into glass molds and left overnight at room temperature to ensure complete reaction. Among them: the mass ratio of chitosan and sodium alginate mixed powder to acrylamide monomer is 1:5, the mass ratio of N,N'-methylenebisacryloyl crosslinking agent to acrylamide monomer is 0.0006, sulfuric acid The mass ratio of calcium to acrylamide monomer is 0.016, the mass ratio of ammonium persulfate to acrylamide monomer is 0.006, and the mass ratio of N,N,N',N'-tetramethylethylenediamine to acrylamide monomer is 0.0025.

(3) The prepared hydrogel was completely soaked in 0.5M CaCl ₂ solution for 12 hours, the cations diffused into the hydrogel network structure, induced the cross-linking of chitosan and sodium alginate, and produced high strength and high toughness Composite hydrogel anti-adhesion material.

A tensile test was performed on the prepared hydrogel to obtain a tensile strength of 995.3 kPa; a tensile modulus of elasticity of 200 kPa.

Example 2

(1) Weigh a certain amount of glacial acetic acid with an electronic balance to make an acetic acid aqueous solution with a mass fraction of 1w/v%, weigh a certain mass of CS/SA (10/2) powder and add it to the acetic acid aqueous solution to form a 1w /v% mixed solution, stir it with a magnetic stirrer to fully dissolve it, and obtain a uniform and stable solution.

(2) Add acrylamide monomers to the above mixed solution in sequence, and stir the mixed solution at room temperature for 2 days until the solution is uniformly dissolved; then gradually add N,N'-methylenebisacryloyl and calcium sulfate as cross-linking agents, Use ammonium persulfate and N,N,N' N'-tetramethylethylenediamine as a catalyst, continue to stir at room temperature for 1h, and leave the prepared solution at room temperature for 0.5-2h to defoam; The solution was poured into glass molds and left overnight at room temperature to ensure complete reaction. Among them: the mass ratio of chitosan and sodium alginate mixed powder to acrylamide monomer is 1:7, the mass ratio of N,N'-methylenebisacryloyl crosslinking agent to acrylamide monomer is 0.0010, sulfuric acid The mass ratio of calcium to acrylamide monomer is 0.016, the mass ratio of ammonium persulfate to acrylamide monomer is 0.010, and the mass ratio of N,N,N',N'-tetramethylethylenediamine to acrylamide monomer is 0.0030.

(3) The prepared hydrogel was completely soaked in 0.5M CaCl ₂ solution for 12 hours, the cations diffused into the hydrogel network structure, induced the cross-linking of chitosan and sodium alginate, and produced high strength and high toughness Composite hydrogel anti-adhesion material.

A tensile test was performed on the prepared hydrogel to obtain a tensile strength of 999.8 kPa; a tensile modulus of elasticity of 285 kPa.

Example 3

(1) Weigh a certain amount of glacial acetic acid with an electronic balance to make an acetic acid aqueous solution with a mass fraction of 0.5w/v%, weigh a certain mass of CS/SA (9/3) powder and add it to the acetic acid aqueous solution to configure 1w/v% mixed solution, stirred with a magnetic stirrer to fully dissolve, to obtain a uniform and stable solution.

(2) Add acrylamide monomers to the above mixed solution in sequence, and stir the mixed solution at room temperature for 2 days until the solution is uniformly dissolved; then gradually add N,N'-methylenebisacryloyl and calcium sulfate as cross-linking agents, Use ammonium persulfate and N,N,N' N'-tetramethylethylenediamine as a catalyst, continue to stir at room temperature for 1.5h, and leave the prepared solution at room temperature for 0.5-2h to defoam; The solution was poured into glass molds and left overnight at room temperature to ensure complete reaction. The mass ratio of chitosan and sodium alginate mixed powder to acrylamide monomer is 1:8, the mass ratio of N,N'-methylenebisacryloyl crosslinking agent to acrylamide monomer is 0.0012, calcium sulfate and The mass ratio of acrylamide monomer is 0.016, the mass ratio of ammonium persulfate to acrylamide monomer is 0.012, and the mass ratio of N,N,N',N'-tetramethylethylenediamine to acrylamide monomer is 0.0035 .

(3) The prepared hydrogel was completely soaked in 1M CaCl ₂ solution for 12 hours, the cations diffused into the hydrogel network structure, induced the cross-linking of chitosan and sodium alginate, and produced a high-strength and high-toughness composite Hydrogel anti-adhesion material.

A tensile test was performed on the prepared hydrogel, and the tensile strength was 1166.5 kPa; the tensile elastic modulus was 190.5 kPa.

Example 4

(1) Weigh a certain amount of glacial acetic acid with an electronic balance to make an acetic acid aqueous solution with a mass fraction of 1.5w/v%, weigh a certain mass of CS/SA (10/2) powder and add it to the acetic acid aqueous solution to prepare The mixed solution of 1.5w/v% was stirred with a magnetic stirrer to fully dissolve it to obtain a uniform and stable solution.

(2) Add acrylamide monomers to the above mixed solution in sequence, and stir the mixed solution at room temperature for 2 days until the solution is uniformly dissolved; then gradually add N,N'-methylenebisacryloyl and calcium sulfate as cross-linking agents, Use ammonium persulfate and N,N,N' N'-tetramethylethylenediamine as a catalyst, continue to stir at room temperature for 1.5h, and leave the prepared solution at room temperature for 0.5-2h to defoam; The solution was poured into glass molds and left overnight at room temperature to ensure complete reaction. Among them: the mass ratio of chitosan and sodium alginate mixed powder to acrylamide monomer is 1:10, the mass ratio of N,N'-methylenebisacryloyl crosslinking agent to acrylamide monomer is 0.0018, sulfuric acid The mass ratio of calcium to acrylamide monomer is 0.016, the mass ratio of ammonium persulfate to acrylamide monomer is 0.018, and the mass ratio of N,N,N',N'-tetramethylethylenediamine to acrylamide monomer is 0.0025.

(3) The prepared hydrogel was completely soaked in 1M CaCl ₂ solution for 12 hours, the cations diffused into the hydrogel network structure, induced the cross-linking of chitosan and sodium alginate, and produced a high-strength and high-toughness composite Hydrogel anti-adhesion material.

A tensile test was performed on the prepared hydrogel, and the tensile strength was 736.5 kPa; the tensile elastic modulus was 68.5 kPa.

Example 5

(1) Weigh a certain amount of glacial acetic acid with an electronic balance to make an acetic acid aqueous solution with a mass fraction of 2w/v%, weigh a certain mass of CS/SA (8/3) powder and add it to the acetic acid aqueous solution to form a 2w /v% mixed solution, stir it with a magnetic stirrer to fully dissolve it, and obtain a uniform and stable solution.

(2) Add acrylamide monomers to the above mixed solution in sequence, and stir the mixed solution at room temperature for 2 days until the solution is uniformly dissolved; then gradually add N,N'-methylenebisacryloyl and calcium sulfate as cross-linking agents, Use ammonium persulfate and N,N,N' N'-tetramethylethylenediamine as a catalyst, continue to stir at room temperature for 2h, and leave the prepared solution at room temperature for 0.5-2h to defoam; The solution was poured into glass molds and left overnight at room temperature to ensure complete reaction. Among them: the mass ratio of chitosan and sodium alginate mixed powder to acrylamide monomer is 1:10, the mass ratio of N,N'-methylenebisacryloyl crosslinking agent to acrylamide monomer is 0.0025, sulfuric acid The mass ratio of calcium to acrylamide monomer is 0.016, the mass ratio of ammonium persulfate to acrylamide monomer is 0.025, and the mass ratio of N,N,N',N'-tetramethylethylenediamine to acrylamide monomer is 0.0055.

(3) The prepared hydrogel was completely immersed in 1M CaCl ₂ solution for 24 hours, the cations diffused into the hydrogel network structure, induced the cross-linking of chitosan and sodium alginate, and produced a composite with high strength and high toughness. Hydrogel anti-adhesion material.

A tensile test was performed on the prepared hydrogel, and the tensile strength was 683.7kPa; the tensile elastic modulus was 78.7kPa.

Chitosan (CS) used in the above examples is a milky white powder with a degree of deacetylation>70%, and the grade is medical grade. Described sodium alginate (SA) is white powder, grade is medical grade.

Claims (10)

1. a kind of post-operation adhesion preventing hydrogel, it is characterised in that the hydrogel is by sodium alginate powder, Chitosan powder, propylene Amide monomer, N, N '-methylene-bisacrylamide, calcium sulfate, Ammonium Persulfate 98.5 and N, N, N ' N '-tetramethylethylenediamine prepare and Into, wherein, the mass ratio of Chitosan powder and sodium alginate powder is 8-10：1-3, chitosan and sodium alginate mixed-powder with The mass ratio of acrylamide monomer is 1：The mass ratio of 3-20, N, N '-methylene-bisacrylamide and acrylamide monomer is The mass ratio of 0.0006-0.0025, calcium sulfate and acrylamide monomer is 0.016, the matter of ammonium persulfate and acrylamide monomer Amount is than being 0.006-0.03, N, N, N ', the mass ratio of N '-tetramethylethylenediamine and acrylamide monomer is 0.0025-0.0055.

2. post-operation adhesion preventing hydrogel according to claim 1, it is characterised in that the Chitosan powder and sodium alginate The mass ratio of powder is 9：1, chitosan and the mass ratio of sodium alginate mixed-powder and acrylamide monomer are 1:5, N, N '-sub- The mass ratio of bisacrylamide and acrylamide monomer is 0.0006, and the mass ratio of calcium sulfate and acrylamide monomer is 0.016, the mass ratio of ammonium persulfate and acrylamide monomer is 0.006, N, N, N ', N '-tetramethylethylenediamine and acrylamide The mass ratio of monomer is 0.0025.

3. post-operation adhesion preventing hydrogel according to claim 1, it is characterised in that the Chitosan powder and sodium alginate The mass ratio of powder is 10：2, chitosan and the mass ratio of sodium alginate mixed-powder and acrylamide monomer are 1:7, N, N '- The mass ratio of methylene-bisacrylamide and acrylamide monomer is 0.0010, and the mass ratio of calcium sulfate and acrylamide monomer is 0.016, the mass ratio of ammonium persulfate and acrylamide monomer is 0.010, N, N, N ', N '-tetramethylethylenediamine and acrylamide The mass ratio of monomer is 0.0030.

4. post-operation adhesion preventing hydrogel according to claim 1, it is characterised in that the Chitosan powder and sodium alginate The mass ratio of powder is 9：3, chitosan and the mass ratio of sodium alginate mixed-powder and acrylamide monomer are 1:8, N, N '-sub- The mass ratio of bisacrylamide and acrylamide monomer is 0.0012, and the mass ratio of calcium sulfate and acrylamide monomer is 0.016, the mass ratio of ammonium persulfate and acrylamide monomer is 0.012, N, N, N ', N '-tetramethylethylenediamine and acrylamide The mass ratio of monomer is 0.0035.

5. post-operation adhesion preventing hydrogel according to claim 1, it is characterised in that the Chitosan powder and sodium alginate The mass ratio of powder is 10：2, chitosan and the mass ratio of sodium alginate mixed-powder and acrylamide monomer are 1:10, N, N '- The mass ratio of methylene-bisacrylamide and acrylamide monomer is 0.0018, and the mass ratio of calcium sulfate and acrylamide monomer is 0.016, the mass ratio of ammonium persulfate and acrylamide monomer is 0.018, N, N, N ', N '-tetramethylethylenediamine and acrylamide The mass ratio of monomer is 0.0025.

6. post-operation adhesion preventing hydrogel according to claim 1, it is characterised in that the Chitosan powder and sodium alginate The mass ratio of powder is 8：3, chitosan and the mass ratio of sodium alginate mixed-powder and acrylamide monomer are 1:10, N, N '- The mass ratio of methylene-bisacrylamide and acrylamide monomer is 0.0025, and the mass ratio of calcium sulfate and acrylamide monomer is 0.016, the mass ratio of ammonium persulfate and acrylamide monomer is 0.025, N, N, N ', N '-tetramethylethylenediamine and acrylamide The mass ratio of monomer is 0.0055.

7. according to the post-operation adhesion preventing hydrogel described in claim 1,2,3,4,5 or 6, it is characterised in that the chitosan is breast White powder, deacetylation>70%, rank is medical grade；Sodium alginate is white powder, and rank is medical grade.

8. a kind of preparation method of the post-operation adhesion preventing hydrogel described in claim 1-6 any claims, it is characterised in that The method step is as follows：

The first step：Chitosan and sodium alginate mixed-powder are dissolved in aqueous acetic acid at ambient temperature, stirred with magnetic force Mixing device stirring makes it fully dissolve, and obtains the mixed solution of stable homogeneous；

Second step：Acrylamide monomer is added in into the mixed solution that the first step obtains successively, mixed solution is stirred at room temperature 10-48h is mixed until solution is uniformly dissolved；Be then gradually adding N, N '-methylene-bisacrylamide, calcium sulfate as crosslinking agent, Ammonium Persulfate 98.5 and N, N, N ' N '-tetramethylethylenediamine continues to stir 0.5-3h at room temperature as catalyst, will be prepared molten Liquid stands 0.5-2h deaerations at room temperature；The solution stood is poured into glass mold, standing 6-10h at room temperature ensures it Reaction completely, obtains hydrogel；

Third walks：The hydrogel that second step prepares is fully immersed in the CaCl of a concentration of 0.05-1.5M₂3-36h in solution, Cation is diffused into hydrogel network structure, is induced chitosan and sodium alginate cross-linking, is prepared answering for high-strength and high-ductility Heshui gel adherence preventing material.

9. the preparation method of post-operation adhesion preventing hydrogel according to claim 8, it is characterised in that the first step acetic acid A concentration of 0.5-2w/v% of aqueous solution, a concentration of 0.5-2% of chitosan and sodium alginate mixed-powder in mixed solution（w/ w）.

10. the preparation method of post-operation adhesion preventing hydrogel according to claim 8, it is characterised in that shell in the first step Glycan is off-white powder, deacetylation>70%, rank is medical grade, and sodium alginate is white powder, and rank is medical grade.