CN1039590C - Medical stick-resistant silastic membrane and preparation thereof - Google Patents

Abstract

A medical anti-adhesion silicone rubber film, the methyl vinyl silicone raw rubber, fumed white carbon and hydroxyl silicone oil are sequentially mixed in a weight ratio of 100:45-55:3-8, and pressed to a thickness of 0.2-0.5mm The silicone rubber diaphragm is subjected to radiation cross-linking, and the irradiation dose is 50:100 kilograys; then immersed in the grafting solution prepared by HEMA, ethanol and water amine in a weight ratio of 20:60-80:20-0, the Radiation grafting, the irradiation dose is 3-5 kGy. The prepared silicone rubber graft membrane can be used to implant wound repair sites in surgery to prevent tissue adhesion.

Description

A kind of preparation method of medical anti-adhesion silicone rubber film

The invention relates to the preparation of medical polymer membranes by means of radiation crosslinking and radiation grafting.

Silicone rubber has stable physical and chemical properties, has physiological properties, is non-toxic, can withstand harsh disinfection conditions, and can be easily made into pipes, sheets, films or special-shaped components according to needs. It is an ideal medical polymer material. The current medical silicone rubber is mostly vulcanized by chemical method. Due to the presence of peroxide residues in chemical vulcanization, silicone rubber products are prone to aging, and it is easy to cause foreign body reactions when used in living organisms. In recent years, there have been researches at home and abroad to graft hydrophilic monomers to medical polymer materials such as silicone rubber by radiation to improve their biocompatibility. For example, the Journal of Shanghai University of Science and Technology, No. 2, 1987, pages 37-41, American ACS Polymer Preprints 13, 729-735 (1972) and Polymer Sci. Tehol. Series No 7, 159-171, (1975), introduced the silicon Rubber has carried out research on radiation grafting of hydrophilic monomers or hydrophilic and hydrophobic mixed monomers to improve its performance, and a small amount of animal burial experiments have been done. However, there have been no reports of successfully preparing a silicone rubber membrane that can be applied clinically as an anti-adhesion in surgical operations.

The purpose of the present invention is to provide a method for preparing a silicone rubber film with high purity, good compatibility with organisms, and which can be used for anti-adhesion in surgical operations.

The invention adopts radiation cross-linking and radiation grafting, and adopts appropriate raw material formula and process conditions to achieve the above object. The specific method is as follows:

(1) Batching and film making: mix the raw materials according to the weight ratio of 100 parts of methyl vinyl silicon raw rubber, 45-55 parts of fumed white carbon black, and 3-8 parts of hydroxy silicone oil in sequence, and mix them evenly through thinning, parking, Remelting and pressure molding to make a silicone rubber diaphragm with a thickness of 0.2-0.5 mm;

(2) Radiation cross-linking: place the above-mentioned membrane in an irradiation field, and perform radiation vulcanization at a certain irradiation temperature. The irradiation dose is 50-100 kilograys, so that the cross-linked gel The fraction is greater than 94%; the irradiation temperature is from room temperature to 55°C;

(3) Radiation grafting: Soak the above-mentioned radiation-crosslinked silicone rubber diaphragm in ethanol for more than 4 hours at room temperature to 60°C, take it out, dry it to constant weight, and then immerse the diaphragm in the bonding In the branch liquid, seal, pass nitrogen and deoxygenate, place in the irradiation field, the irradiation dose is 3-5 kGy; put the irradiated grafted membrane into distilled water and repeatedly soak and wash for more than 4 hours , and then soaked and washed with ethanol to remove the surface homopolymer, and then dried; the weight ratio of the grafting liquid is HEMA: ethanol: water = 20: 60-80: 20-0. A silicone rubber graft film with a graft rate of 10-30% and a water absorption rate of ≥ 30% is obtained.

The irradiation field can be cobalt-60 or a linear accelerator.

Described grafting rate and water absorption rate are measured according to the following method:

The pretreated membrane before grafting and drying to constant weight W ₀ was irradiated and grafted, the homopolymer was removed, washed and dried to constant weight Wg, soaked in distilled water for 24 hours, taken out, and used Blot the water stains with filter paper, weigh it as Wh, and calculate it according to the following formula:

The gel fraction is determined by the following method: Weigh a certain weight W _{of 1} gram of radiation cross-linked film, cut it into ^fragments with a size of about 0.3×0.3 mm, wrap it with copper wire mesh, put Put in the fat extractor, weigh W ₂ grams after extracting with benzene for 48 hours, calculate according to the following formula:

The effect of the product of the present invention is confirmed by animal burial contrast test and surgical operation trial.

The animal burial comparison test is as follows:

Be respectively 4%, 8% and 15% silicon rubber graft film test piece and the silicon rubber film test piece of chemical method vulcanization by the graft rate prepared by radiation method vulcanization of the present invention, radiation method grafting method, with 75% After soaking in alcohol for 24 hours, and then soaking in sterilized physiological saline for 24 hours for disinfection, a test piece of different materials with a size of 1.0×3.0 ^cm2 was respectively implanted under the deep fascia on both sides of the back and back of healthy rabbits. Bring it flat to the tissue and suture the skin. After burying for a certain period of time, samples were taken for pathological examination. The results are shown in Table I and Table II: Table 1 Test piece number Burial time Capillary Fibrous connective Inflammatory cells Foreign matter giant C

(Hours) Propaganda Organization reacts A chemical method vulcanization 84 +++++++B radiation method vulcanization 84 +++++ -c branches 4 % 84 ++ ++++-E connection rate 15 % 84+ + + + -

Table 11 Test piece No. Rabbit No. Burial time Capillary Fibrous connective Inflammatory cells Foreign body giant C

(Sky) Propaganda Organization response to A chemical method sulfide 1 3.5 +++ ++ ++ -b radiation method vulcanization 2 3.5 +++++ -c branches rate 8 % 3 3.5++++ -E-to-E connection rate 15 % 4 3.5+++-a chemical method vulcanization 5 15-+++B radiation method vulcanization 6 15++-+C connection rate 4 % 7 15-++-E-to-E-connection rate 15 % 8 15+ +--A chemical method vulcanization 930-+-b radiation method vulcanization 10 30-+-D branches rate 8 % 12 30+--E-connection rate 15 % 13 30--A chemical method Vulcanization 14 45 +++++B radiation method vulcanization 15 45-+++C connection rate 8 % 1645-+--E connection rate 15 % 17 45-+-

It can be seen from animal experiments that the radiation cross-linked and radiation-grafted silicone rubber diaphragm test pieces were taken out for observation after the operation, and their color and luster and smoothness did not change, and there was no aging or deformation. The surrounding inflammatory cells, capillary hyperplasia and Foreign body giant cells are less. There is no adhesion between the test piece and the surrounding tissue. If it is buried for more than one month, a fibrous sheath can be formed around it. The inner surface of the sheath is smooth, and there is no inflammatory reaction in the local tissue. use.

According to the animal test results, the present invention selects a grafting rate of 10-30% as the technical condition of the irradiation grafting. If the grafting rate is too low, the biocompatibility of the membrane will not be significantly improved; if the grafting rate is too high, the hardness of the membrane will be relatively high, making it inconvenient to use in surgery.

The silicone rubber grafted film of the present invention is clinically used to prevent tissue adhesion after surgery such as bone and joint damage, disease, and tendon injury. Before use, the silicone rubber grafted film is sterilized by conventional high-pressure steam method or soaked in 75% alcohol solution More than 24 hours, and then soaked in sterilized saline for later use.

According to the site and scope of the wound, the hydrogel membrane is cut according to the required size, and implanted in the site prone to adhesion. For example, the knee joint is placed in the joint cavity until the suprapatellar pouch; the elbow joint is placed in the space between the humeral joint and the deep surface of the triceps close to the backbone. For those with tendon injuries, place them on both sides of the deep and superficial tendons, and do not cover them with a sleeve method. One end of the implanted anti-adhesion membrane is sutured with 1-2 stitches to the deep tendon tissue, and a thread with a length of about 1.5 cm is left as a mark when the membrane is taken later. The time to place the membrane is generally 4-8 weeks. When taking the membrane, you can enter from a section of the original incision, and the membrane can be taken out smoothly according to the mark, and the integrity of the membrane can be checked.

From the follow-up observation of 50 routine cases, the treatment effect is as follows:

Trauma group: 35 cases, 32 cases were followed up after operation, the longest was 5 years, the shortest was one year. Among them, 10 cases were knee joint, 7 cases were excellent, 2 cases were good, 1 case was fair; 11 cases were elbow joint, 8 cases were excellent, 2 cases were good, 2 cases were fair, 4 cases were wrist joint, 1 case was fair; 1 case was hip joint, 1 case was excellent Case; ankle joint in 1 case, excellent in 1 case. There were 5 cases of repair of extensor tendon rupture, 4 cases were excellent, 1 case was poor, 1 case of Achilles tendon, and 1 case was excellent. The excellent rate was 86%.

Rheumatoid arthritis group: Among the 7 cases, 6 cases had 8 knee joints (2 cases on both sides) were followed up, the longest was 4 years, and the shortest was 2 years and 1 month. Among the 8 knees, 5 knees were excellent, 2 knees were good, and 1 knee was fair. The excellent rate is 80%.

Among the 50 cases in this group, there were 2 cases of congenital malformation, 3 cases of aseptic necrosis of the second metatarsal head (for half joints), 1 case of lunate osteonecrosis, and 2 cases of benign bone tumors, a total of 8 cases. After more than two years of follow-up, 7 cases were excellent and 1 case was good.

The evaluation criteria of excellent, good, fair, and poor curative effects above are as follows:

Trauma group (including tendon injury): according to the functional recovery of the injured part and adjacent joints, the functional recovery after fresh injury was compared with that of normal joints, and the functional recovery after old injury was compared with the preoperative joint function.

Excellent: The joint function completely returned to normal.

Good: the recovery of joint function is less than 20° from normal or more than 40° from preoperative.

Can: the recovery of joint function is less than 20° from normal, or the increase is less than 40° from preoperative.

Poor: No improvement in joint function.

For the rheumatoid arthritis group, it was determined according to the postoperative joint pain relief, detumescence and functional improvement.

Excellent: no pain, no swelling, and the range of motion of the joint increased by more than 40°.

Good: the pain and swelling were slightly relieved, and the joint range of motion increased between 20°-40°.

Possible: the pain and arsenic swelling were slightly relieved, and the range of motion of the joints increased by less than 20°.

Poor: joint pain and swelling, no improvement in function.

In the clinical trial of the product of the present invention, no bad situation occurs, and the total excellent and good rate is above 85%.

Applying the product of the present invention to anti-adhesion in surgical operations can alleviate the pain of the patient, restore the activity function of the wounded part of the patient, and restore the labor capacity of the patient. social and economic benefits.

Because the method of the present invention adopts radiation cross-linking, the high purity of the silicone rubber material before grafting is guaranteed, and the shortcomings of impurities such as peroxide residues in chemical cross-linking are avoided, and the material can be sterilized while being irradiated. Function; because the method of the present invention adopts the radiation method to graft hydrophilic monomers, and does not introduce impurities such as catalysts, thereby ensuring the high purity of the final product; the grafted copolymer forms a stable hydrogel after absorbing water, which can reduce the contact between materials and body fluids The interfacial energy is beneficial to the penetration, diffusion and migration of small molecules, which increases the biocompatibility and anticoagulant performance of the material, so that it can be suitable for medical needs.

The invention adds a proper amount of reinforcing agent white carbon black and structure control agent hydroxy silicone oil to the raw materials, and selects suitable irradiation process conditions, thereby ensuring that the product has excellent mechanical properties. After using the Instron-1122 electric universal tensile machine, under the conditions of 24°C, pulling speed 20 cm/min, and finger speed 5 cm/h, the wet test piece of the product of the present invention with a width of 10 mm and a thickness of 0.5 mm was measured, and the fracture was measured. Strength ≥ 4MPa, tear strength ≥ 8KN/m, relative elongation ≥ 100%.

The following examples specify the process of the present invention preparing the medical anti-adhesion silicone rubber graft film:

Example 1:

(1) Mixing and molding of ingredients:

Put 100 parts of methylvinyl silicone raw rubber with a vinyl content of about 4% through roller mixing, then add 50 parts of No. 2 fumed silica for mixing, then add 5 parts of hydroxy silicone oil, thin pass 15 times, and then Tablets, parked for 48 hours. After moderate re-refining, take a certain weight of rubber material, put it between the upper and lower clean polyester films, put the rubber material and these two pieces of polyester film into the tablet press together, at room temperature and pressure 2MPa Under the same conditions, it is pressed into a 0.3 mm film, and then the film is released together with the upper and lower polyester films.

(2) Radiation crosslinking:

The above membrane was placed vertically in a 60,000 Curie cobalt 60 irradiation field, and irradiated for 5 hours at a temperature of 28° C. and a dose rate of 16.7 kGy/hour to complete crosslinking.

Peel off the upper and lower layers of polyester film from the cross-linked film, take a small amount of sample on the middle layer film, dry it, weigh W ₁ =0.3573 grams, and cut it into ^pieces with a size of 0.3×0.3 mm2 , wrapped with copper wire mesh, put into an extractor, extracted with benzene for 48 hours, dried, weighed W ₂ =0.3368 g, and calculated its coagulation fraction according to the gravimetric method to determine whether the gel fraction reached ≥ 94% of requests. Calculate the gel fraction: $\frac{W_2}{W_1}=\frac{0.3368}{0.3573}\×100\%=94.26\%$

(3) Radiation grafting:

The above-mentioned interlayer film was soaked in ethanol at a temperature of 60°C for 4 hours, then placed in a vacuum drying oven, and dried to a constant weight W ₀ at a pressure of 8.66×10 ³ Pa and a temperature of 60°C.

The dried membrane is placed in a grafting bottle, and a grafting solution prepared in advance by HEMA 20% and ethanol 80% is placed in the grafting bottle, so that the membrane is immersed in the grafting solution, filled with nitrogen to remove Sealed after oxygen, placed in cobalt 60 irradiation field, irradiated for 50 minutes at a temperature of 28°C and a dose rate of 5 kGy/hour, took out the diaphragm, and washed it with distilled water first; placed it in distilled water for repeated immersion Wash for 8 hours to remove the homopolymer, then soak and wash with ethanol for 4 hours until clean, put it in a vacuum drying oven and dry to constant weight, and wrap it with clean paper for later use.

Example 2, the ingredients are 100 parts of methyl vinyl raw rubber, 45 parts of fumed silica, and 4 parts of hydroxy silicone oil; when irradiation crosslinking, a dose rate of 25 kGy/hour is used, and the irradiation temperature is 12°C. 2 hours; the grafting solution is 20% HEMA, 60% ethanol, and 20% water by weight, the irradiation dose rate is 3 kGy/hour, the irradiation temperature is 12° C., and the irradiation is 1.5 hours. All the other steps are the same as in Example 1.

Claims (2)

1. a preparation method of medical anti-adhesion silicone rubber film is characterized in that through the following processing steps: (1) Batching and film making: mix the raw materials according to the weight ratio of 100 parts of methyl vinyl silicon raw rubber, 45-55 parts of fumed white carbon black, and 3-8 parts of hydroxy silicone oil in sequence, and mix them evenly through thinning, parking, Remelting and pressure molding to make a silicone rubber diaphragm with a thickness of 0.2-0.5 mm; (2) Radiation cross-linking: place the above-mentioned membrane in an irradiation field, and perform radiation vulcanization at a certain irradiation temperature. The irradiation dose is 50-100 kilograys, so that the cross-linked gel The fraction is greater than 94%; the irradiation temperature is from room temperature to 55°C; (3) Radiation grafting: Soak the above radiation-crosslinked silicone rubber diaphragm in ethanol for more than 4 hours at room temperature to 60°C, take it out after washing, dry to constant weight, and then immerse the diaphragm in In the grafting solution, seal it, pass nitrogen to remove oxygen, and place it in an irradiation field with an irradiation dose of 3-5 kGy; put the irradiated grafted membrane into distilled water and repeatedly soak and wash for 4 hours Above, after soaking with ethanol, dry; the weight ratio of the grafting solution is HEMA:ethanol:water=20:60-80:20-0. 2. the preparation method of silicon rubber membrane as claimed in claim 1 is characterized in that described irradiation field can be cobalt 60, also can be linear accelerator.