WO2017071267A1 - 一种双层结构的防粘连膜及其制备方法 - Google Patents

一种双层结构的防粘连膜及其制备方法 Download PDF

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WO2017071267A1
WO2017071267A1 PCT/CN2016/087193 CN2016087193W WO2017071267A1 WO 2017071267 A1 WO2017071267 A1 WO 2017071267A1 CN 2016087193 W CN2016087193 W CN 2016087193W WO 2017071267 A1 WO2017071267 A1 WO 2017071267A1
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film
adhesion
adhesion film
layer structure
electrospinning
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French (fr)
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万华印
张俊辉
李伟达
朱晋辉
何婷
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广州市电纺生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
    • D04H1/70—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres
    • D04H1/72—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged
    • D04H1/728—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged by electro-spinning

Definitions

  • the invention relates to the field of biomedical materials, in particular to a double-layer structure anti-adhesion film and a preparation method thereof.
  • Tissue adhesion is an important issue after surgery and a common phenomenon in clinical medicine. If postoperative tissue adhesions can lead to serious complications, such as infertility, abdominal pain, intestinal obstruction, etc., and will increase the difficulty of reoperation and the potential risk of further complications.
  • the most effective method is to use a barrier formulation to isolate the surgical wound from other tissues or organs to prevent tissue adhesion.
  • anti-adhesion membranes There are two main types of barrier preparations: anti-adhesion membranes and anti-adhesion fluids.
  • the anti-adhesion liquid has the characteristics of convenient operation and good tissue adhesion, and forms a gel film after contacting the body fluid, thereby preventing the adhesion, but the film thickness is not uniform, and is easily diluted by the body fluid in the body for a short time. Its anti-adhesion effect is not good, which limits its wide clinical application.
  • the Chinese patent with the publication number CN101011606A uses carboxymethyl chitosan and phosphate buffered liquid as the main raw materials, and water is the main solvent to prepare anti-adhesion washing liquid, but it is easily diluted by body fluid and can only be used in the early stage after surgery.
  • the late anti-blocking effect is not good.
  • the anti-adhesion film has a better anti-adhesion effect, but the poor tissue adhesion generally requires suturing, which increases the difficulty of operation, and thus improves the tissue adhesion of the anti-adhesion film, which is a hot spot of research.
  • the Chinese patent with the publication number CN 203379151U has a unique design to make the anti-adhesion film smooth and rough, and to prevent the movement of the anti-adhesion film by increasing the friction between the rough surface and the surgical wound surface. However, the rough surface may affect the wound surface. Healing and prolonging healing time.
  • the nanofiber membrane prepared by electrospinning technology has a unique microporous structure, a large specific surface area and a soft texture, which not only promotes cell adhesion and proliferation but also prevents adhesion while not hindering.
  • CN 104368049A by electrospinning together with a high-viscosity oxidized cellulose and a polymer material, so that oxidized cellulose powder exists in the gap of the high-fiber membrane to increase the tissue adhesion of the membrane, however Oxidized cellulose is distributed in the interfiber space, and it takes a certain time to dissolve it, so it cannot be quickly adhered to the wound surface.
  • One of the technical problems to be solved by the present invention is to provide an anti-adhesion film having a two-layer structure, which prevents sticking without hindering the transport of nutrients.
  • the second technical problem to be solved by the present invention is to provide a method for preparing an anti-adhesion film having a two-layer structure, and the anti-adhesion film prepared by the anti-adhesion film does not hinder the transportation of nutrients.
  • the technical solution of the present invention is: a double-layered anti-adhesion film comprising a biodegradable polymer nanofiber film on the bottom layer and a gel film on the surface layer.
  • the anti-adhesion film is made into a two-layer structure, that is, the electrospun nanofiber film is covered with a viscous gel film.
  • the gel film contacts the body fluid to form a gel instantaneously, and the fiber membrane adheres to the surgical wound surface, which increases the tissue adhesion of the nanofiber membrane to avoid the suturing process, and the fiber membrane maintains its unique microporous structure, while preventing the adhesion. It does not hinder the transmission of nutrients.
  • This method not only changes the defect of the anti-blocking effect of the gel film, but also increases the tissue adhesion property of the electrospun fiber membrane.
  • the material of the polymer nanofiber membrane is polylactic acid PLA, polyglycolic acid PGA, polycaprolactone PCL, polylactic acid-glycolic acid copolymer PLGA, polycaprolactone-glycolic acid copolymer PCGA, polylactic acid One or more of ethylene glycol PELA copolymer and polyethylene glycol, the molecular weight of the polymer material is 5-20 kDa.
  • the material of the gel film is one or more of sodium carboxymethyl cellulose CMC, hyaluronic acid HA and polyvinyl alcohol PVA; the viscosity of sodium carboxymethyl cellulose CMC ranges from 300 to 1200 mpa .s, HA has a molecular weight of 400-1000 kDa, and polyvinyl alcohol PVA has a molecular weight of 80-100 kDa.
  • the technical solution of the present invention is: a method for preparing an anti-adhesion film of a two-layer structure, comprising the following steps:
  • the invention combines the electrospinning technology and the casting film forming technology, and the anti-adhesion film is formed into a two-layer structure, that is, the electrospun nanofiber film is covered with a viscous gel film.
  • the gel film contacts the body fluid to form a gel instantaneously, and the fiber membrane adheres to the surgical wound surface, which increases the tissue adhesion of the nanofiber membrane to avoid the suturing process, and the fiber membrane maintains its unique microporous structure, while preventing the adhesion. It does not hinder the transmission of nutrients.
  • This method not only changes the gel film release The defect of poor effect increases the tissue adhesion of the electrospun fiber membrane.
  • the biodegradable polymer material is polylactic acid PLA, polyglycolic acid PGA, polycaprolactone PCL, polylactic acid-glycolic acid copolymer PLGA, polycaprolactone-glycolic acid copolymer PCGA, polylactic acid-B One or more of a diol PELA copolymer and a polyethylene glycol having a molecular weight of 50-200 kDa.
  • the organic solvent is one or more of chloroform, acetone, dichloromethane, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, and methanol. .
  • the biodegradable polymer has a concentration of from 5% to 30% (m/v).
  • the electrospinning method is a multi-nozzle electrospinning process with a voltage of 10-30 KV; a flow rate of 1.0-15 ml/h, a receiving distance of 5-25 cm; a spinning temperature of 20-50 ° C; and a receiver for rolling
  • the shaft receiver has a shaft speed of 1.0-7.0 m/min; the needle models are 17G, 18G, 19G, 20G, 21G, 22G, 23G, and the drying temperature is 30-50 °C.
  • the concentration of the sodium carboxymethyl cellulose CMC is 2% to 5%; the concentration of hyaluronic acid HA is 1% to 4%; the concentration of polyvinyl alcohol PVA is 4% to 7%, anti-adhesion film
  • the thickness is 0.04-0.4 mm.
  • the anti-adhesion film is prepared, it is sterilized by radiation sterilization or ethylene oxide gas sterilization.
  • the invention combines the electrospinning technology and the casting film forming technology, and the anti-adhesion film is formed into a two-layer structure, that is, the electrospun nanofiber film is covered with a viscous gel film.
  • the gel film contacts the body fluid to form a gel instantaneously, and the fiber membrane adheres to the surgical wound surface, which increases the tissue adhesion of the nanofiber membrane to avoid the suturing process, and the fiber membrane maintains its unique microporous structure, while preventing the adhesion. It does not hinder the transmission of nutrients.
  • the invention not only changes the defect of the anti-blocking effect of the gel film, but also increases the tissue adhesion property of the electrospun fiber membrane.
  • Example 1 is an SEM image of a polylactic acid fiber membrane layer in Example 1.
  • Example 2 is an SEM image of the gel layer in Example 1.
  • Figure 3 is a graph showing the tensile strength in Example 1.
  • PLA/CMC anti-adhesion film including biodegradable polymer nanofiber film located on the bottom layer and located on the table Layer of gel film.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; as shown in Fig. 2, the gel film can increase the adhesion resistance of the anti-adhesion film.
  • step (3) Put the PLA electrospinning solution in step (1) into a syringe, and connect it to the 5 head device to select a 19G needle, adjust the voltage to 20KV, the flow rate is 2.5ml/h, and the spinning temperature is 25°C.
  • the distance between the needle tip and the receiving plate is 13 cm, the receiving rotation speed is 3 m/min, and after continuous electrospinning for 5 hours, the film is peeled off from the aluminum foil;
  • step (3) placing the nanofiber membrane in step (3) under the mold having a thickness of 0.02 mm, pouring 3-4 ml of CMC gel solution, scraping the gel evenly with a spatula, and naturally drying for 5 hours, then removing the mold. Drying at 40 ° C under vacuum to obtain an anti-adhesion film having a two-layer structure;
  • the obtained PLA/CMC double-layer structure anti-adhesion film has a thickness of 0.12 mm, a fiber layer fiber diameter of 500 ⁇ 35 nm, and a tensile strength of 7.87 MPa, as shown in Fig. 3, the elongation rate is 9.53%, and the degradation period is 12 week.
  • the PLGA/CMC anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • the mixing ratio of N-dimethylformamide is 1:1 (volume ratio), and it is completely dissolved by magnetic stirring at room temperature to obtain a uniform transparent PLGA electrospinning solution, which is reserved;
  • step (1) The PLGA electrospinning solution in step (1) is charged into a syringe.
  • the 5 sprinkler of the electrospinning machine is equipped with a 21G needle, the regulating voltage is 15KV, the flow rate is 3.5 ml/h, and the spinning temperature is 40 °C.
  • the distance between the tip and the receiver is 15cm, the receiving speed is 3m/min, and after continuous electrospinning for 2h, vacuum drying at 40°C gives the thickness a nanofiber membrane of 0.08-0.10 mm;
  • the obtained PLGA/CMC double-layer structure anti-adhesion film has a thickness of 0.10-0.13 mm, a fiber layer fiber diameter of 450 ⁇ 45 nm, a tensile strength of 6.77 MPa, a tensile ratio of 15.23%, and a degradation cycle of 10 weeks.
  • the PCL/CMC anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • the PCL electrospinning solution in the step (1) is charged into the syringe, and the 15G needle of the electrospinning machine is selected from an 18G needle, the regulating voltage is 12KV, the flow rate is 5.0 ml/h, and the spinning temperature is 30 °C.
  • the distance between the tip and the receiver is 15cm, the receiving speed is 3m/min, and after continuous electrospinning for 6h, vacuum drying at 40°C to obtain a nanofiber membrane with a thickness of 0.09-0.12mm;
  • the obtained PCL/CMC double-layer structure anti-adhesion film has a thickness of 0.10-0.13 mm, a fiber layer fiber diameter of 493 ⁇ 55 nm, a tensile strength of 8.57 MPa, a tensile ratio of 17.23%, and a degradation period of 14 weeks.
  • the PLA/HA anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • HA having a molecular weight of 1000 kDa was added to deionized water to have a HA concentration of 0.02 g/ml, stirred and dissolved at room temperature, and allowed to stand for 5 h for defoaming to obtain a transparent viscous gel solution;
  • step (3) Put the PLA electrospinning solution in step (1) into the syringe, and connect it to the 5 head device to select the 17G needle, adjust the voltage to 20KV, the flow rate is 4.0ml/h, and the spinning temperature is 35°C.
  • the distance between the needle tip and the receiving plate is 17 cm, the receiving speed is 3 m/min, and after 7 hours of continuous electrospinning, the film is peeled off from the aluminum foil;
  • the obtained PLA/HA double-layer structure anti-adhesion film has a thickness of 0.20 mm, a fiber layer fiber diameter of 600 ⁇ 75 nm, a tensile strength of 5.77 MPa, a tensile ratio of 11.47%, and a degradation period of 16 weeks.
  • the PLGA/HA anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • step (1) The PLA electrospinning solution in step (1) was placed in a syringe, and connected to a 5 head device using a 21G needle, the regulating voltage was 15 kV, the flow rate was 3.0 ml/h, and the spinning temperature was 35 °C.
  • the distance between the needle tip and the receiving plate is 16cm, the receiving speed is 3m/min, and after continuous electrospinning for 5h, the film is peeled off from the aluminum foil and vacuum dried at 40 ° C to obtain a nanofiber film having a thickness of 0.15-0.2 mm;
  • the obtained PLGA/HA double-layer structure anti-adhesion film has a thickness of 0.22 mm, a fiber layer fiber diameter of 350 ⁇ 45 nm, a tensile strength of 7.25 MPa, a tensile ratio of 14.47%, and a degradation period of 8 weeks.
  • the PCL/HA anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • step (3) Put the PCL electrospinning solution in step (1) into the syringe, and connect it to the 5 head device, select 19G needle, adjust the voltage to 15KV, the flow rate is 4.0ml/h, and the spinning temperature is 40°C.
  • the distance between the needle tip and the receiving plate is 12cm, the receiving speed is 4m/min, and after continuous electrospinning for 3h, the film is peeled off from the aluminum foil and vacuum dried at 40 ° C to obtain a nanofiber film having a thickness of 0.14-0.16 mm;
  • the obtained PCL/HA double-layer structure anti-adhesion film has a thickness of 0.20 mm, a fiber layer fiber diameter of 440 ⁇ 65 nm, a tensile strength of 9.25 MPa, a tensile ratio of 17.47%, and a degradation period of 8 weeks.
  • the PCL-PEG/HA anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • step (1) The PCL-PEG electrospinning solution in step (1) was charged into a syringe, and connected to a 5 head device using an 18G needle, the regulating voltage was 20 kV, the flow rate was 4.0 ml/h, and the spinning temperature was 40 ° C, the distance between the tip and the receiving plate is 15 cm, the receiving speed is 4 m / min, after continuous electrospinning for 4 h, the film is removed from the aluminum foil;
  • step (3) placing the nanofiber membrane in step (3) under the mold having a thickness of 0.04 mm, pouring 3-4 ml of the HA gel solution, scraping the gel evenly with a spatula, and naturally drying for 5 hours, then removing the mold. Freeze-drying to obtain an anti-adhesion film having a two-layer structure;
  • the obtained PCL-PEG/HA double-layer structure anti-adhesion film has a thickness of 0.22 mm, a fiber layer fiber diameter of 537 ⁇ 75 nm, a tensile strength of 8.45 MPa, a tensile ratio of 20.55%, and a degradation cycle of 9 weeks.
  • the PCL-PEG/CMC anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • step (1) Put the PCL-PEG electrospinning solution in step (1) into the syringe, and connect it to the 5 head device to select the 18G needle, adjust the voltage to 18KV, the flow rate is 4.0ml/h, and the spinning temperature is 40. °C, the distance between the tip and the receiving plate is 15cm, the receiving speed is 4m / min, after continuous electrospinning for 5h, the film is peeled off from the aluminum foil, vacuum dried at 40 ° C, to obtain a nanofiber film with a thickness of 0.15-0.17mm;
  • step (3) placing the nanofiber membrane in step (3) under the mold having a thickness of 0.04 mm, pouring 3-4 ml of CMC gel solution, scraping the gel evenly with a spatula, and naturally drying for 5 hours, then removing the mold. Vacuum drying at 40 ° C to obtain an anti-adhesion film having a two-layer structure;
  • the obtained PCL-PEG/CMC double-layer structure anti-adhesion film has a thickness of 0.23 mm, a fiber layer fiber diameter of 547 ⁇ 65 nm, a tensile strength of 7.45 MPa, a tensile ratio of 14.55%, and a degradation cycle of 10 weeks.
  • the PLA-PEG/HA anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • step (1) The PLA-PEG electrospinning solution in step (1) was charged into a syringe, and connected to a 5 head device using an 18G needle, the voltage was adjusted to 16 kV, the flow rate was 5.0 ml/h, and the spinning temperature was 40 ° C, the distance between the tip and the receiving plate is 17cm, the receiving speed is 3m / min, after continuous electrospinning for 5h, the film is peeled off from the aluminum foil, vacuum drying at 40 ° C, to obtain a nanofiber film with a thickness of 0.14-0.18mm;
  • step (3) placing the nanofiber membrane in step (3) under the mold having a thickness of 0.04 mm, pouring 3-4 ml of the HA gel solution, scraping the gel evenly with a spatula, and naturally drying for 5 hours, then removing the mold. Freeze-drying to obtain an anti-adhesion film having a two-layer structure;
  • the obtained PCL-PEG/HA double-layer structure anti-adhesion film has a thickness of 0.24 mm, a fiber layer fiber diameter of 577 ⁇ 75 nm, a tensile strength of 7.93 MPa, a tensile ratio of 14.33%, and a degradation cycle of 10 weeks.
  • the PLA-PEG/CMC anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • step (1) Put the PLA-PEG electrospinning solution in step (1) into a syringe and connect it to the 5-spray device.
  • the adjustment voltage is 17KV
  • the flow rate is 4.0ml/h
  • the spinning temperature is 40°C
  • the distance between the needle tip and the receiving plate is 15cm
  • the receiving speed is 4m/min
  • the film is taken from the aluminum foil. Stripping, vacuum drying at 40 ° C, to obtain a nanofiber membrane having a thickness of 0.14-0.16 mm;
  • step (3) placing the nanofiber membrane in step (3) under the mold having a thickness of 0.04 mm, pouring 3-4 ml of CMC gel solution, scraping the gel evenly with a spatula, and naturally drying for 5 hours, then removing the mold. Vacuum drying at 40 ° C to obtain an anti-adhesion film having a two-layer structure;
  • the obtained PLA-PEG/CMC double-layer structure anti-adhesion film has a thickness of 0.27 mm, a fiber layer fiber diameter of 547 ⁇ 65 nm, a tensile strength of 6.33 MPa, a tensile ratio of 12.41%, and a degradation cycle of 10 weeks.
  • the PLA/PVA anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • step (3) Put the PLA electrospinning solution in step (1) into a syringe, and connect it to the 5 head device to select a 19G needle.
  • the adjustment voltage is 18KV
  • the flow rate is 5.0ml/h
  • the spinning temperature is 25°C.
  • the distance between the needle tip and the receiving plate is 17 cm
  • the receiving speed is 2 m/min
  • the film is peeled off from the aluminum foil;
  • step (3) placing the nanofiber membrane in step (3) under the mold having a thickness of 0.02 mm, pouring 3-4 ml of PVA gel solution, scraping the gel evenly with a spatula, and naturally drying for 5 hours, then removing the mold. Drying at 40 ° C under vacuum to obtain an anti-adhesion film having a two-layer structure;
  • the obtained PLA/PVA double-layer structure anti-adhesion film has a thickness of 0.14 mm, a fiber layer fiber diameter of 635 ⁇ 75 nm, a tensile strength of 6.947 MPa, a tensile ratio of 11.8%, and a degradation cycle of 20 weeks.
  • PLA-PEG/PVA anti-adhesion film including biodegradable polymer nanofiber film and bit on the bottom layer Gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • step (1) The PLA-PEG electrospinning solution in step (1) was charged into a syringe, and connected to a 5 head device using an 18G needle, the regulating voltage was 15 kV, the flow rate was 4.5 ml/h, and the spinning temperature was 40 ° C, the distance between the tip and the receiving plate is 15cm, the receiving speed is 3m / min, after continuous electrospinning for 5h, the film is peeled off from the aluminum foil, vacuum drying at 40 ° C, to obtain a nanofiber film with a thickness of 0.15mm;
  • step (3) placing the nanofiber membrane in step (3) under the mold having a thickness of 0.04 mm, pouring 3-4 ml of the PVA gel solution, scraping the gel evenly with a spatula, and naturally drying for 5 hours, then removing the mold. Vacuum drying at 40 ° C to obtain an anti-adhesion film having a two-layer structure;
  • the obtained PLA-PEG/PVA double-layer structure anti-adhesion film has a thickness of 0.20 mm, a fiber layer fiber diameter of 653 ⁇ 65 nm, a tensile strength of 7.945 MPa, a tensile ratio of 11.41%, and a degradation period of 14 weeks.
  • the PLGA/PVA anti-adhesion film comprises a biodegradable polymer nanofiber membrane on the bottom layer and a gel film on the surface layer.
  • the polymer nanofiber membrane has a large specific surface area, mechanical strength and a good anti-blocking effect; the gel film can increase the adhesion resistance of the anti-adhesion film.
  • step (1) The PLGA electrospinning solution in step (1) is charged into a syringe, and the 21-needle device of the electrospinning machine is equipped with a 21G needle, the regulating voltage is 18 kV, the flow rate is 3.0 ml/h, and the spinning temperature is 40 °C.
  • the distance between the tip and the receiver is 16cm, the receiving speed is 2.5m/min, and after continuous electrospinning for 2h, vacuum drying at 40°C gives the thickness.
  • step (3) Place the nanofiber membrane in step (3) under the mold with a thickness of 0.04 mm, pour 3-4 ml of PVA gel solution, scrape the gel evenly with a spatula, and dry it for 7 hours, then remove the mold, 40 Vacuum drying at °C;
  • the obtained PLGA/PVA double-layer structure anti-adhesion film has a thickness of 0.12-0.15 mm, a fiber layer fiber diameter of 459 ⁇ 74 nm, a tensile strength of 7.45 MPa, a tensile ratio of 17.23%, and a degradation period of 12 weeks.
  • SD rats were used as animal models. 88 SD rats were randomly divided into 4 groups, which were designed as normal control group, model control group, PLA/HA anti-adhesion membrane group and PLGA/CMC anti-adhesion membrane group, except normal control. Outside the group, the other groups were treated with multi-factor method for postoperative abdominal adhesion model.
  • the CMC gel surface of PLGA/CMC membrane group and the HA gel surface of PLA/HA anti-adhesion membrane were applied to the wound surface. The wounds were not treated, and blood routine, plasma liver and kidney function and fibrinogen content were measured at different time points. Animals were sacrificed at 1, 2, 4, 6, and 12 weeks after surgery, and the degree of abdominal adhesion and membrane degradation were evaluated.
  • the PLA/HA anti-adhesion group can adhere to the wound surface, but there is displacement, the anti-adhesion effect is better, no adhesion occurs, and it belongs to grade I.
  • the membrane begins to degrade from the second week and does not completely degrade within 12 weeks. According to the detection of fibrinogen content, it was found that the anti-adhesion membrane group can reduce the exudation of fibrinogen and inhibit the proliferation of collagen fibrous tissue, thereby effectively preventing the occurrence of adhesion.

Abstract

一种双层结构的防粘连膜及其制备方法。防粘连膜包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。制备方法包括：第一步将生物可降解的聚合物溶解在有机溶剂中得到聚合物电纺溶液，然后通过静电纺丝法得到聚合物纳米纤维膜；第二步将聚合物纳米纤维膜置于模具底部，然后将配制好的羧甲基纤维素钠CMC、透明质酸HA和聚乙烯醇PVA的水溶液倒入模具内，烘干或者冷冻干燥，得到具有双层结构的防粘连膜。

Description

一种双层结构的防粘连膜及其制备方法 技术领域
本发明涉及生物医用材料领域，具体涉及一种双层结构的防粘连膜及其制备方法。
背景技术
组织粘连是外科手术后的一个重要问题，也是临床医学中的常见现象。如果术后发生组织粘连有可能导致严重的并发症，如不育症、腹腔疼痛、肠梗阻等，并且会增加再次手术的难度和产生进一步并发症的潜在危险。目前而言，最有效的方法是使用屏障制剂，使手术创面与其他组织或器官隔离从而防止组织粘连。
屏障制剂主要有两种类型：防粘连膜和防粘连液。防粘连液具有操作方便，组织粘附性较好的特点，其接触体液后形成凝胶膜，从而起到防粘连的效果，但其膜厚度不均一，易被体液稀释在体内存在时间短，使其防粘连效果不佳，限制了其在临床的广泛应用。公开号为CN101011606A的中国专利采用羧甲基壳聚糖和磷酸盐缓冲充液为主要原料，水为主要溶剂制备成防粘连冲洗液，但其易被体液稀释，只能在手术后初期起到一定的防粘连作用，后期防粘连效果不佳。相对而言，防粘连膜具有更好的防粘连效果，但是其组织粘附性差一般需要缝合，增加操作难度，因此改善防粘连膜的组织粘附性，是研究的一个热点。公开号为CN 203379151U的中国专利，通过独特的设计将防粘连膜制备成一面光滑一面粗糙，通过增大粗糙面与手术创面的摩擦力来防止防粘连膜的移动，然而粗糙面可能会影响创面的愈合，延长愈合时间。
静电纺丝技术制备的纳米纤维膜作为一种新型防粘连膜，其具有独特微孔结构，较大的比表面积，柔软的质地，不仅可以促进细胞的粘附和增殖而且防粘连同时又不阻碍营养物质的传输，但其也具有组织粘附性差的缺陷，一般需要缝合过程。公开号为CN 104368049A的中国专利，通过采用粘性较强的氧化纤维素与高分子材料共同电纺，使氧化纤维素粉末存在于高分纤维膜的间隙从而增大膜的组织粘附性，然而氧化纤维素分布于纤维间隙中，将其溶出需要一定的时间，所以不能迅速的粘附于伤口创面。
发明内容
本发明所要解决的技术问题之一是提供一种双层结构的防粘连膜，防粘连的同时又不阻碍营养物质的传输。
本发明所要解决的技术问题之二是提供一种双层结构的防粘连膜的制备方法，制备出来的防粘连膜防粘连的同时又不阻碍营养物质的传输。
为解决上述技术问题之一，本发明的技术方案是：一种双层结构的防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。本发明将防粘连膜制成双层结构即在电纺的纳米纤维膜上覆盖一层粘性较强凝胶膜。凝胶膜接触体液瞬间形成凝胶将纤维膜粘附在手术创面，增加了纳米纤维膜的组织粘附性避免了缝合过程，同时纤维膜又保持了其独特微孔结构，在防粘连的同时又不阻碍营养物质的传输。这种方法不仅改变了凝胶膜防粘连效果不佳的缺陷，又增加了电纺纤维膜的组织粘附性能。
作为改进，所述聚合物纳米纤维膜的材料为聚乳酸PLA、聚乙醇酸PGA、聚己内酯PCL、聚乳酸-乙醇酸共聚物PLGA、聚己内酯-羟基乙酸共聚物PCGA、聚乳酸-乙二醇PELA共聚物、聚乙二醇中的一种或多种，聚合物材料分子量为5-20kDa。
作为改进，所述凝胶膜的材料为羧甲基纤维素钠CMC、透明质酸HA和聚乙烯醇PVA中的一种或多种；羧甲基纤维素钠CMC的粘度范围为300-1200mpa.s，HA的分子量为400-1000kDa，聚乙烯醇PVA的分子量为80-100kDa。
为解决上述技术问题之二，本发明的技术方案是：一种双层结构的防粘连膜的制备方法，包括以下步骤：
(1)将生物可降解的聚合物溶解在有机溶剂中得到聚合物电纺溶液，然后通过静电纺丝法得到聚合物纳米纤维膜；
(2)将聚合物纳米纤维膜置于模具底部，然后将配制好的羧甲基纤维素钠CMC、透明质酸HA和聚乙烯醇PVA水溶液倒入模具内，流延均匀，在室温下自然干燥3-5h后，放入40-80℃烘箱中烘干或者冷冻干燥，得具有双层结构的防粘连膜。本发明结合了静电纺丝技术和流延成膜技术，将防粘连膜制成双层结构即在电纺的纳米纤维膜上覆盖一层粘性较强凝胶膜。凝胶膜接触体液瞬间形成凝胶将纤维膜粘附在手术创面，增加了纳米纤维膜的组织粘附性避免了缝合过程，同时纤维膜又保持了其独特微孔结构，在防粘连的同时又不阻碍营养物质的传输。这种方法不仅改变了凝胶膜防粘 连效果不佳的缺陷，又增加了电纺纤维膜的组织粘附性能。
作为改进，生物可降解的聚合物材料为聚乳酸PLA、聚乙醇酸PGA、聚己内酯PCL、聚乳酸-乙醇酸共聚物PLGA、聚己内酯-羟基乙酸共聚物PCGA、聚乳酸-乙二醇PELA共聚物、聚乙二醇中的一种或多种，聚合物材料分子量为50-200kDa。
作为改进，所述有机溶剂为氯仿、丙酮、二氯甲烷、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、乙酸乙酯、甲醇中的一种或多种。
作为改进，所述生物可降解的聚合物浓度为5％-30％(m/v)。
作为改进，静电纺丝方法为多喷头电纺工艺，其电压为10-30KV；流速为1.0-15ml/h，接收距离为5-25cm；纺丝温度为20-50℃；其接收器为滚轴接收器，转轴速度为1.0-7.0m/min；其针头型号为17G、18G、19G、20G、21G、22G、23G，烘干温度为30-50℃。
作为改进，所述羧甲基纤维素钠CMC的浓度为2％-5％；透明质酸HA的浓度为1％-4％；聚乙烯醇PVA的浓度为4％-7％，防粘连膜的厚度为0.04-0.4mm。
作为改进，制备出防粘连膜后，采用辐射灭菌或环氧乙烷气体灭菌对其进行消毒。
本发明与现有技术相比所带来的有益效果是：
本发明结合了静电纺丝技术和流延成膜技术，将防粘连膜制成双层结构即在电纺的纳米纤维膜上覆盖一层粘性较强凝胶膜。凝胶膜接触体液瞬间形成凝胶将纤维膜粘附在手术创面，增加了纳米纤维膜的组织粘附性避免了缝合过程，同时纤维膜又保持了其独特微孔结构，在防粘连的同时又不阻碍营养物质的传输。本发明不仅改变了凝胶膜防粘连效果不佳的缺陷，又增加了电纺纤维膜的组织粘附性能。
附图说明
图1为实施例1中聚乳酸纤维膜层的SEM图。
图2为实施例1中凝胶层的SEM图。
图3为实施例1中拉伸强度图。
具体实施方式
下面结合说明书附图对本发明作进一步说明。
实施例1
PLA/CMC防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表 层的凝胶膜。如图1所示，聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；如图2所示，凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝90kDa的PLA，加入氯仿和丙酮的混合溶剂中，使PLA的浓度为0.12g/ml，氯仿和丙酮的混合比例为9:1(体积比)，室温下磁力搅拌使其完全溶解，得到均一透明的PLLA电纺溶液，备用；
(2)将粘度为800-1200mpa.s的CMC加入到去离子水中，使CMC浓度为0.03g/ml，室温下搅拌溶解，并静置5h消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PLA电纺溶液装入注射器中，并将其连接在5喷头装置上选用19G针头，调节电压为20KV，流速为2.5ml/h，纺丝温度为25℃，针尖与接收板的距离为13cm，接收转速为3m/min，连续电纺5h后，将膜从铝箔上剥离；
(4)将步骤(3)中的纳米纤维膜置于厚度为0.02mm的模具下方，倒入3-4ml CMC凝胶溶液，用刮刀将凝胶刮均匀，自然晾干5h后取下模具，40℃下真空干燥，得到具有双层结构的防粘连膜；
(5)将双层结构的防粘连膜封装后，用环氧乙烷气体杀菌消毒。
得到的PLA/CMC双层结构防粘连膜厚度为0.12mm，其纤维层纤维直径为500±35nm，拉伸强度为7.87MPa，如图3所示其拉伸率为9.53％，降解周期为12周。
实施例2
PLGA/CMC防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝90kDa的PLGA(LA:GA＝85:15)，加入氯仿和N,N-二甲基甲酰胺的混合溶剂中，使PLGA的浓度为0.22g/ml，氯仿和N,N-二甲基甲酰胺的混合比例为1:1(体积比)，室温下磁力搅拌使其完全溶解，得到均一透明的PLGA电纺溶液，备用；
(2)将粘度为800-1200mpa.的CMC加入到去离子水中，使CMC浓度为0.02g/ml，室温下搅拌溶解，并静置5h消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PLGA电纺溶液装入注射器中，静电纺丝机的5喷头装置上选用21G针头，调节电压为15KV，流速为3.5ml/h，纺丝温度为40℃，针尖与接收器的距离为15cm，接收转速为3m/min，连续电纺2h后，40℃真空干燥，得到厚度为 0.08-0.10mm的纳米纤维膜；
(4)将(3)中的纳米纤维膜置于厚度为0.04mm的模具下方，倒入3-4mlCMC凝胶溶液，用刮刀将凝胶刮均匀，自然晾干7h后取下模具，40℃下真空干燥；
(5)将双层结构的防粘连膜封装后，用环氧乙烷气体杀菌消毒后。
得到的PLGA/CMC双层结构防粘连膜厚度为0.10-0.13mm，其纤维层纤维直径为450±45nm，拉伸强度为6.77MPa，拉伸率为15.23％，降解周期为10周。
实施例3
PCL/CMC防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝120kDa的PCL，加入氯仿和N,N-二甲基甲酰胺的混合溶剂中，使PCL的浓度为0.08g/ml，氯仿和N,N-二甲基甲酰胺的混合比例为2:1(体积比)，室温下磁力搅拌使其完全溶解，得到均一透明的PCL电纺溶液，备用；
(2)将粘度为800-1200mpa.的CMC，加入到去离子水中，使CMC浓度为0.03g/ml，室温下搅拌溶解，并静置5h消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PCL电纺溶液装入注射器中，静电纺丝机的5喷头装置上选用18G针头，调节电压为12KV，流速为5.0ml/h，纺丝温度为30℃，针尖与接收器的距离为15cm，接收转速为3m/min，连续电纺6h后，40℃真空干燥，得到厚度为0.09-0.12mm的纳米纤维膜；
(4)将(3)中的纳米纤维膜置于厚度为0.02mm的模具下方，倒入3-4mlCMC凝胶溶液，用刮刀将凝胶刮均匀，自然晾干7h后取下模具，40℃下真空干燥；
(5)将双层结构的防粘连膜封装后，用环氧乙烷气体杀菌消毒。
得到的PCL/CMC双层结构防粘连膜厚度为0.10-0.13mm，其纤维层纤维直径为493±55nm，拉伸强度为8.57MPa，拉伸率为17.23％，降解周期为14周。
实施例4
PLA/HA防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝200kDa的PLA，加入氯仿和N,N-二甲基甲酰胺混合溶剂中，使PLA 的浓度为0.07g/ml，氯仿和N,N-二甲基甲酰胺的混合比例为6:4(体积比)，室温下磁力搅拌使其完全溶解，得到均一透明的PLA电纺溶液，备用；
(2)将分子量为1000kDa的HA加入到去离子水中，使HA浓度为0.02g/ml，室温下搅拌溶解，并静置5h消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PLA电纺溶液装入注射器中，并将其连接在5喷头装置上选用17G针头，调节电压为20KV，流速为4.0ml/h，纺丝温度为35℃，针尖与接收板的距离为17cm，接收转速为3m/min，连续电纺7h后，将膜从铝箔上剥离；
(4)将(3)中的纳米纤维膜置于厚度为0.1mm的模具下方，倒入3-4ml HA凝胶溶液，用刮刀将凝胶刮均匀，自然晾干7h后取下模具，冷冻干燥，得到具有双层结构的防粘连膜；
(5)将双层结构的防粘连膜封装后，用紫外辐射杀菌消毒。
得到的PLA/HA双层结构防粘连膜厚度为0.20mm，其纤维层纤维直径为600±75nm，拉伸强度为5.77MPa，拉伸率为11.47％，降解周期为16周。
实施例5
PLGA/HA防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝70kDa的PLGA，加入氯仿和丙酮混合溶剂中，使PLGA的浓度为0.25g/ml，氯仿和丙酮的混合比例为1:1(体积比)，室温下磁力搅拌使其完全溶解，得到均一透明的PLGA电纺溶液，备用；
(2)将分子量为800kDa的HA加入到去离子水中，使HA浓度为0.03g/ml，室温下搅拌溶解，并静置过夜消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PLA电纺溶液装入注射器中，并将其连接在5喷头装置上选用21G针头，调节电压为15KV，流速为3.0ml/h，纺丝温度为35℃，针尖与接收板的距离为16cm，接收转速为3m/min，连续电纺5h后，将膜从铝箔上剥离，40℃真空干燥，得到厚度为0.15-0.2mm的纳米纤维膜；
(4)将(3)中的纳米纤维膜置于厚度为0.1mm的模具下方，倒入3-4ml HA凝胶溶液，用刮刀将凝胶刮均匀，自然晾干6h后取下模具，冷冻干燥，得到具有双层结构的防粘连膜；
(5)将双层结构的防粘连膜封装后，用紫外辐射杀菌消毒后。
得到的PLGA/HA双层结构防粘连膜厚度为0.22mm，其纤维层纤维直径为350±45nm，拉伸强度为7.25MPa，拉伸率为14.47％，降解周期为8周。
实施例6
PCL/HA防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝100kDa的PCL加入丙酮溶剂中，使PCL的浓度为0.09g/ml，室温下磁力搅拌使其完全溶解，得到均一透明的PLGA电纺溶液，备用；
(2)将分子量为600kDa的HA加入到去离子水中，使HA浓度为0.04g/ml，室温下搅拌溶解，并静置过夜消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PCL电纺溶液装入注射器中，并将其连接在5喷头装置上选用19G针头，调节电压为15KV，流速为4.0ml/h，纺丝温度为40℃，针尖与接收板的距离为12cm，接收转速为4m/min，连续电纺3h后，将膜从铝箔上剥离，40℃真空干燥，得到厚度为0.14-0.16mm的纳米纤维膜；
(4)将(3)中的纳米纤维膜置于厚度为0.1mm的模具下方，倒入3-4ml HA凝胶溶液，用刮刀将凝胶刮均匀，自然晾干5h后取下模具，冷冻干燥，得到具有双层结构的防粘连膜；
(5)将双层结构的防粘连膜封装后，用紫外辐射杀菌消毒。
得到的PCL/HA双层结构防粘连膜厚度为0.20mm，其纤维层纤维直径为440±65nm，拉伸强度为9.25MPa，拉伸率为17.47％，降解周期为8周。
实施例7
PCL-PEG/HA防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝80kDa的PCL和Mw＝6kDa的PEG加入体积比为4:1的二氯甲烷和N,N-二甲基甲酰胺溶剂中，使PCL的浓度为0.12g/ml，PEG的浓度为0.03g/ml，室温下磁力搅拌使其完全溶解，得到均一透明的PCL-PEG电纺溶液，备用；
(2)将分子量为400kDa的HA加入到去离子水中，使HA浓度为0.03g/ml，室温 下搅拌溶解，并静置过夜消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PCL-PEG电纺溶液装入注射器中，并将其连接在5喷头装置上选用18G针头，调节电压为20KV，流速为4.0ml/h，纺丝温度为40℃，针尖与接收板的距离为15cm，接收转速为4m/min，连续电纺4h后，将膜从铝箔上；
(4)将步骤(3)中的纳米纤维膜置于厚度为0.04mm的模具下方，倒入3-4ml HA凝胶溶液，用刮刀将凝胶刮均匀，自然晾干5h后取下模具，冷冻干燥，得到具有双层结构的防粘连膜；
(5)将双层结构的防粘连膜封装后，用紫外辐射杀菌消毒后。
得到的PCL-PEG/HA双层结构防粘连膜厚度为0.22mm，其纤维层纤维直径为537±75nm，拉伸强度为8.45MPa，拉伸率为20.55％，降解周期为9周。
实施例8
PCL-PEG/CMC防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝90kDa的PCL和Mw＝6kDa的PEG加入体积比为4:1的二氯甲烷和N,N-二甲基甲酰胺溶剂中，使PCL的浓度为0.09g/ml，PEG的浓度为0.06g/ml，室温下磁力搅拌使其完全溶解，得到均一透明的PCL-PEG电纺溶液，备用；
(2)将粘度为800-1200mpa的CMC加入到去离子水中，使CMC浓度为0.04g/ml，室温下搅拌溶解，并静置过夜消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中PCL-PEG电纺溶液装入注射器中，并将其连接在5喷头装置上选用18G针头，调节电压为18KV，流速为4.0ml/h，纺丝温度为40℃，针尖与接收板的距离为15cm，接收转速为4m/min，连续电纺5h后，将膜从铝箔上剥离，40℃真空干燥，得到厚度为0.15-0.17mm的纳米纤维膜；
(4)将步骤(3)中的纳米纤维膜置于厚度为0.04mm的模具下方，倒入3-4ml CMC凝胶溶液，用刮刀将凝胶刮均匀，自然晾干5h后取下模具，40℃真空干燥得到具有双层结构的防粘连膜；
(5)将双层结构的防粘连膜封装后，用紫外辐射杀菌消毒后。
得到的PCL-PEG/CMC双层结构防粘连膜厚度为0.23mm，其纤维层纤维直径为547±65nm，拉伸强度为7.45MPa，拉伸率为14.55％，降解周期为10周。
实施例9
PLA-PEG/HA防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝90kDa的PLA和Mw＝6kDa的PEG加入体积比为2:1的氯仿和N,N-二甲基甲酰胺混合溶剂中，使PLA的浓度为0.10g/ml，PEG的浓度为0.06g/ml，室温下磁力搅拌使其完全溶解，得到均一透明的PLA-PEG电纺溶液，备用；
(2)将分子量为800kDa的HA加入到去离子水中，使HA浓度为0.04g/ml，室温下搅拌溶解，并静置过夜消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PLA-PEG电纺溶液装入注射器中，并将其连接在5喷头装置上选用18G针头，调节电压为16KV，流速为5.0ml/h，纺丝温度为40℃，针尖与接收板的距离为17cm，接收转速为3m/min，连续电纺5h后，将膜从铝箔上剥离，40℃真空干燥，得到厚度为0.14-0.18mm的纳米纤维膜；
(4)将步骤(3)中的纳米纤维膜置于厚度为0.04mm的模具下方，倒入3-4ml HA凝胶溶液，用刮刀将凝胶刮均匀，自然晾干5h后取下模具，冷冻干燥，得到具有双层结构的防粘连膜；
(5)将双层结构的防粘连膜封装后，用紫外辐射杀菌消毒。
得到的PCL-PEG/HA双层结构防粘连膜厚度为0.24mm，其纤维层纤维直径为577±75nm，拉伸强度为7.93MPa，拉伸率为14.33％，降解周期为10周。
实施例10
PLA-PEG/CMC防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝90kDa的PLA和Mw＝6kDa的PEG加入体积比为2:1的氯仿和N,N-二甲基甲酰胺溶剂中，使PLA的浓度为0.12g/ml，PEG的浓度为0.04g/ml，室温下磁力搅拌使其完全溶解，得到均一透明的PLA-PEG电纺溶液，备用；
(2)将粘度为800-1200mpa的CMC加入到去离子水中，使CMC浓度为0.03g/ml，室温下搅拌溶解，并静置过夜消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中PLA-PEG电纺溶液装入注射器中，并将其连接在5喷头装置上选 用18G针头，调节电压为17KV，流速为4.0ml/h，纺丝温度为40℃，针尖与接收板的距离为15cm，接收转速为4m/min，连续电纺5h后，将膜从铝箔上剥离，40℃真空干燥，得到厚度为0.14-0.16mm的纳米纤维膜；
(4)将步骤(3)中的纳米纤维膜置于厚度为0.04mm的模具下方，倒入3-4ml CMC凝胶溶液，用刮刀将凝胶刮均匀，自然晾干5h后取下模具，40℃真空干燥得到具有双层结构的防粘连膜；
(5)将双层结构的防粘连膜封装后，用紫外辐射杀菌消毒。
得到的PLA-PEG/CMC双层结构防粘连膜厚度为0.27mm，其纤维层纤维直径为547±65nm，拉伸强度为6.33MPa，拉伸率为12.41％，降解周期为10周。
实施例11
PLA/PVA防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝80kDa PLA，加入氯仿和丙酮的混合溶剂中，使PLA的浓度为0.12g/ml，氯仿和丙酮的混合比例为9:1(体积比)，室温下磁力搅拌使其完全溶解，得到均一透明的PLA电纺溶液，备用；
(2)将分子量为80kDa的PVA加入到去离子水中，使PVA浓度为0.05g/ml，室温下搅拌溶解，并静置5h消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PLA电纺溶液装入注射器中，并将其连接在5喷头装置上选用19G针头，调节电压为18KV，流速为5.0ml/h，纺丝温度为25℃，针尖与接收板的距离为17cm，接收转速为2m/min，连续电纺2h后，将膜从铝箔上剥离；
(4)将步骤(3)中的纳米纤维膜置于厚度为0.02mm的模具下方，倒入3-4ml PVA凝胶溶液，用刮刀将凝胶刮均匀，自然晾干5h后取下模具，40℃下真空干燥，得到具有双层结构的防粘连膜；
(5)将双层结构的防粘连膜封装后，用环氧乙烷气体杀菌消毒。
得到的PLA/PVA双层结构防粘连膜厚度为0.14mm，其纤维层纤维直径为635±75nm，拉伸强度为6.947MPa，拉伸率为11.8％，降解周期为20周。
实施例12
PLA-PEG/PVA防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位 于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝90kDa的PLA和Mw＝6kDa的PEG加入体积比为1:1的氯仿和N,N-二甲基甲酰胺溶剂中，使PLA的浓度为0.10g/ml，PEG的浓度为0.04g/ml，室温下磁力搅拌使其完全溶解，得到均一透明的PLA-PEG电纺溶液，备用；
(2)/将分子量为90kDa的PVA加入到去离子水中，使PVA浓度为0.07g/ml，室温下搅拌溶解，并静置过夜消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PLA-PEG电纺溶液装入注射器中，并将其连接在5喷头装置上选用18G针头，调节电压为15KV，流速为4.5ml/h，纺丝温度为40℃，针尖与接收板的距离为15cm，接收转速为3m/min，连续电纺5h后，将膜从铝箔上剥离，40℃真空干燥，得到厚度为0.15mm的纳米纤维膜；
(4)将步骤(3)中的纳米纤维膜置于厚度为0.04mm的模具下方，倒入3-4ml PVA凝胶溶液，用刮刀将凝胶刮均匀，自然晾干5h后取下模具，40℃真空干燥得到具有双层结构的防粘连膜；
(5)将双层结构的防粘连膜封装后，用紫外辐射杀菌消毒。
得到的PLA-PEG/PVA双层结构防粘连膜厚度为0.20mm，其纤维层纤维直径为653±65nm，拉伸强度为7.945MPa，拉伸率为11.41％，降解周期为14周。
实施例13
PLGA/PVA防粘连膜，包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。聚合物纳米纤维膜具有较大的比表面积、机械强度以及较好的防粘连效果；凝胶膜可以增加防粘连膜组织粘附性能。包括以下制备方法：
(1)将Mw＝70kDa的PLGA(LA:GA＝50:50)加入氯仿和N,N-二甲基甲酰胺的混合溶剂中，使PLGA的浓度为0.24g/ml，氯仿和N,N-二甲基甲酰胺的混合比例为3:2(体积比)，室温下磁力搅拌使其完全溶解，得到均一透明的PLGA电纺溶液，备用；
(2)将分子量为100kDa的PVA加入到去离子水中，使CMC浓度为0.06g/ml，室温下搅拌溶解，并静置5h消泡，得到透明粘稠的凝胶溶液；
(3)将步骤(1)中的PLGA电纺溶液装入注射器中，静电纺丝机的5喷头装置上选用21G针头，调节电压为18KV，流速为3.0ml/h，纺丝温度为40℃，针尖与接收器的距离为16cm，接收转速为2.5m/min，连续电纺2h后，40℃真空干燥，得到厚度 为0.08-0.10mm的纳米纤维膜；
(4)将步骤(3)中的纳米纤维膜置于厚度为0.04mm的模具下方，倒入3-4mlPVA凝胶溶液，用刮刀将凝胶刮均匀，自然晾干7h后取下模具，40℃下真空干燥；
(5)将双层结构的防粘连膜封装后，用环氧乙烷气体杀菌消毒后。
得到的PLGA/PVA双层结构防粘连膜厚度为0.12-0.15mm，其纤维层纤维直径为459±74nm，拉伸强度为7.45MPa，拉伸率为17.23％，降解周期为12周。
防粘连效果评价：
采用SD大鼠作为动物模型，将88只SD大鼠随机分为4组，分别设计为正常对照组，模型对照组，PLA/HA防粘连膜组和PLGA/CMC防粘连膜组，除正常对照组外，其余各组均采用多因素法制作大鼠腹腔术后粘连模型，PLGA/CMC膜组的CMC凝胶面和PLA/HA防粘连膜的HA凝胶面贴覆于创面，模型对照组创面不处理，并在不同时间点测定血常规、血浆肝肾功能和纤维蛋白原含量，分别在术后1、2、4、6、12周时，处死动物并评定腹腔粘连程度以及膜的降解情况，并按Hobson分级法进行观察分级(Ⅰ级：无粘连形成；Ⅱ级：1-2处局限性粘连；Ⅲ级：弥漫性粘连，但不广泛；IV级：弥漫性广泛性粘连，但较易松解；V级：弥漫广泛致密的粘连，难于松解)。
结果表明：PLGA/CMC防粘连组能紧粘于创面，起到很好的防粘连效果，无粘连产生，属于I级，且膜从第1周后开始有降解趋势，12周内完全降解。PLA/HA防粘连组能粘附与创面，但有位移出现，防粘连效果较好，无粘连产生，属于I级，膜从第2周后有开始降解，12周内未完全降解。根据对纤维蛋白原含量的检测，发现防粘连膜组能够减少纤维蛋白原的渗出，抑制胶原纤维组织的增生，从而有有效的防止粘连的产生。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。

Claims (10)

  1. 一种双层结构的防粘连膜，其特征在于：包括位于底层的可生物降解的聚合物纳米纤维膜和位于表层的凝胶膜。
  2. 根据权利要求1所述的一种双层结构的防粘连膜，其特征在于：所述聚合物纳米纤维膜的材料为聚乳酸PLA、聚乙醇酸PGA、聚己内酯PCL、聚乳酸-乙醇酸共聚物PLGA、聚己内酯-羟基乙酸共聚物PCGA、聚乳酸-乙二醇PELA共聚物、聚乙二醇中的一种或多种，聚合物材料分子量为5-20kDa。
  3. 根据权利要求1所述的一种双层结构的防粘连膜，其特征在于：所述凝胶膜的材料为羧甲基纤维素钠CMC、透明质酸HA和聚乙烯醇PVA中的一种或多种；羧甲基纤维素钠CMC的粘度范围为300-1200mpa.s，HA的分子量为400-1000kDa，聚乙烯醇PVA的分子量为80-100kDa。
  4. 一种双层结构的防粘连膜的制备方法，其特征在于，包括以下步骤：
    (1)将生物可降解的聚合物溶解在有机溶剂中得到聚合物电纺溶液，然后通过静电纺丝法得到聚合物纳米纤维膜；
    (2)将聚合物纳米纤维膜置于模具底部，然后将配制好的羧甲基纤维素钠CMC、透明质酸HA和聚乙烯醇PVA水溶液倒入模具内，流延均匀，在室温下自然干燥3-5h后，放入40-80℃烘箱中烘干或者冷冻干燥，得具有双层结构的防粘连膜。
  5. 根据权利要求4所述的一种双层结构的防粘连膜的制备方法，其特征在于：生物可降解的聚合物材料为聚乳酸PLA、聚乙醇酸PGA、聚己内酯PCL、聚乳酸-乙醇酸共聚物PLGA、聚己内酯-羟基乙酸共聚物PCGA、聚乳酸-乙二醇PELA共聚物、聚乙二醇中的一种或多种，聚合物材料分子量为50-200kDa。
  6. 根据权利要求4所述的一种双层结构的防粘连膜的制备方法，其特征在于：所述有机溶剂为氯仿、丙酮、二氯甲烷、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、乙酸乙酯、甲醇中的一种或多种。
  7. 根据权利要求4所述的一种双层结构的防粘连膜的制备方法，其特征在于：所述生物可降解的聚合物浓度为5％-30％(m/v)。
  8. 根据权利要求4所述的一种双层结构的防粘连膜的制备方法，其特征在于：静电纺丝方法为多喷头电纺工艺，其电压为10-30KV；流速为1.0-15ml/h，接收距离为5-25cm；纺丝温度为20-50℃；其接收器为滚轴接收器，转轴速度为1.0-7.0m/min； 其针头型号为17G、18G、19G、20G、21G、22G、23G，烘干温度为30-50℃。
  9. 根据权利要求4所述的一种双层结构的防粘连膜的制备方法，其特征在于：所述羧甲基纤维素钠CMC的浓度为2％-5％；透明质酸HA的浓度为1％-4％；聚乙烯醇PVA的浓度为4％-7％，防粘连膜的厚度为0.04-0.4mm。
  10. 根据权利要求4所述的一种双层结构的防粘连膜的制备方法，其特征在于：制备出防粘连膜后，采用辐射灭菌或环氧乙烷气体灭菌对其进行消毒。
PCT/CN2016/087193 2015-10-30 2016-06-25 一种双层结构的防粘连膜及其制备方法 WO2017071267A1 (zh)

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